Medical Grand Rounds

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

 

 

In a US study, mycophenolate or azathioprine was better than cyclophosphamide as maintenance

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

 

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

 

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

 

 

In a US study, mycophenolate or azathioprine was better than cyclophosphamide as maintenance

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

 

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

 

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

 

 

In a US study, mycophenolate or azathioprine was better than cyclophosphamide as maintenance

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

 

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

 

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

Deep brain stimulation is an important therapy for Parkinson disease and other movement disorders. It involves implantation of a pulse generator that can be adjusted by telemetry and can be activated and deactivated by clinicians and patients. It is therefore also a good investigational tool, allowing for double-blind, sham-controlled clinical trials by testing the effects of the stimulation with optimal settings compared with no stimulation.

This article will discuss the approved indications for deep brain stimulation (particularly for managing movement disorders), the benefits that can be expected, the risks, the complications, the maintenance required, how candidates for this treatment are evaluated, and the surgical procedure for implantation of the devices.

DEVICE SIMILAR TO HEART PACEMAKERS

A typical deep brain stimulation system has three components: a pulse generator, which is typically implanted in the subclavicular area; one or two leads, which are inserted into the target area in the brain; and an insulated extension wire passed subcutaneously that connects the generator with the lead (Figure 1). The system generates short electrical pulses, similar to a cardiac pacemaker.

The deep brain stimulation system must be programmed by a physician or midlevel practitioner by observing a symptom and then changing the applied settings to the pulse generator until the symptom improves. This can be a very time-consuming process.

In contrast to heart pacemakers, which run at low frequencies, the brain devices for movement disorders are almost always set to a high frequency, greater than 100 Hz. For this reason, they consume more energy and need larger batteries than those in modern heart pacemakers.

The batteries in these generators typically last 3 to 5 years and are replaced in an outpatient procedure. Newer, smaller, rechargeable devices are expected to last longer but require more maintenance and care by patients, who have to recharge them at home periodically.

INDICATIONS FOR DEEP BRAIN STIMULATION

Deep brain stimulation is approved by the US Food and Drug Administration (FDA) for specific indications:

• Parkinson disease
• Essential tremor
• Primary dystonia (under a humanitarian device exemption)
• Intractable obsessive-compulsive disorder (also under a humanitarian device exemption). We will not discuss this indication further in this paper.

For each of these conditions, deep brain stimulation is considered when nonsurgical management has failed, as is the case for most functional neurosurgical treatments.

Investigations under way in other disorders

Several studies of deep brain stimulation are currently in progress under FDA-approved investigational device exemptions. Some, with funding from industry, are exploring its use in neuropsychiatric conditions other than parkinsonism. Two large clinical trials are evaluating its use for treatment-refractory depression, a common problem and a leading cause of disability in the industrialized world. Multiple investigators are also exploring novel uses of this technology in disorders ranging from obsessive-compulsive disorder to epilepsy.

Investigation is also under way at Cleveland Clinic in a federally funded, prospective, randomized clinical trial of deep brain stimulation for patients with thalamic pain syndrome. The primary hypothesis is that stimulation of the ventral striatal and ventral capsular area will modulate the affective component of this otherwise intractable pain syndrome, reducing pain-related disability and improving quality of life.

DEEP BRAIN STIMULATION VS ABLATION

Before deep brain stimulation became available, the only surgical options for patients with advanced Parkinson disease, tremor, or dystonia were ablative procedures such as pallidotomy (ablation of part of the globus pallidus) and thalamotomy (ablation of part of the thalamus). These procedures had been well known for several decades but fell out of favor when levodopa became available in the 1960s and revolutionized the medical treatment of Parkinson disease.

Surgery for movement disorders, in particular Parkinson disease, had a rebirth in the late 1980s when the limitations and complications associated with the pharmacologic management of Parkinson disease became increasingly evident. Ablative procedures are still used to treat advanced Parkinson disease, but much less commonly in industrialized countries.

Although pallidotomy and thalamotomy can have excellent results, they are not as safe as deep brain stimulation, which has the advantage of being reversible, modulating the function of an area rather than destroying it. Any unwanted effect can be immediately altered or reversed, unlike ablative procedures, in which any change is permanent. In addition, deep brain stimulation is adjustable, and the settings can be optimized as the disease progresses over the years.

Ablative procedures can be risky when performed bilaterally, while deep brain stimulation is routinely done on both hemispheres for patients with bilateral symptoms.

Although deep brain stimulation is today’s surgical treatment of choice, it is not perfect. It has the disadvantage of requiring lifelong maintenance of the hardware, for which the patient remains dependent on a medical center. Patients are usually seen more often at the specialized center in the first few months after surgery for optimization of programming and titration of drugs. (During this time, most patients see a gradual, substantial reduction in medication intake.) They are then followed by their physician and visit the center less often for monitoring of disease status and for further adjustments to the stimulator.

Most patients, to date, receive nonrechargeable pulse generators. As mentioned above, the batteries in these devices typically last 3 to 5 years. Preferably, batteries are replaced before they are completely depleted, to avoid interruption of therapy. Periodic visits to the center allow clinicians to estimate battery expiration ahead of time and plan replacements accordingly.

Rechargeable pulse generators have been recently introduced and are expected to last up to 9 years. They are an option for patients who can comply with the requirements for periodic home recharging of the hardware.

Patients are given a remote control so that they can turn the device on or off and check its status. Most patients keep it turned on all the time, although some turn it off at night to save battery life.

 

WHAT CAN PARKINSON PATIENTS EXPECT FROM THIS THERAPY?

Typically, some parkinsonian symptoms predominate over others, although some patients with advanced disease present with a severe combination of multiple disabling symptoms. Deep brain stimulation is best suited to address some of the cardinal motor symptoms, particularly tremor, rigidity, and bradykinesia, and motor fluctuations such as “wearing off” and dyskinesia.

Improvement in some motor symptoms

As a general rule, appendicular symptoms such as limb tremor and rigidity are more responsive to this therapy than axial symptoms such as gait and balance problems, but some patients experience improvement in gait as well. Other symptoms, such as swallowing or urinary symptoms, are seldom helped.

Although deep brain stimulation can help manage key motor symptoms and improve quality of life, it does not cure Parkinson disease. Also, there is no evidence to date that it slows disease progression, although this is a topic of ongoing investigation.

Fewer motor fluctuations

A common complaint of patients with advanced Parkinson disease is frequent—and often unpredictable—fluctuations between the “on” state (ie, when the effects of the patient’s levodopa therapy are apparent) and the “off” state (ie, when the levodopa doesn’t seem to be working). Sometimes, in the on state, patients experience involuntary choreic or ballistic movements, called dyskinesias. They also complain that the on time progressively lasts shorter and the day is spent alternating between shorter on states (during which the patient may be dyskinetic) and longer off states, limiting the patient’s independence and quality of life.

Deep brain stimulation can help patients prolong the on time while reducing the amplitude of these fluctuations so that the symptoms are not as severe in the off time and dyskinesias are reduced in the on time.

Some patients undergo deep brain stimulation primarily for managing the adverse effects of levodopa rather than for controlling the symptoms of the disease itself. While these patients need levodopa to address the disabling symptoms of the disease, they also present a greater sensitivity for developing levodopa-induced dyskinesias, quickly fluctuating from a lack of movement (the off state) to a state of uncontrollable movements (during the on state).

Deep brain stimulation typically allows the dosage of levodopa to be significantly reduced and gives patients more on time with fewer side effects and less fluctuation between the on and off states.

Response to levodopa predicts deep brain stimulation’s effects

Whether a patient is likely to be helped by deep brain stimulation can be tested with reasonable predictability by giving a single therapeutic dose of levodopa after the patient has been free of the drug for 12 hours. If there is an obvious difference on objective quantitative testing between the off and on states with a single dose, the patient is likely to benefit from deep brain stimulation. Those who do not respond well or are known to have never been well controlled by levodopa are likely poor candidates.

The test is also used as an indicator of whether the patient’s gait can be improved. Patients whose gait is substantially improved by levodopa, even for only a brief period of time, have a better chance of experiencing improvement in this domain with deep brain stimulation than those who do not show any gait improvement.

An important and notable exception to this rule is tremor control. Even Parkinson patients who do not experience significant improvement in tremor with levodopa (ie, who have medication-resistant tremors) are still likely to benefit from deep brain stimulation. Overall, tremor is the symptom that is most consistently improved with deep brain stimulation.

Results of clinical trials

Several clinical trials have demonstrated that deep brain stimulation plus medication works better than medications alone for advanced Parkinson disease.

Deuschl et al¹ conducted a randomized trial in 156 patients with advanced Parkinson disease. Patients receiving subthalamic deep brain stimulation plus medication had significantly greater improvement in motor symptoms as measured by the Unified Parkinson’s Disease Rating Scale as well as in quality-of-life measures than patients receiving medications only.

Krack et al² reported on the outcomes of 49 patients with advanced Parkinson disease who underwent deep brain stimulation and then were prospectively followed. At 5 years, motor function had improved by approximately 55% from baseline, activities-of-daily-living scores had improved by 49%, and patients continued to need significantly less levodopa and to experience less drug-induced dyskinesia.

Complications related to deep brain stimulation occurred in both studies, including two large intracerebral hemorrhages, one of which was fatal.

Weight gain. During the first 3 months after the device was implanted, patients tended to gain weight (mean 3 kg, maximum 5 kg). Although weight gain is considered an adverse effect, many patients are quite thin by the time they are candidates for deep brain stimulation, and in such cases gaining lean weight can be a benefit.

Patients with poorly controlled Parkinson disease lose weight for several reasons: increased calorie expenditure from shaking and excessive movements; diet modification and protein restriction for some patients who realize that protein competes with levodopa absorption; lack of appetite due to depression or from poor taste sensation (due to anosmia); and decreased overall food consumption due to difficulty swallowing.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Essential tremor is more common than Parkinson disease, with a prevalence in the United States estimated at approximately 4,000 per 100,000 people older than 65 years.

The tremor is often bilateral and is characteristically an action tremor, but in many patients it also has a postural, and sometimes a resting, component. It is distinct from parkinsonian tremor, which is usually predominantly a resting tremor. The differential diagnosis includes tremors secondary to central nervous system degenerative disorders as well as psychogenic tremors.

Drinking alcohol tends to relieve essential tremors, a finding that can often be elicited in the patient’s history. Patients whose symptoms improve with an alcoholic beverage are more likely to have essential tremor than another diagnosis.

Response to deep brain stimulation

Most patients with essential tremor respond well to deep brain stimulation of the contralateral ventral intermedius thalamic nucleus.

Treatment is usually started unilaterally, usually aimed at alleviating tremor in the patient’s dominant upper extremity. In selected cases, preference is given to treating the nondominant extremity when it is more severely affected than the dominant extremity.

Implantation of a device on the second side is offered to some patients who continue to be limited in activity and quality of life due to tremor of the untreated extremity. Surgery of the second side can be more complicated than the initial unilateral procedure. In particular, some patients may present with dysarthria, although that seems to be less common in our experience than initially estimated.

In practice, patients with moderate tremors tend to have an excellent response to deep brain stimulation. For this particular indication, if the response is not satisfactory, the treating team tends to consider surgically revising the placement of the lead rather than considering the patient a nonresponder. Patients with very severe tremors may have some residual tremor despite substantial improvement in severity. In our experience, patients with a greater proximal component of tremor tend to have less satisfactory results.

For challenging cases, implantation of additional electrodes in the thalamus or in new targets currently under investigation is sometimes considered, although this is an off-label use.

Treatment of secondary tremors, such as poststroke tremor or tremor due to multiple sclerosis, is sometimes attempted with deep brain stimulation. This is also an off-label option but is considered in selected cases for quality-of-life management.

Patients with axial tremors such as head or voice tremor are less likely to be helped by deep brain stimulation.

 

DEEP BRAIN STIMULATION FOR PRIMARY DYSTONIA

Generalized dystonia is a less common but severely impairing movement disorder.

Deep brain stimulation is approved for primary dystonia under a humanitarian device exemption, a regulatory mechanism for less common conditions. Deep brain stimulation is an option for patients who have significant impairment related to dystonia and who have not responded to conservative management such as anticholinergic agents, muscle relaxants, benzodiazepines, levodopa, or combinations of these drugs. Surgery has been shown to be effective for patients with primary generalized dystonia, whether or not they tested positive for a dystonia-related gene such as DYT1.

Kupsch et al³ evaluated 40 patients with primary dystonia in a randomized controlled trial of pallidal (globus pallidus pars interna) active deep brain stimulation vs sham stimulation (in which the device was implanted but not activated) for 3 months. Treated patients improved significantly more than controls (39% vs 5%) in the Burke-Fahn- Marsden Dystonia Rating Scale (BFMDRS).⁴ Similar improvement was noted when those receiving sham stimulation were switched to active stimulation.

During long-term follow-up, the results were generally sustained, with substantial improvement from deep brain stimulation in all movement symptoms evaluated except for speech and swallowing. Unlike improvement in tremor, which is quickly evident during testing in the operating room, the improvement in dystonia occurs gradually, and it may take months for patients to notice a change. Similarly, if stimulation stops because of device malfunction or dead batteries, symptoms sometimes do not recur for weeks or months.

Deep brain stimulation is sometimes offered to patients with dystonia secondary to conditions such as cerebral palsy or trauma (an off-label use). Although benefits are less consistent, deep brain stimulation remains an option for these individuals, aimed at alleviating some of the disabling symptoms. In patients with cerebral palsy or other secondary dystonias, it is sometimes difficult to distinguish how much of the disability is related to spasticity vs dystonia. Deep brain stimulation aims to alleviate the dystonic component; the spasticity may be managed with other options such as intrathecal baclofen (Lioresal).

Patients with tardive dystonia, which is usually secondary to treatment with antipsychotic agents, have been reported to respond well to bilateral deep brain stimulation. Gruber et al⁵ reported on a series of nine patients with a mean follow-up of 41 months. Patients improved by a mean of approximately 74% on the BFMDRS after 3 to 6 months of deep brain stimulation compared with baseline. None of the patients presented with long-term adverse effects, and quality of life and disability scores also improved significantly.

CANDIDATES ARE EVALUATED BY A MULTIDISCIPLINARY TEAM

Cleveland Clinic conducts a comprehensive 2-day evaluation for patients being considered for deep brain stimulation surgery, including consultations with specialists in neurology, neurosurgery, neuropsychology, and psychiatry.

Patients with significant cognitive deficits—near or meeting the diagnostic criteria for dementia—are usually not recommended to have surgery for Parkinson disease. Deep brain stimulation is not aimed at alleviating cognitive issues related to Parkinson disease or other concomitant dementia. In addition, there is a risk that neurostimulation could further worsen cognitive function in the already compromised brain. Moreover, patients with significant abnormalities detected by neuroimaging may have their diagnosis reconsidered in some cases, and some patients may not be deemed ideal candidates for surgery.

An important part of the process is a discussion with the patient and family about the risks and the potential short-term and long-term benefits. Informed consent requires a good understanding of this equation. Patients are counseled to have realistic expectations about what the procedure can offer. Deep brain stimulation can help some of the symptoms of Parkinson disease but will not cure it, and there is no evidence to date that it reduces its progress. At 5 or 10 years after surgery, patients are expected to be worse overall than they were in the first year after surgery, because of disease progression. However, patients who receive this treatment are expected, in general, to be doing better 5 or 10 years later (or longer) than those who do not receive it.

In addition to the discussion about risks, benefits, and expectations, a careful discussion is also devoted to hardware maintenance, including how to change the batteries. Particularly, younger patients should be informed about the risk of breakage of the leads and the extension wire, as they are likely to outlive their implant. Patients and caregivers should be able to come to the specialized center should hardware malfunction occur.

Patients are also informed that after the system is implanted they cannot undergo magnetic resonance imaging (MRI) except of the head, performed with a specific head coil and under specific parameters. MRI of any other body part and with a body coil is contraindicated.

HOW THE DEVICE IS IMPLANTED

There are several options for implanting a deep brain stimulation device.

Implantation with the patient awake, using a stereotactic headframe

At Cleveland Clinic, we usually prefer implantation with a stereotactic headframe. The base or “halo” of the frame is applied to the head under local anesthesia, followed by imaging via computed tomography (Figure 1). Typically, the tomographic image is fused to a previously acquired MRI image, but the MRI is sometimes either initially performed or repeated on the day of surgery.

Patients are sedated for the beginning of the procedure, while the surgical team is opening the skin and drilling the opening in the skull for placement of the lead. The patient is awakened for placement of the electrodes, which is not painful.

Microelectrode recording is typically performed in order to refine the targeting based on the stereotactic coordinates derived from neuroimaging. Although cadaver atlases exist and provide a guide to the stereotactic localization of subcortical structures, they are not completely accurate in representing the brain anatomy of all patients.

By “listening” to cells and knowing their characteristic signals in specific areas, landmarks can be created, forming an individualized map of the patient’s brain target. Microelectrode recording is invasive and has risks, including the risk of a brain hemorrhage. It is routinely done in most specialized deep brain stimulation centers because it can provide better accuracy and precision in lead placement.

When the target has been located and refined by microelectrode recording, the permanent electrode is inserted. Fluoroscopy is usually used to verify the direction and stability of placement during the procedure.

An intraoperative test of the effects of deep brain stimulation is routinely performed to verify that some benefits can be achieved with the brain lead in its location, to determine the threshold for side effects, or both. For example, the patient may be asked to hold a cup as if trying to drink from it and to write or to draw a spiral on a clipboard to assess for improvements in tremor. Rigidity and bradykinesia can also be tested for improvements.

This intraoperative test is not aimed at assessing the best possible outcome of deep brain stimulation, and not even to see an improvement in all symptoms that burden the patient. Rather, it is to evaluate the likelihood that programming will be feasible with the implanted lead.

Subsequently, implantation of the pulse generator in the chest and connection to the brain lead is completed, usually with the patient under general anesthesia.

Implantation under general anesthesia, with intraoperative MRI

A new alternative to “awake stereotactic surgery” is implantation with the patient under general anesthesia, with intraoperative MRI. We have started to do this procedure in a new operating suite that is attached to an MRI suite. The magnet can be taken in and out of the operating room, allowing the surgeon to verify the location of the implanted leads right at the time of the procedure. In this fashion, intraoperative images are used to guide implantation instead of awake microelectrode recording. This is a new option for patients who cannot tolerate awake surgery and for those who have a contraindication to the regular stereotactic procedure with the patient awake.

Risks of bleeding and infection

The potential complications of implanting a device and leads in the brain can be significant.

Hemorrhage can occur, resulting in a superficial or deep hematoma.

Infection and erosion may require removal of the hardware for antibiotic treatment and possible reimplantation.

Other risks include those related to tunneling the wires from the head to the chest, to implanting the device in the chest, and to serious medical complications after surgery. Hardware failure can occur and requires additional surgery. Finally, environmental risks and risks related to medical devices such as MRI, electrocautery, and cardioversion should also be considered.

Deep brain stimulation is advantageous for its reversibility. If during postoperative programming the brain leads are considered not to be ideally placed, revisions can be done to reposition the leads.

Deep brain stimulation is an important therapy for Parkinson disease and other movement disorders. It involves implantation of a pulse generator that can be adjusted by telemetry and can be activated and deactivated by clinicians and patients. It is therefore also a good investigational tool, allowing for double-blind, sham-controlled clinical trials by testing the effects of the stimulation with optimal settings compared with no stimulation.

This article will discuss the approved indications for deep brain stimulation (particularly for managing movement disorders), the benefits that can be expected, the risks, the complications, the maintenance required, how candidates for this treatment are evaluated, and the surgical procedure for implantation of the devices.

DEVICE SIMILAR TO HEART PACEMAKERS

A typical deep brain stimulation system has three components: a pulse generator, which is typically implanted in the subclavicular area; one or two leads, which are inserted into the target area in the brain; and an insulated extension wire passed subcutaneously that connects the generator with the lead (Figure 1). The system generates short electrical pulses, similar to a cardiac pacemaker.

The deep brain stimulation system must be programmed by a physician or midlevel practitioner by observing a symptom and then changing the applied settings to the pulse generator until the symptom improves. This can be a very time-consuming process.

In contrast to heart pacemakers, which run at low frequencies, the brain devices for movement disorders are almost always set to a high frequency, greater than 100 Hz. For this reason, they consume more energy and need larger batteries than those in modern heart pacemakers.

The batteries in these generators typically last 3 to 5 years and are replaced in an outpatient procedure. Newer, smaller, rechargeable devices are expected to last longer but require more maintenance and care by patients, who have to recharge them at home periodically.

INDICATIONS FOR DEEP BRAIN STIMULATION

Deep brain stimulation is approved by the US Food and Drug Administration (FDA) for specific indications:

• Parkinson disease
• Essential tremor
• Primary dystonia (under a humanitarian device exemption)
• Intractable obsessive-compulsive disorder (also under a humanitarian device exemption). We will not discuss this indication further in this paper.

For each of these conditions, deep brain stimulation is considered when nonsurgical management has failed, as is the case for most functional neurosurgical treatments.

Investigations under way in other disorders

Several studies of deep brain stimulation are currently in progress under FDA-approved investigational device exemptions. Some, with funding from industry, are exploring its use in neuropsychiatric conditions other than parkinsonism. Two large clinical trials are evaluating its use for treatment-refractory depression, a common problem and a leading cause of disability in the industrialized world. Multiple investigators are also exploring novel uses of this technology in disorders ranging from obsessive-compulsive disorder to epilepsy.

Investigation is also under way at Cleveland Clinic in a federally funded, prospective, randomized clinical trial of deep brain stimulation for patients with thalamic pain syndrome. The primary hypothesis is that stimulation of the ventral striatal and ventral capsular area will modulate the affective component of this otherwise intractable pain syndrome, reducing pain-related disability and improving quality of life.

DEEP BRAIN STIMULATION VS ABLATION

Before deep brain stimulation became available, the only surgical options for patients with advanced Parkinson disease, tremor, or dystonia were ablative procedures such as pallidotomy (ablation of part of the globus pallidus) and thalamotomy (ablation of part of the thalamus). These procedures had been well known for several decades but fell out of favor when levodopa became available in the 1960s and revolutionized the medical treatment of Parkinson disease.

Surgery for movement disorders, in particular Parkinson disease, had a rebirth in the late 1980s when the limitations and complications associated with the pharmacologic management of Parkinson disease became increasingly evident. Ablative procedures are still used to treat advanced Parkinson disease, but much less commonly in industrialized countries.

Although pallidotomy and thalamotomy can have excellent results, they are not as safe as deep brain stimulation, which has the advantage of being reversible, modulating the function of an area rather than destroying it. Any unwanted effect can be immediately altered or reversed, unlike ablative procedures, in which any change is permanent. In addition, deep brain stimulation is adjustable, and the settings can be optimized as the disease progresses over the years.

Ablative procedures can be risky when performed bilaterally, while deep brain stimulation is routinely done on both hemispheres for patients with bilateral symptoms.

Although deep brain stimulation is today’s surgical treatment of choice, it is not perfect. It has the disadvantage of requiring lifelong maintenance of the hardware, for which the patient remains dependent on a medical center. Patients are usually seen more often at the specialized center in the first few months after surgery for optimization of programming and titration of drugs. (During this time, most patients see a gradual, substantial reduction in medication intake.) They are then followed by their physician and visit the center less often for monitoring of disease status and for further adjustments to the stimulator.

Most patients, to date, receive nonrechargeable pulse generators. As mentioned above, the batteries in these devices typically last 3 to 5 years. Preferably, batteries are replaced before they are completely depleted, to avoid interruption of therapy. Periodic visits to the center allow clinicians to estimate battery expiration ahead of time and plan replacements accordingly.

Rechargeable pulse generators have been recently introduced and are expected to last up to 9 years. They are an option for patients who can comply with the requirements for periodic home recharging of the hardware.

Patients are given a remote control so that they can turn the device on or off and check its status. Most patients keep it turned on all the time, although some turn it off at night to save battery life.

 

WHAT CAN PARKINSON PATIENTS EXPECT FROM THIS THERAPY?

Typically, some parkinsonian symptoms predominate over others, although some patients with advanced disease present with a severe combination of multiple disabling symptoms. Deep brain stimulation is best suited to address some of the cardinal motor symptoms, particularly tremor, rigidity, and bradykinesia, and motor fluctuations such as “wearing off” and dyskinesia.

Improvement in some motor symptoms

As a general rule, appendicular symptoms such as limb tremor and rigidity are more responsive to this therapy than axial symptoms such as gait and balance problems, but some patients experience improvement in gait as well. Other symptoms, such as swallowing or urinary symptoms, are seldom helped.

Although deep brain stimulation can help manage key motor symptoms and improve quality of life, it does not cure Parkinson disease. Also, there is no evidence to date that it slows disease progression, although this is a topic of ongoing investigation.

Fewer motor fluctuations

A common complaint of patients with advanced Parkinson disease is frequent—and often unpredictable—fluctuations between the “on” state (ie, when the effects of the patient’s levodopa therapy are apparent) and the “off” state (ie, when the levodopa doesn’t seem to be working). Sometimes, in the on state, patients experience involuntary choreic or ballistic movements, called dyskinesias. They also complain that the on time progressively lasts shorter and the day is spent alternating between shorter on states (during which the patient may be dyskinetic) and longer off states, limiting the patient’s independence and quality of life.

Deep brain stimulation can help patients prolong the on time while reducing the amplitude of these fluctuations so that the symptoms are not as severe in the off time and dyskinesias are reduced in the on time.

Some patients undergo deep brain stimulation primarily for managing the adverse effects of levodopa rather than for controlling the symptoms of the disease itself. While these patients need levodopa to address the disabling symptoms of the disease, they also present a greater sensitivity for developing levodopa-induced dyskinesias, quickly fluctuating from a lack of movement (the off state) to a state of uncontrollable movements (during the on state).

Deep brain stimulation typically allows the dosage of levodopa to be significantly reduced and gives patients more on time with fewer side effects and less fluctuation between the on and off states.

Response to levodopa predicts deep brain stimulation’s effects

Whether a patient is likely to be helped by deep brain stimulation can be tested with reasonable predictability by giving a single therapeutic dose of levodopa after the patient has been free of the drug for 12 hours. If there is an obvious difference on objective quantitative testing between the off and on states with a single dose, the patient is likely to benefit from deep brain stimulation. Those who do not respond well or are known to have never been well controlled by levodopa are likely poor candidates.

The test is also used as an indicator of whether the patient’s gait can be improved. Patients whose gait is substantially improved by levodopa, even for only a brief period of time, have a better chance of experiencing improvement in this domain with deep brain stimulation than those who do not show any gait improvement.

An important and notable exception to this rule is tremor control. Even Parkinson patients who do not experience significant improvement in tremor with levodopa (ie, who have medication-resistant tremors) are still likely to benefit from deep brain stimulation. Overall, tremor is the symptom that is most consistently improved with deep brain stimulation.

Results of clinical trials

Several clinical trials have demonstrated that deep brain stimulation plus medication works better than medications alone for advanced Parkinson disease.

Deuschl et al¹ conducted a randomized trial in 156 patients with advanced Parkinson disease. Patients receiving subthalamic deep brain stimulation plus medication had significantly greater improvement in motor symptoms as measured by the Unified Parkinson’s Disease Rating Scale as well as in quality-of-life measures than patients receiving medications only.

Krack et al² reported on the outcomes of 49 patients with advanced Parkinson disease who underwent deep brain stimulation and then were prospectively followed. At 5 years, motor function had improved by approximately 55% from baseline, activities-of-daily-living scores had improved by 49%, and patients continued to need significantly less levodopa and to experience less drug-induced dyskinesia.

Complications related to deep brain stimulation occurred in both studies, including two large intracerebral hemorrhages, one of which was fatal.

Weight gain. During the first 3 months after the device was implanted, patients tended to gain weight (mean 3 kg, maximum 5 kg). Although weight gain is considered an adverse effect, many patients are quite thin by the time they are candidates for deep brain stimulation, and in such cases gaining lean weight can be a benefit.

Patients with poorly controlled Parkinson disease lose weight for several reasons: increased calorie expenditure from shaking and excessive movements; diet modification and protein restriction for some patients who realize that protein competes with levodopa absorption; lack of appetite due to depression or from poor taste sensation (due to anosmia); and decreased overall food consumption due to difficulty swallowing.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Essential tremor is more common than Parkinson disease, with a prevalence in the United States estimated at approximately 4,000 per 100,000 people older than 65 years.

The tremor is often bilateral and is characteristically an action tremor, but in many patients it also has a postural, and sometimes a resting, component. It is distinct from parkinsonian tremor, which is usually predominantly a resting tremor. The differential diagnosis includes tremors secondary to central nervous system degenerative disorders as well as psychogenic tremors.

Drinking alcohol tends to relieve essential tremors, a finding that can often be elicited in the patient’s history. Patients whose symptoms improve with an alcoholic beverage are more likely to have essential tremor than another diagnosis.

Response to deep brain stimulation

Most patients with essential tremor respond well to deep brain stimulation of the contralateral ventral intermedius thalamic nucleus.

Treatment is usually started unilaterally, usually aimed at alleviating tremor in the patient’s dominant upper extremity. In selected cases, preference is given to treating the nondominant extremity when it is more severely affected than the dominant extremity.

Implantation of a device on the second side is offered to some patients who continue to be limited in activity and quality of life due to tremor of the untreated extremity. Surgery of the second side can be more complicated than the initial unilateral procedure. In particular, some patients may present with dysarthria, although that seems to be less common in our experience than initially estimated.

In practice, patients with moderate tremors tend to have an excellent response to deep brain stimulation. For this particular indication, if the response is not satisfactory, the treating team tends to consider surgically revising the placement of the lead rather than considering the patient a nonresponder. Patients with very severe tremors may have some residual tremor despite substantial improvement in severity. In our experience, patients with a greater proximal component of tremor tend to have less satisfactory results.

For challenging cases, implantation of additional electrodes in the thalamus or in new targets currently under investigation is sometimes considered, although this is an off-label use.

Treatment of secondary tremors, such as poststroke tremor or tremor due to multiple sclerosis, is sometimes attempted with deep brain stimulation. This is also an off-label option but is considered in selected cases for quality-of-life management.

Patients with axial tremors such as head or voice tremor are less likely to be helped by deep brain stimulation.

 

DEEP BRAIN STIMULATION FOR PRIMARY DYSTONIA

Generalized dystonia is a less common but severely impairing movement disorder.

Deep brain stimulation is approved for primary dystonia under a humanitarian device exemption, a regulatory mechanism for less common conditions. Deep brain stimulation is an option for patients who have significant impairment related to dystonia and who have not responded to conservative management such as anticholinergic agents, muscle relaxants, benzodiazepines, levodopa, or combinations of these drugs. Surgery has been shown to be effective for patients with primary generalized dystonia, whether or not they tested positive for a dystonia-related gene such as DYT1.

Kupsch et al³ evaluated 40 patients with primary dystonia in a randomized controlled trial of pallidal (globus pallidus pars interna) active deep brain stimulation vs sham stimulation (in which the device was implanted but not activated) for 3 months. Treated patients improved significantly more than controls (39% vs 5%) in the Burke-Fahn- Marsden Dystonia Rating Scale (BFMDRS).⁴ Similar improvement was noted when those receiving sham stimulation were switched to active stimulation.

During long-term follow-up, the results were generally sustained, with substantial improvement from deep brain stimulation in all movement symptoms evaluated except for speech and swallowing. Unlike improvement in tremor, which is quickly evident during testing in the operating room, the improvement in dystonia occurs gradually, and it may take months for patients to notice a change. Similarly, if stimulation stops because of device malfunction or dead batteries, symptoms sometimes do not recur for weeks or months.

Deep brain stimulation is sometimes offered to patients with dystonia secondary to conditions such as cerebral palsy or trauma (an off-label use). Although benefits are less consistent, deep brain stimulation remains an option for these individuals, aimed at alleviating some of the disabling symptoms. In patients with cerebral palsy or other secondary dystonias, it is sometimes difficult to distinguish how much of the disability is related to spasticity vs dystonia. Deep brain stimulation aims to alleviate the dystonic component; the spasticity may be managed with other options such as intrathecal baclofen (Lioresal).

Patients with tardive dystonia, which is usually secondary to treatment with antipsychotic agents, have been reported to respond well to bilateral deep brain stimulation. Gruber et al⁵ reported on a series of nine patients with a mean follow-up of 41 months. Patients improved by a mean of approximately 74% on the BFMDRS after 3 to 6 months of deep brain stimulation compared with baseline. None of the patients presented with long-term adverse effects, and quality of life and disability scores also improved significantly.

CANDIDATES ARE EVALUATED BY A MULTIDISCIPLINARY TEAM

Cleveland Clinic conducts a comprehensive 2-day evaluation for patients being considered for deep brain stimulation surgery, including consultations with specialists in neurology, neurosurgery, neuropsychology, and psychiatry.

Patients with significant cognitive deficits—near or meeting the diagnostic criteria for dementia—are usually not recommended to have surgery for Parkinson disease. Deep brain stimulation is not aimed at alleviating cognitive issues related to Parkinson disease or other concomitant dementia. In addition, there is a risk that neurostimulation could further worsen cognitive function in the already compromised brain. Moreover, patients with significant abnormalities detected by neuroimaging may have their diagnosis reconsidered in some cases, and some patients may not be deemed ideal candidates for surgery.

An important part of the process is a discussion with the patient and family about the risks and the potential short-term and long-term benefits. Informed consent requires a good understanding of this equation. Patients are counseled to have realistic expectations about what the procedure can offer. Deep brain stimulation can help some of the symptoms of Parkinson disease but will not cure it, and there is no evidence to date that it reduces its progress. At 5 or 10 years after surgery, patients are expected to be worse overall than they were in the first year after surgery, because of disease progression. However, patients who receive this treatment are expected, in general, to be doing better 5 or 10 years later (or longer) than those who do not receive it.

In addition to the discussion about risks, benefits, and expectations, a careful discussion is also devoted to hardware maintenance, including how to change the batteries. Particularly, younger patients should be informed about the risk of breakage of the leads and the extension wire, as they are likely to outlive their implant. Patients and caregivers should be able to come to the specialized center should hardware malfunction occur.

Patients are also informed that after the system is implanted they cannot undergo magnetic resonance imaging (MRI) except of the head, performed with a specific head coil and under specific parameters. MRI of any other body part and with a body coil is contraindicated.

HOW THE DEVICE IS IMPLANTED

There are several options for implanting a deep brain stimulation device.

Implantation with the patient awake, using a stereotactic headframe

At Cleveland Clinic, we usually prefer implantation with a stereotactic headframe. The base or “halo” of the frame is applied to the head under local anesthesia, followed by imaging via computed tomography (Figure 1). Typically, the tomographic image is fused to a previously acquired MRI image, but the MRI is sometimes either initially performed or repeated on the day of surgery.

Patients are sedated for the beginning of the procedure, while the surgical team is opening the skin and drilling the opening in the skull for placement of the lead. The patient is awakened for placement of the electrodes, which is not painful.

Microelectrode recording is typically performed in order to refine the targeting based on the stereotactic coordinates derived from neuroimaging. Although cadaver atlases exist and provide a guide to the stereotactic localization of subcortical structures, they are not completely accurate in representing the brain anatomy of all patients.

By “listening” to cells and knowing their characteristic signals in specific areas, landmarks can be created, forming an individualized map of the patient’s brain target. Microelectrode recording is invasive and has risks, including the risk of a brain hemorrhage. It is routinely done in most specialized deep brain stimulation centers because it can provide better accuracy and precision in lead placement.

When the target has been located and refined by microelectrode recording, the permanent electrode is inserted. Fluoroscopy is usually used to verify the direction and stability of placement during the procedure.

An intraoperative test of the effects of deep brain stimulation is routinely performed to verify that some benefits can be achieved with the brain lead in its location, to determine the threshold for side effects, or both. For example, the patient may be asked to hold a cup as if trying to drink from it and to write or to draw a spiral on a clipboard to assess for improvements in tremor. Rigidity and bradykinesia can also be tested for improvements.

This intraoperative test is not aimed at assessing the best possible outcome of deep brain stimulation, and not even to see an improvement in all symptoms that burden the patient. Rather, it is to evaluate the likelihood that programming will be feasible with the implanted lead.

Subsequently, implantation of the pulse generator in the chest and connection to the brain lead is completed, usually with the patient under general anesthesia.

Implantation under general anesthesia, with intraoperative MRI

A new alternative to “awake stereotactic surgery” is implantation with the patient under general anesthesia, with intraoperative MRI. We have started to do this procedure in a new operating suite that is attached to an MRI suite. The magnet can be taken in and out of the operating room, allowing the surgeon to verify the location of the implanted leads right at the time of the procedure. In this fashion, intraoperative images are used to guide implantation instead of awake microelectrode recording. This is a new option for patients who cannot tolerate awake surgery and for those who have a contraindication to the regular stereotactic procedure with the patient awake.

Risks of bleeding and infection

The potential complications of implanting a device and leads in the brain can be significant.

Hemorrhage can occur, resulting in a superficial or deep hematoma.

Infection and erosion may require removal of the hardware for antibiotic treatment and possible reimplantation.

Other risks include those related to tunneling the wires from the head to the chest, to implanting the device in the chest, and to serious medical complications after surgery. Hardware failure can occur and requires additional surgery. Finally, environmental risks and risks related to medical devices such as MRI, electrocautery, and cardioversion should also be considered.

Deep brain stimulation is advantageous for its reversibility. If during postoperative programming the brain leads are considered not to be ideally placed, revisions can be done to reposition the leads.

Deep brain stimulation is an important therapy for Parkinson disease and other movement disorders. It involves implantation of a pulse generator that can be adjusted by telemetry and can be activated and deactivated by clinicians and patients. It is therefore also a good investigational tool, allowing for double-blind, sham-controlled clinical trials by testing the effects of the stimulation with optimal settings compared with no stimulation.

This article will discuss the approved indications for deep brain stimulation (particularly for managing movement disorders), the benefits that can be expected, the risks, the complications, the maintenance required, how candidates for this treatment are evaluated, and the surgical procedure for implantation of the devices.

DEVICE SIMILAR TO HEART PACEMAKERS

A typical deep brain stimulation system has three components: a pulse generator, which is typically implanted in the subclavicular area; one or two leads, which are inserted into the target area in the brain; and an insulated extension wire passed subcutaneously that connects the generator with the lead (Figure 1). The system generates short electrical pulses, similar to a cardiac pacemaker.

The deep brain stimulation system must be programmed by a physician or midlevel practitioner by observing a symptom and then changing the applied settings to the pulse generator until the symptom improves. This can be a very time-consuming process.

In contrast to heart pacemakers, which run at low frequencies, the brain devices for movement disorders are almost always set to a high frequency, greater than 100 Hz. For this reason, they consume more energy and need larger batteries than those in modern heart pacemakers.

The batteries in these generators typically last 3 to 5 years and are replaced in an outpatient procedure. Newer, smaller, rechargeable devices are expected to last longer but require more maintenance and care by patients, who have to recharge them at home periodically.

INDICATIONS FOR DEEP BRAIN STIMULATION

Deep brain stimulation is approved by the US Food and Drug Administration (FDA) for specific indications:

• Parkinson disease
• Essential tremor
• Primary dystonia (under a humanitarian device exemption)
• Intractable obsessive-compulsive disorder (also under a humanitarian device exemption). We will not discuss this indication further in this paper.

For each of these conditions, deep brain stimulation is considered when nonsurgical management has failed, as is the case for most functional neurosurgical treatments.

Investigations under way in other disorders

Several studies of deep brain stimulation are currently in progress under FDA-approved investigational device exemptions. Some, with funding from industry, are exploring its use in neuropsychiatric conditions other than parkinsonism. Two large clinical trials are evaluating its use for treatment-refractory depression, a common problem and a leading cause of disability in the industrialized world. Multiple investigators are also exploring novel uses of this technology in disorders ranging from obsessive-compulsive disorder to epilepsy.

Investigation is also under way at Cleveland Clinic in a federally funded, prospective, randomized clinical trial of deep brain stimulation for patients with thalamic pain syndrome. The primary hypothesis is that stimulation of the ventral striatal and ventral capsular area will modulate the affective component of this otherwise intractable pain syndrome, reducing pain-related disability and improving quality of life.

DEEP BRAIN STIMULATION VS ABLATION

Before deep brain stimulation became available, the only surgical options for patients with advanced Parkinson disease, tremor, or dystonia were ablative procedures such as pallidotomy (ablation of part of the globus pallidus) and thalamotomy (ablation of part of the thalamus). These procedures had been well known for several decades but fell out of favor when levodopa became available in the 1960s and revolutionized the medical treatment of Parkinson disease.

Surgery for movement disorders, in particular Parkinson disease, had a rebirth in the late 1980s when the limitations and complications associated with the pharmacologic management of Parkinson disease became increasingly evident. Ablative procedures are still used to treat advanced Parkinson disease, but much less commonly in industrialized countries.

Although pallidotomy and thalamotomy can have excellent results, they are not as safe as deep brain stimulation, which has the advantage of being reversible, modulating the function of an area rather than destroying it. Any unwanted effect can be immediately altered or reversed, unlike ablative procedures, in which any change is permanent. In addition, deep brain stimulation is adjustable, and the settings can be optimized as the disease progresses over the years.

Ablative procedures can be risky when performed bilaterally, while deep brain stimulation is routinely done on both hemispheres for patients with bilateral symptoms.

Although deep brain stimulation is today’s surgical treatment of choice, it is not perfect. It has the disadvantage of requiring lifelong maintenance of the hardware, for which the patient remains dependent on a medical center. Patients are usually seen more often at the specialized center in the first few months after surgery for optimization of programming and titration of drugs. (During this time, most patients see a gradual, substantial reduction in medication intake.) They are then followed by their physician and visit the center less often for monitoring of disease status and for further adjustments to the stimulator.

Most patients, to date, receive nonrechargeable pulse generators. As mentioned above, the batteries in these devices typically last 3 to 5 years. Preferably, batteries are replaced before they are completely depleted, to avoid interruption of therapy. Periodic visits to the center allow clinicians to estimate battery expiration ahead of time and plan replacements accordingly.

Rechargeable pulse generators have been recently introduced and are expected to last up to 9 years. They are an option for patients who can comply with the requirements for periodic home recharging of the hardware.

Patients are given a remote control so that they can turn the device on or off and check its status. Most patients keep it turned on all the time, although some turn it off at night to save battery life.

 

WHAT CAN PARKINSON PATIENTS EXPECT FROM THIS THERAPY?

Typically, some parkinsonian symptoms predominate over others, although some patients with advanced disease present with a severe combination of multiple disabling symptoms. Deep brain stimulation is best suited to address some of the cardinal motor symptoms, particularly tremor, rigidity, and bradykinesia, and motor fluctuations such as “wearing off” and dyskinesia.

Improvement in some motor symptoms

As a general rule, appendicular symptoms such as limb tremor and rigidity are more responsive to this therapy than axial symptoms such as gait and balance problems, but some patients experience improvement in gait as well. Other symptoms, such as swallowing or urinary symptoms, are seldom helped.

Although deep brain stimulation can help manage key motor symptoms and improve quality of life, it does not cure Parkinson disease. Also, there is no evidence to date that it slows disease progression, although this is a topic of ongoing investigation.

Fewer motor fluctuations

A common complaint of patients with advanced Parkinson disease is frequent—and often unpredictable—fluctuations between the “on” state (ie, when the effects of the patient’s levodopa therapy are apparent) and the “off” state (ie, when the levodopa doesn’t seem to be working). Sometimes, in the on state, patients experience involuntary choreic or ballistic movements, called dyskinesias. They also complain that the on time progressively lasts shorter and the day is spent alternating between shorter on states (during which the patient may be dyskinetic) and longer off states, limiting the patient’s independence and quality of life.

Deep brain stimulation can help patients prolong the on time while reducing the amplitude of these fluctuations so that the symptoms are not as severe in the off time and dyskinesias are reduced in the on time.

Some patients undergo deep brain stimulation primarily for managing the adverse effects of levodopa rather than for controlling the symptoms of the disease itself. While these patients need levodopa to address the disabling symptoms of the disease, they also present a greater sensitivity for developing levodopa-induced dyskinesias, quickly fluctuating from a lack of movement (the off state) to a state of uncontrollable movements (during the on state).

Deep brain stimulation typically allows the dosage of levodopa to be significantly reduced and gives patients more on time with fewer side effects and less fluctuation between the on and off states.

Response to levodopa predicts deep brain stimulation’s effects

Whether a patient is likely to be helped by deep brain stimulation can be tested with reasonable predictability by giving a single therapeutic dose of levodopa after the patient has been free of the drug for 12 hours. If there is an obvious difference on objective quantitative testing between the off and on states with a single dose, the patient is likely to benefit from deep brain stimulation. Those who do not respond well or are known to have never been well controlled by levodopa are likely poor candidates.

The test is also used as an indicator of whether the patient’s gait can be improved. Patients whose gait is substantially improved by levodopa, even for only a brief period of time, have a better chance of experiencing improvement in this domain with deep brain stimulation than those who do not show any gait improvement.

An important and notable exception to this rule is tremor control. Even Parkinson patients who do not experience significant improvement in tremor with levodopa (ie, who have medication-resistant tremors) are still likely to benefit from deep brain stimulation. Overall, tremor is the symptom that is most consistently improved with deep brain stimulation.

Results of clinical trials

Several clinical trials have demonstrated that deep brain stimulation plus medication works better than medications alone for advanced Parkinson disease.

Deuschl et al¹ conducted a randomized trial in 156 patients with advanced Parkinson disease. Patients receiving subthalamic deep brain stimulation plus medication had significantly greater improvement in motor symptoms as measured by the Unified Parkinson’s Disease Rating Scale as well as in quality-of-life measures than patients receiving medications only.

Krack et al² reported on the outcomes of 49 patients with advanced Parkinson disease who underwent deep brain stimulation and then were prospectively followed. At 5 years, motor function had improved by approximately 55% from baseline, activities-of-daily-living scores had improved by 49%, and patients continued to need significantly less levodopa and to experience less drug-induced dyskinesia.

Complications related to deep brain stimulation occurred in both studies, including two large intracerebral hemorrhages, one of which was fatal.

Weight gain. During the first 3 months after the device was implanted, patients tended to gain weight (mean 3 kg, maximum 5 kg). Although weight gain is considered an adverse effect, many patients are quite thin by the time they are candidates for deep brain stimulation, and in such cases gaining lean weight can be a benefit.

Patients with poorly controlled Parkinson disease lose weight for several reasons: increased calorie expenditure from shaking and excessive movements; diet modification and protein restriction for some patients who realize that protein competes with levodopa absorption; lack of appetite due to depression or from poor taste sensation (due to anosmia); and decreased overall food consumption due to difficulty swallowing.

DEEP BRAIN STIMULATION FOR ESSENTIAL TREMOR

Essential tremor is more common than Parkinson disease, with a prevalence in the United States estimated at approximately 4,000 per 100,000 people older than 65 years.

The tremor is often bilateral and is characteristically an action tremor, but in many patients it also has a postural, and sometimes a resting, component. It is distinct from parkinsonian tremor, which is usually predominantly a resting tremor. The differential diagnosis includes tremors secondary to central nervous system degenerative disorders as well as psychogenic tremors.

Drinking alcohol tends to relieve essential tremors, a finding that can often be elicited in the patient’s history. Patients whose symptoms improve with an alcoholic beverage are more likely to have essential tremor than another diagnosis.

Response to deep brain stimulation

Most patients with essential tremor respond well to deep brain stimulation of the contralateral ventral intermedius thalamic nucleus.

Treatment is usually started unilaterally, usually aimed at alleviating tremor in the patient’s dominant upper extremity. In selected cases, preference is given to treating the nondominant extremity when it is more severely affected than the dominant extremity.

Implantation of a device on the second side is offered to some patients who continue to be limited in activity and quality of life due to tremor of the untreated extremity. Surgery of the second side can be more complicated than the initial unilateral procedure. In particular, some patients may present with dysarthria, although that seems to be less common in our experience than initially estimated.

In practice, patients with moderate tremors tend to have an excellent response to deep brain stimulation. For this particular indication, if the response is not satisfactory, the treating team tends to consider surgically revising the placement of the lead rather than considering the patient a nonresponder. Patients with very severe tremors may have some residual tremor despite substantial improvement in severity. In our experience, patients with a greater proximal component of tremor tend to have less satisfactory results.

For challenging cases, implantation of additional electrodes in the thalamus or in new targets currently under investigation is sometimes considered, although this is an off-label use.

Treatment of secondary tremors, such as poststroke tremor or tremor due to multiple sclerosis, is sometimes attempted with deep brain stimulation. This is also an off-label option but is considered in selected cases for quality-of-life management.

Patients with axial tremors such as head or voice tremor are less likely to be helped by deep brain stimulation.

 

DEEP BRAIN STIMULATION FOR PRIMARY DYSTONIA

Generalized dystonia is a less common but severely impairing movement disorder.

Deep brain stimulation is approved for primary dystonia under a humanitarian device exemption, a regulatory mechanism for less common conditions. Deep brain stimulation is an option for patients who have significant impairment related to dystonia and who have not responded to conservative management such as anticholinergic agents, muscle relaxants, benzodiazepines, levodopa, or combinations of these drugs. Surgery has been shown to be effective for patients with primary generalized dystonia, whether or not they tested positive for a dystonia-related gene such as DYT1.

Kupsch et al³ evaluated 40 patients with primary dystonia in a randomized controlled trial of pallidal (globus pallidus pars interna) active deep brain stimulation vs sham stimulation (in which the device was implanted but not activated) for 3 months. Treated patients improved significantly more than controls (39% vs 5%) in the Burke-Fahn- Marsden Dystonia Rating Scale (BFMDRS).⁴ Similar improvement was noted when those receiving sham stimulation were switched to active stimulation.

During long-term follow-up, the results were generally sustained, with substantial improvement from deep brain stimulation in all movement symptoms evaluated except for speech and swallowing. Unlike improvement in tremor, which is quickly evident during testing in the operating room, the improvement in dystonia occurs gradually, and it may take months for patients to notice a change. Similarly, if stimulation stops because of device malfunction or dead batteries, symptoms sometimes do not recur for weeks or months.

Deep brain stimulation is sometimes offered to patients with dystonia secondary to conditions such as cerebral palsy or trauma (an off-label use). Although benefits are less consistent, deep brain stimulation remains an option for these individuals, aimed at alleviating some of the disabling symptoms. In patients with cerebral palsy or other secondary dystonias, it is sometimes difficult to distinguish how much of the disability is related to spasticity vs dystonia. Deep brain stimulation aims to alleviate the dystonic component; the spasticity may be managed with other options such as intrathecal baclofen (Lioresal).

Patients with tardive dystonia, which is usually secondary to treatment with antipsychotic agents, have been reported to respond well to bilateral deep brain stimulation. Gruber et al⁵ reported on a series of nine patients with a mean follow-up of 41 months. Patients improved by a mean of approximately 74% on the BFMDRS after 3 to 6 months of deep brain stimulation compared with baseline. None of the patients presented with long-term adverse effects, and quality of life and disability scores also improved significantly.

CANDIDATES ARE EVALUATED BY A MULTIDISCIPLINARY TEAM

Cleveland Clinic conducts a comprehensive 2-day evaluation for patients being considered for deep brain stimulation surgery, including consultations with specialists in neurology, neurosurgery, neuropsychology, and psychiatry.

Patients with significant cognitive deficits—near or meeting the diagnostic criteria for dementia—are usually not recommended to have surgery for Parkinson disease. Deep brain stimulation is not aimed at alleviating cognitive issues related to Parkinson disease or other concomitant dementia. In addition, there is a risk that neurostimulation could further worsen cognitive function in the already compromised brain. Moreover, patients with significant abnormalities detected by neuroimaging may have their diagnosis reconsidered in some cases, and some patients may not be deemed ideal candidates for surgery.

An important part of the process is a discussion with the patient and family about the risks and the potential short-term and long-term benefits. Informed consent requires a good understanding of this equation. Patients are counseled to have realistic expectations about what the procedure can offer. Deep brain stimulation can help some of the symptoms of Parkinson disease but will not cure it, and there is no evidence to date that it reduces its progress. At 5 or 10 years after surgery, patients are expected to be worse overall than they were in the first year after surgery, because of disease progression. However, patients who receive this treatment are expected, in general, to be doing better 5 or 10 years later (or longer) than those who do not receive it.

In addition to the discussion about risks, benefits, and expectations, a careful discussion is also devoted to hardware maintenance, including how to change the batteries. Particularly, younger patients should be informed about the risk of breakage of the leads and the extension wire, as they are likely to outlive their implant. Patients and caregivers should be able to come to the specialized center should hardware malfunction occur.

Patients are also informed that after the system is implanted they cannot undergo magnetic resonance imaging (MRI) except of the head, performed with a specific head coil and under specific parameters. MRI of any other body part and with a body coil is contraindicated.

HOW THE DEVICE IS IMPLANTED

There are several options for implanting a deep brain stimulation device.

Implantation with the patient awake, using a stereotactic headframe

At Cleveland Clinic, we usually prefer implantation with a stereotactic headframe. The base or “halo” of the frame is applied to the head under local anesthesia, followed by imaging via computed tomography (Figure 1). Typically, the tomographic image is fused to a previously acquired MRI image, but the MRI is sometimes either initially performed or repeated on the day of surgery.

Patients are sedated for the beginning of the procedure, while the surgical team is opening the skin and drilling the opening in the skull for placement of the lead. The patient is awakened for placement of the electrodes, which is not painful.

Microelectrode recording is typically performed in order to refine the targeting based on the stereotactic coordinates derived from neuroimaging. Although cadaver atlases exist and provide a guide to the stereotactic localization of subcortical structures, they are not completely accurate in representing the brain anatomy of all patients.

By “listening” to cells and knowing their characteristic signals in specific areas, landmarks can be created, forming an individualized map of the patient’s brain target. Microelectrode recording is invasive and has risks, including the risk of a brain hemorrhage. It is routinely done in most specialized deep brain stimulation centers because it can provide better accuracy and precision in lead placement.

When the target has been located and refined by microelectrode recording, the permanent electrode is inserted. Fluoroscopy is usually used to verify the direction and stability of placement during the procedure.

An intraoperative test of the effects of deep brain stimulation is routinely performed to verify that some benefits can be achieved with the brain lead in its location, to determine the threshold for side effects, or both. For example, the patient may be asked to hold a cup as if trying to drink from it and to write or to draw a spiral on a clipboard to assess for improvements in tremor. Rigidity and bradykinesia can also be tested for improvements.

This intraoperative test is not aimed at assessing the best possible outcome of deep brain stimulation, and not even to see an improvement in all symptoms that burden the patient. Rather, it is to evaluate the likelihood that programming will be feasible with the implanted lead.

Subsequently, implantation of the pulse generator in the chest and connection to the brain lead is completed, usually with the patient under general anesthesia.

Implantation under general anesthesia, with intraoperative MRI

A new alternative to “awake stereotactic surgery” is implantation with the patient under general anesthesia, with intraoperative MRI. We have started to do this procedure in a new operating suite that is attached to an MRI suite. The magnet can be taken in and out of the operating room, allowing the surgeon to verify the location of the implanted leads right at the time of the procedure. In this fashion, intraoperative images are used to guide implantation instead of awake microelectrode recording. This is a new option for patients who cannot tolerate awake surgery and for those who have a contraindication to the regular stereotactic procedure with the patient awake.

Risks of bleeding and infection

The potential complications of implanting a device and leads in the brain can be significant.

Hemorrhage can occur, resulting in a superficial or deep hematoma.

Infection and erosion may require removal of the hardware for antibiotic treatment and possible reimplantation.

Other risks include those related to tunneling the wires from the head to the chest, to implanting the device in the chest, and to serious medical complications after surgery. Hardware failure can occur and requires additional surgery. Finally, environmental risks and risks related to medical devices such as MRI, electrocautery, and cardioversion should also be considered.

Deep brain stimulation is advantageous for its reversibility. If during postoperative programming the brain leads are considered not to be ideally placed, revisions can be done to reposition the leads.

More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

• Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
• Rigidity, which is felt by the examiner rather than seen by an observer.
• Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
• Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Although the archetypical patient is an elderly man with shaking, masked facies, and slow gait, these features are only the tip of the iceberg of the syndrome, and nonmotor features are often more disabling (Table 1).

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

• 10 to 20 years: juvenile-onset
• 21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

• Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
• Strokes in the basal ganglia
• Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

• Progressive supranuclear palsy
• Multiple system atrophy
• Corticobasal degeneration
• Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

 

MANAGING PARKINSON DISEASE

Most general neurologists follow an algorithm for treating Parkinson disease (Figure 1).

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

 

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

 

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

• Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
• Rigidity, which is felt by the examiner rather than seen by an observer.
• Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
• Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Although the archetypical patient is an elderly man with shaking, masked facies, and slow gait, these features are only the tip of the iceberg of the syndrome, and nonmotor features are often more disabling (Table 1).

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

• 10 to 20 years: juvenile-onset
• 21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

• Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
• Strokes in the basal ganglia
• Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

• Progressive supranuclear palsy
• Multiple system atrophy
• Corticobasal degeneration
• Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

 

MANAGING PARKINSON DISEASE

Most general neurologists follow an algorithm for treating Parkinson disease (Figure 1).

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

 

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

 

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

More than a dozen drugs have been approved by the US Food and Drug Administration (FDA) for treating Parkinson disease, and more are expected in the near future. Many are currently in clinical trials, with the goals of finding ways to better control the disease with fewer adverse effects and, ultimately, to provide neuroprotection.

This article will review the features of Parkinson disease, the treatment options, and the complications in moderate to advanced disease.

PARKINSON DISEASE IS MULTIFACTORIAL

Although the cure for Parkinson disease is still elusive, much has been learned over the nearly 200 years since it was first described by James Parkinson in 1817. It is now understood to be a progressive neurodegenerative disease of multifactorial etiology: although a small proportion of patients have a direct inherited mutation that causes it, multiple genetic predisposition factors and environmental factors are more commonly involved.

The central pathology is dopaminergic loss in the basal ganglia, but other neurotransmitters are also involved and the disease extends to other areas of the brain.

CARDINAL MOTOR SYMPTOMS

In general, Parkinson disease is easy to identify. The classic patient has¹:

• Tremor at rest, which can be subtle—such as only involving a thumb or a few fingers—and is absent in 20% of patients at presentation.
• Rigidity, which is felt by the examiner rather than seen by an observer.
• Bradykinesia (slow movements), which is characteristic of all Parkinson patients.
• Gait and balance problems, which usually arise after a few years, although occasionally patients present with them. Patients typically walk with small steps with occasional freezing, as if their foot were stuck. Balance problems are the most difficult to treat among the motor problems.

Asymmetry of motor problems is apparent in 75% of patients at presentation, although problems become bilateral later in the course of the disease.

NONMOTOR FEATURES CAN BE MORE DISABLING

Although the archetypical patient is an elderly man with shaking, masked facies, and slow gait, these features are only the tip of the iceberg of the syndrome, and nonmotor features are often more disabling (Table 1).

Pain is common, but years ago it was not recognized as a specific feature of Parkinson disease. The pain from other conditions may also worsen.

Fatigue is very common and, if present, is usually one of the most disabling features.

Neuropsychiatric disturbances are among the most difficult problems, and they become increasingly common as motor symptoms are better controlled with treatment and patients live longer.

INCREASINGLY PREVALENT AS THE POPULATION AGES

Parkinson disease can present from the teenage years up to age 90, but it is most often diagnosed in patients from 60 to 70 years old (mean onset, 62.5 years). A different nomenclature is used depending on the age of onset:

• 10 to 20 years: juvenile-onset
• 21 to 40 years: young-onset.

Parkinson disease is now an epidemic, with an estimated 1 million people having it in the United States, representing 0.3% of the population and 1% of those older than 60 years.² More people can be expected to develop it as our population ages in the next decades. It is estimated that in 2040 more people will die from Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (all of which are neurodegenerative diseases) than from kidney cancer, malignant melanoma, colon cancer, and lung cancer combined.

DIAGNOSIS IS STILL MAINLY CLINICAL

The diagnosis of Parkinson disease remains clinical. In addition to the motor features, the best test is a clear response to dopaminergic treatment with levodopa. If all these features are present, the diagnosis of Parkinson disease is usually correct.³

Imaging useful in select patients

The FDA recently approved a radiopharmaceutical contrast agent, DaTscan, to use with single-photon emission computed tomography (SPECT) to help diagnose Parkinson disease. DaTscan is a dopamine transporter ligand that tags presynaptic dopaminergic neurons in the basal ganglia; a patient with Parkinson disease has less signal.

The test can be used to distinguish parkinsonian syndromes from disorders that can mimic them, such as essential tremor or a psychogenic disorder. However, it cannot differentiate various Parkinson-plus syndromes (see below) such as multiple system atrophy or progressive nuclear palsy. It also cannot be used to detect drug-induced or vascular parkinsonism.

Check for Wilson disease or brain tumors in young or atypical cases

For most patients, no imaging or blood tests are needed to make the diagnosis. However, in patients younger than 50, Wilson disease, a rare inherited disorder characterized by excess copper accumulation, must be considered. Testing for Wilson disease includes serum ceruloplasmin, 24-hour urinary copper excretion, and an ophthalmologic slit-lamp examination for Kaiser-Fleischer rings.

For patients who do not quite fit the picture of Parkinson disease, such as those who have spasticity with little tremor, or who have a minimal response to levodopa, magnetic resonance imaging should be done to see if a structural lesion is present.

Consider secondary parkinsonism

Although idiopathic Parkinson disease is by far the most common form of parkinsonism in the United States and in most developing countries, secondary causes must also be considered in a patient presenting with symptoms of parkinsonism. They include:

• Dopamine-receptor blocking agents: metoclopramide (Reglan), prochlorperazine (Compazine), haloperidol (Haldol), thioridazine (Mellaril), risperidone (Risperdal), olanzapine (Zyprexa)
• Strokes in the basal ganglia
• Normal pressure hydrocephalus.

Parkinson-plus syndromes

Parkinson-plus syndromes have other features in addition to the classic features of idiopathic Parkinson disease. They occur commonly and can be difficult to distinguish from Parkinson disease and from each other.

Parkinson-plus syndromes include:

• Progressive supranuclear palsy
• Multiple system atrophy
• Corticobasal degeneration
• Lewy body dementia.

Clinical features that suggest a diagnosis other than Parkinson disease include poor response to adequate dosages of levodopa, early onset of postural instability, axial more than appendicular rigidity, early dementia, and inability to look up or down without needing to move the head (supranuclear palsy).⁴

 

MANAGING PARKINSON DISEASE

Most general neurologists follow an algorithm for treating Parkinson disease (Figure 1).

Nonpharmacologic therapy is very important. Because patients tend to live longer because of better treatment, education is particularly important. The benefits of exercise go beyond general conditioning and cardiovascular health. People who exercise vigorously at least three times a week for 30 to 45 minutes are less likely to develop Parkinson disease and, if they develop it, they tend to have slower progression.

Prevention with neuroprotective drugs is not yet an option but hopefully will be in the near future.

Drug treatment generally starts when the patient is functionally impaired. If so, either levodopa or a dopamine agonist is started, depending on the patient’s age and the severity of symptoms. With increasing severity, other drugs can be added, and when those fail to control symptoms, surgery should be considered.

Deep brain stimulation surgery can make a tremendous difference in a patient’s quality of life. Other than levodopa, it is probably the best therapy available; however, it is very expensive and is not without risks.

Levodopa: The most effective drug, until it wears off

All current drugs for Parkinson disease activate dopamine neurotransmission in the brain. The most effective—and the cheapest—is still carbidopa/levodopa (Sinemet, Parcopa, Atamet). Levodopa converts to dopamine both peripherally and after it crosses the blood-brain barrier. Carbidopa prevents the peripheral conversion of levodopa to dopamine, reducing the peripheral adverse effects of levodopa, such as nausea and vomiting. The combination drug is usually given three times a day, with different doses available (10 mg carbidopa/100 mg levodopa, 25/100, 50/200, and 25/250) and as immediate-release and controlled-release formulations as well as an orally dissolving form (Parcopa) for patients with difficulty swallowing.

The major problem with levodopa is that after 4 to 6 years of treatment, about 40% of patients develop motor fluctuations and dyskinesias.⁵ If treatment is started too soon or at too high a dose, these problems tend to develop even earlier, especially among younger patients.

Motor fluctuations can take many forms: slow wearing-off, abrupt loss of effectiveness, and random on-and-off effectiveness (“yo-yoing”).

Dyskinesias typically involve constant chorea (dance-like) movements and occur at peak dose. Although chorea is easily treated by lowering the dosage, patients generally prefer having these movements rather than the Parkinson symptoms that recur from underdosing.

Dopamine agonists may be best for younger patients in early stages

The next most effective class of drugs are the dopamine agonists: pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel). A fourth drug, pergolide, is no longer available because of associated valvular heart complications. Each can be used as monotherapy in mild, early Parkinson disease or as an additional drug for moderate to severe disease. They are longer-acting than levodopa and can be taken once daily. Although they are less likely than levodopa to cause wearing-off or dyskinesias, they are associated with more nonmotor side effects: nausea and vomiting, hallucinations, confusion, somnolence or sleep attacks, low blood pressure, edema, and impulse control disorders.

Multiple clinical trials have been conducted to test the efficacy of dopamine agonists vs levodopa for treating Parkinson disease.^6–9 Almost always, levodopa is more effective but involves more wearing-off and dyskinesias. For this reason, for patients with milder parkinsonism who may not need the strongest drug available, trying one of the dopamine agonists first may be worthwhile.

In addition, patients younger than age 60 are more prone to develop motor fluctuations and dyskinesias, so a dopamine agonist should be tried first in patients in that age group. For patients over age 65 for whom cost may be of concern, levodopa is the preferred starting drug.

Anticholinergic drugs for tremor

Before 1969, only anticholinergic drugs were available to treat Parkinson disease. Examples include trihexyphenidyl (Artane, Trihexane) and benztropine (Cogentin). These drugs are effective for treating tremor and drooling but are much less useful against rigidity, bradykinesia, and balance problems. Side effects include confusion, dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment.

Anticholinergics should only be considered for young patients in whom tremor is a large problem and who have not responded well to the traditional Parkinson drugs. Because tremor is mostly a cosmetic problem, anticholinergics can also be useful for treating actors, musicians, and other patients with a public role.

Monoamine oxidase B inhibitors are well tolerated but less effective

In the brain, dopamine is broken down by monoamine oxidase B (MAO-B); therefore, inhibiting this enzyme increases dopamine’s availability. The MAO-B inhibitors selegiline (Eldepryl, Zelapar) and rasagiline (Azilect) are effective for monotherapy for Parkinson disease but are not as effective as levodopa. Most physicians feel MAO-B inhibitors are also less effective than dopamine agonists, although double-blind, randomized clinical trials have not proven this.^6,10,11

MAO-B inhibitors have a long half-life, allowing once-daily dosing, and they are very well tolerated, with a side-effect profile similar to that of placebo. As with all MAO inhibitors, caution is needed regarding drug and food interactions.

 

EFFECTIVE NEUROPROTECTIVE AGENTS REMAIN ELUSIVE

Although numerous drugs are now available to treat the symptoms of Parkinson disease, the ability to slow the progression of the disease remains elusive. The only factor consistently shown by epidemiologic evidence to be protective is cigarette smoking, but we don’t recommend it.

A number of agents have been tested for neuroprotective efficacy:

Coenzyme Q10 has been tested at low and high dosages but was not found to be effective.

Pramipexole, a dopamine agonist, has also been studied without success.

Creatine is currently being studied and shows promise, possibly because of its effects on complex-I, part of the electron transport chain in mitochondria, which may be disrupted in Parkinson disease.

Inosine, which elevates uric acid, is also promising. The link between high uric acid and Parkinson disease was serendipitously discovered: when evaluating numerous blood panels taken from patients with Parkinson disease who were in clinical trials (using what turned out to be ineffective agents), it was noted that patients with the slowest progression of disease tended to have the highest uric acid levels. This has led to trials evaluating the effect of elevating uric acid to a pre-gout threshold.

Calcium channel blockers may be protective, according to epidemiologic evidence. Experiments involving injecting isradipine (DynaCirc) in rat models of Parkinson disease have indicated that the drug is promising.

Rasagiline: Protective effects still unknown

A large study of the neuroprotective effects of the MAO-B inhibitor rasagiline has just been completed, but the results are uncertain.¹² A unique “delayed-start” clinical trial design was used to try to evaluate whether this agent that is known to reduce symptoms may also be neuroprotective. More than 1,000 people with untreated Parkinson disease from 14 countries were randomly assigned to receive rasagiline (the early-start group) or placebo (the delayed-start group) for 36 weeks. Afterward, both groups were given rasagiline for another 36 weeks. Rasagiline was given in a daily dose of either 1 mg or 2 mg.

The investigators anticipated that if the benefits of rasagiline were purely symptomatic, the early- and delayed-start groups would have equivalent disease severity at the end of the study. If rasagiline were protective, the early-start group would be better off at the end of the study. Unfortunately, the results were ambiguous: the early- and delayed-start groups were equivalent at the end of the study if they received the 2-mg daily dose, apparently indicating no protective effect. But at the 1-mg daily dose, the delayed-start group developed more severe disease at 36 weeks and did not catch up to the early-start group after treatment with rasagiline, apparently indicating a protective benefit. As a result, no definitive conclusion can be drawn.

EXTENDING TREATMENT EFFECTS IN ADVANCED PARKINSON DISEASE

For most patients, the first 5 years after being diagnosed with Parkinson disease is the “honeymoon phase,” when almost any treatment is effective. During this time, patients tend to have enough surviving dopaminergic neurons to store levodopa, despite its very short half-life of only 60 minutes.

As the disease progresses, fewer dopaminergic neurons survive, the therapeutic window narrows, and dosing becomes a balancing act: too much dopamine causes dyskinesias, hallucinations, delusions, and impulsive behavior, and too little dopamine causes worsening of Parkinson symptoms, freezing, and wearing-off, with ensuing falls and fractures. At this stage, some patients are prescribed levodopa every 1.5 or 2 hours.

Drugs are now available that extend the half-life of levodopa by slowing the breakdown of dopamine.

Catechol-O-methyltransferase (COMT) inhibitors—including tolcapone (Tasmar) and entacapone (Comtan) (also available as combined cardidopa, entacapone, and levodopa [Stalevo])—reduce off periods by about 1 hour per day.¹³ Given that the price is about $2,500 per year, the cost and benefits to the patient must be considered.^14–17

Rasagiline, an MAO-B inhibitor, can also be added to levodopa to extend the “on” time for about 1 hour a day and to reduce freezing of gait. Clinical trials have shown it to be well tolerated, although common side effects include worsening dyskinesias and nausea.^18,19

Apomorphine (Apokyn) is a dopamine agonist given by subcutaneous injection, allowing it to avoid first-pass metabolism by the liver. The benefits start just 10 minutes after injection, but only last for about 1 hour. It is a good option for rescue therapy for patients who cannot swallow or who have severe, unpredictable, or painful off-periods. It is also useful for situations in which it is especially inconvenient to have an off-period, such as being away from home.

Many agents have been tested for improving the off-period, but most work for about 1 to 2 hours, which is not nearly as effective as deep brain stimulation.

Managing dyskinesias

Dyskinesias can be managed by giving lower doses of levodopa more often. If wearing-off is a problem, a dopamine agonist or MAO-B inhibitor can be added. For patients at this stage, a specialist should be consulted.

Amantadine (Symmetrel), an N-methyl-d-aspartate (NMDA) receptor antagonist and dopamine-releasing agent used to treat influenza, is also effective against dyskinesias. Adverse effects include anxiety, insomnia, nightmares, anticholinergic effects, and livedo reticularis.^20,21

Deep brain stimulation is the best treatment for dyskinesias in a patient for whom the procedure is appropriate and who has medical insurance that covers it.

 

NONMOTOR FEATURES OF PARKINSON DISEASE

Dementia: One of the most limiting nonmotor features

Often the most limiting nonmotor feature of Parkinson disease is dementia, which develops at about four to six times the rate for age-matched controls. At a given time, about 40% of patients with Parkinson disease have dementia, and the risk is 80% over 15 years of the disease.

If dementia is present, many of the drugs effective against Parkinson disease cannot be used because of exacerbating side effects. Treatment is mainly restricted to levodopa.

The only FDA-approved drug to treat dementia in Parkinson disease is the same drug for Alzheimer disease, rivastigmine (Exelon). Its effects are only modest, and its cholinergic side effects may transiently worsen parkinsonian features.²²

Psychosis: Also very common

About half of patients with Parkinson disease have an episode of hallucinations or delusions in their lifetime, and about 20% are actively psychotic at any time. Delusions typically have the theme of spousal infidelity. Psychosis is associated with a higher rate of death compared with patients with Parkinson disease who do not develop it. Rebound psychosis may occur on withdrawal of antipsychotic medication.^23–27

Patients who develop psychosis should have a physical examination and laboratory evaluation to determine if an infection or electrolyte imbalance is the cause. Medications should be discontinued in the following order: anticholinergic drug, amantadine, MAO-B inhibitor, dopamine agonist, and COMT inhibitor. Levodopa and carbidopa should be reduced to the minimum tolerable yet effective dosages.

For a patient who still has psychosis despite a minimum Parkinson drug regimen, an atypical antipsychotic drug should be used. Although clozapine (Clozaril, FazaClo) is very effective without worsening parkinsonism, it requires weekly monitoring with a complete blood count because of the small (< 1%) risk of agranulocytosis. For that reason, the first-line drug is quetiapine (Seroquel). Most double-blind studies have not found it to be effective, yet it is the drug most often used. No other antipsychotic drugs are safe to treat Parkinson psychosis.

Many patients with Parkinson disease who are hospitalized become agitated and confused soon after they are admitted to the hospital. The best treatment is quetiapine if an oral drug can be prescribed. A benzodiazepine—eg, clonazepam (Klonopin), lorazepam (Ativan), diazepam (Valium)—at a low dose may also be effective. Haloperidol, risperidone, and olanzapine should not be given, as they block dopamine receptors and worsen rigidity.

Mood disturbances

Depression occurs in about half of patients with Parkinson disease and is a significant cause of functional impairment. About 25% of patients have anxiety, and 20% are apathetic.

Depression appears to be secondary to underlying neuroanatomic degeneration rather than a reaction to disability.²⁸ Fortunately, most antidepressants are effective in patients with Parkinson disease.^29,30 Bupropion (Wellbutrin) is a dopamine reuptake inhibitor and so increases the availability of dopamine, and it should also have antiparkinsonian effects, but unfortunately it does not. Conversely, selective serotonin reuptake inhibitors (SSRIs) theoretically can worsen or cause parkinsonism, but evidence shows that they are safe to use in patients with Parkinson disease. Some evidence indicates that tricyclic antidepressants may be superior to SSRIs for treating depression in patients with Parkinson disease, so they might be the better choice in patients who can tolerate them.

Compulsive behaviors such as punding (prolonged performance of repetitive, mechanical tasks, such as disassembling and reassembling household objects) may occur from levodopa.

In addition, impulse control disorders involving pathologic gambling, hypersexuality, compulsive shopping, or binge eating occur in about 8% of patients with Parkinson disease taking dopamine agonists. These behaviors are more likely to arise in young, single patients, who are also more likely to have a family history of impulsive control disorder.³¹

THE FUTURE OF DRUG THERAPY

Clinical trials are now testing new therapies that work the traditional way through dopaminergic mechanisms, as well as those that work in novel ways.

A large international trial is studying patients with newly diagnosed Parkinson disease to try to discover a biomarker. Parkinson disease is unlike many other diseases in that physicians can only use clinical features to measure improvement, which is very crude. Identifying a biomarker will make evaluating and monitoring treatment a more exact science, and will lead to faster development of effective treatments.

The US health care system cannot continue with “business as usual.” The current model is broken: it does not deliver the kind of care we want for our patients, ourselves, our families, and our communities. It is our role as professionals to help drive change and make medical care more cost-effective and of higher quality, with better satisfaction for patients as well as for providers.

Central to efforts to reform the system are two concepts. One is the “patient-centered medical home,” in which a single provider is responsible for coordinating care for individual patients. The other is “accountable care organizations,” a new way of organizing care along a continuum from doctor to hospital, mandated by the new health care reform law (technically known as the Patient Protection and Affordable Care Act).

CURRENT STATE OF HEALTH CARE: HIGH COST AND POOR QUALITY

Since health care reform was initially proposed in the 1990s, trends in the United States have grown steadily worse. Escalating health care costs have outstripped inflation, consuming an increasing percentage of the gross domestic product (GDP) at an unsustainable rate. Despite increased spending, quality outcomes are suboptimal. In addition, with the emergence of specialization and technology, care is increasingly fragmented and poorly coordinated, with multiple providers and poorly managed resources.

Over the last 15 years, the United States has far surpassed most countries in the developed world for total health care expenditures per capita.^1,2 In 2009, we spent 17.4% of our GDP on health care, translating to $7,960 per capita, while Japan spent only 8.5% of its GDP, averaging $2,878 per capita.² At the current rate, health care spending in the United States will increase from $2.5 trillion in 2009 to over $4.6 trillion in 2020.³

Paradoxically, costlier care is often of poorer quality. Many countries that spend far less per capita on health care achieve far better outcomes. Even within the United States, greater Medicare spending on a state and regional basis tends to correlate with poorer quality of care.⁴ Spending among Medicare beneficiaries is not standardized and varies widely throughout the country.⁵ The amount of care a patient receives also varies dramatically by region. The number of specialists involved in care during the last year of life is steadily increasing in many regions of the country, indicating poor care coordination.⁶

PATIENT-CENTERED MEDICAL HOMES: A POSITIVE TREND

The problems of high cost, poor quality, and poor coordination of care have led to the emergence of the concept of the patient-centered medical home. Originally proposed in 1967 by the American Academy of Pediatrics in response to the need for care coordination by a single physician, the idea did not really take root until the early 1990s. In 2002, the American Academy of Family Medicine embraced the concept and moved it forward.

According to the National Committee for Quality Assurance (NCQA), a nonprofit organization that provides voluntary certification for medical organizations, the patient-centered medical home is a model of care in which “patients have a direct relationship with a provider who coordinates a cooperative team of healthcare professionals, takes collective responsibility for the care provided to the patient, and arranges for appropriate care with other qualified providers as needed.”⁷

Patient-centered medical homes are supposed to improve quality outcomes and lower costs. In addition, they can compete for public or private incentives that reward this model of care and, as we will see later, are at the heart of ACO readiness.

Medical homes meet certification standards

NCQA first formally licensed patient-centered medical homes in 2008, based on nine standards and six key elements. A scoring system was used to rank the level of certification from level 1 (the lowest) to level 3. From 2008 to the end of 2010, the number of certified homes grew from 28 to 1,506. New York has the largest number of medical homes.

In January 2011, NCQA instituted certification standards that are more stringent, with six standards and a number of key elements in each standard. Each standard has one “mustpass” element (Table 1). NCQA has built on previous standards but with increased emphasis on patient-centeredness, including a stronger focus on integrating behavioral health and chronic disease management and involving patients and families in quality improvement with the use of patient surveys. Also, starting in January 2012, a new standardized patient experience survey will be required, known as the Consumer Assessment of Healthcare Providers and Systems (CAHPS).

The new elements in the NCQA program align more closely with federal programs that are designed to drive quality, including the Centers for Medicare and Medicaid Services program to encourage the use of the electronic medical record, and with federal rule-making this last spring designed to implement accountable care organizations (ACOs).

Same-day access is now emphasized, as is managing patient populations—rather than just individual patients—with certain chronic diseases, such as diabetes and congestive heart failure. The requirements for tracking and coordinating care have profound implications about how resources are allocated. Ideally, coordinators of chronic disease management are embedded within practices to help manage high-risk patients, although the current reimbursement mechanism does not support this model. Population management may not be feasible for institutions that still rely on paper-based medical records.

 

 

Medical homes lower costs, improve quality

Integrated delivery system models such as patient-centered medical homes have demonstrated cost-savings while improving quality of care.^8,9 Reducing hospital admissions and visits to the emergency department shows the greatest cost-savings in these models. Several projects have shown significant cost-savings¹⁰:

The Group Health Cooperative of Puget Sound reduced total costs by $10 per member per month (from $498 to $488, P = 0.76), with a 16% reduction in hospital admissions (P < .001) and a 29% reduction in emergency department visits (P < .001).

The Geisinger Health System Proven-Health Navigator in Pennsylvania reduced readmissions by 18% (P < .01). They also had a 7% reduction in total costs per member per month relative to a matched control group also in the Geisinger system but not in a medical home, although this difference did not reach statistical significance. Private payer demonstration projects of patient-centered medical homes have also shown cost-savings.

Blue Cross Blue Shield of South Carolina randomized patients to participate in either a patient-centered medical home or their standard system. The patient-centered medical home group had 36% fewer hospital days, 12.4% fewer emergency department visits, and a 6.5% reduction in total medical and pharmacy costs compared with controls.

Finally, the use of chronic care coordinators in a patient-centered medical home has been shown to be cost-effective and can lower the overall cost of care despite the investment to hire them. Johns Hopkins Guided Care program demonstrated a 24% reduction in hospital days, 15% fewer emergency department visits, and a 37% reduction in days in a skilled nursing facility. The annual net Medicare savings was $75,000 per coordinator nurse hired.

ACCOUNTABLE CARE ORGANIZATIONS: A NEW SYSTEM OF HEALTH CARE DELIVERY

While the patient-centered medical home is designed to improve the coordination of care among physicians, ACOs have the broader goal of coordinating care across the entire continuum of health care, from physicians to hospitals to other clinicians. The concept of ACOs was spawned in 2006 by Elliott S. Fisher, MD, MPH, of the Dartmouth Institute for Health Policy and Clinical Practice. The idea is that, by improving care coordination within an ACO and reducing fragmented care, costs can be controlled and outcomes improved. Of course, the devil is in the details.

As part of its health care reform initiative, the state of Massachusetts’ Special Commission on the Health Care Payment System defined ACOs as health care delivery systems composed of hospitals, physicians, and other clinician and nonclinician providers that manage care across the entire spectrum of care. An ACO could be a real (incorporated) or virtual (contractually networked) organization, for example, a large physician organization that would contract with one or more hospitals and ancillary providers.¹¹

In a 2009 report to Congress, the Medicare Payment Advisory Committee (MedPac) similarly defined ACOs for the Medicare population. But MedPac also introduced the concept of financial risk: providers in the ACO would share in efficiency gains from improved care coordination and could be subjected to financial penalties for poor performance, depending on the structure of the ACO.¹²

But what has placed ACOs at center stage is the new health care reform law, which encourages the formation of ACOs. On March 31, 2011, the Centers for Medicare and Medicaid Services published proposed rules to implement ACOs for Medicare patients (they appeared in the Federal Register on April 7, 2011).^13,14 Comments on the 129-page proposed rules were due by June 6, 2011. Final rules are supposed to be published later this year.

The proposed new rule has a three-part aim:

• Better care for individuals, as described by all six dimensions of quality in the Institute of Medicine report “Crossing the Quality Chasm”¹⁵: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity
• Better health for populations, with respect to educating beneficiaries about the major causes of ill health—poor nutrition, physical inactivity, substance abuse, and poverty—as well as about the importance of preventive services such as an annual physical examination and annual influenza vaccination
• Lower growth in expenditures by eliminating waste and inefficiencies while not withholding any needed care that helps beneficiaries.

DETAILS OF THE PROPOSED ACO RULE

Here are some of the highlights of the proposed ACO rule.

Two shared-savings options

Although the program could start as soon as January 1, 2012, the application process is formidable, so this timeline may not be realistic. Moreover, a final rule is pending.

The proposed rule requires at least a 3-year contract, and primary care physicians must be included. Shared savings will be available and will depend on an ACO’s ability to manage costs and to achieve quality target performances. Two shared-savings options will be available: one with no risk until the third year and the other with risk during all 3 years but greater potential benefit. In the one-sided model with no risk until year 3, an ACO would begin to accrue shared savings at a rate of 50% after an initial 2% of savings compared with a risk-adjusted per capita benchmark based on performance during the previous 3 years. In the second plan, an ACO would immediately realize shared savings at a rate of 60% as long as savings were achieved compared with prior benchmark performance. However, in this second model, the ACO would be at risk to repay a share of all losses that were more than 2% higher than the benchmark expenditures, with loss caps of 5%, 7.5%, and 10% above benchmark in years 1, 2, and 3, respectively.

 

 

Structure of an ACO

Under the proposed rule, the minimum population size of Medicare beneficiaries is 5,000 patients, with some exceptions in rural or other shortage areas, or areas with critical access hospitals. ACO founders can be primary care physicians, primary care independent practice associations, or employee groups. Participants may include hospitals, critical access hospitals, specialists, and other providers. The ACO must be a legal entity with its own tax identification number and its own governance and management structure.

Concerns have been expressed that, in some markets, certain groups may come together and achieve market dominance with more than half of the population. Proposed ACOs with less than 30% of the market share will be exempt from antitrust concerns, and those with greater than 50% of market share will undergo detailed review.

Patient assignment

Patients will be assigned to an ACO retrospectively, at the end of the 3 years. The Centers for Medicare and Medicaid Services argues that retrospective assignment will encourage the ACO to design a system to help all patients, not just those assigned to the ACO.

Patients may not opt out of being counted against ACO performance measures. Although Medicare will share beneficiaries’ data with the ACO retrospectively so that it can learn more about costs per patient, patients may opt out of this data-sharing. Patients also retain unrestricted choice to see other providers, with attribution of costs incurred to the ACO.

Quality and reporting

The proposed rule has 65 equally weighted quality measures, many of which are not presently reported by most health care organizations. The measures fall within five broad categories: patient and caregiver experience, care coordination, patient safety, preventive health, and managing at-risk populations, including the frail elderly. Bonus payments for cost-savings will be adjusted based on meeting the quality measures.

Governance and management

Under the proposed rule, an ACO must meet stringent governance requirements. It must be a distinct legal entity as governed by state law. There must be proportional representation of all participants (eg, hospitals, community organizations, providers), comprising at least 75% of its Board of Trustees. These members must have authority to execute statutory functions of the ACO. Medicare beneficiaries and community stakeholder organizations must also be represented on the Board.

ACO operations must be managed by an executive director, manager, or general partner, who may or may not be a physician. A board-certified physician who is licensed in the state in which the ACO is domiciled must serve on location as the full-time, senior-level medical director, overseeing and managing clinical operations. A leadership team must be able to influence clinical practice, and a physician-directed process-improvement and quality-assurance committee is required.

Infrastructure and policies

The proposed rule outlines a number of infrastructure and policy requirements that must be addressed in the application process. These include:

• Written performance standards for quality and efficiency
• Evidence-based practice guidelines
• Tools to collect, evaluate, and share data to influence decision-making at the point of care
• Processes to identify and correct poor performance
• Description of how shared savings will be used to further improve care.

The concept of patient-centered care is a critical focus of the proposed ACO rule, and it includes involving the beneficiaries in governance as well as plans to assess and care for the needs of the patient population (Table 2).

CONCERNS ABOUT THE PROPOSED NEW ACO RULE

While there is broad consensus in the health care community that the current system of care delivery fails to achieve the desired outcomes and is financially unsustainable and in need of reform, many concerns have been expressed about the proposed new ACO rule.

The regulations are too detailed. The regulations are highly prescriptive with detailed application, reporting, and regulatory requirements that create significant administrative burdens. Small medical groups are unlikely to have the administrative infrastructure to become involved.

Potential savings are inadequate. The shared savings concept has modest upside gain when modeled with holdback.¹⁶ Moreover, a recent analysis from the University Health System Consortium suggested that 50% of ACOs with 5,000 or more attributed lives would sustain unwarranted penalties as a result of random fluctuation of expenditures in the population.¹⁷

Participation involves a big investment. Participation requires significant resource investment, such as hiring chronic-disease managers and, in some practices, creating a whole new concept of managing wellness and continuity of care.

Retrospective beneficiary assignment is unpopular. Groups would generally prefer to know beforehand for whom they are responsible financially. A prospective assignment model was considered for the proposed rule but was ultimately rejected.

The patient assignment system is too risky. The plurality rule requires only a single visit with the ACO in order to be responsible for a patient for the entire year. In addition, the fact that the patient has the freedom to choose care elsewhere with expense assigned to the ACO confers significant financial risk.

There are too many quality measures. The high number of quality metrics—65—required to be measured and reported is onerous for most organizations.

Advertising is micromanaged. All marketing materials that are sent to patients about the ACO and any subsequent revisions must first be approved by Medicare, a potentially burdensome and time-consuming requirement.

Specialists are excluded. Using only generalists could actually be less cost-effective for some patients, such as those with human immunodeficiency virus, end-stage renal disease, certain malignancies, or advanced congestive heart failure.

Provider replacement is prohibited. Providers cannot be replaced over the 3 years of the demonstration, but the departing physician’s patients are still the responsibility of the plan. This would be especially problematic for small practices.

 

PREDICTING ACO READINESS

I believe there are five core competencies that are required to be an ACO:

• Operational excellence in care delivery
• Ability to deliver care across the continuum
• Cultural alignment among participating organizations
• Technical and informatics support to manage individual and population data
• Physician alignment around the concept of the ACO.

Certain strategies will increase the chances of success of an ACO:

Reduce emergency department usage and hospitalization. Cost-savings in patient-centered medical homes have been greatest by reducing hospitalizations, rehospitalizations, and emergency department visits.

Develop a high-quality, efficient primary care network. Have enough of a share in the primary care physician network to deliver effective primary care. Make sure there is good access to care and effective communication between patients and the primary care network. Deliver comprehensive services and have good care coordination. Aggressively manage communication, care coordination, and “hand-offs” across the care continuum and with specialists.

Create an effective patient-centered medical home. The current reimbursement climate fails to incentivize all of the necessary elements, which ultimately need to include chronic-care coordinators for medically complex patients, pharmacy support for patient medication management, adequate support staff to optimize efficiency, and a culture of wellness and necessary resources to support wellness.

PHYSICIANS NEED TO DRIVE SOLUTIONS

Soaring health care costs in the United States, poor quality outcomes, and increasing fragmentation of care are the major drivers of health care reform. The Patient Centered Medical Home is a key component to the solution and has already been shown to improve outcomes and lower costs. Further refinement of this concept and implementation should be priorities for primary care physicians and health care organizations.

The ACO concept attempts to further improve quality and lower costs. The proposed ACO rule released by the Centers for Medicare and Medicaid Services on March 31, 2011, has generated significant controversy in the health care community. In its current form, few health care systems are likely to participate. A revised rule is awaited in the coming months. In the meantime, the Centers for Medicare and Medicaid Services has released a request for application for a Pioneer ACO model, which offers up to 30 organizations the opportunity to participate in an ACO pilot that allows for prospective patient assignment and greater shared savings.

Whether ACOs as proposed achieve widespread implementation remains to be seen. However, the current system of health care delivery in this country is broken. Physicians and health care systems need to drive solutions to the challenges we face about quality, cost, access, care coordination, and outcomes.

The US health care system cannot continue with “business as usual.” The current model is broken: it does not deliver the kind of care we want for our patients, ourselves, our families, and our communities. It is our role as professionals to help drive change and make medical care more cost-effective and of higher quality, with better satisfaction for patients as well as for providers.

Central to efforts to reform the system are two concepts. One is the “patient-centered medical home,” in which a single provider is responsible for coordinating care for individual patients. The other is “accountable care organizations,” a new way of organizing care along a continuum from doctor to hospital, mandated by the new health care reform law (technically known as the Patient Protection and Affordable Care Act).

CURRENT STATE OF HEALTH CARE: HIGH COST AND POOR QUALITY

Since health care reform was initially proposed in the 1990s, trends in the United States have grown steadily worse. Escalating health care costs have outstripped inflation, consuming an increasing percentage of the gross domestic product (GDP) at an unsustainable rate. Despite increased spending, quality outcomes are suboptimal. In addition, with the emergence of specialization and technology, care is increasingly fragmented and poorly coordinated, with multiple providers and poorly managed resources.

Over the last 15 years, the United States has far surpassed most countries in the developed world for total health care expenditures per capita.^1,2 In 2009, we spent 17.4% of our GDP on health care, translating to $7,960 per capita, while Japan spent only 8.5% of its GDP, averaging $2,878 per capita.² At the current rate, health care spending in the United States will increase from $2.5 trillion in 2009 to over $4.6 trillion in 2020.³

Paradoxically, costlier care is often of poorer quality. Many countries that spend far less per capita on health care achieve far better outcomes. Even within the United States, greater Medicare spending on a state and regional basis tends to correlate with poorer quality of care.⁴ Spending among Medicare beneficiaries is not standardized and varies widely throughout the country.⁵ The amount of care a patient receives also varies dramatically by region. The number of specialists involved in care during the last year of life is steadily increasing in many regions of the country, indicating poor care coordination.⁶

PATIENT-CENTERED MEDICAL HOMES: A POSITIVE TREND

The problems of high cost, poor quality, and poor coordination of care have led to the emergence of the concept of the patient-centered medical home. Originally proposed in 1967 by the American Academy of Pediatrics in response to the need for care coordination by a single physician, the idea did not really take root until the early 1990s. In 2002, the American Academy of Family Medicine embraced the concept and moved it forward.

According to the National Committee for Quality Assurance (NCQA), a nonprofit organization that provides voluntary certification for medical organizations, the patient-centered medical home is a model of care in which “patients have a direct relationship with a provider who coordinates a cooperative team of healthcare professionals, takes collective responsibility for the care provided to the patient, and arranges for appropriate care with other qualified providers as needed.”⁷

Patient-centered medical homes are supposed to improve quality outcomes and lower costs. In addition, they can compete for public or private incentives that reward this model of care and, as we will see later, are at the heart of ACO readiness.

Medical homes meet certification standards

NCQA first formally licensed patient-centered medical homes in 2008, based on nine standards and six key elements. A scoring system was used to rank the level of certification from level 1 (the lowest) to level 3. From 2008 to the end of 2010, the number of certified homes grew from 28 to 1,506. New York has the largest number of medical homes.

In January 2011, NCQA instituted certification standards that are more stringent, with six standards and a number of key elements in each standard. Each standard has one “mustpass” element (Table 1). NCQA has built on previous standards but with increased emphasis on patient-centeredness, including a stronger focus on integrating behavioral health and chronic disease management and involving patients and families in quality improvement with the use of patient surveys. Also, starting in January 2012, a new standardized patient experience survey will be required, known as the Consumer Assessment of Healthcare Providers and Systems (CAHPS).

The new elements in the NCQA program align more closely with federal programs that are designed to drive quality, including the Centers for Medicare and Medicaid Services program to encourage the use of the electronic medical record, and with federal rule-making this last spring designed to implement accountable care organizations (ACOs).

Same-day access is now emphasized, as is managing patient populations—rather than just individual patients—with certain chronic diseases, such as diabetes and congestive heart failure. The requirements for tracking and coordinating care have profound implications about how resources are allocated. Ideally, coordinators of chronic disease management are embedded within practices to help manage high-risk patients, although the current reimbursement mechanism does not support this model. Population management may not be feasible for institutions that still rely on paper-based medical records.

 

 

Medical homes lower costs, improve quality

Integrated delivery system models such as patient-centered medical homes have demonstrated cost-savings while improving quality of care.^8,9 Reducing hospital admissions and visits to the emergency department shows the greatest cost-savings in these models. Several projects have shown significant cost-savings¹⁰:

The Group Health Cooperative of Puget Sound reduced total costs by $10 per member per month (from $498 to $488, P = 0.76), with a 16% reduction in hospital admissions (P < .001) and a 29% reduction in emergency department visits (P < .001).

The Geisinger Health System Proven-Health Navigator in Pennsylvania reduced readmissions by 18% (P < .01). They also had a 7% reduction in total costs per member per month relative to a matched control group also in the Geisinger system but not in a medical home, although this difference did not reach statistical significance. Private payer demonstration projects of patient-centered medical homes have also shown cost-savings.

Blue Cross Blue Shield of South Carolina randomized patients to participate in either a patient-centered medical home or their standard system. The patient-centered medical home group had 36% fewer hospital days, 12.4% fewer emergency department visits, and a 6.5% reduction in total medical and pharmacy costs compared with controls.

Finally, the use of chronic care coordinators in a patient-centered medical home has been shown to be cost-effective and can lower the overall cost of care despite the investment to hire them. Johns Hopkins Guided Care program demonstrated a 24% reduction in hospital days, 15% fewer emergency department visits, and a 37% reduction in days in a skilled nursing facility. The annual net Medicare savings was $75,000 per coordinator nurse hired.

ACCOUNTABLE CARE ORGANIZATIONS: A NEW SYSTEM OF HEALTH CARE DELIVERY

While the patient-centered medical home is designed to improve the coordination of care among physicians, ACOs have the broader goal of coordinating care across the entire continuum of health care, from physicians to hospitals to other clinicians. The concept of ACOs was spawned in 2006 by Elliott S. Fisher, MD, MPH, of the Dartmouth Institute for Health Policy and Clinical Practice. The idea is that, by improving care coordination within an ACO and reducing fragmented care, costs can be controlled and outcomes improved. Of course, the devil is in the details.

As part of its health care reform initiative, the state of Massachusetts’ Special Commission on the Health Care Payment System defined ACOs as health care delivery systems composed of hospitals, physicians, and other clinician and nonclinician providers that manage care across the entire spectrum of care. An ACO could be a real (incorporated) or virtual (contractually networked) organization, for example, a large physician organization that would contract with one or more hospitals and ancillary providers.¹¹

In a 2009 report to Congress, the Medicare Payment Advisory Committee (MedPac) similarly defined ACOs for the Medicare population. But MedPac also introduced the concept of financial risk: providers in the ACO would share in efficiency gains from improved care coordination and could be subjected to financial penalties for poor performance, depending on the structure of the ACO.¹²

But what has placed ACOs at center stage is the new health care reform law, which encourages the formation of ACOs. On March 31, 2011, the Centers for Medicare and Medicaid Services published proposed rules to implement ACOs for Medicare patients (they appeared in the Federal Register on April 7, 2011).^13,14 Comments on the 129-page proposed rules were due by June 6, 2011. Final rules are supposed to be published later this year.

The proposed new rule has a three-part aim:

• Better care for individuals, as described by all six dimensions of quality in the Institute of Medicine report “Crossing the Quality Chasm”¹⁵: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity
• Better health for populations, with respect to educating beneficiaries about the major causes of ill health—poor nutrition, physical inactivity, substance abuse, and poverty—as well as about the importance of preventive services such as an annual physical examination and annual influenza vaccination
• Lower growth in expenditures by eliminating waste and inefficiencies while not withholding any needed care that helps beneficiaries.

DETAILS OF THE PROPOSED ACO RULE

Here are some of the highlights of the proposed ACO rule.

Two shared-savings options

Although the program could start as soon as January 1, 2012, the application process is formidable, so this timeline may not be realistic. Moreover, a final rule is pending.

The proposed rule requires at least a 3-year contract, and primary care physicians must be included. Shared savings will be available and will depend on an ACO’s ability to manage costs and to achieve quality target performances. Two shared-savings options will be available: one with no risk until the third year and the other with risk during all 3 years but greater potential benefit. In the one-sided model with no risk until year 3, an ACO would begin to accrue shared savings at a rate of 50% after an initial 2% of savings compared with a risk-adjusted per capita benchmark based on performance during the previous 3 years. In the second plan, an ACO would immediately realize shared savings at a rate of 60% as long as savings were achieved compared with prior benchmark performance. However, in this second model, the ACO would be at risk to repay a share of all losses that were more than 2% higher than the benchmark expenditures, with loss caps of 5%, 7.5%, and 10% above benchmark in years 1, 2, and 3, respectively.

 

 

Structure of an ACO

Under the proposed rule, the minimum population size of Medicare beneficiaries is 5,000 patients, with some exceptions in rural or other shortage areas, or areas with critical access hospitals. ACO founders can be primary care physicians, primary care independent practice associations, or employee groups. Participants may include hospitals, critical access hospitals, specialists, and other providers. The ACO must be a legal entity with its own tax identification number and its own governance and management structure.

Concerns have been expressed that, in some markets, certain groups may come together and achieve market dominance with more than half of the population. Proposed ACOs with less than 30% of the market share will be exempt from antitrust concerns, and those with greater than 50% of market share will undergo detailed review.

Patient assignment

Patients will be assigned to an ACO retrospectively, at the end of the 3 years. The Centers for Medicare and Medicaid Services argues that retrospective assignment will encourage the ACO to design a system to help all patients, not just those assigned to the ACO.

Patients may not opt out of being counted against ACO performance measures. Although Medicare will share beneficiaries’ data with the ACO retrospectively so that it can learn more about costs per patient, patients may opt out of this data-sharing. Patients also retain unrestricted choice to see other providers, with attribution of costs incurred to the ACO.

Quality and reporting

The proposed rule has 65 equally weighted quality measures, many of which are not presently reported by most health care organizations. The measures fall within five broad categories: patient and caregiver experience, care coordination, patient safety, preventive health, and managing at-risk populations, including the frail elderly. Bonus payments for cost-savings will be adjusted based on meeting the quality measures.

Governance and management

Under the proposed rule, an ACO must meet stringent governance requirements. It must be a distinct legal entity as governed by state law. There must be proportional representation of all participants (eg, hospitals, community organizations, providers), comprising at least 75% of its Board of Trustees. These members must have authority to execute statutory functions of the ACO. Medicare beneficiaries and community stakeholder organizations must also be represented on the Board.

ACO operations must be managed by an executive director, manager, or general partner, who may or may not be a physician. A board-certified physician who is licensed in the state in which the ACO is domiciled must serve on location as the full-time, senior-level medical director, overseeing and managing clinical operations. A leadership team must be able to influence clinical practice, and a physician-directed process-improvement and quality-assurance committee is required.

Infrastructure and policies

The proposed rule outlines a number of infrastructure and policy requirements that must be addressed in the application process. These include:

• Written performance standards for quality and efficiency
• Evidence-based practice guidelines
• Tools to collect, evaluate, and share data to influence decision-making at the point of care
• Processes to identify and correct poor performance
• Description of how shared savings will be used to further improve care.

The concept of patient-centered care is a critical focus of the proposed ACO rule, and it includes involving the beneficiaries in governance as well as plans to assess and care for the needs of the patient population (Table 2).

CONCERNS ABOUT THE PROPOSED NEW ACO RULE

While there is broad consensus in the health care community that the current system of care delivery fails to achieve the desired outcomes and is financially unsustainable and in need of reform, many concerns have been expressed about the proposed new ACO rule.

The regulations are too detailed. The regulations are highly prescriptive with detailed application, reporting, and regulatory requirements that create significant administrative burdens. Small medical groups are unlikely to have the administrative infrastructure to become involved.

Potential savings are inadequate. The shared savings concept has modest upside gain when modeled with holdback.¹⁶ Moreover, a recent analysis from the University Health System Consortium suggested that 50% of ACOs with 5,000 or more attributed lives would sustain unwarranted penalties as a result of random fluctuation of expenditures in the population.¹⁷

Participation involves a big investment. Participation requires significant resource investment, such as hiring chronic-disease managers and, in some practices, creating a whole new concept of managing wellness and continuity of care.

Retrospective beneficiary assignment is unpopular. Groups would generally prefer to know beforehand for whom they are responsible financially. A prospective assignment model was considered for the proposed rule but was ultimately rejected.

The patient assignment system is too risky. The plurality rule requires only a single visit with the ACO in order to be responsible for a patient for the entire year. In addition, the fact that the patient has the freedom to choose care elsewhere with expense assigned to the ACO confers significant financial risk.

There are too many quality measures. The high number of quality metrics—65—required to be measured and reported is onerous for most organizations.

Advertising is micromanaged. All marketing materials that are sent to patients about the ACO and any subsequent revisions must first be approved by Medicare, a potentially burdensome and time-consuming requirement.

Specialists are excluded. Using only generalists could actually be less cost-effective for some patients, such as those with human immunodeficiency virus, end-stage renal disease, certain malignancies, or advanced congestive heart failure.

Provider replacement is prohibited. Providers cannot be replaced over the 3 years of the demonstration, but the departing physician’s patients are still the responsibility of the plan. This would be especially problematic for small practices.

 

PREDICTING ACO READINESS

I believe there are five core competencies that are required to be an ACO:

• Operational excellence in care delivery
• Ability to deliver care across the continuum
• Cultural alignment among participating organizations
• Technical and informatics support to manage individual and population data
• Physician alignment around the concept of the ACO.

Certain strategies will increase the chances of success of an ACO:

Reduce emergency department usage and hospitalization. Cost-savings in patient-centered medical homes have been greatest by reducing hospitalizations, rehospitalizations, and emergency department visits.

Develop a high-quality, efficient primary care network. Have enough of a share in the primary care physician network to deliver effective primary care. Make sure there is good access to care and effective communication between patients and the primary care network. Deliver comprehensive services and have good care coordination. Aggressively manage communication, care coordination, and “hand-offs” across the care continuum and with specialists.

Create an effective patient-centered medical home. The current reimbursement climate fails to incentivize all of the necessary elements, which ultimately need to include chronic-care coordinators for medically complex patients, pharmacy support for patient medication management, adequate support staff to optimize efficiency, and a culture of wellness and necessary resources to support wellness.

PHYSICIANS NEED TO DRIVE SOLUTIONS

Soaring health care costs in the United States, poor quality outcomes, and increasing fragmentation of care are the major drivers of health care reform. The Patient Centered Medical Home is a key component to the solution and has already been shown to improve outcomes and lower costs. Further refinement of this concept and implementation should be priorities for primary care physicians and health care organizations.

The ACO concept attempts to further improve quality and lower costs. The proposed ACO rule released by the Centers for Medicare and Medicaid Services on March 31, 2011, has generated significant controversy in the health care community. In its current form, few health care systems are likely to participate. A revised rule is awaited in the coming months. In the meantime, the Centers for Medicare and Medicaid Services has released a request for application for a Pioneer ACO model, which offers up to 30 organizations the opportunity to participate in an ACO pilot that allows for prospective patient assignment and greater shared savings.

Whether ACOs as proposed achieve widespread implementation remains to be seen. However, the current system of health care delivery in this country is broken. Physicians and health care systems need to drive solutions to the challenges we face about quality, cost, access, care coordination, and outcomes.

The US health care system cannot continue with “business as usual.” The current model is broken: it does not deliver the kind of care we want for our patients, ourselves, our families, and our communities. It is our role as professionals to help drive change and make medical care more cost-effective and of higher quality, with better satisfaction for patients as well as for providers.

Central to efforts to reform the system are two concepts. One is the “patient-centered medical home,” in which a single provider is responsible for coordinating care for individual patients. The other is “accountable care organizations,” a new way of organizing care along a continuum from doctor to hospital, mandated by the new health care reform law (technically known as the Patient Protection and Affordable Care Act).

CURRENT STATE OF HEALTH CARE: HIGH COST AND POOR QUALITY

Since health care reform was initially proposed in the 1990s, trends in the United States have grown steadily worse. Escalating health care costs have outstripped inflation, consuming an increasing percentage of the gross domestic product (GDP) at an unsustainable rate. Despite increased spending, quality outcomes are suboptimal. In addition, with the emergence of specialization and technology, care is increasingly fragmented and poorly coordinated, with multiple providers and poorly managed resources.

Over the last 15 years, the United States has far surpassed most countries in the developed world for total health care expenditures per capita.^1,2 In 2009, we spent 17.4% of our GDP on health care, translating to $7,960 per capita, while Japan spent only 8.5% of its GDP, averaging $2,878 per capita.² At the current rate, health care spending in the United States will increase from $2.5 trillion in 2009 to over $4.6 trillion in 2020.³

Paradoxically, costlier care is often of poorer quality. Many countries that spend far less per capita on health care achieve far better outcomes. Even within the United States, greater Medicare spending on a state and regional basis tends to correlate with poorer quality of care.⁴ Spending among Medicare beneficiaries is not standardized and varies widely throughout the country.⁵ The amount of care a patient receives also varies dramatically by region. The number of specialists involved in care during the last year of life is steadily increasing in many regions of the country, indicating poor care coordination.⁶

PATIENT-CENTERED MEDICAL HOMES: A POSITIVE TREND

The problems of high cost, poor quality, and poor coordination of care have led to the emergence of the concept of the patient-centered medical home. Originally proposed in 1967 by the American Academy of Pediatrics in response to the need for care coordination by a single physician, the idea did not really take root until the early 1990s. In 2002, the American Academy of Family Medicine embraced the concept and moved it forward.

According to the National Committee for Quality Assurance (NCQA), a nonprofit organization that provides voluntary certification for medical organizations, the patient-centered medical home is a model of care in which “patients have a direct relationship with a provider who coordinates a cooperative team of healthcare professionals, takes collective responsibility for the care provided to the patient, and arranges for appropriate care with other qualified providers as needed.”⁷

Patient-centered medical homes are supposed to improve quality outcomes and lower costs. In addition, they can compete for public or private incentives that reward this model of care and, as we will see later, are at the heart of ACO readiness.

Medical homes meet certification standards

NCQA first formally licensed patient-centered medical homes in 2008, based on nine standards and six key elements. A scoring system was used to rank the level of certification from level 1 (the lowest) to level 3. From 2008 to the end of 2010, the number of certified homes grew from 28 to 1,506. New York has the largest number of medical homes.

In January 2011, NCQA instituted certification standards that are more stringent, with six standards and a number of key elements in each standard. Each standard has one “mustpass” element (Table 1). NCQA has built on previous standards but with increased emphasis on patient-centeredness, including a stronger focus on integrating behavioral health and chronic disease management and involving patients and families in quality improvement with the use of patient surveys. Also, starting in January 2012, a new standardized patient experience survey will be required, known as the Consumer Assessment of Healthcare Providers and Systems (CAHPS).

The new elements in the NCQA program align more closely with federal programs that are designed to drive quality, including the Centers for Medicare and Medicaid Services program to encourage the use of the electronic medical record, and with federal rule-making this last spring designed to implement accountable care organizations (ACOs).

Same-day access is now emphasized, as is managing patient populations—rather than just individual patients—with certain chronic diseases, such as diabetes and congestive heart failure. The requirements for tracking and coordinating care have profound implications about how resources are allocated. Ideally, coordinators of chronic disease management are embedded within practices to help manage high-risk patients, although the current reimbursement mechanism does not support this model. Population management may not be feasible for institutions that still rely on paper-based medical records.

 

 

Medical homes lower costs, improve quality

Integrated delivery system models such as patient-centered medical homes have demonstrated cost-savings while improving quality of care.^8,9 Reducing hospital admissions and visits to the emergency department shows the greatest cost-savings in these models. Several projects have shown significant cost-savings¹⁰:

The Group Health Cooperative of Puget Sound reduced total costs by $10 per member per month (from $498 to $488, P = 0.76), with a 16% reduction in hospital admissions (P < .001) and a 29% reduction in emergency department visits (P < .001).

The Geisinger Health System Proven-Health Navigator in Pennsylvania reduced readmissions by 18% (P < .01). They also had a 7% reduction in total costs per member per month relative to a matched control group also in the Geisinger system but not in a medical home, although this difference did not reach statistical significance. Private payer demonstration projects of patient-centered medical homes have also shown cost-savings.

Blue Cross Blue Shield of South Carolina randomized patients to participate in either a patient-centered medical home or their standard system. The patient-centered medical home group had 36% fewer hospital days, 12.4% fewer emergency department visits, and a 6.5% reduction in total medical and pharmacy costs compared with controls.

Finally, the use of chronic care coordinators in a patient-centered medical home has been shown to be cost-effective and can lower the overall cost of care despite the investment to hire them. Johns Hopkins Guided Care program demonstrated a 24% reduction in hospital days, 15% fewer emergency department visits, and a 37% reduction in days in a skilled nursing facility. The annual net Medicare savings was $75,000 per coordinator nurse hired.

ACCOUNTABLE CARE ORGANIZATIONS: A NEW SYSTEM OF HEALTH CARE DELIVERY

While the patient-centered medical home is designed to improve the coordination of care among physicians, ACOs have the broader goal of coordinating care across the entire continuum of health care, from physicians to hospitals to other clinicians. The concept of ACOs was spawned in 2006 by Elliott S. Fisher, MD, MPH, of the Dartmouth Institute for Health Policy and Clinical Practice. The idea is that, by improving care coordination within an ACO and reducing fragmented care, costs can be controlled and outcomes improved. Of course, the devil is in the details.

As part of its health care reform initiative, the state of Massachusetts’ Special Commission on the Health Care Payment System defined ACOs as health care delivery systems composed of hospitals, physicians, and other clinician and nonclinician providers that manage care across the entire spectrum of care. An ACO could be a real (incorporated) or virtual (contractually networked) organization, for example, a large physician organization that would contract with one or more hospitals and ancillary providers.¹¹

In a 2009 report to Congress, the Medicare Payment Advisory Committee (MedPac) similarly defined ACOs for the Medicare population. But MedPac also introduced the concept of financial risk: providers in the ACO would share in efficiency gains from improved care coordination and could be subjected to financial penalties for poor performance, depending on the structure of the ACO.¹²

But what has placed ACOs at center stage is the new health care reform law, which encourages the formation of ACOs. On March 31, 2011, the Centers for Medicare and Medicaid Services published proposed rules to implement ACOs for Medicare patients (they appeared in the Federal Register on April 7, 2011).^13,14 Comments on the 129-page proposed rules were due by June 6, 2011. Final rules are supposed to be published later this year.

The proposed new rule has a three-part aim:

• Better care for individuals, as described by all six dimensions of quality in the Institute of Medicine report “Crossing the Quality Chasm”¹⁵: safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity
• Better health for populations, with respect to educating beneficiaries about the major causes of ill health—poor nutrition, physical inactivity, substance abuse, and poverty—as well as about the importance of preventive services such as an annual physical examination and annual influenza vaccination
• Lower growth in expenditures by eliminating waste and inefficiencies while not withholding any needed care that helps beneficiaries.

DETAILS OF THE PROPOSED ACO RULE

Here are some of the highlights of the proposed ACO rule.

Two shared-savings options

Although the program could start as soon as January 1, 2012, the application process is formidable, so this timeline may not be realistic. Moreover, a final rule is pending.

The proposed rule requires at least a 3-year contract, and primary care physicians must be included. Shared savings will be available and will depend on an ACO’s ability to manage costs and to achieve quality target performances. Two shared-savings options will be available: one with no risk until the third year and the other with risk during all 3 years but greater potential benefit. In the one-sided model with no risk until year 3, an ACO would begin to accrue shared savings at a rate of 50% after an initial 2% of savings compared with a risk-adjusted per capita benchmark based on performance during the previous 3 years. In the second plan, an ACO would immediately realize shared savings at a rate of 60% as long as savings were achieved compared with prior benchmark performance. However, in this second model, the ACO would be at risk to repay a share of all losses that were more than 2% higher than the benchmark expenditures, with loss caps of 5%, 7.5%, and 10% above benchmark in years 1, 2, and 3, respectively.

 

 

Structure of an ACO

Under the proposed rule, the minimum population size of Medicare beneficiaries is 5,000 patients, with some exceptions in rural or other shortage areas, or areas with critical access hospitals. ACO founders can be primary care physicians, primary care independent practice associations, or employee groups. Participants may include hospitals, critical access hospitals, specialists, and other providers. The ACO must be a legal entity with its own tax identification number and its own governance and management structure.

Concerns have been expressed that, in some markets, certain groups may come together and achieve market dominance with more than half of the population. Proposed ACOs with less than 30% of the market share will be exempt from antitrust concerns, and those with greater than 50% of market share will undergo detailed review.

Patient assignment

Patients will be assigned to an ACO retrospectively, at the end of the 3 years. The Centers for Medicare and Medicaid Services argues that retrospective assignment will encourage the ACO to design a system to help all patients, not just those assigned to the ACO.

Patients may not opt out of being counted against ACO performance measures. Although Medicare will share beneficiaries’ data with the ACO retrospectively so that it can learn more about costs per patient, patients may opt out of this data-sharing. Patients also retain unrestricted choice to see other providers, with attribution of costs incurred to the ACO.

Quality and reporting

The proposed rule has 65 equally weighted quality measures, many of which are not presently reported by most health care organizations. The measures fall within five broad categories: patient and caregiver experience, care coordination, patient safety, preventive health, and managing at-risk populations, including the frail elderly. Bonus payments for cost-savings will be adjusted based on meeting the quality measures.

Governance and management

Under the proposed rule, an ACO must meet stringent governance requirements. It must be a distinct legal entity as governed by state law. There must be proportional representation of all participants (eg, hospitals, community organizations, providers), comprising at least 75% of its Board of Trustees. These members must have authority to execute statutory functions of the ACO. Medicare beneficiaries and community stakeholder organizations must also be represented on the Board.

ACO operations must be managed by an executive director, manager, or general partner, who may or may not be a physician. A board-certified physician who is licensed in the state in which the ACO is domiciled must serve on location as the full-time, senior-level medical director, overseeing and managing clinical operations. A leadership team must be able to influence clinical practice, and a physician-directed process-improvement and quality-assurance committee is required.

Infrastructure and policies

The proposed rule outlines a number of infrastructure and policy requirements that must be addressed in the application process. These include:

• Written performance standards for quality and efficiency
• Evidence-based practice guidelines
• Tools to collect, evaluate, and share data to influence decision-making at the point of care
• Processes to identify and correct poor performance
• Description of how shared savings will be used to further improve care.

The concept of patient-centered care is a critical focus of the proposed ACO rule, and it includes involving the beneficiaries in governance as well as plans to assess and care for the needs of the patient population (Table 2).

CONCERNS ABOUT THE PROPOSED NEW ACO RULE

While there is broad consensus in the health care community that the current system of care delivery fails to achieve the desired outcomes and is financially unsustainable and in need of reform, many concerns have been expressed about the proposed new ACO rule.

The regulations are too detailed. The regulations are highly prescriptive with detailed application, reporting, and regulatory requirements that create significant administrative burdens. Small medical groups are unlikely to have the administrative infrastructure to become involved.

Potential savings are inadequate. The shared savings concept has modest upside gain when modeled with holdback.¹⁶ Moreover, a recent analysis from the University Health System Consortium suggested that 50% of ACOs with 5,000 or more attributed lives would sustain unwarranted penalties as a result of random fluctuation of expenditures in the population.¹⁷

Participation involves a big investment. Participation requires significant resource investment, such as hiring chronic-disease managers and, in some practices, creating a whole new concept of managing wellness and continuity of care.

Retrospective beneficiary assignment is unpopular. Groups would generally prefer to know beforehand for whom they are responsible financially. A prospective assignment model was considered for the proposed rule but was ultimately rejected.

The patient assignment system is too risky. The plurality rule requires only a single visit with the ACO in order to be responsible for a patient for the entire year. In addition, the fact that the patient has the freedom to choose care elsewhere with expense assigned to the ACO confers significant financial risk.

There are too many quality measures. The high number of quality metrics—65—required to be measured and reported is onerous for most organizations.

Advertising is micromanaged. All marketing materials that are sent to patients about the ACO and any subsequent revisions must first be approved by Medicare, a potentially burdensome and time-consuming requirement.

Specialists are excluded. Using only generalists could actually be less cost-effective for some patients, such as those with human immunodeficiency virus, end-stage renal disease, certain malignancies, or advanced congestive heart failure.

Provider replacement is prohibited. Providers cannot be replaced over the 3 years of the demonstration, but the departing physician’s patients are still the responsibility of the plan. This would be especially problematic for small practices.

 

PREDICTING ACO READINESS

I believe there are five core competencies that are required to be an ACO:

• Operational excellence in care delivery
• Ability to deliver care across the continuum
• Cultural alignment among participating organizations
• Technical and informatics support to manage individual and population data
• Physician alignment around the concept of the ACO.

Certain strategies will increase the chances of success of an ACO:

Reduce emergency department usage and hospitalization. Cost-savings in patient-centered medical homes have been greatest by reducing hospitalizations, rehospitalizations, and emergency department visits.

Develop a high-quality, efficient primary care network. Have enough of a share in the primary care physician network to deliver effective primary care. Make sure there is good access to care and effective communication between patients and the primary care network. Deliver comprehensive services and have good care coordination. Aggressively manage communication, care coordination, and “hand-offs” across the care continuum and with specialists.

Create an effective patient-centered medical home. The current reimbursement climate fails to incentivize all of the necessary elements, which ultimately need to include chronic-care coordinators for medically complex patients, pharmacy support for patient medication management, adequate support staff to optimize efficiency, and a culture of wellness and necessary resources to support wellness.

PHYSICIANS NEED TO DRIVE SOLUTIONS

Soaring health care costs in the United States, poor quality outcomes, and increasing fragmentation of care are the major drivers of health care reform. The Patient Centered Medical Home is a key component to the solution and has already been shown to improve outcomes and lower costs. Further refinement of this concept and implementation should be priorities for primary care physicians and health care organizations.

The ACO concept attempts to further improve quality and lower costs. The proposed ACO rule released by the Centers for Medicare and Medicaid Services on March 31, 2011, has generated significant controversy in the health care community. In its current form, few health care systems are likely to participate. A revised rule is awaited in the coming months. In the meantime, the Centers for Medicare and Medicaid Services has released a request for application for a Pioneer ACO model, which offers up to 30 organizations the opportunity to participate in an ACO pilot that allows for prospective patient assignment and greater shared savings.

Whether ACOs as proposed achieve widespread implementation remains to be seen. However, the current system of health care delivery in this country is broken. Physicians and health care systems need to drive solutions to the challenges we face about quality, cost, access, care coordination, and outcomes.

A number of studies published in the last few years will likely affect the way we practice medicine in the hospital. Here, we will use a hypothetical case scenario to focus on the issues of anticoagulants, patient safety, quality improvement, critical care, transitions of care, and perioperative medicine.

AN ELDERLY MAN WITH NEW-ONSET ATRIAL FIBRILLATION

P.G. is an 80-year-old man with a history of hypertension and type 2 diabetes mellitus who is admitted with new-onset atrial fibrillation. In the hospital, his heart rate is brought under control with intravenous metoprolol (Lopressor). On discharge, he will be followed by his primary care physician (PCP). He does not have access to an anticoagulation clinic.

1. What are this patient’s options for stroke prevention?

• Aspirin 81 mg daily and clopidogrel (Plavix) 75 mg daily
• Warfarin (Coumadin) with a target international normalized ratio (INR) of 2.0 to 3.0
• Aspirin mg daily by itself
• Dabigatran (Pradaxa) 150 mg daily

A new oral anticoagulant agent

In deciding what type of anticoagulation to give to a patient with atrial fibrillation, it is useful to look at the CHADS₂ score (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack. This patient has a CHADS₂ score of 3, indicating that he should receive warfarin. An alternative is dabigatran, the first new anticoagulant agent in more than 50 years.

In a multicenter, international trial, Connolly et al¹ randomized 18,113 patients (mean age 71, 64% men) to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin with a target INR of 2.0 to 3.0. In this noninferiority trial, dabigatran was given in a blinded manner, but the use of warfarin was open-label. Patients were eligible if they had atrial fibrillation at screening or within the previous 6 months and were at risk of stroke—ie, if they had at least one of the following: a history of stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, symptoms of congestive heart failure (New York Heart Association class II or higher), and an age of 75 or older or an age of 65 to 74 with diabetes mellitus, hypertension, or coronary artery disease.

At a mean follow-up of 2 years, the rate of stroke or systolic embolism was 1.69% per year in the warfarin group compared with 1.1% in the higher-dose dabigatran group (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rates of major hemorrhage were similar between these two groups. Comparing lower-dose dabigatran and warfarin, the rates of stroke or systolic embolism were not significantly different, but the rate of major bleeding was significantly lower with lower-dose dabigatran.

In a trial in patients with acute venous thromboembolism, Schulman et al² found that dabigatran was not inferior to warfarin in preventing venous thromboembolism.

Guidelines from the American College of Cardiology Foundation and the American Heart Association now endorse dabigatran as an alternative to warfarin for patients with atrial fibrillation.³ However, the guidelines state that it should be reserved for those patients who:

• Do not have a prosthetic heart valve or hemodynamically significant valve disease
• Have good kidney function (dabigatran is cleared by the kidney; the creatinine clearance rate should be greater than 30 mL/min for patients to receive dabigatran 150 mg twice a day, and at least 15 mL/min to receive 75 mg twice a day)
• Do not have severe hepatic dysfunction (which would impair baseline clotting function).

They note that other factors to consider are whether the patient:

• Can comply with the twice-daily dosing required
• Can afford the drug
• Has access to an anticoagulation management program (which would argue in favor of using warfarin).

Dabigatran is not yet approved to prevent venous thromboembolism.

CASE CONTINUED: HE GETS AN INFECTION

P.G. is started on dabigatran 150 mg by mouth twice a day.

While in the hospital he develops shortness of breath and needs intravenous furosemide (Lasix). Because he has bad veins, a percutaneous intravenous central catheter (PICC) line is placed. However, 2 days later, his temperature is 101.5°F, and his systolic blood pressure is 70 mm Hg. He is transferred to the medical intensive care unit (ICU) for treatment of sepsis. The anticoagulant is held, the PICC line is removed, and a new central catheter is inserted.

2. Which of the following directions is incorrect?

• Wash your hands before inserting the catheter. The accompanying nurse is required to directly observe this procedure or, if this step is not observed, to confirm that the physician did it.
• Before inserting the catheter, clean the patient’s skin with chlorhexidine antiseptic.
• Place sterile drapes over the entire patient.
• Wear any mask, hat, gown, and gloves available.
• Put a sterile dressing over the catheter.

A checklist can prevent infections when inserting central catheters

A checklist developed at Johns Hopkins Hospital consists of the five statements above, except for the second to last one—you should wear a sterile mask, hat, gown and gloves. This is important to ensure that sterility is not broken at any point during the procedure.

Pronovost et al⁴ launched a multicenter initiative at 90 ICUs, predominantly in the state of Michigan, to implement interventions to improve staff culture and teamwork and to translate research into practice by increasing the extent to which these five evidence-based recommendations were applied. The mean rate of catheter-related blood stream infections at baseline was 7.7%; this dropped to 2.8% during the implementation period, 2.3% in the first 3 months after implementation, 1.3% in months 16 through 18, and 1.1% in months 34 through 36, demonstrating that the gains from this quality-improvement project were sustainable.

If this intervention and collaborative model were implemented in all ICUs across the United States and if similar success rates were achieved, substantial and sustained reductions could be made in the 82,000 infections, 28,000 deaths, and $2.3 billion in costs attributed to these infections annually.

 

CASE CONTINUED: HE IS RESUSCITATED

P.G. is started on a 1-L fluid bolus but he remains hypotensive, necessitating a norepinephrine drip. He does well for about 6 hours, but in the middle of the night he develops ventricular tachycardia and ventricular fibrillation, and a code is called. He is successfully resuscitated, but the family is looking for prognostic information.

3. What are P.G.’s chances of surviving and leaving the hospital?

• 5%
• 8%
• 15%
• 23%

A registry of cardiopulmonary resuscitation

Tian et al⁵ evaluated outcomes in the largest registry of cardiopulmonary resuscitation to date. In this analysis, 49,656 adult patients with a first cardiopulmonary arrest occurring in an ICU between January 1, 2000, and August 26, 2008, were evaluated for their outcomes on pressors vs those not on pressors.

The overall rate of survival until discharge was 15.9%. However, the rate was lower by more than half in those who were receiving pressor agents than in those not on pressors (9.3% vs 21.2%; P < .0001). The rate was lower still—6.4%—in those receiving two or more pressors (compared with 11.5% in those receiving one pressor). In patients on a single pressor, the rates varied by agent: 7.8% with vasopressin, 8.0% with norepinephrine, 11.2% with phenylephrine, 11.3% with dopamine, 23.0% with dobutamine, and 19.8% with epinephrine (Table  1).

Other independent predictors of a lower survival rate were nonwhite race, mechanical ventilation, having three or more immediate causes of cardiopulmonary arrest, age 65 years or older, and cardiopulmonary arrest occurring at night or over the weekend.

Fortunately, for our patient, survival rates were higher for patients with ventricular tachycardia or fibrillation than with other causes of cardiopulmonary arrest: 22.6% for those on pressors (like our patient) and 40.7% for those on no pressors.

CASE CONTINUED: HE RECOVERS AND GOES HOME

P.G. makes a remarkable recovery and is now ready to go home. It is the weekend, and you are unable to schedule a follow-up appointment before his discharge, so you ask him to make an appointment with his PCP.

4. What is the likelihood that P.G. will be readmitted within 1 month?

• 5%
• 12%
• 20%
• 25%
• 30%

The importance of follow-up with a primary care physician

Misky et al,⁶ in a small study, attempted to identify the characteristics and outcomes of discharged patients who lack timely follow-up with a PCP. They prospectively enrolled 65 patients admitted to University of Colorado Hospital, an urban 425-bed tertiary care center, collecting information about patient demographics, diagnosis, payer source, and PCPs. After discharge, they called the patients to determine their PCP follow-up and readmission status. Thirty-day readmission rates and hospital length of stay were compared in patients with and without timely PCP follow-up (ie, within 4 weeks).

Patients lacking timely PCP follow-up were 10 times more likely to be readmitted (odds ratio [OR] = 9.9, P = .04): the rate was 21% in patients lacking timely PCP follow-up vs 3% in patients with timely PCP follow-up, P = .03. Lack of insurance was associated with lower rates of timely PCP follow-up: 29% vs 56% (P = .06), but did not independently increase the readmission rate or length of stay (OR = 1.0, P = .96). Index hospital length of stay was longer in patients lacking timely PCP follow-up: 4.4 days vs 6.3 days, P = 0.11.

Comment. Nearly half of the patients in this study, who were discharged from a large urban academic center, lacked timely follow-up with a PCP, resulting in higher rates of readmission and a nonsignificant trend toward longer length of stay. Timely follow-up is necessary for vulnerable patients.

Since the lack of timely PCP follow-up results in higher readmission rates and possibly a longer length of stay, a PCP appointment at discharge should perhaps be considered a core quality measure. This would be problematic in our American health care system, in which many patients lack health insurance and do not have a PCP.

A MAN UNDERGOING GASTRIC BYPASS SURGERY

A 55-year-old morbidly obese man (body mass index 45 kg/m²) with a history of type 2 diabetes mellitus, chronic renal insufficiency (serum creatinine level 2.1 mg/dL), hypercholesterolemia, and previous stroke is scheduled for gastric bypass surgery. His functional capacity is low, but he is able to do his activities of daily living. He reports having dyspnea on exertion and intermittently at rest, but no chest pain. His medications include insulin, atorvastatin (Lipitor), aspirin, and atenolol (Tenormin). He is afebrile; his blood pressure is 130/80 mm Hg, pulse 75, and oxygen saturation 97% on room air. His baseline electrocardiogram shows no Q waves.

5. Which of the following is an appropriate next step before proceeding to surgery?

• Echocardiography
• Cardiac catheterization
• Dobutamine stress echocardiography or adenosine thallium scanning
• No cardiac testing is necessary before surgery

 

 

Is cardiac testing necessary before noncardiac surgery?

Wijeysundera et al⁷ performed a retrospective cohort study of patients who underwent elective surgery at acute care hospitals in Ontario, Canada, in the years 1994 through 2004. The aim was to determine the association of noninvasive cardiac stress testing before surgery with survival rates and length of hospital stay. Included were 271,082 patients, of whom 23,991 (8.9%) underwent stress testing less than 6 months before surgery. These patients were matched with 46,120 who did not undergo testing.

One year after surgery, fewer patients who underwent stress testing had died: 1,622 (7.0%) vs 1,738 (7.5%); hazard ratio 0.92, 95% CI 0.86–0.99, P = .03. The number needed to treat (ie, to be tested) to prevent one death was 221. The tested patients also had a shorter mean hospital stay: 8.72 vs 8.96 days, a difference of 0.24 days (95% CI −0.07 to −0.43; P < .001).

However, the elderly patients (ie, older than 66 years) who underwent testing were more likely to be on beta-blockers and statins than those who did not undergo testing, which may be a confounding factor.

Furthermore, the benefit was all in the patients at intermediate or high risk. The authors performed a subgroup analysis, dividing the patients on the basis of their Revised Cardiac Risk Index (RCRI; 1 point each for ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes, renal insufficiency, and high-risk surgery).⁸ Patients with an RCRI of 0 points (indicating low risk) actually had a higher risk of death with testing than without testing: hazard ratio 1.35 (95% CI 1.03–1.74), number needed to harm 179—ie, for every 179 low-risk patients tested, one excess death occurred. Those with an RCRI of 1 or 2 points (indicating intermediate risk) had a hazard ratio of 0.92 with testing (95% CI 085–0.99), and those with an RCRI of 3 to 6 points (indicating high risk) had a hazard ratio of 0.80 with testing (95% CI 0.67- 0.97; number needed to treat = 38).

Comment. These findings indicate that cardiac stress testing should be done selectively before noncardiac surgery, and primarily for patients at high risk (with an RCRI of 3 or higher) and in some patients at intermediate risk, but not in patients at low risk, in whom it may be harmful. Stress testing may change patient management because a positive stress test allows one to start a beta-blocker or a statin, use more aggressive intraoperative and postoperative care, and identify patients who have indications for revascularization.

A number of studies published in the last few years will likely affect the way we practice medicine in the hospital. Here, we will use a hypothetical case scenario to focus on the issues of anticoagulants, patient safety, quality improvement, critical care, transitions of care, and perioperative medicine.

AN ELDERLY MAN WITH NEW-ONSET ATRIAL FIBRILLATION

P.G. is an 80-year-old man with a history of hypertension and type 2 diabetes mellitus who is admitted with new-onset atrial fibrillation. In the hospital, his heart rate is brought under control with intravenous metoprolol (Lopressor). On discharge, he will be followed by his primary care physician (PCP). He does not have access to an anticoagulation clinic.

1. What are this patient’s options for stroke prevention?

• Aspirin 81 mg daily and clopidogrel (Plavix) 75 mg daily
• Warfarin (Coumadin) with a target international normalized ratio (INR) of 2.0 to 3.0
• Aspirin mg daily by itself
• Dabigatran (Pradaxa) 150 mg daily

A new oral anticoagulant agent

In deciding what type of anticoagulation to give to a patient with atrial fibrillation, it is useful to look at the CHADS₂ score (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack. This patient has a CHADS₂ score of 3, indicating that he should receive warfarin. An alternative is dabigatran, the first new anticoagulant agent in more than 50 years.

In a multicenter, international trial, Connolly et al¹ randomized 18,113 patients (mean age 71, 64% men) to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin with a target INR of 2.0 to 3.0. In this noninferiority trial, dabigatran was given in a blinded manner, but the use of warfarin was open-label. Patients were eligible if they had atrial fibrillation at screening or within the previous 6 months and were at risk of stroke—ie, if they had at least one of the following: a history of stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, symptoms of congestive heart failure (New York Heart Association class II or higher), and an age of 75 or older or an age of 65 to 74 with diabetes mellitus, hypertension, or coronary artery disease.

At a mean follow-up of 2 years, the rate of stroke or systolic embolism was 1.69% per year in the warfarin group compared with 1.1% in the higher-dose dabigatran group (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rates of major hemorrhage were similar between these two groups. Comparing lower-dose dabigatran and warfarin, the rates of stroke or systolic embolism were not significantly different, but the rate of major bleeding was significantly lower with lower-dose dabigatran.

In a trial in patients with acute venous thromboembolism, Schulman et al² found that dabigatran was not inferior to warfarin in preventing venous thromboembolism.

Guidelines from the American College of Cardiology Foundation and the American Heart Association now endorse dabigatran as an alternative to warfarin for patients with atrial fibrillation.³ However, the guidelines state that it should be reserved for those patients who:

• Do not have a prosthetic heart valve or hemodynamically significant valve disease
• Have good kidney function (dabigatran is cleared by the kidney; the creatinine clearance rate should be greater than 30 mL/min for patients to receive dabigatran 150 mg twice a day, and at least 15 mL/min to receive 75 mg twice a day)
• Do not have severe hepatic dysfunction (which would impair baseline clotting function).

They note that other factors to consider are whether the patient:

• Can comply with the twice-daily dosing required
• Can afford the drug
• Has access to an anticoagulation management program (which would argue in favor of using warfarin).

Dabigatran is not yet approved to prevent venous thromboembolism.

CASE CONTINUED: HE GETS AN INFECTION

P.G. is started on dabigatran 150 mg by mouth twice a day.

While in the hospital he develops shortness of breath and needs intravenous furosemide (Lasix). Because he has bad veins, a percutaneous intravenous central catheter (PICC) line is placed. However, 2 days later, his temperature is 101.5°F, and his systolic blood pressure is 70 mm Hg. He is transferred to the medical intensive care unit (ICU) for treatment of sepsis. The anticoagulant is held, the PICC line is removed, and a new central catheter is inserted.

2. Which of the following directions is incorrect?

• Wash your hands before inserting the catheter. The accompanying nurse is required to directly observe this procedure or, if this step is not observed, to confirm that the physician did it.
• Before inserting the catheter, clean the patient’s skin with chlorhexidine antiseptic.
• Place sterile drapes over the entire patient.
• Wear any mask, hat, gown, and gloves available.
• Put a sterile dressing over the catheter.

A checklist can prevent infections when inserting central catheters

A checklist developed at Johns Hopkins Hospital consists of the five statements above, except for the second to last one—you should wear a sterile mask, hat, gown and gloves. This is important to ensure that sterility is not broken at any point during the procedure.

Pronovost et al⁴ launched a multicenter initiative at 90 ICUs, predominantly in the state of Michigan, to implement interventions to improve staff culture and teamwork and to translate research into practice by increasing the extent to which these five evidence-based recommendations were applied. The mean rate of catheter-related blood stream infections at baseline was 7.7%; this dropped to 2.8% during the implementation period, 2.3% in the first 3 months after implementation, 1.3% in months 16 through 18, and 1.1% in months 34 through 36, demonstrating that the gains from this quality-improvement project were sustainable.

If this intervention and collaborative model were implemented in all ICUs across the United States and if similar success rates were achieved, substantial and sustained reductions could be made in the 82,000 infections, 28,000 deaths, and $2.3 billion in costs attributed to these infections annually.

 

CASE CONTINUED: HE IS RESUSCITATED

P.G. is started on a 1-L fluid bolus but he remains hypotensive, necessitating a norepinephrine drip. He does well for about 6 hours, but in the middle of the night he develops ventricular tachycardia and ventricular fibrillation, and a code is called. He is successfully resuscitated, but the family is looking for prognostic information.

3. What are P.G.’s chances of surviving and leaving the hospital?

• 5%
• 8%
• 15%
• 23%

A registry of cardiopulmonary resuscitation

Tian et al⁵ evaluated outcomes in the largest registry of cardiopulmonary resuscitation to date. In this analysis, 49,656 adult patients with a first cardiopulmonary arrest occurring in an ICU between January 1, 2000, and August 26, 2008, were evaluated for their outcomes on pressors vs those not on pressors.

The overall rate of survival until discharge was 15.9%. However, the rate was lower by more than half in those who were receiving pressor agents than in those not on pressors (9.3% vs 21.2%; P < .0001). The rate was lower still—6.4%—in those receiving two or more pressors (compared with 11.5% in those receiving one pressor). In patients on a single pressor, the rates varied by agent: 7.8% with vasopressin, 8.0% with norepinephrine, 11.2% with phenylephrine, 11.3% with dopamine, 23.0% with dobutamine, and 19.8% with epinephrine (Table  1).

Other independent predictors of a lower survival rate were nonwhite race, mechanical ventilation, having three or more immediate causes of cardiopulmonary arrest, age 65 years or older, and cardiopulmonary arrest occurring at night or over the weekend.

Fortunately, for our patient, survival rates were higher for patients with ventricular tachycardia or fibrillation than with other causes of cardiopulmonary arrest: 22.6% for those on pressors (like our patient) and 40.7% for those on no pressors.

CASE CONTINUED: HE RECOVERS AND GOES HOME

P.G. makes a remarkable recovery and is now ready to go home. It is the weekend, and you are unable to schedule a follow-up appointment before his discharge, so you ask him to make an appointment with his PCP.

4. What is the likelihood that P.G. will be readmitted within 1 month?

• 5%
• 12%
• 20%
• 25%
• 30%

The importance of follow-up with a primary care physician

Misky et al,⁶ in a small study, attempted to identify the characteristics and outcomes of discharged patients who lack timely follow-up with a PCP. They prospectively enrolled 65 patients admitted to University of Colorado Hospital, an urban 425-bed tertiary care center, collecting information about patient demographics, diagnosis, payer source, and PCPs. After discharge, they called the patients to determine their PCP follow-up and readmission status. Thirty-day readmission rates and hospital length of stay were compared in patients with and without timely PCP follow-up (ie, within 4 weeks).

Patients lacking timely PCP follow-up were 10 times more likely to be readmitted (odds ratio [OR] = 9.9, P = .04): the rate was 21% in patients lacking timely PCP follow-up vs 3% in patients with timely PCP follow-up, P = .03. Lack of insurance was associated with lower rates of timely PCP follow-up: 29% vs 56% (P = .06), but did not independently increase the readmission rate or length of stay (OR = 1.0, P = .96). Index hospital length of stay was longer in patients lacking timely PCP follow-up: 4.4 days vs 6.3 days, P = 0.11.

Comment. Nearly half of the patients in this study, who were discharged from a large urban academic center, lacked timely follow-up with a PCP, resulting in higher rates of readmission and a nonsignificant trend toward longer length of stay. Timely follow-up is necessary for vulnerable patients.

Since the lack of timely PCP follow-up results in higher readmission rates and possibly a longer length of stay, a PCP appointment at discharge should perhaps be considered a core quality measure. This would be problematic in our American health care system, in which many patients lack health insurance and do not have a PCP.

A MAN UNDERGOING GASTRIC BYPASS SURGERY

A 55-year-old morbidly obese man (body mass index 45 kg/m²) with a history of type 2 diabetes mellitus, chronic renal insufficiency (serum creatinine level 2.1 mg/dL), hypercholesterolemia, and previous stroke is scheduled for gastric bypass surgery. His functional capacity is low, but he is able to do his activities of daily living. He reports having dyspnea on exertion and intermittently at rest, but no chest pain. His medications include insulin, atorvastatin (Lipitor), aspirin, and atenolol (Tenormin). He is afebrile; his blood pressure is 130/80 mm Hg, pulse 75, and oxygen saturation 97% on room air. His baseline electrocardiogram shows no Q waves.

5. Which of the following is an appropriate next step before proceeding to surgery?

• Echocardiography
• Cardiac catheterization
• Dobutamine stress echocardiography or adenosine thallium scanning
• No cardiac testing is necessary before surgery

 

 

Is cardiac testing necessary before noncardiac surgery?

Wijeysundera et al⁷ performed a retrospective cohort study of patients who underwent elective surgery at acute care hospitals in Ontario, Canada, in the years 1994 through 2004. The aim was to determine the association of noninvasive cardiac stress testing before surgery with survival rates and length of hospital stay. Included were 271,082 patients, of whom 23,991 (8.9%) underwent stress testing less than 6 months before surgery. These patients were matched with 46,120 who did not undergo testing.

One year after surgery, fewer patients who underwent stress testing had died: 1,622 (7.0%) vs 1,738 (7.5%); hazard ratio 0.92, 95% CI 0.86–0.99, P = .03. The number needed to treat (ie, to be tested) to prevent one death was 221. The tested patients also had a shorter mean hospital stay: 8.72 vs 8.96 days, a difference of 0.24 days (95% CI −0.07 to −0.43; P < .001).

However, the elderly patients (ie, older than 66 years) who underwent testing were more likely to be on beta-blockers and statins than those who did not undergo testing, which may be a confounding factor.

Furthermore, the benefit was all in the patients at intermediate or high risk. The authors performed a subgroup analysis, dividing the patients on the basis of their Revised Cardiac Risk Index (RCRI; 1 point each for ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes, renal insufficiency, and high-risk surgery).⁸ Patients with an RCRI of 0 points (indicating low risk) actually had a higher risk of death with testing than without testing: hazard ratio 1.35 (95% CI 1.03–1.74), number needed to harm 179—ie, for every 179 low-risk patients tested, one excess death occurred. Those with an RCRI of 1 or 2 points (indicating intermediate risk) had a hazard ratio of 0.92 with testing (95% CI 085–0.99), and those with an RCRI of 3 to 6 points (indicating high risk) had a hazard ratio of 0.80 with testing (95% CI 0.67- 0.97; number needed to treat = 38).

Comment. These findings indicate that cardiac stress testing should be done selectively before noncardiac surgery, and primarily for patients at high risk (with an RCRI of 3 or higher) and in some patients at intermediate risk, but not in patients at low risk, in whom it may be harmful. Stress testing may change patient management because a positive stress test allows one to start a beta-blocker or a statin, use more aggressive intraoperative and postoperative care, and identify patients who have indications for revascularization.

A number of studies published in the last few years will likely affect the way we practice medicine in the hospital. Here, we will use a hypothetical case scenario to focus on the issues of anticoagulants, patient safety, quality improvement, critical care, transitions of care, and perioperative medicine.

AN ELDERLY MAN WITH NEW-ONSET ATRIAL FIBRILLATION

P.G. is an 80-year-old man with a history of hypertension and type 2 diabetes mellitus who is admitted with new-onset atrial fibrillation. In the hospital, his heart rate is brought under control with intravenous metoprolol (Lopressor). On discharge, he will be followed by his primary care physician (PCP). He does not have access to an anticoagulation clinic.

1. What are this patient’s options for stroke prevention?

• Aspirin 81 mg daily and clopidogrel (Plavix) 75 mg daily
• Warfarin (Coumadin) with a target international normalized ratio (INR) of 2.0 to 3.0
• Aspirin mg daily by itself
• Dabigatran (Pradaxa) 150 mg daily

A new oral anticoagulant agent

In deciding what type of anticoagulation to give to a patient with atrial fibrillation, it is useful to look at the CHADS₂ score (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack. This patient has a CHADS₂ score of 3, indicating that he should receive warfarin. An alternative is dabigatran, the first new anticoagulant agent in more than 50 years.

In a multicenter, international trial, Connolly et al¹ randomized 18,113 patients (mean age 71, 64% men) to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin with a target INR of 2.0 to 3.0. In this noninferiority trial, dabigatran was given in a blinded manner, but the use of warfarin was open-label. Patients were eligible if they had atrial fibrillation at screening or within the previous 6 months and were at risk of stroke—ie, if they had at least one of the following: a history of stroke or transient ischemic attack, a left ventricular ejection fraction of less than 40%, symptoms of congestive heart failure (New York Heart Association class II or higher), and an age of 75 or older or an age of 65 to 74 with diabetes mellitus, hypertension, or coronary artery disease.

At a mean follow-up of 2 years, the rate of stroke or systolic embolism was 1.69% per year in the warfarin group compared with 1.1% in the higher-dose dabigatran group (relative risk 0.66, 95% confidence interval [CI] 0.53–0.82, P < .001). The rates of major hemorrhage were similar between these two groups. Comparing lower-dose dabigatran and warfarin, the rates of stroke or systolic embolism were not significantly different, but the rate of major bleeding was significantly lower with lower-dose dabigatran.

In a trial in patients with acute venous thromboembolism, Schulman et al² found that dabigatran was not inferior to warfarin in preventing venous thromboembolism.

Guidelines from the American College of Cardiology Foundation and the American Heart Association now endorse dabigatran as an alternative to warfarin for patients with atrial fibrillation.³ However, the guidelines state that it should be reserved for those patients who:

• Do not have a prosthetic heart valve or hemodynamically significant valve disease
• Have good kidney function (dabigatran is cleared by the kidney; the creatinine clearance rate should be greater than 30 mL/min for patients to receive dabigatran 150 mg twice a day, and at least 15 mL/min to receive 75 mg twice a day)
• Do not have severe hepatic dysfunction (which would impair baseline clotting function).

They note that other factors to consider are whether the patient:

• Can comply with the twice-daily dosing required
• Can afford the drug
• Has access to an anticoagulation management program (which would argue in favor of using warfarin).

Dabigatran is not yet approved to prevent venous thromboembolism.

CASE CONTINUED: HE GETS AN INFECTION

P.G. is started on dabigatran 150 mg by mouth twice a day.

While in the hospital he develops shortness of breath and needs intravenous furosemide (Lasix). Because he has bad veins, a percutaneous intravenous central catheter (PICC) line is placed. However, 2 days later, his temperature is 101.5°F, and his systolic blood pressure is 70 mm Hg. He is transferred to the medical intensive care unit (ICU) for treatment of sepsis. The anticoagulant is held, the PICC line is removed, and a new central catheter is inserted.

2. Which of the following directions is incorrect?

• Wash your hands before inserting the catheter. The accompanying nurse is required to directly observe this procedure or, if this step is not observed, to confirm that the physician did it.
• Before inserting the catheter, clean the patient’s skin with chlorhexidine antiseptic.
• Place sterile drapes over the entire patient.
• Wear any mask, hat, gown, and gloves available.
• Put a sterile dressing over the catheter.

A checklist can prevent infections when inserting central catheters

A checklist developed at Johns Hopkins Hospital consists of the five statements above, except for the second to last one—you should wear a sterile mask, hat, gown and gloves. This is important to ensure that sterility is not broken at any point during the procedure.

Pronovost et al⁴ launched a multicenter initiative at 90 ICUs, predominantly in the state of Michigan, to implement interventions to improve staff culture and teamwork and to translate research into practice by increasing the extent to which these five evidence-based recommendations were applied. The mean rate of catheter-related blood stream infections at baseline was 7.7%; this dropped to 2.8% during the implementation period, 2.3% in the first 3 months after implementation, 1.3% in months 16 through 18, and 1.1% in months 34 through 36, demonstrating that the gains from this quality-improvement project were sustainable.

If this intervention and collaborative model were implemented in all ICUs across the United States and if similar success rates were achieved, substantial and sustained reductions could be made in the 82,000 infections, 28,000 deaths, and $2.3 billion in costs attributed to these infections annually.

 

CASE CONTINUED: HE IS RESUSCITATED

P.G. is started on a 1-L fluid bolus but he remains hypotensive, necessitating a norepinephrine drip. He does well for about 6 hours, but in the middle of the night he develops ventricular tachycardia and ventricular fibrillation, and a code is called. He is successfully resuscitated, but the family is looking for prognostic information.

3. What are P.G.’s chances of surviving and leaving the hospital?

• 5%
• 8%
• 15%
• 23%

A registry of cardiopulmonary resuscitation

Tian et al⁵ evaluated outcomes in the largest registry of cardiopulmonary resuscitation to date. In this analysis, 49,656 adult patients with a first cardiopulmonary arrest occurring in an ICU between January 1, 2000, and August 26, 2008, were evaluated for their outcomes on pressors vs those not on pressors.

The overall rate of survival until discharge was 15.9%. However, the rate was lower by more than half in those who were receiving pressor agents than in those not on pressors (9.3% vs 21.2%; P < .0001). The rate was lower still—6.4%—in those receiving two or more pressors (compared with 11.5% in those receiving one pressor). In patients on a single pressor, the rates varied by agent: 7.8% with vasopressin, 8.0% with norepinephrine, 11.2% with phenylephrine, 11.3% with dopamine, 23.0% with dobutamine, and 19.8% with epinephrine (Table  1).

Other independent predictors of a lower survival rate were nonwhite race, mechanical ventilation, having three or more immediate causes of cardiopulmonary arrest, age 65 years or older, and cardiopulmonary arrest occurring at night or over the weekend.

Fortunately, for our patient, survival rates were higher for patients with ventricular tachycardia or fibrillation than with other causes of cardiopulmonary arrest: 22.6% for those on pressors (like our patient) and 40.7% for those on no pressors.

CASE CONTINUED: HE RECOVERS AND GOES HOME

P.G. makes a remarkable recovery and is now ready to go home. It is the weekend, and you are unable to schedule a follow-up appointment before his discharge, so you ask him to make an appointment with his PCP.

4. What is the likelihood that P.G. will be readmitted within 1 month?

• 5%
• 12%
• 20%
• 25%
• 30%

The importance of follow-up with a primary care physician

Misky et al,⁶ in a small study, attempted to identify the characteristics and outcomes of discharged patients who lack timely follow-up with a PCP. They prospectively enrolled 65 patients admitted to University of Colorado Hospital, an urban 425-bed tertiary care center, collecting information about patient demographics, diagnosis, payer source, and PCPs. After discharge, they called the patients to determine their PCP follow-up and readmission status. Thirty-day readmission rates and hospital length of stay were compared in patients with and without timely PCP follow-up (ie, within 4 weeks).

Patients lacking timely PCP follow-up were 10 times more likely to be readmitted (odds ratio [OR] = 9.9, P = .04): the rate was 21% in patients lacking timely PCP follow-up vs 3% in patients with timely PCP follow-up, P = .03. Lack of insurance was associated with lower rates of timely PCP follow-up: 29% vs 56% (P = .06), but did not independently increase the readmission rate or length of stay (OR = 1.0, P = .96). Index hospital length of stay was longer in patients lacking timely PCP follow-up: 4.4 days vs 6.3 days, P = 0.11.

Comment. Nearly half of the patients in this study, who were discharged from a large urban academic center, lacked timely follow-up with a PCP, resulting in higher rates of readmission and a nonsignificant trend toward longer length of stay. Timely follow-up is necessary for vulnerable patients.

Since the lack of timely PCP follow-up results in higher readmission rates and possibly a longer length of stay, a PCP appointment at discharge should perhaps be considered a core quality measure. This would be problematic in our American health care system, in which many patients lack health insurance and do not have a PCP.

A MAN UNDERGOING GASTRIC BYPASS SURGERY

A 55-year-old morbidly obese man (body mass index 45 kg/m²) with a history of type 2 diabetes mellitus, chronic renal insufficiency (serum creatinine level 2.1 mg/dL), hypercholesterolemia, and previous stroke is scheduled for gastric bypass surgery. His functional capacity is low, but he is able to do his activities of daily living. He reports having dyspnea on exertion and intermittently at rest, but no chest pain. His medications include insulin, atorvastatin (Lipitor), aspirin, and atenolol (Tenormin). He is afebrile; his blood pressure is 130/80 mm Hg, pulse 75, and oxygen saturation 97% on room air. His baseline electrocardiogram shows no Q waves.

5. Which of the following is an appropriate next step before proceeding to surgery?

• Echocardiography
• Cardiac catheterization
• Dobutamine stress echocardiography or adenosine thallium scanning
• No cardiac testing is necessary before surgery

 

 

Is cardiac testing necessary before noncardiac surgery?

Wijeysundera et al⁷ performed a retrospective cohort study of patients who underwent elective surgery at acute care hospitals in Ontario, Canada, in the years 1994 through 2004. The aim was to determine the association of noninvasive cardiac stress testing before surgery with survival rates and length of hospital stay. Included were 271,082 patients, of whom 23,991 (8.9%) underwent stress testing less than 6 months before surgery. These patients were matched with 46,120 who did not undergo testing.

One year after surgery, fewer patients who underwent stress testing had died: 1,622 (7.0%) vs 1,738 (7.5%); hazard ratio 0.92, 95% CI 0.86–0.99, P = .03. The number needed to treat (ie, to be tested) to prevent one death was 221. The tested patients also had a shorter mean hospital stay: 8.72 vs 8.96 days, a difference of 0.24 days (95% CI −0.07 to −0.43; P < .001).

However, the elderly patients (ie, older than 66 years) who underwent testing were more likely to be on beta-blockers and statins than those who did not undergo testing, which may be a confounding factor.

Furthermore, the benefit was all in the patients at intermediate or high risk. The authors performed a subgroup analysis, dividing the patients on the basis of their Revised Cardiac Risk Index (RCRI; 1 point each for ischemic heart disease, congestive heart failure, cerebrovascular disease, diabetes, renal insufficiency, and high-risk surgery).⁸ Patients with an RCRI of 0 points (indicating low risk) actually had a higher risk of death with testing than without testing: hazard ratio 1.35 (95% CI 1.03–1.74), number needed to harm 179—ie, for every 179 low-risk patients tested, one excess death occurred. Those with an RCRI of 1 or 2 points (indicating intermediate risk) had a hazard ratio of 0.92 with testing (95% CI 085–0.99), and those with an RCRI of 3 to 6 points (indicating high risk) had a hazard ratio of 0.80 with testing (95% CI 0.67- 0.97; number needed to treat = 38).

Comment. These findings indicate that cardiac stress testing should be done selectively before noncardiac surgery, and primarily for patients at high risk (with an RCRI of 3 or higher) and in some patients at intermediate risk, but not in patients at low risk, in whom it may be harmful. Stress testing may change patient management because a positive stress test allows one to start a beta-blocker or a statin, use more aggressive intraoperative and postoperative care, and identify patients who have indications for revascularization.

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

In its January 2010 recommendations,⁹ the ADA lists criteria for the categories of normal, prediabetes, and diabetes, based on fasting and 2-hour postprandial plasma glucose levels and hemoglobin A_1c (Table 1).

 

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

 

 

Basal-bolus vs sliding-scale insulin for surgical patients: The RABBIT 2 Surgery trial

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

In its January 2010 recommendations,⁹ the ADA lists criteria for the categories of normal, prediabetes, and diabetes, based on fasting and 2-hour postprandial plasma glucose levels and hemoglobin A_1c (Table 1).

 

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

 

 

Basal-bolus vs sliding-scale insulin for surgical patients: The RABBIT 2 Surgery trial

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

Hyperglycemia and diabetes mellitus are very common in hospitalized patients. Although more data are available on the prevalence of this problem and on how to manage it in the intensive care unit (ICU) than on regular hospital floors, the situation is changing. Information is emerging on the prevalence and impact of hyperglycemia and diabetes in the non-ICU setting, which is the focus of this paper.

HYPERGLYCEMIA IS COMMON AND PREDICTS POOR OUTCOMES

Cook et al,¹ in a survey of 126 US hospitals, found that the prevalence of hyperglycemia (blood glucose > 180 mg/dL) was 46% in the ICU and 32% in regular wards.

Kosiborod et al² reported that hyperglycemia (blood glucose > 140 mg/dL) was present in 78% of diabetic patients hospitalized with acute coronary syndrome and 26% of similar hospitalized nondiabetic patients.

Hyperglycemia is a common comorbidity in medical-surgical patients in community hospitals. Our group³ found that, in our hospital, 62% of patients were normoglycemic (ie, had a fasting blood glucose < 126 mg/dL or a random blood glucose < 200 mg/dL on two occasions), 26% had known diabetes, and 12% had new hyperglycemia. Further, new hyperglycemia was associated with a higher in-hospital death rate than the other two conditions.

Failure to identify diabetes is a predictor of rehospitalization. Robbins and Webb⁴ reported that 30.6% of those who had diabetes that was missed during hospitalization were readmitted within 30 days, compared with 9.4% of patients with diabetes first diagnosed during hospitalization.

WHAT DIAGNOSTIC CRITERIA SHOULD WE USE?

Blood glucose greater than 140 mg/dL

A consensus statement from the American Association of Clinical Endocrinologists (ACE) and the American Diabetes Association (ADA)⁵ defines in-hospital hyperglycemia as a blood glucose level greater than 140 mg/dL on admission or in the hospital. If the blood glucose is higher than this, the question arises as to whether the patient has preexisting diabetes or has stress hyperglycemia.

Hemoglobin A_1c of 6.5% or higher

In view of the uncertainty as to whether a patient with an elevated blood glucose level has preexisting diabetes or stress hyperglycemia, upcoming guidelines will recommend measuring the hemoglobin A_1c level if the blood glucose level is higher than 140 mg/dL.

A patient with an elevated blood glucose level (>140 mg/dL) whose hemoglobin A_1c level is 6.5% or higher can be identified as having diabetes that preceded the hospitalization. Hemoglobin A_1c testing can also be useful to assess glycemic control before admission and in designing an optional regimen at the time of discharge. In patients with newly recognized hyperglycemia, a hemoglobin A_1c measurement can help differentiate patients with previously undiagnosed diabetes from those with stress-induced hyperglycemia.

Clinicians should keep in mind that a hemoglobin A_1c cutoff of 6.5% identifies fewer cases of undiagnosed diabetes than does a high fasting glucose concentration, and that a level less than 6.5% does not rule out the diagnosis of diabetes. Several epidemiologic studies⁶ have reported a low sensitivity (44% to 66%) but a high specificity (76% to 99%) for hemoglobin A_1c values higher than 6.5% in an outpatient population. The high specificity therefore supports the use of hemoglobin A_1c to confirm the diagnosis of diabetes in patients with hyperglycemia, but the low sensitivity indicates that this test should not be used for universal screening in the hospital.

Many factors can influence the hemoglobin A_1c level, such as anemia, iron deficiency, blood transfusions, hemolytic anemia, and renal failure.

Until now, if patients had hyperglycemia but no prior diagnosis of diabetes, the recommendation was for an oral 2-hour glucose tolerance test shortly after discharge to confirm the diagnosis of diabetes. Norhammar et al⁷ performed oral glucose tolerance tests in patients admitted with acute myocardial infarction, and Matz et al⁸ performed glucose tolerance tests in patients with acute stroke. They found that impaired glucose tolerance and undiagnosed type 2 diabetes were very common in these two groups. However, physicians rarely order oral glucose tolerance tests. We believe that hemoglobin A_1c will be a better tool than an oral glucose tolerance test to confirm diabetes in hyperglycemic patients in the hospital setting.

In its January 2010 recommendations,⁹ the ADA lists criteria for the categories of normal, prediabetes, and diabetes, based on fasting and 2-hour postprandial plasma glucose levels and hemoglobin A_1c (Table 1).

 

WHAT IS THE ASSOCIATION BETWEEN HYPERGLYCEMIA AND OUTCOMES?

In 2,471 patients admitted to the hospital with community-acquired pneumonia, McAlister et al¹⁰ found that the rates of hospital complications and of death rose with blood glucose levels.

Falguera et al¹¹ found that, in 660 episodes of community-acquired pneumonia, the rates of hospitalization, death, pleural effusion, and concomitant illnesses were all significantly higher in diabetic patients than in nondiabetic patients.

Noordzij et al¹² performed a case-control study of 108,593 patients who underwent noncardiac surgery. The odds ratio for perioperative death was 1.19 (95% confidence interval [CI] 1.1–1.3) for every 1-mmol/L increase in the glucose level.

Frisch et al,¹³ in patients undergoing noncardiac surgery, found that the 30-day rates of death and of in-hospital complications were all higher in patients with diabetes than without diabetes.

Our group³ identified hyperglycemia as an independent marker of in-hospital death in patients with undiagnosed diabetes. The rates of death were 1.7% in those with normoglycemia, 3.0% in those with known diabetes, and 16.0% (P < .01) in those with new hyperglycemia.

The ACE/ADA consensus panel¹⁴ set the following glucose targets for patients in the non-ICU setting:

• Pre-meal blood glucose < 140 mg/dL
• Random blood glucose < 180 mg/dL.

On the other hand, hypoglycemia is also associated with adverse outcomes. Therefore, to avoid hypoglycemia, the insulin regimen should be reassessed if blood glucose levels fall below 100 mg/dL. New guidelines will suggest keeping the blood glucose between 100 and 140 mg/dL.

HOW SHOULD WE MANAGE HYPERGLYCEMIA IN THE NON-ICU SETTING?

The ACE/ADA guidelines recommend subcutaneous insulin therapy for most medical-surgical patients with diabetes, reserving intravenous insulin therapy for hyperglycemic crises and uncontrolled hyperglycemia.¹⁴

Oral antidiabetic agents are not generally recommended, as we have no data to support their use in the hospital. Another argument against using noninsulin therapies in the hospital is that sulfonylureas, especially glyburide (Diabeta, Micronase) are a major cause of hypoglycemia. Metformin (Glucophage) is contraindicated in decreased renal function, in hemodynamic instability, in surgical patients, and with the use of iodinated contrast dye. Thiazolidinediones are associated with edema and congestive heart failure, and they take up to 12 weeks to lower blood glucose levels. Alpha-glucosidase inhibitors are weak glucose-lowering agents. Also, therapies directed at glucagon-like-protein 1 can cause nausea and have a greater effect on postprandial glucose.¹⁴

The two main options for managing hyperglycemia and diabetes in the non-ICU setting are short-acting insulin on a sliding scale and basal-bolus therapy, the latter with either NPH plus regular insulin or long-acting plus rapid-acting insulin analogues.

Basal-bolus vs sliding scale insulin: The RABBIT-2 trial

In the RABBIT 2 trial (Randomized Basal Bolus Versus Sliding Scale Regular Insulin in Patients With Type 2 Diabetes Mellitus),¹⁵ our group compared the efficacy and safety of a basal-bolus regimen and a sliding-scale regimen in 130 hospitalized patients with type 2 diabetes treated with diet, with oral hypoglycemic agents, or with both. Oral antidiabetic drugs were discontinued on admission, and patients were randomized to one of the treatment groups.

In the basal-bolus group, the starting total daily dose was 0.4 U/kg/day if the blood glucose level on admission was between 140 and 200 mg/dL, or 0.5 U/kg/day if the glucose level was between 201 and 400 mg/dL. Half of the total daily dose was given as insulin glargine (Lantus) once daily, and the other half was given as insulin glulisine (Apidra) before meals. These doses were adjusted if the patient’s fasting or pre-meal blood glucose levels rose above 140 mg/dL or fell below 70 mg/dL.

The sliding-scale group received regular insulin four times daily (before meals and at bedtime) for glucose levels higher than 140 mg/dL; the higher the level, the more they got.

The basal-bolus regimen was better than sliding-scale regular insulin. At admission, the mean glucose values and hemoglobin A_1c values were similar in both groups, but the mean glucose level on therapy was significantly lower in the basal-bolus group than in the sliding-scale group, 166 ± 32 mg/dL vs 193 ± 54 mg/dL, P < .001). About two-thirds of the basal-bolus group achieved a blood glucose target of less than 140 mg/dL, compared with only about one-third of the sliding-scale group. The basal-bolus group received more insulin, a mean of 42 units per day vs 12.5 units per day in the sliding-scale group. Yet the incidence of hypoglycemia was 3% in both groups.

NPH plus regular vs detemir plus aspart: The DEAN trial

Several long-acting insulin analogues are available and have a longer duration of action than NPH. Similarly, several newer rapid-acting analogues act more rapidly than regular insulin. Do these pharmacokinetic advantages matter? And do they justify the higher costs of the newer agents?

In the randomized Insulin Detemir Versus NPH Insulin in Hospitalized Patients With Diabetes (DEAN) trial,¹⁶ we compared two regimens: detemir plus aspart in a basal-bolus regimen, and NPH plus regular insulin in two divided doses, two-thirds of the total daily dose in the morning before breakfast and one-third before dinner, both doses in a ratio of two-thirds NPH and one-third regular, mixed in the same syringe. We recruited 130 patients with type 2 diabetes mellitus who were on oral hypoglycemic agents or insulin therapy.

NPH plus regular was just as good as detemir plus aspart in improving glycemic control. Blood glucose levels fell during the first day of therapy and were similar in both groups throughout the trial, as measured before breakfast, lunch, and dinner and at bedtime. The mean total daily insulin dose was not significantly different between treatment groups: 56 ± 45 units in the basal-bolus detemir-aspart group and 45 ± 32 units in the NPH-regular group. However, the basal-bolus group received significantly more short-acting insulin: 27 ± 20 units a day of aspart vs 18 ± 14 units of regular.

Somewhat fewer patients in the NPH-regular group had episodes of hypoglycemia, although the difference between groups was not statistically significant.

In a univariate analysis of the RABBIT-2 and DEAN trials,¹⁷ factors that predicted a blood glucose level less than 60 mg/dL were older age, lower body weight, higher serum creatinine level, and previous insulin therapy. Factors that were not predictive were the hemoglobin A_1c level and the enrollment blood glucose level. Based on these data, we believe that to reduce the rate of hypoglycemia, lower insulin doses are needed in elderly patients and patients with renal impairment, and that if patients have been taking insulin before they come to the hospital, the dose should be cut back by about 25% while they are hospitalized.

 

 

Basal-bolus vs sliding-scale insulin for surgical patients: The RABBIT 2 Surgery trial

Does better glucose control in surgical patients affect outcomes in patients undergoing general surgery? To find out, we performed a prospective, multicenter, randomized, open-label trial in general surgery patients not in the ICU.¹⁸ We recruited and randomized 211 patients with type 2 diabetes who were on diet therapy or oral hypoglycemic agents or insulin in low doses (< 0.4 U/kg/day).

Oral drugs were discontinued on admission, and patients were randomized to receive either a basal-bolus regimen of glargine plus glulisine or regular insulin on a sliding scale. The basal-bolus group got 0.5 U/kg/day, half of it as glargine once daily and half as glulisine before meals. The total daily dose was reduced to 0.3 U/kg/day in patients age 70 and older or who had a serum creatinine level of 2.0 mg/dL or higher.

The goal was to maintain fasting and pre-meal glucose concentrations between 100 and 140 mg/dL. The total daily dose was raised by 10% (mostly in the glargine dose) if the blood glucose level was in the range of 141 to 180 mg/dL, and by 20% if the glucose level was higher than 181 mg/dL. The dose was decreased by 10% for glucose levels between 70 and 99 mg/dL, was decreased by 20% if the glucose level was between 40 and 69, and was held if the glucose level was lower than 40 mg/dL. If a patient was not able to eat, insulin glulisine was held until meals were resumed.

The sliding-scale group received regular insulin four times a day for blood glucose levels higher than 140 mg/dL.

The primary outcomes measured were the difference between groups in mean daily blood glucose concentration and a composite of hospital complications including postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcomes were differences between groups in mean fasting and pre-meal blood glucose, number of hypoglycemic episodes (blood glucose < 70 mg/dL), hyperglycemic episodes (blood glucose > 200 mg/dL), length of hospital stay, need for intensive care, and rate of complications including wound infection, pneumonia, acute renal failure, and death.

Blood glucose levels were significantly lower in the basal-bolus group through the first 7 days after randomization, as measured before breakfast, lunch, and dinner, and at bedtime, and then they converged.

More patients in the sliding-scale group had hospital complications, 26 vs 9, P = .003. On the other hand, more patients in the basal-bolus group had episodes of hypoglycemia: 24 (23%) vs 5 (4.7%) had episodes of less than 70 mg/dL (P < .001), 12 (12%) vs 2 (1.9%) had episodes of less than 60 mg/dL (P = .005), and 4 (3.8%) vs 0 had episodes of less than 40 mg/dL (P = .057). The mean total daily dose of insulin was 33.4 units in the basal-bolus group and 12.3 units in the sliding-scale group.

WHAT HAVE WE LEARNED?

Don’t use a sliding-scale regimen as a single agent in patients with diabetes. Glycemic control is better with a basal-bolus regimen than with a sliding-scale regimen, and a basal-bolus insulin regimen is preferred for most patients with hyperglycemia.

The old human insulins (ie, regular and NPH) are still good and improve glycemic control as well as the new basal insulin analogues (detemir and aspart) do.

Improved control may reduce the rate of hospital complications, according to preliminary evidence. More studies are under way.

One size does not fit all. Those who are elderly or who have impaired renal function should receive lower doses of insulin, eg, 0.3 U/kg/day instead of 0.5 U/kg/day. Those who are on insulin should have their dose decreased when they are admitted to the hospital. Perhaps lean patients with type 2 diabetes should also have a lower dose.

Most hospitalized patients with diabetes and elevated blood glucose values (or hyperglycemia) should receive subcutaneous insulin treatment with a basal-bolus regimen or a multidose combination of NPH plus regular insulin. Selected patients with severe insulin resistance and persistent hyperglycemia despite subcutaneous insulin may benefit from continuous intravenous insulin infusion.

Patients treated with insulin at home should continue to receive insulin therapy in the hospital. However, the insulin dosage should be reduced by about 25% to allow for lower food intake.

QUESTIONS FOR FURTHER STUDY

Should we modify the standard basal-bolus regimen?

In a typical basal-bolus regimen, patients get 50% of their total daily insulin dose in the form of a basal injection and 50% in the form of rapid-acting boluses before meals. However, for a variety of reasons, hospitalized patients do not eat very much. Thus, a 50-50 basal-bolus regimen may not be ideal for patients with poor oral intake.

In the Basal-PLUS trial, currently under way, we are comparing the safety and efficacy of a daily dose of basal insulin (glargine) plus correction doses of a rapid-acting insulin analogue (glulisine) on a sliding scale and a standard basal-bolus regimen in medical and surgical patients.

Does one glycemic target fit all patients?

Falciglia et al¹⁹ found an association between hyperglycemia and death in patients with unstable angina, arrhythmias, stroke, pneumonia, gastrointestinal bleeding, respiratory failure, sepsis, acute renal failure, and congestive heart failure. However, they found no such association in patients with chronic obstructive pulmonary disease, liver failure, diabetic ketoacidosis, gastrointestinal neoplasm, musculoskeletal disease, peripheral vascular disease with bypass, hip fracture, amputation due to peripheral vascular disease, or prostate surgery. Should patients in this second group be treated with a less-intensive insulin regimen?

What is the best regimen after hospital discharge?

We are conducting a prospective clinical trial to assess the impact of insulin after hospital discharge. Our current practice when a patient is discharged from the hospital is as follows:

• If the admission hemoglobin A_1c level is less than 7%, we restart the previous outpatient treatment regimen of oral antidiabetic agents, or insulin, or both.
• If the admission hemoglobin A_1c is between 7% and 9%, we restart the outpatient oral agents and continue glargine once daily at 50% to 80% of the hospital dose.
• If the hemoglobin A_1c level is higher than 9%, we discharge the patient on a basal-bolus regimen at the same dosage as in the hospital. As an alternative, we could restart the oral agents and add glargine once daily at 80% of the hospital dose.

Once regarded as idiopathic, immune thrombocytopenia (ITP) is now understood to have a complex pathogenesis, involving the evolution of antibodies against multiple platelet antigens leading to reduced platelet survival as well as impaired platelet production. For this reason, multiple therapies with different mechanisms of action are available to treat ITP, though not all of them are effective for individual patients.

In this article, I discuss the pathogenesis, demographics, manifestations, diagnosis, and management of ITP.

THE NAME AND THE CUTOFF HAVE CHANGED

The term ITP formerly was used to refer to “idiopathic” or “immune” thrombocytopenic purpura. However, although not all aspects of the pathogenesis of ITP are understood, the disease can no longer be considered idiopathic. In addition, many patients do not have purpura at the time of diagnosis. Though the abbreviation “ITP” remains the same, it now refers to immune thrombocytopenia, which can be either primary or secondary.¹

ITP is defined as a platelet count of less than 100 × 10⁹/L (100,000/μL) with no evidence of leukopenia or anemia. This cutoff point is new: in the past, ITP was defined as a platelet count of less than 150 × 10⁹/L, which is the threshold for a normal platelet count in most laboratories.

The platelet threshold of 100 × 10⁹/L was based on a study by Stasi et al,² who followed 217 otherwise healthy people who had an incidental finding of mild thrombocytopenia (platelet count 100–150 × 10⁹/L). Within 6 months, the platelet count rose to more than 150 × 10⁹/L in 23, while three had either worsening thrombocytopenia or were diagnosed with other conditions. During long-term follow-up (median 64 months), 109 of the remaining 191 individuals remained stable, 13 developed counts greater than 150 × 10⁹/L, 12 developed ITP, 13 developed an autoimmune disorder, 18 developed other disorders, and 26 were lost to follow-up. The 10-year probability of developing ITP, defined as a platelet count persistently below 100 × 10⁹/L, was only 6.9%, indicating that the chances are small that a person with an isolated finding of mild, stable thrombocytopenia will develop ITP.

Categories of ITP

An international working group designated to standardize terminology has divided ITP into two major diagnostic categories.¹ The proportion of patients within each is not well established and varies by region and demographic characteristics.

Primary ITP accounts for the majority of cases in most studies; other conditions associated with thrombocytopenia are absent.

Secondary ITP can be due to infection with a number of agents, including hepatitis C virus (HCV), human immunodeficiency virus (HIV), and Helicobacter pylori. Other causes include underlying autoimmune and lymphoproliferative disorders such as systemic lupus erythematosus, Wiskott-Aldrich syndrome, chronic lymphocytic leukemia, antiphospholipid syndrome, and common variable immunodeficiency, as well as drugs such as quinine and trimethoprim-sulfamethoxazole.

Categories of ITP have also been established to facilitate management decisions, as follows:

Newly diagnosed ITP refers to ITP diagnosed within the preceding 3 months.

Persistent ITP refers to ITP diagnosed 3 to 12 months previously, and includes ITP in patients not reaching spontaneous remission and in those not maintaining a complete response off therapy. (When ITP spontaneously remits in adults, it usually does so within the first 12 months after the condition is diagnosed.)

Chronic ITP: Lasting for more than 12 months.

Severe ITP is defined by bleeding at presentation sufficient to mandate treatment, or new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dosage of a current agent.

ITP IS COMMON IN OLDER ADULTS

We previously believed that ITP was a disorder that primarily affected women in their third and fourth decades. However, this was not borne out in recent epidemiologic studies, which have demonstrated that the highest age-specific incidence of ITP occurs in the elderly. This may potentially reflect the development of immune dysregulation as a consequence of aging. There is a female preponderance in the incidence of ITP throughout adulthood until around age 60, after which the overall incidence increases in both sexes, and the ratio of affected women to men is about equal.^3,4 Thus, even though thrombocytopenia in the elderly may reflect myelodysplasia in some individuals, ITP is much more common than previously appreciated.

Previous guidelines from the American Society of Hematology suggested that a bone marrow examination be strongly considered in patients over age 60 with suspected ITP. With the realization that ITP occurs more commonly in the elderly, it is apparent that bone marrow examination is not necessary in this group if there are no other cytopenias present and the physical examination and blood smear are consistent with ITP.

In children, ITP has a peak incidence between ages 5 and 6, and behaves differently from the adult syndrome. ITP in children usually follows an apparent viral infection and tends to be self-limited, with approximately 80% of cases resolving spontaneously within 6 months. In contrast, adult ITP usually develops into a chronic disease.

 

BLEEDING MAY NOT BE PRESENT AT DIAGNOSIS

ITP is now recognized as a diverse syndrome with a constellation of signs and symptoms.

Petechiae are pinpoint microvascular hemorrhages that do not blanch with pressure. This distinguishes them from small hemangiomas, which look similar but blanch transiently with pressure. Petechiae tend to occur on dependent areas, particularly the hands and feet, when the platelet count drops below approximately 15 × 10⁹/L.

Ecchymoses (dry purpura) appear as large bruises.

Mucosal bleeding (wet purpura) involves the oral mucosa. Particularly in children, wet purpura tends to be associated with systemic bleeding complications, involving the gastrointestinal tract for example. The incidence of intracranial hemorrhage, though very low, may also be increased in patients with wet purpura.

Other bleeding manifestations may include heavy menstrual bleeding, oral bleeding, and epistaxis.

Bleeding is generally but not entirely proportional to the platelet count. In a study of adults with newly diagnosed ITP and a platelet count of less than 50 × 10⁹/L,⁴ the presenting symptom was hemorrhage in 12% and purpura in 58%.⁴ Remarkably, 28% of cases were asymptomatic, with some patients remaining free of symptoms for years despite very low platelet counts. More than half of patients with a platelet count of 30 to 50 × 10⁹/L have no symptoms.^3,4

A PARADOXICAL RISK OF THROMBOSIS

Although ITP is primarily a bleeding disorder, it is paradoxically also associated with thrombosis. Sarpatwari et al,⁵ in a study in the United Kingdom, found that the 4-year incidence of thromboembolic events was about 1.3 times higher in patients with ITP than in matched controls.

The reason for the increased risk of thrombosis is not clear. It is possible that in some patients, antiphospholipid antibodies may contribute to the development of thrombosis, although this has not been confirmed in all studies.

A DIAGNOSIS OF EXCLUSION

The evaluation of any patient suspected of having ITP should include the following:

• Personal history, with special attention to drugs and to medical conditions that could cause thrombocytopenia.
• Family history. ITP may occasionally be mistaken for an inherited cause of thrombocytopenia. The presence of the latter can often be confirmed by review of the peripheral blood film of the patient as well as other family members with thrombocytopenia. ITP is generally not considered to be an inherited disorder, although some HLA alleles may be more prevalent in ITP patients.
• Physical examination, with special attention to lymphadenopathy or splenomegaly, which may suggest an underlying malignancy such as a lymphoproliferative disorder. In general, patients with ITP have a normal physical examination, except for signs of bleeding or bruising in some.
• Laboratory tests, including a complete blood cell count, blood smear, reticulocyte count, Rh typing, and direct antiglobulin (Coombs) test.

In ITP, the peripheral blood smear should appear normal except for the presence of thrombocytopenia, although platelets may be mildly enlarged in some individuals. Red cell and leukocyte morphology is normal. It is important to exclude the presence of schistocytes (red cell fragments) and nucleated red blood cells, which often indicate a microangiopathic hemolytic anemia caused by disorders such as thrombotic thrombocytopenic purpura.

International guidelines suggest that testing for reduced immunoglobulin levels (as seen in common variable hypogammaglobulinemia) and HIV, HCV, and H pylori infections should also be considered. Coincident HCV infection is particularly high in some regions. Other cytopenias or abnormalities in the history or physical examination may prompt bone marrow examination. Testing for antiphospholipid antibodies, antinuclear antibodies, parvovirus, and cytomegalovirus may also be indicated in specific individuals. Testing for antiplatelet antibodies is not commonly performed in the current era because of its relatively low sensitivity and specificity.

Ultimately, the diagnosis of ITP is clinical, however, and cannot be established by any specific laboratory assay. Perhaps the best diagnostic study is assessment of the patient’s response to ITP therapy.

ITP INVOLVES ACCELERATED PLATELET DESTRUCTION

In 1951, William Harrington, a fellow at Washington University, infused blood from a patient with ITP into himself and, subsequently, into normal volunteers.⁶ The majority of recipients demonstrated significant reductions in the platelet count, sometimes severe. This fascinating and bold experiment provided the first demonstration that ITP was caused by a factor that circulates in blood. What is often not emphasized, however, is that some recipients did not develop thrombocytopenia, suggesting an alternative mechanism.

Later, Luiken et al⁷ and Hirschman and Shulman⁸ demonstrated that the transmissible agent in the blood was immunoglobulin, primarily immunoglobulin G (IgG). We now understand that much of the pathogenesis of ITP is caused by antibodies against platelet glycoproteins, most commonly platelet glycoprotein IIb/IIIa, the platelet fibrinogen receptor. Most patients, especially those with chronic ITP, also have antibodies against other platelet glycoproteins, including glycoprotein Ib/IX (the receptor for von Willebrand factor), and glycoprotein Ia/IIa, a collagen receptor. It is commonly believed that ITP may begin with antibodies against a single glycoprotein, which leads to accelerated clearance of antibody-coated platelets in the spleen. Degradation of cleared platelets by splenic macrophages leads to the release and subsequent presentation of antigenic peptides from proteolyzed platelet components, including glycoproteins, on the macrophage or dendritic cell. This may lead to recruitment and activation of specific T cells that in turn interact with and stimulate B cells to produce new antibodies against the platelet-derived peptides. This phenomenon, known as epitope spreading, may be responsible for the fact that most patients with long-standing, chronic ITP develop autoantibodies against multiple platelet glycoprotein targets.⁹

Several agents used in the treatment of ITP may work by impairing clearance of antibody-coated platelets by the reticuloendothelial system. One of many potential mechanisms underlying the therapeutic efficacy of intravenous immunoglobulin (IVIG) may be its ability to interact with a specific type of Fc gamma receptor, Fc gamma RIIb. IVIG therapy stimulates increased expression of this receptor, which in turn may impair the function of other “activating” Fc gamma receptors responsible for platelet clearance.^10,11

ITP associated with infection may arise due to molecular mimicry. HCV, HIV, and H pylori contain amino acid sequences that may have structural similarity to regions within platelet glycoproteins. Thus, antibodies directed against the pathogen may cross-react with the glycoprotein, leading to thrombocytopenia.^12–15

HCV has been found in up to one-third of cases of ITP in some centers.^16–20H pylori-associated ITP is very common in some regions, particularly in Japan, and may often resolve after eradication of the infection. However, in the United States, eradication of H pylori generally does not improve the course of ITP. This may reflect antigen mimicry, in particular the fact that different cagA proteins are expressed by different strains of H pylori in certain regions of the world.

Our understanding of the immunologic basis of ITP has greatly expanded over the last decade. Although it has long been known that B cells produce autoantibodies, T cells have more recently been shown to play a critical role in regulating B-cell-mediated autoantibody production in ITP. In some situations, T cells may directly lyse platelets, or suppress megakaryopoiesis. This may explain why some patients who do not respond to standard B-cell-targeted therapy may respond to cyclosporine or other T-cell-directed agents.

 

ANOTHER MECHANISM OF ITP: REDUCED PLATELET PRODUCTION

In addition to accelerated platelet destruction, ITP is also associated with decreased platelet production by megakaryocytes in the bone marrow.^21–25

Increased platelet destruction and reduced platelet production are likely two ends of a spectrum of ITP, and most patients likely have some degree of both processes. This concept helps explain why different drug strategies are more effective in some patients than in others.

ARE THE RISKS OF THERAPY JUSTIFIED?

It is important to understand the natural history of ITP to determine whether the risks of therapy are justified.

A 2001 study from the Netherlands²⁶ followed 134 patients with primary ITP for 10 years: 90% had taken prednisone or had had a splenectomy. Within 2 years, 85% of these patients had platelet counts above 30 × 10⁹/L off therapy. Although this group likely experienced more bleeding and bruising than the general population, the mortality rate was not increased. Another 6% also achieved a platelet count above 30 × 10⁹/L, but required chronic maintenance therapy (usually steroids) to do so. This group led a nearly normal life but had more hospitalizations. The remaining 9% of patients had refractory ITP, with platelet counts remaining below 30 × 10⁹/L despite therapy. This group had a death rate 4.2 times that of age-matched controls. About half died of bleeding and the others died of opportunistic infections to which they were susceptible because of long-term steroid therapy.

This study was influential in the general opinion that 30 × 10⁹/L is a reasonable cutoff for treating ITP. An international consensus report states that treatment is rarely indicated in patients with platelet counts above 50 × 10⁹/L in the absence of bleeding due to platelet dysfunction or other hemostatic defect, trauma, or surgery.²⁷ Although this number is not supported by evidence-based data, it is a reasonable threshold endorsed by an international working group.²⁷ Individual factors must be weighed heavily: for example, an athlete involved in contact sports requires a higher platelet count in order to play safely.

Recommendations regarding thresholds for safe platelet counts for specific medical interventions vary widely. Guidelines from the British Committee for Standards in Haematology are somewhat arbitrary but reasonable (Table 1).²⁸

FIRST-LINE THERAPIES

First-line therapies for ITP include corticosteroids, IVIG, and anti-Rho(D) immune globulin (WinRho).²⁷

Corticosteroids are standard therapy

Corticosteroids can be given in one of two ways:

Standard prednisone therapy, ie, 1 to 2 mg/kg per day, is given until a response is seen, and then tapered. Some maintain therapy for an additional week before tapering. There are no guidelines on how to taper: some decrease the dosage by 50% per week, although many recommend going more slowly, particularly at the lower range of dosing.

Up to 85% of patients achieve a clinical response, usually within 7 to 10 days, with platelet counts peaking in 2 to 4 weeks. Unfortunately, only about 15% of patients maintain the response over the subsequent 6 to 12 months. Restarting prednisone often initiates a vicious circle and makes patients vulnerable to steroid toxicities.

“Pulse” dexamethasone therapy consists of 40 mg per day for 4 days for one to three cycles. (Dexamethasone 1 mg is equivalent to about 10 mg of prednisone.)

Pulse dexamethasone therapy as an initial approach to ITP has been developed during the past decade and has been used primarily in research studies. This regimen evolved from studies of patients with multiple myelomas and has the potential to induce more durable remissions in some patients with newly diagnosed ITP.²⁹ However, high-dose corticosteroids may be associated with increased toxicity, at least in the short term, and should be used cautiously. A study to address the role of high-dose vs standard-dose steroid therapy has recently been opened under the guidance of the Transfusion Medicine–Hemostasis Clinical Trials Network of the National Heart, Lung, and Blood Institute.

Immunoglobulin is useful for very low platelet counts and bleeding

Another primary therapy for ITP is IVIG 0.5 to 2.0 g/kg over 2 to 5 days. Its efficacy is similar to that of prednisone: about 65% of patients achieve a platelet count above 100 × 10⁹/L, and 85% achieve 50 × 10⁹/L. However, most responses are transient, and a significant minority of cases become refractory to IVIG after repeated infusions.

IVIG is associated with numerous adverse effects, including thrombosis, renal insufficiency, headache, and anaphylaxis in IgA-deficient patients. It also converts the direct antiglobulin test to positive. IVIG is expensive, is inconvenient to administer, and may require lengthy infusions depending on the formulation.

Although IVIG is not a good long-term therapy, it can help raise the platelet count relatively quickly in patients who present with severe thrombocytopenia accompanied by bleeding. Such patients should be treated with high-dose steroids, IVIG, and platelet transfusions. IVIG may also be useful to increase platelet counts prior to interventional procedures.

Intravenous anti-Rho(D)

Anti-Rho(D) is an alternative to IVIG in patients who are Rho(D)-positive and have an intact spleen. Anti-Rho(D) binds to Rh-positive red blood cells, causing them to be cleared in the reticuloendothelial system and blocking the clearance of antibody-coated platelets. In effect, red cells are sacrificed to save platelets, but because there are many more red cells than platelets, the benefits usually outweigh the risks.

The initial dose is 50 μg/kg given intravenously over 2 to 5 minutes. Anti-Rho(D) should not be given to patients whose hemoglobin level is less than 10 g/dL or who have compromised bone marrow function. It is ineffective in Rh-negative patients or those who have undergone splenectomy.

Accelerated hemolysis is a rare but severe possible adverse event associated with this therapy, occurring in slightly more than 1 in 1,000 infusions. About 1 out of every 20,000 patients develops disseminated intravascular coagulation.³⁰ Its cause is poorly understood, and it is probably an accelerated extravascular rather than an intravascular event. The US Food and Drug Administration has recently issued a black-box warning cautioning that patients who receive anti-Rho(D) should remain in a health care setting for 8 hours after treatment, although most cases of accelerated hemolysis occur within 4 hours. Moreover, it is possible that many of these cases can be avoided by appropriate patient selection.

 

SECOND-LINE THERAPIES

Second-line therapies, as designated by the international working group, include azathioprine (Imuran), cyclosporine A, cyclophosphamide (Cytoxan), danazol (Danocrine), dapsone, mycophenolate mofetil (CellCept), rituximab (Rituxan), splenectomy, thrombopoietin receptor agonists, and vinca alkaloids.²⁷ Only the most commonly used therapies will be briefly discussed below.

The evidence for efficacy of the cytotoxic agents, ie, cyclophosphamide, the vinca alkaloids, and azathioprine, comes from small, nonrandomized studies.³¹ Although these agents are useful in some patients, they may be associated with significant toxicities, and they are used less commonly than in the past.

Splenectomy has a high success rate

Splenectomy probably offers the best response of any treatment for ITP. About 80% of patients with ITP respond rapidly—often within 1 week. Of those, 15% relapse within the first year, and after 10 years, two-thirds remain in remission.^32,33

Because there is no well-accepted predictor of a short- or long-term response to splenectomy, and because more medical options are currently available, the use of splenectomy has declined over the past 10 years. Nevertheless, splenectomy remains a useful option for therapy of ITP.

Whether and which second-line drugs should be tried before splenectomy is still controversial and should be determined on a case-by-case basis. Some patients are poor candidates for splenectomy because of comorbidities. If possible, splenectomy should be delayed until at least a year after diagnosis to allow an opportunity for spontaneous remission.

Splenectomy increases the risk of subsequent infection by encapsulated organisms, and patients should be immunized with pneumococcal, Haemophilus influenzae type B, and meningococcal vaccines, preferably at least 3 weeks before the spleen is removed.

Splenectomy is associated with pulmonary hypertension and thrombosis, primarily in patients who have had their spleens removed because of accelerated red cell destruction. Whether these risks are applicable to patients with ITP is unknown, but if so they are probably much lower than in patients with red cell disorders.

Rituximab

Rituximab, a humanized monoclonal antibody against the CD20 antigen on B lymphocytes, was developed for treating lymphoma. However, it has been found to have significant activity in a number of immunohematologic disorders. Although many studies of rituximab for ITP have been published,^34–38 it has never been tested in a randomized controlled study. The response rate is generally around 50%, and it is effective in patients with or without a spleen.

In one study,³⁹ 44 (32%) of 137 patients with chronic ITP who were given rituximab achieved a complete remission that was sustained 1 year. After more than 5 years, 63% of this group (ie, approximately 20% of the original group) were still in remission.

Potential drawbacks of rituximab include its expense as well as the risk of first-infusion reactions, which may be severe or, rarely, fatal. Rituxan has also been associated with rare cases of progressive multifocal leukoencephalopathy, usually in patients heavily treated with other immunosuppressive agents; however, very rare cases of progressive multifocal leukoencephalopathy have been reported in patients with ITP who received rituximab.

Thrombopoietin receptor agonists increase platelet production

Thrombopoietin receptor agonists are approved for patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Rather than inhibit platelet destruction, as do all the other ITP therapies, they enhance platelet production.

Diseases involving bone marrow failure that also involve a low platelet count tend to be associated with very high levels of serum thrombopoietin, which is produced constitutively by the liver. In ITP, thrombopoeitin levels tend to be close to normal and not significantly elevated, most likely because of accelerated thrombopoietin clearance when bound to antibody-coated platelets.⁴⁰ This provides a rationale for the use of thrombopoietic agents in the treatment of ITP.

Earlier-generation thrombopoietic drugs had significant amino acid homology with natural thrombopoietin, and some patients who were treated with these drugs developed antibodies against them that cross-reacted with endogenous thrombopoietin. In some cases, this led to severe, refractory thrombocytopenia. Because the newer thrombopoietic agents have no sequence homology to natural thrombopoietin, antibody production has not been a significant problem.

Two drugs in this class are currently available for treating ITP:

Romiplostim (Nplate) is a peptibody (comprising an IgG Fc region and four peptidometic regions that interact with the thrombopoietin receptor, c-mpl) that is given subcutaneously once a week.

Romiplostim performed well in several phase I clinical trials.⁴¹ In a 24-week phase III trial that compared romiplostim against placebo in patients with ITP that had been refractory to other primary treatments, 79% of splenectomized patients and 88% of nonsplenectomized patients had an overall response (defined as a platelet count > 50 × 10⁹/L for 4 weeks during the study period), and 38% of splenectomized patients and 61% of nonsplenectomized patients had a durable response (platelet count > 50 × 10⁹/L for 6 of the last 8 weeks of the study).⁴²

In an ongoing long-term extension study of romiplostim that allows dose adjustments to maintain a platelet count between 50 and 200 × 10⁹/L, romiplostim dosage and efficacy have remained stable over 5 years.^42,43

Eltrombopag (Promacta) is a nonpeptide small-molecule c-mpl agonist that is taken orally once daily. A recent randomized, placebo-controlled study in patients with ITP refractory to other primary treatments found that eltrombopag was highly effective in raising platelet counts over the 6 months of the study.⁴⁴ Like romiplostim, it was effective in both splenectomized and nonsplenectomized patients.

Although eltrombopag has not been studied for as long as romiplostim, data over 3 years indicate that increased platelet counts are maintained without the emergence of drug resistance or cumulative toxicity.⁴⁵

Several other drugs in this class are currently in development.

Adverse effects of thrombopoietic agents

Thrombopoietic agents have several associated toxicities:

Rebound thrombocytopenia occurs in up to 10% of patients following treatment with either romiplostim or eltrombopag. Rebound thrombocytopenia is defined as a fall in the platelet count that occurs following discontinuation of a thrombopoietic agent that may result in more severe thrombocytopenia, transiently, than before the drug was initiated. Thus, the platelet count must be closely monitored after treatment with these drugs is discontinued.

Bone marrow fibrosis, which consists primarily of increased marrow reticulin content, occurs in less than 10% of treated patients, and all patients on therapy must be monitored for this potential complication by close examination of the peripheral blood film on a frequent basis. Appearance of abnormalities such as teardrop cells or nucleated red blood cells in the peripheral blood smear should prompt at least temporary discontinuation of the drug and consideration of bone marrow examination. There have been no cases of actual irreversible myelofibrosis in which thrombopoietic agents have been clearly implicated in causation. Interestingly, some reports suggest that increased reticulin is a common finding in marrow from ITP patients who have not been treated with thrombopoietic agents.⁴⁶

Thrombosis must be considered a risk of treatment with thrombopoietic agents, which increase the platelet count in a disease that may already be thrombogenic. However, in the placebo-controlled studies, a significantly increased incidence of thrombosis was not observed in the treatment arms vs placebo. Moreover, even in treated patients who developed thrombosis, there was no clear association with the degree of elevation in the platelet count. Nevertheless, thrombopoietic agents should be used according to the manufacturer’s recommendations, to increase the platelet count to a range of 50 to 200 × 10⁹/L, but not to exceed that.

Progression of hematologic malignancies. Thrombopoietin receptor agonists act not only on megakaryocytes but also on stem cells and other hematopoieic precursors. Although trials for treating patients with hematologic malignancies and bone marrow failure with thrombopoietic agents are ongoing, there is concern that they could worsen certain hematologic malignancies, though there are no controlled data to either support or refute this concern at present. At this time, these drugs are approved only for ITP and should not be used for other conditions.

Hepatotoxicity has been seen with eltrombopag, but it is usually reversible and may resolve with continued therapy. Nevertheless, close monitoring for this potential complication is indicated.