Jennie Smith

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, “the evidence is starting to become overwhelming,” Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (age 52.4 + 11.9 years, 43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over a mean follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These “might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension,” they wrote in their analysis.

The Scottish Health Survey is funded by the Scottish Executive. Dr. Hamer's and his colleagues' research was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, “the evidence is starting to become overwhelming,” Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (age 52.4 + 11.9 years, 43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over a mean follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These “might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension,” they wrote in their analysis.

The Scottish Health Survey is funded by the Scottish Executive. Dr. Hamer's and his colleagues' research was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, “the evidence is starting to become overwhelming,” Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (age 52.4 + 11.9 years, 43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over a mean follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These “might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension,” they wrote in their analysis.

The Scottish Health Survey is funded by the Scottish Executive. Dr. Hamer's and his colleagues' research was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large, retrospective cohort study is the latest to look at the association between isotretinoin and attempted suicide. Concerns about a link between isotretinoin and suicidal behavior have abounded for years, although previous studies have failed to show a conclusive link.

By studying when (before, during, or up to 15 years after treatment) suicidal behavior is most likely to occur in relation to treatment, researchers found that although the risk is increased during and up to 1 year after treatment, such risk is more likely related to the psychological effects associated with the disease – severe acne – than with the isotretinoin, and may be affected by treatment failure.

Pharmacoepidemiologist Anders Sundström of the Karolinska Institute in Stockholm and colleagues examined named records for 5,756 Swedish patients (aged 15–49 years) who were prescribed isotretinoin in 1980–1989. The men had a mean age of 22.3 years (women, 27.1 years) at first prescription, and were taking mean daily doses of 44.5 mg and 39.2 mg isotretinoin, respectively, for severe acne. Mean length of treatment was 4 months for men and 3.9 months for women. The patients' clinical records were compared with hospital-discharge and cause-of-death registers for the 1980–2001 period.

In all, 128 patients in the cohort were hospitalized for attempted suicide on 210 occasions during the study period; there were 24 completed suicides during this time. When the study cohort was compared with the general population, the standardized incidence ratios for suicide attempts rose from 0.89 (95% confidence interval, 0.54–1.37) at 3 years before treatment to 1.36 (95% CI, 0.65–2.50) in the year before treatment for first attempts, and from 0.99 (95% CI, 0.65–1.44) at 3 years before treatment to 1.57 (95% CI, 0.86–2.63) in the year before treatment for all attempts.

The risks were shown to be highest within 6 months after the start of treatment: 1.93 (95% CI, 1.08–3.18) for first attempts and 1.78 (95% CI, 1.04–2.85) for all attempts. The investigators also found that women who made suicide attempts received two or three treatments more often than did women who did not attempt suicide, suggesting treatment failure as a possible contributor.

After treatment, the standardized incidence ratio declined to 0.97 (95% CI, 0.64–1.40) for first attempts and 1.04 (95% CI, 0.74–1.43) for all attempts within 3 years. After 3 years and for the duration of follow-up, the rate remained on par with the background rate for the population.

The investigators concluded that “an increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin.” However, they wrote, “the risk of attempted suicide was already rising before treatment, so an additional risk due to the isotretinoin treatment cannot be established.” Patients with a history of suicide attempts need not be denied treatment with isotretinoin, they wrote, but “close monitoring of patients for suicidal behavior for up to a year after treatment has ended” would be advisable (BMJ 2010 Nov. 12 [doi:10/1136/bmj.c5812]).

The investigators acknowledged some limitations of their study, including a lack of data on potential confounding factors other than age, sex, and calendar year. Low statistical precision was also a limitation: Although standardized incidence ratios were clearly rising before treatment, they wrote, “we found no statistical significance until six months after treatment. In the internal cohort crossover analysis – that is, analyzing outcomes before and after treatment in the same population – the differences in incidence did not reach statistical significance, making the estimated number needed to harm uncertain.”

Also, they wrote, “we had no information on the effect of treatment. A bias would exist if the patients who made suicide attempts had a poorer effect of treatment than did those who did not make such attempts. In that case, the suicidal behavior should be attributed to the treatment resistant acne and not to the treatment. However, such bias would only strengthen the assumed association between severe acne and suicidal behavior.”

In an editorial comment, Dr. Parker Magin of the University of Newcastle in Callaghan, New South Wales, Australia, and Dr. John Sullivan of the University of New South Wales in Sydney, said that clinicians could draw important practical conclusions from the study – namely, that during and after treatment with isotretinoin (and especially when treatment is unsuccessful), “patients should be carefully monitored for depression and suicidal thoughts. Patients probably have an increased risk before treatment, however, so all patients with acne of a severity for which isotretinoin is indicated should have psychosocial factors and suicidal intent monitored.”

As for who should perform the monitoring, Dr. Magin said that although dermatologists generally take on that role, general practitioners “have more appropriate training and experience in psychological medicine … and could add invaluable expertise in the psychological aspects of management in a shared care model with dermatologists.” Families of patients, Dr. Magin added, may also help with monitoring. (BMJ 2010 Nov. 12 [doi:10.1136/bmj.c5866])

The study was funded by the Swedish Research Council. Mr. Sundström and his coauthors declared that they had no conflicts of interest. Dr. Magin and Dr. Sullivan have been members of All About Acne, an organization supported by unrestricted educational grants from drug companies. Neither Dr. Magin nor Dr. Sullivan received payment from the organization, and the drug companies that provide support do not manufacture isotretinoin.

A large, retrospective cohort study is the latest to look at the association between isotretinoin and attempted suicide. Concerns about a link between isotretinoin and suicidal behavior have abounded for years, although previous studies have failed to show a conclusive link.

By studying when (before, during, or up to 15 years after treatment) suicidal behavior is most likely to occur in relation to treatment, researchers found that although the risk is increased during and up to 1 year after treatment, such risk is more likely related to the psychological effects associated with the disease – severe acne – than with the isotretinoin, and may be affected by treatment failure.

Pharmacoepidemiologist Anders Sundström of the Karolinska Institute in Stockholm and colleagues examined named records for 5,756 Swedish patients (aged 15–49 years) who were prescribed isotretinoin in 1980–1989. The men had a mean age of 22.3 years (women, 27.1 years) at first prescription, and were taking mean daily doses of 44.5 mg and 39.2 mg isotretinoin, respectively, for severe acne. Mean length of treatment was 4 months for men and 3.9 months for women. The patients' clinical records were compared with hospital-discharge and cause-of-death registers for the 1980–2001 period.

In all, 128 patients in the cohort were hospitalized for attempted suicide on 210 occasions during the study period; there were 24 completed suicides during this time. When the study cohort was compared with the general population, the standardized incidence ratios for suicide attempts rose from 0.89 (95% confidence interval, 0.54–1.37) at 3 years before treatment to 1.36 (95% CI, 0.65–2.50) in the year before treatment for first attempts, and from 0.99 (95% CI, 0.65–1.44) at 3 years before treatment to 1.57 (95% CI, 0.86–2.63) in the year before treatment for all attempts.

The risks were shown to be highest within 6 months after the start of treatment: 1.93 (95% CI, 1.08–3.18) for first attempts and 1.78 (95% CI, 1.04–2.85) for all attempts. The investigators also found that women who made suicide attempts received two or three treatments more often than did women who did not attempt suicide, suggesting treatment failure as a possible contributor.

After treatment, the standardized incidence ratio declined to 0.97 (95% CI, 0.64–1.40) for first attempts and 1.04 (95% CI, 0.74–1.43) for all attempts within 3 years. After 3 years and for the duration of follow-up, the rate remained on par with the background rate for the population.

The investigators concluded that “an increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin.” However, they wrote, “the risk of attempted suicide was already rising before treatment, so an additional risk due to the isotretinoin treatment cannot be established.” Patients with a history of suicide attempts need not be denied treatment with isotretinoin, they wrote, but “close monitoring of patients for suicidal behavior for up to a year after treatment has ended” would be advisable (BMJ 2010 Nov. 12 [doi:10/1136/bmj.c5812]).

The investigators acknowledged some limitations of their study, including a lack of data on potential confounding factors other than age, sex, and calendar year. Low statistical precision was also a limitation: Although standardized incidence ratios were clearly rising before treatment, they wrote, “we found no statistical significance until six months after treatment. In the internal cohort crossover analysis – that is, analyzing outcomes before and after treatment in the same population – the differences in incidence did not reach statistical significance, making the estimated number needed to harm uncertain.”

Also, they wrote, “we had no information on the effect of treatment. A bias would exist if the patients who made suicide attempts had a poorer effect of treatment than did those who did not make such attempts. In that case, the suicidal behavior should be attributed to the treatment resistant acne and not to the treatment. However, such bias would only strengthen the assumed association between severe acne and suicidal behavior.”

In an editorial comment, Dr. Parker Magin of the University of Newcastle in Callaghan, New South Wales, Australia, and Dr. John Sullivan of the University of New South Wales in Sydney, said that clinicians could draw important practical conclusions from the study – namely, that during and after treatment with isotretinoin (and especially when treatment is unsuccessful), “patients should be carefully monitored for depression and suicidal thoughts. Patients probably have an increased risk before treatment, however, so all patients with acne of a severity for which isotretinoin is indicated should have psychosocial factors and suicidal intent monitored.”

As for who should perform the monitoring, Dr. Magin said that although dermatologists generally take on that role, general practitioners “have more appropriate training and experience in psychological medicine … and could add invaluable expertise in the psychological aspects of management in a shared care model with dermatologists.” Families of patients, Dr. Magin added, may also help with monitoring. (BMJ 2010 Nov. 12 [doi:10.1136/bmj.c5866])

The study was funded by the Swedish Research Council. Mr. Sundström and his coauthors declared that they had no conflicts of interest. Dr. Magin and Dr. Sullivan have been members of All About Acne, an organization supported by unrestricted educational grants from drug companies. Neither Dr. Magin nor Dr. Sullivan received payment from the organization, and the drug companies that provide support do not manufacture isotretinoin.

A large, retrospective cohort study is the latest to look at the association between isotretinoin and attempted suicide. Concerns about a link between isotretinoin and suicidal behavior have abounded for years, although previous studies have failed to show a conclusive link.

By studying when (before, during, or up to 15 years after treatment) suicidal behavior is most likely to occur in relation to treatment, researchers found that although the risk is increased during and up to 1 year after treatment, such risk is more likely related to the psychological effects associated with the disease – severe acne – than with the isotretinoin, and may be affected by treatment failure.

Pharmacoepidemiologist Anders Sundström of the Karolinska Institute in Stockholm and colleagues examined named records for 5,756 Swedish patients (aged 15–49 years) who were prescribed isotretinoin in 1980–1989. The men had a mean age of 22.3 years (women, 27.1 years) at first prescription, and were taking mean daily doses of 44.5 mg and 39.2 mg isotretinoin, respectively, for severe acne. Mean length of treatment was 4 months for men and 3.9 months for women. The patients' clinical records were compared with hospital-discharge and cause-of-death registers for the 1980–2001 period.

In all, 128 patients in the cohort were hospitalized for attempted suicide on 210 occasions during the study period; there were 24 completed suicides during this time. When the study cohort was compared with the general population, the standardized incidence ratios for suicide attempts rose from 0.89 (95% confidence interval, 0.54–1.37) at 3 years before treatment to 1.36 (95% CI, 0.65–2.50) in the year before treatment for first attempts, and from 0.99 (95% CI, 0.65–1.44) at 3 years before treatment to 1.57 (95% CI, 0.86–2.63) in the year before treatment for all attempts.

The risks were shown to be highest within 6 months after the start of treatment: 1.93 (95% CI, 1.08–3.18) for first attempts and 1.78 (95% CI, 1.04–2.85) for all attempts. The investigators also found that women who made suicide attempts received two or three treatments more often than did women who did not attempt suicide, suggesting treatment failure as a possible contributor.

After treatment, the standardized incidence ratio declined to 0.97 (95% CI, 0.64–1.40) for first attempts and 1.04 (95% CI, 0.74–1.43) for all attempts within 3 years. After 3 years and for the duration of follow-up, the rate remained on par with the background rate for the population.

The investigators concluded that “an increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin.” However, they wrote, “the risk of attempted suicide was already rising before treatment, so an additional risk due to the isotretinoin treatment cannot be established.” Patients with a history of suicide attempts need not be denied treatment with isotretinoin, they wrote, but “close monitoring of patients for suicidal behavior for up to a year after treatment has ended” would be advisable (BMJ 2010 Nov. 12 [doi:10/1136/bmj.c5812]).

The investigators acknowledged some limitations of their study, including a lack of data on potential confounding factors other than age, sex, and calendar year. Low statistical precision was also a limitation: Although standardized incidence ratios were clearly rising before treatment, they wrote, “we found no statistical significance until six months after treatment. In the internal cohort crossover analysis – that is, analyzing outcomes before and after treatment in the same population – the differences in incidence did not reach statistical significance, making the estimated number needed to harm uncertain.”

Also, they wrote, “we had no information on the effect of treatment. A bias would exist if the patients who made suicide attempts had a poorer effect of treatment than did those who did not make such attempts. In that case, the suicidal behavior should be attributed to the treatment resistant acne and not to the treatment. However, such bias would only strengthen the assumed association between severe acne and suicidal behavior.”

In an editorial comment, Dr. Parker Magin of the University of Newcastle in Callaghan, New South Wales, Australia, and Dr. John Sullivan of the University of New South Wales in Sydney, said that clinicians could draw important practical conclusions from the study – namely, that during and after treatment with isotretinoin (and especially when treatment is unsuccessful), “patients should be carefully monitored for depression and suicidal thoughts. Patients probably have an increased risk before treatment, however, so all patients with acne of a severity for which isotretinoin is indicated should have psychosocial factors and suicidal intent monitored.”

As for who should perform the monitoring, Dr. Magin said that although dermatologists generally take on that role, general practitioners “have more appropriate training and experience in psychological medicine … and could add invaluable expertise in the psychological aspects of management in a shared care model with dermatologists.” Families of patients, Dr. Magin added, may also help with monitoring. (BMJ 2010 Nov. 12 [doi:10.1136/bmj.c5866])

The study was funded by the Swedish Research Council. Mr. Sundström and his coauthors declared that they had no conflicts of interest. Dr. Magin and Dr. Sullivan have been members of All About Acne, an organization supported by unrestricted educational grants from drug companies. Neither Dr. Magin nor Dr. Sullivan received payment from the organization, and the drug companies that provide support do not manufacture isotretinoin.

Consumption of omega-3 polyunsaturated fatty acid supplements has no measurable effect on cognition in older adults, according to U.K. researchers who sought to detect whether daily use of the supplements could prevent cognitive decline.

For their 2-year, blinded study, funded by U.K. health and nutrition agencies, a team of investigators led by Alan Dangour, Ph.D., of the London School of Hygiene & Tropical Medicine, randomly assigned 867 older adults in good cognitive health and who did not take fish-oil supplements to a daily dose of 200 mg eicosapentaenoic acid (EPA) plus 500 mg docosahexaenoic acid (DHA), or an olive-oil placebo.

The mean age of participants was 75 years; 55% were men, according to the study (doi: 10.3945/ajcn.2009.29121).

Though concentrations of EPA and DHA were significantly higher in blood samples from the treatment group, no decline in cognitive function was detected in either group. “After 2 years we can say definitively that there's no benefit,” Dr. Dangour said in an interview.

“We're disappointed, but we conducted the best possible study and certainly the largest to date.”

Standardized tests of memory and cognitive function and serum EPA and DHA levels were administered at baseline and after 24 months.

In the treatment arm, 376 subjects completed the study, compared with 368 in the control arm. Analysis was by intention to treat

The findings appear in stark contrast to those of a 2006 study of 899 similar-age subjects from a large cohort (Arch. Neurol. 2006;63:1545–50). In that study, people in the top quartile of plasma DHA levels saw a 47% reduction in the risk of developing all-cause dementia after 9 years.

But cohort studies are difficult to compare with randomized, controlled trials, Dr. Dangour pointed out, and “there are loads of other studies that say there's a benefit for people who eat more fish.”

The point of this study, specifically, was to detect a measurable benefit from a dietary change rather than the accumulated benefits of a lifelong habit.

Neither Dr. Dangour nor his coauthors declared any competing interests. Fish oil for the study was donated by Ocean Nutrition Canada Ltd.

Consumption of omega-3 polyunsaturated fatty acid supplements has no measurable effect on cognition in older adults, according to U.K. researchers who sought to detect whether daily use of the supplements could prevent cognitive decline.

For their 2-year, blinded study, funded by U.K. health and nutrition agencies, a team of investigators led by Alan Dangour, Ph.D., of the London School of Hygiene & Tropical Medicine, randomly assigned 867 older adults in good cognitive health and who did not take fish-oil supplements to a daily dose of 200 mg eicosapentaenoic acid (EPA) plus 500 mg docosahexaenoic acid (DHA), or an olive-oil placebo.

The mean age of participants was 75 years; 55% were men, according to the study (doi: 10.3945/ajcn.2009.29121).

Though concentrations of EPA and DHA were significantly higher in blood samples from the treatment group, no decline in cognitive function was detected in either group. “After 2 years we can say definitively that there's no benefit,” Dr. Dangour said in an interview.

“We're disappointed, but we conducted the best possible study and certainly the largest to date.”

Standardized tests of memory and cognitive function and serum EPA and DHA levels were administered at baseline and after 24 months.

In the treatment arm, 376 subjects completed the study, compared with 368 in the control arm. Analysis was by intention to treat

The findings appear in stark contrast to those of a 2006 study of 899 similar-age subjects from a large cohort (Arch. Neurol. 2006;63:1545–50). In that study, people in the top quartile of plasma DHA levels saw a 47% reduction in the risk of developing all-cause dementia after 9 years.

But cohort studies are difficult to compare with randomized, controlled trials, Dr. Dangour pointed out, and “there are loads of other studies that say there's a benefit for people who eat more fish.”

The point of this study, specifically, was to detect a measurable benefit from a dietary change rather than the accumulated benefits of a lifelong habit.

Neither Dr. Dangour nor his coauthors declared any competing interests. Fish oil for the study was donated by Ocean Nutrition Canada Ltd.

Consumption of omega-3 polyunsaturated fatty acid supplements has no measurable effect on cognition in older adults, according to U.K. researchers who sought to detect whether daily use of the supplements could prevent cognitive decline.

For their 2-year, blinded study, funded by U.K. health and nutrition agencies, a team of investigators led by Alan Dangour, Ph.D., of the London School of Hygiene & Tropical Medicine, randomly assigned 867 older adults in good cognitive health and who did not take fish-oil supplements to a daily dose of 200 mg eicosapentaenoic acid (EPA) plus 500 mg docosahexaenoic acid (DHA), or an olive-oil placebo.

The mean age of participants was 75 years; 55% were men, according to the study (doi: 10.3945/ajcn.2009.29121).

Though concentrations of EPA and DHA were significantly higher in blood samples from the treatment group, no decline in cognitive function was detected in either group. “After 2 years we can say definitively that there's no benefit,” Dr. Dangour said in an interview.

“We're disappointed, but we conducted the best possible study and certainly the largest to date.”

Standardized tests of memory and cognitive function and serum EPA and DHA levels were administered at baseline and after 24 months.

In the treatment arm, 376 subjects completed the study, compared with 368 in the control arm. Analysis was by intention to treat

The findings appear in stark contrast to those of a 2006 study of 899 similar-age subjects from a large cohort (Arch. Neurol. 2006;63:1545–50). In that study, people in the top quartile of plasma DHA levels saw a 47% reduction in the risk of developing all-cause dementia after 9 years.

But cohort studies are difficult to compare with randomized, controlled trials, Dr. Dangour pointed out, and “there are loads of other studies that say there's a benefit for people who eat more fish.”

The point of this study, specifically, was to detect a measurable benefit from a dietary change rather than the accumulated benefits of a lifelong habit.

Neither Dr. Dangour nor his coauthors declared any competing interests. Fish oil for the study was donated by Ocean Nutrition Canada Ltd.

 The Food and Drug Administration has approved the antidepressant duloxetine for the management of chronic musculoskeletal pain in adults, the agency announced.

The approval marks the fifth of duloxetine's U.S. licensed indications to date and its third for treatment of pain. Duloxetine, marketed as Cymbalta, was first approved in 2004 to treat depression, and later the drug gained indications for generalized anxiety disorder, diabetic neuropathy, and fibromyalgia. All of the indications are for people aged 18 years and older. The drug has received European Union marketing authorization for depression, anxiety, and diabetic neuropathy only.

The mechanism by which duloxetine, a serotonin and norepinephrine reuptake inhibitor, works on pain is uncertain, Eli Lilly said in a press statement accompanying the announcement. However, it is believed to increase the availability of both neurotransmitters, enhancing the body's natural pain-suppressing system.

In August the FDA's Anesthetic and Life Support Drugs Advisory Committee had voted 8–6 to recommend the extension of indication for duloxetine, a vote that was considered too narrow to predict what the agency would ultimately decide. The drug's effectiveness was not well agreed upon, either, with an 8–5 vote in favor, and 1 member abstaining.

Evidence from two studies submitted to the agency by the manufacturer (n= 236 and n = 401) showed that duloxetine at oral doses of 60–120 mg daily reduced chronic lower back pain better than placebo after 12 and 13 weeks. Evidence from a third study (n = 404) showed no benefit. For osteoarthritis, one study (n = 256) showed a statistically significant reduction in pain after 13 weeks in people taking between 60 and 120 mg, and another study (n = 231) did not.

The maximum dosage for the musculoskeletal pain indication, which includes osteoarthritis and lower back pain, is 60 mg/day, the same as the maximum recommended dosage for depression. Adverse events included nausea, dry mouth, insomnia, sleepiness, constipation, dizziness, and fatigue.

Osteoarthritis affects 27 million American adults, the company said. About 70%–85% experience low back pain at some time, with some reports estimating that up to a tenth of these will go on to have chronic back pain.

 The Food and Drug Administration has approved the antidepressant duloxetine for the management of chronic musculoskeletal pain in adults, the agency announced.

The approval marks the fifth of duloxetine's U.S. licensed indications to date and its third for treatment of pain. Duloxetine, marketed as Cymbalta, was first approved in 2004 to treat depression, and later the drug gained indications for generalized anxiety disorder, diabetic neuropathy, and fibromyalgia. All of the indications are for people aged 18 years and older. The drug has received European Union marketing authorization for depression, anxiety, and diabetic neuropathy only.

The mechanism by which duloxetine, a serotonin and norepinephrine reuptake inhibitor, works on pain is uncertain, Eli Lilly said in a press statement accompanying the announcement. However, it is believed to increase the availability of both neurotransmitters, enhancing the body's natural pain-suppressing system.

In August the FDA's Anesthetic and Life Support Drugs Advisory Committee had voted 8–6 to recommend the extension of indication for duloxetine, a vote that was considered too narrow to predict what the agency would ultimately decide. The drug's effectiveness was not well agreed upon, either, with an 8–5 vote in favor, and 1 member abstaining.

Evidence from two studies submitted to the agency by the manufacturer (n= 236 and n = 401) showed that duloxetine at oral doses of 60–120 mg daily reduced chronic lower back pain better than placebo after 12 and 13 weeks. Evidence from a third study (n = 404) showed no benefit. For osteoarthritis, one study (n = 256) showed a statistically significant reduction in pain after 13 weeks in people taking between 60 and 120 mg, and another study (n = 231) did not.

The maximum dosage for the musculoskeletal pain indication, which includes osteoarthritis and lower back pain, is 60 mg/day, the same as the maximum recommended dosage for depression. Adverse events included nausea, dry mouth, insomnia, sleepiness, constipation, dizziness, and fatigue.

Osteoarthritis affects 27 million American adults, the company said. About 70%–85% experience low back pain at some time, with some reports estimating that up to a tenth of these will go on to have chronic back pain.

 The Food and Drug Administration has approved the antidepressant duloxetine for the management of chronic musculoskeletal pain in adults, the agency announced.

The approval marks the fifth of duloxetine's U.S. licensed indications to date and its third for treatment of pain. Duloxetine, marketed as Cymbalta, was first approved in 2004 to treat depression, and later the drug gained indications for generalized anxiety disorder, diabetic neuropathy, and fibromyalgia. All of the indications are for people aged 18 years and older. The drug has received European Union marketing authorization for depression, anxiety, and diabetic neuropathy only.

The mechanism by which duloxetine, a serotonin and norepinephrine reuptake inhibitor, works on pain is uncertain, Eli Lilly said in a press statement accompanying the announcement. However, it is believed to increase the availability of both neurotransmitters, enhancing the body's natural pain-suppressing system.

In August the FDA's Anesthetic and Life Support Drugs Advisory Committee had voted 8–6 to recommend the extension of indication for duloxetine, a vote that was considered too narrow to predict what the agency would ultimately decide. The drug's effectiveness was not well agreed upon, either, with an 8–5 vote in favor, and 1 member abstaining.

Evidence from two studies submitted to the agency by the manufacturer (n= 236 and n = 401) showed that duloxetine at oral doses of 60–120 mg daily reduced chronic lower back pain better than placebo after 12 and 13 weeks. Evidence from a third study (n = 404) showed no benefit. For osteoarthritis, one study (n = 256) showed a statistically significant reduction in pain after 13 weeks in people taking between 60 and 120 mg, and another study (n = 231) did not.

The maximum dosage for the musculoskeletal pain indication, which includes osteoarthritis and lower back pain, is 60 mg/day, the same as the maximum recommended dosage for depression. Adverse events included nausea, dry mouth, insomnia, sleepiness, constipation, dizziness, and fatigue.

Osteoarthritis affects 27 million American adults, the company said. About 70%–85% experience low back pain at some time, with some reports estimating that up to a tenth of these will go on to have chronic back pain.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published Dec. 1 in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, "the evidence is starting to become overwhelming," Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over an average follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was found to be elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These "might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension," they wrote in their analysis.

Dr. Hamer and his colleagues said that because they had shown the association between antidepressant use and CVD risk to be partly independent of psychiatric symptoms, "there may be some characteristic of TCA that is raising CVD risk." Or, they said, the risk could be explained by "residual confounding due to unmeasured or unknown risk factors."

Dr. Hamer and his colleagues wrote that the strengths of the study include its large sample size from a general population, its detailed information about hospital admissions, and the well-characterized participants, which could "facilitate insights into the role of potential confounding factors, particularly existing depression and mental illness." Among the study’s weaknesses, they acknowledged, was the inability to measure compliance to medication over time.

The Scottish Health Survey is funded by the Scottish Executive. The research conducted by Dr. Hamer and his colleagues was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published Dec. 1 in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, "the evidence is starting to become overwhelming," Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over an average follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was found to be elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These "might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension," they wrote in their analysis.

Dr. Hamer and his colleagues said that because they had shown the association between antidepressant use and CVD risk to be partly independent of psychiatric symptoms, "there may be some characteristic of TCA that is raising CVD risk." Or, they said, the risk could be explained by "residual confounding due to unmeasured or unknown risk factors."

Dr. Hamer and his colleagues wrote that the strengths of the study include its large sample size from a general population, its detailed information about hospital admissions, and the well-characterized participants, which could "facilitate insights into the role of potential confounding factors, particularly existing depression and mental illness." Among the study’s weaknesses, they acknowledged, was the inability to measure compliance to medication over time.

The Scottish Health Survey is funded by the Scottish Executive. The research conducted by Dr. Hamer and his colleagues was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published Dec. 1 in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, "the evidence is starting to become overwhelming," Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over an average follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was found to be elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These "might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension," they wrote in their analysis.

Dr. Hamer and his colleagues said that because they had shown the association between antidepressant use and CVD risk to be partly independent of psychiatric symptoms, "there may be some characteristic of TCA that is raising CVD risk." Or, they said, the risk could be explained by "residual confounding due to unmeasured or unknown risk factors."

Dr. Hamer and his colleagues wrote that the strengths of the study include its large sample size from a general population, its detailed information about hospital admissions, and the well-characterized participants, which could "facilitate insights into the role of potential confounding factors, particularly existing depression and mental illness." Among the study’s weaknesses, they acknowledged, was the inability to measure compliance to medication over time.

The Scottish Health Survey is funded by the Scottish Executive. The research conducted by Dr. Hamer and his colleagues was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published Dec. 1 in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, "the evidence is starting to become overwhelming," Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over an average follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was found to be elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These "might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension," they wrote in their analysis.

Dr. Hamer and his colleagues said that because they had shown the association between antidepressant use and CVD risk to be partly independent of psychiatric symptoms, "there may be some characteristic of TCA that is raising CVD risk." Or, they said, the risk could be explained by "residual confounding due to unmeasured or unknown risk factors."

Dr. Hamer and his colleagues wrote that the strengths of the study include its large sample size from a general population, its detailed information about hospital admissions, and the well-characterized participants, which could "facilitate insights into the role of potential confounding factors, particularly existing depression and mental illness." Among the study’s weaknesses, they acknowledged, was the inability to measure compliance to medication over time.

The Scottish Health Survey is funded by the Scottish Executive. The research conducted by Dr. Hamer and his colleagues was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published Dec. 1 in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, "the evidence is starting to become overwhelming," Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over an average follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was found to be elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These "might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension," they wrote in their analysis.

Dr. Hamer and his colleagues said that because they had shown the association between antidepressant use and CVD risk to be partly independent of psychiatric symptoms, "there may be some characteristic of TCA that is raising CVD risk." Or, they said, the risk could be explained by "residual confounding due to unmeasured or unknown risk factors."

Dr. Hamer and his colleagues wrote that the strengths of the study include its large sample size from a general population, its detailed information about hospital admissions, and the well-characterized participants, which could "facilitate insights into the role of potential confounding factors, particularly existing depression and mental illness." Among the study’s weaknesses, they acknowledged, was the inability to measure compliance to medication over time.

The Scottish Health Survey is funded by the Scottish Executive. The research conducted by Dr. Hamer and his colleagues was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

A large population-based study has shown a link between tricyclic antidepressant medications and an increased risk of cardiovascular disease, adding to a growing body of evidence that the medications carry cardiovascular risks – both for people with and without existing disease.

In a cohort study of 14,784 adults without known CVD in Scotland, the use of tricyclic antidepressants for any amount of time and for any reason was associated with a 35% higher risk of being diagnosed with CVD within 8 years, even after accounting for potential confounders, including symptoms of anxiety and depression, which are also linked to CVD.

Tricyclic antidepressants have been shown to increase cardiac events, including myocardial infarction, in patients with CVD; however, few population-based studies have examined the effects on people without known CVD, said Mark Hamer, Ph.D., of University College London, the lead author of the findings published Dec. 1 in the European Heart Journal (doi:10.1093/eurheartj/ehq438). Now, "the evidence is starting to become overwhelming," Dr. Hamer said.

Tricyclic antidepressants are an older class of medication whose psychiatric use has fallen off in favor of newer agents such as selective serotonin reuptake inhibitors. However, TCAs are still used widely to treat headache, Dr. Hamer said, citing a recent meta-analysis (BMJ 2010;341:c5222) revealing tricyclics to be more effective than SSRIs and placebo in preventing migraine and tension headaches, and also to be increasingly effective with longer-term use.

For their research, Dr. Hamer and his colleagues used data from the Scottish Health Survey, an ongoing cohort study conducted every 3-5 years in Scottish households. They combined data from surveys in 1995, 1998, and 2003 in adults aged 35 years and older (43.9% men) without clinically confirmed CVD. Of the total study group, 2.2%, 2.0%, and 0.7% reported taking TCAs, SSRIs, or other antidepressants (including monoamine oxidase inhibitors), respectively.

Over an average follow-up of 8 years, there were 1,434 CVD events in the study group, 26.2% of which were fatal, and 67.5% of the events were related to coronary heart disease. The risk of CVD events (including death, nonfatal myocardial infarction, coronary artery bypass, percutaneous transluminal coronary angioplasty, stroke, and heart failure) was found to be elevated in TCA users, but this was not significant after adjusting for confounding factors. No associations were found between SSRI use and CVD. Dr. Hamer and his colleagues also found no significant associations between any antidepressant use and all-cause mortality.

However, the TCA users saw a 35% higher risk of CVD (multivariate-adjusted hazard ratio 1.35, 95% confidence interval 1.03-1.77) even after adjustment for confounding factors, which included physical activity, smoking status, alcohol use, socioeconomic status, body mass index, marital status, a history of psychiatric illness, and the presence of preclinical CVD risk factors as measured by the use of cardiovascular medication and antihypertension drugs.

The investigators noted that tricyclic antidepressants have been associated with weight gain and have been shown to have cardiotoxic effects. These "might explain the increased risk of CVD, including orthostatic hypotension, reduced heart rate variability, QT interval prolongation, and greater risk of hypertension," they wrote in their analysis.

Dr. Hamer and his colleagues said that because they had shown the association between antidepressant use and CVD risk to be partly independent of psychiatric symptoms, "there may be some characteristic of TCA that is raising CVD risk." Or, they said, the risk could be explained by "residual confounding due to unmeasured or unknown risk factors."

Dr. Hamer and his colleagues wrote that the strengths of the study include its large sample size from a general population, its detailed information about hospital admissions, and the well-characterized participants, which could "facilitate insights into the role of potential confounding factors, particularly existing depression and mental illness." Among the study’s weaknesses, they acknowledged, was the inability to measure compliance to medication over time.

The Scottish Health Survey is funded by the Scottish Executive. The research conducted by Dr. Hamer and his colleagues was funded in part by grant support from foundations, including the Wellcome Trust; the British Heart Foundation; the National Heart, Lung, and Blood Institute; and the National Institute on Aging. Neither Dr. Hamer nor his colleagues declared any conflicts of interest.

The European Science Foundation is warning that too little attention and money are being paid to the issue of male reproductive health in European countries, where a host of issues affecting young men might be contributing to lower fertility rates.

Reduced semen quality, increased incidence of testicular cancer, and high incidence of congenital reproductive malformations such as cryptorchidism, combined with women delaying pregnancy, "will lead to increased fertility problems in couples and its attendant socioeconomic impacts," the organization said in a report published Nov. 29. "The crucial question is whether semen quality among young men in Europe is now so low that it has reached a threshold at which fertility rates may be affected."

An estimated one-fifth of 18- to 25-year-old European men have oligospermia, as measured by World Health Organization guidelines, according to results from a large cohort study (Am. J. Epidemiol. 2009 September 1;170(5):559-65) cited in the report.

The report’s corresponding author, Dr. Niels E. Skakkebaek of the University of Copenhagen, has been among Europe’s most vocal proponents of the need to increase attention to male reproductive problems, having conducted investigations into factors as diverse as caffeine intake, pesticide exposure, consumption of hormone-treated beef, and a history of febrile illness in affecting semen quality. Increasingly, Dr. Skakkebaek and other fertility researchers have focused on threats to male reproductive health that emerge during fetal development, particularly testicular abnormalities – frequently precursors to poor fertility – associated with mothers’ exposure to environmental chemicals.

Poor male reproductive health also is linked to obesity, Dr. Skakkebaek and his colleagues noted, with more research needed into the associations between male reproductive, endocrine, and cardiovascular health.

Six other authors contributed to the ESF report, which identified conflicting data and wide regional differences in reported semen quality as measured by sperm count. While sperm counts across Europe have long been reported to be dropping, possibly because of environmental factors, large variations in reported sperm counts among geographic regions are suggestive, the report’s authors said, of "insufficient quality management systems in different geographic areas which may affect the validity of the results."

The ESF, a nongovernmental organization made up of 79 European research institutions, declared a need for increased funds to attack the problem, suggesting that each country set aside up to 5 million euros a year to investigate causes of male reproductive decline, and standardize methodologies for reporting sperm counts according to World Health Organization guidelines.

The group also called for a transnational, multidisciplinary research project, with funding of 5 million euros per year over a decade, for research to examine environmental chemicals and genetic background factors affecting on male reproductive fitness. The project should "utilize available methods, birth and adult cohorts, to tease apart the relative importance of developmental vs. adult causes of low sperm counts/infertility," ESF said.

The European Science Foundation is warning that too little attention and money are being paid to the issue of male reproductive health in European countries, where a host of issues affecting young men might be contributing to lower fertility rates.

Reduced semen quality, increased incidence of testicular cancer, and high incidence of congenital reproductive malformations such as cryptorchidism, combined with women delaying pregnancy, "will lead to increased fertility problems in couples and its attendant socioeconomic impacts," the organization said in a report published Nov. 29. "The crucial question is whether semen quality among young men in Europe is now so low that it has reached a threshold at which fertility rates may be affected."

An estimated one-fifth of 18- to 25-year-old European men have oligospermia, as measured by World Health Organization guidelines, according to results from a large cohort study (Am. J. Epidemiol. 2009 September 1;170(5):559-65) cited in the report.

The report’s corresponding author, Dr. Niels E. Skakkebaek of the University of Copenhagen, has been among Europe’s most vocal proponents of the need to increase attention to male reproductive problems, having conducted investigations into factors as diverse as caffeine intake, pesticide exposure, consumption of hormone-treated beef, and a history of febrile illness in affecting semen quality. Increasingly, Dr. Skakkebaek and other fertility researchers have focused on threats to male reproductive health that emerge during fetal development, particularly testicular abnormalities – frequently precursors to poor fertility – associated with mothers’ exposure to environmental chemicals.

Poor male reproductive health also is linked to obesity, Dr. Skakkebaek and his colleagues noted, with more research needed into the associations between male reproductive, endocrine, and cardiovascular health.

Six other authors contributed to the ESF report, which identified conflicting data and wide regional differences in reported semen quality as measured by sperm count. While sperm counts across Europe have long been reported to be dropping, possibly because of environmental factors, large variations in reported sperm counts among geographic regions are suggestive, the report’s authors said, of "insufficient quality management systems in different geographic areas which may affect the validity of the results."

The ESF, a nongovernmental organization made up of 79 European research institutions, declared a need for increased funds to attack the problem, suggesting that each country set aside up to 5 million euros a year to investigate causes of male reproductive decline, and standardize methodologies for reporting sperm counts according to World Health Organization guidelines.

The group also called for a transnational, multidisciplinary research project, with funding of 5 million euros per year over a decade, for research to examine environmental chemicals and genetic background factors affecting on male reproductive fitness. The project should "utilize available methods, birth and adult cohorts, to tease apart the relative importance of developmental vs. adult causes of low sperm counts/infertility," ESF said.

The European Science Foundation is warning that too little attention and money are being paid to the issue of male reproductive health in European countries, where a host of issues affecting young men might be contributing to lower fertility rates.

Reduced semen quality, increased incidence of testicular cancer, and high incidence of congenital reproductive malformations such as cryptorchidism, combined with women delaying pregnancy, "will lead to increased fertility problems in couples and its attendant socioeconomic impacts," the organization said in a report published Nov. 29. "The crucial question is whether semen quality among young men in Europe is now so low that it has reached a threshold at which fertility rates may be affected."

An estimated one-fifth of 18- to 25-year-old European men have oligospermia, as measured by World Health Organization guidelines, according to results from a large cohort study (Am. J. Epidemiol. 2009 September 1;170(5):559-65) cited in the report.

The report’s corresponding author, Dr. Niels E. Skakkebaek of the University of Copenhagen, has been among Europe’s most vocal proponents of the need to increase attention to male reproductive problems, having conducted investigations into factors as diverse as caffeine intake, pesticide exposure, consumption of hormone-treated beef, and a history of febrile illness in affecting semen quality. Increasingly, Dr. Skakkebaek and other fertility researchers have focused on threats to male reproductive health that emerge during fetal development, particularly testicular abnormalities – frequently precursors to poor fertility – associated with mothers’ exposure to environmental chemicals.

Poor male reproductive health also is linked to obesity, Dr. Skakkebaek and his colleagues noted, with more research needed into the associations between male reproductive, endocrine, and cardiovascular health.

Six other authors contributed to the ESF report, which identified conflicting data and wide regional differences in reported semen quality as measured by sperm count. While sperm counts across Europe have long been reported to be dropping, possibly because of environmental factors, large variations in reported sperm counts among geographic regions are suggestive, the report’s authors said, of "insufficient quality management systems in different geographic areas which may affect the validity of the results."

The ESF, a nongovernmental organization made up of 79 European research institutions, declared a need for increased funds to attack the problem, suggesting that each country set aside up to 5 million euros a year to investigate causes of male reproductive decline, and standardize methodologies for reporting sperm counts according to World Health Organization guidelines.

The group also called for a transnational, multidisciplinary research project, with funding of 5 million euros per year over a decade, for research to examine environmental chemicals and genetic background factors affecting on male reproductive fitness. The project should "utilize available methods, birth and adult cohorts, to tease apart the relative importance of developmental vs. adult causes of low sperm counts/infertility," ESF said.

A new analysis of nearly 30,000 stroke patients has shown thrombolysis treatment to be helpful for people aged 80 years and older, who show functional outcomes similar to those of much younger stroke patients after 90 days, and comparable mortality.

The findings, published online Nov. 24 in BMJ (BMJ 2010;341:c6046) and using data from the Safe Implementation of Treatment in Stroke–International Stroke Thrombolysis Register (SITS-ISTR) and the Virtual International Stroke Trials Archive (VISTA), suggest that treatment with intravenous alteplase should not be withheld on the basis of age alone, despite current European licensing rules and guidelines that restrict the use of recombinant tissue plasminogen activators to stroke victims under age 80.

The reason for the European Medicine Agency’s alteplase restriction was concern over a potential increased risk of symptomatic, treatment-related intracranial hemorrhage in older people, and the fact that there was not yet enough clinical evidence for the safety and effectiveness of alteplase and other recombinant tissue plasminogen activators in this patient group, as older people had been under-represented in clinical trials.

Yet, as the BMJ study’s investigators, led Dr. Kennedy R. Lees of the University of Glasgow (U.K.), noted in their analysis, some 30% of stroke victims are over age 80, and the percentage of people in this age group is growing in developed nations. In the study Dr. Lees and his colleagues built upon years of increasing speculation that thrombolysis, administered within 3 hours after stroke, was effective and safe in this patient group too, with clinicians increasingly administering it and reporting good outcomes.

The SITS registry provided Dr. Lees and his colleagues an ongoing source of data on elderly patients who had received thrombolysis. Of the 29,500 stroke patients available for analysis, 3,439 were older than age 80 (mean age 84.6 years). A total of 23,334 patients had undergone thrombolysis with alteplase (mean 145 minutes after stroke onset). Data on 6,166 patients who did not receive thrombolysis but received placebo or a neuroprotective agent were available from the VISTA registry, and these patients served as controls. Median baseline stroke severity was equal for patients and controls (median National Institutes of Health (NIH) stroke scale score 12). A total of 272 patients from both groups were removed from the analysis for missing stroke severity data, leaving data on 29,228 available for final analysis.

Dr. Lees and his colleagues found that functional outcomes 90 days post stroke, measured by modified Rankin scale scores, which measure debilitation, were significantly better in patients who received thrombolysis, and that this was true in patients both younger than 80 years (odds ratio 1.6) and over 80 years (OR 1.4). The number needed to treat for one more elderly patient to achieve a favorable Rankin score of 0-2 (no disability or slight disability that does not affect independence) at 3 months was 8.2, compared with 8.5 for younger patients.

Rates of intracerebral hemorrhage – avoidance of which was the original rationale for denying thrombolysis to older patients – were shown to be only slightly increased in the older patients, depending on how the hemorrhage was defined and diagnosed. Symptomatic hemorrhage occurred in 2.5% of the 80 and older group and 1.9% of the younger patients, according to a SITS definition, and in 11% vs. 8.3%, respectively, when measured according to an NIH definition. However, the odds ratio for mortality was almost exactly the same – 0.89 (0.76-1.04) in elderly patients receiving thrombolysis, compared with 0.87 (0.79-0.95) in younger patients.

The investigators saw no benefit associated with thrombolysis in patients older than 90 or younger than 40. However, they noted, "the small number of patients in these groups greatly reduced statistical power for these analyses, and the trends mostly followed the same pattern as for intermediate ages." They concluded that clinical treatment guidelines "should be revised to remove the age restriction in use of intravenous alteplase for acute ischemic stroke. Age alone should not be a barrier to treatment."

In an editorial accompanying Dr. Lees and colleagues’ article, neurologist Laurent Derex of Inserm and the Neurological Hospital in Lyon, France, characterized the results as "quite robust," noting that the odds ratios were consistent across all 10-year age ranges. Moreover, Dr. Derex said, "elderly patients may be especially vulnerable to subjective judgments of the benefit of optimal stroke care, particularly when medical resources are limited."

But Dr. Derex also cautioned that the study’s nonrandomized design was not ideal, as the investigators themselves acknowledged. "As a post hoc analysis of a thrombolysis registry, the study is prone to selection bias," Dr. Derex wrote. "If the elderly patients with stroke included in this registry were more carefully selected for administration of intravenous recombinant tissue plasminogen activator, the findings would be less generalizable to all elderly patients. ... Ongoing randomized controlled thrombolytic trials that include patients aged over 80 years should yield more robust conclusions" (BMJ 2010; 341:c5891)

Dr. Lees and six of his seven coauthors disclosed having received grants, honoraria, or other forms of financial support from Boehringer Ingelheim, the German manufacturer of alteplase, along with other pharmaceutical companies. They noted that the SITS and VISA registries, from which all their data were derived, receive ongoing funding from Boehringer Ingelheim. Dr. Derex disclosed no current support relevant to the accompanying editorial, but acknowledged past honoraria from Boehringer Ingelheim and work as an investigator on trials sponsored by that company.

A new analysis of nearly 30,000 stroke patients has shown thrombolysis treatment to be helpful for people aged 80 years and older, who show functional outcomes similar to those of much younger stroke patients after 90 days, and comparable mortality.

The findings, published online Nov. 24 in BMJ (BMJ 2010;341:c6046) and using data from the Safe Implementation of Treatment in Stroke–International Stroke Thrombolysis Register (SITS-ISTR) and the Virtual International Stroke Trials Archive (VISTA), suggest that treatment with intravenous alteplase should not be withheld on the basis of age alone, despite current European licensing rules and guidelines that restrict the use of recombinant tissue plasminogen activators to stroke victims under age 80.

The reason for the European Medicine Agency’s alteplase restriction was concern over a potential increased risk of symptomatic, treatment-related intracranial hemorrhage in older people, and the fact that there was not yet enough clinical evidence for the safety and effectiveness of alteplase and other recombinant tissue plasminogen activators in this patient group, as older people had been under-represented in clinical trials.

Yet, as the BMJ study’s investigators, led Dr. Kennedy R. Lees of the University of Glasgow (U.K.), noted in their analysis, some 30% of stroke victims are over age 80, and the percentage of people in this age group is growing in developed nations. In the study Dr. Lees and his colleagues built upon years of increasing speculation that thrombolysis, administered within 3 hours after stroke, was effective and safe in this patient group too, with clinicians increasingly administering it and reporting good outcomes.

The SITS registry provided Dr. Lees and his colleagues an ongoing source of data on elderly patients who had received thrombolysis. Of the 29,500 stroke patients available for analysis, 3,439 were older than age 80 (mean age 84.6 years). A total of 23,334 patients had undergone thrombolysis with alteplase (mean 145 minutes after stroke onset). Data on 6,166 patients who did not receive thrombolysis but received placebo or a neuroprotective agent were available from the VISTA registry, and these patients served as controls. Median baseline stroke severity was equal for patients and controls (median National Institutes of Health (NIH) stroke scale score 12). A total of 272 patients from both groups were removed from the analysis for missing stroke severity data, leaving data on 29,228 available for final analysis.

Dr. Lees and his colleagues found that functional outcomes 90 days post stroke, measured by modified Rankin scale scores, which measure debilitation, were significantly better in patients who received thrombolysis, and that this was true in patients both younger than 80 years (odds ratio 1.6) and over 80 years (OR 1.4). The number needed to treat for one more elderly patient to achieve a favorable Rankin score of 0-2 (no disability or slight disability that does not affect independence) at 3 months was 8.2, compared with 8.5 for younger patients.

Rates of intracerebral hemorrhage – avoidance of which was the original rationale for denying thrombolysis to older patients – were shown to be only slightly increased in the older patients, depending on how the hemorrhage was defined and diagnosed. Symptomatic hemorrhage occurred in 2.5% of the 80 and older group and 1.9% of the younger patients, according to a SITS definition, and in 11% vs. 8.3%, respectively, when measured according to an NIH definition. However, the odds ratio for mortality was almost exactly the same – 0.89 (0.76-1.04) in elderly patients receiving thrombolysis, compared with 0.87 (0.79-0.95) in younger patients.

The investigators saw no benefit associated with thrombolysis in patients older than 90 or younger than 40. However, they noted, "the small number of patients in these groups greatly reduced statistical power for these analyses, and the trends mostly followed the same pattern as for intermediate ages." They concluded that clinical treatment guidelines "should be revised to remove the age restriction in use of intravenous alteplase for acute ischemic stroke. Age alone should not be a barrier to treatment."

In an editorial accompanying Dr. Lees and colleagues’ article, neurologist Laurent Derex of Inserm and the Neurological Hospital in Lyon, France, characterized the results as "quite robust," noting that the odds ratios were consistent across all 10-year age ranges. Moreover, Dr. Derex said, "elderly patients may be especially vulnerable to subjective judgments of the benefit of optimal stroke care, particularly when medical resources are limited."

But Dr. Derex also cautioned that the study’s nonrandomized design was not ideal, as the investigators themselves acknowledged. "As a post hoc analysis of a thrombolysis registry, the study is prone to selection bias," Dr. Derex wrote. "If the elderly patients with stroke included in this registry were more carefully selected for administration of intravenous recombinant tissue plasminogen activator, the findings would be less generalizable to all elderly patients. ... Ongoing randomized controlled thrombolytic trials that include patients aged over 80 years should yield more robust conclusions" (BMJ 2010; 341:c5891)

Dr. Lees and six of his seven coauthors disclosed having received grants, honoraria, or other forms of financial support from Boehringer Ingelheim, the German manufacturer of alteplase, along with other pharmaceutical companies. They noted that the SITS and VISA registries, from which all their data were derived, receive ongoing funding from Boehringer Ingelheim. Dr. Derex disclosed no current support relevant to the accompanying editorial, but acknowledged past honoraria from Boehringer Ingelheim and work as an investigator on trials sponsored by that company.

A new analysis of nearly 30,000 stroke patients has shown thrombolysis treatment to be helpful for people aged 80 years and older, who show functional outcomes similar to those of much younger stroke patients after 90 days, and comparable mortality.

The findings, published online Nov. 24 in BMJ (BMJ 2010;341:c6046) and using data from the Safe Implementation of Treatment in Stroke–International Stroke Thrombolysis Register (SITS-ISTR) and the Virtual International Stroke Trials Archive (VISTA), suggest that treatment with intravenous alteplase should not be withheld on the basis of age alone, despite current European licensing rules and guidelines that restrict the use of recombinant tissue plasminogen activators to stroke victims under age 80.

The reason for the European Medicine Agency’s alteplase restriction was concern over a potential increased risk of symptomatic, treatment-related intracranial hemorrhage in older people, and the fact that there was not yet enough clinical evidence for the safety and effectiveness of alteplase and other recombinant tissue plasminogen activators in this patient group, as older people had been under-represented in clinical trials.

Yet, as the BMJ study’s investigators, led Dr. Kennedy R. Lees of the University of Glasgow (U.K.), noted in their analysis, some 30% of stroke victims are over age 80, and the percentage of people in this age group is growing in developed nations. In the study Dr. Lees and his colleagues built upon years of increasing speculation that thrombolysis, administered within 3 hours after stroke, was effective and safe in this patient group too, with clinicians increasingly administering it and reporting good outcomes.

The SITS registry provided Dr. Lees and his colleagues an ongoing source of data on elderly patients who had received thrombolysis. Of the 29,500 stroke patients available for analysis, 3,439 were older than age 80 (mean age 84.6 years). A total of 23,334 patients had undergone thrombolysis with alteplase (mean 145 minutes after stroke onset). Data on 6,166 patients who did not receive thrombolysis but received placebo or a neuroprotective agent were available from the VISTA registry, and these patients served as controls. Median baseline stroke severity was equal for patients and controls (median National Institutes of Health (NIH) stroke scale score 12). A total of 272 patients from both groups were removed from the analysis for missing stroke severity data, leaving data on 29,228 available for final analysis.

Dr. Lees and his colleagues found that functional outcomes 90 days post stroke, measured by modified Rankin scale scores, which measure debilitation, were significantly better in patients who received thrombolysis, and that this was true in patients both younger than 80 years (odds ratio 1.6) and over 80 years (OR 1.4). The number needed to treat for one more elderly patient to achieve a favorable Rankin score of 0-2 (no disability or slight disability that does not affect independence) at 3 months was 8.2, compared with 8.5 for younger patients.

Rates of intracerebral hemorrhage – avoidance of which was the original rationale for denying thrombolysis to older patients – were shown to be only slightly increased in the older patients, depending on how the hemorrhage was defined and diagnosed. Symptomatic hemorrhage occurred in 2.5% of the 80 and older group and 1.9% of the younger patients, according to a SITS definition, and in 11% vs. 8.3%, respectively, when measured according to an NIH definition. However, the odds ratio for mortality was almost exactly the same – 0.89 (0.76-1.04) in elderly patients receiving thrombolysis, compared with 0.87 (0.79-0.95) in younger patients.

The investigators saw no benefit associated with thrombolysis in patients older than 90 or younger than 40. However, they noted, "the small number of patients in these groups greatly reduced statistical power for these analyses, and the trends mostly followed the same pattern as for intermediate ages." They concluded that clinical treatment guidelines "should be revised to remove the age restriction in use of intravenous alteplase for acute ischemic stroke. Age alone should not be a barrier to treatment."

In an editorial accompanying Dr. Lees and colleagues’ article, neurologist Laurent Derex of Inserm and the Neurological Hospital in Lyon, France, characterized the results as "quite robust," noting that the odds ratios were consistent across all 10-year age ranges. Moreover, Dr. Derex said, "elderly patients may be especially vulnerable to subjective judgments of the benefit of optimal stroke care, particularly when medical resources are limited."

But Dr. Derex also cautioned that the study’s nonrandomized design was not ideal, as the investigators themselves acknowledged. "As a post hoc analysis of a thrombolysis registry, the study is prone to selection bias," Dr. Derex wrote. "If the elderly patients with stroke included in this registry were more carefully selected for administration of intravenous recombinant tissue plasminogen activator, the findings would be less generalizable to all elderly patients. ... Ongoing randomized controlled thrombolytic trials that include patients aged over 80 years should yield more robust conclusions" (BMJ 2010; 341:c5891)

Dr. Lees and six of his seven coauthors disclosed having received grants, honoraria, or other forms of financial support from Boehringer Ingelheim, the German manufacturer of alteplase, along with other pharmaceutical companies. They noted that the SITS and VISA registries, from which all their data were derived, receive ongoing funding from Boehringer Ingelheim. Dr. Derex disclosed no current support relevant to the accompanying editorial, but acknowledged past honoraria from Boehringer Ingelheim and work as an investigator on trials sponsored by that company.

Widespread predictive genetic screening of people at elevated risk of developing Lynch syndrome, a genetic disorder present in up to 4% of colorectal cancers and 5% of endometrial cancers, is life saving and cost effective, compared with current standard practice, researchers reported Nov. 18 in Cancer Prevention Research.

Lynch syndrome is a predisposition to certain cancers, prominently colorectal and endometrial cancers, caused by germline mutations in the genes that regulate DNA mismatch repair. Currently, people are tested only when presenting with cancers; if the syndrome is found to be present, predictive testing is also offered to their relatives, though uptake is low.

The study findings suggest that colorectal and endometrial cancers caused by Lynch syndrome might be better and more cheaply reduced with a broad, population-based screening strategy involving family history–based risk assessment and tests for mutations in MLH1, MSH2, MSH6, and PMS2 – genes associated with Lynch syndrome.

For their research, Tuan A. Dinh, Ph.D., of Archimedes Inc., a health care modeling firm in San Francisco, and colleagues at clinical institutions in the United States and the Netherlands employed a mathematical model using a simulation, or "virtual population," of 100,000 U.S. individuals to assess the ideal age and risk level at which predictive Lynch syndrome screening becomes cost effective.

The virtual population was constructed using data from published literature that included, among other things, population prevalence of the syndrome and of colorectal and endometrial cancers. The researchers also created a family history model of cancer validated against data on family histories of colorectal cancer in the general population and from a Lynch syndrome registry. Prices used to help determine cost effectiveness were derived from Medicare reimbursement rates.

The modeling showed that a family history–based risk assessment beginning between the ages of 25 and 35 years, followed by genetic testing of anyone with a 5% or higher risk of having the mutations, "reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%," respectively, the investigators said (Cancer Prev. Res. 2010;4:1-13).

For a population of 100,000 individuals containing 392 mutation carriers, "this strategy increased quality adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY," Dr. Dinh and colleagues wrote, putting it on par for cost effectiveness with other cancer-prevention strategies in the general population, "such as colorectal cancer screening, cervical cancer screening, and breast cancer screening."

Genetic screening of unaffected at-risk individuals, conducted after appropriate risk assessment and followed by surveillance for colorectal and endometrial cancer, "would cost-effectively improve health outcomes. Furthermore, it offers an evidence-based justification for a shift in the clinical approach to Lynch syndrome from one that is reactive to proactive," Dr. Dinh and colleagues wrote.

The study was carried out by Archimedes Inc., a firm that produces epidemiological models using "virtual populations," under a grant from Myriad Genetics Laboratory. Neither Dr. Dinh nor his coauthors disclosed potential conflicts of interest.

Widespread predictive genetic screening of people at elevated risk of developing Lynch syndrome, a genetic disorder present in up to 4% of colorectal cancers and 5% of endometrial cancers, is life saving and cost effective, compared with current standard practice, researchers reported Nov. 18 in Cancer Prevention Research.

Lynch syndrome is a predisposition to certain cancers, prominently colorectal and endometrial cancers, caused by germline mutations in the genes that regulate DNA mismatch repair. Currently, people are tested only when presenting with cancers; if the syndrome is found to be present, predictive testing is also offered to their relatives, though uptake is low.

The study findings suggest that colorectal and endometrial cancers caused by Lynch syndrome might be better and more cheaply reduced with a broad, population-based screening strategy involving family history–based risk assessment and tests for mutations in MLH1, MSH2, MSH6, and PMS2 – genes associated with Lynch syndrome.

For their research, Tuan A. Dinh, Ph.D., of Archimedes Inc., a health care modeling firm in San Francisco, and colleagues at clinical institutions in the United States and the Netherlands employed a mathematical model using a simulation, or "virtual population," of 100,000 U.S. individuals to assess the ideal age and risk level at which predictive Lynch syndrome screening becomes cost effective.

The virtual population was constructed using data from published literature that included, among other things, population prevalence of the syndrome and of colorectal and endometrial cancers. The researchers also created a family history model of cancer validated against data on family histories of colorectal cancer in the general population and from a Lynch syndrome registry. Prices used to help determine cost effectiveness were derived from Medicare reimbursement rates.

The modeling showed that a family history–based risk assessment beginning between the ages of 25 and 35 years, followed by genetic testing of anyone with a 5% or higher risk of having the mutations, "reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%," respectively, the investigators said (Cancer Prev. Res. 2010;4:1-13).

For a population of 100,000 individuals containing 392 mutation carriers, "this strategy increased quality adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY," Dr. Dinh and colleagues wrote, putting it on par for cost effectiveness with other cancer-prevention strategies in the general population, "such as colorectal cancer screening, cervical cancer screening, and breast cancer screening."

Genetic screening of unaffected at-risk individuals, conducted after appropriate risk assessment and followed by surveillance for colorectal and endometrial cancer, "would cost-effectively improve health outcomes. Furthermore, it offers an evidence-based justification for a shift in the clinical approach to Lynch syndrome from one that is reactive to proactive," Dr. Dinh and colleagues wrote.

The study was carried out by Archimedes Inc., a firm that produces epidemiological models using "virtual populations," under a grant from Myriad Genetics Laboratory. Neither Dr. Dinh nor his coauthors disclosed potential conflicts of interest.

Widespread predictive genetic screening of people at elevated risk of developing Lynch syndrome, a genetic disorder present in up to 4% of colorectal cancers and 5% of endometrial cancers, is life saving and cost effective, compared with current standard practice, researchers reported Nov. 18 in Cancer Prevention Research.

Lynch syndrome is a predisposition to certain cancers, prominently colorectal and endometrial cancers, caused by germline mutations in the genes that regulate DNA mismatch repair. Currently, people are tested only when presenting with cancers; if the syndrome is found to be present, predictive testing is also offered to their relatives, though uptake is low.

The study findings suggest that colorectal and endometrial cancers caused by Lynch syndrome might be better and more cheaply reduced with a broad, population-based screening strategy involving family history–based risk assessment and tests for mutations in MLH1, MSH2, MSH6, and PMS2 – genes associated with Lynch syndrome.

For their research, Tuan A. Dinh, Ph.D., of Archimedes Inc., a health care modeling firm in San Francisco, and colleagues at clinical institutions in the United States and the Netherlands employed a mathematical model using a simulation, or "virtual population," of 100,000 U.S. individuals to assess the ideal age and risk level at which predictive Lynch syndrome screening becomes cost effective.

The virtual population was constructed using data from published literature that included, among other things, population prevalence of the syndrome and of colorectal and endometrial cancers. The researchers also created a family history model of cancer validated against data on family histories of colorectal cancer in the general population and from a Lynch syndrome registry. Prices used to help determine cost effectiveness were derived from Medicare reimbursement rates.

The modeling showed that a family history–based risk assessment beginning between the ages of 25 and 35 years, followed by genetic testing of anyone with a 5% or higher risk of having the mutations, "reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%," respectively, the investigators said (Cancer Prev. Res. 2010;4:1-13).

For a population of 100,000 individuals containing 392 mutation carriers, "this strategy increased quality adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY," Dr. Dinh and colleagues wrote, putting it on par for cost effectiveness with other cancer-prevention strategies in the general population, "such as colorectal cancer screening, cervical cancer screening, and breast cancer screening."

Genetic screening of unaffected at-risk individuals, conducted after appropriate risk assessment and followed by surveillance for colorectal and endometrial cancer, "would cost-effectively improve health outcomes. Furthermore, it offers an evidence-based justification for a shift in the clinical approach to Lynch syndrome from one that is reactive to proactive," Dr. Dinh and colleagues wrote.

The study was carried out by Archimedes Inc., a firm that produces epidemiological models using "virtual populations," under a grant from Myriad Genetics Laboratory. Neither Dr. Dinh nor his coauthors disclosed potential conflicts of interest.

Mutational analysis using a Sequenom-based technique of ovarian cancer samples has unveiled more mutations than were previously known, and could become part of a personalized standard of care for these difficult-to-treat cancers, according to investigators.

Dr. Ursula Matulonis of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, plans to elaborate on the findings Nov. 17 at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Berlin.

For their research, Dr. Matulonis and her colleagues subjected samples from high-grade serous ovarian cancers (stage III or IV) without known BRCA mutations to the technique, which is called OncoMap.

OncoMap uses spectronomic gene sequencing to identify more than 1,100 mutations on 114 oncogenes. It works using fresh-frozen or formalin-fixed paraffin embedded (FFPE) tissue samples; Dr. Matulonis’ team used FFPE samples only.

The team, testing 203 samples with OncoMap, found mutations of 50 genes in total. Some mutations were in genes previously identified in ovarian cancer, including KRAS, CTNNB1, and PIK3CA. Others were not previously known to occur in this disease, but, importantly, are potential drug targets with existing agents.

"It’s not like HER2 in breast cancer where that is found in about 30% of breast cancers – we found many mutations in the ovarian cancer samples and they were infrequent," Dr. Matulonis said in a telephone interview prior to the conference; she noted, however, that OncoMap identified KRAS and PIK3CA mutations as the most common, occurring in about 25% of tumors, and "that was reassuring," as it was in line with expectations.

While many of the additional mutations were found in lower frequency, "we can still increase treatment options, as we get smarter with drugs," said Dr. Matulonis, medical director of gynecologic oncology at Dana-Farber,

She said she has already referred ovarian cancer patients to clinical trials based on OncoMap results and hopes to refer more for personalized drug treatments. For example, XL147 and GDC-0941, novel inhibitors of P13 kinase mutations, are in clinical trials; ovarian cancer patients with these mutations could be enrolled in those trials. Similarly, if an ovarian cancer were shown to exhibit an ALK alteration, the patient could be treated with a drug that targets that protein.

Dr. Matulonis’ team is now using OncoMap on all new ovarian cancers, including nonserous cancers, diagnosed at Dana-Farber, and she predicted the test will become standard in clinical practice within 6 months to a year.

The investigators disclosed funding for the study from Madeline Franchi Ovarian Cancer Research Fund, twoAM Fund and the Sally Cooke Ovarian Cancer Research Fund.

Mutational analysis using a Sequenom-based technique of ovarian cancer samples has unveiled more mutations than were previously known, and could become part of a personalized standard of care for these difficult-to-treat cancers, according to investigators.

Dr. Ursula Matulonis of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, plans to elaborate on the findings Nov. 17 at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Berlin.

For their research, Dr. Matulonis and her colleagues subjected samples from high-grade serous ovarian cancers (stage III or IV) without known BRCA mutations to the technique, which is called OncoMap.

OncoMap uses spectronomic gene sequencing to identify more than 1,100 mutations on 114 oncogenes. It works using fresh-frozen or formalin-fixed paraffin embedded (FFPE) tissue samples; Dr. Matulonis’ team used FFPE samples only.

The team, testing 203 samples with OncoMap, found mutations of 50 genes in total. Some mutations were in genes previously identified in ovarian cancer, including KRAS, CTNNB1, and PIK3CA. Others were not previously known to occur in this disease, but, importantly, are potential drug targets with existing agents.

"It’s not like HER2 in breast cancer where that is found in about 30% of breast cancers – we found many mutations in the ovarian cancer samples and they were infrequent," Dr. Matulonis said in a telephone interview prior to the conference; she noted, however, that OncoMap identified KRAS and PIK3CA mutations as the most common, occurring in about 25% of tumors, and "that was reassuring," as it was in line with expectations.

While many of the additional mutations were found in lower frequency, "we can still increase treatment options, as we get smarter with drugs," said Dr. Matulonis, medical director of gynecologic oncology at Dana-Farber,

She said she has already referred ovarian cancer patients to clinical trials based on OncoMap results and hopes to refer more for personalized drug treatments. For example, XL147 and GDC-0941, novel inhibitors of P13 kinase mutations, are in clinical trials; ovarian cancer patients with these mutations could be enrolled in those trials. Similarly, if an ovarian cancer were shown to exhibit an ALK alteration, the patient could be treated with a drug that targets that protein.

Dr. Matulonis’ team is now using OncoMap on all new ovarian cancers, including nonserous cancers, diagnosed at Dana-Farber, and she predicted the test will become standard in clinical practice within 6 months to a year.

The investigators disclosed funding for the study from Madeline Franchi Ovarian Cancer Research Fund, twoAM Fund and the Sally Cooke Ovarian Cancer Research Fund.

Mutational analysis using a Sequenom-based technique of ovarian cancer samples has unveiled more mutations than were previously known, and could become part of a personalized standard of care for these difficult-to-treat cancers, according to investigators.

Dr. Ursula Matulonis of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, plans to elaborate on the findings Nov. 17 at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Berlin.

For their research, Dr. Matulonis and her colleagues subjected samples from high-grade serous ovarian cancers (stage III or IV) without known BRCA mutations to the technique, which is called OncoMap.

OncoMap uses spectronomic gene sequencing to identify more than 1,100 mutations on 114 oncogenes. It works using fresh-frozen or formalin-fixed paraffin embedded (FFPE) tissue samples; Dr. Matulonis’ team used FFPE samples only.

The team, testing 203 samples with OncoMap, found mutations of 50 genes in total. Some mutations were in genes previously identified in ovarian cancer, including KRAS, CTNNB1, and PIK3CA. Others were not previously known to occur in this disease, but, importantly, are potential drug targets with existing agents.

"It’s not like HER2 in breast cancer where that is found in about 30% of breast cancers – we found many mutations in the ovarian cancer samples and they were infrequent," Dr. Matulonis said in a telephone interview prior to the conference; she noted, however, that OncoMap identified KRAS and PIK3CA mutations as the most common, occurring in about 25% of tumors, and "that was reassuring," as it was in line with expectations.

While many of the additional mutations were found in lower frequency, "we can still increase treatment options, as we get smarter with drugs," said Dr. Matulonis, medical director of gynecologic oncology at Dana-Farber,

She said she has already referred ovarian cancer patients to clinical trials based on OncoMap results and hopes to refer more for personalized drug treatments. For example, XL147 and GDC-0941, novel inhibitors of P13 kinase mutations, are in clinical trials; ovarian cancer patients with these mutations could be enrolled in those trials. Similarly, if an ovarian cancer were shown to exhibit an ALK alteration, the patient could be treated with a drug that targets that protein.

Dr. Matulonis’ team is now using OncoMap on all new ovarian cancers, including nonserous cancers, diagnosed at Dana-Farber, and she predicted the test will become standard in clinical practice within 6 months to a year.

The investigators disclosed funding for the study from Madeline Franchi Ovarian Cancer Research Fund, twoAM Fund and the Sally Cooke Ovarian Cancer Research Fund.