Michele G. Sullivan

Treatment-resistant depression seems to respond better when medication decisions are made by referenced electroencephalogram than by the STAR*D algorithm, according to a 12-week randomized trial.

Among 114 patients randomized to the two treatment methods, those whose medication was guided by referenced-EEG (rEEG) improved significantly more than did those treated by Sequenced Treatment Alternatives to Relieve Depression (STAR*D) guidelines in both primary measures of depression, as well as in most of the secondary measurements, Dr. Charles DeBattista and his colleagues wrote in the January issue of Journal of Psychiatric Research (doi:10.1016/j.jpsychires.2010.05.009).

"These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression, and perhaps in other psychiatric disorders," wrote Dr. DeBattista of Stanford (Calif.) University and his coauthors. "If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice."

The rEEG relies on a large database built over an 18-year period. It now contains information on more than 1,800 patients who were followed for an average of 405 days. The database includes the patients’ unmedicated EEGs, along with outcomes of more than 17,000 medical trials. The result, according to Dr. DeBattista and his colleagues, is the availability of 74 EEG biomarkers that "provide a very large collection of outcomes data allowing calculation of statistical correlation between the biomarkers found in a patient’s EEG and the treatment response predictions to many medications, based on patients who had similar EEG biomarkers."

The STAR*D algorithm study (pdf), published in 2006, is a four-step treatment algorithm; most patients start at level 1 with citalopram. If they do not enter remission within 14 weeks, they either switch drugs or add another medication; this pattern can continue for four levels, ending with tranylcypromine or mirtazapine plus extended-release venlafaxine.

The trial by Dr. DeBattista and his colleagues randomized 114 patients with treatment-resistant depression. After undergoing a drug washout period consisting of five consecutive half-life days, patients in the active group were randomized to a treatment regimen based on rEEG, constructed after review of their baseline EEG.

Control patients who had failed only selective serotonin reuptake inhibitors received extended-release venlafaxine; those who had failed two or more classes of antidepressants received a medication regimen from steps 2-4 of STAR*D.

The primary end points were changes in the Quick Inventory of Depressive Symptomatology (pdf) (QIDS-SR16) and the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (pdf) (Q-LES-Q SF).

Secondary end points were changes in the Clinical Global Impression severity scale (pdf) (CGI-severity), the Clinical Global Impression improvement scale (pdf) (CGI-improvement), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Patient Health Questionnaire-9 (PHQ-9).

The patients’ mean age was 44 years; most (63%) were women and white (66%). Overall, they had failed a mean of four previous central nervous system medications.

After 12 weeks, those in the rEEG group had improved significantly more than the control patients on the QIDS-16 (–7 vs. –4.5) and the Q-LES-Q-SF (18 vs. 9).

The rEEG group also improved significantly more in most of the secondary end points, including the CGI-improvement scores, the CGI-severity scores, and the final number of responders as measured by the MADRS system. However, the authors pointed out, the mean MADRS change from baseline to the study’s end was not significantly greater in the rEEG group than in the control groups.

The PHQ-9 end point also showed significant benefit in favor of rEEG, but in its remission measurement, rEEG was not significantly different from the control group (47% vs. 37%).

In a treatment curve, the authors noted that the groups began to separate as early as 2 weeks after the initiation of therapy, with the rEEG group continuing to improve more than the control group each week.

Treatment-related adverse events occurred in 45% of the rEEG group and 48% of the control groups – not significantly different. The most common in both groups were nausea/vomiting, fatigue, headache, anxiety, and insomnia. None of the adverse events or their rates was different from what could have been expected given the drugs employed, the authors noted.

Even in the absence of final remission superiority, the benefit of rEEG-guided treatment over STAR*D-guided treatment was clear and clinically relevant, the investigators said. "For example, the magnitude of improvement on the QIDS-SR16 response rate was 65% for rEEG compared with only 39% for the controls. Likewise the secondary measures on the Q-LES-Q-SF were also quite consistent in supporting the efficacy of the rEEG-guided therapy."

In addition, the investigators said, the early and continuous separation of treatment curves suggested that "rEEG’s superiority in reducing patients’ depressive symptoms might have continued had the trial continued."

The study was sponsored by CNS Response Inc., the company that owns the rEEG platform. Dr. DeBattista said he has received research support from the company, as have 4 of the other 14 investigators. Four other investigators are company employees and own stock in CNS Response.

Treatment-resistant depression seems to respond better when medication decisions are made by referenced electroencephalogram than by the STAR*D algorithm, according to a 12-week randomized trial.

Among 114 patients randomized to the two treatment methods, those whose medication was guided by referenced-EEG (rEEG) improved significantly more than did those treated by Sequenced Treatment Alternatives to Relieve Depression (STAR*D) guidelines in both primary measures of depression, as well as in most of the secondary measurements, Dr. Charles DeBattista and his colleagues wrote in the January issue of Journal of Psychiatric Research (doi:10.1016/j.jpsychires.2010.05.009).

"These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression, and perhaps in other psychiatric disorders," wrote Dr. DeBattista of Stanford (Calif.) University and his coauthors. "If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice."

The rEEG relies on a large database built over an 18-year period. It now contains information on more than 1,800 patients who were followed for an average of 405 days. The database includes the patients’ unmedicated EEGs, along with outcomes of more than 17,000 medical trials. The result, according to Dr. DeBattista and his colleagues, is the availability of 74 EEG biomarkers that "provide a very large collection of outcomes data allowing calculation of statistical correlation between the biomarkers found in a patient’s EEG and the treatment response predictions to many medications, based on patients who had similar EEG biomarkers."

The STAR*D algorithm study (pdf), published in 2006, is a four-step treatment algorithm; most patients start at level 1 with citalopram. If they do not enter remission within 14 weeks, they either switch drugs or add another medication; this pattern can continue for four levels, ending with tranylcypromine or mirtazapine plus extended-release venlafaxine.

The trial by Dr. DeBattista and his colleagues randomized 114 patients with treatment-resistant depression. After undergoing a drug washout period consisting of five consecutive half-life days, patients in the active group were randomized to a treatment regimen based on rEEG, constructed after review of their baseline EEG.

Control patients who had failed only selective serotonin reuptake inhibitors received extended-release venlafaxine; those who had failed two or more classes of antidepressants received a medication regimen from steps 2-4 of STAR*D.

The primary end points were changes in the Quick Inventory of Depressive Symptomatology (pdf) (QIDS-SR16) and the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (pdf) (Q-LES-Q SF).

Secondary end points were changes in the Clinical Global Impression severity scale (pdf) (CGI-severity), the Clinical Global Impression improvement scale (pdf) (CGI-improvement), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Patient Health Questionnaire-9 (PHQ-9).

The patients’ mean age was 44 years; most (63%) were women and white (66%). Overall, they had failed a mean of four previous central nervous system medications.

After 12 weeks, those in the rEEG group had improved significantly more than the control patients on the QIDS-16 (–7 vs. –4.5) and the Q-LES-Q-SF (18 vs. 9).

The rEEG group also improved significantly more in most of the secondary end points, including the CGI-improvement scores, the CGI-severity scores, and the final number of responders as measured by the MADRS system. However, the authors pointed out, the mean MADRS change from baseline to the study’s end was not significantly greater in the rEEG group than in the control groups.

The PHQ-9 end point also showed significant benefit in favor of rEEG, but in its remission measurement, rEEG was not significantly different from the control group (47% vs. 37%).

In a treatment curve, the authors noted that the groups began to separate as early as 2 weeks after the initiation of therapy, with the rEEG group continuing to improve more than the control group each week.

Treatment-related adverse events occurred in 45% of the rEEG group and 48% of the control groups – not significantly different. The most common in both groups were nausea/vomiting, fatigue, headache, anxiety, and insomnia. None of the adverse events or their rates was different from what could have been expected given the drugs employed, the authors noted.

Even in the absence of final remission superiority, the benefit of rEEG-guided treatment over STAR*D-guided treatment was clear and clinically relevant, the investigators said. "For example, the magnitude of improvement on the QIDS-SR16 response rate was 65% for rEEG compared with only 39% for the controls. Likewise the secondary measures on the Q-LES-Q-SF were also quite consistent in supporting the efficacy of the rEEG-guided therapy."

In addition, the investigators said, the early and continuous separation of treatment curves suggested that "rEEG’s superiority in reducing patients’ depressive symptoms might have continued had the trial continued."

The study was sponsored by CNS Response Inc., the company that owns the rEEG platform. Dr. DeBattista said he has received research support from the company, as have 4 of the other 14 investigators. Four other investigators are company employees and own stock in CNS Response.

Treatment-resistant depression seems to respond better when medication decisions are made by referenced electroencephalogram than by the STAR*D algorithm, according to a 12-week randomized trial.

Among 114 patients randomized to the two treatment methods, those whose medication was guided by referenced-EEG (rEEG) improved significantly more than did those treated by Sequenced Treatment Alternatives to Relieve Depression (STAR*D) guidelines in both primary measures of depression, as well as in most of the secondary measurements, Dr. Charles DeBattista and his colleagues wrote in the January issue of Journal of Psychiatric Research (doi:10.1016/j.jpsychires.2010.05.009).

"These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression, and perhaps in other psychiatric disorders," wrote Dr. DeBattista of Stanford (Calif.) University and his coauthors. "If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice."

The rEEG relies on a large database built over an 18-year period. It now contains information on more than 1,800 patients who were followed for an average of 405 days. The database includes the patients’ unmedicated EEGs, along with outcomes of more than 17,000 medical trials. The result, according to Dr. DeBattista and his colleagues, is the availability of 74 EEG biomarkers that "provide a very large collection of outcomes data allowing calculation of statistical correlation between the biomarkers found in a patient’s EEG and the treatment response predictions to many medications, based on patients who had similar EEG biomarkers."

The STAR*D algorithm study (pdf), published in 2006, is a four-step treatment algorithm; most patients start at level 1 with citalopram. If they do not enter remission within 14 weeks, they either switch drugs or add another medication; this pattern can continue for four levels, ending with tranylcypromine or mirtazapine plus extended-release venlafaxine.

The trial by Dr. DeBattista and his colleagues randomized 114 patients with treatment-resistant depression. After undergoing a drug washout period consisting of five consecutive half-life days, patients in the active group were randomized to a treatment regimen based on rEEG, constructed after review of their baseline EEG.

Control patients who had failed only selective serotonin reuptake inhibitors received extended-release venlafaxine; those who had failed two or more classes of antidepressants received a medication regimen from steps 2-4 of STAR*D.

The primary end points were changes in the Quick Inventory of Depressive Symptomatology (pdf) (QIDS-SR16) and the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (pdf) (Q-LES-Q SF).

Secondary end points were changes in the Clinical Global Impression severity scale (pdf) (CGI-severity), the Clinical Global Impression improvement scale (pdf) (CGI-improvement), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Patient Health Questionnaire-9 (PHQ-9).

The patients’ mean age was 44 years; most (63%) were women and white (66%). Overall, they had failed a mean of four previous central nervous system medications.

After 12 weeks, those in the rEEG group had improved significantly more than the control patients on the QIDS-16 (–7 vs. –4.5) and the Q-LES-Q-SF (18 vs. 9).

The rEEG group also improved significantly more in most of the secondary end points, including the CGI-improvement scores, the CGI-severity scores, and the final number of responders as measured by the MADRS system. However, the authors pointed out, the mean MADRS change from baseline to the study’s end was not significantly greater in the rEEG group than in the control groups.

The PHQ-9 end point also showed significant benefit in favor of rEEG, but in its remission measurement, rEEG was not significantly different from the control group (47% vs. 37%).

In a treatment curve, the authors noted that the groups began to separate as early as 2 weeks after the initiation of therapy, with the rEEG group continuing to improve more than the control group each week.

Treatment-related adverse events occurred in 45% of the rEEG group and 48% of the control groups – not significantly different. The most common in both groups were nausea/vomiting, fatigue, headache, anxiety, and insomnia. None of the adverse events or their rates was different from what could have been expected given the drugs employed, the authors noted.

Even in the absence of final remission superiority, the benefit of rEEG-guided treatment over STAR*D-guided treatment was clear and clinically relevant, the investigators said. "For example, the magnitude of improvement on the QIDS-SR16 response rate was 65% for rEEG compared with only 39% for the controls. Likewise the secondary measures on the Q-LES-Q-SF were also quite consistent in supporting the efficacy of the rEEG-guided therapy."

In addition, the investigators said, the early and continuous separation of treatment curves suggested that "rEEG’s superiority in reducing patients’ depressive symptoms might have continued had the trial continued."

The study was sponsored by CNS Response Inc., the company that owns the rEEG platform. Dr. DeBattista said he has received research support from the company, as have 4 of the other 14 investigators. Four other investigators are company employees and own stock in CNS Response.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES – People who consume an excessive amount of sodium each day or drink diet soda daily have a significantly increased risk for stroke or other vascular events, according to two separate analyses of participants in the prospective, observational Northern Manhattan Study.

Consumption of greater than 4,000 mg of sodium daily, when compared with the American Heart Association’s new recommendation of 1,500 mg/day, was associated with a nearly threefold higher risk of stroke. This increased risk occurred independently of the confounding effects of hypertension.

A separate analysis of diet soda intake among many of the same individuals also found that having at least one diet soda each day was associated with nearly a 50% increase in the risk of stroke, myocardial infarction, or vascular death, compared with people who did not drink soda at all.

The Northern Manhattan Study began in 1993 and enrolled 3,298 area residents by 2001. These individuals have been followed for up to 10 years. The subsets of individuals from the study that were included in each analysis were very similar: Their mean age was 69 years and 36% were male. The multiethnic makeup represented the northern Manhattan area, comprising approximately 53% Hispanics, 23%-24% blacks, 20%-21% whites, and 2%-4% other ethnic groups.

At baseline, all of the subjects underwent a battery of tests, including sociodemographics; a vascular risk profile; blood pressure; anthropometric measurements; fasting blood sugar; and a neurologic exam. They also completed the National Cancer Institute Food Frequency Questionnaire, which was modified to reflect Hispanic dietary patterns.

"Most of our study population [88%] consumed more than the American Heart Association’s 1,500 mg/day recommendation" for sodium intake, Hannah Gardener, Sc.D., said at the conference. "More importantly, 21% consumed more than 4,000 mg of sodium per day and, at this level, there was an increased stroke risk of more than 2.5-fold, independent of baseline hypertension, and across all the ethnic groups in the study."

The AHA recommendation was issued in January. An AHA science advisory board said that the 1,500-mg daily limit would promote optimal cardiovascular health. However, it’s much less than the U.S. Dietary Guidelines, which call for a daily intake of no more than 2,300 mg – about a teaspoonful of salt.

Dr. Gardener and her colleagues’ analysis of sodium intake and stroke risk included 2,657 participants who had full dietary and sodium intake information available and had not experienced a prior heart attack or stroke.

The participants’ mean daily sodium intake was 3,031 mg (median was 2,787 mg). "Only 12% of the cohort adhered to the AHA recommendation of less than 1,500 mg/day, and 44% consumed more than 3,000 mg/day," said Dr. Gardener, an epidemiologist at the University of Miami. Nearly one-fourth of the group (21%) consumed 4,000 mg or more of sodium each day.

During a mean 10-year follow-up period, 227 strokes occurred. A multivariate analysis found that the risk of stroke steadily increased with increases in sodium intake, although the difference in intake did not achieve statistical significance until intake reached 4,000 mg/day or more. At that level, subjects had nearly three times greater risk for stroke than did those who kept to the 1,500 mg/day recommendation (risk ratio 2.67). This analysis was adjusted for demographics and behavioral risk factors (education, alcohol, smoking, physical activity, and daily caloric intake), as well as vascular disease risk factors (diabetes, hyperlipidemia, hypertension, body mass index, and prior cardiac disease).

When salt intake was treated as a continuous variable, each 500-mg increase above 1,500 mg corresponded to an 18% increase in risk for stroke.

Because the risk was so dramatically elevated in the highest intake group, Dr. Gardener voiced support for the revised sodium intake recommendation. "Our results suggest that the new AHA strategic dietary goal will help promote cardiovascular and brain health and can be used to target dietary behavior as a method of modifying disease risk."

In the other analysis, Dr. Gardener reported that study participants who reported drinking diet soda every day had 48% greater risk for stroke or heart attack than did non–soda drinkers. This association was adjusted for cardiovascular risk factors, including smoking, physical activity, alcohol and caloric intake, metabolic syndrome, peripheral vascular disease, and prior cardiac disease.

This analysis included 2,564 individuals who provided information about soda intake and who had not experienced a previous heart attack.

The investigators divided the cohort into seven categories based on soda consumption. These included no diet or regular soda (less than one per month, 35%), occasional regular soda (from one per month to six per week, 30%), daily regular soda (seven or more per week, 11%), occasional diet soda (8%), daily diet soda (5%), occasional diet plus any regular soda (9%), and daily diet plus any regular soda (2%).

Diet soft drink consumption was significantly associated with white race; diabetes and elevated blood sugar; low HDL cholesterol; elevated waist circumference and body mass index; and metabolic syndrome. Regular soft drink consumption was associated with black race; high total daily calories; and low HDL cholesterol.

The primary end point was a combination of incident vascular events, including stroke, heart attack, or vascular death. Over the mean follow-up period of 9 years, 559 new vascular events occurred, including 212 strokes and 149 heart attacks.

Because the study showed association – not causation – it’s impossible to determine the exact link between diet soda and vascular disease, Dr. Gardener said.

"We don’t have any information about previous dietary behavior, so we can’t presume cause and effect," she said. "The mechanism is really unknown; further studies are needed to elucidate this. Previous studies have shown a relationship between regular soda consumption and the metabolic syndrome of elevated blood pressure, waist circumference, high triglycerides, and low HDL – which are all important vascular risk factors. We can control for those at baseline, but that doesn’t exclude them as a possibility in the causal pathway."

Because she considers the findings preliminary, Dr. Gardener said it’s too early to make any recommendations about soda consumption. "The next steps are for longitudinal cohort studies, preferably conducted in a younger population with more diet soda consumption and with collection of dietary data at multiple time points," she said. "Only if the results are confirmed can we suggest that diet soda may not be an optimum substitute for sugar-sweetened beverages, which have been shown to have health consequences."

The Northern Manhattan Study is supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Gardener had no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

LOS ANGELES - Carotid artery bypass surgery was no better than medical therapy in the secondary prevention of ischemic stroke, despite excellent graft patency at up to 2 years, in the Carotid Occlusion Surgery Study.

The rate of subsequent ipsilateral stroke was almost exactly the same at 2 years, regardless of whether patients were randomized to the surgical or medical arm of the Carotid Occlusion Surgery Study (COSS), Dr. William J. Powers said at a late-breaking science session during the International Stroke Conference.

"In spite of excellent graft patency and a significant improvement in cerebral hemodynamics, the bypass surgery failed to provide an overall benefit on 2-year stroke outcomes," said Dr. Powers, chairman of the department of neurology at the University of North Carolina at Chapel Hill.

The failure of surgery to improve outcomes relative to medical treatment was probably due to a much lower than expected rate of subsequent stroke among patients in the medical group (23%), compared with those in the surgical group (21%), Dr. Powers said. The investigators had projected a subsequent stroke rate of 40% for the medical therapy group and 24% for the surgical group, based on results of the St. Louis Carotid Occlusion Study and the Extracranial-Intracranial (EC-IC) Bypass study.

Investigators began COSS in 2003 but terminated it in June 2010 when it became obvious that surgery would confer no additional benefit over medical therapy. "The Data Safety Monitoring Board found that the prespecified futility analysis point was reached when we had full 2-year follow-up data on 139 of our patients," Dr. Powers said. "At that point, it was highly unlikely that the study would show any significant difference between the groups."

The COSS cohort included patients at very high risk for a second stroke. Patients had to have experienced a transient ischemic attack or a mild to moderate stroke within 3 months of enrollment and symptomatic occlusion of the internal carotid artery. Patients also were required to have evidence of hemodynamic cerebral ischemia, as shown by an ipsilateral increased oxygen extraction fraction (OEF) ratio of greater than 1.130 on PET. "This [ratio] has been determined previously to put patients at a very high risk of subsequent stroke," Dr. Powers noted.

The trial compared outcomes in 98 patients who were treated by best available medical treatment with antithrombolytic agents and risk-factor intervention vs. 97 patients who received the same medical therapy with the addition of superficial temporal artery to middle cerebral artery bypass. The primary end points for the surgical group were any stroke or death from surgery within the first 30 days after randomization and ipsilateral ischemic stroke by 2 years. The medical therapy group had the same 2-year end point, with a 30-day end point of all stroke and death during the first month after randomization.

Dr. Powers did not provide the baseline characteristics of the group, except to say that the systolic blood pressure was slightly lower in the surgical group.

In the surgical group, 93 were operated on within the first 10 days of randomization. None experienced a stroke during that intervening time. In all, 14 strokes (15%) occurred within 30 days of the procedure. "This was not significantly different [from what] was seen in the EC-IC Bypass trial," Dr. Powers noted. He did not provide information on surgical complications, except to say that "the perisurgical complications were what we expected and in line with the EC-IC Bypass trial."

At 30 days, graft patency was 98% and the mean OEF ratio had improved from 1.258 to 1.109. "So the surgery did what we thought it would do: It dropped the OEF ratio," he said.

At 2 years, graft patency was 96%. By this time, subsequent ipsilateral stroke had occurred in 21% of the surgical cohort, which was similar to the expected 24% rate.

Dr. Powers did not present 30-day outcomes in the medical therapy group. However, by 2 years, subsequent ipsilateral stroke had occurred in 23% of the group, "far lower than 40% rate we projected based on historical controls, and not significantly different from the surgical group," he said.

Following Dr. Powers’ presentation, several audience members asked for additional information, including any possible explanation of the unexpectedly good results in the medical therapy group. "Was it because they were all on statins, or because their hypertension was better controlled?" asked Dr. Gary Steinberg of Stanford (Calif.) University. "A theme we’ve heard over and over at this stroke meeting is that we can’t rely on historical data anymore because the medical treatments are getting so much better."

Dr. Powers replied that more complete data will be presented at the annual meeting of the American Academy of Neurology in April.

COSS was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Powers reported having no financial disclosures.

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PD-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD flares in patients with severe disease, according to the agency.

The decision stands in contrast to an FDA advisory panel’s recommendation. In April 2010, members of the Pulmonary-Allergy Drugs Advisory Committee voted 10-5 that the efficacy and safety data on the drug did not support approval for the maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

This was the original proposed indication, but in January 2010 – a month after Forest Research Institute Inc., acquired the drug from another company – Forest changed the proposed indication to a more focused one: "Maintenance treatment to reduce exacerbations of COPD." Because this was done 6 months into the FDA review period, however, the panel was asked to vote on the original indication.

The reasons panelists gave for voting against approval of the original, broader indication included what some described as the "meager" or modest beneficial effect of roflumilast in studies, the need to compare it with other COPD treatments like theophylline (a nonspecific PDE inhibitor and the only PDE inhibitor marketed in the United States), and the need to evaluate its efficacy when added to standard COPD treatments like inhaled corticosteroids.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including long- and short-acting beta-2 agonists or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Fourteen percent of patients taking roflumilast withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, "patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored."

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C), according to the company’s statement.

Other safety warnings will appear on the packaging:

• Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.

• The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.

• Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. "It is thought to be related to the effects of increased intracellular adenosine monophosphate."