M. Alexander Otto

NEW ORLEANS – There should be no hesitation to use rituximab or cyclophosphamide in anti–N-methyl-d-aspartate receptor encephalitis patients who do not respond to steroids, immunoglobulins, or plasma exchange within the first 4 weeks, according to neurologist Maarten Titulaer, the lead investigator on a 467-patient study of the disease.

"Treat aggressively. The quicker you treat, the better the outcome. If first-line therapy fails, progress to second-line treatment," said Dr. Titulaer, a visiting research fellow at the University of Pennsylvania, Philadelphia.

Rituximab (Rituxan) and cyclophosphamide made relapse less likely. "The chance is only 5% that [patients] will relapse in the first 2 years" if they received either drug. "It was 20% in patients treated only with, for example, steroids or [intravenous immunoglobulin]," he said at the annual meeting of the American Academy of Neurology.

Dr. Titulaer’s team tracked 2-year outcomes in the patients. Just over half responded to first-line treatment within 4 weeks. Of those, 98% were back home and independent in daily activities within 2 years; 90% had returned to school or work.

Just under half, however, did not respond to first-line agents; just over half of those went on to either rituximab or cyclophosphamide. Of those, 55% recovered fully within 2 years, 76% were back home and independent in daily activities, and about 20% had died or were in a vegetative state.

Of those who did not get rituximab or cyclophosphamide after failing first-line treatments but who instead got another round of those treatments or no further treatment, 37% were fully recovered at 2 years; 55% were back home and independent in daily activities; and 33% had died or were in a vegetative state. The differences in response between the groups after they failed first-line therapies were statistically significant.

In a group of approximately 25 patients who were not treated at all because the diagnosis was missed (or for some other reason), 38% were dead or in a vegetative state after 2 years.

First identified in 2007, N-methyl-d-aspartate (NMDA) receptor encephalitis predominately attacks young women and is associated with ovarian teratomas. The disease is thought to be caused by an autoantibody attack on subunits of brain NMDA glutamate receptors, which are believed to control synaptic plasticity and memory function (N. Engl. J. Med. 2009;361:302-3).

In all, 81% of the cases were female; their median age was 19 years (range, 1-85 years). In patients younger than 12 years and older than 45 years of age, incidence split more evenly between sexes. A tumor occurred in 39% of patients, and almost all were teratomas. An ovarian teratoma occurred in 54% of females older than 12 years, compared with only 4% of girls younger than 12. Patients with tumors had slightly more severe disease.

Immunotherapy plus tumor removal, when appropriate, resulted in full recovery or substantial improvement in about two-thirds of patients by 8 months, and in 77% at 2 years. Relapses occurred in 14% of patients, about three-quarters of them without teratomas.

As currently understood, the disease has protean manifestations, including cognitive problems, psychiatric issues, seizures, dyskinesias, decreased consciousness, behavioral changes, autonomic instability, hypoventilation, movement disorders, and memory and speech disorders.

Almost all of the patients in the study presented with three or more of those symptoms. Adults tended to present with behavioral changes and memory problems; children tended to present with seizures, movement disorders, and – less commonly – abnormal behavior. Within the first month, memory problems and hypoventilation were more common in adults; movement disorders and ataxia were more frequent in children.

Dr. Titulaer said that he had no disclosures.

NEW ORLEANS – There should be no hesitation to use rituximab or cyclophosphamide in anti–N-methyl-d-aspartate receptor encephalitis patients who do not respond to steroids, immunoglobulins, or plasma exchange within the first 4 weeks, according to neurologist Maarten Titulaer, the lead investigator on a 467-patient study of the disease.

"Treat aggressively. The quicker you treat, the better the outcome. If first-line therapy fails, progress to second-line treatment," said Dr. Titulaer, a visiting research fellow at the University of Pennsylvania, Philadelphia.

Rituximab (Rituxan) and cyclophosphamide made relapse less likely. "The chance is only 5% that [patients] will relapse in the first 2 years" if they received either drug. "It was 20% in patients treated only with, for example, steroids or [intravenous immunoglobulin]," he said at the annual meeting of the American Academy of Neurology.

Dr. Titulaer’s team tracked 2-year outcomes in the patients. Just over half responded to first-line treatment within 4 weeks. Of those, 98% were back home and independent in daily activities within 2 years; 90% had returned to school or work.

Just under half, however, did not respond to first-line agents; just over half of those went on to either rituximab or cyclophosphamide. Of those, 55% recovered fully within 2 years, 76% were back home and independent in daily activities, and about 20% had died or were in a vegetative state.

Of those who did not get rituximab or cyclophosphamide after failing first-line treatments but who instead got another round of those treatments or no further treatment, 37% were fully recovered at 2 years; 55% were back home and independent in daily activities; and 33% had died or were in a vegetative state. The differences in response between the groups after they failed first-line therapies were statistically significant.

In a group of approximately 25 patients who were not treated at all because the diagnosis was missed (or for some other reason), 38% were dead or in a vegetative state after 2 years.

First identified in 2007, N-methyl-d-aspartate (NMDA) receptor encephalitis predominately attacks young women and is associated with ovarian teratomas. The disease is thought to be caused by an autoantibody attack on subunits of brain NMDA glutamate receptors, which are believed to control synaptic plasticity and memory function (N. Engl. J. Med. 2009;361:302-3).

In all, 81% of the cases were female; their median age was 19 years (range, 1-85 years). In patients younger than 12 years and older than 45 years of age, incidence split more evenly between sexes. A tumor occurred in 39% of patients, and almost all were teratomas. An ovarian teratoma occurred in 54% of females older than 12 years, compared with only 4% of girls younger than 12. Patients with tumors had slightly more severe disease.

Immunotherapy plus tumor removal, when appropriate, resulted in full recovery or substantial improvement in about two-thirds of patients by 8 months, and in 77% at 2 years. Relapses occurred in 14% of patients, about three-quarters of them without teratomas.

As currently understood, the disease has protean manifestations, including cognitive problems, psychiatric issues, seizures, dyskinesias, decreased consciousness, behavioral changes, autonomic instability, hypoventilation, movement disorders, and memory and speech disorders.

Almost all of the patients in the study presented with three or more of those symptoms. Adults tended to present with behavioral changes and memory problems; children tended to present with seizures, movement disorders, and – less commonly – abnormal behavior. Within the first month, memory problems and hypoventilation were more common in adults; movement disorders and ataxia were more frequent in children.

Dr. Titulaer said that he had no disclosures.

NEW ORLEANS – There should be no hesitation to use rituximab or cyclophosphamide in anti–N-methyl-d-aspartate receptor encephalitis patients who do not respond to steroids, immunoglobulins, or plasma exchange within the first 4 weeks, according to neurologist Maarten Titulaer, the lead investigator on a 467-patient study of the disease.

"Treat aggressively. The quicker you treat, the better the outcome. If first-line therapy fails, progress to second-line treatment," said Dr. Titulaer, a visiting research fellow at the University of Pennsylvania, Philadelphia.

Rituximab (Rituxan) and cyclophosphamide made relapse less likely. "The chance is only 5% that [patients] will relapse in the first 2 years" if they received either drug. "It was 20% in patients treated only with, for example, steroids or [intravenous immunoglobulin]," he said at the annual meeting of the American Academy of Neurology.

Dr. Titulaer’s team tracked 2-year outcomes in the patients. Just over half responded to first-line treatment within 4 weeks. Of those, 98% were back home and independent in daily activities within 2 years; 90% had returned to school or work.

Just under half, however, did not respond to first-line agents; just over half of those went on to either rituximab or cyclophosphamide. Of those, 55% recovered fully within 2 years, 76% were back home and independent in daily activities, and about 20% had died or were in a vegetative state.

Of those who did not get rituximab or cyclophosphamide after failing first-line treatments but who instead got another round of those treatments or no further treatment, 37% were fully recovered at 2 years; 55% were back home and independent in daily activities; and 33% had died or were in a vegetative state. The differences in response between the groups after they failed first-line therapies were statistically significant.

In a group of approximately 25 patients who were not treated at all because the diagnosis was missed (or for some other reason), 38% were dead or in a vegetative state after 2 years.

First identified in 2007, N-methyl-d-aspartate (NMDA) receptor encephalitis predominately attacks young women and is associated with ovarian teratomas. The disease is thought to be caused by an autoantibody attack on subunits of brain NMDA glutamate receptors, which are believed to control synaptic plasticity and memory function (N. Engl. J. Med. 2009;361:302-3).

In all, 81% of the cases were female; their median age was 19 years (range, 1-85 years). In patients younger than 12 years and older than 45 years of age, incidence split more evenly between sexes. A tumor occurred in 39% of patients, and almost all were teratomas. An ovarian teratoma occurred in 54% of females older than 12 years, compared with only 4% of girls younger than 12. Patients with tumors had slightly more severe disease.

Immunotherapy plus tumor removal, when appropriate, resulted in full recovery or substantial improvement in about two-thirds of patients by 8 months, and in 77% at 2 years. Relapses occurred in 14% of patients, about three-quarters of them without teratomas.

As currently understood, the disease has protean manifestations, including cognitive problems, psychiatric issues, seizures, dyskinesias, decreased consciousness, behavioral changes, autonomic instability, hypoventilation, movement disorders, and memory and speech disorders.

Almost all of the patients in the study presented with three or more of those symptoms. Adults tended to present with behavioral changes and memory problems; children tended to present with seizures, movement disorders, and – less commonly – abnormal behavior. Within the first month, memory problems and hypoventilation were more common in adults; movement disorders and ataxia were more frequent in children.

Dr. Titulaer said that he had no disclosures.

NEW ORLEANS – Dopamine agonist–induced impulse control disorders may be more likely in Parkinson’s disease patients who smoke, drink, or consume caffeine, according to the first prospective cohort study of the problem.

"We found a number of interesting things" when the 18 patients (39%) in the study who developed an impulse control disorder (ICD) were compared with the 28 who did not, said lead author Jesse Bastiaens, a medical student at Cornell University, New York.

The 18 had a higher baseline prevalence of caffeine use (100% vs. 67%; P = .007), lifetime prevalence of cigarette smoking (44% vs. 14%; P = .04), and cumulative exposure to both caffeine (72 vs. 38 cup-years; P = .04) and cigarettes (median 2 vs. 0 pack-years; P = .07). There was also a nonsignificant trend towards a higher baseline prevalence of alcohol use.

At baseline, ICD patients also had a greater prevalence of motor complications (61% vs. 25%; P = .01) and lower baseline modified Hoehn and Yahr Scale scores (mean 1.6 vs. 1.9; P = .05), despite comparable total Parkinson’s disease (PD) drug use in both groups (median, 150 levodopa equivalents in both groups).

ICD patients had higher peak-dopamine agonist (DA) doses (median, 300 vs. 165 levodopa equivalents; P = .03) but no significant differences in DA treatment duration or cumulative exposure.

"The risk of ICDs in PD is related to both patient-specific factors and peak DA dosage. Attention to these susceptibility factors may help to reduce the incidence of ICDs in PD," Mr. Bastiaens said at the annual meeting of the American Academy of Neurology.

Besides counseling patients about the risk, "you might be less eager to use a dopamine agonists or use lower doses in people with prior histories of smoking or heavy drinking or other addictive behaviors," said Dr. Ronald Pfeiffer, vice chair of the department of neurology at the University of Tennessee, Memphis, who moderated Mr. Bastiaens’ presentation.

Patients who developed an impulse disorder did so after a mean treatment duration of 23 months (range, 3-114 months). Age, age of PD onset, sex, depression, anxiety, and other factors were not predictive.

None of the 46 patients (all outpatients) had previous histories of ICDs, and none were demented. Their mean age was 62 years, and about half were women. ICD was diagnosed by semistructured interviews and clinical data, with criteria that were perhaps a bit less strict than were those in the DSM-IV, according to Mr. Bastiaens, who said that the researchers thought that casting a slightly wider net might be useful.

There was 1 case per 100 person-months of DA exposure. "We found that impulse control disorders can really occur at anytime during dopamine agonist therapy – as early as 3 months or 9 or more years," said Mr. Bastiaens, who noted that a questionnaire to assess for ICDs in Parkinson’s patients has been recently validated (Mov. Disord. 2012;27:242-7).

A 2010 cross-sectional study in 3,090 Parkinson’s patients found an association between ICDs and current cigarette smoking and family histories of gambling problems, among other factors. It did not find an association with DA dosage. Just over 17% of patients on the drugs developed ICDs (Arch. Neurol. 2010;67:589-95).

The study was supported by the Parkinson’s Disease Foundation. Mr. Bastiaens said that he had nothing to disclose. Dr. Pfeiffer reported personal compensation from several pharmaceutical companies, none of which were involved in the study.

NEW ORLEANS – Dopamine agonist–induced impulse control disorders may be more likely in Parkinson’s disease patients who smoke, drink, or consume caffeine, according to the first prospective cohort study of the problem.

"We found a number of interesting things" when the 18 patients (39%) in the study who developed an impulse control disorder (ICD) were compared with the 28 who did not, said lead author Jesse Bastiaens, a medical student at Cornell University, New York.

The 18 had a higher baseline prevalence of caffeine use (100% vs. 67%; P = .007), lifetime prevalence of cigarette smoking (44% vs. 14%; P = .04), and cumulative exposure to both caffeine (72 vs. 38 cup-years; P = .04) and cigarettes (median 2 vs. 0 pack-years; P = .07). There was also a nonsignificant trend towards a higher baseline prevalence of alcohol use.

At baseline, ICD patients also had a greater prevalence of motor complications (61% vs. 25%; P = .01) and lower baseline modified Hoehn and Yahr Scale scores (mean 1.6 vs. 1.9; P = .05), despite comparable total Parkinson’s disease (PD) drug use in both groups (median, 150 levodopa equivalents in both groups).

ICD patients had higher peak-dopamine agonist (DA) doses (median, 300 vs. 165 levodopa equivalents; P = .03) but no significant differences in DA treatment duration or cumulative exposure.

"The risk of ICDs in PD is related to both patient-specific factors and peak DA dosage. Attention to these susceptibility factors may help to reduce the incidence of ICDs in PD," Mr. Bastiaens said at the annual meeting of the American Academy of Neurology.

Besides counseling patients about the risk, "you might be less eager to use a dopamine agonists or use lower doses in people with prior histories of smoking or heavy drinking or other addictive behaviors," said Dr. Ronald Pfeiffer, vice chair of the department of neurology at the University of Tennessee, Memphis, who moderated Mr. Bastiaens’ presentation.

Patients who developed an impulse disorder did so after a mean treatment duration of 23 months (range, 3-114 months). Age, age of PD onset, sex, depression, anxiety, and other factors were not predictive.

None of the 46 patients (all outpatients) had previous histories of ICDs, and none were demented. Their mean age was 62 years, and about half were women. ICD was diagnosed by semistructured interviews and clinical data, with criteria that were perhaps a bit less strict than were those in the DSM-IV, according to Mr. Bastiaens, who said that the researchers thought that casting a slightly wider net might be useful.

There was 1 case per 100 person-months of DA exposure. "We found that impulse control disorders can really occur at anytime during dopamine agonist therapy – as early as 3 months or 9 or more years," said Mr. Bastiaens, who noted that a questionnaire to assess for ICDs in Parkinson’s patients has been recently validated (Mov. Disord. 2012;27:242-7).

A 2010 cross-sectional study in 3,090 Parkinson’s patients found an association between ICDs and current cigarette smoking and family histories of gambling problems, among other factors. It did not find an association with DA dosage. Just over 17% of patients on the drugs developed ICDs (Arch. Neurol. 2010;67:589-95).

The study was supported by the Parkinson’s Disease Foundation. Mr. Bastiaens said that he had nothing to disclose. Dr. Pfeiffer reported personal compensation from several pharmaceutical companies, none of which were involved in the study.

NEW ORLEANS – Dopamine agonist–induced impulse control disorders may be more likely in Parkinson’s disease patients who smoke, drink, or consume caffeine, according to the first prospective cohort study of the problem.

"We found a number of interesting things" when the 18 patients (39%) in the study who developed an impulse control disorder (ICD) were compared with the 28 who did not, said lead author Jesse Bastiaens, a medical student at Cornell University, New York.

The 18 had a higher baseline prevalence of caffeine use (100% vs. 67%; P = .007), lifetime prevalence of cigarette smoking (44% vs. 14%; P = .04), and cumulative exposure to both caffeine (72 vs. 38 cup-years; P = .04) and cigarettes (median 2 vs. 0 pack-years; P = .07). There was also a nonsignificant trend towards a higher baseline prevalence of alcohol use.

At baseline, ICD patients also had a greater prevalence of motor complications (61% vs. 25%; P = .01) and lower baseline modified Hoehn and Yahr Scale scores (mean 1.6 vs. 1.9; P = .05), despite comparable total Parkinson’s disease (PD) drug use in both groups (median, 150 levodopa equivalents in both groups).

ICD patients had higher peak-dopamine agonist (DA) doses (median, 300 vs. 165 levodopa equivalents; P = .03) but no significant differences in DA treatment duration or cumulative exposure.

"The risk of ICDs in PD is related to both patient-specific factors and peak DA dosage. Attention to these susceptibility factors may help to reduce the incidence of ICDs in PD," Mr. Bastiaens said at the annual meeting of the American Academy of Neurology.

Besides counseling patients about the risk, "you might be less eager to use a dopamine agonists or use lower doses in people with prior histories of smoking or heavy drinking or other addictive behaviors," said Dr. Ronald Pfeiffer, vice chair of the department of neurology at the University of Tennessee, Memphis, who moderated Mr. Bastiaens’ presentation.

Patients who developed an impulse disorder did so after a mean treatment duration of 23 months (range, 3-114 months). Age, age of PD onset, sex, depression, anxiety, and other factors were not predictive.

None of the 46 patients (all outpatients) had previous histories of ICDs, and none were demented. Their mean age was 62 years, and about half were women. ICD was diagnosed by semistructured interviews and clinical data, with criteria that were perhaps a bit less strict than were those in the DSM-IV, according to Mr. Bastiaens, who said that the researchers thought that casting a slightly wider net might be useful.

There was 1 case per 100 person-months of DA exposure. "We found that impulse control disorders can really occur at anytime during dopamine agonist therapy – as early as 3 months or 9 or more years," said Mr. Bastiaens, who noted that a questionnaire to assess for ICDs in Parkinson’s patients has been recently validated (Mov. Disord. 2012;27:242-7).

A 2010 cross-sectional study in 3,090 Parkinson’s patients found an association between ICDs and current cigarette smoking and family histories of gambling problems, among other factors. It did not find an association with DA dosage. Just over 17% of patients on the drugs developed ICDs (Arch. Neurol. 2010;67:589-95).

The study was supported by the Parkinson’s Disease Foundation. Mr. Bastiaens said that he had nothing to disclose. Dr. Pfeiffer reported personal compensation from several pharmaceutical companies, none of which were involved in the study.

SAN FRANCISCO – Thromboprophylaxis with enoxaparin (Lovenox) did not reduce mortality among acutely ill, hospitalized medical patients in a trial funded by the maker of the low molecular weight heparin, Sanofi-Aventis.

Among 4,171 patients randomized to enoxaparin 40 mg subcutaneously for 10 days, plus or minus 4 days, all-cause 30-day mortality was 4.9%; among 4,136 randomized to placebo for the same amount of time, it was 4.8% (relative risk, 1.0; P = .83).

The major bleeding rate was below a half percent in both groups and not statistically different. Minor bleeding was seen in 1.8% in the enoxaparin group and 1.1% in the placebo group, a statistically significant difference, Dr. Samuel Goldhaber said at an international conference of the American Thoracic Society.

Commenting on the study, New England Journal of Medicine editor Dr. Jeffrey Drazen noted that, in the United States, the reflex has been to use prophylaxis on even low-risk patients for venous thromboembolism. "The reason we published these data was that maybe we should rethink this. Maybe we should be making decisions about who should be receiving pharmacologic prophylaxis based on factors other than the fact that they are in the hospital for an acute medical illness," he said.

Patients were hospitalized for acute decompensated heart failure, severe systemic infections, or active cancer. No mortality benefit was found for enoxaparin on subgroup analysis. Both groups wore knee-high elastic graduated compression stockings during the treatment phase of the trial (N. Engl. J. Med. 2011;365:2463-72).

The all-cause 1-90 day mortality curves for the two groups "were absolutely superimposable. We were quite surprised by the results," said Dr. Goldhaber, professor of medicine at Harvard Medical School and director of the venous thromboembolism research group at Brigham and Women’s Hospital, both in Boston.

They were surprised because enoxaparin has been proven to reduce venous thromboembolism in both surgical and medical patients, and to reduce the incidence of fatal pulmonary embolism and all-cause mortality in surgical patients.

There was a presumption it would save medical patients’ lives, too, although they have a lower pulmonary embolism rate. Current U.S. treatment guidelines recommend pharmacologic prophylaxis in both surgical and acutely-ill medical inpatients.

The study was conducted in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia because, in those places, enoxaparin prophylaxis for medical patients is "still considered an open question," Dr. Goldhaber said.

About 88% of the subjects were Asian, 63% were men. Their average age was 65 years and average body mass index about 23 kg/m². There were no statistically significant baseline differences between the placebo and enoxaparin groups.

Perhaps enoxaparin didn’t cut mortality in the trial because "the natural history of deep vein thrombosis differs between medical and surgical patients." It’s been assumed that "the natural history would be the same. This assumption may be incorrect," Dr. Goldhaber said.

It’s also possible that the elastic stockings used in the trial were enough to prevent fatal pulmonary embolisms in the mostly-Asian subjects, a group known historically to have a lower pulmonary embolism risk than Westerners. Just one patient in each group died from a pulmonary embolism in the study; infections were the main cause of death.

At this point, Dr. Goldhaber still tends to prophylaxis even low-risk medical inpatients. "In our world, the quality measures are in place, but I’d be thinking to myself that prophylaxis is not going, in all likelihood, to save [their lives] from a pulmonary embolism because [they’re] probably not going to develop that problem," he said.

Dr. Goldhaber disclosed that he is a paid consultant for Sanofi-Aventis, Boehringer Ingelheim, Bristol Myers Squibb, Merck, and several other companies. Dr. Drazen reported having no disclosures.

SAN FRANCISCO – Thromboprophylaxis with enoxaparin (Lovenox) did not reduce mortality among acutely ill, hospitalized medical patients in a trial funded by the maker of the low molecular weight heparin, Sanofi-Aventis.

Among 4,171 patients randomized to enoxaparin 40 mg subcutaneously for 10 days, plus or minus 4 days, all-cause 30-day mortality was 4.9%; among 4,136 randomized to placebo for the same amount of time, it was 4.8% (relative risk, 1.0; P = .83).

The major bleeding rate was below a half percent in both groups and not statistically different. Minor bleeding was seen in 1.8% in the enoxaparin group and 1.1% in the placebo group, a statistically significant difference, Dr. Samuel Goldhaber said at an international conference of the American Thoracic Society.

Commenting on the study, New England Journal of Medicine editor Dr. Jeffrey Drazen noted that, in the United States, the reflex has been to use prophylaxis on even low-risk patients for venous thromboembolism. "The reason we published these data was that maybe we should rethink this. Maybe we should be making decisions about who should be receiving pharmacologic prophylaxis based on factors other than the fact that they are in the hospital for an acute medical illness," he said.

Patients were hospitalized for acute decompensated heart failure, severe systemic infections, or active cancer. No mortality benefit was found for enoxaparin on subgroup analysis. Both groups wore knee-high elastic graduated compression stockings during the treatment phase of the trial (N. Engl. J. Med. 2011;365:2463-72).

The all-cause 1-90 day mortality curves for the two groups "were absolutely superimposable. We were quite surprised by the results," said Dr. Goldhaber, professor of medicine at Harvard Medical School and director of the venous thromboembolism research group at Brigham and Women’s Hospital, both in Boston.

They were surprised because enoxaparin has been proven to reduce venous thromboembolism in both surgical and medical patients, and to reduce the incidence of fatal pulmonary embolism and all-cause mortality in surgical patients.

There was a presumption it would save medical patients’ lives, too, although they have a lower pulmonary embolism rate. Current U.S. treatment guidelines recommend pharmacologic prophylaxis in both surgical and acutely-ill medical inpatients.

The study was conducted in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia because, in those places, enoxaparin prophylaxis for medical patients is "still considered an open question," Dr. Goldhaber said.

About 88% of the subjects were Asian, 63% were men. Their average age was 65 years and average body mass index about 23 kg/m². There were no statistically significant baseline differences between the placebo and enoxaparin groups.

Perhaps enoxaparin didn’t cut mortality in the trial because "the natural history of deep vein thrombosis differs between medical and surgical patients." It’s been assumed that "the natural history would be the same. This assumption may be incorrect," Dr. Goldhaber said.

It’s also possible that the elastic stockings used in the trial were enough to prevent fatal pulmonary embolisms in the mostly-Asian subjects, a group known historically to have a lower pulmonary embolism risk than Westerners. Just one patient in each group died from a pulmonary embolism in the study; infections were the main cause of death.

At this point, Dr. Goldhaber still tends to prophylaxis even low-risk medical inpatients. "In our world, the quality measures are in place, but I’d be thinking to myself that prophylaxis is not going, in all likelihood, to save [their lives] from a pulmonary embolism because [they’re] probably not going to develop that problem," he said.

Dr. Goldhaber disclosed that he is a paid consultant for Sanofi-Aventis, Boehringer Ingelheim, Bristol Myers Squibb, Merck, and several other companies. Dr. Drazen reported having no disclosures.

SAN FRANCISCO – Thromboprophylaxis with enoxaparin (Lovenox) did not reduce mortality among acutely ill, hospitalized medical patients in a trial funded by the maker of the low molecular weight heparin, Sanofi-Aventis.

Among 4,171 patients randomized to enoxaparin 40 mg subcutaneously for 10 days, plus or minus 4 days, all-cause 30-day mortality was 4.9%; among 4,136 randomized to placebo for the same amount of time, it was 4.8% (relative risk, 1.0; P = .83).

The major bleeding rate was below a half percent in both groups and not statistically different. Minor bleeding was seen in 1.8% in the enoxaparin group and 1.1% in the placebo group, a statistically significant difference, Dr. Samuel Goldhaber said at an international conference of the American Thoracic Society.

Commenting on the study, New England Journal of Medicine editor Dr. Jeffrey Drazen noted that, in the United States, the reflex has been to use prophylaxis on even low-risk patients for venous thromboembolism. "The reason we published these data was that maybe we should rethink this. Maybe we should be making decisions about who should be receiving pharmacologic prophylaxis based on factors other than the fact that they are in the hospital for an acute medical illness," he said.

Patients were hospitalized for acute decompensated heart failure, severe systemic infections, or active cancer. No mortality benefit was found for enoxaparin on subgroup analysis. Both groups wore knee-high elastic graduated compression stockings during the treatment phase of the trial (N. Engl. J. Med. 2011;365:2463-72).

The all-cause 1-90 day mortality curves for the two groups "were absolutely superimposable. We were quite surprised by the results," said Dr. Goldhaber, professor of medicine at Harvard Medical School and director of the venous thromboembolism research group at Brigham and Women’s Hospital, both in Boston.

They were surprised because enoxaparin has been proven to reduce venous thromboembolism in both surgical and medical patients, and to reduce the incidence of fatal pulmonary embolism and all-cause mortality in surgical patients.

There was a presumption it would save medical patients’ lives, too, although they have a lower pulmonary embolism rate. Current U.S. treatment guidelines recommend pharmacologic prophylaxis in both surgical and acutely-ill medical inpatients.

The study was conducted in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia because, in those places, enoxaparin prophylaxis for medical patients is "still considered an open question," Dr. Goldhaber said.

About 88% of the subjects were Asian, 63% were men. Their average age was 65 years and average body mass index about 23 kg/m². There were no statistically significant baseline differences between the placebo and enoxaparin groups.

Perhaps enoxaparin didn’t cut mortality in the trial because "the natural history of deep vein thrombosis differs between medical and surgical patients." It’s been assumed that "the natural history would be the same. This assumption may be incorrect," Dr. Goldhaber said.

It’s also possible that the elastic stockings used in the trial were enough to prevent fatal pulmonary embolisms in the mostly-Asian subjects, a group known historically to have a lower pulmonary embolism risk than Westerners. Just one patient in each group died from a pulmonary embolism in the study; infections were the main cause of death.

At this point, Dr. Goldhaber still tends to prophylaxis even low-risk medical inpatients. "In our world, the quality measures are in place, but I’d be thinking to myself that prophylaxis is not going, in all likelihood, to save [their lives] from a pulmonary embolism because [they’re] probably not going to develop that problem," he said.

Dr. Goldhaber disclosed that he is a paid consultant for Sanofi-Aventis, Boehringer Ingelheim, Bristol Myers Squibb, Merck, and several other companies. Dr. Drazen reported having no disclosures.

SAN DIEGO – Cirrhotics with spontaneous bacterial peritonitis probably need albumin only if their total bilirubin is above 4 mg/dL and/or their blood urea nitrogen (BUN) is above 30 mg/dL, according to transplant hepatologist Dr. James Burton.

Supplementation expands plasma volume to attenuate the splanchnic and systemic vasodilation associated with spontaneous bacterial peritonitis (SBP), increasing blood flow to the kidneys and preserving renal function, said Dr. Burton, medical director of liver transplantation at the University of Colorado Hospital, Aurora.

But it seems to be needed only when SBP patients are at high risk for renal failure, according to two studies.

The first randomized 63 cirrhotic SBP patients to cefotaxime alone and 63 to cefotaxime plus albumin, 1.5 g/kg on day 1 and 1.0 g/kg on day 3. The regimen wiped out the infection in most patients. Renal impairment and mortality were significantly lower in the albumin group, but only patients with total baseline bilirubins above 4 mg/dL and/or BUNs greater than 30 mg/dL benefited from albumin, Dr. Burton said (N. Engl. J. Med. 1999;341:403-9).

A follow-up 28-subject study limited albumin supplementation, again 1.5 g/kg on day 1 and 1.0 g/kg on day 3, to SBP patients with similar parameters or creatinines above 1 mg/dL. It was the right choice; none of the 15 patients with lower baseline values developed renal impairment, Dr. Burton said (Gut 2007;56:597-9).

He noted that it’s possible for patients to have SBP without obvious symptoms, so "if you’re sick enough to have cirrhosis and be in the hospital, you need a needle in your abdomen to rule out" the condition.

In general, cirrhotics have low levels of albumin, which is responsible for about 80% of plasma’s oncotic pressure. Also, what they have "may not work as well" to transport fatty acids, hormones, and enzymes, and drugs.

Outpatient supplementation for cirrhotics not only seems to reduce the need for paracentesis, but also makes patients feel better. "I am a believer because my patients tell me it works. Some of my patients refer to it as ‘nectar of the gods.’ This is more than just the oncotic things. I also think they are transporting hormones, carrying drugs, and other stuff better. So I am a big believer," Dr. Burton said.

He opts for 25% albumin instead of 5%, to reduce fluid load and also because "there is a lot of sodium in 5% albumin. Obviously, these patients need to have their sodium restricted," he said.

When paracentesis is needed, "studies suggest you can probably [remove] 4-6 liters without giving albumin." Even so, "we often give albumin during paracentesis," he said.

Dr. Burton said he has no relevant financial disclosures.

SAN DIEGO – Cirrhotics with spontaneous bacterial peritonitis probably need albumin only if their total bilirubin is above 4 mg/dL and/or their blood urea nitrogen (BUN) is above 30 mg/dL, according to transplant hepatologist Dr. James Burton.

Supplementation expands plasma volume to attenuate the splanchnic and systemic vasodilation associated with spontaneous bacterial peritonitis (SBP), increasing blood flow to the kidneys and preserving renal function, said Dr. Burton, medical director of liver transplantation at the University of Colorado Hospital, Aurora.

But it seems to be needed only when SBP patients are at high risk for renal failure, according to two studies.

The first randomized 63 cirrhotic SBP patients to cefotaxime alone and 63 to cefotaxime plus albumin, 1.5 g/kg on day 1 and 1.0 g/kg on day 3. The regimen wiped out the infection in most patients. Renal impairment and mortality were significantly lower in the albumin group, but only patients with total baseline bilirubins above 4 mg/dL and/or BUNs greater than 30 mg/dL benefited from albumin, Dr. Burton said (N. Engl. J. Med. 1999;341:403-9).

A follow-up 28-subject study limited albumin supplementation, again 1.5 g/kg on day 1 and 1.0 g/kg on day 3, to SBP patients with similar parameters or creatinines above 1 mg/dL. It was the right choice; none of the 15 patients with lower baseline values developed renal impairment, Dr. Burton said (Gut 2007;56:597-9).

He noted that it’s possible for patients to have SBP without obvious symptoms, so "if you’re sick enough to have cirrhosis and be in the hospital, you need a needle in your abdomen to rule out" the condition.

In general, cirrhotics have low levels of albumin, which is responsible for about 80% of plasma’s oncotic pressure. Also, what they have "may not work as well" to transport fatty acids, hormones, and enzymes, and drugs.

Outpatient supplementation for cirrhotics not only seems to reduce the need for paracentesis, but also makes patients feel better. "I am a believer because my patients tell me it works. Some of my patients refer to it as ‘nectar of the gods.’ This is more than just the oncotic things. I also think they are transporting hormones, carrying drugs, and other stuff better. So I am a big believer," Dr. Burton said.

He opts for 25% albumin instead of 5%, to reduce fluid load and also because "there is a lot of sodium in 5% albumin. Obviously, these patients need to have their sodium restricted," he said.

When paracentesis is needed, "studies suggest you can probably [remove] 4-6 liters without giving albumin." Even so, "we often give albumin during paracentesis," he said.

Dr. Burton said he has no relevant financial disclosures.

SAN DIEGO – Cirrhotics with spontaneous bacterial peritonitis probably need albumin only if their total bilirubin is above 4 mg/dL and/or their blood urea nitrogen (BUN) is above 30 mg/dL, according to transplant hepatologist Dr. James Burton.

Supplementation expands plasma volume to attenuate the splanchnic and systemic vasodilation associated with spontaneous bacterial peritonitis (SBP), increasing blood flow to the kidneys and preserving renal function, said Dr. Burton, medical director of liver transplantation at the University of Colorado Hospital, Aurora.

But it seems to be needed only when SBP patients are at high risk for renal failure, according to two studies.

The first randomized 63 cirrhotic SBP patients to cefotaxime alone and 63 to cefotaxime plus albumin, 1.5 g/kg on day 1 and 1.0 g/kg on day 3. The regimen wiped out the infection in most patients. Renal impairment and mortality were significantly lower in the albumin group, but only patients with total baseline bilirubins above 4 mg/dL and/or BUNs greater than 30 mg/dL benefited from albumin, Dr. Burton said (N. Engl. J. Med. 1999;341:403-9).

A follow-up 28-subject study limited albumin supplementation, again 1.5 g/kg on day 1 and 1.0 g/kg on day 3, to SBP patients with similar parameters or creatinines above 1 mg/dL. It was the right choice; none of the 15 patients with lower baseline values developed renal impairment, Dr. Burton said (Gut 2007;56:597-9).

He noted that it’s possible for patients to have SBP without obvious symptoms, so "if you’re sick enough to have cirrhosis and be in the hospital, you need a needle in your abdomen to rule out" the condition.

In general, cirrhotics have low levels of albumin, which is responsible for about 80% of plasma’s oncotic pressure. Also, what they have "may not work as well" to transport fatty acids, hormones, and enzymes, and drugs.

Outpatient supplementation for cirrhotics not only seems to reduce the need for paracentesis, but also makes patients feel better. "I am a believer because my patients tell me it works. Some of my patients refer to it as ‘nectar of the gods.’ This is more than just the oncotic things. I also think they are transporting hormones, carrying drugs, and other stuff better. So I am a big believer," Dr. Burton said.

He opts for 25% albumin instead of 5%, to reduce fluid load and also because "there is a lot of sodium in 5% albumin. Obviously, these patients need to have their sodium restricted," he said.

When paracentesis is needed, "studies suggest you can probably [remove] 4-6 liters without giving albumin." Even so, "we often give albumin during paracentesis," he said.

Dr. Burton said he has no relevant financial disclosures.

SAN FRANCISCO – Overnight intensivist coverage reduces ICU mortality, but only in ICUs that don’t have robust intensivist coverage during the day, according to University of Pittsburgh researchers.

The team linked the outcomes of 65,752 ICU patients in the APACHE (Acute Physiologic and Chronic Health Evaluation) database from 2009-2010 to survey-assessed staffing practices at the 49 ICUs where they were treated.

In the 22 ICUs with low-intensity daytime staffing (meaning that intensivists weren’t routinely involved in patient care during the day and intensivist consults were only optional), having an intensivist present in the ICU at night – or at least immediately available to manage overnight ICU emergencies – was associated with a significant reduction in risk-adjusted, in-hospital mortality (odds ratio, 0.62; P = .04), the researchers said.

That wasn’t the case in the 27 ICUs with high-intensity daytime staffing, where intensivists had primary responsibility for patients during the day or intensivist consults were required for daytime admissions. Adding an overnight intensivist to expand that coverage to 24 hours did not significantly reduce risk-adjusted, in-hospital mortality (OR, 1.08; P = .78) (N. Engl. J. Med. 2012 May 21 [doi:10.1056/NEJMsa1201918]).

The critical care community – as well as hospitals, insurance providers, and legislators – have debated ICU staffing in the wake of studies showing that outcomes improve when intensivists manage ICU patients during the day (JAMA 2002;288:2151-62).

Among other questions on their minds was whether nighttime coverage would improve outcomes even more, senior author Dr. Jeremy Kahn, of the departments of critical care medicine and health policy at the University of Pittsburgh, said at the international conference of the American Thoracic Society.

"Our study indicates" that "ICUs with low-intensity daytime staffing, the most common staffing model in the United States, have better outcomes when intensivists are present at night. Nationally, two-thirds of ICUs have no intensivists at night, so expanding the role of intensivists in these ICUs could translate into improved health care quality," he said.

But ICUs with robust intensivist coverage during the day – and, frequently, resident coverage at night – do "not share the same benefit from nighttime intensivists. This shows that the movement to expand intensivist presence in these hospitals may be premature, especially since intensivists are in relatively short supply," Dr. Kahn said.

"Individual hospitals and ICUs will need to weigh the anticipated benefits of expanding intensivist nighttime coverage against those of other quality-improvement efforts in order to best serve their patients, staff, and community," he and his colleagues concluded in their report.

It’s unclear why overnight intensivists reduced mortality in ICUs where they did not have a robust daytime presence. Perhaps they ensured more timely resuscitation of unstable patients, quicker treatment initiations, and more efficient adjustments of complex therapies, the researchers said.

Dr. Kahn and Dr. Campbell reported no relevant disclosures.

SAN FRANCISCO – Overnight intensivist coverage reduces ICU mortality, but only in ICUs that don’t have robust intensivist coverage during the day, according to University of Pittsburgh researchers.

The team linked the outcomes of 65,752 ICU patients in the APACHE (Acute Physiologic and Chronic Health Evaluation) database from 2009-2010 to survey-assessed staffing practices at the 49 ICUs where they were treated.

In the 22 ICUs with low-intensity daytime staffing (meaning that intensivists weren’t routinely involved in patient care during the day and intensivist consults were only optional), having an intensivist present in the ICU at night – or at least immediately available to manage overnight ICU emergencies – was associated with a significant reduction in risk-adjusted, in-hospital mortality (odds ratio, 0.62; P = .04), the researchers said.

That wasn’t the case in the 27 ICUs with high-intensity daytime staffing, where intensivists had primary responsibility for patients during the day or intensivist consults were required for daytime admissions. Adding an overnight intensivist to expand that coverage to 24 hours did not significantly reduce risk-adjusted, in-hospital mortality (OR, 1.08; P = .78) (N. Engl. J. Med. 2012 May 21 [doi:10.1056/NEJMsa1201918]).

The critical care community – as well as hospitals, insurance providers, and legislators – have debated ICU staffing in the wake of studies showing that outcomes improve when intensivists manage ICU patients during the day (JAMA 2002;288:2151-62).

Among other questions on their minds was whether nighttime coverage would improve outcomes even more, senior author Dr. Jeremy Kahn, of the departments of critical care medicine and health policy at the University of Pittsburgh, said at the international conference of the American Thoracic Society.

"Our study indicates" that "ICUs with low-intensity daytime staffing, the most common staffing model in the United States, have better outcomes when intensivists are present at night. Nationally, two-thirds of ICUs have no intensivists at night, so expanding the role of intensivists in these ICUs could translate into improved health care quality," he said.

But ICUs with robust intensivist coverage during the day – and, frequently, resident coverage at night – do "not share the same benefit from nighttime intensivists. This shows that the movement to expand intensivist presence in these hospitals may be premature, especially since intensivists are in relatively short supply," Dr. Kahn said.

"Individual hospitals and ICUs will need to weigh the anticipated benefits of expanding intensivist nighttime coverage against those of other quality-improvement efforts in order to best serve their patients, staff, and community," he and his colleagues concluded in their report.

It’s unclear why overnight intensivists reduced mortality in ICUs where they did not have a robust daytime presence. Perhaps they ensured more timely resuscitation of unstable patients, quicker treatment initiations, and more efficient adjustments of complex therapies, the researchers said.

Dr. Kahn and Dr. Campbell reported no relevant disclosures.

SAN FRANCISCO – Overnight intensivist coverage reduces ICU mortality, but only in ICUs that don’t have robust intensivist coverage during the day, according to University of Pittsburgh researchers.

The team linked the outcomes of 65,752 ICU patients in the APACHE (Acute Physiologic and Chronic Health Evaluation) database from 2009-2010 to survey-assessed staffing practices at the 49 ICUs where they were treated.

In the 22 ICUs with low-intensity daytime staffing (meaning that intensivists weren’t routinely involved in patient care during the day and intensivist consults were only optional), having an intensivist present in the ICU at night – or at least immediately available to manage overnight ICU emergencies – was associated with a significant reduction in risk-adjusted, in-hospital mortality (odds ratio, 0.62; P = .04), the researchers said.

That wasn’t the case in the 27 ICUs with high-intensity daytime staffing, where intensivists had primary responsibility for patients during the day or intensivist consults were required for daytime admissions. Adding an overnight intensivist to expand that coverage to 24 hours did not significantly reduce risk-adjusted, in-hospital mortality (OR, 1.08; P = .78) (N. Engl. J. Med. 2012 May 21 [doi:10.1056/NEJMsa1201918]).

The critical care community – as well as hospitals, insurance providers, and legislators – have debated ICU staffing in the wake of studies showing that outcomes improve when intensivists manage ICU patients during the day (JAMA 2002;288:2151-62).

Among other questions on their minds was whether nighttime coverage would improve outcomes even more, senior author Dr. Jeremy Kahn, of the departments of critical care medicine and health policy at the University of Pittsburgh, said at the international conference of the American Thoracic Society.

"Our study indicates" that "ICUs with low-intensity daytime staffing, the most common staffing model in the United States, have better outcomes when intensivists are present at night. Nationally, two-thirds of ICUs have no intensivists at night, so expanding the role of intensivists in these ICUs could translate into improved health care quality," he said.

But ICUs with robust intensivist coverage during the day – and, frequently, resident coverage at night – do "not share the same benefit from nighttime intensivists. This shows that the movement to expand intensivist presence in these hospitals may be premature, especially since intensivists are in relatively short supply," Dr. Kahn said.

"Individual hospitals and ICUs will need to weigh the anticipated benefits of expanding intensivist nighttime coverage against those of other quality-improvement efforts in order to best serve their patients, staff, and community," he and his colleagues concluded in their report.

It’s unclear why overnight intensivists reduced mortality in ICUs where they did not have a robust daytime presence. Perhaps they ensured more timely resuscitation of unstable patients, quicker treatment initiations, and more efficient adjustments of complex therapies, the researchers said.

Dr. Kahn and Dr. Campbell reported no relevant disclosures.

SAN DIEGO – Patients with bileaflet aortic valves have a low risk of perioperative thromboembolism, as long as they don’t have atrial fibrillation or other stroke risks, according to recent perioperative antithrombotic therapy guidelines from the American College of Chest Physicians.

That means they’ll likely be okay if their anticoagulation therapy is temporarily discontinued for an invasive procedure; they do not need to bridged with low-molecular-weight or unfractionated heparin, said Dr. Daniel Brotman of the department of medicine and director of the hospitalist program at Johns Hopkins Hospital in Baltimore (Chest 2012;141:e326S-50S).

Even so, there’s a good chance those patients will be bridged anyway because "we are petrified not to bridge patients with valves," even though "we are comfortable not bridging patients with [uncomplicated] atrial fibrillation," who have a similar perioperative thromboembolism risk, he said at the annual meeting of the Society of Hospital Medicine.

Maybe it’s because older caged-ball and tilting-disc aortic valves were more thrombogenic, so "we got in the habit" of bridging, "but the data just don’t support that with [bileaflet] aortic valves," he said. The guidelines do note that patients with caged-ball and tilting-disc aortic valves, and mitral valves, are at high-risk for perioperative thromboembolic events.

In general, bridging practices vary considerably in the United States, and bridging itself is not without risks, Dr. Brotman and his colleagues found in a study of nine hospital centers.

Two bridged more than 80% of their anticoagulation patients with full-dose perioperative heparin; the remaining seven used full-dose heparin in just 22%. The variation persisted after adjustment for patient characteristics.

Patients "at one of these more aggressive centers were three to four times more likely to have a bleeding episode. Not surprisingly, if you take patients who have recently been through surgery and treat them with full-dose heparin products, they are likely to bleed," he said (Am. J. Med. 2010;123:141-150).

When needed, Dr. Brotman prefers to bridge with low-molecular-weight heparin (enoxaparin), delivered on an outpatient basis. "This is a much more cost effective than admitting [valve patients] for unfractionated heparin treatment," he said.

Some might worry about the approach because of an "ugly history related to the [Food and Drug Administration] getting very upset about some very bad outcomes in a small number" of mitral valve patients bridged with low-molecular-weight heparin several years ago, he said.

"They put in a black box warning against using enoxaparin in valve patients, but subsequently realized that patients on anticoagulation with prosthetic mitral valves are at high risk for having bad things happen to them, and that when they have periods of anticoagulation cessation, they are at risk of having something happen regardless of what you bridge them with," Dr. Brotman said. The black box was eventually removed (Circulation 2006;113:470-2).

So "anybody who says it’s safer to bridge patients with unfractionated heparin, you can ask them, ‘well, show me the data.’ There are no head-to-head trials vs. low-molecular-weight heparin, and the data for unfractionated heparin are over 30 years old. It’s not safer; it’s just something that’s been traditional. Anecdotally, I’ve had patients have adverse outcomes with unfractionated heparin," he said.

Dr. Brotman said he has no disclosures.

SAN DIEGO – Patients with bileaflet aortic valves have a low risk of perioperative thromboembolism, as long as they don’t have atrial fibrillation or other stroke risks, according to recent perioperative antithrombotic therapy guidelines from the American College of Chest Physicians.

That means they’ll likely be okay if their anticoagulation therapy is temporarily discontinued for an invasive procedure; they do not need to bridged with low-molecular-weight or unfractionated heparin, said Dr. Daniel Brotman of the department of medicine and director of the hospitalist program at Johns Hopkins Hospital in Baltimore (Chest 2012;141:e326S-50S).

Even so, there’s a good chance those patients will be bridged anyway because "we are petrified not to bridge patients with valves," even though "we are comfortable not bridging patients with [uncomplicated] atrial fibrillation," who have a similar perioperative thromboembolism risk, he said at the annual meeting of the Society of Hospital Medicine.

Maybe it’s because older caged-ball and tilting-disc aortic valves were more thrombogenic, so "we got in the habit" of bridging, "but the data just don’t support that with [bileaflet] aortic valves," he said. The guidelines do note that patients with caged-ball and tilting-disc aortic valves, and mitral valves, are at high-risk for perioperative thromboembolic events.

In general, bridging practices vary considerably in the United States, and bridging itself is not without risks, Dr. Brotman and his colleagues found in a study of nine hospital centers.

Two bridged more than 80% of their anticoagulation patients with full-dose perioperative heparin; the remaining seven used full-dose heparin in just 22%. The variation persisted after adjustment for patient characteristics.

Patients "at one of these more aggressive centers were three to four times more likely to have a bleeding episode. Not surprisingly, if you take patients who have recently been through surgery and treat them with full-dose heparin products, they are likely to bleed," he said (Am. J. Med. 2010;123:141-150).

When needed, Dr. Brotman prefers to bridge with low-molecular-weight heparin (enoxaparin), delivered on an outpatient basis. "This is a much more cost effective than admitting [valve patients] for unfractionated heparin treatment," he said.

Some might worry about the approach because of an "ugly history related to the [Food and Drug Administration] getting very upset about some very bad outcomes in a small number" of mitral valve patients bridged with low-molecular-weight heparin several years ago, he said.

"They put in a black box warning against using enoxaparin in valve patients, but subsequently realized that patients on anticoagulation with prosthetic mitral valves are at high risk for having bad things happen to them, and that when they have periods of anticoagulation cessation, they are at risk of having something happen regardless of what you bridge them with," Dr. Brotman said. The black box was eventually removed (Circulation 2006;113:470-2).

So "anybody who says it’s safer to bridge patients with unfractionated heparin, you can ask them, ‘well, show me the data.’ There are no head-to-head trials vs. low-molecular-weight heparin, and the data for unfractionated heparin are over 30 years old. It’s not safer; it’s just something that’s been traditional. Anecdotally, I’ve had patients have adverse outcomes with unfractionated heparin," he said.

Dr. Brotman said he has no disclosures.

SAN DIEGO – Patients with bileaflet aortic valves have a low risk of perioperative thromboembolism, as long as they don’t have atrial fibrillation or other stroke risks, according to recent perioperative antithrombotic therapy guidelines from the American College of Chest Physicians.

That means they’ll likely be okay if their anticoagulation therapy is temporarily discontinued for an invasive procedure; they do not need to bridged with low-molecular-weight or unfractionated heparin, said Dr. Daniel Brotman of the department of medicine and director of the hospitalist program at Johns Hopkins Hospital in Baltimore (Chest 2012;141:e326S-50S).

Even so, there’s a good chance those patients will be bridged anyway because "we are petrified not to bridge patients with valves," even though "we are comfortable not bridging patients with [uncomplicated] atrial fibrillation," who have a similar perioperative thromboembolism risk, he said at the annual meeting of the Society of Hospital Medicine.

Maybe it’s because older caged-ball and tilting-disc aortic valves were more thrombogenic, so "we got in the habit" of bridging, "but the data just don’t support that with [bileaflet] aortic valves," he said. The guidelines do note that patients with caged-ball and tilting-disc aortic valves, and mitral valves, are at high-risk for perioperative thromboembolic events.

In general, bridging practices vary considerably in the United States, and bridging itself is not without risks, Dr. Brotman and his colleagues found in a study of nine hospital centers.

Two bridged more than 80% of their anticoagulation patients with full-dose perioperative heparin; the remaining seven used full-dose heparin in just 22%. The variation persisted after adjustment for patient characteristics.

Patients "at one of these more aggressive centers were three to four times more likely to have a bleeding episode. Not surprisingly, if you take patients who have recently been through surgery and treat them with full-dose heparin products, they are likely to bleed," he said (Am. J. Med. 2010;123:141-150).

When needed, Dr. Brotman prefers to bridge with low-molecular-weight heparin (enoxaparin), delivered on an outpatient basis. "This is a much more cost effective than admitting [valve patients] for unfractionated heparin treatment," he said.

Some might worry about the approach because of an "ugly history related to the [Food and Drug Administration] getting very upset about some very bad outcomes in a small number" of mitral valve patients bridged with low-molecular-weight heparin several years ago, he said.

"They put in a black box warning against using enoxaparin in valve patients, but subsequently realized that patients on anticoagulation with prosthetic mitral valves are at high risk for having bad things happen to them, and that when they have periods of anticoagulation cessation, they are at risk of having something happen regardless of what you bridge them with," Dr. Brotman said. The black box was eventually removed (Circulation 2006;113:470-2).

So "anybody who says it’s safer to bridge patients with unfractionated heparin, you can ask them, ‘well, show me the data.’ There are no head-to-head trials vs. low-molecular-weight heparin, and the data for unfractionated heparin are over 30 years old. It’s not safer; it’s just something that’s been traditional. Anecdotally, I’ve had patients have adverse outcomes with unfractionated heparin," he said.

Dr. Brotman said he has no disclosures.

SAN FRANCISCO – Inhaled hypertonic saline did not reduce the number of pulmonary exacerbations in infants and children with cystic fibrosis in a randomized trial.

The trial pitted 7% hypertonic saline in 158 pediatric patients against 0.9% isotonic saline as a control in 163 patients. The solutions were nebulized twice daily for 48 weeks, with both groups getting albuterol or levalbuterol beforehand. The patients ranged in age from 4 to 60 months. Adherence was at least 75% in each group, judging from returned study drug ampoules, reported lead investigator Dr. Margaret Rosenfeld at an international conference of the American Thoracic Society.

In the hypertonic saline group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% confidence interval [CI], 2.0-2.5), and the mean number of total antibiotic treatment days for pulmonary exacerbations was 60 (95% CI, 49-70). In the control group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% CI, 2.1-2.6), and the mean total number of antibiotic treatment days was 52 (95% CI, 43-61).

No significant differences were seen in secondary end points, including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Adverse event profiles were similar, with cough the most common adverse event in about 40% of each group (JAMA 2012 May 20 [doi:10.1001/jama.2012.5214]).

"There is great interest in the CF [cystic fibrosis] community about developing early intervention strategies to delay or prevent CF lung disease before the bronchiectasis becomes irreversible. From our current evidence, hypertonic saline does not fulfill that role. Based on its inability to reduce the rate of pulmonary exacerbations, we would not recommend that it be used in this age range," said Dr. Rosenfeld, a pediatric pulmonologist and associate professor of pediatrics at the University of Washington in Seattle.

The finding was a surprise because hypertonic saline is known to prevent exacerbations in older children and adults, perhaps by helping the lungs cough out bacteria. There has been hope it would also help very young children, and its use in that population has increased substantially in recent years, Dr. Rosenfeld noted (N. Engl. J. Med. 2006;354:229-40).

"We’ve been scratching our heads about" why that hope didn’t pan out in the trial. "We have a number of hypotheses. The first one is that pulmonary exacerbations may be really different beasts in infants and young children. [Perhaps] they are mostly triggered by viral respiratory infections. Hypertonic saline can’t prevent people from getting respiratory viruses," she said at the conference.

Exacerbations might have been too blunt a primary outcome measure, according to an editorial that accompanied the published study in JAMA.

Very young children with CF have not yet developed the outright lung damage that makes older patients particularly susceptible to exacerbations. Perhaps more subtle markers of early disease onset and progression were needed in the trial, wrote Dr. Elliott Dasenbrook, associate director of the Adult Cystic Fibrosis Program at Case Western Reserve University, Cleveland, and Dr. Michael Konstan, director of the school’s Cystic Fibrosis Center and chairman of its pediatrics department.

"Although the results of the study suggest that inhaled hypertonic saline should not be used routinely in young children, the final verdict on its use for infants and young children has not been rendered. It would be disheartening if a viable therapeutic option was discarded because of negative study results when more sensitive end points might have detected benefit from the intervention. Testing therapeutic agents in infants and young children may require different end points capable of assessing onset and progression of disease," they wrote (JAMA 2012 May 20 [doi: 10.1001/jama.2012.5853]).

There was one "tantalizing" hint in the trial that hypertonic saline may delay structural damage, Dr. Rosenfeld said. Among the 22 children aged 4-16 months in the hypertonic saline group who had pulmonary function tests, forced expiratory volume in 0.5 seconds (FEV_0.5) was a mean of 38 mL greater (95% CI, 1-76) than among the 23 children tested in the control group, the only significant pulmonary function difference.

Perhaps that could be a marker in future trials, but "statistically significant difference does not necessarily imply clinical significance," Dr. Dasenbrook and Dr. Konstan noted. "Even though the results of infant pulmonary function testing appear encouraging, ... these exploratory end points should be viewed as hypothesis generating, and research exploring the clinical effects of these differences is needed."

That research is likely to happen. "We would like to study [hypertonic saline] further and see if we get a signal if we choose more physiologic end points," Dr. Rosenfeld said.

Dr. Rosenfeld disclosed that she is an adviser to Genentech and Vertex Pharmaceuticals, and receives research grants from Vertex. Dr. Dasenbrook is a consultant for Savara and Gilead. Dr. Konstan is an adviser to Aradigm and a consultant for Boehringer Ingelheim, Genentech, Novartis, PARI Respiratory Equipment, Vertex, and several other companies. He receives grants or has grants pending from several companies, and receives speaker’s fees from Genentech and Novartis.

SAN FRANCISCO – Inhaled hypertonic saline did not reduce the number of pulmonary exacerbations in infants and children with cystic fibrosis in a randomized trial.

The trial pitted 7% hypertonic saline in 158 pediatric patients against 0.9% isotonic saline as a control in 163 patients. The solutions were nebulized twice daily for 48 weeks, with both groups getting albuterol or levalbuterol beforehand. The patients ranged in age from 4 to 60 months. Adherence was at least 75% in each group, judging from returned study drug ampoules, reported lead investigator Dr. Margaret Rosenfeld at an international conference of the American Thoracic Society.

In the hypertonic saline group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% confidence interval [CI], 2.0-2.5), and the mean number of total antibiotic treatment days for pulmonary exacerbations was 60 (95% CI, 49-70). In the control group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% CI, 2.1-2.6), and the mean total number of antibiotic treatment days was 52 (95% CI, 43-61).

No significant differences were seen in secondary end points, including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Adverse event profiles were similar, with cough the most common adverse event in about 40% of each group (JAMA 2012 May 20 [doi:10.1001/jama.2012.5214]).

"There is great interest in the CF [cystic fibrosis] community about developing early intervention strategies to delay or prevent CF lung disease before the bronchiectasis becomes irreversible. From our current evidence, hypertonic saline does not fulfill that role. Based on its inability to reduce the rate of pulmonary exacerbations, we would not recommend that it be used in this age range," said Dr. Rosenfeld, a pediatric pulmonologist and associate professor of pediatrics at the University of Washington in Seattle.

The finding was a surprise because hypertonic saline is known to prevent exacerbations in older children and adults, perhaps by helping the lungs cough out bacteria. There has been hope it would also help very young children, and its use in that population has increased substantially in recent years, Dr. Rosenfeld noted (N. Engl. J. Med. 2006;354:229-40).

"We’ve been scratching our heads about" why that hope didn’t pan out in the trial. "We have a number of hypotheses. The first one is that pulmonary exacerbations may be really different beasts in infants and young children. [Perhaps] they are mostly triggered by viral respiratory infections. Hypertonic saline can’t prevent people from getting respiratory viruses," she said at the conference.

Exacerbations might have been too blunt a primary outcome measure, according to an editorial that accompanied the published study in JAMA.

Very young children with CF have not yet developed the outright lung damage that makes older patients particularly susceptible to exacerbations. Perhaps more subtle markers of early disease onset and progression were needed in the trial, wrote Dr. Elliott Dasenbrook, associate director of the Adult Cystic Fibrosis Program at Case Western Reserve University, Cleveland, and Dr. Michael Konstan, director of the school’s Cystic Fibrosis Center and chairman of its pediatrics department.

"Although the results of the study suggest that inhaled hypertonic saline should not be used routinely in young children, the final verdict on its use for infants and young children has not been rendered. It would be disheartening if a viable therapeutic option was discarded because of negative study results when more sensitive end points might have detected benefit from the intervention. Testing therapeutic agents in infants and young children may require different end points capable of assessing onset and progression of disease," they wrote (JAMA 2012 May 20 [doi: 10.1001/jama.2012.5853]).

There was one "tantalizing" hint in the trial that hypertonic saline may delay structural damage, Dr. Rosenfeld said. Among the 22 children aged 4-16 months in the hypertonic saline group who had pulmonary function tests, forced expiratory volume in 0.5 seconds (FEV_0.5) was a mean of 38 mL greater (95% CI, 1-76) than among the 23 children tested in the control group, the only significant pulmonary function difference.

Perhaps that could be a marker in future trials, but "statistically significant difference does not necessarily imply clinical significance," Dr. Dasenbrook and Dr. Konstan noted. "Even though the results of infant pulmonary function testing appear encouraging, ... these exploratory end points should be viewed as hypothesis generating, and research exploring the clinical effects of these differences is needed."

That research is likely to happen. "We would like to study [hypertonic saline] further and see if we get a signal if we choose more physiologic end points," Dr. Rosenfeld said.

Dr. Rosenfeld disclosed that she is an adviser to Genentech and Vertex Pharmaceuticals, and receives research grants from Vertex. Dr. Dasenbrook is a consultant for Savara and Gilead. Dr. Konstan is an adviser to Aradigm and a consultant for Boehringer Ingelheim, Genentech, Novartis, PARI Respiratory Equipment, Vertex, and several other companies. He receives grants or has grants pending from several companies, and receives speaker’s fees from Genentech and Novartis.

SAN FRANCISCO – Inhaled hypertonic saline did not reduce the number of pulmonary exacerbations in infants and children with cystic fibrosis in a randomized trial.

The trial pitted 7% hypertonic saline in 158 pediatric patients against 0.9% isotonic saline as a control in 163 patients. The solutions were nebulized twice daily for 48 weeks, with both groups getting albuterol or levalbuterol beforehand. The patients ranged in age from 4 to 60 months. Adherence was at least 75% in each group, judging from returned study drug ampoules, reported lead investigator Dr. Margaret Rosenfeld at an international conference of the American Thoracic Society.

In the hypertonic saline group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% confidence interval [CI], 2.0-2.5), and the mean number of total antibiotic treatment days for pulmonary exacerbations was 60 (95% CI, 49-70). In the control group, the mean pulmonary exacerbation rate was 2.3 events/person-year (95% CI, 2.1-2.6), and the mean total number of antibiotic treatment days was 52 (95% CI, 43-61).

No significant differences were seen in secondary end points, including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Adverse event profiles were similar, with cough the most common adverse event in about 40% of each group (JAMA 2012 May 20 [doi:10.1001/jama.2012.5214]).

"There is great interest in the CF [cystic fibrosis] community about developing early intervention strategies to delay or prevent CF lung disease before the bronchiectasis becomes irreversible. From our current evidence, hypertonic saline does not fulfill that role. Based on its inability to reduce the rate of pulmonary exacerbations, we would not recommend that it be used in this age range," said Dr. Rosenfeld, a pediatric pulmonologist and associate professor of pediatrics at the University of Washington in Seattle.

The finding was a surprise because hypertonic saline is known to prevent exacerbations in older children and adults, perhaps by helping the lungs cough out bacteria. There has been hope it would also help very young children, and its use in that population has increased substantially in recent years, Dr. Rosenfeld noted (N. Engl. J. Med. 2006;354:229-40).

"We’ve been scratching our heads about" why that hope didn’t pan out in the trial. "We have a number of hypotheses. The first one is that pulmonary exacerbations may be really different beasts in infants and young children. [Perhaps] they are mostly triggered by viral respiratory infections. Hypertonic saline can’t prevent people from getting respiratory viruses," she said at the conference.

Exacerbations might have been too blunt a primary outcome measure, according to an editorial that accompanied the published study in JAMA.

Very young children with CF have not yet developed the outright lung damage that makes older patients particularly susceptible to exacerbations. Perhaps more subtle markers of early disease onset and progression were needed in the trial, wrote Dr. Elliott Dasenbrook, associate director of the Adult Cystic Fibrosis Program at Case Western Reserve University, Cleveland, and Dr. Michael Konstan, director of the school’s Cystic Fibrosis Center and chairman of its pediatrics department.

"Although the results of the study suggest that inhaled hypertonic saline should not be used routinely in young children, the final verdict on its use for infants and young children has not been rendered. It would be disheartening if a viable therapeutic option was discarded because of negative study results when more sensitive end points might have detected benefit from the intervention. Testing therapeutic agents in infants and young children may require different end points capable of assessing onset and progression of disease," they wrote (JAMA 2012 May 20 [doi: 10.1001/jama.2012.5853]).

There was one "tantalizing" hint in the trial that hypertonic saline may delay structural damage, Dr. Rosenfeld said. Among the 22 children aged 4-16 months in the hypertonic saline group who had pulmonary function tests, forced expiratory volume in 0.5 seconds (FEV_0.5) was a mean of 38 mL greater (95% CI, 1-76) than among the 23 children tested in the control group, the only significant pulmonary function difference.

Perhaps that could be a marker in future trials, but "statistically significant difference does not necessarily imply clinical significance," Dr. Dasenbrook and Dr. Konstan noted. "Even though the results of infant pulmonary function testing appear encouraging, ... these exploratory end points should be viewed as hypothesis generating, and research exploring the clinical effects of these differences is needed."

That research is likely to happen. "We would like to study [hypertonic saline] further and see if we get a signal if we choose more physiologic end points," Dr. Rosenfeld said.

Dr. Rosenfeld disclosed that she is an adviser to Genentech and Vertex Pharmaceuticals, and receives research grants from Vertex. Dr. Dasenbrook is a consultant for Savara and Gilead. Dr. Konstan is an adviser to Aradigm and a consultant for Boehringer Ingelheim, Genentech, Novartis, PARI Respiratory Equipment, Vertex, and several other companies. He receives grants or has grants pending from several companies, and receives speaker’s fees from Genentech and Novartis.

NEW ORLEANS – A reformulated version of the previously withdrawn Neupro rotigotine patch had favorable results in separate studies of patients with advanced idiopathic Parkinson’s disease and restless legs syndrome, according to reports given prior to the planned return of the patch to the U.S. market in July.

The dopamine agonist patch was originally approved by the Food and Drug Administration in 2007 for early-stage idiopathic Parkinson’s disease, but UCB Pharma withdrew it from the U.S. market in 2008 because rotigotine was crystallizing out of the delivery matrix. The agency approved a reformulated version in April along with revised labeling that now indicates Neupro for all stages of idiopathic Parkinson’s, plus moderate to severe primary restless legs syndrome (RLS).

The return of the patch is "terrific news for the Parkinson’s disease community. ... Because Parkinson’s disease patients typically have to take many doses of medications each day, the re-approval of the patch will hopefully help a lot of sufferers," by cutting pill burden, among other things, said Dr. Michael Okun, medical director of the National Parkinson Foundation, in a written statement.

In a 16-week, randomized trial involving 514 advanced idiopathic Parkinson’s disease (PD) patients, 8 mg/24 hours reduced off-time by 2.4 hours per day after 12 weeks of maintenance therapy, a statistically significant benefit over placebo, which reduced off-time by 1.5 hours. Lower patch doses reduced off-time as well, but not significantly better than did placebo. All patients in the trial were on levodopa; other medications were allowed. Off-time was assessed by home diaries.

The benefit of 8 mg/24 hour is in line with the new label, which recommends that dosage for advanced Parkinson’s, and 6 mg/24 hours for early-stage disease. The recommended RLS dosage is up to 3 mg/24 hours.

The label details two clinical trials for RLS. In one involving 505 patients, scores on the 40-point IRLS (International RLS) rating scale improved by 14.2 points in patients who were randomized to 3 mg/24 hours for 6 months, whereas placebo improved scores by 9 points. That difference was statistically significant, as were lower Neupro doses. UCB fleshed out the results at the annual meeting of the American Academy of Neurology, noting the magnitude of statistically significant improvements, compared with placebo, in individual components of the IRLS, such as sleep disturbances (0.4-point improvement over placebo on a 5-point scale), impact on daily activities (0.3-point improvement over placebo on a 5-point scale), and frequency of symptoms (0.9-point improvement over placebo on a 5-point scale).

The company also presented post hoc analyses of previous trials that showed that Neupro may help fatigue, apathy, anhedonia, anxiety, and depression in PD. Another post hoc analysis of a 287-patient trial suggested that it might also help with pain; PD patients with a score equal to 1 (any pain) on a 10-point Likert pain scale had a 0.54-point improvement over placebo after being maintained at 2-16 mg/24 hours for 4 weeks.

The patch’s new labeling adds advice on discontinuing the drug, as well as information about the risk of augmentation and rebound in RLS, plus additional detail on somnolence, hypotension, hallucination, impulse control disorder, and other possible side effects.

In the recent randomized trial of 514 patients with PD, "the most common adverse events included application site reactions [15% vs. 7% placebo], nausea [12% vs. 7% placebo], and dyskinesias [8% vs. 3% placebo]. The remainder of the safety profile was similar to previous studies of rotigotine in patients with advanced Parkinson’s," said Dr. Lawrence Elmer, medical director of the center for neurological disorders at the University of Toledo (Ohio), who presented the findings at the meeting.

Dr. Elmer disclosed unrestricted educational grants and payments for consulting, advisory, and speaking services from UCB Pharma and other pharmaceutical companies. Dr. Okun had no current, relevant disclosures.

NEW ORLEANS – A reformulated version of the previously withdrawn Neupro rotigotine patch had favorable results in separate studies of patients with advanced idiopathic Parkinson’s disease and restless legs syndrome, according to reports given prior to the planned return of the patch to the U.S. market in July.

The dopamine agonist patch was originally approved by the Food and Drug Administration in 2007 for early-stage idiopathic Parkinson’s disease, but UCB Pharma withdrew it from the U.S. market in 2008 because rotigotine was crystallizing out of the delivery matrix. The agency approved a reformulated version in April along with revised labeling that now indicates Neupro for all stages of idiopathic Parkinson’s, plus moderate to severe primary restless legs syndrome (RLS).

The return of the patch is "terrific news for the Parkinson’s disease community. ... Because Parkinson’s disease patients typically have to take many doses of medications each day, the re-approval of the patch will hopefully help a lot of sufferers," by cutting pill burden, among other things, said Dr. Michael Okun, medical director of the National Parkinson Foundation, in a written statement.

In a 16-week, randomized trial involving 514 advanced idiopathic Parkinson’s disease (PD) patients, 8 mg/24 hours reduced off-time by 2.4 hours per day after 12 weeks of maintenance therapy, a statistically significant benefit over placebo, which reduced off-time by 1.5 hours. Lower patch doses reduced off-time as well, but not significantly better than did placebo. All patients in the trial were on levodopa; other medications were allowed. Off-time was assessed by home diaries.

The benefit of 8 mg/24 hour is in line with the new label, which recommends that dosage for advanced Parkinson’s, and 6 mg/24 hours for early-stage disease. The recommended RLS dosage is up to 3 mg/24 hours.

The label details two clinical trials for RLS. In one involving 505 patients, scores on the 40-point IRLS (International RLS) rating scale improved by 14.2 points in patients who were randomized to 3 mg/24 hours for 6 months, whereas placebo improved scores by 9 points. That difference was statistically significant, as were lower Neupro doses. UCB fleshed out the results at the annual meeting of the American Academy of Neurology, noting the magnitude of statistically significant improvements, compared with placebo, in individual components of the IRLS, such as sleep disturbances (0.4-point improvement over placebo on a 5-point scale), impact on daily activities (0.3-point improvement over placebo on a 5-point scale), and frequency of symptoms (0.9-point improvement over placebo on a 5-point scale).

The company also presented post hoc analyses of previous trials that showed that Neupro may help fatigue, apathy, anhedonia, anxiety, and depression in PD. Another post hoc analysis of a 287-patient trial suggested that it might also help with pain; PD patients with a score equal to 1 (any pain) on a 10-point Likert pain scale had a 0.54-point improvement over placebo after being maintained at 2-16 mg/24 hours for 4 weeks.

The patch’s new labeling adds advice on discontinuing the drug, as well as information about the risk of augmentation and rebound in RLS, plus additional detail on somnolence, hypotension, hallucination, impulse control disorder, and other possible side effects.

In the recent randomized trial of 514 patients with PD, "the most common adverse events included application site reactions [15% vs. 7% placebo], nausea [12% vs. 7% placebo], and dyskinesias [8% vs. 3% placebo]. The remainder of the safety profile was similar to previous studies of rotigotine in patients with advanced Parkinson’s," said Dr. Lawrence Elmer, medical director of the center for neurological disorders at the University of Toledo (Ohio), who presented the findings at the meeting.

Dr. Elmer disclosed unrestricted educational grants and payments for consulting, advisory, and speaking services from UCB Pharma and other pharmaceutical companies. Dr. Okun had no current, relevant disclosures.

NEW ORLEANS – A reformulated version of the previously withdrawn Neupro rotigotine patch had favorable results in separate studies of patients with advanced idiopathic Parkinson’s disease and restless legs syndrome, according to reports given prior to the planned return of the patch to the U.S. market in July.

The dopamine agonist patch was originally approved by the Food and Drug Administration in 2007 for early-stage idiopathic Parkinson’s disease, but UCB Pharma withdrew it from the U.S. market in 2008 because rotigotine was crystallizing out of the delivery matrix. The agency approved a reformulated version in April along with revised labeling that now indicates Neupro for all stages of idiopathic Parkinson’s, plus moderate to severe primary restless legs syndrome (RLS).

The return of the patch is "terrific news for the Parkinson’s disease community. ... Because Parkinson’s disease patients typically have to take many doses of medications each day, the re-approval of the patch will hopefully help a lot of sufferers," by cutting pill burden, among other things, said Dr. Michael Okun, medical director of the National Parkinson Foundation, in a written statement.

In a 16-week, randomized trial involving 514 advanced idiopathic Parkinson’s disease (PD) patients, 8 mg/24 hours reduced off-time by 2.4 hours per day after 12 weeks of maintenance therapy, a statistically significant benefit over placebo, which reduced off-time by 1.5 hours. Lower patch doses reduced off-time as well, but not significantly better than did placebo. All patients in the trial were on levodopa; other medications were allowed. Off-time was assessed by home diaries.

The benefit of 8 mg/24 hour is in line with the new label, which recommends that dosage for advanced Parkinson’s, and 6 mg/24 hours for early-stage disease. The recommended RLS dosage is up to 3 mg/24 hours.

The label details two clinical trials for RLS. In one involving 505 patients, scores on the 40-point IRLS (International RLS) rating scale improved by 14.2 points in patients who were randomized to 3 mg/24 hours for 6 months, whereas placebo improved scores by 9 points. That difference was statistically significant, as were lower Neupro doses. UCB fleshed out the results at the annual meeting of the American Academy of Neurology, noting the magnitude of statistically significant improvements, compared with placebo, in individual components of the IRLS, such as sleep disturbances (0.4-point improvement over placebo on a 5-point scale), impact on daily activities (0.3-point improvement over placebo on a 5-point scale), and frequency of symptoms (0.9-point improvement over placebo on a 5-point scale).

The company also presented post hoc analyses of previous trials that showed that Neupro may help fatigue, apathy, anhedonia, anxiety, and depression in PD. Another post hoc analysis of a 287-patient trial suggested that it might also help with pain; PD patients with a score equal to 1 (any pain) on a 10-point Likert pain scale had a 0.54-point improvement over placebo after being maintained at 2-16 mg/24 hours for 4 weeks.

The patch’s new labeling adds advice on discontinuing the drug, as well as information about the risk of augmentation and rebound in RLS, plus additional detail on somnolence, hypotension, hallucination, impulse control disorder, and other possible side effects.

In the recent randomized trial of 514 patients with PD, "the most common adverse events included application site reactions [15% vs. 7% placebo], nausea [12% vs. 7% placebo], and dyskinesias [8% vs. 3% placebo]. The remainder of the safety profile was similar to previous studies of rotigotine in patients with advanced Parkinson’s," said Dr. Lawrence Elmer, medical director of the center for neurological disorders at the University of Toledo (Ohio), who presented the findings at the meeting.

Dr. Elmer disclosed unrestricted educational grants and payments for consulting, advisory, and speaking services from UCB Pharma and other pharmaceutical companies. Dr. Okun had no current, relevant disclosures.

SAN FRANCISCO – Patients aged 55-74 years who have at least a 30 pack-year smoking history should be offered annual low-dose CT lung cancer screening, even if they have quit within the past 15 years, according to a systematic review published online May 20 in JAMA.

The review forms the basis of the new lung cancer screening clinical practice guidelines from the American College of Chest Physicians and the American Society of Clinical Oncology. The recommendations are based largely on the 53,454-patient, randomized NLST (National Lung Screening Trial), which found that for every 1,000 high-risk smokers, three rounds of annual CT screening saved approximately three lives over about 7 years, which is comparable, at least, to the absolute benefit of screening mammographies in older women (N. Engl. J. Med. 2011;365:395-409).

The risks – including misdiagnosis and unnecessary surgery – and potential benefits should be explained to patients before they opt for screening. "People need to know" that "19 out of 20 positive results are going to be false positive. A positive screen does not equal a diagnosis of lung cancer," said coauthor Dr. Michael K. Gould, assistant director for health services research at Kaiser Permanente of Southern California, Pasadena.

In addition, "CT screening should not be performed" in smokers and ex-smokers who fall outside of the high-risk group, or in those with severe comorbidities that limit life expectancy or preclude treatment, according to the guidelines (JAMA 2012 May 20 [doi:10.1001/jama.2012.5521]).

The risks and benefits of screening are just "too close to call" for those patients, said lead author Dr. Peter Bach, director of the center for health policy and outcomes at Memorial Sloan-Kettering Cancer Center in New York.

After an extensive literature review, the researchers included eight randomized trials and 13 cohort studies in its final analysis. Although they are confident that screening benefits high-risk patients – based mostly on the NLST, with some added input from smaller trials – they are also concerned about the lack of data on the potential harms of screening, which led to the recommendation to offer screening only to high-risk patients, Dr. Bach said.

Overall, the lack of additional research led both recommendations to be characterized as "weak" under the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

The impact of screening even high-risk patients "on smoking cessation, quality of life, and cost-effectiveness is really quite unclear. We don’t know in any sense what the frequency should be or the duration," Dr. Bach said.

Also unclear is how screening will play out in settings less rigorous than the academic centers where the NLST was conducted. Patient compliance with screening at those centers was 90%, adverse events were rare, and subsequent diagnostic work-ups and interventions were available.

To mitigate potential problems, the guidelines recommend that screening be done in similar multidisciplinary settings.

The authors also call for a screening registry "that records each patient’s experience [to] help us develop a quality measurement system similar to mammography screening that could maximize the benefits and minimize the harm for individuals who undergo screening," Dr. Bach said.

A supplement to the JAMA article includes a section entitled "Components of a Conversation About CT Screening," which addresses how to talk with patients about these issues.

The American Thoracic Society has endorsed the guidelines.

Dr. Bach reported that he has received speaking fees from Genentech. Coauthors reported ties to pharmaceutical companies such as Oncimmune and governmental agencies such as the National Cancer Institute. Dr. Gould and Dr. Bauchner said they have no relevant disclosures.

SAN FRANCISCO – Patients aged 55-74 years who have at least a 30 pack-year smoking history should be offered annual low-dose CT lung cancer screening, even if they have quit within the past 15 years, according to a systematic review published online May 20 in JAMA.

The review forms the basis of the new lung cancer screening clinical practice guidelines from the American College of Chest Physicians and the American Society of Clinical Oncology. The recommendations are based largely on the 53,454-patient, randomized NLST (National Lung Screening Trial), which found that for every 1,000 high-risk smokers, three rounds of annual CT screening saved approximately three lives over about 7 years, which is comparable, at least, to the absolute benefit of screening mammographies in older women (N. Engl. J. Med. 2011;365:395-409).

The risks – including misdiagnosis and unnecessary surgery – and potential benefits should be explained to patients before they opt for screening. "People need to know" that "19 out of 20 positive results are going to be false positive. A positive screen does not equal a diagnosis of lung cancer," said coauthor Dr. Michael K. Gould, assistant director for health services research at Kaiser Permanente of Southern California, Pasadena.

In addition, "CT screening should not be performed" in smokers and ex-smokers who fall outside of the high-risk group, or in those with severe comorbidities that limit life expectancy or preclude treatment, according to the guidelines (JAMA 2012 May 20 [doi:10.1001/jama.2012.5521]).

The risks and benefits of screening are just "too close to call" for those patients, said lead author Dr. Peter Bach, director of the center for health policy and outcomes at Memorial Sloan-Kettering Cancer Center in New York.

After an extensive literature review, the researchers included eight randomized trials and 13 cohort studies in its final analysis. Although they are confident that screening benefits high-risk patients – based mostly on the NLST, with some added input from smaller trials – they are also concerned about the lack of data on the potential harms of screening, which led to the recommendation to offer screening only to high-risk patients, Dr. Bach said.

Overall, the lack of additional research led both recommendations to be characterized as "weak" under the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

The impact of screening even high-risk patients "on smoking cessation, quality of life, and cost-effectiveness is really quite unclear. We don’t know in any sense what the frequency should be or the duration," Dr. Bach said.

Also unclear is how screening will play out in settings less rigorous than the academic centers where the NLST was conducted. Patient compliance with screening at those centers was 90%, adverse events were rare, and subsequent diagnostic work-ups and interventions were available.

To mitigate potential problems, the guidelines recommend that screening be done in similar multidisciplinary settings.

The authors also call for a screening registry "that records each patient’s experience [to] help us develop a quality measurement system similar to mammography screening that could maximize the benefits and minimize the harm for individuals who undergo screening," Dr. Bach said.

A supplement to the JAMA article includes a section entitled "Components of a Conversation About CT Screening," which addresses how to talk with patients about these issues.

The American Thoracic Society has endorsed the guidelines.

Dr. Bach reported that he has received speaking fees from Genentech. Coauthors reported ties to pharmaceutical companies such as Oncimmune and governmental agencies such as the National Cancer Institute. Dr. Gould and Dr. Bauchner said they have no relevant disclosures.

SAN FRANCISCO – Patients aged 55-74 years who have at least a 30 pack-year smoking history should be offered annual low-dose CT lung cancer screening, even if they have quit within the past 15 years, according to a systematic review published online May 20 in JAMA.

The review forms the basis of the new lung cancer screening clinical practice guidelines from the American College of Chest Physicians and the American Society of Clinical Oncology. The recommendations are based largely on the 53,454-patient, randomized NLST (National Lung Screening Trial), which found that for every 1,000 high-risk smokers, three rounds of annual CT screening saved approximately three lives over about 7 years, which is comparable, at least, to the absolute benefit of screening mammographies in older women (N. Engl. J. Med. 2011;365:395-409).

The risks – including misdiagnosis and unnecessary surgery – and potential benefits should be explained to patients before they opt for screening. "People need to know" that "19 out of 20 positive results are going to be false positive. A positive screen does not equal a diagnosis of lung cancer," said coauthor Dr. Michael K. Gould, assistant director for health services research at Kaiser Permanente of Southern California, Pasadena.

In addition, "CT screening should not be performed" in smokers and ex-smokers who fall outside of the high-risk group, or in those with severe comorbidities that limit life expectancy or preclude treatment, according to the guidelines (JAMA 2012 May 20 [doi:10.1001/jama.2012.5521]).

The risks and benefits of screening are just "too close to call" for those patients, said lead author Dr. Peter Bach, director of the center for health policy and outcomes at Memorial Sloan-Kettering Cancer Center in New York.

After an extensive literature review, the researchers included eight randomized trials and 13 cohort studies in its final analysis. Although they are confident that screening benefits high-risk patients – based mostly on the NLST, with some added input from smaller trials – they are also concerned about the lack of data on the potential harms of screening, which led to the recommendation to offer screening only to high-risk patients, Dr. Bach said.

Overall, the lack of additional research led both recommendations to be characterized as "weak" under the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

The impact of screening even high-risk patients "on smoking cessation, quality of life, and cost-effectiveness is really quite unclear. We don’t know in any sense what the frequency should be or the duration," Dr. Bach said.

Also unclear is how screening will play out in settings less rigorous than the academic centers where the NLST was conducted. Patient compliance with screening at those centers was 90%, adverse events were rare, and subsequent diagnostic work-ups and interventions were available.

To mitigate potential problems, the guidelines recommend that screening be done in similar multidisciplinary settings.

The authors also call for a screening registry "that records each patient’s experience [to] help us develop a quality measurement system similar to mammography screening that could maximize the benefits and minimize the harm for individuals who undergo screening," Dr. Bach said.

A supplement to the JAMA article includes a section entitled "Components of a Conversation About CT Screening," which addresses how to talk with patients about these issues.

The American Thoracic Society has endorsed the guidelines.

Dr. Bach reported that he has received speaking fees from Genentech. Coauthors reported ties to pharmaceutical companies such as Oncimmune and governmental agencies such as the National Cancer Institute. Dr. Gould and Dr. Bauchner said they have no relevant disclosures.

NEW ORLEANS – Higher vitamin D levels are associated with slightly less disability and greater preservation of gray matter in patients with multiple sclerosis, according to a 5-year observational study.

The researchers assessed 25-hydroxyvitamin D levels, clinical disability, and MRI brain volumes annually in 469 patients with relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome, all members of a longitudinal MS cohort study at the University of California, San Francisco.

They found that for every 10-ng/mL increase in 25-hydroxyvitamin D levels, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% confidence interval –0.091 to –0.003; P = .037), and subsequent normalized gray matter volume was 7 cc higher (95% CI 2.4, 11.5; P = .003). The results were adjusted for age, sex, ethnicity, smoking status, body mass index, and use of MS treatments.

Based on the results and a growing body of literature suggesting a role for vitamin D in MS, lead investigator Dr. Ellen Mowry, an assistant professor of neuroimmunology at Johns Hopkins University, Baltimore, often supplements her patients to a vitamin D level of 40-60 ng/mL, which usually takes 2,000-4,000 international units a day.

"The preponderance of the observational evidence is in favor of supplementing, and I think those levels are the most strongly supported by the data. Above 60 ng/mL, there are very few data to say whether or not the effect remains the same," she said at the annual meeting of the American Academy of Neurology.

Dr. Mowry said she is careful to tell her MS patients that although observational studies suggest vitamin D is safe and helpful, ongoing randomized trials may prove otherwise.

The average age of patients in her study was 42 years; their median disease duration was 5 years, and about two-thirds were women. Their baseline vitamin D levels were low at around 28 ng/mL.

Mean EDSS scores were about 1.5 at the start of the study, and about 2 at its end. Mean normalized gray matter volumes were 985 cc at baseline and 964 cc at the end of 4 years. Only 9% of the subjects took vitamin D supplements at the start of the study, but almost half (43%) took them at its end.

Trends were favorable for an association between vitamin D levels and preservation of brain parenchymal volume, but the results were not statistically significant.

The results are in line with a 2006 study that found an inverse association between vitamin D levels and the risk for developing MS (JAMA 2006;296:2832-8).

Previously, Dr. Mowry and other researchers have demonstrated that vitamin D levels are inversely associated with MS relapse risk in both children and adults (Ann. Neurol. 2010;67:618-24; Ann. Neurol. 2010;68:193-203).

Dr. Mowry is the principal investigator in a randomized treatment trial that will assess the impact of high- and low-dose vitamin D supplementation on attack rates, numbers of new lesions, and changes in brain volume in relapsing-remitting MS.

The study was funded by a grant from the National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals.

NEW ORLEANS – Higher vitamin D levels are associated with slightly less disability and greater preservation of gray matter in patients with multiple sclerosis, according to a 5-year observational study.

The researchers assessed 25-hydroxyvitamin D levels, clinical disability, and MRI brain volumes annually in 469 patients with relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome, all members of a longitudinal MS cohort study at the University of California, San Francisco.

They found that for every 10-ng/mL increase in 25-hydroxyvitamin D levels, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% confidence interval –0.091 to –0.003; P = .037), and subsequent normalized gray matter volume was 7 cc higher (95% CI 2.4, 11.5; P = .003). The results were adjusted for age, sex, ethnicity, smoking status, body mass index, and use of MS treatments.

Based on the results and a growing body of literature suggesting a role for vitamin D in MS, lead investigator Dr. Ellen Mowry, an assistant professor of neuroimmunology at Johns Hopkins University, Baltimore, often supplements her patients to a vitamin D level of 40-60 ng/mL, which usually takes 2,000-4,000 international units a day.

"The preponderance of the observational evidence is in favor of supplementing, and I think those levels are the most strongly supported by the data. Above 60 ng/mL, there are very few data to say whether or not the effect remains the same," she said at the annual meeting of the American Academy of Neurology.

Dr. Mowry said she is careful to tell her MS patients that although observational studies suggest vitamin D is safe and helpful, ongoing randomized trials may prove otherwise.

The average age of patients in her study was 42 years; their median disease duration was 5 years, and about two-thirds were women. Their baseline vitamin D levels were low at around 28 ng/mL.

Mean EDSS scores were about 1.5 at the start of the study, and about 2 at its end. Mean normalized gray matter volumes were 985 cc at baseline and 964 cc at the end of 4 years. Only 9% of the subjects took vitamin D supplements at the start of the study, but almost half (43%) took them at its end.

Trends were favorable for an association between vitamin D levels and preservation of brain parenchymal volume, but the results were not statistically significant.

The results are in line with a 2006 study that found an inverse association between vitamin D levels and the risk for developing MS (JAMA 2006;296:2832-8).

Previously, Dr. Mowry and other researchers have demonstrated that vitamin D levels are inversely associated with MS relapse risk in both children and adults (Ann. Neurol. 2010;67:618-24; Ann. Neurol. 2010;68:193-203).

Dr. Mowry is the principal investigator in a randomized treatment trial that will assess the impact of high- and low-dose vitamin D supplementation on attack rates, numbers of new lesions, and changes in brain volume in relapsing-remitting MS.

The study was funded by a grant from the National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals.

NEW ORLEANS – Higher vitamin D levels are associated with slightly less disability and greater preservation of gray matter in patients with multiple sclerosis, according to a 5-year observational study.

The researchers assessed 25-hydroxyvitamin D levels, clinical disability, and MRI brain volumes annually in 469 patients with relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome, all members of a longitudinal MS cohort study at the University of California, San Francisco.

They found that for every 10-ng/mL increase in 25-hydroxyvitamin D levels, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% confidence interval –0.091 to –0.003; P = .037), and subsequent normalized gray matter volume was 7 cc higher (95% CI 2.4, 11.5; P = .003). The results were adjusted for age, sex, ethnicity, smoking status, body mass index, and use of MS treatments.

Based on the results and a growing body of literature suggesting a role for vitamin D in MS, lead investigator Dr. Ellen Mowry, an assistant professor of neuroimmunology at Johns Hopkins University, Baltimore, often supplements her patients to a vitamin D level of 40-60 ng/mL, which usually takes 2,000-4,000 international units a day.

"The preponderance of the observational evidence is in favor of supplementing, and I think those levels are the most strongly supported by the data. Above 60 ng/mL, there are very few data to say whether or not the effect remains the same," she said at the annual meeting of the American Academy of Neurology.

Dr. Mowry said she is careful to tell her MS patients that although observational studies suggest vitamin D is safe and helpful, ongoing randomized trials may prove otherwise.

The average age of patients in her study was 42 years; their median disease duration was 5 years, and about two-thirds were women. Their baseline vitamin D levels were low at around 28 ng/mL.

Mean EDSS scores were about 1.5 at the start of the study, and about 2 at its end. Mean normalized gray matter volumes were 985 cc at baseline and 964 cc at the end of 4 years. Only 9% of the subjects took vitamin D supplements at the start of the study, but almost half (43%) took them at its end.

Trends were favorable for an association between vitamin D levels and preservation of brain parenchymal volume, but the results were not statistically significant.

The results are in line with a 2006 study that found an inverse association between vitamin D levels and the risk for developing MS (JAMA 2006;296:2832-8).

Previously, Dr. Mowry and other researchers have demonstrated that vitamin D levels are inversely associated with MS relapse risk in both children and adults (Ann. Neurol. 2010;67:618-24; Ann. Neurol. 2010;68:193-203).

Dr. Mowry is the principal investigator in a randomized treatment trial that will assess the impact of high- and low-dose vitamin D supplementation on attack rates, numbers of new lesions, and changes in brain volume in relapsing-remitting MS.

The study was funded by a grant from the National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals.