Diana Mahoney

BOSTON — The use of vitamin E supplements among patients with nonalcoholic steatohepatitis was associated with a greater improvement in nonalcoholic fatty liver disease activity scores and cytologic ballooning, compared with the use of pioglitazone or placebo, results from a randomized, controlled trial showed.

The investigation was spurred by findings suggesting that oxidative damage and insulin resistance both play a role in the chronic liver disease, Dr. Arun J. Sanyal said at the American Association for the Study of Liver Diseases. He and his colleagues at Virginia Commonwealth University, Richmond, sought to evaluate the role of vitamin E, an antioxidant, and pioglitazone, an insulin-sensitizing agent, in the treatment of nonalcoholic steatohepatitis (NASH).

The 247 patients were randomized to receive 800 IU of vitamin E once daily, 30 mg of pioglitazone once daily, or placebo for 96 weeks. All of the patients had biopsy-proven steatohepatitis with a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher within 6 months prior to randomization, Dr. Sanyal said.

The study's primary end point was improvement—defined as a decrease in NAFLD activity score of 2 points or more and a decrease of at least 1 point in cytologic ballooning—and no worsening of fibrosis. Secondary end points included changes in histologic features, liver enzymes, insulin resistance, anthropometric measures, and quality of life, Dr. Sanyal explained.

Compared with placebo, both vitamin E and pioglitazone were associated with liver function improvement, decreased ballooning, and better fibrosis stabilization at 96 weeks, although only vitamin E met the prespecified level of significance for thepreimary end point, he said.

Of the 84 patients randomized to vitamin E, 43% showed the predefined composite improvement, compared with 34% of the pioglitazone group and 19% of the placebo group, he said.

The failure of pioglitazone to meet the end point criteria can likely be attributed to the fact that substantially fewer patients in that group had ballooning at baseline “and therefore couldn't demonstrate a reduction with treatment,” Dr. Sanyal said.

Improvement in steatosis as measured by poststudy biopsy, lobular inflammation, ballooning scores, and serum alanine aminotransferase levels was observed in both treatment groups, compared with placebo, Dr. Sanyal reported.

Patients on pioglitazone had greater weight gain (mean 4.7 kg) than did those on vitamin E (0.4 kg) or placebo (0.8 kg), but they also were the only group to demonstrate an improvement in insulin resistance, said Dr. Sanyal.

Although this study suggests that both vitamin E and pioglitazone can lead to biochemical and histologic improvement in NASH, additional studies are needed to determine the sustainability of the observed outcomes, and the long-term safety of the agents. “With the exception of weight gain, there were no drug-related adverse events, but the study was not powered to assess safety issues,” he said.

With respect to the vitamin E findings in particular, “this should resurrect our efforts to use antioxidants [for NASH] and, more importantly, to develop very potent antioxidants that are well tolerated in these patients,” Dr. Scott Friedman, AASLD president, said in a press conference. The key is to make sure the vitamin E is of sufficient quality to be effective, said Dr. Friedman, of the Mount Sinai School of Medicine, New York.

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Sanyal and Dr. Friedman disclosed financial relationships with several pharmaceutical companies.

Only vitamin E met the prespecified level of significance for the primary end point.

Source DR. SANYAL

BOSTON — The use of vitamin E supplements among patients with nonalcoholic steatohepatitis was associated with a greater improvement in nonalcoholic fatty liver disease activity scores and cytologic ballooning, compared with the use of pioglitazone or placebo, results from a randomized, controlled trial showed.

The investigation was spurred by findings suggesting that oxidative damage and insulin resistance both play a role in the chronic liver disease, Dr. Arun J. Sanyal said at the American Association for the Study of Liver Diseases. He and his colleagues at Virginia Commonwealth University, Richmond, sought to evaluate the role of vitamin E, an antioxidant, and pioglitazone, an insulin-sensitizing agent, in the treatment of nonalcoholic steatohepatitis (NASH).

The 247 patients were randomized to receive 800 IU of vitamin E once daily, 30 mg of pioglitazone once daily, or placebo for 96 weeks. All of the patients had biopsy-proven steatohepatitis with a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher within 6 months prior to randomization, Dr. Sanyal said.

The study's primary end point was improvement—defined as a decrease in NAFLD activity score of 2 points or more and a decrease of at least 1 point in cytologic ballooning—and no worsening of fibrosis. Secondary end points included changes in histologic features, liver enzymes, insulin resistance, anthropometric measures, and quality of life, Dr. Sanyal explained.

Compared with placebo, both vitamin E and pioglitazone were associated with liver function improvement, decreased ballooning, and better fibrosis stabilization at 96 weeks, although only vitamin E met the prespecified level of significance for thepreimary end point, he said.

Of the 84 patients randomized to vitamin E, 43% showed the predefined composite improvement, compared with 34% of the pioglitazone group and 19% of the placebo group, he said.

The failure of pioglitazone to meet the end point criteria can likely be attributed to the fact that substantially fewer patients in that group had ballooning at baseline “and therefore couldn't demonstrate a reduction with treatment,” Dr. Sanyal said.

Improvement in steatosis as measured by poststudy biopsy, lobular inflammation, ballooning scores, and serum alanine aminotransferase levels was observed in both treatment groups, compared with placebo, Dr. Sanyal reported.

Patients on pioglitazone had greater weight gain (mean 4.7 kg) than did those on vitamin E (0.4 kg) or placebo (0.8 kg), but they also were the only group to demonstrate an improvement in insulin resistance, said Dr. Sanyal.

Although this study suggests that both vitamin E and pioglitazone can lead to biochemical and histologic improvement in NASH, additional studies are needed to determine the sustainability of the observed outcomes, and the long-term safety of the agents. “With the exception of weight gain, there were no drug-related adverse events, but the study was not powered to assess safety issues,” he said.

With respect to the vitamin E findings in particular, “this should resurrect our efforts to use antioxidants [for NASH] and, more importantly, to develop very potent antioxidants that are well tolerated in these patients,” Dr. Scott Friedman, AASLD president, said in a press conference. The key is to make sure the vitamin E is of sufficient quality to be effective, said Dr. Friedman, of the Mount Sinai School of Medicine, New York.

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Sanyal and Dr. Friedman disclosed financial relationships with several pharmaceutical companies.

Only vitamin E met the prespecified level of significance for the primary end point.

Source DR. SANYAL

BOSTON — The use of vitamin E supplements among patients with nonalcoholic steatohepatitis was associated with a greater improvement in nonalcoholic fatty liver disease activity scores and cytologic ballooning, compared with the use of pioglitazone or placebo, results from a randomized, controlled trial showed.

The investigation was spurred by findings suggesting that oxidative damage and insulin resistance both play a role in the chronic liver disease, Dr. Arun J. Sanyal said at the American Association for the Study of Liver Diseases. He and his colleagues at Virginia Commonwealth University, Richmond, sought to evaluate the role of vitamin E, an antioxidant, and pioglitazone, an insulin-sensitizing agent, in the treatment of nonalcoholic steatohepatitis (NASH).

The 247 patients were randomized to receive 800 IU of vitamin E once daily, 30 mg of pioglitazone once daily, or placebo for 96 weeks. All of the patients had biopsy-proven steatohepatitis with a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher within 6 months prior to randomization, Dr. Sanyal said.

The study's primary end point was improvement—defined as a decrease in NAFLD activity score of 2 points or more and a decrease of at least 1 point in cytologic ballooning—and no worsening of fibrosis. Secondary end points included changes in histologic features, liver enzymes, insulin resistance, anthropometric measures, and quality of life, Dr. Sanyal explained.

Compared with placebo, both vitamin E and pioglitazone were associated with liver function improvement, decreased ballooning, and better fibrosis stabilization at 96 weeks, although only vitamin E met the prespecified level of significance for thepreimary end point, he said.

Of the 84 patients randomized to vitamin E, 43% showed the predefined composite improvement, compared with 34% of the pioglitazone group and 19% of the placebo group, he said.

The failure of pioglitazone to meet the end point criteria can likely be attributed to the fact that substantially fewer patients in that group had ballooning at baseline “and therefore couldn't demonstrate a reduction with treatment,” Dr. Sanyal said.

Improvement in steatosis as measured by poststudy biopsy, lobular inflammation, ballooning scores, and serum alanine aminotransferase levels was observed in both treatment groups, compared with placebo, Dr. Sanyal reported.

Patients on pioglitazone had greater weight gain (mean 4.7 kg) than did those on vitamin E (0.4 kg) or placebo (0.8 kg), but they also were the only group to demonstrate an improvement in insulin resistance, said Dr. Sanyal.

Although this study suggests that both vitamin E and pioglitazone can lead to biochemical and histologic improvement in NASH, additional studies are needed to determine the sustainability of the observed outcomes, and the long-term safety of the agents. “With the exception of weight gain, there were no drug-related adverse events, but the study was not powered to assess safety issues,” he said.

With respect to the vitamin E findings in particular, “this should resurrect our efforts to use antioxidants [for NASH] and, more importantly, to develop very potent antioxidants that are well tolerated in these patients,” Dr. Scott Friedman, AASLD president, said in a press conference. The key is to make sure the vitamin E is of sufficient quality to be effective, said Dr. Friedman, of the Mount Sinai School of Medicine, New York.

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Sanyal and Dr. Friedman disclosed financial relationships with several pharmaceutical companies.

Only vitamin E met the prespecified level of significance for the primary end point.

Source DR. SANYAL

A number of groundbreaking developments in systemic lupus erythematosus have injected a much-needed boost into the lupus community, which has been repeatedly disappointed by setbacks and failures in clinical trials of “promising” new agents.

Clinicians are optimistic about two positive late-stage clinical trials, the validation of an evidence-based responder index to measure disease activity, the discovery of genetic markers that may help predict the clinical outcome of patients who are treated with existing therapies, and the introduction of new guidelines to facilitate and better control clinical trials, according to Dr. Richard Furie, chief of rheumatology and allergy–clinical immunology at North Shore–Long Island Jewish Health System in New York.

In fact, the announcement in July that the monoclonal antibody belimumab showed effectiveness against lupus in the first of two phase III clinical trials—the first drug to ever do so, according to a statement from Human Genome Sciences, which codeveloped the biologic with Glaxo SmithKline—was in some ways a surprise. The drug, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), had nearly been counted out after it failed to meet its primary efficacy end point in a phase II clinical trial, except in a subgroup of patients who experienced a statistically significant improvement in lupus signs and symptoms, according to Dr. Daniel J. Wallace of the University of California, Los Angeles.

Based on extensive post hoc analysis of the phase II data, investigators identified factors that could have contributed to the negative trial and redesigned the study accordingly. The revised trial excluded the 28% of patients in the phase II study who were not seropositive for antinuclear antibodies or anti–double-stranded DNA antibodies; it extended the response time to 52 weeks, and it utilized a new composite end point, called the SLE Responder Index, to measure an individual patient's improvement from baseline, Dr. Wallace explained.

“The new index looks at whether the patient feels better, whether the doctor thinks the patient feels better, and whether there are any new disease manifestations,” Dr. Wallace said. Given the heterogeneous nature of lupus and the longstanding difficulty of assessing disease activity in clinical trials, the responder index “represents a breakthrough for finally utilizing a methodology that enables researchers to demonstrate disease improvement,” he said.

And although the success of the SLE Responder Index is limited to just one data set, “the fact that it worked prospectively and not just post hoc should be encouraging to drug developers,” Dr. Furie said. “Perhaps it will become the standard or at least serve as the foundation for further refinements.”

On the heels of the belimumab announcement was the news that another experimental lupus drug, epratuzumab, performed well in a phase IIB clinical trial. In a 12-week, dose- and regimen-ranging, placebo-controlled study of 227 patients with moderately to severely active lupus, epratuzumab (a humanized anti-CD22 monoclonal antibody) showed a “clinically meaningful” effect over placebo, according to a statement by Belgium's UCB SA, which bought rights to epratuzumab from Immunomedics. Specifically, at week 12, the treatment effect of epratuzumab was nearly 25%, compared with placebo, the report noted.

If one or both of these new drugs ultimately receive Food and Drug Administration approval for the treatment of lupus, they most likely will be used initially in patients who have chronically active disease despite treatment with steroids or other immunosuppressive therapies, according to Dr. Wallace. “Belimumab in particular does not work fast. It is not a replacement for corticosteroids in the treatment of acute disease.”

If approved, belimumab will be a major advance for those with moderate or inadequately controlled disease activity who require prednisone, because it may enable lower corticosteroid doses, said Dr. Michelle Petri, professor of rheumatology at Johns Hopkins University, Baltimore.

“The reality is prednisone is not going away. Approximately 80% of our lupus patients are on it—and for good reason, as it remains the most effective immunosuppressive therapy we have for the disease, and it works fast. The problem is that nearly 80% of organ damage in lupus is directly or indirectly due to steroids,” Dr. Petri said at the annual meeting of the European Congress of Rheumatology this year in Copenhagen.

The risk for prednisone-associated organ damage increases by an order of magnitude as the cumulative dose increases, said Dr. Petri, referring to a recent study in which she and Mae Thamer, Ph.D., from the Medical Technology and Practice Patterns Institute in Bethesda, Md., evaluated the effect of corticosteroid use in 525 patients with incident SLE who were enrolled in the Hopkins Lupus Cohort. Using a marginal structural model to adjust for time-dependent confounding associated with disease activity, the investigators determined that patients who received cumulative doses of prednisone in the lowest range (0-180 mg/month) had only a small increased risk of irreversible organ damage, compared with nonprednisone use (hazard ratio 1.16), whereas the risk among those receiving cumulative doses in the highest range (more than 540 mg/month) was more than doubled (HR 2.51). The hazard ratios for the middle-range doses (180-360 mg/month and 360-540 mg/month) were 1.50 and 1.64, respectively (J. Rheumatol. 2009; 36:560-64).

“When you look at the models, it's pretty clear that when the prednisone gets above 11 mg daily, there is a huge increase in the hazard ratio for organ damage,” Dr. Petri said. “That is when to start to think about adding other therapies, if you haven't already, to achieve better control of disease activity and to limit the prednisone dose.” It is at this point, she noted, that the expansion of treatment options is needed.

With respect to other steroid-sparing options, however, the “ideal” immunomodulatory therapy in lupus continues to be the antimalarial hydroxychloroquine (Plaquenil), Dr. Petri said. Hydroxychloroquine “has been shown to prevent severe flares in lupus. It also reduces the risk of lupus nephritis, organ damage, cardiovascular risk factors, and thrombosis, and it improves survival.” In reality, she added, “if we could just convince our patients to stay on Plaquenil, I don't think we would need as much immunosuppressive therapy.”

In fact, hydroxychloroquine is undergoing a rebirth of sorts, according to Dr. Furie. “Many people believe that all SLE patients should be on this drug. It's effective and fairly benign, and we are learning that it has pleiotropic effects,” he said, including protection against thrombotic events and a beneficial effect on lipid profiles, which could potentially help reduce SLE patients' high risk of cardiovascular disease.

The recent finding by Spanish investigators that antimalarial drugs are more effective in SLE patients with polymorphisms on the tumor necrosis factor–alpha (TNF-alpha) and interleukin-10 (IL-10) genes associated with unusually high TNF-alpha levels and unusually low IL-10 levels may eventually allow the identification of lupus patients who are the most likely to benefit from antimalarial therapy (J. Rheumatol. 2008;35:1559-66).

Finally, the lupus research community is encouraged by the development of new recommendations for monitoring SLE in clinical practice, which were introduced at the annual European Congress of Rheumatology this year by Dr. Marta Mosca of the University of Pisa (Italy), the lead author of the recommendation paper, which is slated for publication in the Annals of the Rheumatic Diseases later this year. The guidelines are intended to provide a “road map” for clinicians in terms of assessing disease activity, kidney and other organ involvement, comorbidities, and the various cardiovascular, ophthalmologic, neuropsychiatric, and other risks associated with SLE and its treatment.

“The guidelines will be an important tool for helping rheumatologists make clinical management decisions,” Dr. Mosca said. “As new therapies are developed, the guidelines will help ensure the quality control of patient care and will allow us to better standardize the collection and comparison of data in observational studies.”

The SLE Responder Index 'represents a breakthrough' in detecting disease improvement.

Source DR. WALLACE

A number of groundbreaking developments in systemic lupus erythematosus have injected a much-needed boost into the lupus community, which has been repeatedly disappointed by setbacks and failures in clinical trials of “promising” new agents.

Clinicians are optimistic about two positive late-stage clinical trials, the validation of an evidence-based responder index to measure disease activity, the discovery of genetic markers that may help predict the clinical outcome of patients who are treated with existing therapies, and the introduction of new guidelines to facilitate and better control clinical trials, according to Dr. Richard Furie, chief of rheumatology and allergy–clinical immunology at North Shore–Long Island Jewish Health System in New York.

In fact, the announcement in July that the monoclonal antibody belimumab showed effectiveness against lupus in the first of two phase III clinical trials—the first drug to ever do so, according to a statement from Human Genome Sciences, which codeveloped the biologic with Glaxo SmithKline—was in some ways a surprise. The drug, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), had nearly been counted out after it failed to meet its primary efficacy end point in a phase II clinical trial, except in a subgroup of patients who experienced a statistically significant improvement in lupus signs and symptoms, according to Dr. Daniel J. Wallace of the University of California, Los Angeles.

Based on extensive post hoc analysis of the phase II data, investigators identified factors that could have contributed to the negative trial and redesigned the study accordingly. The revised trial excluded the 28% of patients in the phase II study who were not seropositive for antinuclear antibodies or anti–double-stranded DNA antibodies; it extended the response time to 52 weeks, and it utilized a new composite end point, called the SLE Responder Index, to measure an individual patient's improvement from baseline, Dr. Wallace explained.

“The new index looks at whether the patient feels better, whether the doctor thinks the patient feels better, and whether there are any new disease manifestations,” Dr. Wallace said. Given the heterogeneous nature of lupus and the longstanding difficulty of assessing disease activity in clinical trials, the responder index “represents a breakthrough for finally utilizing a methodology that enables researchers to demonstrate disease improvement,” he said.

And although the success of the SLE Responder Index is limited to just one data set, “the fact that it worked prospectively and not just post hoc should be encouraging to drug developers,” Dr. Furie said. “Perhaps it will become the standard or at least serve as the foundation for further refinements.”

On the heels of the belimumab announcement was the news that another experimental lupus drug, epratuzumab, performed well in a phase IIB clinical trial. In a 12-week, dose- and regimen-ranging, placebo-controlled study of 227 patients with moderately to severely active lupus, epratuzumab (a humanized anti-CD22 monoclonal antibody) showed a “clinically meaningful” effect over placebo, according to a statement by Belgium's UCB SA, which bought rights to epratuzumab from Immunomedics. Specifically, at week 12, the treatment effect of epratuzumab was nearly 25%, compared with placebo, the report noted.

If one or both of these new drugs ultimately receive Food and Drug Administration approval for the treatment of lupus, they most likely will be used initially in patients who have chronically active disease despite treatment with steroids or other immunosuppressive therapies, according to Dr. Wallace. “Belimumab in particular does not work fast. It is not a replacement for corticosteroids in the treatment of acute disease.”

If approved, belimumab will be a major advance for those with moderate or inadequately controlled disease activity who require prednisone, because it may enable lower corticosteroid doses, said Dr. Michelle Petri, professor of rheumatology at Johns Hopkins University, Baltimore.

“The reality is prednisone is not going away. Approximately 80% of our lupus patients are on it—and for good reason, as it remains the most effective immunosuppressive therapy we have for the disease, and it works fast. The problem is that nearly 80% of organ damage in lupus is directly or indirectly due to steroids,” Dr. Petri said at the annual meeting of the European Congress of Rheumatology this year in Copenhagen.

The risk for prednisone-associated organ damage increases by an order of magnitude as the cumulative dose increases, said Dr. Petri, referring to a recent study in which she and Mae Thamer, Ph.D., from the Medical Technology and Practice Patterns Institute in Bethesda, Md., evaluated the effect of corticosteroid use in 525 patients with incident SLE who were enrolled in the Hopkins Lupus Cohort. Using a marginal structural model to adjust for time-dependent confounding associated with disease activity, the investigators determined that patients who received cumulative doses of prednisone in the lowest range (0-180 mg/month) had only a small increased risk of irreversible organ damage, compared with nonprednisone use (hazard ratio 1.16), whereas the risk among those receiving cumulative doses in the highest range (more than 540 mg/month) was more than doubled (HR 2.51). The hazard ratios for the middle-range doses (180-360 mg/month and 360-540 mg/month) were 1.50 and 1.64, respectively (J. Rheumatol. 2009; 36:560-64).

“When you look at the models, it's pretty clear that when the prednisone gets above 11 mg daily, there is a huge increase in the hazard ratio for organ damage,” Dr. Petri said. “That is when to start to think about adding other therapies, if you haven't already, to achieve better control of disease activity and to limit the prednisone dose.” It is at this point, she noted, that the expansion of treatment options is needed.

With respect to other steroid-sparing options, however, the “ideal” immunomodulatory therapy in lupus continues to be the antimalarial hydroxychloroquine (Plaquenil), Dr. Petri said. Hydroxychloroquine “has been shown to prevent severe flares in lupus. It also reduces the risk of lupus nephritis, organ damage, cardiovascular risk factors, and thrombosis, and it improves survival.” In reality, she added, “if we could just convince our patients to stay on Plaquenil, I don't think we would need as much immunosuppressive therapy.”

In fact, hydroxychloroquine is undergoing a rebirth of sorts, according to Dr. Furie. “Many people believe that all SLE patients should be on this drug. It's effective and fairly benign, and we are learning that it has pleiotropic effects,” he said, including protection against thrombotic events and a beneficial effect on lipid profiles, which could potentially help reduce SLE patients' high risk of cardiovascular disease.

The recent finding by Spanish investigators that antimalarial drugs are more effective in SLE patients with polymorphisms on the tumor necrosis factor–alpha (TNF-alpha) and interleukin-10 (IL-10) genes associated with unusually high TNF-alpha levels and unusually low IL-10 levels may eventually allow the identification of lupus patients who are the most likely to benefit from antimalarial therapy (J. Rheumatol. 2008;35:1559-66).

Finally, the lupus research community is encouraged by the development of new recommendations for monitoring SLE in clinical practice, which were introduced at the annual European Congress of Rheumatology this year by Dr. Marta Mosca of the University of Pisa (Italy), the lead author of the recommendation paper, which is slated for publication in the Annals of the Rheumatic Diseases later this year. The guidelines are intended to provide a “road map” for clinicians in terms of assessing disease activity, kidney and other organ involvement, comorbidities, and the various cardiovascular, ophthalmologic, neuropsychiatric, and other risks associated with SLE and its treatment.

“The guidelines will be an important tool for helping rheumatologists make clinical management decisions,” Dr. Mosca said. “As new therapies are developed, the guidelines will help ensure the quality control of patient care and will allow us to better standardize the collection and comparison of data in observational studies.”

The SLE Responder Index 'represents a breakthrough' in detecting disease improvement.

Source DR. WALLACE

A number of groundbreaking developments in systemic lupus erythematosus have injected a much-needed boost into the lupus community, which has been repeatedly disappointed by setbacks and failures in clinical trials of “promising” new agents.

Clinicians are optimistic about two positive late-stage clinical trials, the validation of an evidence-based responder index to measure disease activity, the discovery of genetic markers that may help predict the clinical outcome of patients who are treated with existing therapies, and the introduction of new guidelines to facilitate and better control clinical trials, according to Dr. Richard Furie, chief of rheumatology and allergy–clinical immunology at North Shore–Long Island Jewish Health System in New York.

In fact, the announcement in July that the monoclonal antibody belimumab showed effectiveness against lupus in the first of two phase III clinical trials—the first drug to ever do so, according to a statement from Human Genome Sciences, which codeveloped the biologic with Glaxo SmithKline—was in some ways a surprise. The drug, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), had nearly been counted out after it failed to meet its primary efficacy end point in a phase II clinical trial, except in a subgroup of patients who experienced a statistically significant improvement in lupus signs and symptoms, according to Dr. Daniel J. Wallace of the University of California, Los Angeles.

Based on extensive post hoc analysis of the phase II data, investigators identified factors that could have contributed to the negative trial and redesigned the study accordingly. The revised trial excluded the 28% of patients in the phase II study who were not seropositive for antinuclear antibodies or anti–double-stranded DNA antibodies; it extended the response time to 52 weeks, and it utilized a new composite end point, called the SLE Responder Index, to measure an individual patient's improvement from baseline, Dr. Wallace explained.

“The new index looks at whether the patient feels better, whether the doctor thinks the patient feels better, and whether there are any new disease manifestations,” Dr. Wallace said. Given the heterogeneous nature of lupus and the longstanding difficulty of assessing disease activity in clinical trials, the responder index “represents a breakthrough for finally utilizing a methodology that enables researchers to demonstrate disease improvement,” he said.

And although the success of the SLE Responder Index is limited to just one data set, “the fact that it worked prospectively and not just post hoc should be encouraging to drug developers,” Dr. Furie said. “Perhaps it will become the standard or at least serve as the foundation for further refinements.”

On the heels of the belimumab announcement was the news that another experimental lupus drug, epratuzumab, performed well in a phase IIB clinical trial. In a 12-week, dose- and regimen-ranging, placebo-controlled study of 227 patients with moderately to severely active lupus, epratuzumab (a humanized anti-CD22 monoclonal antibody) showed a “clinically meaningful” effect over placebo, according to a statement by Belgium's UCB SA, which bought rights to epratuzumab from Immunomedics. Specifically, at week 12, the treatment effect of epratuzumab was nearly 25%, compared with placebo, the report noted.

If one or both of these new drugs ultimately receive Food and Drug Administration approval for the treatment of lupus, they most likely will be used initially in patients who have chronically active disease despite treatment with steroids or other immunosuppressive therapies, according to Dr. Wallace. “Belimumab in particular does not work fast. It is not a replacement for corticosteroids in the treatment of acute disease.”

If approved, belimumab will be a major advance for those with moderate or inadequately controlled disease activity who require prednisone, because it may enable lower corticosteroid doses, said Dr. Michelle Petri, professor of rheumatology at Johns Hopkins University, Baltimore.

“The reality is prednisone is not going away. Approximately 80% of our lupus patients are on it—and for good reason, as it remains the most effective immunosuppressive therapy we have for the disease, and it works fast. The problem is that nearly 80% of organ damage in lupus is directly or indirectly due to steroids,” Dr. Petri said at the annual meeting of the European Congress of Rheumatology this year in Copenhagen.

The risk for prednisone-associated organ damage increases by an order of magnitude as the cumulative dose increases, said Dr. Petri, referring to a recent study in which she and Mae Thamer, Ph.D., from the Medical Technology and Practice Patterns Institute in Bethesda, Md., evaluated the effect of corticosteroid use in 525 patients with incident SLE who were enrolled in the Hopkins Lupus Cohort. Using a marginal structural model to adjust for time-dependent confounding associated with disease activity, the investigators determined that patients who received cumulative doses of prednisone in the lowest range (0-180 mg/month) had only a small increased risk of irreversible organ damage, compared with nonprednisone use (hazard ratio 1.16), whereas the risk among those receiving cumulative doses in the highest range (more than 540 mg/month) was more than doubled (HR 2.51). The hazard ratios for the middle-range doses (180-360 mg/month and 360-540 mg/month) were 1.50 and 1.64, respectively (J. Rheumatol. 2009; 36:560-64).

“When you look at the models, it's pretty clear that when the prednisone gets above 11 mg daily, there is a huge increase in the hazard ratio for organ damage,” Dr. Petri said. “That is when to start to think about adding other therapies, if you haven't already, to achieve better control of disease activity and to limit the prednisone dose.” It is at this point, she noted, that the expansion of treatment options is needed.

With respect to other steroid-sparing options, however, the “ideal” immunomodulatory therapy in lupus continues to be the antimalarial hydroxychloroquine (Plaquenil), Dr. Petri said. Hydroxychloroquine “has been shown to prevent severe flares in lupus. It also reduces the risk of lupus nephritis, organ damage, cardiovascular risk factors, and thrombosis, and it improves survival.” In reality, she added, “if we could just convince our patients to stay on Plaquenil, I don't think we would need as much immunosuppressive therapy.”

In fact, hydroxychloroquine is undergoing a rebirth of sorts, according to Dr. Furie. “Many people believe that all SLE patients should be on this drug. It's effective and fairly benign, and we are learning that it has pleiotropic effects,” he said, including protection against thrombotic events and a beneficial effect on lipid profiles, which could potentially help reduce SLE patients' high risk of cardiovascular disease.

The recent finding by Spanish investigators that antimalarial drugs are more effective in SLE patients with polymorphisms on the tumor necrosis factor–alpha (TNF-alpha) and interleukin-10 (IL-10) genes associated with unusually high TNF-alpha levels and unusually low IL-10 levels may eventually allow the identification of lupus patients who are the most likely to benefit from antimalarial therapy (J. Rheumatol. 2008;35:1559-66).

Finally, the lupus research community is encouraged by the development of new recommendations for monitoring SLE in clinical practice, which were introduced at the annual European Congress of Rheumatology this year by Dr. Marta Mosca of the University of Pisa (Italy), the lead author of the recommendation paper, which is slated for publication in the Annals of the Rheumatic Diseases later this year. The guidelines are intended to provide a “road map” for clinicians in terms of assessing disease activity, kidney and other organ involvement, comorbidities, and the various cardiovascular, ophthalmologic, neuropsychiatric, and other risks associated with SLE and its treatment.

“The guidelines will be an important tool for helping rheumatologists make clinical management decisions,” Dr. Mosca said. “As new therapies are developed, the guidelines will help ensure the quality control of patient care and will allow us to better standardize the collection and comparison of data in observational studies.”

The SLE Responder Index 'represents a breakthrough' in detecting disease improvement.

Source DR. WALLACE

DESTIN, FLA. — Structural, functional, and chemical changes that were observed in the brains of fibromyalgia patients suggest that the clinical symptoms of the chronic pain syndrome may have a neurologic basis, M. Catherine Bushnell, Ph.D., said at the Congress of Clinical Rheumatology.

“Fibromyalgia is very different from other rheumatologic diseases, probably because it isn't a rheumatologic disease,” said Dr. Bushnell, director of the Alan Edwards Centre for Research on Pain at McGill University in Montreal.

Although the diagnosis of fibromyalgia continues to be based on the subjective report of widespread pain and sensitivity to palpation, the identification in recent years of various psychophysical and neurophysiologic alterations in fibromyalgia patients provides evidence that altered CNS physiology may underlie fibromyalgia symptoms, she said.

In addition to the characteristic joint and muscle pains that bring fibromyalgia patients to the rheumatology clinic, multiple studies have shown that these patients are hypersensitive in many ways, Dr. Bushnell said. “In one study, we used heat stimuli on the arms of fibromyalgia and control patients, and compared their reactions over a period of 20 seconds. The fibromyalgia patients graded it as a significantly more intense pain stimulus” than did the healthy controls, she said, noting that similar results were seen in separate studies in which patients and controls rated their response to an injection of hypertonic saline solution into the anterior tibialis muscle and in assessments of auditory and olfactory sensitivity.

Although fibromyalgia patients appear to have altered thresholds to pain, they have normal responses to innocuous sensations. “The threshold for fibromyalgia patients' detection of warmth and cold is not different” than that of healthy controls, said Dr. Bushnell. “But when you ask them to indicate when it becomes painfully hot or painfully cold, they will say it's painful at a lower temperature or higher temperature.”

These findings suggest that “an endogenous pain modulatory system in the brain is not working,” Dr. Bushnell said, “which is what more and more researchers who study this think about fibromyalgia: that it is not only a problem of the brain, but specifically that it is a problem of the normal modulatory system.”

Hallmark changes in brain anatomy have also been linked to fibromyalgia. “The most commonly observed change is a decrease in brain gray matter relative to healthy controls,” Dr. Bushnell said. One 2007 study comparing total brain gray matter volume in 10 fibromyalgia patients and 10 healthy controls showed that the fibromyalgia patients had a more than threefold greater age-associated decrease (J. Neurosci. 2007;27:4004-7).

“The longer the disease duration, the greater the gray matter loss,” Dr. Bushnell noted. “Each year of fibromyalgia was equivalent to approximately 9.5 times the gray matter loss seen in normal aging.” Analyses of regional gray matter density showed that the regions of gray matter loss were those associated with pain modulation or stress, including the cingulate, insular, and medial frontal cortices, parahippocampal gyri, and thalamus.

The observed gray matter changes are not unique to fibromyalgia patients. “In fact, similar changes have been observed in the brains of other patients with chronic pain syndromes, including chronic tension-type headaches and irritable bowel syndrome,” said Dr. Bushnell. “This suggests that the pathology in the brain in fibromyalgia patients is linked to their experience of pain.”

Changes in white matter tracts of fibromyalgia patients have also been observed. A recent German study in which investigators used a combination of magnetic resonance diffusion-tensor imaging (MR-DTI) and MR imaging of voxel-based morphometry (MR-VBM) demonstrated microstructural and volume changes in the central neuronal networks involved in the sensory-discriminative and affective-motivational characteristics of pain, anxiety, memory, and regulation of the stress response, Dr. Bushnell said. According to the study investigators, the results revealed that the organization of cerebral microstructures is more complex and active in the areas of the brain involved in pain processing, emotion, and the stress response (Arthritis Rheum. 2008;58:3960-9).

In addition to anatomical abnormalities, studies of brain neurochemistry in fibromyalgia patients have linked changes in this domain to patients' experience of pain, Dr. Bushnell said. In a study designed to evaluate the release of dopamine (which has a role in pain modulation) in response to muscle pain among fibromyalgia patients, she and her colleagues used PET to examine the binding potential of a specific dopamine receptor in the brains of fibromyalgia and healthy controls during an injection of a painful hypertonic saline and nonpainful normal saline. The control subjects released dopamine in the basal ganglia during the painful stimulation, whereas the fibromyalgia patients did not. The amount of dopamine release correlated with the amount of perceived pain in the healthy controls only, indicating that fibromyalgia patients have an abnormal dopamine response to pain (Eur. J. Neurosci. 2007;25:3576-82).

More recently, researchers have demonstrated disruptions in the mu-opioid binding potential in brain regions that are known to play a role in pain modulation (J. Neurosci. 2007;27:10,000-6), as well as correlations between the clinical features of fibromyalgia and hippocampal metabolite abnormalities (J. Pain 2009;10:47-52) and between dopamine metabolism and changes in graymatter density (J. Pain 2009;10:609-18).

The brain changes in fibromyalgia may have an impact on the emotional and cognitive status of fibromyalgia patients. “Fibromyalgia patients routinely complain of what they call 'fibrofog.' They can't think straight, they can't remember things, and in fact studies have shown deficits on various cognitive performance tests, particularly in working-memory capacity, long-term memory, and verbal fluency,” Dr. Bushnell said. “When our data came out showing the changes in gray matter in fibromyalgia, I started getting e-mails from patients saying, 'That makes sense. I now know why I'm feeling this way.' We don't know yet if there is a relationship there, but it's something we're studying.”

Additionally, she noted, “there has been one small study so far showing a correlation between some of the anatomical changes in the brain and cognitive deficits, which suggests that it's possible that some of these neurological and chemical changes in the brain may underlie these various symptoms” (Brain 2008;131:3222-31).

Based on the research to date, “we know that fibromyalgia patients have altered pain processing, loss of brain gray matter, changes in white matter tracts, changes in neurochemical function, and cognitive deficits,” Dr. Bushnell said. Despite all of the brain alterations, however, it's still not clear whether fibromyalgia is a primary disorder of the brain.

“It might be a consequence of early life stress or prolonged or severe stress, which in turn affects brain function and structure in some people,” she said. “More data are accumulating from chronic pain studies suggesting that the longer the pain goes on, the more anatomical changes you see in the brain, indicating that the brain changes may be related to the duration of pain, so it is probably very important that treatment begins as early as possible.”

Dr. Bushnell has served as a consultant for and received research support from several pharmaceutical companies and is a member of the speakers bureau for Eli Lilly & Co.

DESTIN, FLA. — Structural, functional, and chemical changes that were observed in the brains of fibromyalgia patients suggest that the clinical symptoms of the chronic pain syndrome may have a neurologic basis, M. Catherine Bushnell, Ph.D., said at the Congress of Clinical Rheumatology.

“Fibromyalgia is very different from other rheumatologic diseases, probably because it isn't a rheumatologic disease,” said Dr. Bushnell, director of the Alan Edwards Centre for Research on Pain at McGill University in Montreal.

Although the diagnosis of fibromyalgia continues to be based on the subjective report of widespread pain and sensitivity to palpation, the identification in recent years of various psychophysical and neurophysiologic alterations in fibromyalgia patients provides evidence that altered CNS physiology may underlie fibromyalgia symptoms, she said.

In addition to the characteristic joint and muscle pains that bring fibromyalgia patients to the rheumatology clinic, multiple studies have shown that these patients are hypersensitive in many ways, Dr. Bushnell said. “In one study, we used heat stimuli on the arms of fibromyalgia and control patients, and compared their reactions over a period of 20 seconds. The fibromyalgia patients graded it as a significantly more intense pain stimulus” than did the healthy controls, she said, noting that similar results were seen in separate studies in which patients and controls rated their response to an injection of hypertonic saline solution into the anterior tibialis muscle and in assessments of auditory and olfactory sensitivity.

Although fibromyalgia patients appear to have altered thresholds to pain, they have normal responses to innocuous sensations. “The threshold for fibromyalgia patients' detection of warmth and cold is not different” than that of healthy controls, said Dr. Bushnell. “But when you ask them to indicate when it becomes painfully hot or painfully cold, they will say it's painful at a lower temperature or higher temperature.”

These findings suggest that “an endogenous pain modulatory system in the brain is not working,” Dr. Bushnell said, “which is what more and more researchers who study this think about fibromyalgia: that it is not only a problem of the brain, but specifically that it is a problem of the normal modulatory system.”

Hallmark changes in brain anatomy have also been linked to fibromyalgia. “The most commonly observed change is a decrease in brain gray matter relative to healthy controls,” Dr. Bushnell said. One 2007 study comparing total brain gray matter volume in 10 fibromyalgia patients and 10 healthy controls showed that the fibromyalgia patients had a more than threefold greater age-associated decrease (J. Neurosci. 2007;27:4004-7).

“The longer the disease duration, the greater the gray matter loss,” Dr. Bushnell noted. “Each year of fibromyalgia was equivalent to approximately 9.5 times the gray matter loss seen in normal aging.” Analyses of regional gray matter density showed that the regions of gray matter loss were those associated with pain modulation or stress, including the cingulate, insular, and medial frontal cortices, parahippocampal gyri, and thalamus.

The observed gray matter changes are not unique to fibromyalgia patients. “In fact, similar changes have been observed in the brains of other patients with chronic pain syndromes, including chronic tension-type headaches and irritable bowel syndrome,” said Dr. Bushnell. “This suggests that the pathology in the brain in fibromyalgia patients is linked to their experience of pain.”

Changes in white matter tracts of fibromyalgia patients have also been observed. A recent German study in which investigators used a combination of magnetic resonance diffusion-tensor imaging (MR-DTI) and MR imaging of voxel-based morphometry (MR-VBM) demonstrated microstructural and volume changes in the central neuronal networks involved in the sensory-discriminative and affective-motivational characteristics of pain, anxiety, memory, and regulation of the stress response, Dr. Bushnell said. According to the study investigators, the results revealed that the organization of cerebral microstructures is more complex and active in the areas of the brain involved in pain processing, emotion, and the stress response (Arthritis Rheum. 2008;58:3960-9).

In addition to anatomical abnormalities, studies of brain neurochemistry in fibromyalgia patients have linked changes in this domain to patients' experience of pain, Dr. Bushnell said. In a study designed to evaluate the release of dopamine (which has a role in pain modulation) in response to muscle pain among fibromyalgia patients, she and her colleagues used PET to examine the binding potential of a specific dopamine receptor in the brains of fibromyalgia and healthy controls during an injection of a painful hypertonic saline and nonpainful normal saline. The control subjects released dopamine in the basal ganglia during the painful stimulation, whereas the fibromyalgia patients did not. The amount of dopamine release correlated with the amount of perceived pain in the healthy controls only, indicating that fibromyalgia patients have an abnormal dopamine response to pain (Eur. J. Neurosci. 2007;25:3576-82).

More recently, researchers have demonstrated disruptions in the mu-opioid binding potential in brain regions that are known to play a role in pain modulation (J. Neurosci. 2007;27:10,000-6), as well as correlations between the clinical features of fibromyalgia and hippocampal metabolite abnormalities (J. Pain 2009;10:47-52) and between dopamine metabolism and changes in graymatter density (J. Pain 2009;10:609-18).

The brain changes in fibromyalgia may have an impact on the emotional and cognitive status of fibromyalgia patients. “Fibromyalgia patients routinely complain of what they call 'fibrofog.' They can't think straight, they can't remember things, and in fact studies have shown deficits on various cognitive performance tests, particularly in working-memory capacity, long-term memory, and verbal fluency,” Dr. Bushnell said. “When our data came out showing the changes in gray matter in fibromyalgia, I started getting e-mails from patients saying, 'That makes sense. I now know why I'm feeling this way.' We don't know yet if there is a relationship there, but it's something we're studying.”

Additionally, she noted, “there has been one small study so far showing a correlation between some of the anatomical changes in the brain and cognitive deficits, which suggests that it's possible that some of these neurological and chemical changes in the brain may underlie these various symptoms” (Brain 2008;131:3222-31).

Based on the research to date, “we know that fibromyalgia patients have altered pain processing, loss of brain gray matter, changes in white matter tracts, changes in neurochemical function, and cognitive deficits,” Dr. Bushnell said. Despite all of the brain alterations, however, it's still not clear whether fibromyalgia is a primary disorder of the brain.

“It might be a consequence of early life stress or prolonged or severe stress, which in turn affects brain function and structure in some people,” she said. “More data are accumulating from chronic pain studies suggesting that the longer the pain goes on, the more anatomical changes you see in the brain, indicating that the brain changes may be related to the duration of pain, so it is probably very important that treatment begins as early as possible.”

Dr. Bushnell has served as a consultant for and received research support from several pharmaceutical companies and is a member of the speakers bureau for Eli Lilly & Co.

DESTIN, FLA. — Structural, functional, and chemical changes that were observed in the brains of fibromyalgia patients suggest that the clinical symptoms of the chronic pain syndrome may have a neurologic basis, M. Catherine Bushnell, Ph.D., said at the Congress of Clinical Rheumatology.

“Fibromyalgia is very different from other rheumatologic diseases, probably because it isn't a rheumatologic disease,” said Dr. Bushnell, director of the Alan Edwards Centre for Research on Pain at McGill University in Montreal.

Although the diagnosis of fibromyalgia continues to be based on the subjective report of widespread pain and sensitivity to palpation, the identification in recent years of various psychophysical and neurophysiologic alterations in fibromyalgia patients provides evidence that altered CNS physiology may underlie fibromyalgia symptoms, she said.

In addition to the characteristic joint and muscle pains that bring fibromyalgia patients to the rheumatology clinic, multiple studies have shown that these patients are hypersensitive in many ways, Dr. Bushnell said. “In one study, we used heat stimuli on the arms of fibromyalgia and control patients, and compared their reactions over a period of 20 seconds. The fibromyalgia patients graded it as a significantly more intense pain stimulus” than did the healthy controls, she said, noting that similar results were seen in separate studies in which patients and controls rated their response to an injection of hypertonic saline solution into the anterior tibialis muscle and in assessments of auditory and olfactory sensitivity.

Although fibromyalgia patients appear to have altered thresholds to pain, they have normal responses to innocuous sensations. “The threshold for fibromyalgia patients' detection of warmth and cold is not different” than that of healthy controls, said Dr. Bushnell. “But when you ask them to indicate when it becomes painfully hot or painfully cold, they will say it's painful at a lower temperature or higher temperature.”

These findings suggest that “an endogenous pain modulatory system in the brain is not working,” Dr. Bushnell said, “which is what more and more researchers who study this think about fibromyalgia: that it is not only a problem of the brain, but specifically that it is a problem of the normal modulatory system.”

Hallmark changes in brain anatomy have also been linked to fibromyalgia. “The most commonly observed change is a decrease in brain gray matter relative to healthy controls,” Dr. Bushnell said. One 2007 study comparing total brain gray matter volume in 10 fibromyalgia patients and 10 healthy controls showed that the fibromyalgia patients had a more than threefold greater age-associated decrease (J. Neurosci. 2007;27:4004-7).

“The longer the disease duration, the greater the gray matter loss,” Dr. Bushnell noted. “Each year of fibromyalgia was equivalent to approximately 9.5 times the gray matter loss seen in normal aging.” Analyses of regional gray matter density showed that the regions of gray matter loss were those associated with pain modulation or stress, including the cingulate, insular, and medial frontal cortices, parahippocampal gyri, and thalamus.

The observed gray matter changes are not unique to fibromyalgia patients. “In fact, similar changes have been observed in the brains of other patients with chronic pain syndromes, including chronic tension-type headaches and irritable bowel syndrome,” said Dr. Bushnell. “This suggests that the pathology in the brain in fibromyalgia patients is linked to their experience of pain.”

Changes in white matter tracts of fibromyalgia patients have also been observed. A recent German study in which investigators used a combination of magnetic resonance diffusion-tensor imaging (MR-DTI) and MR imaging of voxel-based morphometry (MR-VBM) demonstrated microstructural and volume changes in the central neuronal networks involved in the sensory-discriminative and affective-motivational characteristics of pain, anxiety, memory, and regulation of the stress response, Dr. Bushnell said. According to the study investigators, the results revealed that the organization of cerebral microstructures is more complex and active in the areas of the brain involved in pain processing, emotion, and the stress response (Arthritis Rheum. 2008;58:3960-9).

In addition to anatomical abnormalities, studies of brain neurochemistry in fibromyalgia patients have linked changes in this domain to patients' experience of pain, Dr. Bushnell said. In a study designed to evaluate the release of dopamine (which has a role in pain modulation) in response to muscle pain among fibromyalgia patients, she and her colleagues used PET to examine the binding potential of a specific dopamine receptor in the brains of fibromyalgia and healthy controls during an injection of a painful hypertonic saline and nonpainful normal saline. The control subjects released dopamine in the basal ganglia during the painful stimulation, whereas the fibromyalgia patients did not. The amount of dopamine release correlated with the amount of perceived pain in the healthy controls only, indicating that fibromyalgia patients have an abnormal dopamine response to pain (Eur. J. Neurosci. 2007;25:3576-82).

More recently, researchers have demonstrated disruptions in the mu-opioid binding potential in brain regions that are known to play a role in pain modulation (J. Neurosci. 2007;27:10,000-6), as well as correlations between the clinical features of fibromyalgia and hippocampal metabolite abnormalities (J. Pain 2009;10:47-52) and between dopamine metabolism and changes in graymatter density (J. Pain 2009;10:609-18).

The brain changes in fibromyalgia may have an impact on the emotional and cognitive status of fibromyalgia patients. “Fibromyalgia patients routinely complain of what they call 'fibrofog.' They can't think straight, they can't remember things, and in fact studies have shown deficits on various cognitive performance tests, particularly in working-memory capacity, long-term memory, and verbal fluency,” Dr. Bushnell said. “When our data came out showing the changes in gray matter in fibromyalgia, I started getting e-mails from patients saying, 'That makes sense. I now know why I'm feeling this way.' We don't know yet if there is a relationship there, but it's something we're studying.”

Additionally, she noted, “there has been one small study so far showing a correlation between some of the anatomical changes in the brain and cognitive deficits, which suggests that it's possible that some of these neurological and chemical changes in the brain may underlie these various symptoms” (Brain 2008;131:3222-31).

Based on the research to date, “we know that fibromyalgia patients have altered pain processing, loss of brain gray matter, changes in white matter tracts, changes in neurochemical function, and cognitive deficits,” Dr. Bushnell said. Despite all of the brain alterations, however, it's still not clear whether fibromyalgia is a primary disorder of the brain.

“It might be a consequence of early life stress or prolonged or severe stress, which in turn affects brain function and structure in some people,” she said. “More data are accumulating from chronic pain studies suggesting that the longer the pain goes on, the more anatomical changes you see in the brain, indicating that the brain changes may be related to the duration of pain, so it is probably very important that treatment begins as early as possible.”

Dr. Bushnell has served as a consultant for and received research support from several pharmaceutical companies and is a member of the speakers bureau for Eli Lilly & Co.

BOSTON — Data suggesting that pregnant women with psoriasis have poorer outcomes than those without it highlight the need for more research to determine whether the outcome discrepancies are a function of the disease itself, comorbidities, or treatment side effects, according to Dr. Alexa Boer Kimball.

“We know that pregnancy can have an impact on psoriasis—studies have shown that about 50% of women report improvements; 15%-25% worsen; and the rest don't change—but we know less about the effect of psoriasis on pregnancy,” said Dr. Kimball of the department of dermatology at Harvard Medical School in Boston.

In a case-control study of 145 live births in women with psoriasis between 1998 and 2004, investigators at Ben Gurion University of the Negev in Beer-Sheva, Israel, demonstrated an association between pregnancy complications and psoriasis. Specifically, recurrent abortions and chronic hypertension were significantly associated with psoriasis in a multivariate analysis, and psoriasis was an independent risk factor for cesarean delivery (J. Reprod. Med. 2008;53:183–7).

“The findings are not really surprising when you think about the [inflammatory bowel disease] literature and the lupus literature, for example. It's clear that systemic autoimmune diseases can have adverse effects on pregnancies,” Dr. Kimball said at the American Academy of Dermatology's Academy 2009 meeting.

“Unfortunately, our knowledge about pregnancy outcomes in psoriasis is very limited, which in turn limits the treatment guidance that we can offer.” This is due, she said, to the dearth of literature on the topic, the exclusion of pregnant women from most clinical trials, and the low enrollment in pregnancy registries.

Further, said Dr. Kimball, the various regulatory agencies are not consistent in interpreting numerical data regarding drug safety in pregnancy.

In one study comparing the pregnancy risk classification of 236 commonly used drugs by three international regulatory agencies—the U.S. Food and Drug Administration, the Australian Drug Evaluation Committee, and the Swedish Catalogue of Approved Drugs—only 26% of the drugs were placed into the same risk category, she said (Drug Saf. 2000;23:245–53).

“Theoretically, these groups should be looking at the same data and arriving at essentially the same conclusions. The fact that they're not tells you that there is a substantial subjective review component to how we evaluate this information,” she said.

For these reasons, providing therapeutic guidance to pregnant women with psoriasis is “incredibly challenging,” Dr. Kimball said. The challenge is exacerbated by several social and environmental considerations, including the fact that “women today are under extraordinary pressure not to expose their babies to unknown and unnecessary risks, which may make them more likely to forego therapy that they might actually need,” she said. “In counseling these patients, there really obviously has to be a very open communication about that, although you really can't make the choice for them. It's a very personal decision about the risks they're willing to take.”

Similarly, there is tremendous pressure on women to breastfeed for long periods of time, which can also have an impact on treatment decisions. “A woman may decide to hold off on treatment while she's breastfeeding, and again that's a personal decision, but recognize that it may be a really substantial sacrifice, and in cases of psoriatic arthritis in particular, it may not be all that good for them over time,” she said.

In addition to helping patients determine how to proceed with treatment once they are pregnant, patient counseling should address exposures that might have already happened. “The critical period in all pregnancies for fetal malformations is early, in the first trimester, and lots of women are exposed to drugs before they even know they're pregnant,” said Dr. Kimball.

“In situations involving major risks, referral to a genetics counselor can be useful, but it's also important to remind patients that, under the best of circumstances, not all pregnancies turn out perfectly. The developmental disorder rate [in the general population] is about 3% at birth and about 8% by age 5. It's important to give that information to women so they don't feel overly guilty about the choices they're making,” she said.

“So what can we actually recommend?” Dr. Kimball asked. “For first-line therapy, moisturizers can be used with reckless abandon, and low-potency topical steroids have been determined to not be a risk.” Systemic steroids, on the other hand, should be avoided in the first trimester because of the association with cleft palate, she said.

The second-line treatment algorithm includes narrow band ultraviolet B (UVB) phototherapy, if feasible, “but this may be a challenge if, for example, the pregnant woman has other kids at home or just doesn't have the flexibility in terms of scheduling,” Dr. Kimball said. “Home UVB is an option, and tanning beds—although problematic for other reasons—in a severe patient might be worth considering if they really have no other options.”

Concern regarding the possibility that folate levels might be affected by light therapy, Dr. Kimball noted, has been put to rest by a new study showing that UVB phototherapy does not influence serum and red cell folate levels in psoriasis (J. Am. Acad. Dermatol. 2009;61:259–62).

The question of heat exposure has not been addressed, however. “There are recommendations against hot tubs and hot baths in the first trimester, for example, because of potential injury to the fetus, so if you have someone way up on the light scale, that might be something worth thinking about.”

Tumor necrosis factor inhibitors fall under third-line therapies. “Obviously we have limited data on these. They are generally risk category B, so most people feel reasonably comfortable if we had to go that direction, but there are potential risks that are unclear,” Dr. Kimball said.

Cyclosporine, which was the therapy of choice prior to the biologics era, is another third-line treatment, said Dr. Kimball. “Although cyclosporine is [risk] category C, we probably have the best information about this drug due to the transplant registries that are out there,” she noted.

It is associated with a low birth rate and prematurity, “so there are known risks associated with it, but malformations do not seem to be an issue.” Systemic steroids in the second and third trimester would be another third-line option if needed, she said.

Among the systemic therapies to avoid in pregnancy are PUVA, which can potentially lead to premature labor or fetal abnormalities; methotrexate, which is a teratogen and immunogen; and systemic retinoids, which are also known teratogens, Dr. Kimball said.

With respect to methotrexate in pregnancy, “the current recommendation extends to males, who should be advised to cease its use for 3 months prior to conception because of theoretical concern about chromosomal abnormalities,” she noted.

Regarding topical therapies, tazarotene, anthralin, calcipotriol, and coal tar should be avoided as well, said Dr. Kimball.

In all cases, putting a patient's risk into context is difficult given the limited and conflicting information that is available, Dr. Kimball said. “At the end of the day, you really have to guide women about the personal nature of these choices,” based on experience and the information that is available.

In order to improve research in this area, it is imperative that health care providers and patient advocacy organizations encourage individuals with psoriasis to enroll in pregnancy registries, Dr. Kimball stressed. “Pregnancy registries are one of our most valuable tools for collecting information about how to best manage and counsel women prepartum, during pregnancy, and post partum, yet they are so [undersubscribed]. This is something that we can help change.”

Dr. Kimball said she has served as a consultant and an investigator for Amgen Inc., Centocor Inc., Abbott Laboratories, NeoStrata Co., and Galderma; she is an investigator for Stiefel Laboratories Inc.; and she has a fellowship program funded by Centocor.

BOSTON — Data suggesting that pregnant women with psoriasis have poorer outcomes than those without it highlight the need for more research to determine whether the outcome discrepancies are a function of the disease itself, comorbidities, or treatment side effects, according to Dr. Alexa Boer Kimball.

“We know that pregnancy can have an impact on psoriasis—studies have shown that about 50% of women report improvements; 15%-25% worsen; and the rest don't change—but we know less about the effect of psoriasis on pregnancy,” said Dr. Kimball of the department of dermatology at Harvard Medical School in Boston.

In a case-control study of 145 live births in women with psoriasis between 1998 and 2004, investigators at Ben Gurion University of the Negev in Beer-Sheva, Israel, demonstrated an association between pregnancy complications and psoriasis. Specifically, recurrent abortions and chronic hypertension were significantly associated with psoriasis in a multivariate analysis, and psoriasis was an independent risk factor for cesarean delivery (J. Reprod. Med. 2008;53:183–7).

“The findings are not really surprising when you think about the [inflammatory bowel disease] literature and the lupus literature, for example. It's clear that systemic autoimmune diseases can have adverse effects on pregnancies,” Dr. Kimball said at the American Academy of Dermatology's Academy 2009 meeting.

“Unfortunately, our knowledge about pregnancy outcomes in psoriasis is very limited, which in turn limits the treatment guidance that we can offer.” This is due, she said, to the dearth of literature on the topic, the exclusion of pregnant women from most clinical trials, and the low enrollment in pregnancy registries.

Further, said Dr. Kimball, the various regulatory agencies are not consistent in interpreting numerical data regarding drug safety in pregnancy.

In one study comparing the pregnancy risk classification of 236 commonly used drugs by three international regulatory agencies—the U.S. Food and Drug Administration, the Australian Drug Evaluation Committee, and the Swedish Catalogue of Approved Drugs—only 26% of the drugs were placed into the same risk category, she said (Drug Saf. 2000;23:245–53).

“Theoretically, these groups should be looking at the same data and arriving at essentially the same conclusions. The fact that they're not tells you that there is a substantial subjective review component to how we evaluate this information,” she said.

For these reasons, providing therapeutic guidance to pregnant women with psoriasis is “incredibly challenging,” Dr. Kimball said. The challenge is exacerbated by several social and environmental considerations, including the fact that “women today are under extraordinary pressure not to expose their babies to unknown and unnecessary risks, which may make them more likely to forego therapy that they might actually need,” she said. “In counseling these patients, there really obviously has to be a very open communication about that, although you really can't make the choice for them. It's a very personal decision about the risks they're willing to take.”

Similarly, there is tremendous pressure on women to breastfeed for long periods of time, which can also have an impact on treatment decisions. “A woman may decide to hold off on treatment while she's breastfeeding, and again that's a personal decision, but recognize that it may be a really substantial sacrifice, and in cases of psoriatic arthritis in particular, it may not be all that good for them over time,” she said.

In addition to helping patients determine how to proceed with treatment once they are pregnant, patient counseling should address exposures that might have already happened. “The critical period in all pregnancies for fetal malformations is early, in the first trimester, and lots of women are exposed to drugs before they even know they're pregnant,” said Dr. Kimball.

“In situations involving major risks, referral to a genetics counselor can be useful, but it's also important to remind patients that, under the best of circumstances, not all pregnancies turn out perfectly. The developmental disorder rate [in the general population] is about 3% at birth and about 8% by age 5. It's important to give that information to women so they don't feel overly guilty about the choices they're making,” she said.

“So what can we actually recommend?” Dr. Kimball asked. “For first-line therapy, moisturizers can be used with reckless abandon, and low-potency topical steroids have been determined to not be a risk.” Systemic steroids, on the other hand, should be avoided in the first trimester because of the association with cleft palate, she said.

The second-line treatment algorithm includes narrow band ultraviolet B (UVB) phototherapy, if feasible, “but this may be a challenge if, for example, the pregnant woman has other kids at home or just doesn't have the flexibility in terms of scheduling,” Dr. Kimball said. “Home UVB is an option, and tanning beds—although problematic for other reasons—in a severe patient might be worth considering if they really have no other options.”

Concern regarding the possibility that folate levels might be affected by light therapy, Dr. Kimball noted, has been put to rest by a new study showing that UVB phototherapy does not influence serum and red cell folate levels in psoriasis (J. Am. Acad. Dermatol. 2009;61:259–62).

The question of heat exposure has not been addressed, however. “There are recommendations against hot tubs and hot baths in the first trimester, for example, because of potential injury to the fetus, so if you have someone way up on the light scale, that might be something worth thinking about.”

Tumor necrosis factor inhibitors fall under third-line therapies. “Obviously we have limited data on these. They are generally risk category B, so most people feel reasonably comfortable if we had to go that direction, but there are potential risks that are unclear,” Dr. Kimball said.

Cyclosporine, which was the therapy of choice prior to the biologics era, is another third-line treatment, said Dr. Kimball. “Although cyclosporine is [risk] category C, we probably have the best information about this drug due to the transplant registries that are out there,” she noted.

It is associated with a low birth rate and prematurity, “so there are known risks associated with it, but malformations do not seem to be an issue.” Systemic steroids in the second and third trimester would be another third-line option if needed, she said.

Among the systemic therapies to avoid in pregnancy are PUVA, which can potentially lead to premature labor or fetal abnormalities; methotrexate, which is a teratogen and immunogen; and systemic retinoids, which are also known teratogens, Dr. Kimball said.

With respect to methotrexate in pregnancy, “the current recommendation extends to males, who should be advised to cease its use for 3 months prior to conception because of theoretical concern about chromosomal abnormalities,” she noted.

Regarding topical therapies, tazarotene, anthralin, calcipotriol, and coal tar should be avoided as well, said Dr. Kimball.

In all cases, putting a patient's risk into context is difficult given the limited and conflicting information that is available, Dr. Kimball said. “At the end of the day, you really have to guide women about the personal nature of these choices,” based on experience and the information that is available.

In order to improve research in this area, it is imperative that health care providers and patient advocacy organizations encourage individuals with psoriasis to enroll in pregnancy registries, Dr. Kimball stressed. “Pregnancy registries are one of our most valuable tools for collecting information about how to best manage and counsel women prepartum, during pregnancy, and post partum, yet they are so [undersubscribed]. This is something that we can help change.”

Dr. Kimball said she has served as a consultant and an investigator for Amgen Inc., Centocor Inc., Abbott Laboratories, NeoStrata Co., and Galderma; she is an investigator for Stiefel Laboratories Inc.; and she has a fellowship program funded by Centocor.

BOSTON — Data suggesting that pregnant women with psoriasis have poorer outcomes than those without it highlight the need for more research to determine whether the outcome discrepancies are a function of the disease itself, comorbidities, or treatment side effects, according to Dr. Alexa Boer Kimball.

“We know that pregnancy can have an impact on psoriasis—studies have shown that about 50% of women report improvements; 15%-25% worsen; and the rest don't change—but we know less about the effect of psoriasis on pregnancy,” said Dr. Kimball of the department of dermatology at Harvard Medical School in Boston.

In a case-control study of 145 live births in women with psoriasis between 1998 and 2004, investigators at Ben Gurion University of the Negev in Beer-Sheva, Israel, demonstrated an association between pregnancy complications and psoriasis. Specifically, recurrent abortions and chronic hypertension were significantly associated with psoriasis in a multivariate analysis, and psoriasis was an independent risk factor for cesarean delivery (J. Reprod. Med. 2008;53:183–7).

“The findings are not really surprising when you think about the [inflammatory bowel disease] literature and the lupus literature, for example. It's clear that systemic autoimmune diseases can have adverse effects on pregnancies,” Dr. Kimball said at the American Academy of Dermatology's Academy 2009 meeting.

“Unfortunately, our knowledge about pregnancy outcomes in psoriasis is very limited, which in turn limits the treatment guidance that we can offer.” This is due, she said, to the dearth of literature on the topic, the exclusion of pregnant women from most clinical trials, and the low enrollment in pregnancy registries.

Further, said Dr. Kimball, the various regulatory agencies are not consistent in interpreting numerical data regarding drug safety in pregnancy.

In one study comparing the pregnancy risk classification of 236 commonly used drugs by three international regulatory agencies—the U.S. Food and Drug Administration, the Australian Drug Evaluation Committee, and the Swedish Catalogue of Approved Drugs—only 26% of the drugs were placed into the same risk category, she said (Drug Saf. 2000;23:245–53).

“Theoretically, these groups should be looking at the same data and arriving at essentially the same conclusions. The fact that they're not tells you that there is a substantial subjective review component to how we evaluate this information,” she said.

For these reasons, providing therapeutic guidance to pregnant women with psoriasis is “incredibly challenging,” Dr. Kimball said. The challenge is exacerbated by several social and environmental considerations, including the fact that “women today are under extraordinary pressure not to expose their babies to unknown and unnecessary risks, which may make them more likely to forego therapy that they might actually need,” she said. “In counseling these patients, there really obviously has to be a very open communication about that, although you really can't make the choice for them. It's a very personal decision about the risks they're willing to take.”

Similarly, there is tremendous pressure on women to breastfeed for long periods of time, which can also have an impact on treatment decisions. “A woman may decide to hold off on treatment while she's breastfeeding, and again that's a personal decision, but recognize that it may be a really substantial sacrifice, and in cases of psoriatic arthritis in particular, it may not be all that good for them over time,” she said.

In addition to helping patients determine how to proceed with treatment once they are pregnant, patient counseling should address exposures that might have already happened. “The critical period in all pregnancies for fetal malformations is early, in the first trimester, and lots of women are exposed to drugs before they even know they're pregnant,” said Dr. Kimball.

“In situations involving major risks, referral to a genetics counselor can be useful, but it's also important to remind patients that, under the best of circumstances, not all pregnancies turn out perfectly. The developmental disorder rate [in the general population] is about 3% at birth and about 8% by age 5. It's important to give that information to women so they don't feel overly guilty about the choices they're making,” she said.

“So what can we actually recommend?” Dr. Kimball asked. “For first-line therapy, moisturizers can be used with reckless abandon, and low-potency topical steroids have been determined to not be a risk.” Systemic steroids, on the other hand, should be avoided in the first trimester because of the association with cleft palate, she said.

The second-line treatment algorithm includes narrow band ultraviolet B (UVB) phototherapy, if feasible, “but this may be a challenge if, for example, the pregnant woman has other kids at home or just doesn't have the flexibility in terms of scheduling,” Dr. Kimball said. “Home UVB is an option, and tanning beds—although problematic for other reasons—in a severe patient might be worth considering if they really have no other options.”

Concern regarding the possibility that folate levels might be affected by light therapy, Dr. Kimball noted, has been put to rest by a new study showing that UVB phototherapy does not influence serum and red cell folate levels in psoriasis (J. Am. Acad. Dermatol. 2009;61:259–62).

The question of heat exposure has not been addressed, however. “There are recommendations against hot tubs and hot baths in the first trimester, for example, because of potential injury to the fetus, so if you have someone way up on the light scale, that might be something worth thinking about.”

Tumor necrosis factor inhibitors fall under third-line therapies. “Obviously we have limited data on these. They are generally risk category B, so most people feel reasonably comfortable if we had to go that direction, but there are potential risks that are unclear,” Dr. Kimball said.

Cyclosporine, which was the therapy of choice prior to the biologics era, is another third-line treatment, said Dr. Kimball. “Although cyclosporine is [risk] category C, we probably have the best information about this drug due to the transplant registries that are out there,” she noted.

It is associated with a low birth rate and prematurity, “so there are known risks associated with it, but malformations do not seem to be an issue.” Systemic steroids in the second and third trimester would be another third-line option if needed, she said.

Among the systemic therapies to avoid in pregnancy are PUVA, which can potentially lead to premature labor or fetal abnormalities; methotrexate, which is a teratogen and immunogen; and systemic retinoids, which are also known teratogens, Dr. Kimball said.

With respect to methotrexate in pregnancy, “the current recommendation extends to males, who should be advised to cease its use for 3 months prior to conception because of theoretical concern about chromosomal abnormalities,” she noted.

Regarding topical therapies, tazarotene, anthralin, calcipotriol, and coal tar should be avoided as well, said Dr. Kimball.

In all cases, putting a patient's risk into context is difficult given the limited and conflicting information that is available, Dr. Kimball said. “At the end of the day, you really have to guide women about the personal nature of these choices,” based on experience and the information that is available.

In order to improve research in this area, it is imperative that health care providers and patient advocacy organizations encourage individuals with psoriasis to enroll in pregnancy registries, Dr. Kimball stressed. “Pregnancy registries are one of our most valuable tools for collecting information about how to best manage and counsel women prepartum, during pregnancy, and post partum, yet they are so [undersubscribed]. This is something that we can help change.”

Dr. Kimball said she has served as a consultant and an investigator for Amgen Inc., Centocor Inc., Abbott Laboratories, NeoStrata Co., and Galderma; she is an investigator for Stiefel Laboratories Inc.; and she has a fellowship program funded by Centocor.

BOSTON — Performance improvement intervention for outpatient care of heart failure patients increases the use of evidence-based, guideline-recommended processes and therapies, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America.

Provision of prompts, pocket cards, check lists, and guideline-based decision-support algorithms significantly increases the likelihood that physicians will use evidence-based therapies, devices, and patient education, according to primary findings from the large-scale, prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

To assess conformity with established heart failure (HF) performance measures based on class I recommendations of the national HF guidelines (Circulation 2005;112:e154–235), the IMPROVE-HF investigators reviewed the charts of 35,000 HF outpatients treated at the study's 167 sites at baseline, then 12 and 24 months after the implementation of the practice-specific process-of-care initiative, said Dr. Yancy of Baylor University Medical Center at Dallas.

The baseline findings suggested suboptimal conformity with performance measures for all of the practices considered, and significant variation in the use of evidence-based, guideline-recommended therapies, especially for women and the elderly. Large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and HF education. In all, only 27% of patients who were assessed with HF at baseline were receiving treatments for which they were eligible, based on the guidelines, Dr. Yancy reported.

But 24 months after the start of the initiative, significantly more patients received treatments for which they were eligible, across nearly all measures, Dr. Yancy said. The largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, from 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%. Use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, and the provision of HF education, also improved significantly.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study is supported by Medtronic Inc.

After 24 months, significantly more patients received treatments for which they were eligible.

Source DR. YANCY

BOSTON — Performance improvement intervention for outpatient care of heart failure patients increases the use of evidence-based, guideline-recommended processes and therapies, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America.

Provision of prompts, pocket cards, check lists, and guideline-based decision-support algorithms significantly increases the likelihood that physicians will use evidence-based therapies, devices, and patient education, according to primary findings from the large-scale, prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

To assess conformity with established heart failure (HF) performance measures based on class I recommendations of the national HF guidelines (Circulation 2005;112:e154–235), the IMPROVE-HF investigators reviewed the charts of 35,000 HF outpatients treated at the study's 167 sites at baseline, then 12 and 24 months after the implementation of the practice-specific process-of-care initiative, said Dr. Yancy of Baylor University Medical Center at Dallas.

The baseline findings suggested suboptimal conformity with performance measures for all of the practices considered, and significant variation in the use of evidence-based, guideline-recommended therapies, especially for women and the elderly. Large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and HF education. In all, only 27% of patients who were assessed with HF at baseline were receiving treatments for which they were eligible, based on the guidelines, Dr. Yancy reported.

But 24 months after the start of the initiative, significantly more patients received treatments for which they were eligible, across nearly all measures, Dr. Yancy said. The largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, from 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%. Use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, and the provision of HF education, also improved significantly.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study is supported by Medtronic Inc.

After 24 months, significantly more patients received treatments for which they were eligible.

Source DR. YANCY

BOSTON — Performance improvement intervention for outpatient care of heart failure patients increases the use of evidence-based, guideline-recommended processes and therapies, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America.

Provision of prompts, pocket cards, check lists, and guideline-based decision-support algorithms significantly increases the likelihood that physicians will use evidence-based therapies, devices, and patient education, according to primary findings from the large-scale, prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

To assess conformity with established heart failure (HF) performance measures based on class I recommendations of the national HF guidelines (Circulation 2005;112:e154–235), the IMPROVE-HF investigators reviewed the charts of 35,000 HF outpatients treated at the study's 167 sites at baseline, then 12 and 24 months after the implementation of the practice-specific process-of-care initiative, said Dr. Yancy of Baylor University Medical Center at Dallas.

The baseline findings suggested suboptimal conformity with performance measures for all of the practices considered, and significant variation in the use of evidence-based, guideline-recommended therapies, especially for women and the elderly. Large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and HF education. In all, only 27% of patients who were assessed with HF at baseline were receiving treatments for which they were eligible, based on the guidelines, Dr. Yancy reported.

But 24 months after the start of the initiative, significantly more patients received treatments for which they were eligible, across nearly all measures, Dr. Yancy said. The largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, from 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%. Use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, and the provision of HF education, also improved significantly.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study is supported by Medtronic Inc.

After 24 months, significantly more patients received treatments for which they were eligible.

Source DR. YANCY

BOSTON — Patients with heart failure do not maintain protective levels of antibody titres following influenza vaccination, leaving this already at-risk population even more vulnerable to influenza-related complications, according to a study presented at the annual scientific meeting of the Heart Failure Society of America.

To determine whether heart failure patients sustain postvaccination influenza seroprotection throughout the flu season, Orly Vardeny, Pharm.D., of the University of Wisconsin at Madison, and colleagues evaluated 62 heart failure patients (median age 57) and 40 healthy controls (median age 49) during the 2006-2007 and 2007-2008 influenza seasons. The investigators measured serum antibody production via hemagglutination inhibition assay before influenza vaccination and 2-4 weeks and 6 months after vaccination, and compared antibody titers to individual vaccine viral strains after flu season to measure the persistence of antibody response.

All participants showed early antibody seroprotection, defined as postvaccination hemagglutination inhibition (HAI) antibody titer greater of at least 40, with similar rates of seroconversion between the heart failure patients and the healthy controls. Antibody titers decreased over time in both groups throughout the influenza season, said Dr. Vardeny. But the decreases observed among the healthy controls did not drop below the threshold of protective levels, whereas those observed in the heart failure patients did, “which made the heart failure patients more susceptible to influenza,” she said.

Specifically, titer levels to the A(H3N2) viral strain fell from a peak of 320 to 60 post season in the healthy controls and from 160 to 30 in the heart failure patients, and titer levels to the A(H1N1) strain fell from 160 to 80 in the healthy controls and from 60 to 30 in the heart failure patients, Dr. Vardeny reported. Titers to the less virulent B-type strain fell similarly in both groups, she noted.

In a study published earlier this year, Dr. Vardeny and her colleagues identified differences in immune responses to influenza vaccination in heart failure patients compared to healthy controls. The investigators determined that patients with heart failure had higher vaccine-induced interleukin-10 concentrations, suggesting a different cytotoxic T-lymphocyte phenotype for vaccine responses, and that heart failure patients mounted a less vigorous antibody immune response to the newest vaccine viral strain than did the healthy controls (J. Card. Fail. 2009;15:368-73).

The findings may help explain the reduced efficacy in heart failure patients of the vaccine targeting the more powerful influenza A strain and they highlight the need for a solution, said Dr. Vardeny. “It's clear that people with heart failure, who are already at risk for influenza-related complications, need better protection against influenza,” she said. Possible solutions that should be considered include higher doses of the vaccine, which might offer season-long seroprotection, or mid-season booster shots, she suggested.

Dr. Vardeny reported having no financial relationships to disclose.

BOSTON — Patients with heart failure do not maintain protective levels of antibody titres following influenza vaccination, leaving this already at-risk population even more vulnerable to influenza-related complications, according to a study presented at the annual scientific meeting of the Heart Failure Society of America.

To determine whether heart failure patients sustain postvaccination influenza seroprotection throughout the flu season, Orly Vardeny, Pharm.D., of the University of Wisconsin at Madison, and colleagues evaluated 62 heart failure patients (median age 57) and 40 healthy controls (median age 49) during the 2006-2007 and 2007-2008 influenza seasons. The investigators measured serum antibody production via hemagglutination inhibition assay before influenza vaccination and 2-4 weeks and 6 months after vaccination, and compared antibody titers to individual vaccine viral strains after flu season to measure the persistence of antibody response.

All participants showed early antibody seroprotection, defined as postvaccination hemagglutination inhibition (HAI) antibody titer greater of at least 40, with similar rates of seroconversion between the heart failure patients and the healthy controls. Antibody titers decreased over time in both groups throughout the influenza season, said Dr. Vardeny. But the decreases observed among the healthy controls did not drop below the threshold of protective levels, whereas those observed in the heart failure patients did, “which made the heart failure patients more susceptible to influenza,” she said.

Specifically, titer levels to the A(H3N2) viral strain fell from a peak of 320 to 60 post season in the healthy controls and from 160 to 30 in the heart failure patients, and titer levels to the A(H1N1) strain fell from 160 to 80 in the healthy controls and from 60 to 30 in the heart failure patients, Dr. Vardeny reported. Titers to the less virulent B-type strain fell similarly in both groups, she noted.

In a study published earlier this year, Dr. Vardeny and her colleagues identified differences in immune responses to influenza vaccination in heart failure patients compared to healthy controls. The investigators determined that patients with heart failure had higher vaccine-induced interleukin-10 concentrations, suggesting a different cytotoxic T-lymphocyte phenotype for vaccine responses, and that heart failure patients mounted a less vigorous antibody immune response to the newest vaccine viral strain than did the healthy controls (J. Card. Fail. 2009;15:368-73).

The findings may help explain the reduced efficacy in heart failure patients of the vaccine targeting the more powerful influenza A strain and they highlight the need for a solution, said Dr. Vardeny. “It's clear that people with heart failure, who are already at risk for influenza-related complications, need better protection against influenza,” she said. Possible solutions that should be considered include higher doses of the vaccine, which might offer season-long seroprotection, or mid-season booster shots, she suggested.

Dr. Vardeny reported having no financial relationships to disclose.

BOSTON — Patients with heart failure do not maintain protective levels of antibody titres following influenza vaccination, leaving this already at-risk population even more vulnerable to influenza-related complications, according to a study presented at the annual scientific meeting of the Heart Failure Society of America.

To determine whether heart failure patients sustain postvaccination influenza seroprotection throughout the flu season, Orly Vardeny, Pharm.D., of the University of Wisconsin at Madison, and colleagues evaluated 62 heart failure patients (median age 57) and 40 healthy controls (median age 49) during the 2006-2007 and 2007-2008 influenza seasons. The investigators measured serum antibody production via hemagglutination inhibition assay before influenza vaccination and 2-4 weeks and 6 months after vaccination, and compared antibody titers to individual vaccine viral strains after flu season to measure the persistence of antibody response.

All participants showed early antibody seroprotection, defined as postvaccination hemagglutination inhibition (HAI) antibody titer greater of at least 40, with similar rates of seroconversion between the heart failure patients and the healthy controls. Antibody titers decreased over time in both groups throughout the influenza season, said Dr. Vardeny. But the decreases observed among the healthy controls did not drop below the threshold of protective levels, whereas those observed in the heart failure patients did, “which made the heart failure patients more susceptible to influenza,” she said.

Specifically, titer levels to the A(H3N2) viral strain fell from a peak of 320 to 60 post season in the healthy controls and from 160 to 30 in the heart failure patients, and titer levels to the A(H1N1) strain fell from 160 to 80 in the healthy controls and from 60 to 30 in the heart failure patients, Dr. Vardeny reported. Titers to the less virulent B-type strain fell similarly in both groups, she noted.

In a study published earlier this year, Dr. Vardeny and her colleagues identified differences in immune responses to influenza vaccination in heart failure patients compared to healthy controls. The investigators determined that patients with heart failure had higher vaccine-induced interleukin-10 concentrations, suggesting a different cytotoxic T-lymphocyte phenotype for vaccine responses, and that heart failure patients mounted a less vigorous antibody immune response to the newest vaccine viral strain than did the healthy controls (J. Card. Fail. 2009;15:368-73).

The findings may help explain the reduced efficacy in heart failure patients of the vaccine targeting the more powerful influenza A strain and they highlight the need for a solution, said Dr. Vardeny. “It's clear that people with heart failure, who are already at risk for influenza-related complications, need better protection against influenza,” she said. Possible solutions that should be considered include higher doses of the vaccine, which might offer season-long seroprotection, or mid-season booster shots, she suggested.

Dr. Vardeny reported having no financial relationships to disclose.

BOSTON — Using a performance improvement intervention for the outpatient care of heart failure patients increases the use of evidence-based, guideline-recommended processes and therapies, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America.

Providing physicians with prompts, pocket cards, check lists, and guidelines-based decision-support algorithms significantly increases the likelihood that they will use evidence-based therapies, devices, and patient education, according to the primary findings from the large-scale, prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

To assess conformity with established heart failure performance measures based on class I recommendations of the national heart failure guidelines published jointly by the American College of Cardiology and the American Heart Association in 2005 (Circulation 2005;112:e154-235), the IMPROVE-HF investigators reviewed the charts of about 35,000 heart failure outpatients who were being treated at the study's 167 sites at baseline and then at 12 months and 24 months after the implementation of the practice-specific process-of-care initiative, said Dr. Yancy of Baylor University Medical Center at Dallas.

The baseline findings suggested suboptimal conformity with performance measures for all of the practices considered, as well as significant variation in the utilization of evidence-based, guideline-recommended therapies, especially for women and the elderly. In particular, large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and heart failure education.

In all, only 27% of patients who were assessed with a heart failure indication at baseline were receiving the treatments for which they were eligible, based on the guidelines, Dr. Yancy said.

But 24 months after the introduction of the performance improvement program, significantly more patients were receiving the treatments for which they were eligible across nearly all measures, Dr. Yancy reported, noting that the largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, which went from being used in 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%.

The use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, as well as the provision of heart failure education, also improved significantly, but the use of anticoagulation therapy in the setting of atrial fibrillation remained the same.

The findings are promising in that they suggest that systematic process improvement is a real possibility, although the study is limited both by the absence of patient outcome data related to the improved adherence to quality measures and by the fact that it was conducted among cardiologists, whereas the majority of outpatient heart failure patients in actual practice are managed in the primary care setting, Dr. Yancy said.

“We don't know yet if we can scale the other 80% of the patient population” who are treated in a primary care setting, he said. Even so, he added, offering practical information and practice-specific disease management tools can help close gaps in heart failure treatment.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study is supported by Medtronic Inc.

The findings suggest that systematic process improvement is a real possibility.

Source DR. YANCY

BOSTON — Using a performance improvement intervention for the outpatient care of heart failure patients increases the use of evidence-based, guideline-recommended processes and therapies, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America.

Providing physicians with prompts, pocket cards, check lists, and guidelines-based decision-support algorithms significantly increases the likelihood that they will use evidence-based therapies, devices, and patient education, according to the primary findings from the large-scale, prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

To assess conformity with established heart failure performance measures based on class I recommendations of the national heart failure guidelines published jointly by the American College of Cardiology and the American Heart Association in 2005 (Circulation 2005;112:e154-235), the IMPROVE-HF investigators reviewed the charts of about 35,000 heart failure outpatients who were being treated at the study's 167 sites at baseline and then at 12 months and 24 months after the implementation of the practice-specific process-of-care initiative, said Dr. Yancy of Baylor University Medical Center at Dallas.

The baseline findings suggested suboptimal conformity with performance measures for all of the practices considered, as well as significant variation in the utilization of evidence-based, guideline-recommended therapies, especially for women and the elderly. In particular, large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and heart failure education.

In all, only 27% of patients who were assessed with a heart failure indication at baseline were receiving the treatments for which they were eligible, based on the guidelines, Dr. Yancy said.

But 24 months after the introduction of the performance improvement program, significantly more patients were receiving the treatments for which they were eligible across nearly all measures, Dr. Yancy reported, noting that the largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, which went from being used in 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%.

The use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, as well as the provision of heart failure education, also improved significantly, but the use of anticoagulation therapy in the setting of atrial fibrillation remained the same.

The findings are promising in that they suggest that systematic process improvement is a real possibility, although the study is limited both by the absence of patient outcome data related to the improved adherence to quality measures and by the fact that it was conducted among cardiologists, whereas the majority of outpatient heart failure patients in actual practice are managed in the primary care setting, Dr. Yancy said.

“We don't know yet if we can scale the other 80% of the patient population” who are treated in a primary care setting, he said. Even so, he added, offering practical information and practice-specific disease management tools can help close gaps in heart failure treatment.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study is supported by Medtronic Inc.

The findings suggest that systematic process improvement is a real possibility.

Source DR. YANCY

BOSTON — Using a performance improvement intervention for the outpatient care of heart failure patients increases the use of evidence-based, guideline-recommended processes and therapies, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America.

Providing physicians with prompts, pocket cards, check lists, and guidelines-based decision-support algorithms significantly increases the likelihood that they will use evidence-based therapies, devices, and patient education, according to the primary findings from the large-scale, prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

To assess conformity with established heart failure performance measures based on class I recommendations of the national heart failure guidelines published jointly by the American College of Cardiology and the American Heart Association in 2005 (Circulation 2005;112:e154-235), the IMPROVE-HF investigators reviewed the charts of about 35,000 heart failure outpatients who were being treated at the study's 167 sites at baseline and then at 12 months and 24 months after the implementation of the practice-specific process-of-care initiative, said Dr. Yancy of Baylor University Medical Center at Dallas.

The baseline findings suggested suboptimal conformity with performance measures for all of the practices considered, as well as significant variation in the utilization of evidence-based, guideline-recommended therapies, especially for women and the elderly. In particular, large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and heart failure education.

In all, only 27% of patients who were assessed with a heart failure indication at baseline were receiving the treatments for which they were eligible, based on the guidelines, Dr. Yancy said.

But 24 months after the introduction of the performance improvement program, significantly more patients were receiving the treatments for which they were eligible across nearly all measures, Dr. Yancy reported, noting that the largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, which went from being used in 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%.

The use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, as well as the provision of heart failure education, also improved significantly, but the use of anticoagulation therapy in the setting of atrial fibrillation remained the same.

The findings are promising in that they suggest that systematic process improvement is a real possibility, although the study is limited both by the absence of patient outcome data related to the improved adherence to quality measures and by the fact that it was conducted among cardiologists, whereas the majority of outpatient heart failure patients in actual practice are managed in the primary care setting, Dr. Yancy said.

“We don't know yet if we can scale the other 80% of the patient population” who are treated in a primary care setting, he said. Even so, he added, offering practical information and practice-specific disease management tools can help close gaps in heart failure treatment.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study is supported by Medtronic Inc.

The findings suggest that systematic process improvement is a real possibility.

Source DR. YANCY

BOSTON — A performance-improvement intervention for the outpatient care of heart failure patients increased the use of evidence-based treatment in the prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

The investigators reviewed the charts of 35,000 HF outpatients treated at the study's 167 sites at baseline, then 12 and 24 months after implementation of a practice-specific process-of-care initiative, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America. A baseline assessment suggested suboptimal conformity with established heart failure (HF) performance measures for all of the practices, based on class I recommendations of the national HF guidelines (Circulation 2005;112:e154–235). The use of evidence-based, guideline-recommended therapies varied significantly, especially for women and the elderly.

Large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and HF education. In all, only 27% of patients with HF at baseline were receiving treatments for which they were eligible, based on the guidelines, said Dr. Yancy of Baylor University Medical Center at Dallas.

But 24 months after the start of the performance improvement program, which included prompts, pocket cards, checklists, and decision-support algorithms, significantly more patients received treatments for which they were eligible, across nearly all measures. The largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, from 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%. The use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, and the provision of HF education, also improved significantly, Dr. Yancy reported.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study was supported by Medtronic Inc.

BOSTON — A performance-improvement intervention for the outpatient care of heart failure patients increased the use of evidence-based treatment in the prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

The investigators reviewed the charts of 35,000 HF outpatients treated at the study's 167 sites at baseline, then 12 and 24 months after implementation of a practice-specific process-of-care initiative, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America. A baseline assessment suggested suboptimal conformity with established heart failure (HF) performance measures for all of the practices, based on class I recommendations of the national HF guidelines (Circulation 2005;112:e154–235). The use of evidence-based, guideline-recommended therapies varied significantly, especially for women and the elderly.

Large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and HF education. In all, only 27% of patients with HF at baseline were receiving treatments for which they were eligible, based on the guidelines, said Dr. Yancy of Baylor University Medical Center at Dallas.

But 24 months after the start of the performance improvement program, which included prompts, pocket cards, checklists, and decision-support algorithms, significantly more patients received treatments for which they were eligible, across nearly all measures. The largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, from 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%. The use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, and the provision of HF education, also improved significantly, Dr. Yancy reported.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study was supported by Medtronic Inc.

BOSTON — A performance-improvement intervention for the outpatient care of heart failure patients increased the use of evidence-based treatment in the prospective IMPROVE-HF (Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) study.

The investigators reviewed the charts of 35,000 HF outpatients treated at the study's 167 sites at baseline, then 12 and 24 months after implementation of a practice-specific process-of-care initiative, Dr. Clyde W. Yancy said at the annual meeting of the Heart Failure Society of America. A baseline assessment suggested suboptimal conformity with established heart failure (HF) performance measures for all of the practices, based on class I recommendations of the national HF guidelines (Circulation 2005;112:e154–235). The use of evidence-based, guideline-recommended therapies varied significantly, especially for women and the elderly.

Large variations were observed in the use of anticoagulation for atrial fibrillation, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and HF education. In all, only 27% of patients with HF at baseline were receiving treatments for which they were eligible, based on the guidelines, said Dr. Yancy of Baylor University Medical Center at Dallas.

But 24 months after the start of the performance improvement program, which included prompts, pocket cards, checklists, and decision-support algorithms, significantly more patients received treatments for which they were eligible, across nearly all measures. The largest changes were observed in the use of ICDs, aldosterone receptor antagonists, and CRT, from 39%, 35%, and 50% of eligible patients, respectively, to 68%, 60%, and 56%. The use of ACE inhibitors or angiotensin receptor blockers and beta-blockers, and the provision of HF education, also improved significantly, Dr. Yancy reported.

Dr. Yancy reported having no financial disclosures relative to his presentation. The IMPROVE-HF study was supported by Medtronic Inc.

BOSTON — Monitoring fluid build-up in the chest by intrathoracic impedance is more predictive of events in heart failure patients compared with daily weight monitoring, according to the findings of a multicenter, prospective, double-blind investigation.

Still, experts agreed that the results do not suggest that impedance monitoring can replace daily weight monitoring of heart failure patients as a means for predicting events and guiding therapy.

Dr. William T. Abraham of Ohio State University in Columbus and his colleagues conducted the Fluid Accumulation Status Trial (FAST), comparing the results of intrathoracic impedance monitoring with those attained through daily weight monitoring—the current standard of care—in 156 heart failure patients.

The investigators used a drop in intrathoracic impedance as a surrogate for identifying presymptomatic, treatable fluid build-up. Changes in impedance were detected with the help of software that had been downloaded onto the patients' implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy defibrillator (CRT-D) devices.

The participants all had heart failure symptoms for a mean of 18 months. At baseline, 85% were in New York Heart Association (NYHA) class II or III and most of the rest were in NYHA class I, he reported in a late-breaking abstract presented at the annual meeting of the Heart Failure Society of America.

The investigators compared the data collected by the impedance monitoring software with data collected by patient-completed daily weight diaries. While the impedance data were available for nearly every day of the trial, only 76% of the patients complied with daily weight monitoring, Dr. Abraham said.

Of the 65 heart failure events that occurred in 31 patients, intrathoracic impedance monitoring accurately predicted 48 of the events, compared with just 13 of the events predicted by daily weight monitoring. “The adjusted sensitivity for [impedance monitoring] was more than three times higher than with daily weight monitoring,” at 76% and 23%, respectively, he reported.

Of the predicted events, 40 of those detected by impedance monitoring were not detected by weight monitoring and 5 of those detected by weight monitoring were not detected by fluid monitoring, Dr. Abraham said.

Both impedance and weight monitoring set off many false alarms. The impedance monitoring system identified 417 “impedance crossings,” which are the signals predicting a heart failure event, while there were 890 changes in weight that met the warning level criteria (at least 3 pounds gained in 1 day or at least 5 pounds gained over 3 days), Dr. Abraham reported.

“With daily weight [monitoring], you have less sensitivity and more false alarms to respond to,” compared with impedance monitoring, suggesting that impedance status monitoring may be the better option and should be used in addition to the daily weight monitoring in patients with implanted devices that have this capability, he said.

Dr. Abraham didn't suggest doing away with daily weight monitoring as a heart failure maintenance strategy, as it has a proven role in helping predict heart failure progression and in guiding therapy. But he suggested that its reliability and effectiveness should be reevaluated and that other measurement systems be considered.

The FAST study was sponsored by Medtronic Inc., the manufacturer of the OptiVol Fluid Status Monitoring System used in the investigation. Dr. Abraham reported having received research grants and/or consulting fees from Medtronic, Biotronik Inc., Boston Scientific Corporation, and St. Jude Medical, Inc.

BOSTON — Monitoring fluid build-up in the chest by intrathoracic impedance is more predictive of events in heart failure patients compared with daily weight monitoring, according to the findings of a multicenter, prospective, double-blind investigation.

Still, experts agreed that the results do not suggest that impedance monitoring can replace daily weight monitoring of heart failure patients as a means for predicting events and guiding therapy.

Dr. William T. Abraham of Ohio State University in Columbus and his colleagues conducted the Fluid Accumulation Status Trial (FAST), comparing the results of intrathoracic impedance monitoring with those attained through daily weight monitoring—the current standard of care—in 156 heart failure patients.

The investigators used a drop in intrathoracic impedance as a surrogate for identifying presymptomatic, treatable fluid build-up. Changes in impedance were detected with the help of software that had been downloaded onto the patients' implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy defibrillator (CRT-D) devices.

The participants all had heart failure symptoms for a mean of 18 months. At baseline, 85% were in New York Heart Association (NYHA) class II or III and most of the rest were in NYHA class I, he reported in a late-breaking abstract presented at the annual meeting of the Heart Failure Society of America.

The investigators compared the data collected by the impedance monitoring software with data collected by patient-completed daily weight diaries. While the impedance data were available for nearly every day of the trial, only 76% of the patients complied with daily weight monitoring, Dr. Abraham said.

Of the 65 heart failure events that occurred in 31 patients, intrathoracic impedance monitoring accurately predicted 48 of the events, compared with just 13 of the events predicted by daily weight monitoring. “The adjusted sensitivity for [impedance monitoring] was more than three times higher than with daily weight monitoring,” at 76% and 23%, respectively, he reported.

Of the predicted events, 40 of those detected by impedance monitoring were not detected by weight monitoring and 5 of those detected by weight monitoring were not detected by fluid monitoring, Dr. Abraham said.

Both impedance and weight monitoring set off many false alarms. The impedance monitoring system identified 417 “impedance crossings,” which are the signals predicting a heart failure event, while there were 890 changes in weight that met the warning level criteria (at least 3 pounds gained in 1 day or at least 5 pounds gained over 3 days), Dr. Abraham reported.

“With daily weight [monitoring], you have less sensitivity and more false alarms to respond to,” compared with impedance monitoring, suggesting that impedance status monitoring may be the better option and should be used in addition to the daily weight monitoring in patients with implanted devices that have this capability, he said.

Dr. Abraham didn't suggest doing away with daily weight monitoring as a heart failure maintenance strategy, as it has a proven role in helping predict heart failure progression and in guiding therapy. But he suggested that its reliability and effectiveness should be reevaluated and that other measurement systems be considered.

The FAST study was sponsored by Medtronic Inc., the manufacturer of the OptiVol Fluid Status Monitoring System used in the investigation. Dr. Abraham reported having received research grants and/or consulting fees from Medtronic, Biotronik Inc., Boston Scientific Corporation, and St. Jude Medical, Inc.

BOSTON — Monitoring fluid build-up in the chest by intrathoracic impedance is more predictive of events in heart failure patients compared with daily weight monitoring, according to the findings of a multicenter, prospective, double-blind investigation.

Still, experts agreed that the results do not suggest that impedance monitoring can replace daily weight monitoring of heart failure patients as a means for predicting events and guiding therapy.

Dr. William T. Abraham of Ohio State University in Columbus and his colleagues conducted the Fluid Accumulation Status Trial (FAST), comparing the results of intrathoracic impedance monitoring with those attained through daily weight monitoring—the current standard of care—in 156 heart failure patients.

The investigators used a drop in intrathoracic impedance as a surrogate for identifying presymptomatic, treatable fluid build-up. Changes in impedance were detected with the help of software that had been downloaded onto the patients' implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy defibrillator (CRT-D) devices.

The participants all had heart failure symptoms for a mean of 18 months. At baseline, 85% were in New York Heart Association (NYHA) class II or III and most of the rest were in NYHA class I, he reported in a late-breaking abstract presented at the annual meeting of the Heart Failure Society of America.

The investigators compared the data collected by the impedance monitoring software with data collected by patient-completed daily weight diaries. While the impedance data were available for nearly every day of the trial, only 76% of the patients complied with daily weight monitoring, Dr. Abraham said.

Of the 65 heart failure events that occurred in 31 patients, intrathoracic impedance monitoring accurately predicted 48 of the events, compared with just 13 of the events predicted by daily weight monitoring. “The adjusted sensitivity for [impedance monitoring] was more than three times higher than with daily weight monitoring,” at 76% and 23%, respectively, he reported.

Of the predicted events, 40 of those detected by impedance monitoring were not detected by weight monitoring and 5 of those detected by weight monitoring were not detected by fluid monitoring, Dr. Abraham said.

Both impedance and weight monitoring set off many false alarms. The impedance monitoring system identified 417 “impedance crossings,” which are the signals predicting a heart failure event, while there were 890 changes in weight that met the warning level criteria (at least 3 pounds gained in 1 day or at least 5 pounds gained over 3 days), Dr. Abraham reported.

“With daily weight [monitoring], you have less sensitivity and more false alarms to respond to,” compared with impedance monitoring, suggesting that impedance status monitoring may be the better option and should be used in addition to the daily weight monitoring in patients with implanted devices that have this capability, he said.

Dr. Abraham didn't suggest doing away with daily weight monitoring as a heart failure maintenance strategy, as it has a proven role in helping predict heart failure progression and in guiding therapy. But he suggested that its reliability and effectiveness should be reevaluated and that other measurement systems be considered.

The FAST study was sponsored by Medtronic Inc., the manufacturer of the OptiVol Fluid Status Monitoring System used in the investigation. Dr. Abraham reported having received research grants and/or consulting fees from Medtronic, Biotronik Inc., Boston Scientific Corporation, and St. Jude Medical, Inc.

The prevalence of a low-risk profile for cardiovascular disease among adults in the U.S. population has decreased in recent years, suggesting the “huge potential” for preventing cardiovascular disease is far from being realized, according to an analysis of NHANES data.

Using data from four National Health and Nutrition Examination Surveys, Dr. Earl S. Ford, medical officer of the U.S. Public Health Service at the Centers for Disease Control and Prevention, and his colleagues tracked cardiovascular risk data for American adults aged 25-75 years during 1971-1975, 1976-1980, 1988-1994, and 1999-2004, and showed that the prevalence of a low-risk profile increased from 4.4% at the time of the first survey to 10.5% by the third survey, but then decreased to 7.5% in the fourth survey (1999-2004).

The low-risk-factor profile incorporated the following variables: not currently smoking, total cholesterol less than 200 mg/dL without cholesterol-lowering medications, systolic blood pressure less than 120 mm Hg and diastolic blood pressure less than 80 mm Hg without antihypertensive medications, body mass index less than 25 kg/m

“The limited strides that were made toward achieving low-risk status during the 1970s and 1980s have more recently been negated by the obesity epidemic and increased rates of hypertension and diabetes,” Dr. Ford said in an interview. According to the results, “fewer than 10% of Americans are meeting the low-risk goals.”

The low-risk-factor patterns were similar for men and women, but the prevalence of low-risk profiles was higher in women than in men in each of the surveys, the authors reported. Similarly, the low-risk-factor burden was much higher among survey respondents aged 25-44 years than among those aged 45-64 or 65-74 years in all the surveys, and it was higher among whites than blacks during each survey except 1976-1980. During 1988-1994 and 1999-2004 only, a larger percentage of whites had a low-risk-factor burden, compared with Mexican Americans, they wrote.

An analysis of the individual risk categories showed favorable trends for not currently smoking (60% at the time of the first survey and 74% by the fourth survey) and low concentrations of total cholesterol (35% and 43%, respectively). For blood pressure, the low-risk percentage was higher for the period 1988-1994 than for the 1971-1975 period, but it decreased for the period 1999-2004, “which is worrisome,” the authors wrote. Similarly, “the distribution of body mass index progressively deteriorated over time,” they reported, adding that the unfavorable trends “argue for vigorous population-based approaches to reverse the unhealthy shift in the distributions of blood pressure and body mass index and to sustain or accelerate the improvement in the distribution of total cholesterol.”

Because the NHANES surveyed only noninstitutionalized adults, the true risk-factor burdens “may be even worse” than those reported, which is one of the limitations of the study, the authors noted. Additional limitations include the exclusion of physical activity and a dietary index as part of the risk determination, and changes in the wording of questions for use of current antihypertensive medication and physician-diagnosed diabetes that could potentially have affected the estimates, they wrote.

Despite the possible limitations of the study, “our results clearly demonstrate a great need for prevention; thus, health care providers should have adequate resources, time, and reimbursement to engage in the prevention of cardiovascular disease in individuals,” they authors wrote, adding that those efforts should be in concert with those of state and national agencies charged with developing effective public health interventions.

In an editorial, Rob M. van Dam, Ph.D., of the Harvard School of Public Health in Boston, and Dr. Walter C. Willett of Brigham and Women's Hospital in Boston, commented that the trajectory of the risk factor trends is even more worrisome considering the analyses “do not yet reflect the effects of the current epidemic of childhood obesity, which causes an early onset of type 2 diabetes, hypertension, and dyslipidemia” (Circulation 2009 Sept. 14 [doi:10.1161/CirculationAHA.109.891507]).

The findings, they wrote, “provide an important signal that the health of Americans is at a crossroad. The current path leads toward increasing adiposity, diabetes mellitus, cardiovascular disease, and disability and an unfit, socially isolated population stuffed with pills and subjected to frequent palliative procedures.” To change course, they stressed, physicians can help by working with their patients one on one, but “their help is needed even more as leaders in the effort to reshape policies and our environment.”

The authors said they had no financial disclosures related to this report.

The prevalence of a low-risk profile for cardiovascular disease among adults in the U.S. population has decreased in recent years, suggesting the “huge potential” for preventing cardiovascular disease is far from being realized, according to an analysis of NHANES data.

Using data from four National Health and Nutrition Examination Surveys, Dr. Earl S. Ford, medical officer of the U.S. Public Health Service at the Centers for Disease Control and Prevention, and his colleagues tracked cardiovascular risk data for American adults aged 25-75 years during 1971-1975, 1976-1980, 1988-1994, and 1999-2004, and showed that the prevalence of a low-risk profile increased from 4.4% at the time of the first survey to 10.5% by the third survey, but then decreased to 7.5% in the fourth survey (1999-2004).

The low-risk-factor profile incorporated the following variables: not currently smoking, total cholesterol less than 200 mg/dL without cholesterol-lowering medications, systolic blood pressure less than 120 mm Hg and diastolic blood pressure less than 80 mm Hg without antihypertensive medications, body mass index less than 25 kg/m

“The limited strides that were made toward achieving low-risk status during the 1970s and 1980s have more recently been negated by the obesity epidemic and increased rates of hypertension and diabetes,” Dr. Ford said in an interview. According to the results, “fewer than 10% of Americans are meeting the low-risk goals.”

The low-risk-factor patterns were similar for men and women, but the prevalence of low-risk profiles was higher in women than in men in each of the surveys, the authors reported. Similarly, the low-risk-factor burden was much higher among survey respondents aged 25-44 years than among those aged 45-64 or 65-74 years in all the surveys, and it was higher among whites than blacks during each survey except 1976-1980. During 1988-1994 and 1999-2004 only, a larger percentage of whites had a low-risk-factor burden, compared with Mexican Americans, they wrote.

An analysis of the individual risk categories showed favorable trends for not currently smoking (60% at the time of the first survey and 74% by the fourth survey) and low concentrations of total cholesterol (35% and 43%, respectively). For blood pressure, the low-risk percentage was higher for the period 1988-1994 than for the 1971-1975 period, but it decreased for the period 1999-2004, “which is worrisome,” the authors wrote. Similarly, “the distribution of body mass index progressively deteriorated over time,” they reported, adding that the unfavorable trends “argue for vigorous population-based approaches to reverse the unhealthy shift in the distributions of blood pressure and body mass index and to sustain or accelerate the improvement in the distribution of total cholesterol.”

Because the NHANES surveyed only noninstitutionalized adults, the true risk-factor burdens “may be even worse” than those reported, which is one of the limitations of the study, the authors noted. Additional limitations include the exclusion of physical activity and a dietary index as part of the risk determination, and changes in the wording of questions for use of current antihypertensive medication and physician-diagnosed diabetes that could potentially have affected the estimates, they wrote.

Despite the possible limitations of the study, “our results clearly demonstrate a great need for prevention; thus, health care providers should have adequate resources, time, and reimbursement to engage in the prevention of cardiovascular disease in individuals,” they authors wrote, adding that those efforts should be in concert with those of state and national agencies charged with developing effective public health interventions.

In an editorial, Rob M. van Dam, Ph.D., of the Harvard School of Public Health in Boston, and Dr. Walter C. Willett of Brigham and Women's Hospital in Boston, commented that the trajectory of the risk factor trends is even more worrisome considering the analyses “do not yet reflect the effects of the current epidemic of childhood obesity, which causes an early onset of type 2 diabetes, hypertension, and dyslipidemia” (Circulation 2009 Sept. 14 [doi:10.1161/CirculationAHA.109.891507]).

The findings, they wrote, “provide an important signal that the health of Americans is at a crossroad. The current path leads toward increasing adiposity, diabetes mellitus, cardiovascular disease, and disability and an unfit, socially isolated population stuffed with pills and subjected to frequent palliative procedures.” To change course, they stressed, physicians can help by working with their patients one on one, but “their help is needed even more as leaders in the effort to reshape policies and our environment.”

The authors said they had no financial disclosures related to this report.

The prevalence of a low-risk profile for cardiovascular disease among adults in the U.S. population has decreased in recent years, suggesting the “huge potential” for preventing cardiovascular disease is far from being realized, according to an analysis of NHANES data.

Using data from four National Health and Nutrition Examination Surveys, Dr. Earl S. Ford, medical officer of the U.S. Public Health Service at the Centers for Disease Control and Prevention, and his colleagues tracked cardiovascular risk data for American adults aged 25-75 years during 1971-1975, 1976-1980, 1988-1994, and 1999-2004, and showed that the prevalence of a low-risk profile increased from 4.4% at the time of the first survey to 10.5% by the third survey, but then decreased to 7.5% in the fourth survey (1999-2004).

The low-risk-factor profile incorporated the following variables: not currently smoking, total cholesterol less than 200 mg/dL without cholesterol-lowering medications, systolic blood pressure less than 120 mm Hg and diastolic blood pressure less than 80 mm Hg without antihypertensive medications, body mass index less than 25 kg/m

“The limited strides that were made toward achieving low-risk status during the 1970s and 1980s have more recently been negated by the obesity epidemic and increased rates of hypertension and diabetes,” Dr. Ford said in an interview. According to the results, “fewer than 10% of Americans are meeting the low-risk goals.”

The low-risk-factor patterns were similar for men and women, but the prevalence of low-risk profiles was higher in women than in men in each of the surveys, the authors reported. Similarly, the low-risk-factor burden was much higher among survey respondents aged 25-44 years than among those aged 45-64 or 65-74 years in all the surveys, and it was higher among whites than blacks during each survey except 1976-1980. During 1988-1994 and 1999-2004 only, a larger percentage of whites had a low-risk-factor burden, compared with Mexican Americans, they wrote.

An analysis of the individual risk categories showed favorable trends for not currently smoking (60% at the time of the first survey and 74% by the fourth survey) and low concentrations of total cholesterol (35% and 43%, respectively). For blood pressure, the low-risk percentage was higher for the period 1988-1994 than for the 1971-1975 period, but it decreased for the period 1999-2004, “which is worrisome,” the authors wrote. Similarly, “the distribution of body mass index progressively deteriorated over time,” they reported, adding that the unfavorable trends “argue for vigorous population-based approaches to reverse the unhealthy shift in the distributions of blood pressure and body mass index and to sustain or accelerate the improvement in the distribution of total cholesterol.”

Because the NHANES surveyed only noninstitutionalized adults, the true risk-factor burdens “may be even worse” than those reported, which is one of the limitations of the study, the authors noted. Additional limitations include the exclusion of physical activity and a dietary index as part of the risk determination, and changes in the wording of questions for use of current antihypertensive medication and physician-diagnosed diabetes that could potentially have affected the estimates, they wrote.

Despite the possible limitations of the study, “our results clearly demonstrate a great need for prevention; thus, health care providers should have adequate resources, time, and reimbursement to engage in the prevention of cardiovascular disease in individuals,” they authors wrote, adding that those efforts should be in concert with those of state and national agencies charged with developing effective public health interventions.

In an editorial, Rob M. van Dam, Ph.D., of the Harvard School of Public Health in Boston, and Dr. Walter C. Willett of Brigham and Women's Hospital in Boston, commented that the trajectory of the risk factor trends is even more worrisome considering the analyses “do not yet reflect the effects of the current epidemic of childhood obesity, which causes an early onset of type 2 diabetes, hypertension, and dyslipidemia” (Circulation 2009 Sept. 14 [doi:10.1161/CirculationAHA.109.891507]).

The findings, they wrote, “provide an important signal that the health of Americans is at a crossroad. The current path leads toward increasing adiposity, diabetes mellitus, cardiovascular disease, and disability and an unfit, socially isolated population stuffed with pills and subjected to frequent palliative procedures.” To change course, they stressed, physicians can help by working with their patients one on one, but “their help is needed even more as leaders in the effort to reshape policies and our environment.”

The authors said they had no financial disclosures related to this report.