Mary Ann Moon

Extended-release niacin was clearly superior to ezetimibe when combined with statin therapy in patients who had or were at high risk for atherosclerosis in a prospective study in 363 patients.

Niacin caused the regression of carotid intima-media thickness, a surrogate marker for atherosclerosis progression, while ezetimibe caused no significant change in the first clinical trial to directly compare the two secondary agents in combination with a statin.

In addition, fewer adverse cardiovascular events developed with niacin than with ezetimibe during 14 months of follow-up. Perhaps most important, “We found an unexpected paradoxical relationship of a greater degree of atherosclerosis progression in patients with larger, ezetimibe-induced reductions in LDL cholesterol level,” wrote Dr. Allen J. Taylor, director of advanced cardiac imaging at Washington Hospital Center in Washington, and his associates in the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study. The findings were presented concurrently at the annual scientific sessions of the American Heart Association.

The prospective, open-label study, sponsored by Abbott, the maker of the extended-release niacin used in the trial, was designed to randomly assign 363 patients to receive either extended-release niacin or ezetimibe (Zetia, manufactured by Merck–Shering-Plough Pharmaceuticals) in addition to statin therapy. The study was halted early when an interim analysis showed a clear advantage with niacin, and the trial included complete data from only 208 patients (N. Engl. J. Med. 2009:doi:10.1056/NEJMoa0907569).

Critics have charged that this “premature” termination was “unfortunate and may exaggerate any potential benefit of niacin therapy,” because “more than 40% of the patients did not undergo the measurement at 14 months of the carotid intima-media thickness (the primary end point),” Dr. Roger S. Blumenthal and Dr. Erin D. Michos of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, said in an editorial comment accompanying the report.

“A larger sample size may have either strengthened the provocative results regarding the major adverse cardiovascular events or, alternatively, reduced any evidence of meaningful clinical differences,” they wrote (N. Engl. J. Med. 2009:doi:10.1056/NEJMe0908838).

The ARBITER 6-HALTS trial enrolled 363 men and women, including 279 with known atherosclerotic coronary or vascular disease. In addition, there were 84 patients with a coronary heart disease risk equivalent such as diabetes (38 patients), a 10-year Framingham risk score of 20% or more (26 patients), and/or a high coronary calcium score (20 patients).

The study subjects (80% male, mean age 65 years) were randomly assigned to receive the maximum tolerated dose of extended-release niacin up to 2,000 mg/day or 10 mg of ezetimibe daily. All had already been taking a statin for a mean of 6 years, usually simvastatin or atorvastatin.

Niacin bested ezetimibe in improving both mean and maximal carotid intima media-thickness on ultrasonography at both 8 months and 14 months, Dr. Taylor and his colleagues said.

In addition, the rate of major adverse cardiovascular events was significantly lower with niacin (1%) than with ezetimibe (5%). Both of these benefits were consistent across all subgroups studied, without regard to gender, the presence or absence of diabetes, or baseline HDL cholesterol levels.

A post-hoc analysis showed a significant inverse relation between a decrease in LDL cholesterol and an increase in carotid intima-media thickness only in the ezetimibe group. The reason for this paradoxical effect is not yet known, but the researchers proposed that it is biologically plausible: Ezetimibe may have the unintended effect of disrupting the HDL-mediated reverse transport of cholesterol.

“We believe that prudent clinical practice currently favors the avoidance of ezetimibe, with consideration of further restriction on its use in lieu of clinically validated regimens, until its net effect on clinical outcomes can be fully ascertained,” Dr. Taylor and his associates said.

The two patient groups did not differ in quality of life measures at the end of the study. More subjects in the niacin group (63%) than in the ezetimibe group (33%) withdrew from the study because of adverse drug effects, however.

In their editorial comment, Dr. Blumenthal and Dr. Michos said that using carotid intima-media thickness as a surrogate for coronary atherosclerosis is “controversial.”

It is unknown whether arresting the progression of carotid intima-media thickness, or even reversing it, is consistently associated with a reduction in risk of CV events. “Furthermore, there are therapies other than niacin that retard the progression of carotid intima-media thickness (i.e., estrogen and thiazolidinediones) but do not reduce the incidence of cardiovascular events,” they noted.

“The putative negative effects of ezetimibe (i.e., increase in the carotid intima-media thickness) espoused by the authors are unsubstantiated. In the 111 patients in the ezetimibe group with data reported in the study, the carotid intima-media thickness at 14 months was not significantly different from the thickness at baseline,” Dr. Blumenthal and Dr. Michos added.

“Unfortunately, the premature termination of the ARBITER 6-HALTS trial, the small number of patients studied, and the limited duration of follow-up preclude us from conclusively declaring niacin the adjunctive agent of choice on the basis of the evidence. A decrease of 0.014 mm in the carotid intima-media thickness over 14 months does not necessarily merit changes in our lipid-lowering guidelines at this time,” they said.

Dr. Taylor reports receiving lecture fees from Abbott. Dr. Blumenthal and Dr. Michos report no relevant conflicts of interest.

'We believe that prudent clinical practice currently favors the avoidance of ezetimibe.'

Source DR. TAYLOR

Extended-release niacin was clearly superior to ezetimibe when combined with statin therapy in patients who had or were at high risk for atherosclerosis in a prospective study in 363 patients.

Niacin caused the regression of carotid intima-media thickness, a surrogate marker for atherosclerosis progression, while ezetimibe caused no significant change in the first clinical trial to directly compare the two secondary agents in combination with a statin.

In addition, fewer adverse cardiovascular events developed with niacin than with ezetimibe during 14 months of follow-up. Perhaps most important, “We found an unexpected paradoxical relationship of a greater degree of atherosclerosis progression in patients with larger, ezetimibe-induced reductions in LDL cholesterol level,” wrote Dr. Allen J. Taylor, director of advanced cardiac imaging at Washington Hospital Center in Washington, and his associates in the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study. The findings were presented concurrently at the annual scientific sessions of the American Heart Association.

The prospective, open-label study, sponsored by Abbott, the maker of the extended-release niacin used in the trial, was designed to randomly assign 363 patients to receive either extended-release niacin or ezetimibe (Zetia, manufactured by Merck–Shering-Plough Pharmaceuticals) in addition to statin therapy. The study was halted early when an interim analysis showed a clear advantage with niacin, and the trial included complete data from only 208 patients (N. Engl. J. Med. 2009:doi:10.1056/NEJMoa0907569).

Critics have charged that this “premature” termination was “unfortunate and may exaggerate any potential benefit of niacin therapy,” because “more than 40% of the patients did not undergo the measurement at 14 months of the carotid intima-media thickness (the primary end point),” Dr. Roger S. Blumenthal and Dr. Erin D. Michos of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, said in an editorial comment accompanying the report.

“A larger sample size may have either strengthened the provocative results regarding the major adverse cardiovascular events or, alternatively, reduced any evidence of meaningful clinical differences,” they wrote (N. Engl. J. Med. 2009:doi:10.1056/NEJMe0908838).

The ARBITER 6-HALTS trial enrolled 363 men and women, including 279 with known atherosclerotic coronary or vascular disease. In addition, there were 84 patients with a coronary heart disease risk equivalent such as diabetes (38 patients), a 10-year Framingham risk score of 20% or more (26 patients), and/or a high coronary calcium score (20 patients).

The study subjects (80% male, mean age 65 years) were randomly assigned to receive the maximum tolerated dose of extended-release niacin up to 2,000 mg/day or 10 mg of ezetimibe daily. All had already been taking a statin for a mean of 6 years, usually simvastatin or atorvastatin.

Niacin bested ezetimibe in improving both mean and maximal carotid intima media-thickness on ultrasonography at both 8 months and 14 months, Dr. Taylor and his colleagues said.

In addition, the rate of major adverse cardiovascular events was significantly lower with niacin (1%) than with ezetimibe (5%). Both of these benefits were consistent across all subgroups studied, without regard to gender, the presence or absence of diabetes, or baseline HDL cholesterol levels.

A post-hoc analysis showed a significant inverse relation between a decrease in LDL cholesterol and an increase in carotid intima-media thickness only in the ezetimibe group. The reason for this paradoxical effect is not yet known, but the researchers proposed that it is biologically plausible: Ezetimibe may have the unintended effect of disrupting the HDL-mediated reverse transport of cholesterol.

“We believe that prudent clinical practice currently favors the avoidance of ezetimibe, with consideration of further restriction on its use in lieu of clinically validated regimens, until its net effect on clinical outcomes can be fully ascertained,” Dr. Taylor and his associates said.

The two patient groups did not differ in quality of life measures at the end of the study. More subjects in the niacin group (63%) than in the ezetimibe group (33%) withdrew from the study because of adverse drug effects, however.

In their editorial comment, Dr. Blumenthal and Dr. Michos said that using carotid intima-media thickness as a surrogate for coronary atherosclerosis is “controversial.”

It is unknown whether arresting the progression of carotid intima-media thickness, or even reversing it, is consistently associated with a reduction in risk of CV events. “Furthermore, there are therapies other than niacin that retard the progression of carotid intima-media thickness (i.e., estrogen and thiazolidinediones) but do not reduce the incidence of cardiovascular events,” they noted.

“The putative negative effects of ezetimibe (i.e., increase in the carotid intima-media thickness) espoused by the authors are unsubstantiated. In the 111 patients in the ezetimibe group with data reported in the study, the carotid intima-media thickness at 14 months was not significantly different from the thickness at baseline,” Dr. Blumenthal and Dr. Michos added.

“Unfortunately, the premature termination of the ARBITER 6-HALTS trial, the small number of patients studied, and the limited duration of follow-up preclude us from conclusively declaring niacin the adjunctive agent of choice on the basis of the evidence. A decrease of 0.014 mm in the carotid intima-media thickness over 14 months does not necessarily merit changes in our lipid-lowering guidelines at this time,” they said.

Dr. Taylor reports receiving lecture fees from Abbott. Dr. Blumenthal and Dr. Michos report no relevant conflicts of interest.

'We believe that prudent clinical practice currently favors the avoidance of ezetimibe.'

Source DR. TAYLOR

Extended-release niacin was clearly superior to ezetimibe when combined with statin therapy in patients who had or were at high risk for atherosclerosis in a prospective study in 363 patients.

Niacin caused the regression of carotid intima-media thickness, a surrogate marker for atherosclerosis progression, while ezetimibe caused no significant change in the first clinical trial to directly compare the two secondary agents in combination with a statin.

In addition, fewer adverse cardiovascular events developed with niacin than with ezetimibe during 14 months of follow-up. Perhaps most important, “We found an unexpected paradoxical relationship of a greater degree of atherosclerosis progression in patients with larger, ezetimibe-induced reductions in LDL cholesterol level,” wrote Dr. Allen J. Taylor, director of advanced cardiac imaging at Washington Hospital Center in Washington, and his associates in the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study. The findings were presented concurrently at the annual scientific sessions of the American Heart Association.

The prospective, open-label study, sponsored by Abbott, the maker of the extended-release niacin used in the trial, was designed to randomly assign 363 patients to receive either extended-release niacin or ezetimibe (Zetia, manufactured by Merck–Shering-Plough Pharmaceuticals) in addition to statin therapy. The study was halted early when an interim analysis showed a clear advantage with niacin, and the trial included complete data from only 208 patients (N. Engl. J. Med. 2009:doi:10.1056/NEJMoa0907569).

Critics have charged that this “premature” termination was “unfortunate and may exaggerate any potential benefit of niacin therapy,” because “more than 40% of the patients did not undergo the measurement at 14 months of the carotid intima-media thickness (the primary end point),” Dr. Roger S. Blumenthal and Dr. Erin D. Michos of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, said in an editorial comment accompanying the report.

“A larger sample size may have either strengthened the provocative results regarding the major adverse cardiovascular events or, alternatively, reduced any evidence of meaningful clinical differences,” they wrote (N. Engl. J. Med. 2009:doi:10.1056/NEJMe0908838).

The ARBITER 6-HALTS trial enrolled 363 men and women, including 279 with known atherosclerotic coronary or vascular disease. In addition, there were 84 patients with a coronary heart disease risk equivalent such as diabetes (38 patients), a 10-year Framingham risk score of 20% or more (26 patients), and/or a high coronary calcium score (20 patients).

The study subjects (80% male, mean age 65 years) were randomly assigned to receive the maximum tolerated dose of extended-release niacin up to 2,000 mg/day or 10 mg of ezetimibe daily. All had already been taking a statin for a mean of 6 years, usually simvastatin or atorvastatin.

Niacin bested ezetimibe in improving both mean and maximal carotid intima media-thickness on ultrasonography at both 8 months and 14 months, Dr. Taylor and his colleagues said.

In addition, the rate of major adverse cardiovascular events was significantly lower with niacin (1%) than with ezetimibe (5%). Both of these benefits were consistent across all subgroups studied, without regard to gender, the presence or absence of diabetes, or baseline HDL cholesterol levels.

A post-hoc analysis showed a significant inverse relation between a decrease in LDL cholesterol and an increase in carotid intima-media thickness only in the ezetimibe group. The reason for this paradoxical effect is not yet known, but the researchers proposed that it is biologically plausible: Ezetimibe may have the unintended effect of disrupting the HDL-mediated reverse transport of cholesterol.

“We believe that prudent clinical practice currently favors the avoidance of ezetimibe, with consideration of further restriction on its use in lieu of clinically validated regimens, until its net effect on clinical outcomes can be fully ascertained,” Dr. Taylor and his associates said.

The two patient groups did not differ in quality of life measures at the end of the study. More subjects in the niacin group (63%) than in the ezetimibe group (33%) withdrew from the study because of adverse drug effects, however.

In their editorial comment, Dr. Blumenthal and Dr. Michos said that using carotid intima-media thickness as a surrogate for coronary atherosclerosis is “controversial.”

It is unknown whether arresting the progression of carotid intima-media thickness, or even reversing it, is consistently associated with a reduction in risk of CV events. “Furthermore, there are therapies other than niacin that retard the progression of carotid intima-media thickness (i.e., estrogen and thiazolidinediones) but do not reduce the incidence of cardiovascular events,” they noted.

“The putative negative effects of ezetimibe (i.e., increase in the carotid intima-media thickness) espoused by the authors are unsubstantiated. In the 111 patients in the ezetimibe group with data reported in the study, the carotid intima-media thickness at 14 months was not significantly different from the thickness at baseline,” Dr. Blumenthal and Dr. Michos added.

“Unfortunately, the premature termination of the ARBITER 6-HALTS trial, the small number of patients studied, and the limited duration of follow-up preclude us from conclusively declaring niacin the adjunctive agent of choice on the basis of the evidence. A decrease of 0.014 mm in the carotid intima-media thickness over 14 months does not necessarily merit changes in our lipid-lowering guidelines at this time,” they said.

Dr. Taylor reports receiving lecture fees from Abbott. Dr. Blumenthal and Dr. Michos report no relevant conflicts of interest.

'We believe that prudent clinical practice currently favors the avoidance of ezetimibe.'

Source DR. TAYLOR

Combining the nicotine patch with nicotine lozenges appears to be the most effective approach for smoking cessation, according to a report in the November issue of the Archives of General Psychiatry.

In a study directly comparing the effectiveness of five pharmacotherapies for smoking cessation against placebo, the patch-plus-lozenge combination “emerged as the only efficacious treatment… at 6 months post quit,” said Megan E. Piper, Ph.D., of the Center for Tobacco Research and Intervention at the University of Wisconsin, Madison, and her associates.

This particular combination therapy “has not been previously evaluated,” they noted.

The study involved 1,504 adult smokers who agreed to participate in a 3-year trial of smoking cessation, which reflects their high motivation to quit. Most of the study subjects were white (83%) and female (58%).

These subjects were randomly assigned to one of six treatments for 8 weeks: daily sustained-release bupropion (264 patients), nicotine lozenges (260 patients), nicotine patches (262 patients), nicotine lozenges plus nicotine patches (267 patients), bupropion plus nicotine lozenges (262 patients), or matched placebo (189 patients). All also received six individual counseling sessions of 10- to 20-minute duration with case managers who were supervised by a clinical psychologist.

In the initial analysis, all the active treatments yielded higher rates of cessation at day 1, week 1, the end of treatment, and 6 months after completing treatment. However, further analysis showed that only the combination of nicotine patches plus nicotine lozenges was significantly more effective than placebo at all of these time points.

Patients who received the combination of nicotine patches plus nicotine lozenges also had a longer interval until first “lapse” and a longer interval until full relapse than did subjects in the other study groups, Dr. Piper and her colleagues said (Arch. Gen. Psychiatry 2009;66:1253–62).

It is important to note that the placebo group in this study achieved a much higher smoking cessation rate (22%) than is usual with placebo. This “may have been due to the intensive counseling participants received, or to the high level of motivation required to participate in a 3-year longitudinal trial,” the investigators added.

Treatment effects diminished significantly as soon as the course of therapy was completed. This suggests that longer-term treatment might be more effective, they said.

On average the study subjects used only approximately 77% of their study medication, but the rate of adherence varied widely between groups. Patients assigned to nicotine lozenges used significantly less of that medication–67% of what they were given–than patients in any other group.

This suggests that smokers may be “especially unlikely to use as-needed medications adherently (i.e., a recommendation of nine lozenges per day),” the researchers said.

The investigators cited two limitations of the study. First, because the study was longitudinal, it might have “selected participants with greater motivation to quit than smokers in the general population,” they wrote. Also, the study did not include among the tested medications varenicline–which had not yet been approved by the Food and Drug Administration for smoking cessation. “Therefore, it is unknown how these agents would have fared relative to varenicline, the monotherapy designated as most effective by the 2008 [Public Health Service] Guideline.”

Still, these findings and the 2008 guideline update suggest that a combination of pharmacotherapy made up of the patch and nicotine replacement therapy should be routinely considered for smoking cessation treatment, they wrote.

GlaxoSmithKline provided the medication to patients at no cost under a research agreement. Dr. Piper reported no financial conflicts of interest.

Combining the nicotine patch with nicotine lozenges appears to be the most effective approach for smoking cessation, according to a report in the November issue of the Archives of General Psychiatry.

In a study directly comparing the effectiveness of five pharmacotherapies for smoking cessation against placebo, the patch-plus-lozenge combination “emerged as the only efficacious treatment… at 6 months post quit,” said Megan E. Piper, Ph.D., of the Center for Tobacco Research and Intervention at the University of Wisconsin, Madison, and her associates.

This particular combination therapy “has not been previously evaluated,” they noted.

The study involved 1,504 adult smokers who agreed to participate in a 3-year trial of smoking cessation, which reflects their high motivation to quit. Most of the study subjects were white (83%) and female (58%).

These subjects were randomly assigned to one of six treatments for 8 weeks: daily sustained-release bupropion (264 patients), nicotine lozenges (260 patients), nicotine patches (262 patients), nicotine lozenges plus nicotine patches (267 patients), bupropion plus nicotine lozenges (262 patients), or matched placebo (189 patients). All also received six individual counseling sessions of 10- to 20-minute duration with case managers who were supervised by a clinical psychologist.

In the initial analysis, all the active treatments yielded higher rates of cessation at day 1, week 1, the end of treatment, and 6 months after completing treatment. However, further analysis showed that only the combination of nicotine patches plus nicotine lozenges was significantly more effective than placebo at all of these time points.

Patients who received the combination of nicotine patches plus nicotine lozenges also had a longer interval until first “lapse” and a longer interval until full relapse than did subjects in the other study groups, Dr. Piper and her colleagues said (Arch. Gen. Psychiatry 2009;66:1253–62).

It is important to note that the placebo group in this study achieved a much higher smoking cessation rate (22%) than is usual with placebo. This “may have been due to the intensive counseling participants received, or to the high level of motivation required to participate in a 3-year longitudinal trial,” the investigators added.

Treatment effects diminished significantly as soon as the course of therapy was completed. This suggests that longer-term treatment might be more effective, they said.

On average the study subjects used only approximately 77% of their study medication, but the rate of adherence varied widely between groups. Patients assigned to nicotine lozenges used significantly less of that medication–67% of what they were given–than patients in any other group.

This suggests that smokers may be “especially unlikely to use as-needed medications adherently (i.e., a recommendation of nine lozenges per day),” the researchers said.

The investigators cited two limitations of the study. First, because the study was longitudinal, it might have “selected participants with greater motivation to quit than smokers in the general population,” they wrote. Also, the study did not include among the tested medications varenicline–which had not yet been approved by the Food and Drug Administration for smoking cessation. “Therefore, it is unknown how these agents would have fared relative to varenicline, the monotherapy designated as most effective by the 2008 [Public Health Service] Guideline.”

Still, these findings and the 2008 guideline update suggest that a combination of pharmacotherapy made up of the patch and nicotine replacement therapy should be routinely considered for smoking cessation treatment, they wrote.

GlaxoSmithKline provided the medication to patients at no cost under a research agreement. Dr. Piper reported no financial conflicts of interest.

Combining the nicotine patch with nicotine lozenges appears to be the most effective approach for smoking cessation, according to a report in the November issue of the Archives of General Psychiatry.

In a study directly comparing the effectiveness of five pharmacotherapies for smoking cessation against placebo, the patch-plus-lozenge combination “emerged as the only efficacious treatment… at 6 months post quit,” said Megan E. Piper, Ph.D., of the Center for Tobacco Research and Intervention at the University of Wisconsin, Madison, and her associates.

This particular combination therapy “has not been previously evaluated,” they noted.

The study involved 1,504 adult smokers who agreed to participate in a 3-year trial of smoking cessation, which reflects their high motivation to quit. Most of the study subjects were white (83%) and female (58%).

These subjects were randomly assigned to one of six treatments for 8 weeks: daily sustained-release bupropion (264 patients), nicotine lozenges (260 patients), nicotine patches (262 patients), nicotine lozenges plus nicotine patches (267 patients), bupropion plus nicotine lozenges (262 patients), or matched placebo (189 patients). All also received six individual counseling sessions of 10- to 20-minute duration with case managers who were supervised by a clinical psychologist.

In the initial analysis, all the active treatments yielded higher rates of cessation at day 1, week 1, the end of treatment, and 6 months after completing treatment. However, further analysis showed that only the combination of nicotine patches plus nicotine lozenges was significantly more effective than placebo at all of these time points.

Patients who received the combination of nicotine patches plus nicotine lozenges also had a longer interval until first “lapse” and a longer interval until full relapse than did subjects in the other study groups, Dr. Piper and her colleagues said (Arch. Gen. Psychiatry 2009;66:1253–62).

It is important to note that the placebo group in this study achieved a much higher smoking cessation rate (22%) than is usual with placebo. This “may have been due to the intensive counseling participants received, or to the high level of motivation required to participate in a 3-year longitudinal trial,” the investigators added.

Treatment effects diminished significantly as soon as the course of therapy was completed. This suggests that longer-term treatment might be more effective, they said.

On average the study subjects used only approximately 77% of their study medication, but the rate of adherence varied widely between groups. Patients assigned to nicotine lozenges used significantly less of that medication–67% of what they were given–than patients in any other group.

This suggests that smokers may be “especially unlikely to use as-needed medications adherently (i.e., a recommendation of nine lozenges per day),” the researchers said.

The investigators cited two limitations of the study. First, because the study was longitudinal, it might have “selected participants with greater motivation to quit than smokers in the general population,” they wrote. Also, the study did not include among the tested medications varenicline–which had not yet been approved by the Food and Drug Administration for smoking cessation. “Therefore, it is unknown how these agents would have fared relative to varenicline, the monotherapy designated as most effective by the 2008 [Public Health Service] Guideline.”

Still, these findings and the 2008 guideline update suggest that a combination of pharmacotherapy made up of the patch and nicotine replacement therapy should be routinely considered for smoking cessation treatment, they wrote.

GlaxoSmithKline provided the medication to patients at no cost under a research agreement. Dr. Piper reported no financial conflicts of interest.

Two studies now extend the results of a 2006 paper contending that the Mediterranean diet slows cognitive decline, but the issue is far from settled, according to findings from two studies.

In one study that built on the initial 2006 findings using the same cohort of subjects, Dr. Nikolaos Scarmeas and his associates at Columbia University Medical Center, New York, found that both adherence to the Mediterranean diet and higher levels of physical activity reduced the risk of developing Alzheimer disease (AD).

In the other study, Catherine Féart, Ph.D., of Université Victor Segalen Bordeaux (France) and her associates (including Dr. Scarmeas) found that higher adherence to the Mediterranean diet correlated with slower cognitive decline on one test but not on three others.

Offsetting any benefit was the finding that higher adherence did not reduce the risk of incident dementia.

In an editorial comment that accompanied these reports, Dr. David S. Knopman of the Mayo Clinic, Rochester, Minn., cautioned that clinicians and the public should weigh these findings deliberately and not leap to premature conclusions.

The two studies “provide moderately compelling evidence” in support of the Mediterranean diet, “but following a healthy diet does not occur in isolation,” he noted.

In Dr. Scarmeas' study, 1,880 Manhattan residents participating in an aging study were assessed every 1.5 years from 1992 through 2006.

A total of 282 developed incident AD during that time.

Both higher physical activity and higher adherence to a Mediterranean-type diet were associated with lower risk of AD. Among subjects who had the highest levels of activity and diet adherence, the relative risk of AD was reduced by 35%–44%.

“High physical activity in this cohort of 77-year-old individuals corresponded to approximately 1.3 hours of vigorous activity per week, 2.4 hours of moderate physical activity per week, or 4 hours of light physical activity per week, or a combination thereof… Even this relatively small amount of physical activity was associated with a reduction in risk for developing AD,” Dr. Scarmeas and his colleagues said (JAMA 2009;302:627–37).

In Dr. Féart's study, 1,410 elderly participants in a cohort study of dementia were followed for a median of 4 years. Greater adherence to a Mediterranean-type diet was associated with a slower decline in performance on the Mini Mental State Examination, an index of global cognitive performance.

However, adherence to the healthy diet was not associated with performance on the Isaacs Set Test that assesses semantic verbal fluency abilities and speed of verbal production, the Benton Visual Retention Test that evaluates immediate visual memory, or the Free and Cued Selective Reminding Test that assesses verbal episodic memory.

Moreover, adherence to the Mediterranean diet did not correlate with incident dementia, Dr. Féart and her associates said (JAMA 2009;302:638–48).

In his editorial comment, Dr. Knopman said that the healthy diet's association with improved cognition, much like its association with improved heart disease and cancer profiles, “probably reflect[s] a lifetime of exposure both to the diet and to other healthy behaviors.

“An elderly person's diet is shaped by a life-long set of preferences,” he noted (JAMA 2009;302:686–7).

Dr. Scarmeas' study was supported by the National Institute on Aging. He reported no disclosures. The Féart study was supported in part by Sanofi-Aventis, and Dr. Féart reported no disclosures.

Dr. Knopman reported serving on a data and safety monitoring board for Sanofi-Aventis Pharmaceuticals, for which he received personal compensation.

He will serve on a data and safety monitoring board for Lilly and will receive personal compensation. In addition, Dr. Knopman has served as an investigator for clinical trials sponsored by several pharmaceutical companies.

Two studies now extend the results of a 2006 paper contending that the Mediterranean diet slows cognitive decline, but the issue is far from settled, according to findings from two studies.

In one study that built on the initial 2006 findings using the same cohort of subjects, Dr. Nikolaos Scarmeas and his associates at Columbia University Medical Center, New York, found that both adherence to the Mediterranean diet and higher levels of physical activity reduced the risk of developing Alzheimer disease (AD).

In the other study, Catherine Féart, Ph.D., of Université Victor Segalen Bordeaux (France) and her associates (including Dr. Scarmeas) found that higher adherence to the Mediterranean diet correlated with slower cognitive decline on one test but not on three others.

Offsetting any benefit was the finding that higher adherence did not reduce the risk of incident dementia.

In an editorial comment that accompanied these reports, Dr. David S. Knopman of the Mayo Clinic, Rochester, Minn., cautioned that clinicians and the public should weigh these findings deliberately and not leap to premature conclusions.

The two studies “provide moderately compelling evidence” in support of the Mediterranean diet, “but following a healthy diet does not occur in isolation,” he noted.

In Dr. Scarmeas' study, 1,880 Manhattan residents participating in an aging study were assessed every 1.5 years from 1992 through 2006.

A total of 282 developed incident AD during that time.

Both higher physical activity and higher adherence to a Mediterranean-type diet were associated with lower risk of AD. Among subjects who had the highest levels of activity and diet adherence, the relative risk of AD was reduced by 35%–44%.

“High physical activity in this cohort of 77-year-old individuals corresponded to approximately 1.3 hours of vigorous activity per week, 2.4 hours of moderate physical activity per week, or 4 hours of light physical activity per week, or a combination thereof… Even this relatively small amount of physical activity was associated with a reduction in risk for developing AD,” Dr. Scarmeas and his colleagues said (JAMA 2009;302:627–37).

In Dr. Féart's study, 1,410 elderly participants in a cohort study of dementia were followed for a median of 4 years. Greater adherence to a Mediterranean-type diet was associated with a slower decline in performance on the Mini Mental State Examination, an index of global cognitive performance.

However, adherence to the healthy diet was not associated with performance on the Isaacs Set Test that assesses semantic verbal fluency abilities and speed of verbal production, the Benton Visual Retention Test that evaluates immediate visual memory, or the Free and Cued Selective Reminding Test that assesses verbal episodic memory.

Moreover, adherence to the Mediterranean diet did not correlate with incident dementia, Dr. Féart and her associates said (JAMA 2009;302:638–48).

In his editorial comment, Dr. Knopman said that the healthy diet's association with improved cognition, much like its association with improved heart disease and cancer profiles, “probably reflect[s] a lifetime of exposure both to the diet and to other healthy behaviors.

“An elderly person's diet is shaped by a life-long set of preferences,” he noted (JAMA 2009;302:686–7).

Dr. Scarmeas' study was supported by the National Institute on Aging. He reported no disclosures. The Féart study was supported in part by Sanofi-Aventis, and Dr. Féart reported no disclosures.

Dr. Knopman reported serving on a data and safety monitoring board for Sanofi-Aventis Pharmaceuticals, for which he received personal compensation.

He will serve on a data and safety monitoring board for Lilly and will receive personal compensation. In addition, Dr. Knopman has served as an investigator for clinical trials sponsored by several pharmaceutical companies.

Two studies now extend the results of a 2006 paper contending that the Mediterranean diet slows cognitive decline, but the issue is far from settled, according to findings from two studies.

In one study that built on the initial 2006 findings using the same cohort of subjects, Dr. Nikolaos Scarmeas and his associates at Columbia University Medical Center, New York, found that both adherence to the Mediterranean diet and higher levels of physical activity reduced the risk of developing Alzheimer disease (AD).

In the other study, Catherine Féart, Ph.D., of Université Victor Segalen Bordeaux (France) and her associates (including Dr. Scarmeas) found that higher adherence to the Mediterranean diet correlated with slower cognitive decline on one test but not on three others.

Offsetting any benefit was the finding that higher adherence did not reduce the risk of incident dementia.

In an editorial comment that accompanied these reports, Dr. David S. Knopman of the Mayo Clinic, Rochester, Minn., cautioned that clinicians and the public should weigh these findings deliberately and not leap to premature conclusions.

The two studies “provide moderately compelling evidence” in support of the Mediterranean diet, “but following a healthy diet does not occur in isolation,” he noted.

In Dr. Scarmeas' study, 1,880 Manhattan residents participating in an aging study were assessed every 1.5 years from 1992 through 2006.

A total of 282 developed incident AD during that time.

Both higher physical activity and higher adherence to a Mediterranean-type diet were associated with lower risk of AD. Among subjects who had the highest levels of activity and diet adherence, the relative risk of AD was reduced by 35%–44%.

“High physical activity in this cohort of 77-year-old individuals corresponded to approximately 1.3 hours of vigorous activity per week, 2.4 hours of moderate physical activity per week, or 4 hours of light physical activity per week, or a combination thereof… Even this relatively small amount of physical activity was associated with a reduction in risk for developing AD,” Dr. Scarmeas and his colleagues said (JAMA 2009;302:627–37).

In Dr. Féart's study, 1,410 elderly participants in a cohort study of dementia were followed for a median of 4 years. Greater adherence to a Mediterranean-type diet was associated with a slower decline in performance on the Mini Mental State Examination, an index of global cognitive performance.

However, adherence to the healthy diet was not associated with performance on the Isaacs Set Test that assesses semantic verbal fluency abilities and speed of verbal production, the Benton Visual Retention Test that evaluates immediate visual memory, or the Free and Cued Selective Reminding Test that assesses verbal episodic memory.

Moreover, adherence to the Mediterranean diet did not correlate with incident dementia, Dr. Féart and her associates said (JAMA 2009;302:638–48).

In his editorial comment, Dr. Knopman said that the healthy diet's association with improved cognition, much like its association with improved heart disease and cancer profiles, “probably reflect[s] a lifetime of exposure both to the diet and to other healthy behaviors.

“An elderly person's diet is shaped by a life-long set of preferences,” he noted (JAMA 2009;302:686–7).

Dr. Scarmeas' study was supported by the National Institute on Aging. He reported no disclosures. The Féart study was supported in part by Sanofi-Aventis, and Dr. Féart reported no disclosures.

Dr. Knopman reported serving on a data and safety monitoring board for Sanofi-Aventis Pharmaceuticals, for which he received personal compensation.

He will serve on a data and safety monitoring board for Lilly and will receive personal compensation. In addition, Dr. Knopman has served as an investigator for clinical trials sponsored by several pharmaceutical companies.

Public release of hospital “report cards” did not measurably improve indicators of care for acute MI or chronic heart failure, according to a Canadian study.

Even though most of the hospitals involved in the study undertook at least one quality improvement initiative in response to the report cards, only 1 of 12 indicators of care for acute MI and only 1 of 6 indicators of care for chronic heart failure improved, said Dr. Jack V. Tu, a professor in the department of health policy, management, and evaluation at the University of Toronto, and his associates.

The investigators studied 81 Ontario hospitals, focusing on cardiac care because of the well-known gap between ideal and actual practice in patients hospitalized with acute MI or chronic heart failure.

At each hospital, a sample of 125 charts for 1999–2001 was reviewed. Participating hospitals were randomly assigned to receive early feedback (in October 2003, before the results were released to the public and received extensive media coverage in January 2004) or delayed feedback (in September 2005, at the same time as their results were released to the public but without any media coverage) on a report card of their performance in the reviewed cases.

Follow-up performance data were obtained on 15,997 patients treated for the same conditions at the same hospitals in 2004–2005.

Although 73% of hospitals that received early feedback changed order sets and/or clinical pathways or care maps for these patient groups during that interval, there was no significant change in performance for either the early-feedback or the late-feedback groups.

Only 1 of 12 factors measured in patients with acute MI—percentage receiving fibrinolytic therapy before transfer to a coronary care or ICU—improved significantly more with early feedback. Only 1 of 6 factors measured in patients with chronic heart failure—rate of ACE inhibitor or angiotensin II receptor blocker use in those with left ventricular dysfunction—improved significantly more with early feedback.

These findings “suggest that public release of hospital-specific performance data may not be a particularly effective system-wide intervention for measurably improving processes of care,” Dr. Tu and his associates said (JAMA 2009 Nov. 18; doi:10.1001/jama.2009.1731). The study was released online simultaneously with Dr. Tu's presentation of the data at the annual scientific sessions of the American Heart Association.

A limitation of this study was that it involved one-time-only report cards. “More frequent and timely feedback of publicly released report cards on a regular basis might have been more effective,” they added. Dr. Tu reported no financial conflicts of interest.

Public release of hospital “report cards” did not measurably improve indicators of care for acute MI or chronic heart failure, according to a Canadian study.

Even though most of the hospitals involved in the study undertook at least one quality improvement initiative in response to the report cards, only 1 of 12 indicators of care for acute MI and only 1 of 6 indicators of care for chronic heart failure improved, said Dr. Jack V. Tu, a professor in the department of health policy, management, and evaluation at the University of Toronto, and his associates.

The investigators studied 81 Ontario hospitals, focusing on cardiac care because of the well-known gap between ideal and actual practice in patients hospitalized with acute MI or chronic heart failure.

At each hospital, a sample of 125 charts for 1999–2001 was reviewed. Participating hospitals were randomly assigned to receive early feedback (in October 2003, before the results were released to the public and received extensive media coverage in January 2004) or delayed feedback (in September 2005, at the same time as their results were released to the public but without any media coverage) on a report card of their performance in the reviewed cases.

Follow-up performance data were obtained on 15,997 patients treated for the same conditions at the same hospitals in 2004–2005.

Although 73% of hospitals that received early feedback changed order sets and/or clinical pathways or care maps for these patient groups during that interval, there was no significant change in performance for either the early-feedback or the late-feedback groups.

Only 1 of 12 factors measured in patients with acute MI—percentage receiving fibrinolytic therapy before transfer to a coronary care or ICU—improved significantly more with early feedback. Only 1 of 6 factors measured in patients with chronic heart failure—rate of ACE inhibitor or angiotensin II receptor blocker use in those with left ventricular dysfunction—improved significantly more with early feedback.

These findings “suggest that public release of hospital-specific performance data may not be a particularly effective system-wide intervention for measurably improving processes of care,” Dr. Tu and his associates said (JAMA 2009 Nov. 18; doi:10.1001/jama.2009.1731). The study was released online simultaneously with Dr. Tu's presentation of the data at the annual scientific sessions of the American Heart Association.

A limitation of this study was that it involved one-time-only report cards. “More frequent and timely feedback of publicly released report cards on a regular basis might have been more effective,” they added. Dr. Tu reported no financial conflicts of interest.

Public release of hospital “report cards” did not measurably improve indicators of care for acute MI or chronic heart failure, according to a Canadian study.

Even though most of the hospitals involved in the study undertook at least one quality improvement initiative in response to the report cards, only 1 of 12 indicators of care for acute MI and only 1 of 6 indicators of care for chronic heart failure improved, said Dr. Jack V. Tu, a professor in the department of health policy, management, and evaluation at the University of Toronto, and his associates.

The investigators studied 81 Ontario hospitals, focusing on cardiac care because of the well-known gap between ideal and actual practice in patients hospitalized with acute MI or chronic heart failure.

At each hospital, a sample of 125 charts for 1999–2001 was reviewed. Participating hospitals were randomly assigned to receive early feedback (in October 2003, before the results were released to the public and received extensive media coverage in January 2004) or delayed feedback (in September 2005, at the same time as their results were released to the public but without any media coverage) on a report card of their performance in the reviewed cases.

Follow-up performance data were obtained on 15,997 patients treated for the same conditions at the same hospitals in 2004–2005.

Although 73% of hospitals that received early feedback changed order sets and/or clinical pathways or care maps for these patient groups during that interval, there was no significant change in performance for either the early-feedback or the late-feedback groups.

Only 1 of 12 factors measured in patients with acute MI—percentage receiving fibrinolytic therapy before transfer to a coronary care or ICU—improved significantly more with early feedback. Only 1 of 6 factors measured in patients with chronic heart failure—rate of ACE inhibitor or angiotensin II receptor blocker use in those with left ventricular dysfunction—improved significantly more with early feedback.

These findings “suggest that public release of hospital-specific performance data may not be a particularly effective system-wide intervention for measurably improving processes of care,” Dr. Tu and his associates said (JAMA 2009 Nov. 18; doi:10.1001/jama.2009.1731). The study was released online simultaneously with Dr. Tu's presentation of the data at the annual scientific sessions of the American Heart Association.

A limitation of this study was that it involved one-time-only report cards. “More frequent and timely feedback of publicly released report cards on a regular basis might have been more effective,” they added. Dr. Tu reported no financial conflicts of interest.

Extended-release niacin was clearly superior to ezetimibe when combined with statin therapy in patients who had or were at high risk for atherosclerosis in a prospective, open-label study.

Niacin caused the regression of carotid intima-media thickness, a surrogate marker for atherosclerosis progression, while ezetimibe caused no significant change in the first clinical trial to directly compare the two secondary agents in combination with a statin.

In addition, fewer adverse cardiovascular events developed with niacin than with ezetimibe during 14 months of follow-up. Perhaps most important, “we found an unexpected paradoxical relationship of a greater degree of atherosclerosis progression in patients with larger, ezetimibe-induced reductions in LDL cholesterol level,” wrote Dr. Allen J. Taylor, director of advanced cardiac imaging at Washington Hospital Center in Washington, and his associates in the ARBITER6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study. The findings were published online (N. Engl. J. Med. 2009;doi:10.1056/NEJMoa0907569) and presented concurrently at the annual at the annual scientific sessions of the American Heart Association.

The study, sponsored by Abbott, the maker of the extended-release niacin used in the trial, was designed to randomly assign 363 patients to receive either extended-release niacin or ezetimibe (Zetia, Merck–Shering-Plough Pharmaceuticals) in addition to statin therapy. The study was halted early when an interim analysis showed a clear advantage with niacin, and the trial included complete data from only 208 of the patients.

Critics have charged that this “premature” termination was “unfortunate and may exaggerate any potential benefit of niacin therapy” because “more than 40% of the patients did not undergo the measurement at 14 months of the carotid intima-media thickness (the primary end point),” Dr. Roger S. Blumenthal and Dr. Erin D. Michos of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, said in an editorial comment.

“A larger sample size may have either strengthened the provocative results regarding the major adverse cardiovascular events or, alternatively, reduced any evidence of meaningful clinical differences,” they wrote (N. Engl. J. Med. 2009; doi:10.1056/NEJMe0908838).

The ARBITER6-HALTS trial enrolled 363 men and women, including 279 with known atherosclerotic coronary or vascular disease. In addition, there were 84 patients with a coronary heart disease risk equivalent such as diabetes (38 patients), a 10-year Framingham risk score of 20% or more (26 patients), and/or a high coronary calcium score (20 patients).

The study subjects (80% male, mean age 65 years) were randomly assigned to receive the maximum tolerated dose of extended-release niacin up to 2,000 mg/day or 10 mg of ezetimibe daily. All had already been taking a statin for a mean of 6 years, usually simvastatin or atorvastatin.

Niacin bested ezetimibe in improving both mean and maximal carotid intima-media thickness on ultrasonography at both 8 months and 14 months, Dr. Taylor and his colleagues said.

In addition, the rate of major adverse cardiovascular events was significantly lower with niacin (1%) than with ezetimibe (5%). Both of these benefits were consistent across all subgroups studied, without regard to gender, the presence or absence of diabetes, or baseline HDL cholesterol levels.

A post hoc analysis showed a significant inverse relation between a decrease in LDL cholesterol and an increase in carotid intima-media thickness only in the ezetimibe group. The reason for this paradoxical effect is not yet known, but the researchers proposed that it is biologically plausible: Ezetimibe may have the unintended effect of disrupting the HDL-mediated reverse transport of cholesterol.

“We believe that prudent clinical practice currently favors the avoidance of ezetimibe, with consideration of further restriction on its use in lieu of clinically validated regimens, until its net effect on clinical outcomes can be fully ascertained,” Dr. Taylor and his associates said.

The two patient groups did not differ in quality of life measures at the end of the study. More subjects in the niacin group (63%) than in the ezetimibe group (33%) withdrew from the study because of adverse drug effects, however.

In their editorial, Dr. Blumenthal and Dr. Michos said that using carotid intima-media thickness as a surrogate for coronary atherosclerosis is “controversial.”

It is unknown whether arresting the progression of carotid intima-media thickness, or even reversing it, is consistently associated with a reduction in risk of cardiovascular events. “Furthermore, there are therapies other than niacin that retard the progression of carotid intima-media thickness (i.e., estrogen and thiazolidinediones) but do not reduce the incidence of cardiovascular events,” they noted.

“The putative negative effects of ezetimibe (i.e., increase in the carotid intima-media thickness) espoused by the authors are unsubstantiated. In the 111 patients in the ezetimibe group with data reported in the study, the carotid intima-media thickness at 14 months was not significantly different from the thickness at baseline,” Dr. Blumenthal and Dr. Michos added. They cited “the premature termination of the ARBITER6-HALTS trial, the small number of patients studied, and the limited duration of follow-up” as reasons to not rush to change the current clinical approach to lipid lowering.

Rather, they said they “would support the use of niacin as the preferred adjunctive agent to be used in combination with the maximal dose of a potent statin in persons who have low levels of HDL cholesterol and established cardiovascular disease.” More clinical trials are currently underway.

Dr. Taylor reported receiving lecture fees from Abbott. Dr. Blumenthal and Dr. Michos reported no relevant conflicts of interest.

'We believe that prudent clinical practice currently favors the avoidance of ezetimibe.'

Source DR. TAYLOR

Extended-release niacin was clearly superior to ezetimibe when combined with statin therapy in patients who had or were at high risk for atherosclerosis in a prospective, open-label study.

Niacin caused the regression of carotid intima-media thickness, a surrogate marker for atherosclerosis progression, while ezetimibe caused no significant change in the first clinical trial to directly compare the two secondary agents in combination with a statin.

In addition, fewer adverse cardiovascular events developed with niacin than with ezetimibe during 14 months of follow-up. Perhaps most important, “we found an unexpected paradoxical relationship of a greater degree of atherosclerosis progression in patients with larger, ezetimibe-induced reductions in LDL cholesterol level,” wrote Dr. Allen J. Taylor, director of advanced cardiac imaging at Washington Hospital Center in Washington, and his associates in the ARBITER6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study. The findings were published online (N. Engl. J. Med. 2009;doi:10.1056/NEJMoa0907569) and presented concurrently at the annual at the annual scientific sessions of the American Heart Association.

The study, sponsored by Abbott, the maker of the extended-release niacin used in the trial, was designed to randomly assign 363 patients to receive either extended-release niacin or ezetimibe (Zetia, Merck–Shering-Plough Pharmaceuticals) in addition to statin therapy. The study was halted early when an interim analysis showed a clear advantage with niacin, and the trial included complete data from only 208 of the patients.

Critics have charged that this “premature” termination was “unfortunate and may exaggerate any potential benefit of niacin therapy” because “more than 40% of the patients did not undergo the measurement at 14 months of the carotid intima-media thickness (the primary end point),” Dr. Roger S. Blumenthal and Dr. Erin D. Michos of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, said in an editorial comment.

“A larger sample size may have either strengthened the provocative results regarding the major adverse cardiovascular events or, alternatively, reduced any evidence of meaningful clinical differences,” they wrote (N. Engl. J. Med. 2009; doi:10.1056/NEJMe0908838).

The ARBITER6-HALTS trial enrolled 363 men and women, including 279 with known atherosclerotic coronary or vascular disease. In addition, there were 84 patients with a coronary heart disease risk equivalent such as diabetes (38 patients), a 10-year Framingham risk score of 20% or more (26 patients), and/or a high coronary calcium score (20 patients).

The study subjects (80% male, mean age 65 years) were randomly assigned to receive the maximum tolerated dose of extended-release niacin up to 2,000 mg/day or 10 mg of ezetimibe daily. All had already been taking a statin for a mean of 6 years, usually simvastatin or atorvastatin.

Niacin bested ezetimibe in improving both mean and maximal carotid intima-media thickness on ultrasonography at both 8 months and 14 months, Dr. Taylor and his colleagues said.

In addition, the rate of major adverse cardiovascular events was significantly lower with niacin (1%) than with ezetimibe (5%). Both of these benefits were consistent across all subgroups studied, without regard to gender, the presence or absence of diabetes, or baseline HDL cholesterol levels.

A post hoc analysis showed a significant inverse relation between a decrease in LDL cholesterol and an increase in carotid intima-media thickness only in the ezetimibe group. The reason for this paradoxical effect is not yet known, but the researchers proposed that it is biologically plausible: Ezetimibe may have the unintended effect of disrupting the HDL-mediated reverse transport of cholesterol.

“We believe that prudent clinical practice currently favors the avoidance of ezetimibe, with consideration of further restriction on its use in lieu of clinically validated regimens, until its net effect on clinical outcomes can be fully ascertained,” Dr. Taylor and his associates said.

The two patient groups did not differ in quality of life measures at the end of the study. More subjects in the niacin group (63%) than in the ezetimibe group (33%) withdrew from the study because of adverse drug effects, however.

In their editorial, Dr. Blumenthal and Dr. Michos said that using carotid intima-media thickness as a surrogate for coronary atherosclerosis is “controversial.”

It is unknown whether arresting the progression of carotid intima-media thickness, or even reversing it, is consistently associated with a reduction in risk of cardiovascular events. “Furthermore, there are therapies other than niacin that retard the progression of carotid intima-media thickness (i.e., estrogen and thiazolidinediones) but do not reduce the incidence of cardiovascular events,” they noted.

“The putative negative effects of ezetimibe (i.e., increase in the carotid intima-media thickness) espoused by the authors are unsubstantiated. In the 111 patients in the ezetimibe group with data reported in the study, the carotid intima-media thickness at 14 months was not significantly different from the thickness at baseline,” Dr. Blumenthal and Dr. Michos added. They cited “the premature termination of the ARBITER6-HALTS trial, the small number of patients studied, and the limited duration of follow-up” as reasons to not rush to change the current clinical approach to lipid lowering.

Rather, they said they “would support the use of niacin as the preferred adjunctive agent to be used in combination with the maximal dose of a potent statin in persons who have low levels of HDL cholesterol and established cardiovascular disease.” More clinical trials are currently underway.

Dr. Taylor reported receiving lecture fees from Abbott. Dr. Blumenthal and Dr. Michos reported no relevant conflicts of interest.

'We believe that prudent clinical practice currently favors the avoidance of ezetimibe.'

Source DR. TAYLOR

Extended-release niacin was clearly superior to ezetimibe when combined with statin therapy in patients who had or were at high risk for atherosclerosis in a prospective, open-label study.

Niacin caused the regression of carotid intima-media thickness, a surrogate marker for atherosclerosis progression, while ezetimibe caused no significant change in the first clinical trial to directly compare the two secondary agents in combination with a statin.

In addition, fewer adverse cardiovascular events developed with niacin than with ezetimibe during 14 months of follow-up. Perhaps most important, “we found an unexpected paradoxical relationship of a greater degree of atherosclerosis progression in patients with larger, ezetimibe-induced reductions in LDL cholesterol level,” wrote Dr. Allen J. Taylor, director of advanced cardiac imaging at Washington Hospital Center in Washington, and his associates in the ARBITER6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study. The findings were published online (N. Engl. J. Med. 2009;doi:10.1056/NEJMoa0907569) and presented concurrently at the annual at the annual scientific sessions of the American Heart Association.

The study, sponsored by Abbott, the maker of the extended-release niacin used in the trial, was designed to randomly assign 363 patients to receive either extended-release niacin or ezetimibe (Zetia, Merck–Shering-Plough Pharmaceuticals) in addition to statin therapy. The study was halted early when an interim analysis showed a clear advantage with niacin, and the trial included complete data from only 208 of the patients.

Critics have charged that this “premature” termination was “unfortunate and may exaggerate any potential benefit of niacin therapy” because “more than 40% of the patients did not undergo the measurement at 14 months of the carotid intima-media thickness (the primary end point),” Dr. Roger S. Blumenthal and Dr. Erin D. Michos of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, said in an editorial comment.

“A larger sample size may have either strengthened the provocative results regarding the major adverse cardiovascular events or, alternatively, reduced any evidence of meaningful clinical differences,” they wrote (N. Engl. J. Med. 2009; doi:10.1056/NEJMe0908838).

The ARBITER6-HALTS trial enrolled 363 men and women, including 279 with known atherosclerotic coronary or vascular disease. In addition, there were 84 patients with a coronary heart disease risk equivalent such as diabetes (38 patients), a 10-year Framingham risk score of 20% or more (26 patients), and/or a high coronary calcium score (20 patients).

The study subjects (80% male, mean age 65 years) were randomly assigned to receive the maximum tolerated dose of extended-release niacin up to 2,000 mg/day or 10 mg of ezetimibe daily. All had already been taking a statin for a mean of 6 years, usually simvastatin or atorvastatin.

Niacin bested ezetimibe in improving both mean and maximal carotid intima-media thickness on ultrasonography at both 8 months and 14 months, Dr. Taylor and his colleagues said.

In addition, the rate of major adverse cardiovascular events was significantly lower with niacin (1%) than with ezetimibe (5%). Both of these benefits were consistent across all subgroups studied, without regard to gender, the presence or absence of diabetes, or baseline HDL cholesterol levels.

A post hoc analysis showed a significant inverse relation between a decrease in LDL cholesterol and an increase in carotid intima-media thickness only in the ezetimibe group. The reason for this paradoxical effect is not yet known, but the researchers proposed that it is biologically plausible: Ezetimibe may have the unintended effect of disrupting the HDL-mediated reverse transport of cholesterol.

“We believe that prudent clinical practice currently favors the avoidance of ezetimibe, with consideration of further restriction on its use in lieu of clinically validated regimens, until its net effect on clinical outcomes can be fully ascertained,” Dr. Taylor and his associates said.

The two patient groups did not differ in quality of life measures at the end of the study. More subjects in the niacin group (63%) than in the ezetimibe group (33%) withdrew from the study because of adverse drug effects, however.

In their editorial, Dr. Blumenthal and Dr. Michos said that using carotid intima-media thickness as a surrogate for coronary atherosclerosis is “controversial.”

It is unknown whether arresting the progression of carotid intima-media thickness, or even reversing it, is consistently associated with a reduction in risk of cardiovascular events. “Furthermore, there are therapies other than niacin that retard the progression of carotid intima-media thickness (i.e., estrogen and thiazolidinediones) but do not reduce the incidence of cardiovascular events,” they noted.

“The putative negative effects of ezetimibe (i.e., increase in the carotid intima-media thickness) espoused by the authors are unsubstantiated. In the 111 patients in the ezetimibe group with data reported in the study, the carotid intima-media thickness at 14 months was not significantly different from the thickness at baseline,” Dr. Blumenthal and Dr. Michos added. They cited “the premature termination of the ARBITER6-HALTS trial, the small number of patients studied, and the limited duration of follow-up” as reasons to not rush to change the current clinical approach to lipid lowering.

Rather, they said they “would support the use of niacin as the preferred adjunctive agent to be used in combination with the maximal dose of a potent statin in persons who have low levels of HDL cholesterol and established cardiovascular disease.” More clinical trials are currently underway.

Dr. Taylor reported receiving lecture fees from Abbott. Dr. Blumenthal and Dr. Michos reported no relevant conflicts of interest.

'We believe that prudent clinical practice currently favors the avoidance of ezetimibe.'

Source DR. TAYLOR

A vaccine that contained peptides targeting the human papillomavirus-16 oncoproteins E6 and E7 was effective against high-grade, HPV-16-positive vulvar intraepithelial neoplasia, according to the results of a small phase II study.

"This clinical efficacy is probably related to a vaccine-induced HPV-16 T-cell response," said Dr. Gemma G. Kenter and her associates at Leiden (the Netherlands) University Medical Center (N. Engl. J. Med. 2009;361:1838–47).

In the blood of patients with high-grade vulvar intraepithelial neoplasia, researchers have noted that there are low or undetectable numbers of T cells directed against the HPV-16 oncoproteins E6 and E7.

Reasoning that "vaccination might overcome this inertia of the immune system," Dr. Kenter and her colleagues proceeded to develop a vaccine containing synthetic long peptides "that represent the entire length" of these two oncoproteins.

They tested the vaccine in 20 women in a single-center observational study conducted in 2004-2007. The study was sponsored by the Dutch Cancer Society, the European Union, and ISA Pharmaceuticals B.V. These subjects were slated to receive three or four vaccinations at 3-week intervals and they were followed for 24 months.

At the 3-month follow-up, blood samples showed that 17 of the subjects had an HPV-16-specific immunologic response and enhanced production of interferon. Eleven of the patients reported symptom relief. Five patients showed a complete histologic and clinical response, and seven showed partial responses, Dr. Kenter and her associates reported.

After 1 year, the number of women showing a complete response increased to nine, and six continued to show a partial response. Twelve women reported symptom relief.

All nine women who showed a complete response were still free of disease at 2-year follow-up. Tumor microinvasion was found in one woman who had shown a partial response, and carcinoma developed in two other patients 2.5 and 3.5 years after vaccination, the investigators said.

In an editorial comment that accompanied this report, Olivera J. Finn, Ph.D., and Dr. Robert P. Edwards, who are both with the University of Pittsburgh, noted that this study was the latest in a series conducted by the same group of investigators "who over the past several years have tested this vaccine in preclinical settings for its tumor-rejection potential and for its safety and immunogenicity in end-stage cervical cancer."

The findings from this small study suggest that "more effective immune responses can be generated against precursor lesions than against late-stage disease. Many cancer vaccines based on nonviral tumor–associated antigens have been judged to be suboptimal because of their lack of efficacy in advanced disease, yet they might perform very differently if used in patients with premalignant disease," Dr. Finn and Dr. Edwards said.

If the vaccine approach is developed further, it may offer a less invasive and more durable treatment than is currently available for vulvar intraepithelial neoplasia, they said.

The Leiden University Medical Center holds a patent on the use of synthetic long peptides as vaccine. Dr. Kenter reported serving as an unpaid member of the strategy team of ISA Pharmaceuticals. Dr. Edwards reported that he received consulting fees from Fresenius SE and grant support from Sanofi-Aventis.

A vaccine that contained peptides targeting the human papillomavirus-16 oncoproteins E6 and E7 was effective against high-grade, HPV-16-positive vulvar intraepithelial neoplasia, according to the results of a small phase II study.

"This clinical efficacy is probably related to a vaccine-induced HPV-16 T-cell response," said Dr. Gemma G. Kenter and her associates at Leiden (the Netherlands) University Medical Center (N. Engl. J. Med. 2009;361:1838–47).

In the blood of patients with high-grade vulvar intraepithelial neoplasia, researchers have noted that there are low or undetectable numbers of T cells directed against the HPV-16 oncoproteins E6 and E7.

Reasoning that "vaccination might overcome this inertia of the immune system," Dr. Kenter and her colleagues proceeded to develop a vaccine containing synthetic long peptides "that represent the entire length" of these two oncoproteins.

They tested the vaccine in 20 women in a single-center observational study conducted in 2004-2007. The study was sponsored by the Dutch Cancer Society, the European Union, and ISA Pharmaceuticals B.V. These subjects were slated to receive three or four vaccinations at 3-week intervals and they were followed for 24 months.

At the 3-month follow-up, blood samples showed that 17 of the subjects had an HPV-16-specific immunologic response and enhanced production of interferon. Eleven of the patients reported symptom relief. Five patients showed a complete histologic and clinical response, and seven showed partial responses, Dr. Kenter and her associates reported.

After 1 year, the number of women showing a complete response increased to nine, and six continued to show a partial response. Twelve women reported symptom relief.

All nine women who showed a complete response were still free of disease at 2-year follow-up. Tumor microinvasion was found in one woman who had shown a partial response, and carcinoma developed in two other patients 2.5 and 3.5 years after vaccination, the investigators said.

In an editorial comment that accompanied this report, Olivera J. Finn, Ph.D., and Dr. Robert P. Edwards, who are both with the University of Pittsburgh, noted that this study was the latest in a series conducted by the same group of investigators "who over the past several years have tested this vaccine in preclinical settings for its tumor-rejection potential and for its safety and immunogenicity in end-stage cervical cancer."

The findings from this small study suggest that "more effective immune responses can be generated against precursor lesions than against late-stage disease. Many cancer vaccines based on nonviral tumor–associated antigens have been judged to be suboptimal because of their lack of efficacy in advanced disease, yet they might perform very differently if used in patients with premalignant disease," Dr. Finn and Dr. Edwards said.

If the vaccine approach is developed further, it may offer a less invasive and more durable treatment than is currently available for vulvar intraepithelial neoplasia, they said.

The Leiden University Medical Center holds a patent on the use of synthetic long peptides as vaccine. Dr. Kenter reported serving as an unpaid member of the strategy team of ISA Pharmaceuticals. Dr. Edwards reported that he received consulting fees from Fresenius SE and grant support from Sanofi-Aventis.

A vaccine that contained peptides targeting the human papillomavirus-16 oncoproteins E6 and E7 was effective against high-grade, HPV-16-positive vulvar intraepithelial neoplasia, according to the results of a small phase II study.

"This clinical efficacy is probably related to a vaccine-induced HPV-16 T-cell response," said Dr. Gemma G. Kenter and her associates at Leiden (the Netherlands) University Medical Center (N. Engl. J. Med. 2009;361:1838–47).

In the blood of patients with high-grade vulvar intraepithelial neoplasia, researchers have noted that there are low or undetectable numbers of T cells directed against the HPV-16 oncoproteins E6 and E7.

Reasoning that "vaccination might overcome this inertia of the immune system," Dr. Kenter and her colleagues proceeded to develop a vaccine containing synthetic long peptides "that represent the entire length" of these two oncoproteins.

They tested the vaccine in 20 women in a single-center observational study conducted in 2004-2007. The study was sponsored by the Dutch Cancer Society, the European Union, and ISA Pharmaceuticals B.V. These subjects were slated to receive three or four vaccinations at 3-week intervals and they were followed for 24 months.

At the 3-month follow-up, blood samples showed that 17 of the subjects had an HPV-16-specific immunologic response and enhanced production of interferon. Eleven of the patients reported symptom relief. Five patients showed a complete histologic and clinical response, and seven showed partial responses, Dr. Kenter and her associates reported.

After 1 year, the number of women showing a complete response increased to nine, and six continued to show a partial response. Twelve women reported symptom relief.

All nine women who showed a complete response were still free of disease at 2-year follow-up. Tumor microinvasion was found in one woman who had shown a partial response, and carcinoma developed in two other patients 2.5 and 3.5 years after vaccination, the investigators said.

In an editorial comment that accompanied this report, Olivera J. Finn, Ph.D., and Dr. Robert P. Edwards, who are both with the University of Pittsburgh, noted that this study was the latest in a series conducted by the same group of investigators "who over the past several years have tested this vaccine in preclinical settings for its tumor-rejection potential and for its safety and immunogenicity in end-stage cervical cancer."

The findings from this small study suggest that "more effective immune responses can be generated against precursor lesions than against late-stage disease. Many cancer vaccines based on nonviral tumor–associated antigens have been judged to be suboptimal because of their lack of efficacy in advanced disease, yet they might perform very differently if used in patients with premalignant disease," Dr. Finn and Dr. Edwards said.

If the vaccine approach is developed further, it may offer a less invasive and more durable treatment than is currently available for vulvar intraepithelial neoplasia, they said.

The Leiden University Medical Center holds a patent on the use of synthetic long peptides as vaccine. Dr. Kenter reported serving as an unpaid member of the strategy team of ISA Pharmaceuticals. Dr. Edwards reported that he received consulting fees from Fresenius SE and grant support from Sanofi-Aventis.

Genetic mutations that impair dectin-1 function have been tied to susceptibility to fungal infection in two families, according to two separate reports.

In the first study, genetic assessments were performed in a large, consanguineous Iranian family to determine whether a mutated gene was responsible for their nonsyndromic fungal infections, noted Dr. Erik-Oliver Glocker of Royal Free Hospital and University College London and his associates.

The index patient was a 19-year-old man who had had oral candidiasis since the age of 3 years but was otherwise healthy. This patient had a brother with intermittent thrush throughout his childhood and adolescence, and then suddenly died at age 19 of meningitis that proved to be caused by Candida species.

The mother of both boys, aged 50 at the time of the study, had had vaginal candidiasis since age 42. Her adult sister also had had oral and vaginal candidiasis since childhood, and their brother had had dermatophytosis since childhood. Both of this man's daughters, who both died suddenly at age 15, were given postmortem diagnoses of invasive candidal meningoencephalitis. Blood samples were obtained for DNA analysis from 36 family members and were compared with those from 50 healthy Iranian blood donors and 180 healthy white donors of other nationalities.

A previously unknown mutation in the CARD9 gene was found in 4 affected patients and 18 other relatives, but not in any of the control samples. The CARD9 gene "plays a central role in antifungal defense by receiving signals from several antifungal pattern-recognition receptors and stimulating proinflammatory responses," the investigators noted.

"Our study shows that a homozygous point mutation in CARD9 … is associated with a susceptibility to fungal infections," Dr. Glocker and his colleagues wrote. The mutation impairs the function of dectin-1, a transmembrane pattern-recognition receptor that senses the beta-glucan component of fungal cell walls (N. Engl. J. Med. 2009;361:1727–35).

In the second study, genetic analyses were performed on mononuclear cells from a patient with recurrent vulvovaginal and oral or esophageal candidiasis, as well as on cells from four relatives. The patient's two sisters had chronic onychomycosis; one of them also had recurrent vulvovaginal candidiasis. Their mother had chronic onychomycosis, and their father had transient onychomycosis.

The index patient had been found to have defective cytokine production in response to stimulation with C. albicans and with beta-glucan, indicating a potential defect in dectin-1 recognition, according to Bart Ferwerda, Ph.D., of Radboud University, Nijmegen, the Netherlands, and his associates.

The researchers identified a homozygous mutation that caused defective surface expression of dectin-1. This apparently caused an impaired cytokine response by monocytes and macrophages but did not affect the normal killing of C. albicans by neutrophils (N. Engl. J. Med. 2009;361:1760–7). Neither Dr. Glocker nor Dr. Ferwerda reported any financial conflicts of interest.

Fungal infections, such as onychomycosis, have been traced back to genetic mutations found in families.

Source Courtesy Dr. Boni E. Elewski

Genetic mutations that impair dectin-1 function have been tied to susceptibility to fungal infection in two families, according to two separate reports.

In the first study, genetic assessments were performed in a large, consanguineous Iranian family to determine whether a mutated gene was responsible for their nonsyndromic fungal infections, noted Dr. Erik-Oliver Glocker of Royal Free Hospital and University College London and his associates.

The index patient was a 19-year-old man who had had oral candidiasis since the age of 3 years but was otherwise healthy. This patient had a brother with intermittent thrush throughout his childhood and adolescence, and then suddenly died at age 19 of meningitis that proved to be caused by Candida species.

The mother of both boys, aged 50 at the time of the study, had had vaginal candidiasis since age 42. Her adult sister also had had oral and vaginal candidiasis since childhood, and their brother had had dermatophytosis since childhood. Both of this man's daughters, who both died suddenly at age 15, were given postmortem diagnoses of invasive candidal meningoencephalitis. Blood samples were obtained for DNA analysis from 36 family members and were compared with those from 50 healthy Iranian blood donors and 180 healthy white donors of other nationalities.

A previously unknown mutation in the CARD9 gene was found in 4 affected patients and 18 other relatives, but not in any of the control samples. The CARD9 gene "plays a central role in antifungal defense by receiving signals from several antifungal pattern-recognition receptors and stimulating proinflammatory responses," the investigators noted.

"Our study shows that a homozygous point mutation in CARD9 … is associated with a susceptibility to fungal infections," Dr. Glocker and his colleagues wrote. The mutation impairs the function of dectin-1, a transmembrane pattern-recognition receptor that senses the beta-glucan component of fungal cell walls (N. Engl. J. Med. 2009;361:1727–35).

In the second study, genetic analyses were performed on mononuclear cells from a patient with recurrent vulvovaginal and oral or esophageal candidiasis, as well as on cells from four relatives. The patient's two sisters had chronic onychomycosis; one of them also had recurrent vulvovaginal candidiasis. Their mother had chronic onychomycosis, and their father had transient onychomycosis.

The index patient had been found to have defective cytokine production in response to stimulation with C. albicans and with beta-glucan, indicating a potential defect in dectin-1 recognition, according to Bart Ferwerda, Ph.D., of Radboud University, Nijmegen, the Netherlands, and his associates.

The researchers identified a homozygous mutation that caused defective surface expression of dectin-1. This apparently caused an impaired cytokine response by monocytes and macrophages but did not affect the normal killing of C. albicans by neutrophils (N. Engl. J. Med. 2009;361:1760–7). Neither Dr. Glocker nor Dr. Ferwerda reported any financial conflicts of interest.

Fungal infections, such as onychomycosis, have been traced back to genetic mutations found in families.

Source Courtesy Dr. Boni E. Elewski

Genetic mutations that impair dectin-1 function have been tied to susceptibility to fungal infection in two families, according to two separate reports.

In the first study, genetic assessments were performed in a large, consanguineous Iranian family to determine whether a mutated gene was responsible for their nonsyndromic fungal infections, noted Dr. Erik-Oliver Glocker of Royal Free Hospital and University College London and his associates.

The index patient was a 19-year-old man who had had oral candidiasis since the age of 3 years but was otherwise healthy. This patient had a brother with intermittent thrush throughout his childhood and adolescence, and then suddenly died at age 19 of meningitis that proved to be caused by Candida species.

The mother of both boys, aged 50 at the time of the study, had had vaginal candidiasis since age 42. Her adult sister also had had oral and vaginal candidiasis since childhood, and their brother had had dermatophytosis since childhood. Both of this man's daughters, who both died suddenly at age 15, were given postmortem diagnoses of invasive candidal meningoencephalitis. Blood samples were obtained for DNA analysis from 36 family members and were compared with those from 50 healthy Iranian blood donors and 180 healthy white donors of other nationalities.

A previously unknown mutation in the CARD9 gene was found in 4 affected patients and 18 other relatives, but not in any of the control samples. The CARD9 gene "plays a central role in antifungal defense by receiving signals from several antifungal pattern-recognition receptors and stimulating proinflammatory responses," the investigators noted.

"Our study shows that a homozygous point mutation in CARD9 … is associated with a susceptibility to fungal infections," Dr. Glocker and his colleagues wrote. The mutation impairs the function of dectin-1, a transmembrane pattern-recognition receptor that senses the beta-glucan component of fungal cell walls (N. Engl. J. Med. 2009;361:1727–35).

In the second study, genetic analyses were performed on mononuclear cells from a patient with recurrent vulvovaginal and oral or esophageal candidiasis, as well as on cells from four relatives. The patient's two sisters had chronic onychomycosis; one of them also had recurrent vulvovaginal candidiasis. Their mother had chronic onychomycosis, and their father had transient onychomycosis.

The index patient had been found to have defective cytokine production in response to stimulation with C. albicans and with beta-glucan, indicating a potential defect in dectin-1 recognition, according to Bart Ferwerda, Ph.D., of Radboud University, Nijmegen, the Netherlands, and his associates.

The researchers identified a homozygous mutation that caused defective surface expression of dectin-1. This apparently caused an impaired cytokine response by monocytes and macrophages but did not affect the normal killing of C. albicans by neutrophils (N. Engl. J. Med. 2009;361:1760–7). Neither Dr. Glocker nor Dr. Ferwerda reported any financial conflicts of interest.

Fungal infections, such as onychomycosis, have been traced back to genetic mutations found in families.

Source Courtesy Dr. Boni E. Elewski

Automated, liquid-based cytology was found to be no more sensitive or specific than standard Pap smears in detecting cervical intraepithelial neoplasia or cancer, according to a report.

In what they described as “the largest high-quality study performed in a population-based setting with blind verification of follow-up outcomes of all test-positive cases,” the study's investigators found that liquid-based cytology was not superior to Pap testing.

Until now, neither screening method has been definitively established as better than the other, because there haven't been enough well-designed comparative studies, wrote Dr. Albertus G. Siebers of Radboud University Nijmegen (the Netherlands) Medical Center and associates.

Nevertheless, liquid-based cytology has virtually replaced conventional Pap smears in the United States. It is preferred by most laboratories, because specimens are more easily and rapidly scanned under the microscope, Dr. Mark Schiffman and Dr. Diane Solomon wrote in an editorial (JAMA 2009;302:1809-10).

The investigators assessed testing outcomes in 84,322 Dutch women aged 30-60 years who were screened at 246 family practices. A total of 45,818 women attended practices that had been randomly assigned to use liquid-based cytology and 38,504 attended practices that had been assigned to use Pap smears.

In an intention-to-treat analysis, the adjusted detection rate ratios for cervical intraepithelial neoplasia (CIN) grade 1+ was 1.01; for CIN grade 2+ was 1.00; for CIN grade 3+ was 1.05, and for carcinoma was 1.69.

“Our study found no difference in sensitivity in terms of histological detection rates of cervical lesions, or in the positive predictive values between liquid-based cytology and Pap test, indicating that the accuracy of both methods is comparable,” the investigators reported (JAMA 2009;302:1757-64).

Mr. Siebers reported no conflicts of interest. Dr. Schiffman and Dr. Solomon reported that they are serving as medical monitors of the Costa Rican HPV Vaccine Trial, which is supported in part by GSK Biologicals and GlaxoSmithKline.

Automated, liquid-based cytology was found to be no more sensitive or specific than standard Pap smears in detecting cervical intraepithelial neoplasia or cancer, according to a report.

In what they described as “the largest high-quality study performed in a population-based setting with blind verification of follow-up outcomes of all test-positive cases,” the study's investigators found that liquid-based cytology was not superior to Pap testing.

Until now, neither screening method has been definitively established as better than the other, because there haven't been enough well-designed comparative studies, wrote Dr. Albertus G. Siebers of Radboud University Nijmegen (the Netherlands) Medical Center and associates.

Nevertheless, liquid-based cytology has virtually replaced conventional Pap smears in the United States. It is preferred by most laboratories, because specimens are more easily and rapidly scanned under the microscope, Dr. Mark Schiffman and Dr. Diane Solomon wrote in an editorial (JAMA 2009;302:1809-10).

The investigators assessed testing outcomes in 84,322 Dutch women aged 30-60 years who were screened at 246 family practices. A total of 45,818 women attended practices that had been randomly assigned to use liquid-based cytology and 38,504 attended practices that had been assigned to use Pap smears.

In an intention-to-treat analysis, the adjusted detection rate ratios for cervical intraepithelial neoplasia (CIN) grade 1+ was 1.01; for CIN grade 2+ was 1.00; for CIN grade 3+ was 1.05, and for carcinoma was 1.69.

“Our study found no difference in sensitivity in terms of histological detection rates of cervical lesions, or in the positive predictive values between liquid-based cytology and Pap test, indicating that the accuracy of both methods is comparable,” the investigators reported (JAMA 2009;302:1757-64).

Mr. Siebers reported no conflicts of interest. Dr. Schiffman and Dr. Solomon reported that they are serving as medical monitors of the Costa Rican HPV Vaccine Trial, which is supported in part by GSK Biologicals and GlaxoSmithKline.

Automated, liquid-based cytology was found to be no more sensitive or specific than standard Pap smears in detecting cervical intraepithelial neoplasia or cancer, according to a report.

In what they described as “the largest high-quality study performed in a population-based setting with blind verification of follow-up outcomes of all test-positive cases,” the study's investigators found that liquid-based cytology was not superior to Pap testing.

Until now, neither screening method has been definitively established as better than the other, because there haven't been enough well-designed comparative studies, wrote Dr. Albertus G. Siebers of Radboud University Nijmegen (the Netherlands) Medical Center and associates.

Nevertheless, liquid-based cytology has virtually replaced conventional Pap smears in the United States. It is preferred by most laboratories, because specimens are more easily and rapidly scanned under the microscope, Dr. Mark Schiffman and Dr. Diane Solomon wrote in an editorial (JAMA 2009;302:1809-10).

The investigators assessed testing outcomes in 84,322 Dutch women aged 30-60 years who were screened at 246 family practices. A total of 45,818 women attended practices that had been randomly assigned to use liquid-based cytology and 38,504 attended practices that had been assigned to use Pap smears.

In an intention-to-treat analysis, the adjusted detection rate ratios for cervical intraepithelial neoplasia (CIN) grade 1+ was 1.01; for CIN grade 2+ was 1.00; for CIN grade 3+ was 1.05, and for carcinoma was 1.69.

“Our study found no difference in sensitivity in terms of histological detection rates of cervical lesions, or in the positive predictive values between liquid-based cytology and Pap test, indicating that the accuracy of both methods is comparable,” the investigators reported (JAMA 2009;302:1757-64).

Mr. Siebers reported no conflicts of interest. Dr. Schiffman and Dr. Solomon reported that they are serving as medical monitors of the Costa Rican HPV Vaccine Trial, which is supported in part by GSK Biologicals and GlaxoSmithKline.

Combining the nicotine patch with nicotine lozenges appears to be the most effective approach for smoking cessation, according to a report.

In a study directly comparing the effectiveness of five pharmacotherapies for smoking cessation against placebo, the patch-plus-lozenge combination “emerged as the only efficacious treatment… at 6 months post quit,” said Megan E. Piper, Ph.D., of the Center for Tobacco Research and Intervention at the University of Wisconsin, Madison, and her associates.

This particular combination therapy “has not been previously evaluated,” they noted.

The study involved 1,504 adult smokers who agreed to participate in a 3-year trial of smoking cessation, which reflects their high motivation to quit. Most of the study subjects were white (83%) and female (58%).

These subjects were randomly assigned to one of six treatments for 8 weeks: daily sustained-release bupropion (264 patients), nicotine lozenges (260 patients), nicotine patches (262 patients), nicotine lozenges plus nicotine patches (267 patients), bupropion plus nicotine lozenges (262 patients), or matched placebo (189 patients). All also received six individual counseling sessions of 10- to 20-minute duration with case managers who were supervised by a clinical psychologist.

In the initial analysis, all the active treatments yielded higher rates of cessation at day 1, week 1, the end of treatment, and 6 months after completing treatment.

However, further analysis showed that only the combination of nicotine patches plus nicotine lozenges was significantly more effective than placebo at all of these time points.

Patients who received the combination of nicotine patches plus nicotine lozenges also had a longer interval until first “lapse” and a longer interval until full relapse than did subjects in the other study groups, Dr. Piper and her colleagues said (Arch. Gen. Psychiatry 2009;66:1253-62).

It is important to note that the placebo group in this study achieved a much higher smoking cessation rate (22%) than is usual with placebo. This “may have been due to the intensive counseling participants received, or to the high level of motivation required to participate in a 3-year longitudinal trial,” the investigators added.

Treatment effects diminished significantly as soon as the course of therapy was completed. This suggests that longer-term treatment might be more effective, they said.

On average, the study subjects used only approximately 77% of their study medication, but the rate of adherence varied widely between groups. Patients assigned to nicotine lozenges used significantly less of that medication—67% of what they were given—than patients in any other group.

This suggests that smokers may be “especially unlikely to use as-needed medications adherently (i.e., a recommendation of nine lozenges per day),” the researchers said.

The investigators cited two limitations of the study. First, because the study was longitudinal, it might have “selected participants with greater motivation to quit than smokers in the general population,” they wrote.

Also, the study did not include among the tested medications varenicline—which had not yet been approved by the Food and Drug Administration for smoking cessation. “Therefore, it is unknown how these agents would have fared relative to varenicline, the monotherapy designated as most effective by the 2008 [Public Health Service] Guideline.”

Still, these findings and the 2008 guideline update suggest that a combination of pharmacotherapy made up of the patch and nicotine replacement therapy should be routinely considered for smoking cessation treatment, they wrote.

GlaxoSmithKline provided the medication to patients at no cost under a research agreement. Dr. Piper reported no financial conflicts of interest.

Combining the nicotine patch with nicotine lozenges appears to be the most effective approach for smoking cessation, according to a report.

In a study directly comparing the effectiveness of five pharmacotherapies for smoking cessation against placebo, the patch-plus-lozenge combination “emerged as the only efficacious treatment… at 6 months post quit,” said Megan E. Piper, Ph.D., of the Center for Tobacco Research and Intervention at the University of Wisconsin, Madison, and her associates.

This particular combination therapy “has not been previously evaluated,” they noted.

The study involved 1,504 adult smokers who agreed to participate in a 3-year trial of smoking cessation, which reflects their high motivation to quit. Most of the study subjects were white (83%) and female (58%).

These subjects were randomly assigned to one of six treatments for 8 weeks: daily sustained-release bupropion (264 patients), nicotine lozenges (260 patients), nicotine patches (262 patients), nicotine lozenges plus nicotine patches (267 patients), bupropion plus nicotine lozenges (262 patients), or matched placebo (189 patients). All also received six individual counseling sessions of 10- to 20-minute duration with case managers who were supervised by a clinical psychologist.

In the initial analysis, all the active treatments yielded higher rates of cessation at day 1, week 1, the end of treatment, and 6 months after completing treatment.

However, further analysis showed that only the combination of nicotine patches plus nicotine lozenges was significantly more effective than placebo at all of these time points.

Patients who received the combination of nicotine patches plus nicotine lozenges also had a longer interval until first “lapse” and a longer interval until full relapse than did subjects in the other study groups, Dr. Piper and her colleagues said (Arch. Gen. Psychiatry 2009;66:1253-62).

It is important to note that the placebo group in this study achieved a much higher smoking cessation rate (22%) than is usual with placebo. This “may have been due to the intensive counseling participants received, or to the high level of motivation required to participate in a 3-year longitudinal trial,” the investigators added.

Treatment effects diminished significantly as soon as the course of therapy was completed. This suggests that longer-term treatment might be more effective, they said.

On average, the study subjects used only approximately 77% of their study medication, but the rate of adherence varied widely between groups. Patients assigned to nicotine lozenges used significantly less of that medication—67% of what they were given—than patients in any other group.

This suggests that smokers may be “especially unlikely to use as-needed medications adherently (i.e., a recommendation of nine lozenges per day),” the researchers said.

The investigators cited two limitations of the study. First, because the study was longitudinal, it might have “selected participants with greater motivation to quit than smokers in the general population,” they wrote.

Also, the study did not include among the tested medications varenicline—which had not yet been approved by the Food and Drug Administration for smoking cessation. “Therefore, it is unknown how these agents would have fared relative to varenicline, the monotherapy designated as most effective by the 2008 [Public Health Service] Guideline.”

Still, these findings and the 2008 guideline update suggest that a combination of pharmacotherapy made up of the patch and nicotine replacement therapy should be routinely considered for smoking cessation treatment, they wrote.

GlaxoSmithKline provided the medication to patients at no cost under a research agreement. Dr. Piper reported no financial conflicts of interest.

Combining the nicotine patch with nicotine lozenges appears to be the most effective approach for smoking cessation, according to a report.

In a study directly comparing the effectiveness of five pharmacotherapies for smoking cessation against placebo, the patch-plus-lozenge combination “emerged as the only efficacious treatment… at 6 months post quit,” said Megan E. Piper, Ph.D., of the Center for Tobacco Research and Intervention at the University of Wisconsin, Madison, and her associates.

This particular combination therapy “has not been previously evaluated,” they noted.

The study involved 1,504 adult smokers who agreed to participate in a 3-year trial of smoking cessation, which reflects their high motivation to quit. Most of the study subjects were white (83%) and female (58%).

These subjects were randomly assigned to one of six treatments for 8 weeks: daily sustained-release bupropion (264 patients), nicotine lozenges (260 patients), nicotine patches (262 patients), nicotine lozenges plus nicotine patches (267 patients), bupropion plus nicotine lozenges (262 patients), or matched placebo (189 patients). All also received six individual counseling sessions of 10- to 20-minute duration with case managers who were supervised by a clinical psychologist.

In the initial analysis, all the active treatments yielded higher rates of cessation at day 1, week 1, the end of treatment, and 6 months after completing treatment.

However, further analysis showed that only the combination of nicotine patches plus nicotine lozenges was significantly more effective than placebo at all of these time points.

Patients who received the combination of nicotine patches plus nicotine lozenges also had a longer interval until first “lapse” and a longer interval until full relapse than did subjects in the other study groups, Dr. Piper and her colleagues said (Arch. Gen. Psychiatry 2009;66:1253-62).

It is important to note that the placebo group in this study achieved a much higher smoking cessation rate (22%) than is usual with placebo. This “may have been due to the intensive counseling participants received, or to the high level of motivation required to participate in a 3-year longitudinal trial,” the investigators added.

Treatment effects diminished significantly as soon as the course of therapy was completed. This suggests that longer-term treatment might be more effective, they said.

On average, the study subjects used only approximately 77% of their study medication, but the rate of adherence varied widely between groups. Patients assigned to nicotine lozenges used significantly less of that medication—67% of what they were given—than patients in any other group.

This suggests that smokers may be “especially unlikely to use as-needed medications adherently (i.e., a recommendation of nine lozenges per day),” the researchers said.

The investigators cited two limitations of the study. First, because the study was longitudinal, it might have “selected participants with greater motivation to quit than smokers in the general population,” they wrote.

Also, the study did not include among the tested medications varenicline—which had not yet been approved by the Food and Drug Administration for smoking cessation. “Therefore, it is unknown how these agents would have fared relative to varenicline, the monotherapy designated as most effective by the 2008 [Public Health Service] Guideline.”

Still, these findings and the 2008 guideline update suggest that a combination of pharmacotherapy made up of the patch and nicotine replacement therapy should be routinely considered for smoking cessation treatment, they wrote.

GlaxoSmithKline provided the medication to patients at no cost under a research agreement. Dr. Piper reported no financial conflicts of interest.

A variety of outcomes were poorer with off-pump than with on-pump coronary artery bypass graft in a large clinical trial directly comparing the two procedures, said A. Laurie Shroyer, Ph.D., of Northport (N.Y.) Veterans Affairs Medical Center and associates.

In the Randomized On/Off Bypass trial, both short-term and 1-year mortality, as well as rates of major complications, MI, revascularization procedures, and graft patency, all were worse with the off-pump approach. Most surprisingly, rates of neuropsychological sequelae were not significantly different.

“Our trial did not show any overall advantage to the use of the off-pump” coronary artery bypass graft (CABG), the authors wrote (N. Engl. J. Med. 2009;361:1827-37).

The prospective study involved 2,203 patients undergoing elective or urgent CABG between 2002 and 2008 at 18 VA medical centers. Most (over 99%) were white men who were current or former smokers and had at least one comorbid condition; over 40% had diabetes. A majority had three-vessel coronary artery disease and normal left ventricular function.

The study subjects were randomly assigned to on-pump (1,099 patients) or off-pump (1,104 patients) surgery while waiting in the preoperative holding area.

The primary short-term end point was a composite of death or major complications such as reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure requiring dialysis within 30 days. The primary long-term end point was death from any cause, nonfatal MI, or repeat revascularization within 1 year.

The short-term composite outcome was not significantly different between the two groups, affecting 7.0% of the off-pump group and 5.6% of the on-pump group. In contrast, the long-term composite outcome was significantly higher in the off-pump group (9.9%) than in the on-pump group (7.4%).

A subsequent sensitivity analysis of the data “showed even stronger advantages for on-pump procedures,” the investigators said.

The rate of graft patency at 1 year was significantly lower for the off-pump group (82.6%) than the on-pump group (87.8%). Significantly more patients in the off-pump group (36.5%) had at least 1 occluded graft than in the on-pump group (28.7%).

Among those with no occluded grafts, the primary 1-year composite outcome was lower in the on-pump group than in the off-pump (3.3% vs. 6.4%). The researchers speculated that this was because “there was less complete revascularization in the off-pump group.”

A subset of 1,156 study subjects had completed a battery of neuropsychological tests at baseline and was retested at 1 year. Dysfunctions in attention, memory, and visuospatial skills were assessed.

Unexpectedly, there were no significant differences between the two treatment groups on these measures, and the changes in individual test scores either were minimal or showed improvement after surgery for both groups, Dr. Shroyer and colleagues said.

“A number of studies have suggested that cardiopulmonary bypass causes permanent neurologic dysfunction or decreases cognition and motor abilities. Our trial did not show a cognitive decline within 1 year after surgery in either group,” they noted.

Dr. Shroyer reported no potential conflicts of interest.

A variety of outcomes were poorer with off-pump than with on-pump coronary artery bypass graft in a large clinical trial directly comparing the two procedures, said A. Laurie Shroyer, Ph.D., of Northport (N.Y.) Veterans Affairs Medical Center and associates.

In the Randomized On/Off Bypass trial, both short-term and 1-year mortality, as well as rates of major complications, MI, revascularization procedures, and graft patency, all were worse with the off-pump approach. Most surprisingly, rates of neuropsychological sequelae were not significantly different.

“Our trial did not show any overall advantage to the use of the off-pump” coronary artery bypass graft (CABG), the authors wrote (N. Engl. J. Med. 2009;361:1827-37).

The prospective study involved 2,203 patients undergoing elective or urgent CABG between 2002 and 2008 at 18 VA medical centers. Most (over 99%) were white men who were current or former smokers and had at least one comorbid condition; over 40% had diabetes. A majority had three-vessel coronary artery disease and normal left ventricular function.

The study subjects were randomly assigned to on-pump (1,099 patients) or off-pump (1,104 patients) surgery while waiting in the preoperative holding area.

The primary short-term end point was a composite of death or major complications such as reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure requiring dialysis within 30 days. The primary long-term end point was death from any cause, nonfatal MI, or repeat revascularization within 1 year.

The short-term composite outcome was not significantly different between the two groups, affecting 7.0% of the off-pump group and 5.6% of the on-pump group. In contrast, the long-term composite outcome was significantly higher in the off-pump group (9.9%) than in the on-pump group (7.4%).

A subsequent sensitivity analysis of the data “showed even stronger advantages for on-pump procedures,” the investigators said.

The rate of graft patency at 1 year was significantly lower for the off-pump group (82.6%) than the on-pump group (87.8%). Significantly more patients in the off-pump group (36.5%) had at least 1 occluded graft than in the on-pump group (28.7%).

Among those with no occluded grafts, the primary 1-year composite outcome was lower in the on-pump group than in the off-pump (3.3% vs. 6.4%). The researchers speculated that this was because “there was less complete revascularization in the off-pump group.”

A subset of 1,156 study subjects had completed a battery of neuropsychological tests at baseline and was retested at 1 year. Dysfunctions in attention, memory, and visuospatial skills were assessed.

Unexpectedly, there were no significant differences between the two treatment groups on these measures, and the changes in individual test scores either were minimal or showed improvement after surgery for both groups, Dr. Shroyer and colleagues said.

“A number of studies have suggested that cardiopulmonary bypass causes permanent neurologic dysfunction or decreases cognition and motor abilities. Our trial did not show a cognitive decline within 1 year after surgery in either group,” they noted.

Dr. Shroyer reported no potential conflicts of interest.

A variety of outcomes were poorer with off-pump than with on-pump coronary artery bypass graft in a large clinical trial directly comparing the two procedures, said A. Laurie Shroyer, Ph.D., of Northport (N.Y.) Veterans Affairs Medical Center and associates.

In the Randomized On/Off Bypass trial, both short-term and 1-year mortality, as well as rates of major complications, MI, revascularization procedures, and graft patency, all were worse with the off-pump approach. Most surprisingly, rates of neuropsychological sequelae were not significantly different.

“Our trial did not show any overall advantage to the use of the off-pump” coronary artery bypass graft (CABG), the authors wrote (N. Engl. J. Med. 2009;361:1827-37).

The prospective study involved 2,203 patients undergoing elective or urgent CABG between 2002 and 2008 at 18 VA medical centers. Most (over 99%) were white men who were current or former smokers and had at least one comorbid condition; over 40% had diabetes. A majority had three-vessel coronary artery disease and normal left ventricular function.

The study subjects were randomly assigned to on-pump (1,099 patients) or off-pump (1,104 patients) surgery while waiting in the preoperative holding area.

The primary short-term end point was a composite of death or major complications such as reoperation, new mechanical support, cardiac arrest, coma, stroke, or renal failure requiring dialysis within 30 days. The primary long-term end point was death from any cause, nonfatal MI, or repeat revascularization within 1 year.

The short-term composite outcome was not significantly different between the two groups, affecting 7.0% of the off-pump group and 5.6% of the on-pump group. In contrast, the long-term composite outcome was significantly higher in the off-pump group (9.9%) than in the on-pump group (7.4%).

A subsequent sensitivity analysis of the data “showed even stronger advantages for on-pump procedures,” the investigators said.

The rate of graft patency at 1 year was significantly lower for the off-pump group (82.6%) than the on-pump group (87.8%). Significantly more patients in the off-pump group (36.5%) had at least 1 occluded graft than in the on-pump group (28.7%).

Among those with no occluded grafts, the primary 1-year composite outcome was lower in the on-pump group than in the off-pump (3.3% vs. 6.4%). The researchers speculated that this was because “there was less complete revascularization in the off-pump group.”

A subset of 1,156 study subjects had completed a battery of neuropsychological tests at baseline and was retested at 1 year. Dysfunctions in attention, memory, and visuospatial skills were assessed.

Unexpectedly, there were no significant differences between the two treatment groups on these measures, and the changes in individual test scores either were minimal or showed improvement after surgery for both groups, Dr. Shroyer and colleagues said.

“A number of studies have suggested that cardiopulmonary bypass causes permanent neurologic dysfunction or decreases cognition and motor abilities. Our trial did not show a cognitive decline within 1 year after surgery in either group,” they noted.

Dr. Shroyer reported no potential conflicts of interest.