Mary Ann Moon

Intermittent androgen deprivation fell short of proving its noninferiority in a 10-year study comparing survival outcomes for intermittent and standard continuous androgen deprivation in men with metastatic hormone-sensitive prostate cancer.

In the international randomized clinical trial designed to test the noninferiority of intermittent androgen deprivation, the findings were "statistically inconclusive," according to a report published online April 3 in the New England Journal of Medicine.

In short, "the trial results are inconclusive," said Dr. Maha Hussain of the division of hematology/oncology, University of Michigan, Ann Arbor, and her associates. "The median survival after randomization was 5.1 years in the intermittent-therapy group, as compared with 5.8 years in the continuous-therapy group."

The researchers also cautioned that "the lack of a significant difference between the groups does not imply similar survival."

Intermittent therapy might even compromise survival, they said, as a 10% relative increase in the risk of death was associated with that treatment approach. And statistically, a possible 20% relative rise in mortality risk could not be ruled out.

It was hoped that intermittent androgen deprivation would improve patients’ quality of life by reducing adverse effects from the treatment and would improve survival by staving off the androgen resistance, which eventually develops in most patients.

Dr. Hussain and her colleagues compared intermittent with continuous androgen deprivation in 1,749 men enrolled during 1995-2008 at multiple sites across the United States, the United Kingdom, and Canada.

The study subjects all had newly diagnosed, metastatic, hormone-sensitive prostate cancer and a prostate-specific antigen (PSA) level of 5 ng/mL or higher. All had responded to a 7-month induction course of goserelin, bicalutamide, or a similar agent.

The study subjects were stratified by their performance status, prior hormone therapy, and the extent of their metastatic disease. Cancer confined to the spine, pelvic bones, or lymph nodes was considered minimal while that involving the ribs, long bones, or visceral organs was considered extensive.

The subjects were then randomly assigned to receive either intermittent or standard, continuous androgen-deprivation therapy.

In intermittent therapy, treatment was suspended until PSA values returned to baseline levels or to 20 ng/mL. At the discretion of the researchers, androgen deprivation also could be resumed when PSA levels reached 10 ng/mL or when symptoms developed. If patients responded to a subsequent 7-month course of the therapy, another off-treatment interval was begun.

The study subjects were followed for a median of 9.8 years.

Overall median survival was 3.7 years. There were 445 deaths in the continuous-therapy group and 483 deaths in the intermittent-therapy group. Deaths were cancer-related in approximately 80% of the members of both groups, the investigators reported (N. Engl. J. Med. 2013 April 3 [doi: 10.1056/NEJMoa1212299]).

The researchers were unable to show that intermittent androgen-deprivation therapy was either noninferior or inferior to continuous androgen-deprivation therapy.

Treatment effects were "generally consistent" across all subgroups of patients in a post hoc analysis of the data. For example, there was no significant difference in survival between patients who were alive before 2004, when treatment with docetaxel was approved, and those who were alive in 2004 or later. However, "caution should be taken not to overinterpret the results of the subgroup analyses," Dr. Hussain and her associates noted.

The two study groups differed in quality-of-life measures at 3 months after randomization. Men assigned to intermittent therapy were significantly less likely to report impotence and had significantly better mental health scores than did those assigned to continuous androgen deprivation. The intermittent-therapy group also tended to have higher scores for libido, but that difference did not reach statistical significance.

The advantage in quality-of-life measures persisted at 9 months after randomization but gradually declined. By 15 months, the only quality-of-life measure that scored better in the intermittent-therapy group was overall physical functioning.

There was a "remarkably similar" number of grade 3 and grade 4 adverse events in both study groups, the researchers said.

This study was funded by the U.S. National Cancer Institute, the U.S. Public Health Service, and AstraZeneca. AstraZeneca donated goserelin and bicalutamide used in this study but had no role in the study design, data collection or analysis, or writing the manuscript. Dr. Hussain reported ties to AstraZeneca, and her associates reported ties to numerous industry sources.

Intermittent androgen deprivation fell short of proving its noninferiority in a 10-year study comparing survival outcomes for intermittent and standard continuous androgen deprivation in men with metastatic hormone-sensitive prostate cancer.

In the international randomized clinical trial designed to test the noninferiority of intermittent androgen deprivation, the findings were "statistically inconclusive," according to a report published online April 3 in the New England Journal of Medicine.

In short, "the trial results are inconclusive," said Dr. Maha Hussain of the division of hematology/oncology, University of Michigan, Ann Arbor, and her associates. "The median survival after randomization was 5.1 years in the intermittent-therapy group, as compared with 5.8 years in the continuous-therapy group."

The researchers also cautioned that "the lack of a significant difference between the groups does not imply similar survival."

Intermittent therapy might even compromise survival, they said, as a 10% relative increase in the risk of death was associated with that treatment approach. And statistically, a possible 20% relative rise in mortality risk could not be ruled out.

It was hoped that intermittent androgen deprivation would improve patients’ quality of life by reducing adverse effects from the treatment and would improve survival by staving off the androgen resistance, which eventually develops in most patients.

Dr. Hussain and her colleagues compared intermittent with continuous androgen deprivation in 1,749 men enrolled during 1995-2008 at multiple sites across the United States, the United Kingdom, and Canada.

The study subjects all had newly diagnosed, metastatic, hormone-sensitive prostate cancer and a prostate-specific antigen (PSA) level of 5 ng/mL or higher. All had responded to a 7-month induction course of goserelin, bicalutamide, or a similar agent.

The study subjects were stratified by their performance status, prior hormone therapy, and the extent of their metastatic disease. Cancer confined to the spine, pelvic bones, or lymph nodes was considered minimal while that involving the ribs, long bones, or visceral organs was considered extensive.

The subjects were then randomly assigned to receive either intermittent or standard, continuous androgen-deprivation therapy.

In intermittent therapy, treatment was suspended until PSA values returned to baseline levels or to 20 ng/mL. At the discretion of the researchers, androgen deprivation also could be resumed when PSA levels reached 10 ng/mL or when symptoms developed. If patients responded to a subsequent 7-month course of the therapy, another off-treatment interval was begun.

The study subjects were followed for a median of 9.8 years.

Overall median survival was 3.7 years. There were 445 deaths in the continuous-therapy group and 483 deaths in the intermittent-therapy group. Deaths were cancer-related in approximately 80% of the members of both groups, the investigators reported (N. Engl. J. Med. 2013 April 3 [doi: 10.1056/NEJMoa1212299]).

The researchers were unable to show that intermittent androgen-deprivation therapy was either noninferior or inferior to continuous androgen-deprivation therapy.

Treatment effects were "generally consistent" across all subgroups of patients in a post hoc analysis of the data. For example, there was no significant difference in survival between patients who were alive before 2004, when treatment with docetaxel was approved, and those who were alive in 2004 or later. However, "caution should be taken not to overinterpret the results of the subgroup analyses," Dr. Hussain and her associates noted.

The two study groups differed in quality-of-life measures at 3 months after randomization. Men assigned to intermittent therapy were significantly less likely to report impotence and had significantly better mental health scores than did those assigned to continuous androgen deprivation. The intermittent-therapy group also tended to have higher scores for libido, but that difference did not reach statistical significance.

The advantage in quality-of-life measures persisted at 9 months after randomization but gradually declined. By 15 months, the only quality-of-life measure that scored better in the intermittent-therapy group was overall physical functioning.

There was a "remarkably similar" number of grade 3 and grade 4 adverse events in both study groups, the researchers said.

This study was funded by the U.S. National Cancer Institute, the U.S. Public Health Service, and AstraZeneca. AstraZeneca donated goserelin and bicalutamide used in this study but had no role in the study design, data collection or analysis, or writing the manuscript. Dr. Hussain reported ties to AstraZeneca, and her associates reported ties to numerous industry sources.

Intermittent androgen deprivation fell short of proving its noninferiority in a 10-year study comparing survival outcomes for intermittent and standard continuous androgen deprivation in men with metastatic hormone-sensitive prostate cancer.

In the international randomized clinical trial designed to test the noninferiority of intermittent androgen deprivation, the findings were "statistically inconclusive," according to a report published online April 3 in the New England Journal of Medicine.

In short, "the trial results are inconclusive," said Dr. Maha Hussain of the division of hematology/oncology, University of Michigan, Ann Arbor, and her associates. "The median survival after randomization was 5.1 years in the intermittent-therapy group, as compared with 5.8 years in the continuous-therapy group."

The researchers also cautioned that "the lack of a significant difference between the groups does not imply similar survival."

Intermittent therapy might even compromise survival, they said, as a 10% relative increase in the risk of death was associated with that treatment approach. And statistically, a possible 20% relative rise in mortality risk could not be ruled out.

It was hoped that intermittent androgen deprivation would improve patients’ quality of life by reducing adverse effects from the treatment and would improve survival by staving off the androgen resistance, which eventually develops in most patients.

Dr. Hussain and her colleagues compared intermittent with continuous androgen deprivation in 1,749 men enrolled during 1995-2008 at multiple sites across the United States, the United Kingdom, and Canada.

The study subjects all had newly diagnosed, metastatic, hormone-sensitive prostate cancer and a prostate-specific antigen (PSA) level of 5 ng/mL or higher. All had responded to a 7-month induction course of goserelin, bicalutamide, or a similar agent.

The study subjects were stratified by their performance status, prior hormone therapy, and the extent of their metastatic disease. Cancer confined to the spine, pelvic bones, or lymph nodes was considered minimal while that involving the ribs, long bones, or visceral organs was considered extensive.

The subjects were then randomly assigned to receive either intermittent or standard, continuous androgen-deprivation therapy.

In intermittent therapy, treatment was suspended until PSA values returned to baseline levels or to 20 ng/mL. At the discretion of the researchers, androgen deprivation also could be resumed when PSA levels reached 10 ng/mL or when symptoms developed. If patients responded to a subsequent 7-month course of the therapy, another off-treatment interval was begun.

The study subjects were followed for a median of 9.8 years.

Overall median survival was 3.7 years. There were 445 deaths in the continuous-therapy group and 483 deaths in the intermittent-therapy group. Deaths were cancer-related in approximately 80% of the members of both groups, the investigators reported (N. Engl. J. Med. 2013 April 3 [doi: 10.1056/NEJMoa1212299]).

The researchers were unable to show that intermittent androgen-deprivation therapy was either noninferior or inferior to continuous androgen-deprivation therapy.

Treatment effects were "generally consistent" across all subgroups of patients in a post hoc analysis of the data. For example, there was no significant difference in survival between patients who were alive before 2004, when treatment with docetaxel was approved, and those who were alive in 2004 or later. However, "caution should be taken not to overinterpret the results of the subgroup analyses," Dr. Hussain and her associates noted.

The two study groups differed in quality-of-life measures at 3 months after randomization. Men assigned to intermittent therapy were significantly less likely to report impotence and had significantly better mental health scores than did those assigned to continuous androgen deprivation. The intermittent-therapy group also tended to have higher scores for libido, but that difference did not reach statistical significance.

The advantage in quality-of-life measures persisted at 9 months after randomization but gradually declined. By 15 months, the only quality-of-life measure that scored better in the intermittent-therapy group was overall physical functioning.

There was a "remarkably similar" number of grade 3 and grade 4 adverse events in both study groups, the researchers said.

This study was funded by the U.S. National Cancer Institute, the U.S. Public Health Service, and AstraZeneca. AstraZeneca donated goserelin and bicalutamide used in this study but had no role in the study design, data collection or analysis, or writing the manuscript. Dr. Hussain reported ties to AstraZeneca, and her associates reported ties to numerous industry sources.

A behavioral weight-loss intervention significantly reduced excess weight in adults who had serious mental illness, according to a study published online March 21 in the New England Journal of Medicine.

This intervention, which was specifically tailored to the needs of people with mental illness, allowed steady weight loss that progressed over the 18-month duration of the study. In contrast, most studies of lifestyle interventions in the general population show an early peak in weight loss, often followed by weight regain.

These findings suggest that "despite substantial challenges, persons with serious mental illness are able to lose weight with a tailored intervention," said Dr. Gail L. Daumit of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

Courtesy of National Cancer Institute

The prevalence of obesity is nearly twice as high among people with serious mental illness as among the general population. Mortality is two to three times higher, and cardiovascular disease is the primary cause of death in the seriously mentally ill.

Several factors contribute to this high prevalence. Unhealthy diets and physical inactivity are common in this patient population, and many psychotropic medications cause weight gain. Given their often low socioeconomic status, many people with serious mental illness also have reduced access to healthier, more-expensive foods and to safe, affordable places to exercise.

In addition, the stigma associated with mental illness also might make patients reluctant to participate in mainstream physical activities. And many have impairments in memory and executive function as well as psychiatric symptoms that "impede learning and the adoption of new behaviors," said Dr. Daumit, who also is affiliated with Johns Hopkins Bloomberg School of Public Health, and her colleagues.

They tested the effectiveness of an intervention that addressed these needs in the ACHIEVE (Achieving Healthy Lifestyles in Psychiatric Rehabilitation) clinical trial. The trial involved 291 overweight or obese adults who were participating in seven community outpatient psychiatric rehabilitation programs.

Such programs typically offer vocational and skills training, case management, and other services to the mentally ill; they usually have commercial kitchens that provide meals and snacks, as well as communal spaces suitable for group exercise.

"Program enrollees often attend these programs multiple times each week, which facilitates the delivery of lifestyle interventions that involve frequent contact," the researchers said (N. Engl. J. Med. 2013 March 21 [doi:10.1056/NEJMoa1214530]).

A total of 144 study subjects were randomly assigned to receive the intervention and 147 to a control group that received no intervention. The mean subject age was 45 years. Approximately half of the subjects were men, and 38% were black.

Nearly 80% of the study population was unable to work. A total of 58% had schizophrenia or schizoaffective disorder, 22% had bipolar disorder, and 12% had major depression. Patients were taking a mean of three psychotropic medications each.

The intervention addressed deficits in memory and executive function by dividing information into small components and by frequently repeating practice of skills.

Group and individual weight-management sessions focused on cutting caloric intake, especially by avoiding sugary drinks and junk food; consuming five servings of fruits and vegetables every day; controlling portion size; and eating healthy snacks.

Group exercise sessions focused on moderate-intensity aerobic exercise that gradually increased in duration and intensity.

The mean net weight loss increased over time only for patients who participated in the intervention. This loss was 1.8 kg at 6 months, and 3.4 kg at the completion of the trial. Although modest, this amount "compares favorably with weight loss in lifestyle-intervention trials in the general population" and has been associated with benefits such as reducing the risk of cardiovascular disease, Dr. Daumit and her associates said.

Participants in the intervention group continued to lose weight after 6 months and did not regain any weight, even when they attended fewer weight-management and exercise sessions over time. "One possible explanation is that persons with serious mental illness take longer than those without serious mental illness to engage in an intervention and make requisite behavioral changes," the investigators said.

"Our results show that overweight and obese adults with serious mental illness can make substantial lifestyle changes despite the myriad challenges they face," and that similar interventions should be implemented for this high-risk population, they added.

The study was funded by the National Institute of Mental Health. No conflicts of interest were reported.

A behavioral weight-loss intervention significantly reduced excess weight in adults who had serious mental illness, according to a study published online March 21 in the New England Journal of Medicine.

This intervention, which was specifically tailored to the needs of people with mental illness, allowed steady weight loss that progressed over the 18-month duration of the study. In contrast, most studies of lifestyle interventions in the general population show an early peak in weight loss, often followed by weight regain.

These findings suggest that "despite substantial challenges, persons with serious mental illness are able to lose weight with a tailored intervention," said Dr. Gail L. Daumit of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

Courtesy of National Cancer Institute

The prevalence of obesity is nearly twice as high among people with serious mental illness as among the general population. Mortality is two to three times higher, and cardiovascular disease is the primary cause of death in the seriously mentally ill.

Several factors contribute to this high prevalence. Unhealthy diets and physical inactivity are common in this patient population, and many psychotropic medications cause weight gain. Given their often low socioeconomic status, many people with serious mental illness also have reduced access to healthier, more-expensive foods and to safe, affordable places to exercise.

In addition, the stigma associated with mental illness also might make patients reluctant to participate in mainstream physical activities. And many have impairments in memory and executive function as well as psychiatric symptoms that "impede learning and the adoption of new behaviors," said Dr. Daumit, who also is affiliated with Johns Hopkins Bloomberg School of Public Health, and her colleagues.

They tested the effectiveness of an intervention that addressed these needs in the ACHIEVE (Achieving Healthy Lifestyles in Psychiatric Rehabilitation) clinical trial. The trial involved 291 overweight or obese adults who were participating in seven community outpatient psychiatric rehabilitation programs.

Such programs typically offer vocational and skills training, case management, and other services to the mentally ill; they usually have commercial kitchens that provide meals and snacks, as well as communal spaces suitable for group exercise.

"Program enrollees often attend these programs multiple times each week, which facilitates the delivery of lifestyle interventions that involve frequent contact," the researchers said (N. Engl. J. Med. 2013 March 21 [doi:10.1056/NEJMoa1214530]).

A total of 144 study subjects were randomly assigned to receive the intervention and 147 to a control group that received no intervention. The mean subject age was 45 years. Approximately half of the subjects were men, and 38% were black.

Nearly 80% of the study population was unable to work. A total of 58% had schizophrenia or schizoaffective disorder, 22% had bipolar disorder, and 12% had major depression. Patients were taking a mean of three psychotropic medications each.

The intervention addressed deficits in memory and executive function by dividing information into small components and by frequently repeating practice of skills.

Group and individual weight-management sessions focused on cutting caloric intake, especially by avoiding sugary drinks and junk food; consuming five servings of fruits and vegetables every day; controlling portion size; and eating healthy snacks.

Group exercise sessions focused on moderate-intensity aerobic exercise that gradually increased in duration and intensity.

The mean net weight loss increased over time only for patients who participated in the intervention. This loss was 1.8 kg at 6 months, and 3.4 kg at the completion of the trial. Although modest, this amount "compares favorably with weight loss in lifestyle-intervention trials in the general population" and has been associated with benefits such as reducing the risk of cardiovascular disease, Dr. Daumit and her associates said.

Participants in the intervention group continued to lose weight after 6 months and did not regain any weight, even when they attended fewer weight-management and exercise sessions over time. "One possible explanation is that persons with serious mental illness take longer than those without serious mental illness to engage in an intervention and make requisite behavioral changes," the investigators said.

"Our results show that overweight and obese adults with serious mental illness can make substantial lifestyle changes despite the myriad challenges they face," and that similar interventions should be implemented for this high-risk population, they added.

The study was funded by the National Institute of Mental Health. No conflicts of interest were reported.

A behavioral weight-loss intervention significantly reduced excess weight in adults who had serious mental illness, according to a study published online March 21 in the New England Journal of Medicine.

This intervention, which was specifically tailored to the needs of people with mental illness, allowed steady weight loss that progressed over the 18-month duration of the study. In contrast, most studies of lifestyle interventions in the general population show an early peak in weight loss, often followed by weight regain.

These findings suggest that "despite substantial challenges, persons with serious mental illness are able to lose weight with a tailored intervention," said Dr. Gail L. Daumit of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

Courtesy of National Cancer Institute

The prevalence of obesity is nearly twice as high among people with serious mental illness as among the general population. Mortality is two to three times higher, and cardiovascular disease is the primary cause of death in the seriously mentally ill.

Several factors contribute to this high prevalence. Unhealthy diets and physical inactivity are common in this patient population, and many psychotropic medications cause weight gain. Given their often low socioeconomic status, many people with serious mental illness also have reduced access to healthier, more-expensive foods and to safe, affordable places to exercise.

In addition, the stigma associated with mental illness also might make patients reluctant to participate in mainstream physical activities. And many have impairments in memory and executive function as well as psychiatric symptoms that "impede learning and the adoption of new behaviors," said Dr. Daumit, who also is affiliated with Johns Hopkins Bloomberg School of Public Health, and her colleagues.

They tested the effectiveness of an intervention that addressed these needs in the ACHIEVE (Achieving Healthy Lifestyles in Psychiatric Rehabilitation) clinical trial. The trial involved 291 overweight or obese adults who were participating in seven community outpatient psychiatric rehabilitation programs.

Such programs typically offer vocational and skills training, case management, and other services to the mentally ill; they usually have commercial kitchens that provide meals and snacks, as well as communal spaces suitable for group exercise.

"Program enrollees often attend these programs multiple times each week, which facilitates the delivery of lifestyle interventions that involve frequent contact," the researchers said (N. Engl. J. Med. 2013 March 21 [doi:10.1056/NEJMoa1214530]).

A total of 144 study subjects were randomly assigned to receive the intervention and 147 to a control group that received no intervention. The mean subject age was 45 years. Approximately half of the subjects were men, and 38% were black.

Nearly 80% of the study population was unable to work. A total of 58% had schizophrenia or schizoaffective disorder, 22% had bipolar disorder, and 12% had major depression. Patients were taking a mean of three psychotropic medications each.

The intervention addressed deficits in memory and executive function by dividing information into small components and by frequently repeating practice of skills.

Group and individual weight-management sessions focused on cutting caloric intake, especially by avoiding sugary drinks and junk food; consuming five servings of fruits and vegetables every day; controlling portion size; and eating healthy snacks.

Group exercise sessions focused on moderate-intensity aerobic exercise that gradually increased in duration and intensity.

The mean net weight loss increased over time only for patients who participated in the intervention. This loss was 1.8 kg at 6 months, and 3.4 kg at the completion of the trial. Although modest, this amount "compares favorably with weight loss in lifestyle-intervention trials in the general population" and has been associated with benefits such as reducing the risk of cardiovascular disease, Dr. Daumit and her associates said.

Participants in the intervention group continued to lose weight after 6 months and did not regain any weight, even when they attended fewer weight-management and exercise sessions over time. "One possible explanation is that persons with serious mental illness take longer than those without serious mental illness to engage in an intervention and make requisite behavioral changes," the investigators said.

"Our results show that overweight and obese adults with serious mental illness can make substantial lifestyle changes despite the myriad challenges they face," and that similar interventions should be implemented for this high-risk population, they added.

The study was funded by the National Institute of Mental Health. No conflicts of interest were reported.

A group of sedentary older adults with complaints of memory impairment experienced enhanced cognitive function after a 12-week program of mental and physical activity. Members of a control group who did not engaged in such activity also showed the same degree of improvement, according to results reported online April 1 in JAMA Internal Medicine.

These findings suggest that the amount of activity may be more important than the type of activity in improving cognitive function, since all the study groups participated in some form of activity for 60 minutes per day, 3 days per week, for 12 weeks, said Deborah E. Barnes, Ph.D., of the department of psychiatry and the department of epidemiology and biostatistics, University of California, San Francisco, and her associates.

Or the results may simply indicate that repeated testing of cognitive function itself improves performance on those tests, the investigators noted.

Dr. Barnes and her colleagues assessed four combinations of cognitive and physical activity in 126 community-dwelling people aged 65 years and older (mean age, 73 years) who had normal cognition but who reported that their memory or thinking skills had worsened recently. These subjects had relatively high global cognitive function, in line with their relatively high educational attainment.

Approximately 56% of the study population had hypertension, 14% had diabetes, 9% had a history of MI, and half were either past or current smokers.

The participants were randomly assigned to receive a home-based intensive mental activity or a home-based control mental activity, plus a group intensive exercise intervention or a group control intervention.

The mental-activity intervention was a series of computer games that enhanced both speed and accuracy of visual and auditory processing. The games increased in difficulty as subjects’ performance improved. For the control mental activity, participants individually viewed videos of educational lectures on art, history, and science.

The exercise intervention included 30 minutes of intensive aerobic exercise, whereas the control "exercise" substituted 30 minutes of stretching and toning that didn’t raise the heart rate above resting level.

The primary outcome measure was change in cognitive function at week 12, as assessed by a battery of neuropsychological tests of verbal learning and memory, verbal fluency, processing speed, executive function, reaction times, "visuospatial" function, and attention. All the study participants showed significant improvement on this measure during the study period, but there were no significant differences between the intervention groups and the control groups, the investigators said (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.189]).

To assess the possibility that this result was because of practice effects from repeated cognitive testing, an additional 12 participants were enrolled in a post hoc study in which there were no interventions; the subjects simply underwent the same battery of neuropsychological tests after a 12-week interval. Scores improved in these subjects, "suggesting that some, but not all, of the improvements observed may have been due to repeated testing" itself, Dr. Barnes and her associates said.

"It is possible that our 12-week intervention was not long enough or intense enough to achieve a substantially greater aerobic response in the intervention group, and that a difference between the groups would have emerged in a longer study," they added.

A total of 26 participants withdrew from the study because of illness, physical inability to perform the activities, time constraints, or miscellaneous reasons. Another nine withdrew after experiencing an adverse event that may have been related to the study activity, such as dizziness, pain, falls, and pulmonary edema. Thus, the attrition rate was 28%.

This study was funded by the National Institute on Aging, the Alzheimer’s Association, the University of California, and the National Center for Research Resources. None of the investigators reported having any relevant financial conflicts of interest.

A group of sedentary older adults with complaints of memory impairment experienced enhanced cognitive function after a 12-week program of mental and physical activity. Members of a control group who did not engaged in such activity also showed the same degree of improvement, according to results reported online April 1 in JAMA Internal Medicine.

These findings suggest that the amount of activity may be more important than the type of activity in improving cognitive function, since all the study groups participated in some form of activity for 60 minutes per day, 3 days per week, for 12 weeks, said Deborah E. Barnes, Ph.D., of the department of psychiatry and the department of epidemiology and biostatistics, University of California, San Francisco, and her associates.

Or the results may simply indicate that repeated testing of cognitive function itself improves performance on those tests, the investigators noted.

Dr. Barnes and her colleagues assessed four combinations of cognitive and physical activity in 126 community-dwelling people aged 65 years and older (mean age, 73 years) who had normal cognition but who reported that their memory or thinking skills had worsened recently. These subjects had relatively high global cognitive function, in line with their relatively high educational attainment.

Approximately 56% of the study population had hypertension, 14% had diabetes, 9% had a history of MI, and half were either past or current smokers.

The participants were randomly assigned to receive a home-based intensive mental activity or a home-based control mental activity, plus a group intensive exercise intervention or a group control intervention.

The mental-activity intervention was a series of computer games that enhanced both speed and accuracy of visual and auditory processing. The games increased in difficulty as subjects’ performance improved. For the control mental activity, participants individually viewed videos of educational lectures on art, history, and science.

The exercise intervention included 30 minutes of intensive aerobic exercise, whereas the control "exercise" substituted 30 minutes of stretching and toning that didn’t raise the heart rate above resting level.

The primary outcome measure was change in cognitive function at week 12, as assessed by a battery of neuropsychological tests of verbal learning and memory, verbal fluency, processing speed, executive function, reaction times, "visuospatial" function, and attention. All the study participants showed significant improvement on this measure during the study period, but there were no significant differences between the intervention groups and the control groups, the investigators said (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.189]).

To assess the possibility that this result was because of practice effects from repeated cognitive testing, an additional 12 participants were enrolled in a post hoc study in which there were no interventions; the subjects simply underwent the same battery of neuropsychological tests after a 12-week interval. Scores improved in these subjects, "suggesting that some, but not all, of the improvements observed may have been due to repeated testing" itself, Dr. Barnes and her associates said.

"It is possible that our 12-week intervention was not long enough or intense enough to achieve a substantially greater aerobic response in the intervention group, and that a difference between the groups would have emerged in a longer study," they added.

A total of 26 participants withdrew from the study because of illness, physical inability to perform the activities, time constraints, or miscellaneous reasons. Another nine withdrew after experiencing an adverse event that may have been related to the study activity, such as dizziness, pain, falls, and pulmonary edema. Thus, the attrition rate was 28%.

This study was funded by the National Institute on Aging, the Alzheimer’s Association, the University of California, and the National Center for Research Resources. None of the investigators reported having any relevant financial conflicts of interest.

A group of sedentary older adults with complaints of memory impairment experienced enhanced cognitive function after a 12-week program of mental and physical activity. Members of a control group who did not engaged in such activity also showed the same degree of improvement, according to results reported online April 1 in JAMA Internal Medicine.

These findings suggest that the amount of activity may be more important than the type of activity in improving cognitive function, since all the study groups participated in some form of activity for 60 minutes per day, 3 days per week, for 12 weeks, said Deborah E. Barnes, Ph.D., of the department of psychiatry and the department of epidemiology and biostatistics, University of California, San Francisco, and her associates.

Or the results may simply indicate that repeated testing of cognitive function itself improves performance on those tests, the investigators noted.

Dr. Barnes and her colleagues assessed four combinations of cognitive and physical activity in 126 community-dwelling people aged 65 years and older (mean age, 73 years) who had normal cognition but who reported that their memory or thinking skills had worsened recently. These subjects had relatively high global cognitive function, in line with their relatively high educational attainment.

Approximately 56% of the study population had hypertension, 14% had diabetes, 9% had a history of MI, and half were either past or current smokers.

The participants were randomly assigned to receive a home-based intensive mental activity or a home-based control mental activity, plus a group intensive exercise intervention or a group control intervention.

The mental-activity intervention was a series of computer games that enhanced both speed and accuracy of visual and auditory processing. The games increased in difficulty as subjects’ performance improved. For the control mental activity, participants individually viewed videos of educational lectures on art, history, and science.

The exercise intervention included 30 minutes of intensive aerobic exercise, whereas the control "exercise" substituted 30 minutes of stretching and toning that didn’t raise the heart rate above resting level.

The primary outcome measure was change in cognitive function at week 12, as assessed by a battery of neuropsychological tests of verbal learning and memory, verbal fluency, processing speed, executive function, reaction times, "visuospatial" function, and attention. All the study participants showed significant improvement on this measure during the study period, but there were no significant differences between the intervention groups and the control groups, the investigators said (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.189]).

To assess the possibility that this result was because of practice effects from repeated cognitive testing, an additional 12 participants were enrolled in a post hoc study in which there were no interventions; the subjects simply underwent the same battery of neuropsychological tests after a 12-week interval. Scores improved in these subjects, "suggesting that some, but not all, of the improvements observed may have been due to repeated testing" itself, Dr. Barnes and her associates said.

"It is possible that our 12-week intervention was not long enough or intense enough to achieve a substantially greater aerobic response in the intervention group, and that a difference between the groups would have emerged in a longer study," they added.

A total of 26 participants withdrew from the study because of illness, physical inability to perform the activities, time constraints, or miscellaneous reasons. Another nine withdrew after experiencing an adverse event that may have been related to the study activity, such as dizziness, pain, falls, and pulmonary edema. Thus, the attrition rate was 28%.

This study was funded by the National Institute on Aging, the Alzheimer’s Association, the University of California, and the National Center for Research Resources. None of the investigators reported having any relevant financial conflicts of interest.

Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.

Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.

These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.

However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.

"Clinicians should be aware of this association," they noted.

Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.

A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.

All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.

Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)

Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.

New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).

In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.

The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.

In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.

The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.

"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.

This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.

Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.

Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.

These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.

However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.

"Clinicians should be aware of this association," they noted.

Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.

A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.

All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.

Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)

Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.

New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).

In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.

The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.

In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.

The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.

"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.

This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.

Use of all glucocorticoids is associated with a two- to threefold increased risk of venous thromboembolism, depending on the type of glucocorticoid, the route of administration, and other factors, according to a report published online April 1 in JAMA Internal Medicine.

Systemic glucocorticoids, as compared with inhaled ones or glucocorticoids that act on the intestines, were associated with the highest risk of VTE. New use was linked to higher risk than continuing or past use, and the VTE risk increased as the dose of glucocorticoids increased, said Sigrun A. Johannesdottir of the department of clinical epidemiology, Aarhus (the Netherlands) University Hospital, and her associates.

These findings are from a population-based case-control study, which cannot prove a cause-and-effect relationship. Moreover, it is difficult to statistically account for all the confounding effects of patients’ underlying disease – the reason they were taking glucocorticoids in the first place – because such disorders raise the risk of VTE directly or cause immobility that in turn can lead to VTE.

However, the timing of this adverse effect, the strength of the association across all types of glucocorticoids, and the fact that the association persisted after the data were adjusted to account for multiple confounders all "increase our confidence that the results reflect a true biological effect," the investigators said.

"Clinicians should be aware of this association," they noted.

Ms. Johannesdottir and her colleagues used data from several Danish national medical registries to identify all adults who were diagnosed with VTE in Denmark in 2005-2012, all patients who filled prescriptions for glucocorticoids during the study period, and all indications for the drugs as well as all relevant comorbidities. They matched 10 control subjects for age and sex from the general population to each study subject.

A total of 38,765 VTE cases and 387,650 controls were included in this study. The median age was 67 years, and slightly more than half of those studied were women.

All glucocorticoid users were found to be at increased risk for VTE, particularly for pulmonary embolism, compared with nonusers, the researchers said.

Systemic glucocorticoids, including betamethasone, methylprednisolone, prednisolone, prednisone, triamcinolone, and hydrocortisone, raised VTE risk to the highest degree. (No patients filled prescriptions for dexamethasone in this study.)

Inhaled corticosteroids and corticosteroids that act on the intestines also raised VTE risk significantly. Among the systemic glucocorticoids, prednisolone and prednisone raised VTE risk the most.

New use of glucocorticoids was associated with the highest risk of VTE, but current use, continuing use, and former use also raised the risk significantly. Oral formulations were associated with the highest risk of VTE, but injectable formulations also raised the risk significantly, Ms. Johannesdottir and her associates reported (JAMA Intern. Med. 2013 April 1 [doi:10.1001/jamainternmed.2013.122]).

In particular, new use of systemic glucocorticoids was associated with the highest risk for VTE, with an estimated incidence rate ratio of 3.06, compared with nonuse of glucocorticoids.

The risk of VTE also rose with increasing cumulative doses of all glucocorticoids.

In further analyses, elevated risk for VTE persisted across all the subgroups that were examined.

The findings did not change appreciably in a sensitivity analysis that included only subjects who took glucocorticoids for at least 5 years.

"The temporality of the association (i.e., the strongest effect at initiation of therapy and the absence of an effect after discontinuation) is in line with an effect on coagulation," Ms. Johannesdottir and her associates said.

This study was supported by the Clinical Epidemiological Research Foundation at Aarhus University Hospital. No relevant conflicts of interest were reported.

Ganetespib may be an alternative or possibly a complementary strategy for inhibiting anaplastic lymphoma kinase, the protein that drives tumorigenesis in an estimated 7% of non–small cell lung carcincomas, according to a report published online March 26 in Cancer Research.

So far the drug has shown promise in vitro and in animal studies and has been tested in a single patient with ALK-driven NSCLC.

The 24-year-old man had initially responded to crizotinib, but after 1 year he developed resistance to the drug and relapsed. "A single cycle of ganetespib treatment resulted in marked tumor response and discernible shrinkage of lung lesions, highlighting the therapeutic potential of the drug within this refractory population," Dr. Jim Sang and his associates wrote (Cancer Res. 2013 March 26 [doi:10.1158/2159-8290.CD-12-0440]).

If ganetespib proves effective in clinical trials, the drug may become especially helpful for patients who develop resistance to crizotinib, the only targeted therapy for the disease that currently has FDA approval, said Dr. Sang of Synta Pharmaceuticals, Lexington, Mass. and his associates. Almost all NSCLC patients who receive crizotinib acquire resistance to it, they noted.

Ganetespib inhibits Hsp90 (heat shock protein 90), "a molecular chaperone that plays a central role in regulating the correct folding, stability, and function of numerous ‘client proteins,’ " including ALK, they said. Inhibition of Hsp90 is known to disrupt several oncogenic signaling pathways that are crucial to tumor cell proliferation and survival.

"Targeting the chaperone function of Hsp90, therefore, represents an alternative approach to direct kinase inhibition for therapeutic intervention in ALK-driven cancer," Dr. Sang and his colleagues said. Pharmacologic blockade of Hsp90 also may overcome drug resistance mechanisms commonly seen in many cancers.

The researchers first tested ganetespib in a cultured, ALK-positive NSCLC cell line. The drug was 30 times more potent than crizotinib against the carcinoma, causing the complete loss of ALK expression in vitro. Ganetespib also demonstrated strong activity against ALK-positive NSCLC cell lines that were resistant to crizotinib.

The investigators then compared ganetespib with crizotinib in mice that were xenografted with ALK-positive NSCLC cancer cells. Ganetespib showed greater antitumor activity and actually prolonged the survival of the animals, compared with crizotinib.

In further experiments, ganetespib was effective both in vitro and in vivo when combined with other targeted ALK agents.

"Targeting the Hsp90 chaperone pathway with ganetespib represents a potentially effective strategy for therapeutic intervention in multiple ALK-driven malignancies – in particular, NSCLC. The pleiotropic effects of Hsp90 inhibition on both ALLK itself and other client proteins provide more complete and durable responses, compared with direct kinase inhibition," Dr. Sang and his associates wrote.

This study was funded by Synta Pharmaceuticals. Dr. Sang’s associates reported additional ties to numerous industry sources.

Ganetespib may be an alternative or possibly a complementary strategy for inhibiting anaplastic lymphoma kinase, the protein that drives tumorigenesis in an estimated 7% of non–small cell lung carcincomas, according to a report published online March 26 in Cancer Research.

So far the drug has shown promise in vitro and in animal studies and has been tested in a single patient with ALK-driven NSCLC.

The 24-year-old man had initially responded to crizotinib, but after 1 year he developed resistance to the drug and relapsed. "A single cycle of ganetespib treatment resulted in marked tumor response and discernible shrinkage of lung lesions, highlighting the therapeutic potential of the drug within this refractory population," Dr. Jim Sang and his associates wrote (Cancer Res. 2013 March 26 [doi:10.1158/2159-8290.CD-12-0440]).

If ganetespib proves effective in clinical trials, the drug may become especially helpful for patients who develop resistance to crizotinib, the only targeted therapy for the disease that currently has FDA approval, said Dr. Sang of Synta Pharmaceuticals, Lexington, Mass. and his associates. Almost all NSCLC patients who receive crizotinib acquire resistance to it, they noted.

Ganetespib inhibits Hsp90 (heat shock protein 90), "a molecular chaperone that plays a central role in regulating the correct folding, stability, and function of numerous ‘client proteins,’ " including ALK, they said. Inhibition of Hsp90 is known to disrupt several oncogenic signaling pathways that are crucial to tumor cell proliferation and survival.

"Targeting the chaperone function of Hsp90, therefore, represents an alternative approach to direct kinase inhibition for therapeutic intervention in ALK-driven cancer," Dr. Sang and his colleagues said. Pharmacologic blockade of Hsp90 also may overcome drug resistance mechanisms commonly seen in many cancers.

The researchers first tested ganetespib in a cultured, ALK-positive NSCLC cell line. The drug was 30 times more potent than crizotinib against the carcinoma, causing the complete loss of ALK expression in vitro. Ganetespib also demonstrated strong activity against ALK-positive NSCLC cell lines that were resistant to crizotinib.

The investigators then compared ganetespib with crizotinib in mice that were xenografted with ALK-positive NSCLC cancer cells. Ganetespib showed greater antitumor activity and actually prolonged the survival of the animals, compared with crizotinib.

In further experiments, ganetespib was effective both in vitro and in vivo when combined with other targeted ALK agents.

"Targeting the Hsp90 chaperone pathway with ganetespib represents a potentially effective strategy for therapeutic intervention in multiple ALK-driven malignancies – in particular, NSCLC. The pleiotropic effects of Hsp90 inhibition on both ALLK itself and other client proteins provide more complete and durable responses, compared with direct kinase inhibition," Dr. Sang and his associates wrote.

This study was funded by Synta Pharmaceuticals. Dr. Sang’s associates reported additional ties to numerous industry sources.

Ganetespib may be an alternative or possibly a complementary strategy for inhibiting anaplastic lymphoma kinase, the protein that drives tumorigenesis in an estimated 7% of non–small cell lung carcincomas, according to a report published online March 26 in Cancer Research.

So far the drug has shown promise in vitro and in animal studies and has been tested in a single patient with ALK-driven NSCLC.

The 24-year-old man had initially responded to crizotinib, but after 1 year he developed resistance to the drug and relapsed. "A single cycle of ganetespib treatment resulted in marked tumor response and discernible shrinkage of lung lesions, highlighting the therapeutic potential of the drug within this refractory population," Dr. Jim Sang and his associates wrote (Cancer Res. 2013 March 26 [doi:10.1158/2159-8290.CD-12-0440]).

If ganetespib proves effective in clinical trials, the drug may become especially helpful for patients who develop resistance to crizotinib, the only targeted therapy for the disease that currently has FDA approval, said Dr. Sang of Synta Pharmaceuticals, Lexington, Mass. and his associates. Almost all NSCLC patients who receive crizotinib acquire resistance to it, they noted.

Ganetespib inhibits Hsp90 (heat shock protein 90), "a molecular chaperone that plays a central role in regulating the correct folding, stability, and function of numerous ‘client proteins,’ " including ALK, they said. Inhibition of Hsp90 is known to disrupt several oncogenic signaling pathways that are crucial to tumor cell proliferation and survival.

"Targeting the chaperone function of Hsp90, therefore, represents an alternative approach to direct kinase inhibition for therapeutic intervention in ALK-driven cancer," Dr. Sang and his colleagues said. Pharmacologic blockade of Hsp90 also may overcome drug resistance mechanisms commonly seen in many cancers.

The researchers first tested ganetespib in a cultured, ALK-positive NSCLC cell line. The drug was 30 times more potent than crizotinib against the carcinoma, causing the complete loss of ALK expression in vitro. Ganetespib also demonstrated strong activity against ALK-positive NSCLC cell lines that were resistant to crizotinib.

The investigators then compared ganetespib with crizotinib in mice that were xenografted with ALK-positive NSCLC cancer cells. Ganetespib showed greater antitumor activity and actually prolonged the survival of the animals, compared with crizotinib.

In further experiments, ganetespib was effective both in vitro and in vivo when combined with other targeted ALK agents.

"Targeting the Hsp90 chaperone pathway with ganetespib represents a potentially effective strategy for therapeutic intervention in multiple ALK-driven malignancies – in particular, NSCLC. The pleiotropic effects of Hsp90 inhibition on both ALLK itself and other client proteins provide more complete and durable responses, compared with direct kinase inhibition," Dr. Sang and his associates wrote.

This study was funded by Synta Pharmaceuticals. Dr. Sang’s associates reported additional ties to numerous industry sources.

Information pooled in a meta-analysis of 18 data sets may allow clinicians to fine-tune the ultrasonographic surveillance of small abdominal aortic aneurysms, according to a report in JAMA.

"By pooling results from 18 studies, we quantified AAA growth rates and the AAA rupture risk as a function of aortic diameter. Our intent was to provide an objective basis for selecting surveillance intervals for patients with small AAAs," said Simon G. Thompson, D.Sc., of the cardiovascular epidemiology unit, department of public health and primary care, University of Cambridge (England), and his associates.

Their findings suggest that the overall number and frequency of surveillance scans can be reduced, at least for men. However, the picture is still unclear for women, and more research is required before specific recommendations can be made, the investigators said.

The researchers reviewed the literature for data sets with 100 or more patients who had repeated ultrasound measurements of their AAAs over time. This yielded 18 data sets with 15,471 subjects with AAA diameters between 3.0 and 5.4 cm.

The 13,728 men and 1,743 women were followed for an average of 1-8 years. There were "relatively few" AAA ruptures: 178 among men and 50 among women. Among men, a 3-cm AAA took a mean of 7.4 years to have a 10% chance of reaching 5.5 cm, a 4-cm AAA took a mean of 3.2 years to have a 10% chance of reaching 5.5 cm, and a 5-cm AAA took a mean of 0.7 years to have a 10% chance of reaching 5.5 cm. Similarly, rupture rates among men approximately doubled for every 0.5-cm increase in AAA diameter. For AAAs with diameters of 3.0-4.5 cm, the average time to reach a rupture risk of 1% was at least 2 years.

Based on the lower 95% confidence limits, the risk of rupture in men would be less than 1% if surveillance intervals were extended to 3 years for AAAs measuring 3.0-3.9 cm, to 2 years for those measuring 4.0-4.4 cm, and to 1 year for those measuring 4.5-5.4 cm.

"For a U.S. patient with a 3.0-cm AAA detected by screening, this would reduce the average number of surveillance scans from approximately 15 to 7" (JAMA 2013;309:806-13).

However, if the lower 95% prediction limits of the estimates were applied (to acknowledge that the population in each study might have different growth and rupture rates), the risk of rupture in men would be less than 1% if surveillance intervals were extended to 2 years for AAAs measuring 3.0-3.9 cm, to 1 year for those measuring 4.0-4.9 cm, and to 6 months for those measuring 5.0-5.4 cm. This would result in a lesser average reduction in the number of surveillance scans from 15 to 10.

The rate of rupture was four times higher for women than for men, even though the rate of AAA growth was similar. "The clinical implication is that a lower AAA diameter threshold for surgery should be adopted for women, a recommendation already made by the joint council of the American Association for Vascular Surgery and the Society for Vascular Surgery," the researchers wrote.

A threshold of 4.5 cm rather than 5.5 cm might be more appropriate for women, but this decision must be weighed against the evidence that women have operative mortality and a poorer outcome at hospital discharge.

This study was supported by the U.K. National Institute for Health Research. The authors had no conflicts.

Information pooled in a meta-analysis of 18 data sets may allow clinicians to fine-tune the ultrasonographic surveillance of small abdominal aortic aneurysms, according to a report in JAMA.

"By pooling results from 18 studies, we quantified AAA growth rates and the AAA rupture risk as a function of aortic diameter. Our intent was to provide an objective basis for selecting surveillance intervals for patients with small AAAs," said Simon G. Thompson, D.Sc., of the cardiovascular epidemiology unit, department of public health and primary care, University of Cambridge (England), and his associates.

Their findings suggest that the overall number and frequency of surveillance scans can be reduced, at least for men. However, the picture is still unclear for women, and more research is required before specific recommendations can be made, the investigators said.

The researchers reviewed the literature for data sets with 100 or more patients who had repeated ultrasound measurements of their AAAs over time. This yielded 18 data sets with 15,471 subjects with AAA diameters between 3.0 and 5.4 cm.

The 13,728 men and 1,743 women were followed for an average of 1-8 years. There were "relatively few" AAA ruptures: 178 among men and 50 among women. Among men, a 3-cm AAA took a mean of 7.4 years to have a 10% chance of reaching 5.5 cm, a 4-cm AAA took a mean of 3.2 years to have a 10% chance of reaching 5.5 cm, and a 5-cm AAA took a mean of 0.7 years to have a 10% chance of reaching 5.5 cm. Similarly, rupture rates among men approximately doubled for every 0.5-cm increase in AAA diameter. For AAAs with diameters of 3.0-4.5 cm, the average time to reach a rupture risk of 1% was at least 2 years.

Based on the lower 95% confidence limits, the risk of rupture in men would be less than 1% if surveillance intervals were extended to 3 years for AAAs measuring 3.0-3.9 cm, to 2 years for those measuring 4.0-4.4 cm, and to 1 year for those measuring 4.5-5.4 cm.

"For a U.S. patient with a 3.0-cm AAA detected by screening, this would reduce the average number of surveillance scans from approximately 15 to 7" (JAMA 2013;309:806-13).

However, if the lower 95% prediction limits of the estimates were applied (to acknowledge that the population in each study might have different growth and rupture rates), the risk of rupture in men would be less than 1% if surveillance intervals were extended to 2 years for AAAs measuring 3.0-3.9 cm, to 1 year for those measuring 4.0-4.9 cm, and to 6 months for those measuring 5.0-5.4 cm. This would result in a lesser average reduction in the number of surveillance scans from 15 to 10.

The rate of rupture was four times higher for women than for men, even though the rate of AAA growth was similar. "The clinical implication is that a lower AAA diameter threshold for surgery should be adopted for women, a recommendation already made by the joint council of the American Association for Vascular Surgery and the Society for Vascular Surgery," the researchers wrote.

A threshold of 4.5 cm rather than 5.5 cm might be more appropriate for women, but this decision must be weighed against the evidence that women have operative mortality and a poorer outcome at hospital discharge.

This study was supported by the U.K. National Institute for Health Research. The authors had no conflicts.

Information pooled in a meta-analysis of 18 data sets may allow clinicians to fine-tune the ultrasonographic surveillance of small abdominal aortic aneurysms, according to a report in JAMA.

"By pooling results from 18 studies, we quantified AAA growth rates and the AAA rupture risk as a function of aortic diameter. Our intent was to provide an objective basis for selecting surveillance intervals for patients with small AAAs," said Simon G. Thompson, D.Sc., of the cardiovascular epidemiology unit, department of public health and primary care, University of Cambridge (England), and his associates.

Their findings suggest that the overall number and frequency of surveillance scans can be reduced, at least for men. However, the picture is still unclear for women, and more research is required before specific recommendations can be made, the investigators said.

The researchers reviewed the literature for data sets with 100 or more patients who had repeated ultrasound measurements of their AAAs over time. This yielded 18 data sets with 15,471 subjects with AAA diameters between 3.0 and 5.4 cm.

The 13,728 men and 1,743 women were followed for an average of 1-8 years. There were "relatively few" AAA ruptures: 178 among men and 50 among women. Among men, a 3-cm AAA took a mean of 7.4 years to have a 10% chance of reaching 5.5 cm, a 4-cm AAA took a mean of 3.2 years to have a 10% chance of reaching 5.5 cm, and a 5-cm AAA took a mean of 0.7 years to have a 10% chance of reaching 5.5 cm. Similarly, rupture rates among men approximately doubled for every 0.5-cm increase in AAA diameter. For AAAs with diameters of 3.0-4.5 cm, the average time to reach a rupture risk of 1% was at least 2 years.

Based on the lower 95% confidence limits, the risk of rupture in men would be less than 1% if surveillance intervals were extended to 3 years for AAAs measuring 3.0-3.9 cm, to 2 years for those measuring 4.0-4.4 cm, and to 1 year for those measuring 4.5-5.4 cm.

"For a U.S. patient with a 3.0-cm AAA detected by screening, this would reduce the average number of surveillance scans from approximately 15 to 7" (JAMA 2013;309:806-13).

However, if the lower 95% prediction limits of the estimates were applied (to acknowledge that the population in each study might have different growth and rupture rates), the risk of rupture in men would be less than 1% if surveillance intervals were extended to 2 years for AAAs measuring 3.0-3.9 cm, to 1 year for those measuring 4.0-4.9 cm, and to 6 months for those measuring 5.0-5.4 cm. This would result in a lesser average reduction in the number of surveillance scans from 15 to 10.

The rate of rupture was four times higher for women than for men, even though the rate of AAA growth was similar. "The clinical implication is that a lower AAA diameter threshold for surgery should be adopted for women, a recommendation already made by the joint council of the American Association for Vascular Surgery and the Society for Vascular Surgery," the researchers wrote.

A threshold of 4.5 cm rather than 5.5 cm might be more appropriate for women, but this decision must be weighed against the evidence that women have operative mortality and a poorer outcome at hospital discharge.

This study was supported by the U.K. National Institute for Health Research. The authors had no conflicts.

Percutaneous closure of a patent foramen ovale in adults who’ve had cryptogenic stroke or embolism was no more effective than medical therapy alone at preventing a recurrent event, according to two separate reports published online March 20 in the New England Journal of Medicine.

However, one study may have been underpowered to detect a clinically relevant benefit with PFO closure, and secondary analyses of data from the second study suggested that PFO closure with an occlusive device might be beneficial, particularly in certain subgroups of patients.

The findings of these two large, international, randomized clinical trials have long been awaited with anticipation, because it has been unclear whether the benefits of closing a patent foramen ovale outweighed the risks. Observational studies and some meta-analyses have indicated a clear benefit with the procedure, while other meta-analyses and the only clinical trial that examined the issue to date have suggested that it leads to a poorer clinical course than medical therapy does.

Parsing the PC Trial

The first of the two current clinical studies, the PC Trial, was initiated 14 years ago and conducted at 29 sites in Europe, Canada, Brazil, and Australia. It involved 414 adults under age 60 (mean age, 44 years) who had a radiologically verified ischemic stroke, transient ischemic attack (TIA) with a cerebral ischemic lesion, or extracranial thrombolic event, all with no identifiable cause other than a PFO.

The study subjects were randomly assigned either to undergo percutaneous closure of the PFO using an occlusive device manufactured by the study sponsor, St. Jude Medical (204 patients), or to receive antithrombotic agents according to the discretion of the treating physician (210 patients), said Dr. Bernhard Meier of the cardiology department at Bern (Switzerland) University Hospital, and his associates.

The primary endpoint, a composite of death, nonfatal stroke, TIA, or peripheral embolism, occurred in 7 patients (3.4%) in the closure group and 11 patients (5.2%) in the medical therapy group, a nonsignificant difference.

"There were fewer strokes in the closure group; but overall, few patients had a stroke, and the difference was not significant," the investigators reported (N. Engl. J. Med. 2013;368:1083-91).

Thus, closure of the PFO using this method was no more effective than medical therapy at reducing the risk of recurrent embolic events or death.

However, the lower-than-anticipated event rate means that this trial may have been subject to a type II error, the investigators cautioned. Thus, "a clinically relevant benefit of the closure of PFO might exist, but we were unable to detect it."

Analysis of the individual components of this composite endpoint yielded similar results: The rates of recurrent stroke (0.5% and 2.4%, respectively) and of TIA (2.5% and 3.3%, respectively) also were not significantly different between the two study groups.

Similarly, analyses of important subgroups of patients showed that PFO closure was no more beneficial than medical therapy with regard to patient age (older or younger than 45 years), the presence or absence of septal aneurysm, the type of the index embolic event, or the presence or absence of a history of cardiovascular events.

There were 113 adverse events in 71 patients in the closure group (34.8%) and 120 events in 62 patients in the medical therapy group (29.5%). The rates of serious adverse events were similar between the two groups, at 21.1% and 17.6%, respectively. In particular, new-onset atrial fibrillation developed in 6 patients (2.9%) in the closure group and 2 patients (1.0%) in the medical therapy group.

In addition to the possible type II error, this trial was limited by its composite endpoint, which was not specific to the condition studied (embolic events). The study also had an unusually long recruitment period and a selected patient population, which may limit the generalizability of the findings. In addition, a lower-than-expected rate of patient retention might have caused attrition bias, and the clinical events committee "discounted potential primary-end-point events more often in the medical therapy group than in the closure group," Dr. Meier and his associates in the PC Trial said.

Showing RESPECT results

In the second trial, the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) study, 980 patients with cryptogenic ischemic stroke and a PFO were assessed at 69 sites in the United States and Canada. They were randomly assigned either to undergo percutaneous closure of the PFO using an occlusive device manufactured by the study sponsor (St. Jude Medical) or to receive medical therapy alone.

The primary endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death (within 45 days of randomization), said Dr. John D. Carroll of the University of Colorado Hospital, Aurora, and his associates.

During a mean follow-up of 2.6 years, 25 such events – all of them nonfatal ischemic strokes – occurred. Nine of these strokes occurred in the closure group and 16 in the medical therapy group, a nonsignificant difference.

In this primary intention-to-treat analysis, there was a "nominal" 51% risk reduction with the closure procedure, but the difference between the two study groups did not reach statistical significance, the investigators reported (N. Engl. J. Med. 2013;368:1092-1100).

However, in a per-protocol analysis and an as-treated analysis, closure of the PFO was found superior to medical therapy alone in preventing recurrent stroke.

An exploratory subgroup analysis suggested that patients with an atrial-septal aneurysm and patients with exceptionally large shunt size also benefited more from PFO closure than from medical therapy alone. And a post hoc analysis suggested that PFO closure was more effective than medical therapy at preventing larger strokes.

The rates of serious adverse events did not differ significantly between the closure group (23.0%) and the medical therapy group (21.6%). A total of 22 serious adverse events in the closure group were attributed to the procedure or the device, including two cases of pericardial tamponade.

Like the PC Trial, the RESPECT study had several limitations. There was a significant difference between the two study groups in the dropout rate, the authors noted, "which resulted in unequal duration of exposure to the risk of recurrence." Also, both entry and retention biases may have occurred, because the highest-risk patients "were preferentially treated outside the trial," Dr. Carroll and his associates said.

Both the PC Trial and RESPECT study were funded by St. Jude Medical, maker of the percutaneous PFO closure device used in both studies. Dr. Meier reported receiving consulting fees from St. Jude Medical and grant support to his institution from Abbott, Cordis, and Medtronic; and his associates reported numerous ties to industry sources. Dr. Carroll reported ties to St. Jude Medical, Philips Healthcare, and W.L. Gore, and his associates reported numerous ties to industry sources.

Percutaneous closure of a patent foramen ovale in adults who’ve had cryptogenic stroke or embolism was no more effective than medical therapy alone at preventing a recurrent event, according to two separate reports published online March 20 in the New England Journal of Medicine.

However, one study may have been underpowered to detect a clinically relevant benefit with PFO closure, and secondary analyses of data from the second study suggested that PFO closure with an occlusive device might be beneficial, particularly in certain subgroups of patients.

The findings of these two large, international, randomized clinical trials have long been awaited with anticipation, because it has been unclear whether the benefits of closing a patent foramen ovale outweighed the risks. Observational studies and some meta-analyses have indicated a clear benefit with the procedure, while other meta-analyses and the only clinical trial that examined the issue to date have suggested that it leads to a poorer clinical course than medical therapy does.

Parsing the PC Trial

The first of the two current clinical studies, the PC Trial, was initiated 14 years ago and conducted at 29 sites in Europe, Canada, Brazil, and Australia. It involved 414 adults under age 60 (mean age, 44 years) who had a radiologically verified ischemic stroke, transient ischemic attack (TIA) with a cerebral ischemic lesion, or extracranial thrombolic event, all with no identifiable cause other than a PFO.

The study subjects were randomly assigned either to undergo percutaneous closure of the PFO using an occlusive device manufactured by the study sponsor, St. Jude Medical (204 patients), or to receive antithrombotic agents according to the discretion of the treating physician (210 patients), said Dr. Bernhard Meier of the cardiology department at Bern (Switzerland) University Hospital, and his associates.

The primary endpoint, a composite of death, nonfatal stroke, TIA, or peripheral embolism, occurred in 7 patients (3.4%) in the closure group and 11 patients (5.2%) in the medical therapy group, a nonsignificant difference.

"There were fewer strokes in the closure group; but overall, few patients had a stroke, and the difference was not significant," the investigators reported (N. Engl. J. Med. 2013;368:1083-91).

Thus, closure of the PFO using this method was no more effective than medical therapy at reducing the risk of recurrent embolic events or death.

However, the lower-than-anticipated event rate means that this trial may have been subject to a type II error, the investigators cautioned. Thus, "a clinically relevant benefit of the closure of PFO might exist, but we were unable to detect it."

Analysis of the individual components of this composite endpoint yielded similar results: The rates of recurrent stroke (0.5% and 2.4%, respectively) and of TIA (2.5% and 3.3%, respectively) also were not significantly different between the two study groups.

Similarly, analyses of important subgroups of patients showed that PFO closure was no more beneficial than medical therapy with regard to patient age (older or younger than 45 years), the presence or absence of septal aneurysm, the type of the index embolic event, or the presence or absence of a history of cardiovascular events.

There were 113 adverse events in 71 patients in the closure group (34.8%) and 120 events in 62 patients in the medical therapy group (29.5%). The rates of serious adverse events were similar between the two groups, at 21.1% and 17.6%, respectively. In particular, new-onset atrial fibrillation developed in 6 patients (2.9%) in the closure group and 2 patients (1.0%) in the medical therapy group.

In addition to the possible type II error, this trial was limited by its composite endpoint, which was not specific to the condition studied (embolic events). The study also had an unusually long recruitment period and a selected patient population, which may limit the generalizability of the findings. In addition, a lower-than-expected rate of patient retention might have caused attrition bias, and the clinical events committee "discounted potential primary-end-point events more often in the medical therapy group than in the closure group," Dr. Meier and his associates in the PC Trial said.

Showing RESPECT results

In the second trial, the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) study, 980 patients with cryptogenic ischemic stroke and a PFO were assessed at 69 sites in the United States and Canada. They were randomly assigned either to undergo percutaneous closure of the PFO using an occlusive device manufactured by the study sponsor (St. Jude Medical) or to receive medical therapy alone.

The primary endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death (within 45 days of randomization), said Dr. John D. Carroll of the University of Colorado Hospital, Aurora, and his associates.

During a mean follow-up of 2.6 years, 25 such events – all of them nonfatal ischemic strokes – occurred. Nine of these strokes occurred in the closure group and 16 in the medical therapy group, a nonsignificant difference.

In this primary intention-to-treat analysis, there was a "nominal" 51% risk reduction with the closure procedure, but the difference between the two study groups did not reach statistical significance, the investigators reported (N. Engl. J. Med. 2013;368:1092-1100).

However, in a per-protocol analysis and an as-treated analysis, closure of the PFO was found superior to medical therapy alone in preventing recurrent stroke.

An exploratory subgroup analysis suggested that patients with an atrial-septal aneurysm and patients with exceptionally large shunt size also benefited more from PFO closure than from medical therapy alone. And a post hoc analysis suggested that PFO closure was more effective than medical therapy at preventing larger strokes.

The rates of serious adverse events did not differ significantly between the closure group (23.0%) and the medical therapy group (21.6%). A total of 22 serious adverse events in the closure group were attributed to the procedure or the device, including two cases of pericardial tamponade.

Like the PC Trial, the RESPECT study had several limitations. There was a significant difference between the two study groups in the dropout rate, the authors noted, "which resulted in unequal duration of exposure to the risk of recurrence." Also, both entry and retention biases may have occurred, because the highest-risk patients "were preferentially treated outside the trial," Dr. Carroll and his associates said.

Both the PC Trial and RESPECT study were funded by St. Jude Medical, maker of the percutaneous PFO closure device used in both studies. Dr. Meier reported receiving consulting fees from St. Jude Medical and grant support to his institution from Abbott, Cordis, and Medtronic; and his associates reported numerous ties to industry sources. Dr. Carroll reported ties to St. Jude Medical, Philips Healthcare, and W.L. Gore, and his associates reported numerous ties to industry sources.

Percutaneous closure of a patent foramen ovale in adults who’ve had cryptogenic stroke or embolism was no more effective than medical therapy alone at preventing a recurrent event, according to two separate reports published online March 20 in the New England Journal of Medicine.

However, one study may have been underpowered to detect a clinically relevant benefit with PFO closure, and secondary analyses of data from the second study suggested that PFO closure with an occlusive device might be beneficial, particularly in certain subgroups of patients.

The findings of these two large, international, randomized clinical trials have long been awaited with anticipation, because it has been unclear whether the benefits of closing a patent foramen ovale outweighed the risks. Observational studies and some meta-analyses have indicated a clear benefit with the procedure, while other meta-analyses and the only clinical trial that examined the issue to date have suggested that it leads to a poorer clinical course than medical therapy does.

Parsing the PC Trial

The first of the two current clinical studies, the PC Trial, was initiated 14 years ago and conducted at 29 sites in Europe, Canada, Brazil, and Australia. It involved 414 adults under age 60 (mean age, 44 years) who had a radiologically verified ischemic stroke, transient ischemic attack (TIA) with a cerebral ischemic lesion, or extracranial thrombolic event, all with no identifiable cause other than a PFO.

The study subjects were randomly assigned either to undergo percutaneous closure of the PFO using an occlusive device manufactured by the study sponsor, St. Jude Medical (204 patients), or to receive antithrombotic agents according to the discretion of the treating physician (210 patients), said Dr. Bernhard Meier of the cardiology department at Bern (Switzerland) University Hospital, and his associates.

The primary endpoint, a composite of death, nonfatal stroke, TIA, or peripheral embolism, occurred in 7 patients (3.4%) in the closure group and 11 patients (5.2%) in the medical therapy group, a nonsignificant difference.

"There were fewer strokes in the closure group; but overall, few patients had a stroke, and the difference was not significant," the investigators reported (N. Engl. J. Med. 2013;368:1083-91).

Thus, closure of the PFO using this method was no more effective than medical therapy at reducing the risk of recurrent embolic events or death.

However, the lower-than-anticipated event rate means that this trial may have been subject to a type II error, the investigators cautioned. Thus, "a clinically relevant benefit of the closure of PFO might exist, but we were unable to detect it."

Analysis of the individual components of this composite endpoint yielded similar results: The rates of recurrent stroke (0.5% and 2.4%, respectively) and of TIA (2.5% and 3.3%, respectively) also were not significantly different between the two study groups.

Similarly, analyses of important subgroups of patients showed that PFO closure was no more beneficial than medical therapy with regard to patient age (older or younger than 45 years), the presence or absence of septal aneurysm, the type of the index embolic event, or the presence or absence of a history of cardiovascular events.

There were 113 adverse events in 71 patients in the closure group (34.8%) and 120 events in 62 patients in the medical therapy group (29.5%). The rates of serious adverse events were similar between the two groups, at 21.1% and 17.6%, respectively. In particular, new-onset atrial fibrillation developed in 6 patients (2.9%) in the closure group and 2 patients (1.0%) in the medical therapy group.

In addition to the possible type II error, this trial was limited by its composite endpoint, which was not specific to the condition studied (embolic events). The study also had an unusually long recruitment period and a selected patient population, which may limit the generalizability of the findings. In addition, a lower-than-expected rate of patient retention might have caused attrition bias, and the clinical events committee "discounted potential primary-end-point events more often in the medical therapy group than in the closure group," Dr. Meier and his associates in the PC Trial said.

Showing RESPECT results

In the second trial, the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) study, 980 patients with cryptogenic ischemic stroke and a PFO were assessed at 69 sites in the United States and Canada. They were randomly assigned either to undergo percutaneous closure of the PFO using an occlusive device manufactured by the study sponsor (St. Jude Medical) or to receive medical therapy alone.

The primary endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death (within 45 days of randomization), said Dr. John D. Carroll of the University of Colorado Hospital, Aurora, and his associates.

During a mean follow-up of 2.6 years, 25 such events – all of them nonfatal ischemic strokes – occurred. Nine of these strokes occurred in the closure group and 16 in the medical therapy group, a nonsignificant difference.

In this primary intention-to-treat analysis, there was a "nominal" 51% risk reduction with the closure procedure, but the difference between the two study groups did not reach statistical significance, the investigators reported (N. Engl. J. Med. 2013;368:1092-1100).

However, in a per-protocol analysis and an as-treated analysis, closure of the PFO was found superior to medical therapy alone in preventing recurrent stroke.

An exploratory subgroup analysis suggested that patients with an atrial-septal aneurysm and patients with exceptionally large shunt size also benefited more from PFO closure than from medical therapy alone. And a post hoc analysis suggested that PFO closure was more effective than medical therapy at preventing larger strokes.

The rates of serious adverse events did not differ significantly between the closure group (23.0%) and the medical therapy group (21.6%). A total of 22 serious adverse events in the closure group were attributed to the procedure or the device, including two cases of pericardial tamponade.

Like the PC Trial, the RESPECT study had several limitations. There was a significant difference between the two study groups in the dropout rate, the authors noted, "which resulted in unequal duration of exposure to the risk of recurrence." Also, both entry and retention biases may have occurred, because the highest-risk patients "were preferentially treated outside the trial," Dr. Carroll and his associates said.

Both the PC Trial and RESPECT study were funded by St. Jude Medical, maker of the percutaneous PFO closure device used in both studies. Dr. Meier reported receiving consulting fees from St. Jude Medical and grant support to his institution from Abbott, Cordis, and Medtronic; and his associates reported numerous ties to industry sources. Dr. Carroll reported ties to St. Jude Medical, Philips Healthcare, and W.L. Gore, and his associates reported numerous ties to industry sources.