Mary Ann Moon

Both short- and long-acting inhaled anticholinergic medications appear to raise the risk of acute urinary retention in men taking the drugs for treatment of chronic obstructive pulmonary disease, according to a report in the May 23 issue of the Archives of Internal Medicine.

Men who take both types of anticholinergics concomitantly and men who have benign prostatic hypertrophy (BPH) are at highest risk for developing acute urinary retention, which is considered a urologic emergency, said Dr. Anne Stephenson of St. Michael’s Hospital, Toronto, and her associates.

"Physicians and the public need to be aware of the potential for this significant adverse event so that preventive measures and potential therapy can be considered," they said.

Until now, it has been "uncertain" whether inhaled anticholinergics caused detrimental urologic effects. Canadian, European, and American practice guidelines say little about possible adverse effects on prostatic symptoms, and clinical studies offer conflicting results.

To examine the association between exposure to inhaled anticholinergics and the development of acute urinary retention, Dr. Stephenson and her colleagues performed a population-based case-control study, first identifying all 563,705 Ontario residents aged 66 years and older who had COPD and whose records could be followed in a medical database for a median of 5 years.

During that time, 9,432 of the men and 1,806 of the women developed a first episode of acute urinary retention. These cases were matched with 46,865 men and 9,020 women with COPD who did not develop acute urinary retention and served as control subjects.

Men who used inhaled anticholinergics were at significantly increased risk of developing acute urinary retention, but women were not.

Men who initiated inhaled anticholinergic therapy during the study period had more than a 40% higher chance of developing acute urinary retention than were men who didn’t use the drugs. This was true with either short-acting agents (ipratropium products) or a long-acting agent (tiotropium bromide).

Men who initiated combination therapy with both short- and long-acting inhaled anticholinergics were at 169% higher risk than were those who didn’t take the drugs, suggesting a dose-response relationship.

Men who were already taking inhaled anticholinergics at baseline rather than initiating the therapy were at slightly lower but still significantly increased risk of developing acute urinary retention, with an odds ratio of 1.36.

Men with BPH who began taking the drugs had an 80% greater chance of developing acute urinary retention, compared with nonusers. "According to our risk estimates, for men with BPH newly initiating a regimen of inhaled anticholinergics, 1 in 514 will experience this adverse event," the investigators said (Arch. Intern. Med. 2011;171:914-20).

Among new users of the drugs, acute urinary retention tended to develop within 30 days (median, 14 days), "further strengthening a causal relationship.

"These data suggest that [patients] may benefit from close monitoring for signs and symptoms of impending urinary retention within the first month of starting inhaled anticholinergics," they said.

Moreover, any patient taking these drugs who develops urinary changes should be carefully evaluated for possible preventive or therapeutic interventions, Dr. Stephenson and her associates added.

"We suggest that the association between respiratory inhaler use and bladder dysfunction may be underappreciated by the medical profession and by the public. ... Physicians should highlight for patients the possible connection" to urinary symptoms such as incomplete voiding, urinary incontinence, and decreased urinary flow.

This study was somewhat limited in that there were no data available on patient-related variables such as lung function, smoking history, renal impairment, and severity of COPD, all of which could be confounders.

"The lack of effect among women ... could be a reflection of the small sample size within this subgroup." Also, women are known to have substantially lower rates of urinary retention than men, most likely because of anatomical differences in the urinary tract.

Dr. Stephenson’s study was funded by the Canadian Institutes of Health Research and the Ontario Ministry of Health and Long-Term Care. No financial conflicts of interest were reported.

Both short- and long-acting inhaled anticholinergic medications appear to raise the risk of acute urinary retention in men taking the drugs for treatment of chronic obstructive pulmonary disease, according to a report in the May 23 issue of the Archives of Internal Medicine.

Men who take both types of anticholinergics concomitantly and men who have benign prostatic hypertrophy (BPH) are at highest risk for developing acute urinary retention, which is considered a urologic emergency, said Dr. Anne Stephenson of St. Michael’s Hospital, Toronto, and her associates.

"Physicians and the public need to be aware of the potential for this significant adverse event so that preventive measures and potential therapy can be considered," they said.

Until now, it has been "uncertain" whether inhaled anticholinergics caused detrimental urologic effects. Canadian, European, and American practice guidelines say little about possible adverse effects on prostatic symptoms, and clinical studies offer conflicting results.

To examine the association between exposure to inhaled anticholinergics and the development of acute urinary retention, Dr. Stephenson and her colleagues performed a population-based case-control study, first identifying all 563,705 Ontario residents aged 66 years and older who had COPD and whose records could be followed in a medical database for a median of 5 years.

During that time, 9,432 of the men and 1,806 of the women developed a first episode of acute urinary retention. These cases were matched with 46,865 men and 9,020 women with COPD who did not develop acute urinary retention and served as control subjects.

Men who used inhaled anticholinergics were at significantly increased risk of developing acute urinary retention, but women were not.

Men who initiated inhaled anticholinergic therapy during the study period had more than a 40% higher chance of developing acute urinary retention than were men who didn’t use the drugs. This was true with either short-acting agents (ipratropium products) or a long-acting agent (tiotropium bromide).

Men who initiated combination therapy with both short- and long-acting inhaled anticholinergics were at 169% higher risk than were those who didn’t take the drugs, suggesting a dose-response relationship.

Men who were already taking inhaled anticholinergics at baseline rather than initiating the therapy were at slightly lower but still significantly increased risk of developing acute urinary retention, with an odds ratio of 1.36.

Men with BPH who began taking the drugs had an 80% greater chance of developing acute urinary retention, compared with nonusers. "According to our risk estimates, for men with BPH newly initiating a regimen of inhaled anticholinergics, 1 in 514 will experience this adverse event," the investigators said (Arch. Intern. Med. 2011;171:914-20).

Among new users of the drugs, acute urinary retention tended to develop within 30 days (median, 14 days), "further strengthening a causal relationship.

"These data suggest that [patients] may benefit from close monitoring for signs and symptoms of impending urinary retention within the first month of starting inhaled anticholinergics," they said.

Moreover, any patient taking these drugs who develops urinary changes should be carefully evaluated for possible preventive or therapeutic interventions, Dr. Stephenson and her associates added.

"We suggest that the association between respiratory inhaler use and bladder dysfunction may be underappreciated by the medical profession and by the public. ... Physicians should highlight for patients the possible connection" to urinary symptoms such as incomplete voiding, urinary incontinence, and decreased urinary flow.

This study was somewhat limited in that there were no data available on patient-related variables such as lung function, smoking history, renal impairment, and severity of COPD, all of which could be confounders.

"The lack of effect among women ... could be a reflection of the small sample size within this subgroup." Also, women are known to have substantially lower rates of urinary retention than men, most likely because of anatomical differences in the urinary tract.

Dr. Stephenson’s study was funded by the Canadian Institutes of Health Research and the Ontario Ministry of Health and Long-Term Care. No financial conflicts of interest were reported.

Both short- and long-acting inhaled anticholinergic medications appear to raise the risk of acute urinary retention in men taking the drugs for treatment of chronic obstructive pulmonary disease, according to a report in the May 23 issue of the Archives of Internal Medicine.

Men who take both types of anticholinergics concomitantly and men who have benign prostatic hypertrophy (BPH) are at highest risk for developing acute urinary retention, which is considered a urologic emergency, said Dr. Anne Stephenson of St. Michael’s Hospital, Toronto, and her associates.

"Physicians and the public need to be aware of the potential for this significant adverse event so that preventive measures and potential therapy can be considered," they said.

Until now, it has been "uncertain" whether inhaled anticholinergics caused detrimental urologic effects. Canadian, European, and American practice guidelines say little about possible adverse effects on prostatic symptoms, and clinical studies offer conflicting results.

To examine the association between exposure to inhaled anticholinergics and the development of acute urinary retention, Dr. Stephenson and her colleagues performed a population-based case-control study, first identifying all 563,705 Ontario residents aged 66 years and older who had COPD and whose records could be followed in a medical database for a median of 5 years.

During that time, 9,432 of the men and 1,806 of the women developed a first episode of acute urinary retention. These cases were matched with 46,865 men and 9,020 women with COPD who did not develop acute urinary retention and served as control subjects.

Men who used inhaled anticholinergics were at significantly increased risk of developing acute urinary retention, but women were not.

Men who initiated inhaled anticholinergic therapy during the study period had more than a 40% higher chance of developing acute urinary retention than were men who didn’t use the drugs. This was true with either short-acting agents (ipratropium products) or a long-acting agent (tiotropium bromide).

Men who initiated combination therapy with both short- and long-acting inhaled anticholinergics were at 169% higher risk than were those who didn’t take the drugs, suggesting a dose-response relationship.

Men who were already taking inhaled anticholinergics at baseline rather than initiating the therapy were at slightly lower but still significantly increased risk of developing acute urinary retention, with an odds ratio of 1.36.

Men with BPH who began taking the drugs had an 80% greater chance of developing acute urinary retention, compared with nonusers. "According to our risk estimates, for men with BPH newly initiating a regimen of inhaled anticholinergics, 1 in 514 will experience this adverse event," the investigators said (Arch. Intern. Med. 2011;171:914-20).

Among new users of the drugs, acute urinary retention tended to develop within 30 days (median, 14 days), "further strengthening a causal relationship.

"These data suggest that [patients] may benefit from close monitoring for signs and symptoms of impending urinary retention within the first month of starting inhaled anticholinergics," they said.

Moreover, any patient taking these drugs who develops urinary changes should be carefully evaluated for possible preventive or therapeutic interventions, Dr. Stephenson and her associates added.

"We suggest that the association between respiratory inhaler use and bladder dysfunction may be underappreciated by the medical profession and by the public. ... Physicians should highlight for patients the possible connection" to urinary symptoms such as incomplete voiding, urinary incontinence, and decreased urinary flow.

This study was somewhat limited in that there were no data available on patient-related variables such as lung function, smoking history, renal impairment, and severity of COPD, all of which could be confounders.

"The lack of effect among women ... could be a reflection of the small sample size within this subgroup." Also, women are known to have substantially lower rates of urinary retention than men, most likely because of anatomical differences in the urinary tract.

Dr. Stephenson’s study was funded by the Canadian Institutes of Health Research and the Ontario Ministry of Health and Long-Term Care. No financial conflicts of interest were reported.

Neither aspirin nor simvastatin improved outcomes for patients with pulmonary arterial hypertension in a phase II safety and efficacy trial published online May 19 in Circulation and simultaneously presented at the annual meeting of the American Thoracic Society.

The primary end point of 6-minute walk distance did not increase after 6 months of aspirin therapy and actually decreased after 6 months of simvastatin therapy, indicating that neither agent should be used as an add-on therapy in PAH, said Dr. Steven M. Kawut of Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, and his associates.

A recent animal study showed that aspirin decreased pulmonary artery pressure, reduced right ventricular hypertrophy, and improved survival, and several recent studies showed that statins were effective in animal models of pulmonary hypertension. Dr. Kawut and his associates in the ASA-STAT Study Group designed their phase II clinical trial to test the safety and efficacy of both agents against matching placebos, intending to enroll 100 subjects with PAH.

The study, however, was terminated after only 65 subjects had been randomized because an interim analysis showed "a high likelihood of not rejecting the null hypothesis for the simvastatin arm even if fully recruited," they wrote. The investigators reported their findings for those 65 subjects.

The patients’ mean age was 50 years, and 86% were women. Approximately 52% had idiopathic PAH, 19% had PAH associated with systemic sclerosis, 15% had PAH associated with other connective tissue diseases, 9% had congenital systemic-to-pulmonary shunts, and 5% had heritable PAH.

The primary outcome measure was 6-minute walk distance after 6 months of treatment, after adjustment for 6-minute walk distance at baseline.

Patients who received aspirin therapy showed no improvement in this measure, compared with those who received placebo. They also showed no improvement in median Borg dyspnea scores after the walk test, in any scales of the SF-36, or in World Health Organization functional class. And there was no difference between the two groups in time to clinical worsening, Dr. Kawut and his associates said.

Similarly, patients who received simvastatin showed no improvement in 6-minute walk distance after 6 months of treatment, compared with those who received placebo. In fact, the active drug may have reduced this distance, although the number of subjects was not sufficient to detect a statistically significant difference. Moreover, the median Borg dyspnea scores after the walk test tended to be higher in subjects who took simvastatin than in those who took placebo, suggesting greater breathlessness.

As with aspirin, there were no differences on any scales of the SF-36 or in WHO functional class between the subjects who took simvastatin and those who took placebo, the investigators said (Circulation 2011 May 19 [doi:10.1161/CIRCULATIONAHA.110.015693]).

"There was a possible increased risk of major bleeding associated with aspirin use," they noted, but again, the number of subjects was not sufficient to make this determination definitively.

"On the basis of these finding, neither drug can be recommended for the treatment of PAH," Dr. Kawut and his colleagues said.

The study was funded by the National Institutes of Health and the National Center for Research Resources. Aspirin and matching placebo were provided free of charge by Bayer Healthcare. Additional support was provided by Merck. Dr. Kawut and his associates reported ties to numerous industry sources.

Neither aspirin nor simvastatin improved outcomes for patients with pulmonary arterial hypertension in a phase II safety and efficacy trial published online May 19 in Circulation and simultaneously presented at the annual meeting of the American Thoracic Society.

The primary end point of 6-minute walk distance did not increase after 6 months of aspirin therapy and actually decreased after 6 months of simvastatin therapy, indicating that neither agent should be used as an add-on therapy in PAH, said Dr. Steven M. Kawut of Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, and his associates.

A recent animal study showed that aspirin decreased pulmonary artery pressure, reduced right ventricular hypertrophy, and improved survival, and several recent studies showed that statins were effective in animal models of pulmonary hypertension. Dr. Kawut and his associates in the ASA-STAT Study Group designed their phase II clinical trial to test the safety and efficacy of both agents against matching placebos, intending to enroll 100 subjects with PAH.

The study, however, was terminated after only 65 subjects had been randomized because an interim analysis showed "a high likelihood of not rejecting the null hypothesis for the simvastatin arm even if fully recruited," they wrote. The investigators reported their findings for those 65 subjects.

The patients’ mean age was 50 years, and 86% were women. Approximately 52% had idiopathic PAH, 19% had PAH associated with systemic sclerosis, 15% had PAH associated with other connective tissue diseases, 9% had congenital systemic-to-pulmonary shunts, and 5% had heritable PAH.

The primary outcome measure was 6-minute walk distance after 6 months of treatment, after adjustment for 6-minute walk distance at baseline.

Patients who received aspirin therapy showed no improvement in this measure, compared with those who received placebo. They also showed no improvement in median Borg dyspnea scores after the walk test, in any scales of the SF-36, or in World Health Organization functional class. And there was no difference between the two groups in time to clinical worsening, Dr. Kawut and his associates said.

Similarly, patients who received simvastatin showed no improvement in 6-minute walk distance after 6 months of treatment, compared with those who received placebo. In fact, the active drug may have reduced this distance, although the number of subjects was not sufficient to detect a statistically significant difference. Moreover, the median Borg dyspnea scores after the walk test tended to be higher in subjects who took simvastatin than in those who took placebo, suggesting greater breathlessness.

As with aspirin, there were no differences on any scales of the SF-36 or in WHO functional class between the subjects who took simvastatin and those who took placebo, the investigators said (Circulation 2011 May 19 [doi:10.1161/CIRCULATIONAHA.110.015693]).

"There was a possible increased risk of major bleeding associated with aspirin use," they noted, but again, the number of subjects was not sufficient to make this determination definitively.

"On the basis of these finding, neither drug can be recommended for the treatment of PAH," Dr. Kawut and his colleagues said.

The study was funded by the National Institutes of Health and the National Center for Research Resources. Aspirin and matching placebo were provided free of charge by Bayer Healthcare. Additional support was provided by Merck. Dr. Kawut and his associates reported ties to numerous industry sources.

Neither aspirin nor simvastatin improved outcomes for patients with pulmonary arterial hypertension in a phase II safety and efficacy trial published online May 19 in Circulation and simultaneously presented at the annual meeting of the American Thoracic Society.

The primary end point of 6-minute walk distance did not increase after 6 months of aspirin therapy and actually decreased after 6 months of simvastatin therapy, indicating that neither agent should be used as an add-on therapy in PAH, said Dr. Steven M. Kawut of Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, and his associates.

A recent animal study showed that aspirin decreased pulmonary artery pressure, reduced right ventricular hypertrophy, and improved survival, and several recent studies showed that statins were effective in animal models of pulmonary hypertension. Dr. Kawut and his associates in the ASA-STAT Study Group designed their phase II clinical trial to test the safety and efficacy of both agents against matching placebos, intending to enroll 100 subjects with PAH.

The study, however, was terminated after only 65 subjects had been randomized because an interim analysis showed "a high likelihood of not rejecting the null hypothesis for the simvastatin arm even if fully recruited," they wrote. The investigators reported their findings for those 65 subjects.

The patients’ mean age was 50 years, and 86% were women. Approximately 52% had idiopathic PAH, 19% had PAH associated with systemic sclerosis, 15% had PAH associated with other connective tissue diseases, 9% had congenital systemic-to-pulmonary shunts, and 5% had heritable PAH.

The primary outcome measure was 6-minute walk distance after 6 months of treatment, after adjustment for 6-minute walk distance at baseline.

Patients who received aspirin therapy showed no improvement in this measure, compared with those who received placebo. They also showed no improvement in median Borg dyspnea scores after the walk test, in any scales of the SF-36, or in World Health Organization functional class. And there was no difference between the two groups in time to clinical worsening, Dr. Kawut and his associates said.

Similarly, patients who received simvastatin showed no improvement in 6-minute walk distance after 6 months of treatment, compared with those who received placebo. In fact, the active drug may have reduced this distance, although the number of subjects was not sufficient to detect a statistically significant difference. Moreover, the median Borg dyspnea scores after the walk test tended to be higher in subjects who took simvastatin than in those who took placebo, suggesting greater breathlessness.

As with aspirin, there were no differences on any scales of the SF-36 or in WHO functional class between the subjects who took simvastatin and those who took placebo, the investigators said (Circulation 2011 May 19 [doi:10.1161/CIRCULATIONAHA.110.015693]).

"There was a possible increased risk of major bleeding associated with aspirin use," they noted, but again, the number of subjects was not sufficient to make this determination definitively.

"On the basis of these finding, neither drug can be recommended for the treatment of PAH," Dr. Kawut and his colleagues said.

The study was funded by the National Institutes of Health and the National Center for Research Resources. Aspirin and matching placebo were provided free of charge by Bayer Healthcare. Additional support was provided by Merck. Dr. Kawut and his associates reported ties to numerous industry sources.

Neither aspirin nor simvastatin improved outcomes for patients with pulmonary arterial hypertension in a phase II safety and efficacy trial published online May 19 in Circulation and simultaneously presented at the annual meeting of the American Thoracic Society.

The primary end point of 6-minute walk distance did not increase after 6 months of aspirin therapy and actually decreased after 6 months of simvastatin therapy, indicating that neither agent should be used as an add-on therapy in PAH, said Dr. Steven M. Kawut of Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, and his associates.

A recent animal study showed that aspirin decreased pulmonary artery pressure, reduced right ventricular hypertrophy, and improved survival, and several recent studies showed that statins were effective in animal models of pulmonary hypertension. Dr. Kawut and his associates in the ASA-STAT Study Group designed their phase II clinical trial to test the safety and efficacy of both agents against matching placebos, intending to enroll 100 subjects with PAH.

The study, however, was terminated after only 65 subjects had been randomized because an interim analysis showed "a high likelihood of not rejecting the null hypothesis for the simvastatin arm even if fully recruited," they wrote. The investigators reported their findings for those 65 subjects.

The patients’ mean age was 50 years, and 86% were women. Approximately 52% had idiopathic PAH, 19% had PAH associated with systemic sclerosis, 15% had PAH associated with other connective tissue diseases, 9% had congenital systemic-to-pulmonary shunts, and 5% had heritable PAH.

The primary outcome measure was 6-minute walk distance after 6 months of treatment, after adjustment for 6-minute walk distance at baseline.

Patients who received aspirin therapy showed no improvement in this measure, compared with those who received placebo. They also showed no improvement in median Borg dyspnea scores after the walk test, in any scales of the SF-36, or in World Health Organization functional class. And there was no difference between the two groups in time to clinical worsening, Dr. Kawut and his associates said.

Similarly, patients who received simvastatin showed no improvement in 6-minute walk distance after 6 months of treatment, compared with those who received placebo. In fact, the active drug may have reduced this distance, although the number of subjects was not sufficient to detect a statistically significant difference. Moreover, the median Borg dyspnea scores after the walk test tended to be higher in subjects who took simvastatin than in those who took placebo, suggesting greater breathlessness.

As with aspirin, there were no differences on any scales of the SF-36 or in WHO functional class between the subjects who took simvastatin and those who took placebo, the investigators said (Circulation 2011 May 19 [doi:10.1161/CIRCULATIONAHA.110.015693]).

"There was a possible increased risk of major bleeding associated with aspirin use," they noted, but again, the number of subjects was not sufficient to make this determination definitively.

"On the basis of these finding, neither drug can be recommended for the treatment of PAH," Dr. Kawut and his colleagues said.

The study was funded by the National Institutes of Health and the National Center for Research Resources. Aspirin and matching placebo were provided free of charge by Bayer Healthcare. Additional support was provided by Merck. Dr. Kawut and his associates reported ties to numerous industry sources.

Neither aspirin nor simvastatin improved outcomes for patients with pulmonary arterial hypertension in a phase II safety and efficacy trial published online May 19 in Circulation and simultaneously presented at the annual meeting of the American Thoracic Society.

The primary end point of 6-minute walk distance did not increase after 6 months of aspirin therapy and actually decreased after 6 months of simvastatin therapy, indicating that neither agent should be used as an add-on therapy in PAH, said Dr. Steven M. Kawut of Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, and his associates.

A recent animal study showed that aspirin decreased pulmonary artery pressure, reduced right ventricular hypertrophy, and improved survival, and several recent studies showed that statins were effective in animal models of pulmonary hypertension. Dr. Kawut and his associates in the ASA-STAT Study Group designed their phase II clinical trial to test the safety and efficacy of both agents against matching placebos, intending to enroll 100 subjects with PAH.

The study, however, was terminated after only 65 subjects had been randomized because an interim analysis showed "a high likelihood of not rejecting the null hypothesis for the simvastatin arm even if fully recruited," they wrote. The investigators reported their findings for those 65 subjects.

The patients’ mean age was 50 years, and 86% were women. Approximately 52% had idiopathic PAH, 19% had PAH associated with systemic sclerosis, 15% had PAH associated with other connective tissue diseases, 9% had congenital systemic-to-pulmonary shunts, and 5% had heritable PAH.

The primary outcome measure was 6-minute walk distance after 6 months of treatment, after adjustment for 6-minute walk distance at baseline.

Patients who received aspirin therapy showed no improvement in this measure, compared with those who received placebo. They also showed no improvement in median Borg dyspnea scores after the walk test, in any scales of the SF-36, or in World Health Organization functional class. And there was no difference between the two groups in time to clinical worsening, Dr. Kawut and his associates said.

Similarly, patients who received simvastatin showed no improvement in 6-minute walk distance after 6 months of treatment, compared with those who received placebo. In fact, the active drug may have reduced this distance, although the number of subjects was not sufficient to detect a statistically significant difference. Moreover, the median Borg dyspnea scores after the walk test tended to be higher in subjects who took simvastatin than in those who took placebo, suggesting greater breathlessness.

As with aspirin, there were no differences on any scales of the SF-36 or in WHO functional class between the subjects who took simvastatin and those who took placebo, the investigators said (Circulation 2011 May 19 [doi:10.1161/CIRCULATIONAHA.110.015693]).

"There was a possible increased risk of major bleeding associated with aspirin use," they noted, but again, the number of subjects was not sufficient to make this determination definitively.

"On the basis of these finding, neither drug can be recommended for the treatment of PAH," Dr. Kawut and his colleagues said.

The study was funded by the National Institutes of Health and the National Center for Research Resources. Aspirin and matching placebo were provided free of charge by Bayer Healthcare. Additional support was provided by Merck. Dr. Kawut and his associates reported ties to numerous industry sources.

Neither aspirin nor simvastatin improved outcomes for patients with pulmonary arterial hypertension in a phase II safety and efficacy trial published online May 19 in Circulation and simultaneously presented at the annual meeting of the American Thoracic Society.

The primary end point of 6-minute walk distance did not increase after 6 months of aspirin therapy and actually decreased after 6 months of simvastatin therapy, indicating that neither agent should be used as an add-on therapy in PAH, said Dr. Steven M. Kawut of Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, and his associates.

A recent animal study showed that aspirin decreased pulmonary artery pressure, reduced right ventricular hypertrophy, and improved survival, and several recent studies showed that statins were effective in animal models of pulmonary hypertension. Dr. Kawut and his associates in the ASA-STAT Study Group designed their phase II clinical trial to test the safety and efficacy of both agents against matching placebos, intending to enroll 100 subjects with PAH.

The study, however, was terminated after only 65 subjects had been randomized because an interim analysis showed "a high likelihood of not rejecting the null hypothesis for the simvastatin arm even if fully recruited," they wrote. The investigators reported their findings for those 65 subjects.

The patients’ mean age was 50 years, and 86% were women. Approximately 52% had idiopathic PAH, 19% had PAH associated with systemic sclerosis, 15% had PAH associated with other connective tissue diseases, 9% had congenital systemic-to-pulmonary shunts, and 5% had heritable PAH.

The primary outcome measure was 6-minute walk distance after 6 months of treatment, after adjustment for 6-minute walk distance at baseline.

Patients who received aspirin therapy showed no improvement in this measure, compared with those who received placebo. They also showed no improvement in median Borg dyspnea scores after the walk test, in any scales of the SF-36, or in World Health Organization functional class. And there was no difference between the two groups in time to clinical worsening, Dr. Kawut and his associates said.

Similarly, patients who received simvastatin showed no improvement in 6-minute walk distance after 6 months of treatment, compared with those who received placebo. In fact, the active drug may have reduced this distance, although the number of subjects was not sufficient to detect a statistically significant difference. Moreover, the median Borg dyspnea scores after the walk test tended to be higher in subjects who took simvastatin than in those who took placebo, suggesting greater breathlessness.

As with aspirin, there were no differences on any scales of the SF-36 or in WHO functional class between the subjects who took simvastatin and those who took placebo, the investigators said (Circulation 2011 May 19 [doi:10.1161/CIRCULATIONAHA.110.015693]).

"There was a possible increased risk of major bleeding associated with aspirin use," they noted, but again, the number of subjects was not sufficient to make this determination definitively.

"On the basis of these finding, neither drug can be recommended for the treatment of PAH," Dr. Kawut and his colleagues said.

The study was funded by the National Institutes of Health and the National Center for Research Resources. Aspirin and matching placebo were provided free of charge by Bayer Healthcare. Additional support was provided by Merck. Dr. Kawut and his associates reported ties to numerous industry sources.

Oral selenium significantly improves patients’ quality of life and slows the progression of mild Graves’ orbitopathy, according to a report in the May 19 issue of the New England Journal of Medicine.

In an international clinical trial comparing the drug with placebo and pentoxifylline tablets, only selenium improved both visual functioning and appearance, mainly by ameliorating soft-tissue changes and reducing eyelid aperture, said Dr. Claudio Marcocci of the department of endocrinology and metabolism at the University of Pisa (Italy) and his associates in the European Group on Graves’ Orbitopathy.

Selenium (an antioxidant) and pentoxifylline (an anti-inflammatory) were chosen as potentially therapeutic agents to test in this trial because in vitro and small pilot studies have suggested that they might be beneficial in Graves’ orbitopathy. In all, 152 patients in Italy, the Netherlands, Germany, Greece, and Switzerland were randomly assigned to receive selenium (54 subjects), pentoxifylline (48 subjects), or placebo (50 subjects) for 6 months and were followed at intervals for 1 year to assess outcomes. Selenium and placebo tablets were prepared to look the same as pentoxifylline.

The study subjects had only mild signs or symptoms of orbitopathy at baseline, and had been affected for less than 18 months. Scores on the Graves’ orbitopathy–specific quality of life (QOL) questionnaire were similar among the three groups at baseline, showing mild to moderate impairment. Scores on measures of visual functioning and appearance also were comparable at baseline.

At 6 months, QOL scores improved significantly only in the patients who received selenium. Visual functioning improved significantly in 62%, and appearance improved significantly in 75% of that group. No such improvements were reported in the other two study groups.

Moreover, the patients who were treated with selenium had a substantially lower rate of worsening of QOL (9 of 53 patients, or 17%),compared with those given placebo (20 of 46 patients, or 43%).

"The overall ophthalmic outcome at the 6-month evaluation was significantly better in the selenium group than in the placebo group (P = .01), whereas there was no significant difference between the pentoxifylline and placebo groups (P = .12)," Dr. Marcocci and his colleagues wrote (N. Engl. J. Med. 2011;364:1920-31).

"Improvements in eyelid aperture and in soft-tissue involvement, rather than changes in proptosis and eye motility, were the major determinants of the overall ophthalmic outcome in patients treated with selenium," they added.

The median reduction in eyelid aperture was 2 mm at 6 months and 3 mm at 1 year.

Although the Clinical Activity Score was significantly lower in the selenium group than in the other two groups at 6 months, this score declined in all three groups, "probably reflecting the natural history of mild Graves’ orbitopathy, which becomes less active or inactive in most cases," the investigators said.

"The beneficial effect of selenium on QOL and the overall eye evaluation persisted for 6 months after therapy was withdrawn," they noted.

There were no drug-related adverse effects reported for either selenium or placebo. However, seven patients who were taking pentoxifylline reported skin and gastrointestinal disorders, and four of them dropped out of the study during the first month.

The precise mechanism by which selenium exerted these benefits is not yet known, but "we speculate that an intervention aimed at improving the antioxidant-oxidant balance might be helpful in both hyperthyroidism and Graves’ orbitopathy," Dr. Marcocci and his associates said.

The study was limited in that there were no data on actual changes in serum selenium levels. It is possible that some subjects had marginal selenium deficiency at baseline, which may have biased the study results in favor of showing a beneficial treatment effect, they added.

This study was supported by the University of Pisa and the Italian Ministry for Education, University, and Research. Dr. Marcocci’s associates reported ties to GlaxoSmithKline, Merck, Brahms, and Novo Nordisk.

Oral selenium significantly improves patients’ quality of life and slows the progression of mild Graves’ orbitopathy, according to a report in the May 19 issue of the New England Journal of Medicine.

In an international clinical trial comparing the drug with placebo and pentoxifylline tablets, only selenium improved both visual functioning and appearance, mainly by ameliorating soft-tissue changes and reducing eyelid aperture, said Dr. Claudio Marcocci of the department of endocrinology and metabolism at the University of Pisa (Italy) and his associates in the European Group on Graves’ Orbitopathy.

Selenium (an antioxidant) and pentoxifylline (an anti-inflammatory) were chosen as potentially therapeutic agents to test in this trial because in vitro and small pilot studies have suggested that they might be beneficial in Graves’ orbitopathy. In all, 152 patients in Italy, the Netherlands, Germany, Greece, and Switzerland were randomly assigned to receive selenium (54 subjects), pentoxifylline (48 subjects), or placebo (50 subjects) for 6 months and were followed at intervals for 1 year to assess outcomes. Selenium and placebo tablets were prepared to look the same as pentoxifylline.

The study subjects had only mild signs or symptoms of orbitopathy at baseline, and had been affected for less than 18 months. Scores on the Graves’ orbitopathy–specific quality of life (QOL) questionnaire were similar among the three groups at baseline, showing mild to moderate impairment. Scores on measures of visual functioning and appearance also were comparable at baseline.

At 6 months, QOL scores improved significantly only in the patients who received selenium. Visual functioning improved significantly in 62%, and appearance improved significantly in 75% of that group. No such improvements were reported in the other two study groups.

Moreover, the patients who were treated with selenium had a substantially lower rate of worsening of QOL (9 of 53 patients, or 17%),compared with those given placebo (20 of 46 patients, or 43%).

"The overall ophthalmic outcome at the 6-month evaluation was significantly better in the selenium group than in the placebo group (P = .01), whereas there was no significant difference between the pentoxifylline and placebo groups (P = .12)," Dr. Marcocci and his colleagues wrote (N. Engl. J. Med. 2011;364:1920-31).

"Improvements in eyelid aperture and in soft-tissue involvement, rather than changes in proptosis and eye motility, were the major determinants of the overall ophthalmic outcome in patients treated with selenium," they added.

The median reduction in eyelid aperture was 2 mm at 6 months and 3 mm at 1 year.

Although the Clinical Activity Score was significantly lower in the selenium group than in the other two groups at 6 months, this score declined in all three groups, "probably reflecting the natural history of mild Graves’ orbitopathy, which becomes less active or inactive in most cases," the investigators said.

"The beneficial effect of selenium on QOL and the overall eye evaluation persisted for 6 months after therapy was withdrawn," they noted.

There were no drug-related adverse effects reported for either selenium or placebo. However, seven patients who were taking pentoxifylline reported skin and gastrointestinal disorders, and four of them dropped out of the study during the first month.

The precise mechanism by which selenium exerted these benefits is not yet known, but "we speculate that an intervention aimed at improving the antioxidant-oxidant balance might be helpful in both hyperthyroidism and Graves’ orbitopathy," Dr. Marcocci and his associates said.

The study was limited in that there were no data on actual changes in serum selenium levels. It is possible that some subjects had marginal selenium deficiency at baseline, which may have biased the study results in favor of showing a beneficial treatment effect, they added.

This study was supported by the University of Pisa and the Italian Ministry for Education, University, and Research. Dr. Marcocci’s associates reported ties to GlaxoSmithKline, Merck, Brahms, and Novo Nordisk.

Oral selenium significantly improves patients’ quality of life and slows the progression of mild Graves’ orbitopathy, according to a report in the May 19 issue of the New England Journal of Medicine.

In an international clinical trial comparing the drug with placebo and pentoxifylline tablets, only selenium improved both visual functioning and appearance, mainly by ameliorating soft-tissue changes and reducing eyelid aperture, said Dr. Claudio Marcocci of the department of endocrinology and metabolism at the University of Pisa (Italy) and his associates in the European Group on Graves’ Orbitopathy.

Selenium (an antioxidant) and pentoxifylline (an anti-inflammatory) were chosen as potentially therapeutic agents to test in this trial because in vitro and small pilot studies have suggested that they might be beneficial in Graves’ orbitopathy. In all, 152 patients in Italy, the Netherlands, Germany, Greece, and Switzerland were randomly assigned to receive selenium (54 subjects), pentoxifylline (48 subjects), or placebo (50 subjects) for 6 months and were followed at intervals for 1 year to assess outcomes. Selenium and placebo tablets were prepared to look the same as pentoxifylline.

The study subjects had only mild signs or symptoms of orbitopathy at baseline, and had been affected for less than 18 months. Scores on the Graves’ orbitopathy–specific quality of life (QOL) questionnaire were similar among the three groups at baseline, showing mild to moderate impairment. Scores on measures of visual functioning and appearance also were comparable at baseline.

At 6 months, QOL scores improved significantly only in the patients who received selenium. Visual functioning improved significantly in 62%, and appearance improved significantly in 75% of that group. No such improvements were reported in the other two study groups.

Moreover, the patients who were treated with selenium had a substantially lower rate of worsening of QOL (9 of 53 patients, or 17%),compared with those given placebo (20 of 46 patients, or 43%).

"The overall ophthalmic outcome at the 6-month evaluation was significantly better in the selenium group than in the placebo group (P = .01), whereas there was no significant difference between the pentoxifylline and placebo groups (P = .12)," Dr. Marcocci and his colleagues wrote (N. Engl. J. Med. 2011;364:1920-31).

"Improvements in eyelid aperture and in soft-tissue involvement, rather than changes in proptosis and eye motility, were the major determinants of the overall ophthalmic outcome in patients treated with selenium," they added.

The median reduction in eyelid aperture was 2 mm at 6 months and 3 mm at 1 year.

Although the Clinical Activity Score was significantly lower in the selenium group than in the other two groups at 6 months, this score declined in all three groups, "probably reflecting the natural history of mild Graves’ orbitopathy, which becomes less active or inactive in most cases," the investigators said.

"The beneficial effect of selenium on QOL and the overall eye evaluation persisted for 6 months after therapy was withdrawn," they noted.

There were no drug-related adverse effects reported for either selenium or placebo. However, seven patients who were taking pentoxifylline reported skin and gastrointestinal disorders, and four of them dropped out of the study during the first month.

The precise mechanism by which selenium exerted these benefits is not yet known, but "we speculate that an intervention aimed at improving the antioxidant-oxidant balance might be helpful in both hyperthyroidism and Graves’ orbitopathy," Dr. Marcocci and his associates said.

The study was limited in that there were no data on actual changes in serum selenium levels. It is possible that some subjects had marginal selenium deficiency at baseline, which may have biased the study results in favor of showing a beneficial treatment effect, they added.

This study was supported by the University of Pisa and the Italian Ministry for Education, University, and Research. Dr. Marcocci’s associates reported ties to GlaxoSmithKline, Merck, Brahms, and Novo Nordisk.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

Between 1990 and 2009, the number of hospital emergency departments in nonrural areas across the United States declined by 27%, according to a report in the May 18 issue of JAMA.

"The closure of an ED can have profound repercussions for a community ... not only by increasing the distance to the nearest hospital but also by increasing the patient load at neighboring hospitals." This in turn degrades quality of care for insured and uninsured patients alike, prolonging wait times and raising both morbidity and mortality.

"ED closure can displace tens of thousands of uninsured and low-income patients to other EDs, worsening crowding and potentially setting the stage for additional closures," said Dr. Renee Y. Hsia of the department of emergency medicine at San Francisco General Hospital, and her associates.

They studied trends in ED closures using data on all general, acute, nonfederal, short-stay U.S. hospitals that participated in annual national surveys by the American Hospital Association. The investigators excluded rural hospitals from this study because they "are sometimes designated ‘critical access hospitals’ and operate under different federal mandates and supports" than do metropolitan hospitals.

Financial data were obtained from the Centers for Medicare and Medicaid Services’ Healthcare Cost Report Information System.

In 1990 there were 2,446 nonrural hospitals with EDs across the United States, which declined by 27% to 1,779 in 2009.

During that interval, 1,041 EDs closed. At the same time, 374 new EDs were opened, for a net loss of 667 nonrural EDs.

Most (66%) of the ED closures resulted from the closure of the entire hospital that operated the ED. But for the remaining 34%, EDs were closed while the hospitals remained open.

Four factors were associated with ED closure: for-profit ownership, location in a competitive market, low profit margin, and being a "safety-net" facility (that is, an ED that provides more than double the Medicare share, compared with competing hospitals within a 15-mile radius).

"The cumulative probability of an ED remaining open among safety-net hospitals was about 50%, compared with 74% among non–safety-net hospitals." This demonstrates that safety-net hospitals "require particular attention if emergency-care access is to be sustained," Dr. Hsia and her colleagues said (JAMA 2011;305:1978-85).

Similarly, "the cumulative probability for an ED to remain open was 50% among for-profit hospitals, compared with 75%" for not-for-profit and government-run hospitals.

As well, EDs at hospitals in the lowest quartile of profit margin had a 50% probability of remaining open, compared with a 75% probability among EDs at hospitals in the upper three quartiles.

And EDs at hospitals serving a high proportion of low-income patients had a lower probability of remaining open, compared with EDs at hospitals in more economically secure communities. "This could contribute to difficulty in recruiting and maintaining staff at all levels."

Moreover, the closure of EDs at such facilities is "especially compelling, given that vulnerable populations, including those in minority groups and both uninsured and underinsured patients, use EDs for acute care at greater rates than other populations," the researchers said.

Local market competition also was strongly associated with the likelihood that an ED would close. "Our study shows that market forces beyond profit margin alone are substantially related to the ability of an ED to remain open.

"Our findings underscore that market-based approaches to health care do not ensure that care will be equitably distributed. In fact, the opposite may be true.

"As long as tens of millions of Americans are uninsured, and tens of millions more pay well below their cost of care, the push for ‘results-driven competition’ will not correct system-level disparities that markets cannot – and should not – be expected to resolve," Dr. Hsia and her associates said.

This study was supported by the National Institutes of Health; the National Center for Research Resources; the University of California, San Francisco; and the Robert Wood Johnson Foundation. No financial conflicts of interest were reported.

First-trimester exposure to the newer generation of antiepileptic drugs – lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam – does not appear to raise the risk of major birth defects, according to a report in the May 18 issue of JAMA.

In addition, none of these agents was associated with subgroups of major birth defects categorized by organ system, said Ditte Molgaard-Nielsen and Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen.

Noting that "there is only sparse information on the teratogenic effects of most of the newly licensed antiepileptic drugs," the researchers assessed the issue using data from national Danish registries of births, prescriptions, and major congenital anomalies for 1996 through 2008. They excluded cases of birth defects associated with chromosomal aberrations; genetic disorders; and known causes, such as fetal alcohol syndrome, and assessed a final cohort of 837,795 live births.

Of these, there were 19,960 major birth defects diagnosed within the first year of life, for an overall rate of 2.4%.

There were 1,532 pregnancies in which the fetus was exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at some time during the first trimester. A total of 49 of these infants (3.2%) were diagnosed as having a major birth defect, compared with 19,911 (2.4%) of the 836,263 unexposed pregnancies.

After the data were adjusted to account for potential confounders such as maternal use of older-generation antiepileptic drugs, which are known to raise the risk by two- to threefold, or a history of birth defects in siblings, exposure to these newer agents was no longer associated with an increased risk of major birth defects, Ms. Molgaard-Nielsen and Dr. Hviid said (JAMA 2011;305:1996-2002).

In a further analysis of the data, the risk of birth defects was found to be unrelated to the use of any of the five newer-generation antiepileptic drugs individually. Another analysis showed that there was no dose-response effect of increasing risk with escalating doses of lamotrigine, the most frequently used of the five drugs.

"We conducted a number of sensitivity analyses to evaluate the robustness of our results, including adjusting for exposure to drugs in the U.S. Food and Drug Administration’s pregnancy categories D and X. ... No association with major birth defects was found in any of these analyses," they noted.

An exploratory analysis examined whether exposure to all of the drugs was associated with major birth defects categorized by the affected organ system. No significantly increased risk was found, except for a fourfold increase in eye defects associated with the use of lamotrigine.

However, this association "is likely a chance finding." The subgroup of infants with eye defects included only four infants, and they were affected by "4 etiologically different eye defects, which argues against a causal association."

The question of whether maternal epilepsy itself is associated with an increased risk of birth defects is still debated. In this study, maternal epilepsy was associated with a moderately increased risk of birth defects, the investigators noted.

Their study was limited in that it did not include any information on spontaneous or induced abortions. "This will bias an association ... toward the null if the birth defect itself increases the risk of induced or spontaneous abortion," they added.

Although this was the largest cohort study to date on this issue, further research with larger sample sizes is needed to delineate the risks of specific birth defects. This study could not exclude minor to moderate excesses in risks of overall birth defects or of specific birth defects, they said.

This study was supported by the Danish Medical Research Council and the Lundbeck Foundation. Ms. Molgaard-Nielsen and Dr. Hviid reported no relevant financial disclosures.

First-trimester exposure to the newer generation of antiepileptic drugs – lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam – does not appear to raise the risk of major birth defects, according to a report in the May 18 issue of JAMA.

In addition, none of these agents was associated with subgroups of major birth defects categorized by organ system, said Ditte Molgaard-Nielsen and Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen.

Noting that "there is only sparse information on the teratogenic effects of most of the newly licensed antiepileptic drugs," the researchers assessed the issue using data from national Danish registries of births, prescriptions, and major congenital anomalies for 1996 through 2008. They excluded cases of birth defects associated with chromosomal aberrations; genetic disorders; and known causes, such as fetal alcohol syndrome, and assessed a final cohort of 837,795 live births.

Of these, there were 19,960 major birth defects diagnosed within the first year of life, for an overall rate of 2.4%.

There were 1,532 pregnancies in which the fetus was exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at some time during the first trimester. A total of 49 of these infants (3.2%) were diagnosed as having a major birth defect, compared with 19,911 (2.4%) of the 836,263 unexposed pregnancies.

After the data were adjusted to account for potential confounders such as maternal use of older-generation antiepileptic drugs, which are known to raise the risk by two- to threefold, or a history of birth defects in siblings, exposure to these newer agents was no longer associated with an increased risk of major birth defects, Ms. Molgaard-Nielsen and Dr. Hviid said (JAMA 2011;305:1996-2002).

In a further analysis of the data, the risk of birth defects was found to be unrelated to the use of any of the five newer-generation antiepileptic drugs individually. Another analysis showed that there was no dose-response effect of increasing risk with escalating doses of lamotrigine, the most frequently used of the five drugs.

"We conducted a number of sensitivity analyses to evaluate the robustness of our results, including adjusting for exposure to drugs in the U.S. Food and Drug Administration’s pregnancy categories D and X. ... No association with major birth defects was found in any of these analyses," they noted.

An exploratory analysis examined whether exposure to all of the drugs was associated with major birth defects categorized by the affected organ system. No significantly increased risk was found, except for a fourfold increase in eye defects associated with the use of lamotrigine.

However, this association "is likely a chance finding." The subgroup of infants with eye defects included only four infants, and they were affected by "4 etiologically different eye defects, which argues against a causal association."

The question of whether maternal epilepsy itself is associated with an increased risk of birth defects is still debated. In this study, maternal epilepsy was associated with a moderately increased risk of birth defects, the investigators noted.

Their study was limited in that it did not include any information on spontaneous or induced abortions. "This will bias an association ... toward the null if the birth defect itself increases the risk of induced or spontaneous abortion," they added.

Although this was the largest cohort study to date on this issue, further research with larger sample sizes is needed to delineate the risks of specific birth defects. This study could not exclude minor to moderate excesses in risks of overall birth defects or of specific birth defects, they said.

This study was supported by the Danish Medical Research Council and the Lundbeck Foundation. Ms. Molgaard-Nielsen and Dr. Hviid reported no relevant financial disclosures.

First-trimester exposure to the newer generation of antiepileptic drugs – lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam – does not appear to raise the risk of major birth defects, according to a report in the May 18 issue of JAMA.

In addition, none of these agents was associated with subgroups of major birth defects categorized by organ system, said Ditte Molgaard-Nielsen and Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen.

Noting that "there is only sparse information on the teratogenic effects of most of the newly licensed antiepileptic drugs," the researchers assessed the issue using data from national Danish registries of births, prescriptions, and major congenital anomalies for 1996 through 2008. They excluded cases of birth defects associated with chromosomal aberrations; genetic disorders; and known causes, such as fetal alcohol syndrome, and assessed a final cohort of 837,795 live births.

Of these, there were 19,960 major birth defects diagnosed within the first year of life, for an overall rate of 2.4%.

There were 1,532 pregnancies in which the fetus was exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at some time during the first trimester. A total of 49 of these infants (3.2%) were diagnosed as having a major birth defect, compared with 19,911 (2.4%) of the 836,263 unexposed pregnancies.

After the data were adjusted to account for potential confounders such as maternal use of older-generation antiepileptic drugs, which are known to raise the risk by two- to threefold, or a history of birth defects in siblings, exposure to these newer agents was no longer associated with an increased risk of major birth defects, Ms. Molgaard-Nielsen and Dr. Hviid said (JAMA 2011;305:1996-2002).

In a further analysis of the data, the risk of birth defects was found to be unrelated to the use of any of the five newer-generation antiepileptic drugs individually. Another analysis showed that there was no dose-response effect of increasing risk with escalating doses of lamotrigine, the most frequently used of the five drugs.

"We conducted a number of sensitivity analyses to evaluate the robustness of our results, including adjusting for exposure to drugs in the U.S. Food and Drug Administration’s pregnancy categories D and X. ... No association with major birth defects was found in any of these analyses," they noted.

An exploratory analysis examined whether exposure to all of the drugs was associated with major birth defects categorized by the affected organ system. No significantly increased risk was found, except for a fourfold increase in eye defects associated with the use of lamotrigine.

However, this association "is likely a chance finding." The subgroup of infants with eye defects included only four infants, and they were affected by "4 etiologically different eye defects, which argues against a causal association."

The question of whether maternal epilepsy itself is associated with an increased risk of birth defects is still debated. In this study, maternal epilepsy was associated with a moderately increased risk of birth defects, the investigators noted.

Their study was limited in that it did not include any information on spontaneous or induced abortions. "This will bias an association ... toward the null if the birth defect itself increases the risk of induced or spontaneous abortion," they added.

Although this was the largest cohort study to date on this issue, further research with larger sample sizes is needed to delineate the risks of specific birth defects. This study could not exclude minor to moderate excesses in risks of overall birth defects or of specific birth defects, they said.

This study was supported by the Danish Medical Research Council and the Lundbeck Foundation. Ms. Molgaard-Nielsen and Dr. Hviid reported no relevant financial disclosures.

First-trimester exposure to the newer generation of antiepileptic drugs – lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam – does not appear to raise the risk of major birth defects, according to a report in the May 18 issue of JAMA.

In addition, none of these agents was associated with subgroups of major birth defects categorized by organ system, said Ditte Molgaard-Nielsen and Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen.

Noting that "there is only sparse information on the teratogenic effects of most of the newly licensed antiepileptic drugs," the researchers assessed the issue using data from national Danish registries of births, prescriptions, and major congenital anomalies for 1996 through 2008. They excluded cases of birth defects associated with chromosomal aberrations; genetic disorders; and known causes, such as fetal alcohol syndrome, and assessed a final cohort of 837,795 live births.

Of these, there were 19,960 major birth defects diagnosed within the first year of life, for an overall rate of 2.4%.

There were 1,532 pregnancies in which the fetus was exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at some time during the first trimester. A total of 49 of these infants (3.2%) were diagnosed as having a major birth defect, compared with 19,911 (2.4%) of the 836,263 unexposed pregnancies.

After the data were adjusted to account for potential confounders such as maternal use of older-generation antiepileptic drugs, which are known to raise the risk by two- to threefold, or a history of birth defects in siblings, exposure to these newer agents was no longer associated with an increased risk of major birth defects, Ms. Molgaard-Nielsen and Dr. Hviid said (JAMA 2011;305:1996-2002).

In a further analysis of the data, the risk of birth defects was found to be unrelated to the use of any of the five newer-generation antiepileptic drugs individually. Another analysis showed that there was no dose-response effect of increasing risk with escalating doses of lamotrigine, the most frequently used of the five drugs.

"We conducted a number of sensitivity analyses to evaluate the robustness of our results, including adjusting for exposure to drugs in the U.S. Food and Drug Administration’s pregnancy categories D and X. ... No association with major birth defects was found in any of these analyses," they noted.

An exploratory analysis examined whether exposure to all of the drugs was associated with major birth defects categorized by the affected organ system. No significantly increased risk was found, except for a fourfold increase in eye defects associated with the use of lamotrigine.

However, this association "is likely a chance finding." The subgroup of infants with eye defects included only four infants, and they were affected by "4 etiologically different eye defects, which argues against a causal association."

The question of whether maternal epilepsy itself is associated with an increased risk of birth defects is still debated. In this study, maternal epilepsy was associated with a moderately increased risk of birth defects, the investigators noted.

Their study was limited in that it did not include any information on spontaneous or induced abortions. "This will bias an association ... toward the null if the birth defect itself increases the risk of induced or spontaneous abortion," they added.

Although this was the largest cohort study to date on this issue, further research with larger sample sizes is needed to delineate the risks of specific birth defects. This study could not exclude minor to moderate excesses in risks of overall birth defects or of specific birth defects, they said.

This study was supported by the Danish Medical Research Council and the Lundbeck Foundation. Ms. Molgaard-Nielsen and Dr. Hviid reported no relevant financial disclosures.

First-trimester exposure to the newer generation of antiepileptic drugs – lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam – does not appear to raise the risk of major birth defects, according to a report in the May 18 issue of JAMA.

In addition, none of these agents was associated with subgroups of major birth defects categorized by organ system, said Ditte Molgaard-Nielsen and Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen.

Noting that "there is only sparse information on the teratogenic effects of most of the newly licensed antiepileptic drugs," the researchers assessed the issue using data from national Danish registries of births, prescriptions, and major congenital anomalies for 1996 through 2008. They excluded cases of birth defects associated with chromosomal aberrations; genetic disorders; and known causes, such as fetal alcohol syndrome, and assessed a final cohort of 837,795 live births.

Of these, there were 19,960 major birth defects diagnosed within the first year of life, for an overall rate of 2.4%.

There were 1,532 pregnancies in which the fetus was exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at some time during the first trimester. A total of 49 of these infants (3.2%) were diagnosed as having a major birth defect, compared with 19,911 (2.4%) of the 836,263 unexposed pregnancies.

After the data were adjusted to account for potential confounders such as maternal use of older-generation antiepileptic drugs, which are known to raise the risk by two- to threefold, or a history of birth defects in siblings, exposure to these newer agents was no longer associated with an increased risk of major birth defects, Ms. Molgaard-Nielsen and Dr. Hviid said (JAMA 2011;305:1996-2002).

In a further analysis of the data, the risk of birth defects was found to be unrelated to the use of any of the five newer-generation antiepileptic drugs individually. Another analysis showed that there was no dose-response effect of increasing risk with escalating doses of lamotrigine, the most frequently used of the five drugs.

"We conducted a number of sensitivity analyses to evaluate the robustness of our results, including adjusting for exposure to drugs in the U.S. Food and Drug Administration’s pregnancy categories D and X. ... No association with major birth defects was found in any of these analyses," they noted.

An exploratory analysis examined whether exposure to all of the drugs was associated with major birth defects categorized by the affected organ system. No significantly increased risk was found, except for a fourfold increase in eye defects associated with the use of lamotrigine.

However, this association "is likely a chance finding." The subgroup of infants with eye defects included only four infants, and they were affected by "4 etiologically different eye defects, which argues against a causal association."

The question of whether maternal epilepsy itself is associated with an increased risk of birth defects is still debated. In this study, maternal epilepsy was associated with a moderately increased risk of birth defects, the investigators noted.

Their study was limited in that it did not include any information on spontaneous or induced abortions. "This will bias an association ... toward the null if the birth defect itself increases the risk of induced or spontaneous abortion," they added.

Although this was the largest cohort study to date on this issue, further research with larger sample sizes is needed to delineate the risks of specific birth defects. This study could not exclude minor to moderate excesses in risks of overall birth defects or of specific birth defects, they said.

This study was supported by the Danish Medical Research Council and the Lundbeck Foundation. Ms. Molgaard-Nielsen and Dr. Hviid reported no relevant financial disclosures.

First-trimester exposure to the newer generation of antiepileptic drugs – lamotrigine, oxcarbazepine, topiramate, gabapentin, and levetiracetam – does not appear to raise the risk of major birth defects, according to a report in the May 18 issue of JAMA.

In addition, none of these agents was associated with subgroups of major birth defects categorized by organ system, said Ditte Molgaard-Nielsen and Dr. Anders Hviid of the department of epidemiology research, Statens Serum Institut, Copenhagen.

Noting that "there is only sparse information on the teratogenic effects of most of the newly licensed antiepileptic drugs," the researchers assessed the issue using data from national Danish registries of births, prescriptions, and major congenital anomalies for 1996 through 2008. They excluded cases of birth defects associated with chromosomal aberrations; genetic disorders; and known causes, such as fetal alcohol syndrome, and assessed a final cohort of 837,795 live births.

Of these, there were 19,960 major birth defects diagnosed within the first year of life, for an overall rate of 2.4%.

There were 1,532 pregnancies in which the fetus was exposed to lamotrigine, oxcarbazepine, topiramate, gabapentin, or levetiracetam at some time during the first trimester. A total of 49 of these infants (3.2%) were diagnosed as having a major birth defect, compared with 19,911 (2.4%) of the 836,263 unexposed pregnancies.

After the data were adjusted to account for potential confounders such as maternal use of older-generation antiepileptic drugs, which are known to raise the risk by two- to threefold, or a history of birth defects in siblings, exposure to these newer agents was no longer associated with an increased risk of major birth defects, Ms. Molgaard-Nielsen and Dr. Hviid said (JAMA 2011;305:1996-2002).

In a further analysis of the data, the risk of birth defects was found to be unrelated to the use of any of the five newer-generation antiepileptic drugs individually. Another analysis showed that there was no dose-response effect of increasing risk with escalating doses of lamotrigine, the most frequently used of the five drugs.

"We conducted a number of sensitivity analyses to evaluate the robustness of our results, including adjusting for exposure to drugs in the U.S. Food and Drug Administration’s pregnancy categories D and X. ... No association with major birth defects was found in any of these analyses," they noted.

An exploratory analysis examined whether exposure to all of the drugs was associated with major birth defects categorized by the affected organ system. No significantly increased risk was found, except for a fourfold increase in eye defects associated with the use of lamotrigine.

However, this association "is likely a chance finding." The subgroup of infants with eye defects included only four infants, and they were affected by "4 etiologically different eye defects, which argues against a causal association."

The question of whether maternal epilepsy itself is associated with an increased risk of birth defects is still debated. In this study, maternal epilepsy was associated with a moderately increased risk of birth defects, the investigators noted.

Their study was limited in that it did not include any information on spontaneous or induced abortions. "This will bias an association ... toward the null if the birth defect itself increases the risk of induced or spontaneous abortion," they added.

Although this was the largest cohort study to date on this issue, further research with larger sample sizes is needed to delineate the risks of specific birth defects. This study could not exclude minor to moderate excesses in risks of overall birth defects or of specific birth defects, they said.

This study was supported by the Danish Medical Research Council and the Lundbeck Foundation. Ms. Molgaard-Nielsen and Dr. Hviid reported no relevant financial disclosures.