Mary Ann Moon

The risks of attempted suicide, completed suicide, and violent suicide showed “no clinically meaningful variation” by the type of antidepressant used in a large cohort study.

“Our finding of equal event rates across antidepressant agents supports the U.S. Food and Drug Administration's decision to treat all antidepressants alike in their advisory” warning that the drugs might be associated with an increase in suicidal thoughts and behaviors, said Dr. Sebastian Schneeweiss of Brigham and Women's Hospital, Boston, and his associates (Arch. Gen. Psychiatry 2010;67:497-506).

Some studies have suggested that particular antidepressant drugs or drug classes raise the risk of suicide to a greater degree than others, but other studies have refuted that. “We sought to address whether the risk of suicide is equal across antidepressant classes and agents after adjusting for selection factors—or whether there are particular regimens with safety advantages that should be prescribed preferentially,” the investigators said.

They studied all adult residents of British Columbia who initiated the use of an antidepressant medication between 1997 and 2006. They excluded patients who used buproprion because it is sometimes used for smoking cessation rather than depressive symptoms, escitalopram because it was not marketed until near the end of the study period, and duloxetine because it was not marketed in Canada during the study period.

The medications were classified as selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline); serotonin norepinephrine reuptake inhibitors (venlafaxine); tricyclics (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine); newer and atypical agents (mirtazapine, nefazodone, and trazodone); and monoamine oxidase inhibitors (moclobemide, phenelzine, and tranylcypromine).

A total of 287,543 adults were assessed for 1 year. About 5% had been hospitalized previously for a psychiatric condition, and 0.6% had made a previous suicide attempt.

During the first year, 846 adults attempted suicide (751 adults) and/or completed suicide (104 adults), yielding an event rate of 6.06 attempted and completed suicides per 1,000 person-years, they wrote.

There were no significant differences in suicide rates among antidepressant classes or among individual antidepressants. This finding held true when the data were restricted to cases of suicide attempt only, suicide completion only, and violent suicide only.

Although some researchers have posited that some antidepressants might raise suicide risks only in the first few months after they are initiated, Dr. Schneeweiss and his associates found similar results—no differences among the various antidepressants—even when the data were truncated to only 6 months of follow-up.

In initial analyses, a higher rate of suicidal events in venlafaxine users was found compared with SSRI users, but this effect was attenuated when further, more refined analyses were performed. This suggests that there was a confounding effect with venlafaxine, perhaps related to the tendency of clinicians to prescribe venlafaxine for more severe cases of depression.

The findings reinforce that “treatment decisions should be based on efficacy, and clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent,” they said.

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

The risks of attempted suicide, completed suicide, and violent suicide showed “no clinically meaningful variation” by the type of antidepressant used in a large cohort study.

“Our finding of equal event rates across antidepressant agents supports the U.S. Food and Drug Administration's decision to treat all antidepressants alike in their advisory” warning that the drugs might be associated with an increase in suicidal thoughts and behaviors, said Dr. Sebastian Schneeweiss of Brigham and Women's Hospital, Boston, and his associates (Arch. Gen. Psychiatry 2010;67:497-506).

Some studies have suggested that particular antidepressant drugs or drug classes raise the risk of suicide to a greater degree than others, but other studies have refuted that. “We sought to address whether the risk of suicide is equal across antidepressant classes and agents after adjusting for selection factors—or whether there are particular regimens with safety advantages that should be prescribed preferentially,” the investigators said.

They studied all adult residents of British Columbia who initiated the use of an antidepressant medication between 1997 and 2006. They excluded patients who used buproprion because it is sometimes used for smoking cessation rather than depressive symptoms, escitalopram because it was not marketed until near the end of the study period, and duloxetine because it was not marketed in Canada during the study period.

The medications were classified as selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline); serotonin norepinephrine reuptake inhibitors (venlafaxine); tricyclics (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine); newer and atypical agents (mirtazapine, nefazodone, and trazodone); and monoamine oxidase inhibitors (moclobemide, phenelzine, and tranylcypromine).

A total of 287,543 adults were assessed for 1 year. About 5% had been hospitalized previously for a psychiatric condition, and 0.6% had made a previous suicide attempt.

During the first year, 846 adults attempted suicide (751 adults) and/or completed suicide (104 adults), yielding an event rate of 6.06 attempted and completed suicides per 1,000 person-years, they wrote.

There were no significant differences in suicide rates among antidepressant classes or among individual antidepressants. This finding held true when the data were restricted to cases of suicide attempt only, suicide completion only, and violent suicide only.

Although some researchers have posited that some antidepressants might raise suicide risks only in the first few months after they are initiated, Dr. Schneeweiss and his associates found similar results—no differences among the various antidepressants—even when the data were truncated to only 6 months of follow-up.

In initial analyses, a higher rate of suicidal events in venlafaxine users was found compared with SSRI users, but this effect was attenuated when further, more refined analyses were performed. This suggests that there was a confounding effect with venlafaxine, perhaps related to the tendency of clinicians to prescribe venlafaxine for more severe cases of depression.

The findings reinforce that “treatment decisions should be based on efficacy, and clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent,” they said.

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

The risks of attempted suicide, completed suicide, and violent suicide showed “no clinically meaningful variation” by the type of antidepressant used in a large cohort study.

“Our finding of equal event rates across antidepressant agents supports the U.S. Food and Drug Administration's decision to treat all antidepressants alike in their advisory” warning that the drugs might be associated with an increase in suicidal thoughts and behaviors, said Dr. Sebastian Schneeweiss of Brigham and Women's Hospital, Boston, and his associates (Arch. Gen. Psychiatry 2010;67:497-506).

Some studies have suggested that particular antidepressant drugs or drug classes raise the risk of suicide to a greater degree than others, but other studies have refuted that. “We sought to address whether the risk of suicide is equal across antidepressant classes and agents after adjusting for selection factors—or whether there are particular regimens with safety advantages that should be prescribed preferentially,” the investigators said.

They studied all adult residents of British Columbia who initiated the use of an antidepressant medication between 1997 and 2006. They excluded patients who used buproprion because it is sometimes used for smoking cessation rather than depressive symptoms, escitalopram because it was not marketed until near the end of the study period, and duloxetine because it was not marketed in Canada during the study period.

The medications were classified as selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline); serotonin norepinephrine reuptake inhibitors (venlafaxine); tricyclics (amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine); newer and atypical agents (mirtazapine, nefazodone, and trazodone); and monoamine oxidase inhibitors (moclobemide, phenelzine, and tranylcypromine).

A total of 287,543 adults were assessed for 1 year. About 5% had been hospitalized previously for a psychiatric condition, and 0.6% had made a previous suicide attempt.

During the first year, 846 adults attempted suicide (751 adults) and/or completed suicide (104 adults), yielding an event rate of 6.06 attempted and completed suicides per 1,000 person-years, they wrote.

There were no significant differences in suicide rates among antidepressant classes or among individual antidepressants. This finding held true when the data were restricted to cases of suicide attempt only, suicide completion only, and violent suicide only.

Although some researchers have posited that some antidepressants might raise suicide risks only in the first few months after they are initiated, Dr. Schneeweiss and his associates found similar results—no differences among the various antidepressants—even when the data were truncated to only 6 months of follow-up.

In initial analyses, a higher rate of suicidal events in venlafaxine users was found compared with SSRI users, but this effect was attenuated when further, more refined analyses were performed. This suggests that there was a confounding effect with venlafaxine, perhaps related to the tendency of clinicians to prescribe venlafaxine for more severe cases of depression.

The findings reinforce that “treatment decisions should be based on efficacy, and clinicians should be vigilant in monitoring after initiating therapy with any antidepressant agent,” they said.

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

A study testing the hypothesis that vitamin B therapy would slow the progression of diabetic nephropathy and prevent vascular events instead showed just the opposite: Use of high-dose B vitamins worsened renal function and raised the rates of MI and stroke, according to Dr. Andrew A. House of the University of Western Ontario, London, and his associates.

“Our trial is the first study to our knowledge to show significant detrimental effects from pharmacological doses of B vitamins,” they said.

Vitamin B therapy lowers plasma concentrations of homocysteine and improves endothelial function, but most clinical trials in which high-dose B vitamins have been used to decrease homocysteine have failed to demonstrate improved cardiovascular outcomes, according to the researchers (JAMA 2010;303:1603-9).

“Given the recent large-scale clinical trials showing no treatment benefit, and our trial demonstrating harm, it would be prudent to discourage the use of high-dose B vitamins as a homocysteine-lowering strategy outside the framework of properly conducted clinical research,” Dr. House and his colleagues concluded.

The investigators tested their hypothesis that vitamin B therapy would improve nephropathy and vascular events in a study of 238 adults with type 1 or 2 diabetes and stages 1-3 chronic kidney disease who were treated at five university medical centers in Canada.

The participants were randomly assigned in equal numbers to receive either a daily tablet containing folic acid (2.5 mg/day), vitamin B₆ (25 mg/day), and vitamin B₁₂ (1 mg/day) or a matching placebo. They were followed every 6 months for up to 3 years (mean follow-up, 32 months).

As expected, plasma homocysteine levels decreased in the group taking vitamin B therapy but increased in those taking placebo, resulting in a significant mean difference of 4.8 micromol/L between the two groups.

Nevertheless, compared with patients assigned to placebo, those assigned to the B vitamin group had a much greater decrease in renal function, as assessed by one direct and two indirect methods: radionuclide glomerular filtration rate (GFR), estimated GFR using creatinine clearance, and estimated GFR using the Modification of Diet in Renal Disease (MDRD) formula.

“Over 36 months, the GFR decreased by a mean of 16.5 mL/min/1.73 m

There were no differences between the two groups in measures of proteinuria or in need for dialysis.

Participants who received vitamin B therapy also had approximately twice as many cardiovascular and cerebrovascular events as those who received placebo. The 3-year risk of a composite outcome that included MI, stroke, revascularization, and all-cause mortality was 23.5% in the vitamin B group and 14.4% in the placebo group.

The two groups did not differ in rates of all-cause mortality, amputation, or cognitive decline.

The rates of adverse events (88%-90%) and severe adverse events (32%-33%) were not significantly different between the two groups. The rate of serious adverse events was slightly higher in the placebo group (40%) than in the active treatment group (34%).

The study findings suggest that vitamin B therapy is associated with both renal and vascular toxicity. Possible explanations are that folic acid may promote cell proliferation through its role in thymidine synthesis; that folic acid and B₁₂ might alter the methylation potential in vascular cells; or that all the components of vitamin B therapy might increase the methylation of l-arginine to asymmetric dimethylarginine, a nitric oxide synthase inhibitor.

It also is possible that the decrease in homocysteine is actually protective, but that this benefit may be offset by the treatment's toxicity, Dr. House and his associates said.

The study was supported by the Canadian Institutes of Health Research and the Kidney Foundation of Canada. Pan American Laboratories provided the B vitamins and placebos. Dr. House and an associate reported having a patent pending on the use of mesna to reduce homocysteine levels in patients on dialysis. The same associate reported receiving fees from Pan American Laboratories and Medice Arzneimittel Ptter GmbH.

A study testing the hypothesis that vitamin B therapy would slow the progression of diabetic nephropathy and prevent vascular events instead showed just the opposite: Use of high-dose B vitamins worsened renal function and raised the rates of MI and stroke, according to Dr. Andrew A. House of the University of Western Ontario, London, and his associates.

“Our trial is the first study to our knowledge to show significant detrimental effects from pharmacological doses of B vitamins,” they said.

Vitamin B therapy lowers plasma concentrations of homocysteine and improves endothelial function, but most clinical trials in which high-dose B vitamins have been used to decrease homocysteine have failed to demonstrate improved cardiovascular outcomes, according to the researchers (JAMA 2010;303:1603-9).

“Given the recent large-scale clinical trials showing no treatment benefit, and our trial demonstrating harm, it would be prudent to discourage the use of high-dose B vitamins as a homocysteine-lowering strategy outside the framework of properly conducted clinical research,” Dr. House and his colleagues concluded.

The investigators tested their hypothesis that vitamin B therapy would improve nephropathy and vascular events in a study of 238 adults with type 1 or 2 diabetes and stages 1-3 chronic kidney disease who were treated at five university medical centers in Canada.

The participants were randomly assigned in equal numbers to receive either a daily tablet containing folic acid (2.5 mg/day), vitamin B₆ (25 mg/day), and vitamin B₁₂ (1 mg/day) or a matching placebo. They were followed every 6 months for up to 3 years (mean follow-up, 32 months).

As expected, plasma homocysteine levels decreased in the group taking vitamin B therapy but increased in those taking placebo, resulting in a significant mean difference of 4.8 micromol/L between the two groups.

Nevertheless, compared with patients assigned to placebo, those assigned to the B vitamin group had a much greater decrease in renal function, as assessed by one direct and two indirect methods: radionuclide glomerular filtration rate (GFR), estimated GFR using creatinine clearance, and estimated GFR using the Modification of Diet in Renal Disease (MDRD) formula.

“Over 36 months, the GFR decreased by a mean of 16.5 mL/min/1.73 m

There were no differences between the two groups in measures of proteinuria or in need for dialysis.

Participants who received vitamin B therapy also had approximately twice as many cardiovascular and cerebrovascular events as those who received placebo. The 3-year risk of a composite outcome that included MI, stroke, revascularization, and all-cause mortality was 23.5% in the vitamin B group and 14.4% in the placebo group.

The two groups did not differ in rates of all-cause mortality, amputation, or cognitive decline.

The rates of adverse events (88%-90%) and severe adverse events (32%-33%) were not significantly different between the two groups. The rate of serious adverse events was slightly higher in the placebo group (40%) than in the active treatment group (34%).

The study findings suggest that vitamin B therapy is associated with both renal and vascular toxicity. Possible explanations are that folic acid may promote cell proliferation through its role in thymidine synthesis; that folic acid and B₁₂ might alter the methylation potential in vascular cells; or that all the components of vitamin B therapy might increase the methylation of l-arginine to asymmetric dimethylarginine, a nitric oxide synthase inhibitor.

It also is possible that the decrease in homocysteine is actually protective, but that this benefit may be offset by the treatment's toxicity, Dr. House and his associates said.

The study was supported by the Canadian Institutes of Health Research and the Kidney Foundation of Canada. Pan American Laboratories provided the B vitamins and placebos. Dr. House and an associate reported having a patent pending on the use of mesna to reduce homocysteine levels in patients on dialysis. The same associate reported receiving fees from Pan American Laboratories and Medice Arzneimittel Ptter GmbH.

A study testing the hypothesis that vitamin B therapy would slow the progression of diabetic nephropathy and prevent vascular events instead showed just the opposite: Use of high-dose B vitamins worsened renal function and raised the rates of MI and stroke, according to Dr. Andrew A. House of the University of Western Ontario, London, and his associates.

“Our trial is the first study to our knowledge to show significant detrimental effects from pharmacological doses of B vitamins,” they said.

Vitamin B therapy lowers plasma concentrations of homocysteine and improves endothelial function, but most clinical trials in which high-dose B vitamins have been used to decrease homocysteine have failed to demonstrate improved cardiovascular outcomes, according to the researchers (JAMA 2010;303:1603-9).

“Given the recent large-scale clinical trials showing no treatment benefit, and our trial demonstrating harm, it would be prudent to discourage the use of high-dose B vitamins as a homocysteine-lowering strategy outside the framework of properly conducted clinical research,” Dr. House and his colleagues concluded.

The investigators tested their hypothesis that vitamin B therapy would improve nephropathy and vascular events in a study of 238 adults with type 1 or 2 diabetes and stages 1-3 chronic kidney disease who were treated at five university medical centers in Canada.

The participants were randomly assigned in equal numbers to receive either a daily tablet containing folic acid (2.5 mg/day), vitamin B₆ (25 mg/day), and vitamin B₁₂ (1 mg/day) or a matching placebo. They were followed every 6 months for up to 3 years (mean follow-up, 32 months).

As expected, plasma homocysteine levels decreased in the group taking vitamin B therapy but increased in those taking placebo, resulting in a significant mean difference of 4.8 micromol/L between the two groups.

Nevertheless, compared with patients assigned to placebo, those assigned to the B vitamin group had a much greater decrease in renal function, as assessed by one direct and two indirect methods: radionuclide glomerular filtration rate (GFR), estimated GFR using creatinine clearance, and estimated GFR using the Modification of Diet in Renal Disease (MDRD) formula.

“Over 36 months, the GFR decreased by a mean of 16.5 mL/min/1.73 m

There were no differences between the two groups in measures of proteinuria or in need for dialysis.

Participants who received vitamin B therapy also had approximately twice as many cardiovascular and cerebrovascular events as those who received placebo. The 3-year risk of a composite outcome that included MI, stroke, revascularization, and all-cause mortality was 23.5% in the vitamin B group and 14.4% in the placebo group.

The two groups did not differ in rates of all-cause mortality, amputation, or cognitive decline.

The rates of adverse events (88%-90%) and severe adverse events (32%-33%) were not significantly different between the two groups. The rate of serious adverse events was slightly higher in the placebo group (40%) than in the active treatment group (34%).

The study findings suggest that vitamin B therapy is associated with both renal and vascular toxicity. Possible explanations are that folic acid may promote cell proliferation through its role in thymidine synthesis; that folic acid and B₁₂ might alter the methylation potential in vascular cells; or that all the components of vitamin B therapy might increase the methylation of l-arginine to asymmetric dimethylarginine, a nitric oxide synthase inhibitor.

It also is possible that the decrease in homocysteine is actually protective, but that this benefit may be offset by the treatment's toxicity, Dr. House and his associates said.

The study was supported by the Canadian Institutes of Health Research and the Kidney Foundation of Canada. Pan American Laboratories provided the B vitamins and placebos. Dr. House and an associate reported having a patent pending on the use of mesna to reduce homocysteine levels in patients on dialysis. The same associate reported receiving fees from Pan American Laboratories and Medice Arzneimittel Ptter GmbH.

Adding the coronary artery calcium score to traditional risk factors significantly improved asymptomatic patients' risk classification for coronary heart disease, in an analysis of the Multi-Ethnic Study of Atherosclerosis.”

“Incorporation of an individual's CACS leads to a more refined estimation of future risk of CHD events than [do] traditional risk factors alone,” said Dr. Tamar S. Polonsky of Northwestern University, Chicago, and associates.

However, this finding “will need to be validated in additional populations” before CACS can be adopted into routine clinical practice, they noted. More importantly, it still hasn't been determined whether screening for subclinical disease using CACS actually improves patient outcomes, they cautioned.

In an editorial, Dr. John P.A. Ioannidis of the University of Ioannina (Greece) and Harvard School of Public Health, Boston, and Ioanna Tzoulaki, Ph.D., of Imperial College of Medicine, London, agreed that these study results, “no matter how promising, do not suffice to recommend this marker for widespread routine use.”

In addition to the clinical utility of obtaining the CACS, the considerable cost of the procedure and its potential harms due to radiation exposure must be thoroughly examined. “The evidence to date suggests that while CACS is a promising tool, the verdict is not yet in as to whether it is ready for routine use, and much more is still left to do,” Dr. Ioannidis and Dr. Tzoulaki wrote.

Dr. Polonsky and colleagues assessed CACS using data from the Multi-Ethnic Study of Atherosclerosis, a cohort study of more than 6,800 white, black, Hispanic, and Chinese Americans aged 45–84 years who had no known cardiovascular disease at enrollment in 2000–2002. For their study, the investigators included 5,878 of these subjects who had undergone CT scanning for coronary calcium assessment at baseline and who had been followed every 9–12 months for a median of 6 years.

There were 209 CHD events during follow-up, including 96 MIs, 14 CHD deaths, and 12 resuscitated cardiac arrests.

Adding CACS to the risk prediction model resulted in the reclassification of 26% of the sample. “Overall, 728 individuals in the entire cohort were reclassified to a higher risk category, with an event rate of 8.7%, and 814 were reclassified to a lower risk category, with an event rate of 2.7%,” Dr. Polonsky and associates said (JAMA 2010;303:1610–6).

An important measure of a risk marker's usefulness “is whether it separates individuals into more clinically relevant risk categories. Ideally, a model would reclassify most of the individuals out of the intermediate-risk group and into the highest or lowest risk categories.”

Accordingly, adding CACS to the risk prediction model placed 77% of the total study population into definitive highest risk or lowest risk categories, where treatment strategies are more straightforward, as opposed to the somewhat nebulous “intermediate risk” category. In comparison, only 69% of the study population were classified as highest or lowest risk when CACS was not added to the model, they noted.

There were three important caveats to the study's overall finding of improved risk prediction with CACS.

First, for patients who were reclassified from high to lower risk categories, it is questionable whether clinicians could safely decrease or withdraw preventive therapy. If they are going to continue treatment as usual regardless of CACS findings, then obtaining CACS in this patient group would be moot.

Second, patients in this study classified as low risk using CACS actually had an event rate that was higher than was predicted by the model. Therefore an important portion of patients thought to be at low risk did have a coronary event.

Third, nearly 60% of the coronary events in this study occurred in people who were not classified as high risk by either traditional risk factors or by CACS, the investigators noted. Thus, both methods of risk prediction may have underestimated risks for the majority of patients.

In their editorial, Dr. Ioannidis and Dr. Tzoulaki said that the study investigators “cautiously acknowledge that they analyzed a prospective cohort, not a randomized intervention trial. Thus, the authors have not yet demonstrated that the added accuracy in risk stratification can actually aid clinicians in better treating patients or improving their clinical outcomes” (JAMA 2010;303:1646–7).

Disclosures: The study was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Polonsky's coauthors received support from Pfizer and GE/Toshiba.

Adding the coronary artery calcium score to traditional risk factors significantly improved asymptomatic patients' risk classification for coronary heart disease, in an analysis of the Multi-Ethnic Study of Atherosclerosis.”

“Incorporation of an individual's CACS leads to a more refined estimation of future risk of CHD events than [do] traditional risk factors alone,” said Dr. Tamar S. Polonsky of Northwestern University, Chicago, and associates.

However, this finding “will need to be validated in additional populations” before CACS can be adopted into routine clinical practice, they noted. More importantly, it still hasn't been determined whether screening for subclinical disease using CACS actually improves patient outcomes, they cautioned.

In an editorial, Dr. John P.A. Ioannidis of the University of Ioannina (Greece) and Harvard School of Public Health, Boston, and Ioanna Tzoulaki, Ph.D., of Imperial College of Medicine, London, agreed that these study results, “no matter how promising, do not suffice to recommend this marker for widespread routine use.”

In addition to the clinical utility of obtaining the CACS, the considerable cost of the procedure and its potential harms due to radiation exposure must be thoroughly examined. “The evidence to date suggests that while CACS is a promising tool, the verdict is not yet in as to whether it is ready for routine use, and much more is still left to do,” Dr. Ioannidis and Dr. Tzoulaki wrote.

Dr. Polonsky and colleagues assessed CACS using data from the Multi-Ethnic Study of Atherosclerosis, a cohort study of more than 6,800 white, black, Hispanic, and Chinese Americans aged 45–84 years who had no known cardiovascular disease at enrollment in 2000–2002. For their study, the investigators included 5,878 of these subjects who had undergone CT scanning for coronary calcium assessment at baseline and who had been followed every 9–12 months for a median of 6 years.

There were 209 CHD events during follow-up, including 96 MIs, 14 CHD deaths, and 12 resuscitated cardiac arrests.

Adding CACS to the risk prediction model resulted in the reclassification of 26% of the sample. “Overall, 728 individuals in the entire cohort were reclassified to a higher risk category, with an event rate of 8.7%, and 814 were reclassified to a lower risk category, with an event rate of 2.7%,” Dr. Polonsky and associates said (JAMA 2010;303:1610–6).

An important measure of a risk marker's usefulness “is whether it separates individuals into more clinically relevant risk categories. Ideally, a model would reclassify most of the individuals out of the intermediate-risk group and into the highest or lowest risk categories.”

Accordingly, adding CACS to the risk prediction model placed 77% of the total study population into definitive highest risk or lowest risk categories, where treatment strategies are more straightforward, as opposed to the somewhat nebulous “intermediate risk” category. In comparison, only 69% of the study population were classified as highest or lowest risk when CACS was not added to the model, they noted.

There were three important caveats to the study's overall finding of improved risk prediction with CACS.

First, for patients who were reclassified from high to lower risk categories, it is questionable whether clinicians could safely decrease or withdraw preventive therapy. If they are going to continue treatment as usual regardless of CACS findings, then obtaining CACS in this patient group would be moot.

Second, patients in this study classified as low risk using CACS actually had an event rate that was higher than was predicted by the model. Therefore an important portion of patients thought to be at low risk did have a coronary event.

Third, nearly 60% of the coronary events in this study occurred in people who were not classified as high risk by either traditional risk factors or by CACS, the investigators noted. Thus, both methods of risk prediction may have underestimated risks for the majority of patients.

In their editorial, Dr. Ioannidis and Dr. Tzoulaki said that the study investigators “cautiously acknowledge that they analyzed a prospective cohort, not a randomized intervention trial. Thus, the authors have not yet demonstrated that the added accuracy in risk stratification can actually aid clinicians in better treating patients or improving their clinical outcomes” (JAMA 2010;303:1646–7).

Disclosures: The study was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Polonsky's coauthors received support from Pfizer and GE/Toshiba.

Adding the coronary artery calcium score to traditional risk factors significantly improved asymptomatic patients' risk classification for coronary heart disease, in an analysis of the Multi-Ethnic Study of Atherosclerosis.”

“Incorporation of an individual's CACS leads to a more refined estimation of future risk of CHD events than [do] traditional risk factors alone,” said Dr. Tamar S. Polonsky of Northwestern University, Chicago, and associates.

However, this finding “will need to be validated in additional populations” before CACS can be adopted into routine clinical practice, they noted. More importantly, it still hasn't been determined whether screening for subclinical disease using CACS actually improves patient outcomes, they cautioned.

In an editorial, Dr. John P.A. Ioannidis of the University of Ioannina (Greece) and Harvard School of Public Health, Boston, and Ioanna Tzoulaki, Ph.D., of Imperial College of Medicine, London, agreed that these study results, “no matter how promising, do not suffice to recommend this marker for widespread routine use.”

In addition to the clinical utility of obtaining the CACS, the considerable cost of the procedure and its potential harms due to radiation exposure must be thoroughly examined. “The evidence to date suggests that while CACS is a promising tool, the verdict is not yet in as to whether it is ready for routine use, and much more is still left to do,” Dr. Ioannidis and Dr. Tzoulaki wrote.

Dr. Polonsky and colleagues assessed CACS using data from the Multi-Ethnic Study of Atherosclerosis, a cohort study of more than 6,800 white, black, Hispanic, and Chinese Americans aged 45–84 years who had no known cardiovascular disease at enrollment in 2000–2002. For their study, the investigators included 5,878 of these subjects who had undergone CT scanning for coronary calcium assessment at baseline and who had been followed every 9–12 months for a median of 6 years.

There were 209 CHD events during follow-up, including 96 MIs, 14 CHD deaths, and 12 resuscitated cardiac arrests.

Adding CACS to the risk prediction model resulted in the reclassification of 26% of the sample. “Overall, 728 individuals in the entire cohort were reclassified to a higher risk category, with an event rate of 8.7%, and 814 were reclassified to a lower risk category, with an event rate of 2.7%,” Dr. Polonsky and associates said (JAMA 2010;303:1610–6).

An important measure of a risk marker's usefulness “is whether it separates individuals into more clinically relevant risk categories. Ideally, a model would reclassify most of the individuals out of the intermediate-risk group and into the highest or lowest risk categories.”

Accordingly, adding CACS to the risk prediction model placed 77% of the total study population into definitive highest risk or lowest risk categories, where treatment strategies are more straightforward, as opposed to the somewhat nebulous “intermediate risk” category. In comparison, only 69% of the study population were classified as highest or lowest risk when CACS was not added to the model, they noted.

There were three important caveats to the study's overall finding of improved risk prediction with CACS.

First, for patients who were reclassified from high to lower risk categories, it is questionable whether clinicians could safely decrease or withdraw preventive therapy. If they are going to continue treatment as usual regardless of CACS findings, then obtaining CACS in this patient group would be moot.

Second, patients in this study classified as low risk using CACS actually had an event rate that was higher than was predicted by the model. Therefore an important portion of patients thought to be at low risk did have a coronary event.

Third, nearly 60% of the coronary events in this study occurred in people who were not classified as high risk by either traditional risk factors or by CACS, the investigators noted. Thus, both methods of risk prediction may have underestimated risks for the majority of patients.

In their editorial, Dr. Ioannidis and Dr. Tzoulaki said that the study investigators “cautiously acknowledge that they analyzed a prospective cohort, not a randomized intervention trial. Thus, the authors have not yet demonstrated that the added accuracy in risk stratification can actually aid clinicians in better treating patients or improving their clinical outcomes” (JAMA 2010;303:1646–7).

Disclosures: The study was supported by the National Heart, Lung, and Blood Institute and the National Center for Research Resources. Dr. Polonsky's coauthors received support from Pfizer and GE/Toshiba.

Two variants of the APOC3 gene, which encodes apolipoprotein C3, are associated with nonalcoholic fatty liver disease and insulin resistance, according to a new study.

Importantly, seven of the study participants who were found to carry the gene variants and who proved to have both disorders were able to reverse the steatosis and markedly improve whole-body insulin sensitivity by dieting and losing approximately 6 kg, said Dr. Kitt Falk Petersen of Yale University, New Haven, Conn., and her associates (N. Engl. J. Med. 2010;362:1082–9).

Previous studies have suggested that two single nucleotide polymorphisms, C-482T and T-455C, in the apolipoprotein C3 (APOC3) gene appeared to be associated with hypertriglyceridemia. Dr. Petersen and her colleagues recruited from the community 95 healthy men of Asian Indian background—an ethnic group known to have a high prevalence of both nonalcoholic fatty liver disease (NAFLD) and insulin resistance—for genotyping.

The men had no other risk factors such as excessive alcohol consumption, obesity, overt insulin resistance, or diabetes. Mean age was 32 years, and all the men had been of normal birth weight.

Plasma apolipoprotein C3 concentrations were 30% higher, and fasting concentrations 60% higher, in men who carried the gene variants than in those who did not. Postprandial plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test were twice as high among carriers than among noncarriers of the single nucleotide polymorphisms (SNPs).

There were no significant differences between carriers and noncarriers in plasma concentrations of total, HDL, or LDL cholesterol, the investigators noted.

Hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, was markedly higher in men who carried the C-482T and T-455C variants than in those who did not.

Most importantly, prevalence of NAFLD was 38% in men who carried the gene variants, compared with zero prevalence among the men who did not. The men with NAFLD also had marked insulin resistance.

This link between the two SNPs and hepatic steatosis was confirmed in a second cohort of 163 non-Indian men of varied ethnic backgrounds.

A subgroup of 15 carriers of the SNP variants also showed a 46% reduction in plasma triglyceride clearance after being challenged with an intravenous lipid infusion, compared with 4 noncarriers.

“These findings support the hypothesis that the APOC3 variants we studied promote both fasting and postprandial hypertriglyceridemia by reducing triglyceride clearance,” Dr. Petersen and her colleagues said.

Taken together with other genetic studies, “these results suggest that the APOC3 variants C-482T and T-455C lead to increased plasma concentrations of apolipoprotein C3, which in turn inhibit lipoprotein lipase and triglyceride clearance, thus conferring a predisposition to both fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles.

“Increased concentrations of circulating chylomicron-remnant particles are then preferentially taken up by the liver by means of a receptor-mediated process, resulting in NAFLD and hepatic insulin resistance,” they proposed.

Modest weight reduction in seven of the subjects who followed a hypocaloric diet for 3–6 months eliminated the NAFLD and improved insulin sensitivity.

The study was supported by grants from the U.S. Public Health Service and the American Diabetes Association. Financial disclosures were reported with the text of the article at nejm.org.

Two variants of the APOC3 gene, which encodes apolipoprotein C3, are associated with nonalcoholic fatty liver disease and insulin resistance, according to a new study.

Importantly, seven of the study participants who were found to carry the gene variants and who proved to have both disorders were able to reverse the steatosis and markedly improve whole-body insulin sensitivity by dieting and losing approximately 6 kg, said Dr. Kitt Falk Petersen of Yale University, New Haven, Conn., and her associates (N. Engl. J. Med. 2010;362:1082–9).

Previous studies have suggested that two single nucleotide polymorphisms, C-482T and T-455C, in the apolipoprotein C3 (APOC3) gene appeared to be associated with hypertriglyceridemia. Dr. Petersen and her colleagues recruited from the community 95 healthy men of Asian Indian background—an ethnic group known to have a high prevalence of both nonalcoholic fatty liver disease (NAFLD) and insulin resistance—for genotyping.

The men had no other risk factors such as excessive alcohol consumption, obesity, overt insulin resistance, or diabetes. Mean age was 32 years, and all the men had been of normal birth weight.

Plasma apolipoprotein C3 concentrations were 30% higher, and fasting concentrations 60% higher, in men who carried the gene variants than in those who did not. Postprandial plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test were twice as high among carriers than among noncarriers of the single nucleotide polymorphisms (SNPs).

There were no significant differences between carriers and noncarriers in plasma concentrations of total, HDL, or LDL cholesterol, the investigators noted.

Hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, was markedly higher in men who carried the C-482T and T-455C variants than in those who did not.

Most importantly, prevalence of NAFLD was 38% in men who carried the gene variants, compared with zero prevalence among the men who did not. The men with NAFLD also had marked insulin resistance.

This link between the two SNPs and hepatic steatosis was confirmed in a second cohort of 163 non-Indian men of varied ethnic backgrounds.

A subgroup of 15 carriers of the SNP variants also showed a 46% reduction in plasma triglyceride clearance after being challenged with an intravenous lipid infusion, compared with 4 noncarriers.

“These findings support the hypothesis that the APOC3 variants we studied promote both fasting and postprandial hypertriglyceridemia by reducing triglyceride clearance,” Dr. Petersen and her colleagues said.

Taken together with other genetic studies, “these results suggest that the APOC3 variants C-482T and T-455C lead to increased plasma concentrations of apolipoprotein C3, which in turn inhibit lipoprotein lipase and triglyceride clearance, thus conferring a predisposition to both fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles.

“Increased concentrations of circulating chylomicron-remnant particles are then preferentially taken up by the liver by means of a receptor-mediated process, resulting in NAFLD and hepatic insulin resistance,” they proposed.

Modest weight reduction in seven of the subjects who followed a hypocaloric diet for 3–6 months eliminated the NAFLD and improved insulin sensitivity.

The study was supported by grants from the U.S. Public Health Service and the American Diabetes Association. Financial disclosures were reported with the text of the article at nejm.org.

Two variants of the APOC3 gene, which encodes apolipoprotein C3, are associated with nonalcoholic fatty liver disease and insulin resistance, according to a new study.

Importantly, seven of the study participants who were found to carry the gene variants and who proved to have both disorders were able to reverse the steatosis and markedly improve whole-body insulin sensitivity by dieting and losing approximately 6 kg, said Dr. Kitt Falk Petersen of Yale University, New Haven, Conn., and her associates (N. Engl. J. Med. 2010;362:1082–9).

Previous studies have suggested that two single nucleotide polymorphisms, C-482T and T-455C, in the apolipoprotein C3 (APOC3) gene appeared to be associated with hypertriglyceridemia. Dr. Petersen and her colleagues recruited from the community 95 healthy men of Asian Indian background—an ethnic group known to have a high prevalence of both nonalcoholic fatty liver disease (NAFLD) and insulin resistance—for genotyping.

The men had no other risk factors such as excessive alcohol consumption, obesity, overt insulin resistance, or diabetes. Mean age was 32 years, and all the men had been of normal birth weight.

Plasma apolipoprotein C3 concentrations were 30% higher, and fasting concentrations 60% higher, in men who carried the gene variants than in those who did not. Postprandial plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test were twice as high among carriers than among noncarriers of the single nucleotide polymorphisms (SNPs).

There were no significant differences between carriers and noncarriers in plasma concentrations of total, HDL, or LDL cholesterol, the investigators noted.

Hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, was markedly higher in men who carried the C-482T and T-455C variants than in those who did not.

Most importantly, prevalence of NAFLD was 38% in men who carried the gene variants, compared with zero prevalence among the men who did not. The men with NAFLD also had marked insulin resistance.

This link between the two SNPs and hepatic steatosis was confirmed in a second cohort of 163 non-Indian men of varied ethnic backgrounds.

A subgroup of 15 carriers of the SNP variants also showed a 46% reduction in plasma triglyceride clearance after being challenged with an intravenous lipid infusion, compared with 4 noncarriers.

“These findings support the hypothesis that the APOC3 variants we studied promote both fasting and postprandial hypertriglyceridemia by reducing triglyceride clearance,” Dr. Petersen and her colleagues said.

Taken together with other genetic studies, “these results suggest that the APOC3 variants C-482T and T-455C lead to increased plasma concentrations of apolipoprotein C3, which in turn inhibit lipoprotein lipase and triglyceride clearance, thus conferring a predisposition to both fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles.

“Increased concentrations of circulating chylomicron-remnant particles are then preferentially taken up by the liver by means of a receptor-mediated process, resulting in NAFLD and hepatic insulin resistance,” they proposed.

Modest weight reduction in seven of the subjects who followed a hypocaloric diet for 3–6 months eliminated the NAFLD and improved insulin sensitivity.

The study was supported by grants from the U.S. Public Health Service and the American Diabetes Association. Financial disclosures were reported with the text of the article at nejm.org.

Physical activity appears to cancel out the effects of the “obesity gene” in adolescents, as it has been shown to do in adults.

“To our knowledge, our study is the first to report an interaction between the FTO [fat mass– and obesity-associated] rs9939609 polymorphism and physical activity level on adiposity indices using objectively assessed physical activity in adolescents,” said Jonatan R. Ruiz, Ph.D., of the Karolinska Institute, Huddinge, Sweden, and his associates.

The investigators genotyped and assessed body mass index, waist circumference, and body fat percentage in 752 adolescents in the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. They also assessed subjects' physical activity level using an accelerometer attached to the lower back.

As expected, the FTO gene variant known as rs9939609 was significantly associated with higher BMI, greater waist circumference, and higher percentage of body fat. But there was no such association in the subgroup of carriers who engaged in at least 60 minutes per day of moderate to vigorous physical activity, Dr. Ruiz and his colleagues said (Arch. Pediatr. Adolesc. Med. 2010;164:328–33).

The findings “have important public health implications and indicate that meeting the physical activity recommendations [of the Department of Health and Human Services] may offset the genetic predisposition to obesity associated with the FTO polymorphism in adolescents,” the researchers said.

The study was funded by several European government organizations. No financial conflicts were reported.

Physical activity appears to cancel out the effects of the “obesity gene” in adolescents, as it has been shown to do in adults.

“To our knowledge, our study is the first to report an interaction between the FTO [fat mass– and obesity-associated] rs9939609 polymorphism and physical activity level on adiposity indices using objectively assessed physical activity in adolescents,” said Jonatan R. Ruiz, Ph.D., of the Karolinska Institute, Huddinge, Sweden, and his associates.

The investigators genotyped and assessed body mass index, waist circumference, and body fat percentage in 752 adolescents in the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. They also assessed subjects' physical activity level using an accelerometer attached to the lower back.

As expected, the FTO gene variant known as rs9939609 was significantly associated with higher BMI, greater waist circumference, and higher percentage of body fat. But there was no such association in the subgroup of carriers who engaged in at least 60 minutes per day of moderate to vigorous physical activity, Dr. Ruiz and his colleagues said (Arch. Pediatr. Adolesc. Med. 2010;164:328–33).

The findings “have important public health implications and indicate that meeting the physical activity recommendations [of the Department of Health and Human Services] may offset the genetic predisposition to obesity associated with the FTO polymorphism in adolescents,” the researchers said.

The study was funded by several European government organizations. No financial conflicts were reported.

Physical activity appears to cancel out the effects of the “obesity gene” in adolescents, as it has been shown to do in adults.

“To our knowledge, our study is the first to report an interaction between the FTO [fat mass– and obesity-associated] rs9939609 polymorphism and physical activity level on adiposity indices using objectively assessed physical activity in adolescents,” said Jonatan R. Ruiz, Ph.D., of the Karolinska Institute, Huddinge, Sweden, and his associates.

The investigators genotyped and assessed body mass index, waist circumference, and body fat percentage in 752 adolescents in the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. They also assessed subjects' physical activity level using an accelerometer attached to the lower back.

As expected, the FTO gene variant known as rs9939609 was significantly associated with higher BMI, greater waist circumference, and higher percentage of body fat. But there was no such association in the subgroup of carriers who engaged in at least 60 minutes per day of moderate to vigorous physical activity, Dr. Ruiz and his colleagues said (Arch. Pediatr. Adolesc. Med. 2010;164:328–33).

The findings “have important public health implications and indicate that meeting the physical activity recommendations [of the Department of Health and Human Services] may offset the genetic predisposition to obesity associated with the FTO polymorphism in adolescents,” the researchers said.

The study was funded by several European government organizations. No financial conflicts were reported.

The incidences of diabetic retinopathy and macular edema are higher in Latinos than in other racial and ethnic groups, according to a population-based study of more than 4,000 individuals.

This finding from the Los Angeles Latino Eye Study (LALES), the largest study to assess the incidence and progression of these disorders in an American Latino population, emphasizes “the importance of timely dilated ophthalmologic examinations for Latinos who have diabetes and are at risk for vision-threatening retinopathy,” said Dr. Rohit Varma of the Doheny Eye Center, Los Angeles, and his associates.

LALES assessed eye disease among 4,658 self-identified Latinos aged 40 years or older living in L.os A. County. Baseline clinical examinations were performed between 2000 and 2003, and 4-year follow-up examinations were performed between 2004 and 2008.

Dr. Rohit and his colleagues examined data for a subset of 775 diabetic subjects participating in LALES.

The overall incidence of diabetic retinopathy in either eye was 34%; the annualized incidence was 7%. In comparison, the annualized incidence was 4% for the largely white population in the Blue Mountains Eye Study; and in two other studies—the Liverpool Diabetic Eye Study and the Australian Diabetes, Obesity, and Lifestyle Study—the overall incidences were 4% and 14%, respectively, and the annualized incidences were less than 1% and less than 3% among whites, respectively.

In LALES, the incidence of retinopathy declined with age. A total of 45% of those in their 40s were affected, vs. 24% of those aged 70 years or older.

The incidence of diabetic retinopathy was nearly twice as high in patients not receiving diabetes treatment (33% vs.17%). Among patients who had any degree of diabetic retinopathy at baseline, the disorder progressed during the study period in 39%. Progression was more likely to occur in younger patients, and was not associated with duration of diabetes.

Fourteen percent of patients who had retinopathy at baseline showed improvement at follow-up. None reported having undergone retinal photocoagulation therapy, “indicating that their improvement was related to some factor other than surgery,” the researchers wrote (Am. J. Ophthalmol. 2010 Feb. 9 [doi:10.1016/j.ajo.2009.11.014]).

At follow-up, “incidence of diabetic retinopathy in the second eye (among those with DR in one eye at baseline) was nearly twice as high as compared to [the] incidence in the first eye (among those with no DR at baseline).

“This finding is significant from a health-related quality-of-life perspective because individuals with disease in only one eye tend to rely heavily on their contralateral eye for daily tasks. When the healthy eye also develops disease, the ability of people to complete vision-related tasks and normal activities becomes severely impaired,” Dr. Varma and his associates wrote.

The overall incidence of macular edema in either eye was 5.4%. The rate of macular edema increased significantly with duration of diabetes: less than 3% among those diagnosed within 1 year vs. 11% in those diagnosed at least 15 years earlier.

The National Institutes of Health and Research to Prevent Blindness Inc. supported the study. The authors reported no conflicts of interest.

The incidences of diabetic retinopathy and macular edema are higher in Latinos than in other racial and ethnic groups, according to a population-based study of more than 4,000 individuals.

This finding from the Los Angeles Latino Eye Study (LALES), the largest study to assess the incidence and progression of these disorders in an American Latino population, emphasizes “the importance of timely dilated ophthalmologic examinations for Latinos who have diabetes and are at risk for vision-threatening retinopathy,” said Dr. Rohit Varma of the Doheny Eye Center, Los Angeles, and his associates.

LALES assessed eye disease among 4,658 self-identified Latinos aged 40 years or older living in L.os A. County. Baseline clinical examinations were performed between 2000 and 2003, and 4-year follow-up examinations were performed between 2004 and 2008.

Dr. Rohit and his colleagues examined data for a subset of 775 diabetic subjects participating in LALES.

The overall incidence of diabetic retinopathy in either eye was 34%; the annualized incidence was 7%. In comparison, the annualized incidence was 4% for the largely white population in the Blue Mountains Eye Study; and in two other studies—the Liverpool Diabetic Eye Study and the Australian Diabetes, Obesity, and Lifestyle Study—the overall incidences were 4% and 14%, respectively, and the annualized incidences were less than 1% and less than 3% among whites, respectively.

In LALES, the incidence of retinopathy declined with age. A total of 45% of those in their 40s were affected, vs. 24% of those aged 70 years or older.

The incidence of diabetic retinopathy was nearly twice as high in patients not receiving diabetes treatment (33% vs.17%). Among patients who had any degree of diabetic retinopathy at baseline, the disorder progressed during the study period in 39%. Progression was more likely to occur in younger patients, and was not associated with duration of diabetes.

Fourteen percent of patients who had retinopathy at baseline showed improvement at follow-up. None reported having undergone retinal photocoagulation therapy, “indicating that their improvement was related to some factor other than surgery,” the researchers wrote (Am. J. Ophthalmol. 2010 Feb. 9 [doi:10.1016/j.ajo.2009.11.014]).

At follow-up, “incidence of diabetic retinopathy in the second eye (among those with DR in one eye at baseline) was nearly twice as high as compared to [the] incidence in the first eye (among those with no DR at baseline).

“This finding is significant from a health-related quality-of-life perspective because individuals with disease in only one eye tend to rely heavily on their contralateral eye for daily tasks. When the healthy eye also develops disease, the ability of people to complete vision-related tasks and normal activities becomes severely impaired,” Dr. Varma and his associates wrote.

The overall incidence of macular edema in either eye was 5.4%. The rate of macular edema increased significantly with duration of diabetes: less than 3% among those diagnosed within 1 year vs. 11% in those diagnosed at least 15 years earlier.

The National Institutes of Health and Research to Prevent Blindness Inc. supported the study. The authors reported no conflicts of interest.

The incidences of diabetic retinopathy and macular edema are higher in Latinos than in other racial and ethnic groups, according to a population-based study of more than 4,000 individuals.

This finding from the Los Angeles Latino Eye Study (LALES), the largest study to assess the incidence and progression of these disorders in an American Latino population, emphasizes “the importance of timely dilated ophthalmologic examinations for Latinos who have diabetes and are at risk for vision-threatening retinopathy,” said Dr. Rohit Varma of the Doheny Eye Center, Los Angeles, and his associates.

LALES assessed eye disease among 4,658 self-identified Latinos aged 40 years or older living in L.os A. County. Baseline clinical examinations were performed between 2000 and 2003, and 4-year follow-up examinations were performed between 2004 and 2008.

Dr. Rohit and his colleagues examined data for a subset of 775 diabetic subjects participating in LALES.

The overall incidence of diabetic retinopathy in either eye was 34%; the annualized incidence was 7%. In comparison, the annualized incidence was 4% for the largely white population in the Blue Mountains Eye Study; and in two other studies—the Liverpool Diabetic Eye Study and the Australian Diabetes, Obesity, and Lifestyle Study—the overall incidences were 4% and 14%, respectively, and the annualized incidences were less than 1% and less than 3% among whites, respectively.

In LALES, the incidence of retinopathy declined with age. A total of 45% of those in their 40s were affected, vs. 24% of those aged 70 years or older.

The incidence of diabetic retinopathy was nearly twice as high in patients not receiving diabetes treatment (33% vs.17%). Among patients who had any degree of diabetic retinopathy at baseline, the disorder progressed during the study period in 39%. Progression was more likely to occur in younger patients, and was not associated with duration of diabetes.

Fourteen percent of patients who had retinopathy at baseline showed improvement at follow-up. None reported having undergone retinal photocoagulation therapy, “indicating that their improvement was related to some factor other than surgery,” the researchers wrote (Am. J. Ophthalmol. 2010 Feb. 9 [doi:10.1016/j.ajo.2009.11.014]).

At follow-up, “incidence of diabetic retinopathy in the second eye (among those with DR in one eye at baseline) was nearly twice as high as compared to [the] incidence in the first eye (among those with no DR at baseline).

“This finding is significant from a health-related quality-of-life perspective because individuals with disease in only one eye tend to rely heavily on their contralateral eye for daily tasks. When the healthy eye also develops disease, the ability of people to complete vision-related tasks and normal activities becomes severely impaired,” Dr. Varma and his associates wrote.

The overall incidence of macular edema in either eye was 5.4%. The rate of macular edema increased significantly with duration of diabetes: less than 3% among those diagnosed within 1 year vs. 11% in those diagnosed at least 15 years earlier.

The National Institutes of Health and Research to Prevent Blindness Inc. supported the study. The authors reported no conflicts of interest.

Major Finding: Patients who received active treatment showed a mean increase of 25.1 m on the walk test, whereas those who received placebo showed a decrease of 3.0 m, for a differential effect of 28.1 m. Those who received active treatment showed a increase of 1.2 percentage points in predicted FVC, while those who received placebo showed a decrease of 2.2 percentage points, for a differential effect of 3.4 percentage points.

Data Source: A randomized, controlled trial involving 90 patients with late-onset Pompe's disease.

Disclosures: Dr. van der Ploeg and most associates in this study reported receiving support from Genzyme. Some associates reported receiving support from numerous makers of drugs, devices, and technologies. The study was designed and funded by Genzyme Corp., maker of alglucosidase alfa.

Enzyme-replacement therapy with recombinant human alglucosidase alfa “has a positive, if modest, effect on walking distance and pulmonary function” in patients who have late-onset Pompe's disease, according to Dr. Ans T. van der Ploeg of Erasmus University, Rotterdam, the Netherlands, and associates.

Pompe's disease is a rare, autosomal recessive, progressive neuromuscular disorder caused by a deficiency of acid alpha-glucosidase, which leads to deposition of glycogen primarily in skeletal and respiratory muscles.

The late-onset form of the disease is characterized by limb-girdle myopathy and respiratory insufficiency that often eventually proves fatal.

Enzyme-replacement therapy using recombinant human alglucosidase alfa was approved for use in classic infantile-onset Pompe's disease in 2006.

Preliminary studies of the agent's use in children and adults who have the late-onset form of the disease showed “some positive effects,” but those studies were small and uncontrolled, the investigators wrote.

To address those shortcomings, the investigators conducted a randomized, controlled trial involving 90 patients with late-onset Pompe's disease, which is a large population for a clinical trial of an orphan disease but “relatively small when the goal is to judge the progression of a clinically heterogeneous” disorder.

The study subjects were between 10 and 70 years of age at enrollment, and all had developed symptoms while between 2 and 59 years of age (mean age of onset, mid-20s). All had “substantially diminished” health status, but all were able to walk at least 40 m on the 6-minute walk test, with assistive devices permitted, and they had a percentage of predicted forced vital capacity (FVC) of 30%–80% while upright.

Of the 90 study participants, 60 were randomly assigned to receive biweekly infusions of alglucosidase alfa (20 mg/kg of body weight) and 30 to receive placebo infusions.

The dual primary end point was increase in distance walked on the walk test and percentage of predicted FVC after 78 weeks of therapy.

Patients who received active treatment showed a mean increase of 25.1 m on the walk test, while those who received placebo showed a decrease of 3.0 m, for a differential effect of 28.1 m.

Similarly, patients who received active treatment showed a increase of 1.2 percentage points in predicted FVC, while those who received placebo showed a decrease of 2.2 percentage points, for a differential effect of 3.4 percentage points, Dr. van der Ploeg and colleagues said (N. Engl. J. Med. 2010;362:1396–406).

These results were consistent and robust across several methods of data analysis and in all subgroups studied. The findings “indicate that alglucosidase alfa has a positive effect on the complex process that leads to impaired ambulation and respiratory failure in late-onset Pompe's disease,” according to the investigators.

“Patients in the two groups had similar frequencies of adverse events, serious adverse events, treatment-related adverse events, and infusion-associated reactions. Most adverse events were mild or moderate in severity and were not considered to be related to the study drug,” the investigators said.

Major Finding: Patients who received active treatment showed a mean increase of 25.1 m on the walk test, whereas those who received placebo showed a decrease of 3.0 m, for a differential effect of 28.1 m. Those who received active treatment showed a increase of 1.2 percentage points in predicted FVC, while those who received placebo showed a decrease of 2.2 percentage points, for a differential effect of 3.4 percentage points.

Data Source: A randomized, controlled trial involving 90 patients with late-onset Pompe's disease.

Disclosures: Dr. van der Ploeg and most associates in this study reported receiving support from Genzyme. Some associates reported receiving support from numerous makers of drugs, devices, and technologies. The study was designed and funded by Genzyme Corp., maker of alglucosidase alfa.

Enzyme-replacement therapy with recombinant human alglucosidase alfa “has a positive, if modest, effect on walking distance and pulmonary function” in patients who have late-onset Pompe's disease, according to Dr. Ans T. van der Ploeg of Erasmus University, Rotterdam, the Netherlands, and associates.

Pompe's disease is a rare, autosomal recessive, progressive neuromuscular disorder caused by a deficiency of acid alpha-glucosidase, which leads to deposition of glycogen primarily in skeletal and respiratory muscles.

The late-onset form of the disease is characterized by limb-girdle myopathy and respiratory insufficiency that often eventually proves fatal.

Enzyme-replacement therapy using recombinant human alglucosidase alfa was approved for use in classic infantile-onset Pompe's disease in 2006.

Preliminary studies of the agent's use in children and adults who have the late-onset form of the disease showed “some positive effects,” but those studies were small and uncontrolled, the investigators wrote.

To address those shortcomings, the investigators conducted a randomized, controlled trial involving 90 patients with late-onset Pompe's disease, which is a large population for a clinical trial of an orphan disease but “relatively small when the goal is to judge the progression of a clinically heterogeneous” disorder.

The study subjects were between 10 and 70 years of age at enrollment, and all had developed symptoms while between 2 and 59 years of age (mean age of onset, mid-20s). All had “substantially diminished” health status, but all were able to walk at least 40 m on the 6-minute walk test, with assistive devices permitted, and they had a percentage of predicted forced vital capacity (FVC) of 30%–80% while upright.

Of the 90 study participants, 60 were randomly assigned to receive biweekly infusions of alglucosidase alfa (20 mg/kg of body weight) and 30 to receive placebo infusions.

The dual primary end point was increase in distance walked on the walk test and percentage of predicted FVC after 78 weeks of therapy.

Patients who received active treatment showed a mean increase of 25.1 m on the walk test, while those who received placebo showed a decrease of 3.0 m, for a differential effect of 28.1 m.

Similarly, patients who received active treatment showed a increase of 1.2 percentage points in predicted FVC, while those who received placebo showed a decrease of 2.2 percentage points, for a differential effect of 3.4 percentage points, Dr. van der Ploeg and colleagues said (N. Engl. J. Med. 2010;362:1396–406).

These results were consistent and robust across several methods of data analysis and in all subgroups studied. The findings “indicate that alglucosidase alfa has a positive effect on the complex process that leads to impaired ambulation and respiratory failure in late-onset Pompe's disease,” according to the investigators.

“Patients in the two groups had similar frequencies of adverse events, serious adverse events, treatment-related adverse events, and infusion-associated reactions. Most adverse events were mild or moderate in severity and were not considered to be related to the study drug,” the investigators said.

Major Finding: Patients who received active treatment showed a mean increase of 25.1 m on the walk test, whereas those who received placebo showed a decrease of 3.0 m, for a differential effect of 28.1 m. Those who received active treatment showed a increase of 1.2 percentage points in predicted FVC, while those who received placebo showed a decrease of 2.2 percentage points, for a differential effect of 3.4 percentage points.

Data Source: A randomized, controlled trial involving 90 patients with late-onset Pompe's disease.

Disclosures: Dr. van der Ploeg and most associates in this study reported receiving support from Genzyme. Some associates reported receiving support from numerous makers of drugs, devices, and technologies. The study was designed and funded by Genzyme Corp., maker of alglucosidase alfa.

Enzyme-replacement therapy with recombinant human alglucosidase alfa “has a positive, if modest, effect on walking distance and pulmonary function” in patients who have late-onset Pompe's disease, according to Dr. Ans T. van der Ploeg of Erasmus University, Rotterdam, the Netherlands, and associates.

Pompe's disease is a rare, autosomal recessive, progressive neuromuscular disorder caused by a deficiency of acid alpha-glucosidase, which leads to deposition of glycogen primarily in skeletal and respiratory muscles.

The late-onset form of the disease is characterized by limb-girdle myopathy and respiratory insufficiency that often eventually proves fatal.

Enzyme-replacement therapy using recombinant human alglucosidase alfa was approved for use in classic infantile-onset Pompe's disease in 2006.

Preliminary studies of the agent's use in children and adults who have the late-onset form of the disease showed “some positive effects,” but those studies were small and uncontrolled, the investigators wrote.

To address those shortcomings, the investigators conducted a randomized, controlled trial involving 90 patients with late-onset Pompe's disease, which is a large population for a clinical trial of an orphan disease but “relatively small when the goal is to judge the progression of a clinically heterogeneous” disorder.

The study subjects were between 10 and 70 years of age at enrollment, and all had developed symptoms while between 2 and 59 years of age (mean age of onset, mid-20s). All had “substantially diminished” health status, but all were able to walk at least 40 m on the 6-minute walk test, with assistive devices permitted, and they had a percentage of predicted forced vital capacity (FVC) of 30%–80% while upright.

Of the 90 study participants, 60 were randomly assigned to receive biweekly infusions of alglucosidase alfa (20 mg/kg of body weight) and 30 to receive placebo infusions.

The dual primary end point was increase in distance walked on the walk test and percentage of predicted FVC after 78 weeks of therapy.

Patients who received active treatment showed a mean increase of 25.1 m on the walk test, while those who received placebo showed a decrease of 3.0 m, for a differential effect of 28.1 m.

Similarly, patients who received active treatment showed a increase of 1.2 percentage points in predicted FVC, while those who received placebo showed a decrease of 2.2 percentage points, for a differential effect of 3.4 percentage points, Dr. van der Ploeg and colleagues said (N. Engl. J. Med. 2010;362:1396–406).

These results were consistent and robust across several methods of data analysis and in all subgroups studied. The findings “indicate that alglucosidase alfa has a positive effect on the complex process that leads to impaired ambulation and respiratory failure in late-onset Pompe's disease,” according to the investigators.

“Patients in the two groups had similar frequencies of adverse events, serious adverse events, treatment-related adverse events, and infusion-associated reactions. Most adverse events were mild or moderate in severity and were not considered to be related to the study drug,” the investigators said.

The continuation of methotrexate therapy for 12 months after a child with juvenile idiopathic arthritis has achieved remission did not decrease the relapse rate, compared with treatment for 6 months, according to a report in JAMA.

Longer continuation of methotrexate also failed to extend the duration of remission, said Dr. Dirk Foell of the University of Muenster (Germany) and his associates. “Therefore, it cannot be recommended that methotrexate therapy be continued in all patients for longer than 6 months after remission is induced,” an approach that has been advocated even though no controlled prospective studies have examined the issue until now.

Approximately half of patients with JIA experience disease flares after they discontinue methotrexate.

The researchers assessed 364 patients who were treated at rheumatology centers in 29 countries in a randomized, prospective, open-label trial.

Patients with all subtypes of JIA were included, and all subjects had achieved remission with methotrexate therapy. The children were about 11 years old at enrollment; they had been about 5.5-6 years old at JIA onset.

Group 1 (183 children) was randomly assigned to continue the drug for 6 months, whereas group 2 (181) was assigned to continue methotrexate for 12 months. They were then followed every 3 months for at least 1 year (median follow-up, 34 months).

Approximately equal numbers of children in groups 1 and 2 had persistent oligoarthritis (30% and 23%, respectively), extended oligoarthritis (19% and 12%), polyarthritis that was negative for rheumatoid factor (30% and 45%), polyarthritis that was positive for rheumatoid factor (5% and 4%), systemic onset JIA (8% and 12%), enthesitis-related arthritis (4% and 2%), and psoriatic arthritis (6% and 2%).

The relapse rate at 1 year was about 57% in the children who discontinued methotrexate at 6 months, which was not significantly different from the rate of 56% in the group that prolonged methotrexate for 12 months. The median relapse-free intervals were 21 months and 23 months, respectively—a difference that also was not significant, the investigators said (JAMA 2010;303:1266–73). These findings were consistent across all subtypes of JIA, they added.

“Our data are of general relevance because many chronic inflammatory diseases regularly take a relapsing course,” including rheumatoid arthritis, inflammatory bowel disease, and pediatric autoimmune hepatitis, Dr. Foell and his associates noted.

“In clinical practice, physicians are frequently faced with the question of what to do with patients who are clinically well after induction of remission. Physicians have to decide whether continuation of drug therapy is meaningful, because it may maintain inactive disease and induce a more stable remission” but also is likely to induce more adverse effects, they said.

The investigators found that serum concentrations of myeloid-related proteins 8 and 14 helped identify which patients in remission had subclinical disease activity and were at risk for relapse. Study subjects with levels less than 690 ng/mL were unlikely to have a disease flare during follow-up, whereas those with higher levels were at increased risk.

This finding suggests that relapses after methotrexate is withdrawn result from a local disease process that has not been completely resolved by the therapy, even though the clinical impression and standard laboratory testing both indicate that there is remission, Dr. Foell and his colleagues added.

Disclosures: This study was supported by the Paediatric Rheumatology International Trials Organization, a nonprofit group, and the Deutsche Rheuma-Liga. Wyeth Pharmaceuticals funded the patients' insurance in Germany. No other potential financial conflicts of interest were reported.

My Take

When Can We Stop Methotrexate?

The most common question posed by the parents of a child with JIA who has “gone into remission” has always been, “When can we stop giving these drugs?” Any parent who has read the list of warnings and side effects included on the methotrexate package insert is understandably anxious to discontinue therapy. Findings from the research by Dr. Foell and his associates begin to answer this question. When all the patients who were diagnosed as having JIA were randomly mixed, researchers found no difference in the rate of recurrence when therapy was continued for either 6 or 12 months after remission. The significance of this interesting finding is unclear. Although the treatment groups were balanced for JIA subtypes, the researchers do not discuss which subtypes the children who flared belonged to. The investigators clearly state in the methods section that “biased results due to differences between JIA subtypes were excluded by Cox models.” However, because the subtypes were evenly balanced between the two groups, this provides no information about which subgroups were most at risk.

Experienced pediatric rheumatologists have long been aware that the risk of recurrence is much higher for psoriatic arthritis and polyarthritis with a positive rheumatoid factor than for other subgroups. Unfortunately, the results for these subgroups are not separately reported. With the dramatic responses we now see with the newer biologic therapies, the questions of how and when to stop therapy become even more important.

Perhaps the most important lesson in Dr. Foell's study is that more than half of the children ultimately flared. Given that our goal is to prevent joint damage and long-term disability, does the high incidence of recurrence tell us that we should be stopping methotrexate sooner, or perhaps not stopping methotrexate at all? We need careful analysis of each of the many different diseases which masquerade as JIA—with long-term follow-up, including radiographic studies of joint damage—before we can conclude whether we are treating for too long or not long enough. Indeed, for each of the diseases lumped together as JIA, the answer may be different.

THOMAS J.A. LEHMAN, M.D., is chief of pediatric rheumatology at the Hospital for Special Surgery in New York. He reported having no financial conflicts of interest relevant to this research.

The continuation of methotrexate therapy for 12 months after a child with juvenile idiopathic arthritis has achieved remission did not decrease the relapse rate, compared with treatment for 6 months, according to a report in JAMA.

Longer continuation of methotrexate also failed to extend the duration of remission, said Dr. Dirk Foell of the University of Muenster (Germany) and his associates. “Therefore, it cannot be recommended that methotrexate therapy be continued in all patients for longer than 6 months after remission is induced,” an approach that has been advocated even though no controlled prospective studies have examined the issue until now.

Approximately half of patients with JIA experience disease flares after they discontinue methotrexate.

The researchers assessed 364 patients who were treated at rheumatology centers in 29 countries in a randomized, prospective, open-label trial.

Patients with all subtypes of JIA were included, and all subjects had achieved remission with methotrexate therapy. The children were about 11 years old at enrollment; they had been about 5.5-6 years old at JIA onset.

Group 1 (183 children) was randomly assigned to continue the drug for 6 months, whereas group 2 (181) was assigned to continue methotrexate for 12 months. They were then followed every 3 months for at least 1 year (median follow-up, 34 months).

Approximately equal numbers of children in groups 1 and 2 had persistent oligoarthritis (30% and 23%, respectively), extended oligoarthritis (19% and 12%), polyarthritis that was negative for rheumatoid factor (30% and 45%), polyarthritis that was positive for rheumatoid factor (5% and 4%), systemic onset JIA (8% and 12%), enthesitis-related arthritis (4% and 2%), and psoriatic arthritis (6% and 2%).

The relapse rate at 1 year was about 57% in the children who discontinued methotrexate at 6 months, which was not significantly different from the rate of 56% in the group that prolonged methotrexate for 12 months. The median relapse-free intervals were 21 months and 23 months, respectively—a difference that also was not significant, the investigators said (JAMA 2010;303:1266–73). These findings were consistent across all subtypes of JIA, they added.

“Our data are of general relevance because many chronic inflammatory diseases regularly take a relapsing course,” including rheumatoid arthritis, inflammatory bowel disease, and pediatric autoimmune hepatitis, Dr. Foell and his associates noted.

“In clinical practice, physicians are frequently faced with the question of what to do with patients who are clinically well after induction of remission. Physicians have to decide whether continuation of drug therapy is meaningful, because it may maintain inactive disease and induce a more stable remission” but also is likely to induce more adverse effects, they said.

The investigators found that serum concentrations of myeloid-related proteins 8 and 14 helped identify which patients in remission had subclinical disease activity and were at risk for relapse. Study subjects with levels less than 690 ng/mL were unlikely to have a disease flare during follow-up, whereas those with higher levels were at increased risk.

This finding suggests that relapses after methotrexate is withdrawn result from a local disease process that has not been completely resolved by the therapy, even though the clinical impression and standard laboratory testing both indicate that there is remission, Dr. Foell and his colleagues added.

Disclosures: This study was supported by the Paediatric Rheumatology International Trials Organization, a nonprofit group, and the Deutsche Rheuma-Liga. Wyeth Pharmaceuticals funded the patients' insurance in Germany. No other potential financial conflicts of interest were reported.

My Take

When Can We Stop Methotrexate?

The most common question posed by the parents of a child with JIA who has “gone into remission” has always been, “When can we stop giving these drugs?” Any parent who has read the list of warnings and side effects included on the methotrexate package insert is understandably anxious to discontinue therapy. Findings from the research by Dr. Foell and his associates begin to answer this question. When all the patients who were diagnosed as having JIA were randomly mixed, researchers found no difference in the rate of recurrence when therapy was continued for either 6 or 12 months after remission. The significance of this interesting finding is unclear. Although the treatment groups were balanced for JIA subtypes, the researchers do not discuss which subtypes the children who flared belonged to. The investigators clearly state in the methods section that “biased results due to differences between JIA subtypes were excluded by Cox models.” However, because the subtypes were evenly balanced between the two groups, this provides no information about which subgroups were most at risk.

Experienced pediatric rheumatologists have long been aware that the risk of recurrence is much higher for psoriatic arthritis and polyarthritis with a positive rheumatoid factor than for other subgroups. Unfortunately, the results for these subgroups are not separately reported. With the dramatic responses we now see with the newer biologic therapies, the questions of how and when to stop therapy become even more important.

Perhaps the most important lesson in Dr. Foell's study is that more than half of the children ultimately flared. Given that our goal is to prevent joint damage and long-term disability, does the high incidence of recurrence tell us that we should be stopping methotrexate sooner, or perhaps not stopping methotrexate at all? We need careful analysis of each of the many different diseases which masquerade as JIA—with long-term follow-up, including radiographic studies of joint damage—before we can conclude whether we are treating for too long or not long enough. Indeed, for each of the diseases lumped together as JIA, the answer may be different.

THOMAS J.A. LEHMAN, M.D., is chief of pediatric rheumatology at the Hospital for Special Surgery in New York. He reported having no financial conflicts of interest relevant to this research.

The continuation of methotrexate therapy for 12 months after a child with juvenile idiopathic arthritis has achieved remission did not decrease the relapse rate, compared with treatment for 6 months, according to a report in JAMA.

Longer continuation of methotrexate also failed to extend the duration of remission, said Dr. Dirk Foell of the University of Muenster (Germany) and his associates. “Therefore, it cannot be recommended that methotrexate therapy be continued in all patients for longer than 6 months after remission is induced,” an approach that has been advocated even though no controlled prospective studies have examined the issue until now.

Approximately half of patients with JIA experience disease flares after they discontinue methotrexate.

The researchers assessed 364 patients who were treated at rheumatology centers in 29 countries in a randomized, prospective, open-label trial.

Patients with all subtypes of JIA were included, and all subjects had achieved remission with methotrexate therapy. The children were about 11 years old at enrollment; they had been about 5.5-6 years old at JIA onset.

Group 1 (183 children) was randomly assigned to continue the drug for 6 months, whereas group 2 (181) was assigned to continue methotrexate for 12 months. They were then followed every 3 months for at least 1 year (median follow-up, 34 months).

Approximately equal numbers of children in groups 1 and 2 had persistent oligoarthritis (30% and 23%, respectively), extended oligoarthritis (19% and 12%), polyarthritis that was negative for rheumatoid factor (30% and 45%), polyarthritis that was positive for rheumatoid factor (5% and 4%), systemic onset JIA (8% and 12%), enthesitis-related arthritis (4% and 2%), and psoriatic arthritis (6% and 2%).

The relapse rate at 1 year was about 57% in the children who discontinued methotrexate at 6 months, which was not significantly different from the rate of 56% in the group that prolonged methotrexate for 12 months. The median relapse-free intervals were 21 months and 23 months, respectively—a difference that also was not significant, the investigators said (JAMA 2010;303:1266–73). These findings were consistent across all subtypes of JIA, they added.

“Our data are of general relevance because many chronic inflammatory diseases regularly take a relapsing course,” including rheumatoid arthritis, inflammatory bowel disease, and pediatric autoimmune hepatitis, Dr. Foell and his associates noted.

“In clinical practice, physicians are frequently faced with the question of what to do with patients who are clinically well after induction of remission. Physicians have to decide whether continuation of drug therapy is meaningful, because it may maintain inactive disease and induce a more stable remission” but also is likely to induce more adverse effects, they said.

The investigators found that serum concentrations of myeloid-related proteins 8 and 14 helped identify which patients in remission had subclinical disease activity and were at risk for relapse. Study subjects with levels less than 690 ng/mL were unlikely to have a disease flare during follow-up, whereas those with higher levels were at increased risk.

This finding suggests that relapses after methotrexate is withdrawn result from a local disease process that has not been completely resolved by the therapy, even though the clinical impression and standard laboratory testing both indicate that there is remission, Dr. Foell and his colleagues added.

Disclosures: This study was supported by the Paediatric Rheumatology International Trials Organization, a nonprofit group, and the Deutsche Rheuma-Liga. Wyeth Pharmaceuticals funded the patients' insurance in Germany. No other potential financial conflicts of interest were reported.

My Take

When Can We Stop Methotrexate?

The most common question posed by the parents of a child with JIA who has “gone into remission” has always been, “When can we stop giving these drugs?” Any parent who has read the list of warnings and side effects included on the methotrexate package insert is understandably anxious to discontinue therapy. Findings from the research by Dr. Foell and his associates begin to answer this question. When all the patients who were diagnosed as having JIA were randomly mixed, researchers found no difference in the rate of recurrence when therapy was continued for either 6 or 12 months after remission. The significance of this interesting finding is unclear. Although the treatment groups were balanced for JIA subtypes, the researchers do not discuss which subtypes the children who flared belonged to. The investigators clearly state in the methods section that “biased results due to differences between JIA subtypes were excluded by Cox models.” However, because the subtypes were evenly balanced between the two groups, this provides no information about which subgroups were most at risk.

Experienced pediatric rheumatologists have long been aware that the risk of recurrence is much higher for psoriatic arthritis and polyarthritis with a positive rheumatoid factor than for other subgroups. Unfortunately, the results for these subgroups are not separately reported. With the dramatic responses we now see with the newer biologic therapies, the questions of how and when to stop therapy become even more important.

Perhaps the most important lesson in Dr. Foell's study is that more than half of the children ultimately flared. Given that our goal is to prevent joint damage and long-term disability, does the high incidence of recurrence tell us that we should be stopping methotrexate sooner, or perhaps not stopping methotrexate at all? We need careful analysis of each of the many different diseases which masquerade as JIA—with long-term follow-up, including radiographic studies of joint damage—before we can conclude whether we are treating for too long or not long enough. Indeed, for each of the diseases lumped together as JIA, the answer may be different.

THOMAS J.A. LEHMAN, M.D., is chief of pediatric rheumatology at the Hospital for Special Surgery in New York. He reported having no financial conflicts of interest relevant to this research.

Nearly one-fifth of patients with acute heart failure who receive implantable cardioverter defibrillators and cardiac resynchronization devices are at least 80 years old, even though most clinical trials of the devices' safety and effectiveness excluded this age group, according to a report in the Archives of Internal Medicine.

Procedure-related complications are more frequent in elderly than in younger patients, and in-hospital mortality is higher. These findings indicate that additional studies are needed “to clarify the appropriateness of device implantation in older patients with heart failure, as well as the merits of less invasive options,” said Jason P. Swindle of the Center for Outcomes Research at Saint Louis University, and his associates.

The investigators studied age-specific practices in the placement of ICDs and cardiac resynchronization therapy (CRT) because “few data exist on outcomes in older patients, as pivotal device trials have generally enrolled a young cohort of patients relative to those observed in the clinical setting.”

Using a national database comprising several hundred hospitals and health care systems, they assessed the records of 26,887 adults admitted to acute care hospitals for heart failure in 2004–2006 who received an implantable cardiac device. The median patient age was 70 years, markedly older than the median ages of 58–67 years in major clinical trials.

About half of the patients received ICDs, 44% of patients received CRT with defibrillators, and the remainder received CRT without defibrillators.

A total of 17.5% (4,694) of these patients were aged 80 or older; of those, 6.6% (309) were 89 years and older.

In-hospital mortality was significantly higher in patients older than 85 (2.2%) and in those aged 80–85 (1.2%), compared with younger patients (0.7%), Mr. Swindle and his colleagues wrote (Arch. Intern. Med. 2010;170:631-7).

Advanced age also was associated with increased length of stay and higher total costs of hospitalization.

This study was not designed to assess longer-term outcomes such as 30-day or 1-year mortality, nor could it address other outcomes such as readmission rates or quality of life issues, they noted.

In an accompanying editorial, Dr. Fred Kusumoto of the Mayo Clinic, Jacksonville, Fla., said that these findings confirm that patients who receive cardiac devices in actual practice vary significantly from the study subjects in whom the devices were initially tested. “It is imperative that future trial design considers the broad diversity of the U.S. population,” he noted.

More importantly, “we must recognize the shortcomings of our current knowledge and how that affects individual decision making,” Dr. Kusumoto said (Arch. Intern. Med. 2010;170:638-9).

“For ICD implantation, each patient will have different questions and varying clinical benefit. It is important for each of us to understand the medical issues, take our own personal biases into account, and honor our patient's wishes,” he said.

The study was funded in part by the National Institutes of Health. Neither Mr. Swindle nor Dr. Kusumoto reported any financial conflicts of interest.

The average age of ICD and CRT patients is higher than that in clinical trials.

Source ©claudiobaba/iStockPhoto.com

Nearly one-fifth of patients with acute heart failure who receive implantable cardioverter defibrillators and cardiac resynchronization devices are at least 80 years old, even though most clinical trials of the devices' safety and effectiveness excluded this age group, according to a report in the Archives of Internal Medicine.

Procedure-related complications are more frequent in elderly than in younger patients, and in-hospital mortality is higher. These findings indicate that additional studies are needed “to clarify the appropriateness of device implantation in older patients with heart failure, as well as the merits of less invasive options,” said Jason P. Swindle of the Center for Outcomes Research at Saint Louis University, and his associates.

The investigators studied age-specific practices in the placement of ICDs and cardiac resynchronization therapy (CRT) because “few data exist on outcomes in older patients, as pivotal device trials have generally enrolled a young cohort of patients relative to those observed in the clinical setting.”

Using a national database comprising several hundred hospitals and health care systems, they assessed the records of 26,887 adults admitted to acute care hospitals for heart failure in 2004–2006 who received an implantable cardiac device. The median patient age was 70 years, markedly older than the median ages of 58–67 years in major clinical trials.

About half of the patients received ICDs, 44% of patients received CRT with defibrillators, and the remainder received CRT without defibrillators.

A total of 17.5% (4,694) of these patients were aged 80 or older; of those, 6.6% (309) were 89 years and older.

In-hospital mortality was significantly higher in patients older than 85 (2.2%) and in those aged 80–85 (1.2%), compared with younger patients (0.7%), Mr. Swindle and his colleagues wrote (Arch. Intern. Med. 2010;170:631-7).

Advanced age also was associated with increased length of stay and higher total costs of hospitalization.

This study was not designed to assess longer-term outcomes such as 30-day or 1-year mortality, nor could it address other outcomes such as readmission rates or quality of life issues, they noted.

In an accompanying editorial, Dr. Fred Kusumoto of the Mayo Clinic, Jacksonville, Fla., said that these findings confirm that patients who receive cardiac devices in actual practice vary significantly from the study subjects in whom the devices were initially tested. “It is imperative that future trial design considers the broad diversity of the U.S. population,” he noted.

More importantly, “we must recognize the shortcomings of our current knowledge and how that affects individual decision making,” Dr. Kusumoto said (Arch. Intern. Med. 2010;170:638-9).

“For ICD implantation, each patient will have different questions and varying clinical benefit. It is important for each of us to understand the medical issues, take our own personal biases into account, and honor our patient's wishes,” he said.

The study was funded in part by the National Institutes of Health. Neither Mr. Swindle nor Dr. Kusumoto reported any financial conflicts of interest.

The average age of ICD and CRT patients is higher than that in clinical trials.

Source ©claudiobaba/iStockPhoto.com

Nearly one-fifth of patients with acute heart failure who receive implantable cardioverter defibrillators and cardiac resynchronization devices are at least 80 years old, even though most clinical trials of the devices' safety and effectiveness excluded this age group, according to a report in the Archives of Internal Medicine.

Procedure-related complications are more frequent in elderly than in younger patients, and in-hospital mortality is higher. These findings indicate that additional studies are needed “to clarify the appropriateness of device implantation in older patients with heart failure, as well as the merits of less invasive options,” said Jason P. Swindle of the Center for Outcomes Research at Saint Louis University, and his associates.

The investigators studied age-specific practices in the placement of ICDs and cardiac resynchronization therapy (CRT) because “few data exist on outcomes in older patients, as pivotal device trials have generally enrolled a young cohort of patients relative to those observed in the clinical setting.”

Using a national database comprising several hundred hospitals and health care systems, they assessed the records of 26,887 adults admitted to acute care hospitals for heart failure in 2004–2006 who received an implantable cardiac device. The median patient age was 70 years, markedly older than the median ages of 58–67 years in major clinical trials.

About half of the patients received ICDs, 44% of patients received CRT with defibrillators, and the remainder received CRT without defibrillators.

A total of 17.5% (4,694) of these patients were aged 80 or older; of those, 6.6% (309) were 89 years and older.

In-hospital mortality was significantly higher in patients older than 85 (2.2%) and in those aged 80–85 (1.2%), compared with younger patients (0.7%), Mr. Swindle and his colleagues wrote (Arch. Intern. Med. 2010;170:631-7).

Advanced age also was associated with increased length of stay and higher total costs of hospitalization.

This study was not designed to assess longer-term outcomes such as 30-day or 1-year mortality, nor could it address other outcomes such as readmission rates or quality of life issues, they noted.

In an accompanying editorial, Dr. Fred Kusumoto of the Mayo Clinic, Jacksonville, Fla., said that these findings confirm that patients who receive cardiac devices in actual practice vary significantly from the study subjects in whom the devices were initially tested. “It is imperative that future trial design considers the broad diversity of the U.S. population,” he noted.

More importantly, “we must recognize the shortcomings of our current knowledge and how that affects individual decision making,” Dr. Kusumoto said (Arch. Intern. Med. 2010;170:638-9).

“For ICD implantation, each patient will have different questions and varying clinical benefit. It is important for each of us to understand the medical issues, take our own personal biases into account, and honor our patient's wishes,” he said.

The study was funded in part by the National Institutes of Health. Neither Mr. Swindle nor Dr. Kusumoto reported any financial conflicts of interest.

The average age of ICD and CRT patients is higher than that in clinical trials.

Source ©claudiobaba/iStockPhoto.com

Real-time polymerase chain reaction assays of dried blood spots are not sensitive enough to reliably identify cytomegalovirus infection in newborns.

Two such methods missed approximately two-thirds of the CMV infections in a prospective cohort study of 20,448 newborns, said Dr. Suresh B. Boppana of the University of Alabama at Birmingham and associates (JAMA 2010;303:1375–82).

"These results have major public health implications because they indicate that such methods, as currently performed, will not be suitable for the mass screening of newborns for congenital CMV infection—the most common nongenetic cause of deafness in the United States," they noted.

Traditional isolation of CMV from cultured saliva or urine samples is the standard method of identifying the congenital infection, but it is not amenable to mass screening. Experts had been hopeful that PCR technology would prove sensitive and specific at identifying occult CMV infection, since it is much better suited to mass screening "because it does not require tissue culture facilities and is amenable to automation with the screening of large numbers of specimens at low cost," Dr. Boppana and colleagues said.

Dried blood spots already are collected routinely for newborn metabolic screening, and there has been "considerable" enthusiasm for using PCR assays for CMV on such samples. But until now, the sensitivity and specificity of these techniques had not been determined, and their diagnostic accuracy has never been directly compared with that of standard tissue culture methods.

The researchers compared standard saliva culturing with dried blood spot sampling in infants born at seven U.S. medical centers in 2007–2008. Two different PCR techniques, a single-primer and a double-primer assay, were assessed.

A total of 92 infants (0.45%) were found to have congenital CMV infection.

Saliva screening correctly identified 91 of the 92 affected newborns (99%). In contrast, single-primer blood spot PCR identified only 17 of the 60 infants (28%) who were tested by that method and double-primer blood spot PCR detected only 11 of the 32 infants (34%) who were tested by that method.

The sensitivity and specificity of the single-primer blood spot PCR were 28% and 99.9%. The sensitivity and specificity of the double-primer blood spot PCR were 34% and 99.9%.

"Our data indicate that as many as 80% of infants with congenital CMV infections could be missed" with the dried blood spot real-time PCR assays, they said. It is likely that this failure was due to an absence of detectable CMV DNA in the peripheral blood of most newborns who have congenital CMV. These infants may have contracted the infection months before birth, and thus may no longer be viremic when tested.

This study was supported by the National Institute of Deafness and Other Communication Disorders. No financial conflicts of Interest were reported.

Real-time polymerase chain reaction assays of dried blood spots are not sensitive enough to reliably identify cytomegalovirus infection in newborns.

Two such methods missed approximately two-thirds of the CMV infections in a prospective cohort study of 20,448 newborns, said Dr. Suresh B. Boppana of the University of Alabama at Birmingham and associates (JAMA 2010;303:1375–82).

"These results have major public health implications because they indicate that such methods, as currently performed, will not be suitable for the mass screening of newborns for congenital CMV infection—the most common nongenetic cause of deafness in the United States," they noted.

Traditional isolation of CMV from cultured saliva or urine samples is the standard method of identifying the congenital infection, but it is not amenable to mass screening. Experts had been hopeful that PCR technology would prove sensitive and specific at identifying occult CMV infection, since it is much better suited to mass screening "because it does not require tissue culture facilities and is amenable to automation with the screening of large numbers of specimens at low cost," Dr. Boppana and colleagues said.

Dried blood spots already are collected routinely for newborn metabolic screening, and there has been "considerable" enthusiasm for using PCR assays for CMV on such samples. But until now, the sensitivity and specificity of these techniques had not been determined, and their diagnostic accuracy has never been directly compared with that of standard tissue culture methods.

The researchers compared standard saliva culturing with dried blood spot sampling in infants born at seven U.S. medical centers in 2007–2008. Two different PCR techniques, a single-primer and a double-primer assay, were assessed.

A total of 92 infants (0.45%) were found to have congenital CMV infection.

Saliva screening correctly identified 91 of the 92 affected newborns (99%). In contrast, single-primer blood spot PCR identified only 17 of the 60 infants (28%) who were tested by that method and double-primer blood spot PCR detected only 11 of the 32 infants (34%) who were tested by that method.

The sensitivity and specificity of the single-primer blood spot PCR were 28% and 99.9%. The sensitivity and specificity of the double-primer blood spot PCR were 34% and 99.9%.

"Our data indicate that as many as 80% of infants with congenital CMV infections could be missed" with the dried blood spot real-time PCR assays, they said. It is likely that this failure was due to an absence of detectable CMV DNA in the peripheral blood of most newborns who have congenital CMV. These infants may have contracted the infection months before birth, and thus may no longer be viremic when tested.

This study was supported by the National Institute of Deafness and Other Communication Disorders. No financial conflicts of Interest were reported.

Real-time polymerase chain reaction assays of dried blood spots are not sensitive enough to reliably identify cytomegalovirus infection in newborns.

Two such methods missed approximately two-thirds of the CMV infections in a prospective cohort study of 20,448 newborns, said Dr. Suresh B. Boppana of the University of Alabama at Birmingham and associates (JAMA 2010;303:1375–82).

"These results have major public health implications because they indicate that such methods, as currently performed, will not be suitable for the mass screening of newborns for congenital CMV infection—the most common nongenetic cause of deafness in the United States," they noted.

Traditional isolation of CMV from cultured saliva or urine samples is the standard method of identifying the congenital infection, but it is not amenable to mass screening. Experts had been hopeful that PCR technology would prove sensitive and specific at identifying occult CMV infection, since it is much better suited to mass screening "because it does not require tissue culture facilities and is amenable to automation with the screening of large numbers of specimens at low cost," Dr. Boppana and colleagues said.

Dried blood spots already are collected routinely for newborn metabolic screening, and there has been "considerable" enthusiasm for using PCR assays for CMV on such samples. But until now, the sensitivity and specificity of these techniques had not been determined, and their diagnostic accuracy has never been directly compared with that of standard tissue culture methods.

The researchers compared standard saliva culturing with dried blood spot sampling in infants born at seven U.S. medical centers in 2007–2008. Two different PCR techniques, a single-primer and a double-primer assay, were assessed.

A total of 92 infants (0.45%) were found to have congenital CMV infection.

Saliva screening correctly identified 91 of the 92 affected newborns (99%). In contrast, single-primer blood spot PCR identified only 17 of the 60 infants (28%) who were tested by that method and double-primer blood spot PCR detected only 11 of the 32 infants (34%) who were tested by that method.

The sensitivity and specificity of the single-primer blood spot PCR were 28% and 99.9%. The sensitivity and specificity of the double-primer blood spot PCR were 34% and 99.9%.

"Our data indicate that as many as 80% of infants with congenital CMV infections could be missed" with the dried blood spot real-time PCR assays, they said. It is likely that this failure was due to an absence of detectable CMV DNA in the peripheral blood of most newborns who have congenital CMV. These infants may have contracted the infection months before birth, and thus may no longer be viremic when tested.

This study was supported by the National Institute of Deafness and Other Communication Disorders. No financial conflicts of Interest were reported.