AHA Scientific Sessions 2012

LOS ANGELES – Treatment proven to cut platelet reactivity in medically managed patients following an acute coronary syndrome event failed to improve clinical outcomes in a trial substudy with more than 2,500 patients, prompting experts to rethink their approach to managing patients with acute coronary disease who do not receive a coronary stent.

The "lack of a significant, independent association between platelet reactivity and ischemic outcomes may explain the comparable clinical outcomes" in the overall results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, Dr. Paul A. Gurbel said at the annual scientific sessions of the American Heart Association.

"The value of platelet function testing will depend on the risk of the patient," said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He drew a distinction between the patients enrolled in TRILOGY ACS, which by design restricted enrolled acute coronary syndrome patients to only those targeted for exclusively medical management, and ACS patients who need to receive one or more coronary stents.

"In low-risk patients [those who don’t need a stent], it’s hard to do any change of treatment that improves outcomes, but we don’t have data on personalizing antiplatelet treatment for higher-risk patients," who require stenting, he said. "We know that in higher-risk patients, administering a more potent antiplatelet agent does have clinical benefit.

"I think the key is all about risk. The TRILOGY results clearly show that events occurred even at very low levels of platelet reactivity. That tells you something is driving these ischemic events beyond the interaction of ADP with a P2Y₁₂ receptor," the action blocked by the two thienopyridines compared in TRILOGY ACS, prasugrel (Effient) and clopidogrel [Plavix], Dr. Gurbel said in an interview. "This pathway is very important, but it doesn’t seem to play a major role unless the patient has a stent."

Dr. Gurbel suggested that in the nonstented, medically managed ACS patients in TRILOGY ACS, other factors that might drive ischemic events could include endothelial dysfunction and nonthrombotic mediated ischemic events. "With patients who have stents, it’s a purer pathophysiology, where we know that the P2Y₁₂ receptor plays an important role.

To Dr. Gurbel, the new findings he reported from the TRILOGY ACS substudy suggest that a similar comparison of platelet reactivity following prasugrel or clopidogrel treatment should be done in ACS patients who have undergone percutaneous coronary intervention and received a stent.

Mitchel L. Zoler/IMNG Medical Media

Dr. Lars Wallentin had a different take on the findings. He suggested that the way to optimize treatment in medically managed ACS patients is to "try something different," such as ticagrelor (Brilinta), the investigational agent vorapaxar, or an anticoagulant. The substudy results "show you can’t reduce risk by increasing the dose of a thienopyridine," said Dr. Wallentin, professor of medicine and director of the Clinical Research Center at Uppsala University in Sweden.

The TRILOGY ACS platelet-function substudy piggybacked on a clinical-event comparison of prasugrel and clopidogrel in 9,326 ACS patients managed medically. Primary results from the overall trial, first reported last August, showed no difference in clinical end points between patients who received these two thienopyridines.

The prespecified substudy, which included 1,286 patients treated with prasugrel and 1,278 who received clopidogrel, involved serial measurements of platelet reactivity in these patients using VerifyNow devices, at baseline, after 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months into the study. These measurements showed that prasugrel treatment resulted in robust, statistically significant incremental reductions in platelet activity, compared with clopidogrel, within 1 month after the onset of treatment and continuing through the study’s 2.5 years.

In univariate analyses, reduced platelet reactivity significantly linked with reduced numbers of clinical events through 30 months. However, after adjustment for a long list of potential confounders at baseline, the degree of platelet reactivity failed to show any statistically significant relation to the incidence of clinical events, Dr. Gurbel reported.

Concurrent with his talk at the meeting, the findings appeared in an article published online (JAMA 2012;308:1785-94).

The TRILOGY ACS study was sponsored by Eli Lilly and Daiichi Sankyo, which market prasugrel. Dr. Gurbel said that he has been a consultant to and has received research grants from Eli Lilly and from several other drug companies. Dr. Wallentin served as lead investigator for PLATO, the pivotal trial of ticagrelor. He has received research funding and other financial benefit from AstraZeneca, the company that markets ticagrelor, and that he has served as a consultant to and has received research funding from several other drug companies.

LOS ANGELES – Treatment proven to cut platelet reactivity in medically managed patients following an acute coronary syndrome event failed to improve clinical outcomes in a trial substudy with more than 2,500 patients, prompting experts to rethink their approach to managing patients with acute coronary disease who do not receive a coronary stent.

The "lack of a significant, independent association between platelet reactivity and ischemic outcomes may explain the comparable clinical outcomes" in the overall results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, Dr. Paul A. Gurbel said at the annual scientific sessions of the American Heart Association.

"The value of platelet function testing will depend on the risk of the patient," said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He drew a distinction between the patients enrolled in TRILOGY ACS, which by design restricted enrolled acute coronary syndrome patients to only those targeted for exclusively medical management, and ACS patients who need to receive one or more coronary stents.

"In low-risk patients [those who don’t need a stent], it’s hard to do any change of treatment that improves outcomes, but we don’t have data on personalizing antiplatelet treatment for higher-risk patients," who require stenting, he said. "We know that in higher-risk patients, administering a more potent antiplatelet agent does have clinical benefit.

"I think the key is all about risk. The TRILOGY results clearly show that events occurred even at very low levels of platelet reactivity. That tells you something is driving these ischemic events beyond the interaction of ADP with a P2Y₁₂ receptor," the action blocked by the two thienopyridines compared in TRILOGY ACS, prasugrel (Effient) and clopidogrel [Plavix], Dr. Gurbel said in an interview. "This pathway is very important, but it doesn’t seem to play a major role unless the patient has a stent."

Dr. Gurbel suggested that in the nonstented, medically managed ACS patients in TRILOGY ACS, other factors that might drive ischemic events could include endothelial dysfunction and nonthrombotic mediated ischemic events. "With patients who have stents, it’s a purer pathophysiology, where we know that the P2Y₁₂ receptor plays an important role.

To Dr. Gurbel, the new findings he reported from the TRILOGY ACS substudy suggest that a similar comparison of platelet reactivity following prasugrel or clopidogrel treatment should be done in ACS patients who have undergone percutaneous coronary intervention and received a stent.

Mitchel L. Zoler/IMNG Medical Media

Dr. Lars Wallentin had a different take on the findings. He suggested that the way to optimize treatment in medically managed ACS patients is to "try something different," such as ticagrelor (Brilinta), the investigational agent vorapaxar, or an anticoagulant. The substudy results "show you can’t reduce risk by increasing the dose of a thienopyridine," said Dr. Wallentin, professor of medicine and director of the Clinical Research Center at Uppsala University in Sweden.

The TRILOGY ACS platelet-function substudy piggybacked on a clinical-event comparison of prasugrel and clopidogrel in 9,326 ACS patients managed medically. Primary results from the overall trial, first reported last August, showed no difference in clinical end points between patients who received these two thienopyridines.

The prespecified substudy, which included 1,286 patients treated with prasugrel and 1,278 who received clopidogrel, involved serial measurements of platelet reactivity in these patients using VerifyNow devices, at baseline, after 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months into the study. These measurements showed that prasugrel treatment resulted in robust, statistically significant incremental reductions in platelet activity, compared with clopidogrel, within 1 month after the onset of treatment and continuing through the study’s 2.5 years.

In univariate analyses, reduced platelet reactivity significantly linked with reduced numbers of clinical events through 30 months. However, after adjustment for a long list of potential confounders at baseline, the degree of platelet reactivity failed to show any statistically significant relation to the incidence of clinical events, Dr. Gurbel reported.

Concurrent with his talk at the meeting, the findings appeared in an article published online (JAMA 2012;308:1785-94).

The TRILOGY ACS study was sponsored by Eli Lilly and Daiichi Sankyo, which market prasugrel. Dr. Gurbel said that he has been a consultant to and has received research grants from Eli Lilly and from several other drug companies. Dr. Wallentin served as lead investigator for PLATO, the pivotal trial of ticagrelor. He has received research funding and other financial benefit from AstraZeneca, the company that markets ticagrelor, and that he has served as a consultant to and has received research funding from several other drug companies.

LOS ANGELES – Treatment proven to cut platelet reactivity in medically managed patients following an acute coronary syndrome event failed to improve clinical outcomes in a trial substudy with more than 2,500 patients, prompting experts to rethink their approach to managing patients with acute coronary disease who do not receive a coronary stent.

The "lack of a significant, independent association between platelet reactivity and ischemic outcomes may explain the comparable clinical outcomes" in the overall results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, Dr. Paul A. Gurbel said at the annual scientific sessions of the American Heart Association.

"The value of platelet function testing will depend on the risk of the patient," said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore. He drew a distinction between the patients enrolled in TRILOGY ACS, which by design restricted enrolled acute coronary syndrome patients to only those targeted for exclusively medical management, and ACS patients who need to receive one or more coronary stents.

"In low-risk patients [those who don’t need a stent], it’s hard to do any change of treatment that improves outcomes, but we don’t have data on personalizing antiplatelet treatment for higher-risk patients," who require stenting, he said. "We know that in higher-risk patients, administering a more potent antiplatelet agent does have clinical benefit.

"I think the key is all about risk. The TRILOGY results clearly show that events occurred even at very low levels of platelet reactivity. That tells you something is driving these ischemic events beyond the interaction of ADP with a P2Y₁₂ receptor," the action blocked by the two thienopyridines compared in TRILOGY ACS, prasugrel (Effient) and clopidogrel [Plavix], Dr. Gurbel said in an interview. "This pathway is very important, but it doesn’t seem to play a major role unless the patient has a stent."

Dr. Gurbel suggested that in the nonstented, medically managed ACS patients in TRILOGY ACS, other factors that might drive ischemic events could include endothelial dysfunction and nonthrombotic mediated ischemic events. "With patients who have stents, it’s a purer pathophysiology, where we know that the P2Y₁₂ receptor plays an important role.

To Dr. Gurbel, the new findings he reported from the TRILOGY ACS substudy suggest that a similar comparison of platelet reactivity following prasugrel or clopidogrel treatment should be done in ACS patients who have undergone percutaneous coronary intervention and received a stent.

Mitchel L. Zoler/IMNG Medical Media

Dr. Lars Wallentin had a different take on the findings. He suggested that the way to optimize treatment in medically managed ACS patients is to "try something different," such as ticagrelor (Brilinta), the investigational agent vorapaxar, or an anticoagulant. The substudy results "show you can’t reduce risk by increasing the dose of a thienopyridine," said Dr. Wallentin, professor of medicine and director of the Clinical Research Center at Uppsala University in Sweden.

The TRILOGY ACS platelet-function substudy piggybacked on a clinical-event comparison of prasugrel and clopidogrel in 9,326 ACS patients managed medically. Primary results from the overall trial, first reported last August, showed no difference in clinical end points between patients who received these two thienopyridines.

The prespecified substudy, which included 1,286 patients treated with prasugrel and 1,278 who received clopidogrel, involved serial measurements of platelet reactivity in these patients using VerifyNow devices, at baseline, after 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months into the study. These measurements showed that prasugrel treatment resulted in robust, statistically significant incremental reductions in platelet activity, compared with clopidogrel, within 1 month after the onset of treatment and continuing through the study’s 2.5 years.

In univariate analyses, reduced platelet reactivity significantly linked with reduced numbers of clinical events through 30 months. However, after adjustment for a long list of potential confounders at baseline, the degree of platelet reactivity failed to show any statistically significant relation to the incidence of clinical events, Dr. Gurbel reported.

Concurrent with his talk at the meeting, the findings appeared in an article published online (JAMA 2012;308:1785-94).

The TRILOGY ACS study was sponsored by Eli Lilly and Daiichi Sankyo, which market prasugrel. Dr. Gurbel said that he has been a consultant to and has received research grants from Eli Lilly and from several other drug companies. Dr. Wallentin served as lead investigator for PLATO, the pivotal trial of ticagrelor. He has received research funding and other financial benefit from AstraZeneca, the company that markets ticagrelor, and that he has served as a consultant to and has received research funding from several other drug companies.

The investigational anti-PCSK9 antibody AMG145 significantly lowers LDL cholesterol in high-risk patients unable to tolerate statins, the phase II GAUSS trial showed.

Three subcutaneous injections of AMG145 at varying doses reduced LDL cholesterol by up to 51% when used as monotherapy, and by 63% when combined with ezetimibe (Zetia), compared with an expected 15% reduction with ezetimibe and placebo.

These reductions are comparable with those achieved with maximal doses of the most efficacious statins.

If the results are confirmed in larger and longer-term studies, AMG145 could provide a new therapeutic option for high-risk patients who currently have few treatment options, Dr. Evan Stein reported at the annual scientific sessions of the American Heart Association in Los Angeles.

In GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), 84% of all patients were unable to tolerate even low doses of any statin.

Overall, about 10%-20% of people can’t tolerate statins at all or the higher doses needed to achieve recommended LDL cholesterol goals, primarily because of muscle-related side effects. Ezetimibe is frequently used as an alternative for these patients, but without great success.

Evidence and enthusiasm are growing, however, for the use of monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that binds to and destroys LDL receptors. It is thought that blocking the destructive capacity of PCSK9 can lead to more LDL receptors on cells and lower cholesterol levels.

Dr. Stein and his associates recently reported that another PCSK9 monoclonal antibody, REGN727 (Regeneron Pharmaceuticals), significantly lowered LDL cholesterol in three early-phase trials involving healthy volunteers and patients with familial or nonfamilial forms of hypercholesterolemia (N. Engl. J. Med. 2012;366:1108-18). GAUSS investigators at 33 sites in North America, Australia, and Europe enrolled patients, aged 18-75 years, with hypercholesterolemia who were considered intolerant to at least one statin because of muscle-related events and had LDL cholesterol levels above risk-based goals set by the National Cholesterol Education Program (NCEP). At baseline, the average LDL cholesterol level was 193 mg/dL, 50% of patients were at high or moderately high cardiovascular risk according to NCEP categories, and 24% had clinical atherosclerotic disease. Their average age was 62.

In all, 160 patients were randomly assigned to AMG145 monotherapy at doses of 280 mg, 350 mg, or 420 mg every 4 weeks, or 450 mg AMG145 every 4 weeks plus daily oral ezetimibe 10 mg, or placebo every 4 weeks plus ezetimibe 10 mg.

At week 12, the mean change from baseline in LDL cholesterol was –41% in the AMG 280-mg group, –43% in the 350-mg group, –51% in the 420-mg group, and –63% in the AMG plus ezetimibe group, compared with –15% in the placebo plus ezetimibe group, all highly significant differences, reported Dr. Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati.

Notably, the reductions in LDL cholesterol levels with AMG145 monotherapy given every 4 weeks are comparable to those obtained with REGN727 given in addition to statins every 2 weeks.

AMG145 produced modest increases in HDL cholesterol that were statistically significant only in the combination group, and nonsignificant reductions in triglycerides.

Myalgia was the most common treatment-related adverse event, reported in five patients in the 280-mg group, one each in the 350-mg and 420-mg groups, six in the AMG145/ezetimibe group, and one in the placebo/ezetimibe group. Fewer than 5% of patients taking AMG145, with or without ezetimibe, reported fatigue, muscle fatigue, or muscle spasm.

There were four serious adverse events reported in patients given AMG 145 – coronary artery disease, acute pancreatitis, hip fracture, and syncope. These patients did not require treatment discontinuation; these adverse events are not known to be linked to the mechanism of action of PCSK9 inhibition, the authors, led by Dr. David Sullivan of Royal Prince Alfred Hospital, Camperdown, Australia, reported in the paper, simultaneously published online (JAMA 2012;308 [doi:10.1001/jama.2012.25790]).

GAUSS was funded by Amgen, which participated in the design and conduct of the study, as well as the collection and management of data. Dr. Stein and Dr. Sullivan reported financial relationships with Amgen and other firms, and four coauthors are employees of Amgen.

The investigational anti-PCSK9 antibody AMG145 significantly lowers LDL cholesterol in high-risk patients unable to tolerate statins, the phase II GAUSS trial showed.

Three subcutaneous injections of AMG145 at varying doses reduced LDL cholesterol by up to 51% when used as monotherapy, and by 63% when combined with ezetimibe (Zetia), compared with an expected 15% reduction with ezetimibe and placebo.

These reductions are comparable with those achieved with maximal doses of the most efficacious statins.

If the results are confirmed in larger and longer-term studies, AMG145 could provide a new therapeutic option for high-risk patients who currently have few treatment options, Dr. Evan Stein reported at the annual scientific sessions of the American Heart Association in Los Angeles.

In GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), 84% of all patients were unable to tolerate even low doses of any statin.

Overall, about 10%-20% of people can’t tolerate statins at all or the higher doses needed to achieve recommended LDL cholesterol goals, primarily because of muscle-related side effects. Ezetimibe is frequently used as an alternative for these patients, but without great success.

Evidence and enthusiasm are growing, however, for the use of monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that binds to and destroys LDL receptors. It is thought that blocking the destructive capacity of PCSK9 can lead to more LDL receptors on cells and lower cholesterol levels.

Dr. Stein and his associates recently reported that another PCSK9 monoclonal antibody, REGN727 (Regeneron Pharmaceuticals), significantly lowered LDL cholesterol in three early-phase trials involving healthy volunteers and patients with familial or nonfamilial forms of hypercholesterolemia (N. Engl. J. Med. 2012;366:1108-18). GAUSS investigators at 33 sites in North America, Australia, and Europe enrolled patients, aged 18-75 years, with hypercholesterolemia who were considered intolerant to at least one statin because of muscle-related events and had LDL cholesterol levels above risk-based goals set by the National Cholesterol Education Program (NCEP). At baseline, the average LDL cholesterol level was 193 mg/dL, 50% of patients were at high or moderately high cardiovascular risk according to NCEP categories, and 24% had clinical atherosclerotic disease. Their average age was 62.

In all, 160 patients were randomly assigned to AMG145 monotherapy at doses of 280 mg, 350 mg, or 420 mg every 4 weeks, or 450 mg AMG145 every 4 weeks plus daily oral ezetimibe 10 mg, or placebo every 4 weeks plus ezetimibe 10 mg.

At week 12, the mean change from baseline in LDL cholesterol was –41% in the AMG 280-mg group, –43% in the 350-mg group, –51% in the 420-mg group, and –63% in the AMG plus ezetimibe group, compared with –15% in the placebo plus ezetimibe group, all highly significant differences, reported Dr. Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati.

Notably, the reductions in LDL cholesterol levels with AMG145 monotherapy given every 4 weeks are comparable to those obtained with REGN727 given in addition to statins every 2 weeks.

AMG145 produced modest increases in HDL cholesterol that were statistically significant only in the combination group, and nonsignificant reductions in triglycerides.

Myalgia was the most common treatment-related adverse event, reported in five patients in the 280-mg group, one each in the 350-mg and 420-mg groups, six in the AMG145/ezetimibe group, and one in the placebo/ezetimibe group. Fewer than 5% of patients taking AMG145, with or without ezetimibe, reported fatigue, muscle fatigue, or muscle spasm.

There were four serious adverse events reported in patients given AMG 145 – coronary artery disease, acute pancreatitis, hip fracture, and syncope. These patients did not require treatment discontinuation; these adverse events are not known to be linked to the mechanism of action of PCSK9 inhibition, the authors, led by Dr. David Sullivan of Royal Prince Alfred Hospital, Camperdown, Australia, reported in the paper, simultaneously published online (JAMA 2012;308 [doi:10.1001/jama.2012.25790]).

GAUSS was funded by Amgen, which participated in the design and conduct of the study, as well as the collection and management of data. Dr. Stein and Dr. Sullivan reported financial relationships with Amgen and other firms, and four coauthors are employees of Amgen.

The investigational anti-PCSK9 antibody AMG145 significantly lowers LDL cholesterol in high-risk patients unable to tolerate statins, the phase II GAUSS trial showed.

Three subcutaneous injections of AMG145 at varying doses reduced LDL cholesterol by up to 51% when used as monotherapy, and by 63% when combined with ezetimibe (Zetia), compared with an expected 15% reduction with ezetimibe and placebo.

These reductions are comparable with those achieved with maximal doses of the most efficacious statins.

If the results are confirmed in larger and longer-term studies, AMG145 could provide a new therapeutic option for high-risk patients who currently have few treatment options, Dr. Evan Stein reported at the annual scientific sessions of the American Heart Association in Los Angeles.

In GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), 84% of all patients were unable to tolerate even low doses of any statin.

Overall, about 10%-20% of people can’t tolerate statins at all or the higher doses needed to achieve recommended LDL cholesterol goals, primarily because of muscle-related side effects. Ezetimibe is frequently used as an alternative for these patients, but without great success.

Evidence and enthusiasm are growing, however, for the use of monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that binds to and destroys LDL receptors. It is thought that blocking the destructive capacity of PCSK9 can lead to more LDL receptors on cells and lower cholesterol levels.

Dr. Stein and his associates recently reported that another PCSK9 monoclonal antibody, REGN727 (Regeneron Pharmaceuticals), significantly lowered LDL cholesterol in three early-phase trials involving healthy volunteers and patients with familial or nonfamilial forms of hypercholesterolemia (N. Engl. J. Med. 2012;366:1108-18). GAUSS investigators at 33 sites in North America, Australia, and Europe enrolled patients, aged 18-75 years, with hypercholesterolemia who were considered intolerant to at least one statin because of muscle-related events and had LDL cholesterol levels above risk-based goals set by the National Cholesterol Education Program (NCEP). At baseline, the average LDL cholesterol level was 193 mg/dL, 50% of patients were at high or moderately high cardiovascular risk according to NCEP categories, and 24% had clinical atherosclerotic disease. Their average age was 62.

In all, 160 patients were randomly assigned to AMG145 monotherapy at doses of 280 mg, 350 mg, or 420 mg every 4 weeks, or 450 mg AMG145 every 4 weeks plus daily oral ezetimibe 10 mg, or placebo every 4 weeks plus ezetimibe 10 mg.

At week 12, the mean change from baseline in LDL cholesterol was –41% in the AMG 280-mg group, –43% in the 350-mg group, –51% in the 420-mg group, and –63% in the AMG plus ezetimibe group, compared with –15% in the placebo plus ezetimibe group, all highly significant differences, reported Dr. Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati.

Notably, the reductions in LDL cholesterol levels with AMG145 monotherapy given every 4 weeks are comparable to those obtained with REGN727 given in addition to statins every 2 weeks.

AMG145 produced modest increases in HDL cholesterol that were statistically significant only in the combination group, and nonsignificant reductions in triglycerides.

Myalgia was the most common treatment-related adverse event, reported in five patients in the 280-mg group, one each in the 350-mg and 420-mg groups, six in the AMG145/ezetimibe group, and one in the placebo/ezetimibe group. Fewer than 5% of patients taking AMG145, with or without ezetimibe, reported fatigue, muscle fatigue, or muscle spasm.

There were four serious adverse events reported in patients given AMG 145 – coronary artery disease, acute pancreatitis, hip fracture, and syncope. These patients did not require treatment discontinuation; these adverse events are not known to be linked to the mechanism of action of PCSK9 inhibition, the authors, led by Dr. David Sullivan of Royal Prince Alfred Hospital, Camperdown, Australia, reported in the paper, simultaneously published online (JAMA 2012;308 [doi:10.1001/jama.2012.25790]).

GAUSS was funded by Amgen, which participated in the design and conduct of the study, as well as the collection and management of data. Dr. Stein and Dr. Sullivan reported financial relationships with Amgen and other firms, and four coauthors are employees of Amgen.

LOS ANGELES – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

Bruce Jancin/IMNG Medical Media

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the conference.

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

Courtesy of Dr. Gilles Montalescot

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

Bruce Jancin/IMNG Medical Media

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the conference.

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

Courtesy of Dr. Gilles Montalescot

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

Bruce Jancin/IMNG Medical Media

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the conference.

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

Courtesy of Dr. Gilles Montalescot

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES – Taking multivitamins daily did not provide any cardiovascular benefits to a large group of American men who were followed for more than a decade in a randomized trial.

While the results showed that multivitamins posed no health risks, experts said at the annual scientific sessions of the American Heart Association that the findings will help them frame the conversation when advising patients.

©Graça Victoria/iStockphoto.com

"The message needs to remain simple and focused," Dr. Eva M. Lonn, professor of medicine at McMaster University, Ontario, wrote in an editorial (JAMA 2012 Nov. 7;308:1802-3). "CVD is largely preventable, and this can be achieved by eating healthy foods, exercising regularly, avoiding tobacco products, and, for those with high risk factor levels or previous CVD events, taking proven, safe, and effective medications."

This is the second arm of the Physicians’ Health Study II, a randomized, double-blind, placebo-controlled trial, which followed nearly 15,000 male U.S. physicians for 11 years, aiming to evaluate the risk and benefits of a multivitamin, vitamin E, vitamin C, and beta carotene in prevention of cancer, cardiovascular disease, eye disease, and cognitive decline.

The results from the first arm of the large trial, published recently, showed that daily multivitamin supplementation had a modest but significant effect on reducing the risk of cancer. Researchers will present the two remaining studies in the near future.

It’s not clear whether the findings can be applied to the population as a whole, according to the study’s authors and other experts, especially since the study’s participants were relatively homogenous, healthy, and had a good nutritional intake.

Still, "this is a very well-run study," said Dr. John G. Harold, a cardiologist at Cedar Sinai Heart Institute, Los Angeles, who was not involved in the study. "This is one more example of a clinical trial that is changing what was up until now driven by opinion rather than fact."

Multivitamins are the most common supplement consumed by U.S. adults, yet most of the studies about their effect on cardiovascular health have been observational, and their results inconsistent. And while randomized trials like this are needed, conducting them is difficult, said Howard D. Sesso, Sc.D., the study’s lead author and an associate epidemiologist at Brigham and Women’s Hospital, Boston. "Many people who take multivitamins are unwilling to be randomized and receive placebos," he said.

Meanwhile, the physicians who participated in the study were incredibly dedicated to the trial, said Dr. Sesso, showing photos of some who had posed with their multivitamin packets at home, while traveling, or exploring nature.

Researchers followed 14,641 male U.S. physicians, initially 50 years or older, from 1997 to June 2011. There were 7,317 participants in the multivitamin group and 7,324 in the placebo group. They received monthly packs of multivitamins or placebo every 6 months during the first year, and annually thereafter. Morbidity and mortality follow-up were 98.2% and 99.9%, respectively.

Adherence was 67.5% in the multivitamin group and 67.1% in the placebo group at the end of the follow-up period.

The mean age of the study population was 64.3 years, and the population was predominantly white, and relatively healthy. Only 4% said that they were current smokers and close to 60% said that they exercised once or more per week.

In addition, 42% of the participants said that they had a history of hypertension, and 35% had a history of high cholesterol. Almost 6% had a history of diabetes.

At baseline, 5% of the men at a history of cardiovascular disease and 9% had a history of cancer.

The primary end point was major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality. Secondary end points included stroke and MI individually.

Results showed that men who took a daily multivitamin didn’t experience any benefit for the primary end point and secondary end points.

There were 867 major cardiovascular events in the multivitamin group and 856 in the placebo group, or 11.0 and 10.8 events/1,000 person-years, a nonsignificant difference. Likewise, there were no significant differences between groups in total strokes (317 in the multivitamin group and 311 in the placebo group) or cardiovascular deaths (408 and 421, respectively). The results were published simultaneously with the presentation at the meeting (JAMA 2012 Nov. 7;308:1751-60).

The results showed no significant effects on gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration, and migraine.

The population was relatively well nourished, researchers pointed out, "for which supplementation may offer no additional benefit," they wrote.

Also, behavioral interventions such as exercise and medications such as lipid-lowering therapies can effectively lower the CVD risk and make it difficult for a multivitamin to "meaningfully contribute toward risk reduction," researchers wrote.

They added that there is a need to further understand how essential vitamins and minerals, even at standard levels, may differently interact and influence cardiovascular and cancer mechanisms.

"We’re seeing more and more negative studies," about supplements, said Dr. Harold, highlighting the research’s limited understanding of the agents’ biological impact and pathophysiology.

Coinvestigator J. Michael Gaziano, a cardiologist at Brigham and Women’s Hospital, said that he had no problems with his patients taking multivitamins as long as it was to mainly prevent vitamin deficiencies, and for its modest effect in reducing cancer. "But when it comes to preventing heart disease, we don’t have to invest our energy on multivitamins," he said.

Dr. Sesso, who is younger than the study’s cohort, said he did not take multivitamins but kept a good diet and exercised. Dr. Harold said he took multivitamins. Dr. Gaziano said he was trim, had a healthy diet, didn’t smoke, and exercised, but he wouldn’t say whether he took multivitamins. He said he wouldn’t reveal that information until all the data from the Physicians’ Health Study II were published. "I think it’s not unreasonable to take a multivitamin," he said.

Dr. Gaziano reported having received investigator-initiated research funding from the National Institutes of Health, the Veterans Administration, and BASF Corp. He received assistance with the study agents and packaging from BASF and Pfizer. Study packaging was provided by DSM Nutritional Products. Dr. Harold said he had no relevant disclosures. Dr. Sesso received research support from NIH and investigator-initiated grant from BASF. Dr. Lonn reported serving as a consultant to Merck and Servier; providing expert testimony for Merck; receiving grants or grants pending from AstraZeneca, GlaxoSmithKline, and Hoffman-LaRoche; and receiving payment for lectures from Novartis and Merck.

LOS ANGELES – Taking multivitamins daily did not provide any cardiovascular benefits to a large group of American men who were followed for more than a decade in a randomized trial.

While the results showed that multivitamins posed no health risks, experts said at the annual scientific sessions of the American Heart Association that the findings will help them frame the conversation when advising patients.

©Graça Victoria/iStockphoto.com

"The message needs to remain simple and focused," Dr. Eva M. Lonn, professor of medicine at McMaster University, Ontario, wrote in an editorial (JAMA 2012 Nov. 7;308:1802-3). "CVD is largely preventable, and this can be achieved by eating healthy foods, exercising regularly, avoiding tobacco products, and, for those with high risk factor levels or previous CVD events, taking proven, safe, and effective medications."

This is the second arm of the Physicians’ Health Study II, a randomized, double-blind, placebo-controlled trial, which followed nearly 15,000 male U.S. physicians for 11 years, aiming to evaluate the risk and benefits of a multivitamin, vitamin E, vitamin C, and beta carotene in prevention of cancer, cardiovascular disease, eye disease, and cognitive decline.

The results from the first arm of the large trial, published recently, showed that daily multivitamin supplementation had a modest but significant effect on reducing the risk of cancer. Researchers will present the two remaining studies in the near future.

It’s not clear whether the findings can be applied to the population as a whole, according to the study’s authors and other experts, especially since the study’s participants were relatively homogenous, healthy, and had a good nutritional intake.

Still, "this is a very well-run study," said Dr. John G. Harold, a cardiologist at Cedar Sinai Heart Institute, Los Angeles, who was not involved in the study. "This is one more example of a clinical trial that is changing what was up until now driven by opinion rather than fact."

Multivitamins are the most common supplement consumed by U.S. adults, yet most of the studies about their effect on cardiovascular health have been observational, and their results inconsistent. And while randomized trials like this are needed, conducting them is difficult, said Howard D. Sesso, Sc.D., the study’s lead author and an associate epidemiologist at Brigham and Women’s Hospital, Boston. "Many people who take multivitamins are unwilling to be randomized and receive placebos," he said.

Meanwhile, the physicians who participated in the study were incredibly dedicated to the trial, said Dr. Sesso, showing photos of some who had posed with their multivitamin packets at home, while traveling, or exploring nature.

Researchers followed 14,641 male U.S. physicians, initially 50 years or older, from 1997 to June 2011. There were 7,317 participants in the multivitamin group and 7,324 in the placebo group. They received monthly packs of multivitamins or placebo every 6 months during the first year, and annually thereafter. Morbidity and mortality follow-up were 98.2% and 99.9%, respectively.

Adherence was 67.5% in the multivitamin group and 67.1% in the placebo group at the end of the follow-up period.

The mean age of the study population was 64.3 years, and the population was predominantly white, and relatively healthy. Only 4% said that they were current smokers and close to 60% said that they exercised once or more per week.

In addition, 42% of the participants said that they had a history of hypertension, and 35% had a history of high cholesterol. Almost 6% had a history of diabetes.

At baseline, 5% of the men at a history of cardiovascular disease and 9% had a history of cancer.

The primary end point was major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality. Secondary end points included stroke and MI individually.

Results showed that men who took a daily multivitamin didn’t experience any benefit for the primary end point and secondary end points.

There were 867 major cardiovascular events in the multivitamin group and 856 in the placebo group, or 11.0 and 10.8 events/1,000 person-years, a nonsignificant difference. Likewise, there were no significant differences between groups in total strokes (317 in the multivitamin group and 311 in the placebo group) or cardiovascular deaths (408 and 421, respectively). The results were published simultaneously with the presentation at the meeting (JAMA 2012 Nov. 7;308:1751-60).

The results showed no significant effects on gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration, and migraine.

The population was relatively well nourished, researchers pointed out, "for which supplementation may offer no additional benefit," they wrote.

Also, behavioral interventions such as exercise and medications such as lipid-lowering therapies can effectively lower the CVD risk and make it difficult for a multivitamin to "meaningfully contribute toward risk reduction," researchers wrote.

They added that there is a need to further understand how essential vitamins and minerals, even at standard levels, may differently interact and influence cardiovascular and cancer mechanisms.

"We’re seeing more and more negative studies," about supplements, said Dr. Harold, highlighting the research’s limited understanding of the agents’ biological impact and pathophysiology.

Coinvestigator J. Michael Gaziano, a cardiologist at Brigham and Women’s Hospital, said that he had no problems with his patients taking multivitamins as long as it was to mainly prevent vitamin deficiencies, and for its modest effect in reducing cancer. "But when it comes to preventing heart disease, we don’t have to invest our energy on multivitamins," he said.

Dr. Sesso, who is younger than the study’s cohort, said he did not take multivitamins but kept a good diet and exercised. Dr. Harold said he took multivitamins. Dr. Gaziano said he was trim, had a healthy diet, didn’t smoke, and exercised, but he wouldn’t say whether he took multivitamins. He said he wouldn’t reveal that information until all the data from the Physicians’ Health Study II were published. "I think it’s not unreasonable to take a multivitamin," he said.

Dr. Gaziano reported having received investigator-initiated research funding from the National Institutes of Health, the Veterans Administration, and BASF Corp. He received assistance with the study agents and packaging from BASF and Pfizer. Study packaging was provided by DSM Nutritional Products. Dr. Harold said he had no relevant disclosures. Dr. Sesso received research support from NIH and investigator-initiated grant from BASF. Dr. Lonn reported serving as a consultant to Merck and Servier; providing expert testimony for Merck; receiving grants or grants pending from AstraZeneca, GlaxoSmithKline, and Hoffman-LaRoche; and receiving payment for lectures from Novartis and Merck.

LOS ANGELES – Taking multivitamins daily did not provide any cardiovascular benefits to a large group of American men who were followed for more than a decade in a randomized trial.

While the results showed that multivitamins posed no health risks, experts said at the annual scientific sessions of the American Heart Association that the findings will help them frame the conversation when advising patients.

©Graça Victoria/iStockphoto.com

"The message needs to remain simple and focused," Dr. Eva M. Lonn, professor of medicine at McMaster University, Ontario, wrote in an editorial (JAMA 2012 Nov. 7;308:1802-3). "CVD is largely preventable, and this can be achieved by eating healthy foods, exercising regularly, avoiding tobacco products, and, for those with high risk factor levels or previous CVD events, taking proven, safe, and effective medications."

This is the second arm of the Physicians’ Health Study II, a randomized, double-blind, placebo-controlled trial, which followed nearly 15,000 male U.S. physicians for 11 years, aiming to evaluate the risk and benefits of a multivitamin, vitamin E, vitamin C, and beta carotene in prevention of cancer, cardiovascular disease, eye disease, and cognitive decline.

The results from the first arm of the large trial, published recently, showed that daily multivitamin supplementation had a modest but significant effect on reducing the risk of cancer. Researchers will present the two remaining studies in the near future.

It’s not clear whether the findings can be applied to the population as a whole, according to the study’s authors and other experts, especially since the study’s participants were relatively homogenous, healthy, and had a good nutritional intake.

Still, "this is a very well-run study," said Dr. John G. Harold, a cardiologist at Cedar Sinai Heart Institute, Los Angeles, who was not involved in the study. "This is one more example of a clinical trial that is changing what was up until now driven by opinion rather than fact."

Multivitamins are the most common supplement consumed by U.S. adults, yet most of the studies about their effect on cardiovascular health have been observational, and their results inconsistent. And while randomized trials like this are needed, conducting them is difficult, said Howard D. Sesso, Sc.D., the study’s lead author and an associate epidemiologist at Brigham and Women’s Hospital, Boston. "Many people who take multivitamins are unwilling to be randomized and receive placebos," he said.

Meanwhile, the physicians who participated in the study were incredibly dedicated to the trial, said Dr. Sesso, showing photos of some who had posed with their multivitamin packets at home, while traveling, or exploring nature.

Researchers followed 14,641 male U.S. physicians, initially 50 years or older, from 1997 to June 2011. There were 7,317 participants in the multivitamin group and 7,324 in the placebo group. They received monthly packs of multivitamins or placebo every 6 months during the first year, and annually thereafter. Morbidity and mortality follow-up were 98.2% and 99.9%, respectively.

Adherence was 67.5% in the multivitamin group and 67.1% in the placebo group at the end of the follow-up period.

The mean age of the study population was 64.3 years, and the population was predominantly white, and relatively healthy. Only 4% said that they were current smokers and close to 60% said that they exercised once or more per week.

In addition, 42% of the participants said that they had a history of hypertension, and 35% had a history of high cholesterol. Almost 6% had a history of diabetes.

At baseline, 5% of the men at a history of cardiovascular disease and 9% had a history of cancer.

The primary end point was major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality. Secondary end points included stroke and MI individually.

Results showed that men who took a daily multivitamin didn’t experience any benefit for the primary end point and secondary end points.

There were 867 major cardiovascular events in the multivitamin group and 856 in the placebo group, or 11.0 and 10.8 events/1,000 person-years, a nonsignificant difference. Likewise, there were no significant differences between groups in total strokes (317 in the multivitamin group and 311 in the placebo group) or cardiovascular deaths (408 and 421, respectively). The results were published simultaneously with the presentation at the meeting (JAMA 2012 Nov. 7;308:1751-60).

The results showed no significant effects on gastrointestinal tract symptoms, fatigue, drowsiness, skin discoloration, and migraine.

The population was relatively well nourished, researchers pointed out, "for which supplementation may offer no additional benefit," they wrote.

Also, behavioral interventions such as exercise and medications such as lipid-lowering therapies can effectively lower the CVD risk and make it difficult for a multivitamin to "meaningfully contribute toward risk reduction," researchers wrote.

They added that there is a need to further understand how essential vitamins and minerals, even at standard levels, may differently interact and influence cardiovascular and cancer mechanisms.

"We’re seeing more and more negative studies," about supplements, said Dr. Harold, highlighting the research’s limited understanding of the agents’ biological impact and pathophysiology.

Coinvestigator J. Michael Gaziano, a cardiologist at Brigham and Women’s Hospital, said that he had no problems with his patients taking multivitamins as long as it was to mainly prevent vitamin deficiencies, and for its modest effect in reducing cancer. "But when it comes to preventing heart disease, we don’t have to invest our energy on multivitamins," he said.

Dr. Sesso, who is younger than the study’s cohort, said he did not take multivitamins but kept a good diet and exercised. Dr. Harold said he took multivitamins. Dr. Gaziano said he was trim, had a healthy diet, didn’t smoke, and exercised, but he wouldn’t say whether he took multivitamins. He said he wouldn’t reveal that information until all the data from the Physicians’ Health Study II were published. "I think it’s not unreasonable to take a multivitamin," he said.

Dr. Gaziano reported having received investigator-initiated research funding from the National Institutes of Health, the Veterans Administration, and BASF Corp. He received assistance with the study agents and packaging from BASF and Pfizer. Study packaging was provided by DSM Nutritional Products. Dr. Harold said he had no relevant disclosures. Dr. Sesso received research support from NIH and investigator-initiated grant from BASF. Dr. Lonn reported serving as a consultant to Merck and Servier; providing expert testimony for Merck; receiving grants or grants pending from AstraZeneca, GlaxoSmithKline, and Hoffman-LaRoche; and receiving payment for lectures from Novartis and Merck.

Perioperative supplementation with fish oil–derived fatty acids did not prevent postoperative atrial fibrillation in patients undergoing cardiac surgery, according to results from a large, randomized controlled trial.

Atrial fibrillation (AF) affects approximately one-third of patients who undergo cardiac surgery. Animal studies have suggested that the long-chain n-3-polyunsaturated fatty acids (PUFAs) found in fish oil have antiarrhythmic activity, and clinical trials have shown that habitual consumption of fish oil favorably affects physiological pathways that influence AF as well as overall cardiac mortality risk (J. Am. Coll. Cardiol. 2011;58:2047-67).

The new study, published online Nov. 5 in JAMA (doi:10.1001/jama.2012.28733) and presented simultaneously at the annual scientific sessions of the American Heart Association, demonstrated that fish oil supplementation beginning 2-5 days prior to cardiac surgery and continuing until hospital discharge did not reduce risk of postoperative atrial fibrillation.

©Clayton Hansen/iStockphoto

For their research, Dr. Dariush Mozaffarian of the Harvard School of Public Health, Boston, and Dr. Roberto Marchioli of Consorzio Mario Negri Sud in Santa Maria Imbaro, Italy, and their colleagues randomized to fish oil capsules or placebo 1,516 patients who were scheduled for cardiac surgery at 28 centers in the United States, Italy, and Argentina.

Patients took 10 capsules, each 1-g capsule containing at least 840 mg of n-3-PUFAs, eicosapentaenoic acid (approximately 465 mg) plus docosahexaenoic acid (approximately 375 mg) as ethyl esters (Omacor) or matched placebo (olive oil) over 3-5 days before surgery, followed by two capsules per day until discharge or day 10 post surgery, whichever came first. The subjects’ average age was 64 years; 72% were men. Patients who took fish oil regularly were excluded from the study.

Centers were encouraged to use continuous electrocardiographic monitoring for at least 5 days post surgery. Twelve-lead ECGs were recommended daily and more frequently at the discretion of the treating physicians for symptoms or clinically suspected arrhythmia. Confirmatory rhythm strips or 12-lead ECGs were collected for all postoperative arrhythmias of at least 30 seconds’ duration.

AF episodes lasting 30 seconds or longer occurred after surgery in 233 (30.7%) controls and in 227 (30%) subjects given fish oil (odds ratio, 0.96 [95% confidence interval, 0.77-1.20]; P = .74). The two groups did not differ significantly in the number of AF episodes or the incidence of sustained AF episodes. Also, there was no significant difference in the risk of clinical bleeding, even though more than half of the study patients were also taking aspirin or other anticoagulants, the investigators reported.

Though the investigators hypothesized that they would see stronger efficacy of treatment among patients who consumed less than two servings a week of oily fish or those who had lower (<4%) plasma-PUFA levels at enrollment, no significant differences were found in those subgroups, they wrote.

Patients were identified and assigned to receive fish oil capsules for different durations (ranging from 2 to 5 days) prior to surgery, which could have resulted in the shorter durations being less effective, the investigators acknowledged. Subgroup analyses, however, did not detect significantly greater risk reduction associated with more days of fish oil before surgery.

The researchers noted that current best-practice guidelines for preventing postoperative AF were recommended to all participating surgical centers, "which could have reduced the influence of any additional therapy on risk of postoperative AF." Further, the supplement doses may have been too low to produce a benefit, even though phospholipid n-3-PUFA levels increased by an average of 40% by the time of surgery, "providing novel evidence that even short-term supplementation significantly influences circulating levels," they said.

Because of the known benefits of n-3-PUFAs on cardiovascular risk factors and physiologic pathways, "a more promising strategy may be long-term consumption to reduce the primary incidence of AF among ambulatory elderly adults with hypertension or other risk factors; such an approach should be tested in appropriately designed and powered clinical trials," the investigators wrote in their analysis.

The study was funded with grants from the National Institutes of Health, GlaxoSmithKline, Sigma Tau, and Pronova BioPharma, which also provided the capsules used in the study. None of the investigators declared conflicts of interest.

Perioperative supplementation with fish oil–derived fatty acids did not prevent postoperative atrial fibrillation in patients undergoing cardiac surgery, according to results from a large, randomized controlled trial.

Atrial fibrillation (AF) affects approximately one-third of patients who undergo cardiac surgery. Animal studies have suggested that the long-chain n-3-polyunsaturated fatty acids (PUFAs) found in fish oil have antiarrhythmic activity, and clinical trials have shown that habitual consumption of fish oil favorably affects physiological pathways that influence AF as well as overall cardiac mortality risk (J. Am. Coll. Cardiol. 2011;58:2047-67).

The new study, published online Nov. 5 in JAMA (doi:10.1001/jama.2012.28733) and presented simultaneously at the annual scientific sessions of the American Heart Association, demonstrated that fish oil supplementation beginning 2-5 days prior to cardiac surgery and continuing until hospital discharge did not reduce risk of postoperative atrial fibrillation.

©Clayton Hansen/iStockphoto

For their research, Dr. Dariush Mozaffarian of the Harvard School of Public Health, Boston, and Dr. Roberto Marchioli of Consorzio Mario Negri Sud in Santa Maria Imbaro, Italy, and their colleagues randomized to fish oil capsules or placebo 1,516 patients who were scheduled for cardiac surgery at 28 centers in the United States, Italy, and Argentina.

Patients took 10 capsules, each 1-g capsule containing at least 840 mg of n-3-PUFAs, eicosapentaenoic acid (approximately 465 mg) plus docosahexaenoic acid (approximately 375 mg) as ethyl esters (Omacor) or matched placebo (olive oil) over 3-5 days before surgery, followed by two capsules per day until discharge or day 10 post surgery, whichever came first. The subjects’ average age was 64 years; 72% were men. Patients who took fish oil regularly were excluded from the study.

Centers were encouraged to use continuous electrocardiographic monitoring for at least 5 days post surgery. Twelve-lead ECGs were recommended daily and more frequently at the discretion of the treating physicians for symptoms or clinically suspected arrhythmia. Confirmatory rhythm strips or 12-lead ECGs were collected for all postoperative arrhythmias of at least 30 seconds’ duration.

AF episodes lasting 30 seconds or longer occurred after surgery in 233 (30.7%) controls and in 227 (30%) subjects given fish oil (odds ratio, 0.96 [95% confidence interval, 0.77-1.20]; P = .74). The two groups did not differ significantly in the number of AF episodes or the incidence of sustained AF episodes. Also, there was no significant difference in the risk of clinical bleeding, even though more than half of the study patients were also taking aspirin or other anticoagulants, the investigators reported.

Though the investigators hypothesized that they would see stronger efficacy of treatment among patients who consumed less than two servings a week of oily fish or those who had lower (<4%) plasma-PUFA levels at enrollment, no significant differences were found in those subgroups, they wrote.

Patients were identified and assigned to receive fish oil capsules for different durations (ranging from 2 to 5 days) prior to surgery, which could have resulted in the shorter durations being less effective, the investigators acknowledged. Subgroup analyses, however, did not detect significantly greater risk reduction associated with more days of fish oil before surgery.

The researchers noted that current best-practice guidelines for preventing postoperative AF were recommended to all participating surgical centers, "which could have reduced the influence of any additional therapy on risk of postoperative AF." Further, the supplement doses may have been too low to produce a benefit, even though phospholipid n-3-PUFA levels increased by an average of 40% by the time of surgery, "providing novel evidence that even short-term supplementation significantly influences circulating levels," they said.

Because of the known benefits of n-3-PUFAs on cardiovascular risk factors and physiologic pathways, "a more promising strategy may be long-term consumption to reduce the primary incidence of AF among ambulatory elderly adults with hypertension or other risk factors; such an approach should be tested in appropriately designed and powered clinical trials," the investigators wrote in their analysis.

The study was funded with grants from the National Institutes of Health, GlaxoSmithKline, Sigma Tau, and Pronova BioPharma, which also provided the capsules used in the study. None of the investigators declared conflicts of interest.

Perioperative supplementation with fish oil–derived fatty acids did not prevent postoperative atrial fibrillation in patients undergoing cardiac surgery, according to results from a large, randomized controlled trial.

Atrial fibrillation (AF) affects approximately one-third of patients who undergo cardiac surgery. Animal studies have suggested that the long-chain n-3-polyunsaturated fatty acids (PUFAs) found in fish oil have antiarrhythmic activity, and clinical trials have shown that habitual consumption of fish oil favorably affects physiological pathways that influence AF as well as overall cardiac mortality risk (J. Am. Coll. Cardiol. 2011;58:2047-67).

The new study, published online Nov. 5 in JAMA (doi:10.1001/jama.2012.28733) and presented simultaneously at the annual scientific sessions of the American Heart Association, demonstrated that fish oil supplementation beginning 2-5 days prior to cardiac surgery and continuing until hospital discharge did not reduce risk of postoperative atrial fibrillation.

©Clayton Hansen/iStockphoto

For their research, Dr. Dariush Mozaffarian of the Harvard School of Public Health, Boston, and Dr. Roberto Marchioli of Consorzio Mario Negri Sud in Santa Maria Imbaro, Italy, and their colleagues randomized to fish oil capsules or placebo 1,516 patients who were scheduled for cardiac surgery at 28 centers in the United States, Italy, and Argentina.

Patients took 10 capsules, each 1-g capsule containing at least 840 mg of n-3-PUFAs, eicosapentaenoic acid (approximately 465 mg) plus docosahexaenoic acid (approximately 375 mg) as ethyl esters (Omacor) or matched placebo (olive oil) over 3-5 days before surgery, followed by two capsules per day until discharge or day 10 post surgery, whichever came first. The subjects’ average age was 64 years; 72% were men. Patients who took fish oil regularly were excluded from the study.

Centers were encouraged to use continuous electrocardiographic monitoring for at least 5 days post surgery. Twelve-lead ECGs were recommended daily and more frequently at the discretion of the treating physicians for symptoms or clinically suspected arrhythmia. Confirmatory rhythm strips or 12-lead ECGs were collected for all postoperative arrhythmias of at least 30 seconds’ duration.

AF episodes lasting 30 seconds or longer occurred after surgery in 233 (30.7%) controls and in 227 (30%) subjects given fish oil (odds ratio, 0.96 [95% confidence interval, 0.77-1.20]; P = .74). The two groups did not differ significantly in the number of AF episodes or the incidence of sustained AF episodes. Also, there was no significant difference in the risk of clinical bleeding, even though more than half of the study patients were also taking aspirin or other anticoagulants, the investigators reported.

Though the investigators hypothesized that they would see stronger efficacy of treatment among patients who consumed less than two servings a week of oily fish or those who had lower (<4%) plasma-PUFA levels at enrollment, no significant differences were found in those subgroups, they wrote.

Patients were identified and assigned to receive fish oil capsules for different durations (ranging from 2 to 5 days) prior to surgery, which could have resulted in the shorter durations being less effective, the investigators acknowledged. Subgroup analyses, however, did not detect significantly greater risk reduction associated with more days of fish oil before surgery.

The researchers noted that current best-practice guidelines for preventing postoperative AF were recommended to all participating surgical centers, "which could have reduced the influence of any additional therapy on risk of postoperative AF." Further, the supplement doses may have been too low to produce a benefit, even though phospholipid n-3-PUFA levels increased by an average of 40% by the time of surgery, "providing novel evidence that even short-term supplementation significantly influences circulating levels," they said.

Because of the known benefits of n-3-PUFAs on cardiovascular risk factors and physiologic pathways, "a more promising strategy may be long-term consumption to reduce the primary incidence of AF among ambulatory elderly adults with hypertension or other risk factors; such an approach should be tested in appropriately designed and powered clinical trials," the investigators wrote in their analysis.

The study was funded with grants from the National Institutes of Health, GlaxoSmithKline, Sigma Tau, and Pronova BioPharma, which also provided the capsules used in the study. None of the investigators declared conflicts of interest.

LOS ANGELES – Coronary artery bypass graft surgery not only provides better clinical outcomes than percutaneous coronary intervention in diabetic patients with multivessel disease, but it does so in a highly cost-effective manner, according to an economic analysis of the FREEDOM trial.

"The benefits are achieved at an overall cost that represents an attractive use of societal health care resources," Elizabeth A. Magnuson, Sc.D., said at the annual scientific sessions of the American Heart Association.

FREEDOM was a randomized international trial that compared the effectiveness of CABG with percutaneous coronary intervention (PCI) using drug-eluting stents in 1,900 diabetic patients with multivessel coronary artery disease who were candidates for both procedures.

The initial hospitalization for revascularization cost an average of $34,467 in the CABG group, $8,622 more than for PCI-treated patients. But during the next 5 years of follow-up, both repeat revascularizations and mortality were significantly more common in the PCI group.

Based on a conservative model of projected survival that assumed a gradual attenuation of CABG’s clinical benefits over time, bypass surgery was associated with an incremental cost-effectiveness ratio of $8,132 per quality-adjusted year of life (QALY) gained. That’s well below the figure of $50,000 per QALY widely accepted by health policy makers as defining the upper boundary of cost effectiveness, noted Dr. Magnuson, director of health economics and technology assessment at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

"Even if we assume no further benefit beyond the trial period and we just captured the life-years lost due to the in-trial death events, we still get very favorable results for CABG, with an incremental cost-effectiveness ratio of roughly $27,000 per QALY," she said.

Discussant Dr. Mark A. Hlatky agreed with Dr. Magnuson that this was a very conservative analysis and said that the actual cost effectiveness of CABG in diabetes patients with multivessel disease might well be even more favorable than she projected.

"The cost-effectiveness results are quite good. This looks like a very economically attractive therapy for patients who have diabetes with multivessel disease," concluded Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Magnuson and Dr. Hlatky reported having no relevant financial conflicts.

LOS ANGELES – Coronary artery bypass graft surgery not only provides better clinical outcomes than percutaneous coronary intervention in diabetic patients with multivessel disease, but it does so in a highly cost-effective manner, according to an economic analysis of the FREEDOM trial.

"The benefits are achieved at an overall cost that represents an attractive use of societal health care resources," Elizabeth A. Magnuson, Sc.D., said at the annual scientific sessions of the American Heart Association.

FREEDOM was a randomized international trial that compared the effectiveness of CABG with percutaneous coronary intervention (PCI) using drug-eluting stents in 1,900 diabetic patients with multivessel coronary artery disease who were candidates for both procedures.

The initial hospitalization for revascularization cost an average of $34,467 in the CABG group, $8,622 more than for PCI-treated patients. But during the next 5 years of follow-up, both repeat revascularizations and mortality were significantly more common in the PCI group.

Based on a conservative model of projected survival that assumed a gradual attenuation of CABG’s clinical benefits over time, bypass surgery was associated with an incremental cost-effectiveness ratio of $8,132 per quality-adjusted year of life (QALY) gained. That’s well below the figure of $50,000 per QALY widely accepted by health policy makers as defining the upper boundary of cost effectiveness, noted Dr. Magnuson, director of health economics and technology assessment at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

"Even if we assume no further benefit beyond the trial period and we just captured the life-years lost due to the in-trial death events, we still get very favorable results for CABG, with an incremental cost-effectiveness ratio of roughly $27,000 per QALY," she said.

Discussant Dr. Mark A. Hlatky agreed with Dr. Magnuson that this was a very conservative analysis and said that the actual cost effectiveness of CABG in diabetes patients with multivessel disease might well be even more favorable than she projected.

"The cost-effectiveness results are quite good. This looks like a very economically attractive therapy for patients who have diabetes with multivessel disease," concluded Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Magnuson and Dr. Hlatky reported having no relevant financial conflicts.

LOS ANGELES – Coronary artery bypass graft surgery not only provides better clinical outcomes than percutaneous coronary intervention in diabetic patients with multivessel disease, but it does so in a highly cost-effective manner, according to an economic analysis of the FREEDOM trial.

"The benefits are achieved at an overall cost that represents an attractive use of societal health care resources," Elizabeth A. Magnuson, Sc.D., said at the annual scientific sessions of the American Heart Association.

FREEDOM was a randomized international trial that compared the effectiveness of CABG with percutaneous coronary intervention (PCI) using drug-eluting stents in 1,900 diabetic patients with multivessel coronary artery disease who were candidates for both procedures.

The initial hospitalization for revascularization cost an average of $34,467 in the CABG group, $8,622 more than for PCI-treated patients. But during the next 5 years of follow-up, both repeat revascularizations and mortality were significantly more common in the PCI group.

Based on a conservative model of projected survival that assumed a gradual attenuation of CABG’s clinical benefits over time, bypass surgery was associated with an incremental cost-effectiveness ratio of $8,132 per quality-adjusted year of life (QALY) gained. That’s well below the figure of $50,000 per QALY widely accepted by health policy makers as defining the upper boundary of cost effectiveness, noted Dr. Magnuson, director of health economics and technology assessment at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

"Even if we assume no further benefit beyond the trial period and we just captured the life-years lost due to the in-trial death events, we still get very favorable results for CABG, with an incremental cost-effectiveness ratio of roughly $27,000 per QALY," she said.

Discussant Dr. Mark A. Hlatky agreed with Dr. Magnuson that this was a very conservative analysis and said that the actual cost effectiveness of CABG in diabetes patients with multivessel disease might well be even more favorable than she projected.

"The cost-effectiveness results are quite good. This looks like a very economically attractive therapy for patients who have diabetes with multivessel disease," concluded Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Magnuson and Dr. Hlatky reported having no relevant financial conflicts.

Adjusting antiplatelet therapy on the basis of platelet function doesn’t confer any significant clinical benefits over a course of standard antiplatelet therapy for patients undergoing coronary stenting.

By the end of 1 year, about a third of patients in each group had died or experienced a heart attack, stent thrombosis, cerebrovascular accident, or urgent revascularization, Dr. Gilles Montalescot and his colleagues reported simultaneously at the annual scientific sessions of the American Heart Association and in the Nov. 4 issue of the New England Journal of Medicine (2012 [doi:10.1056/NEJMoa12099979]).

"We observed no hint of improvement in ischemic outcomes and no better safety outcomes with a strategy of monitoring and drug adjustment as compared with a conventional strategy," wrote Dr. Montalescot of the University Pierre and Marie Curie, Paris, and his co-investigators in the ARCTIC trial (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy vs. a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption vs. Continuation 1 Year After Stenting).

ARCTIC comprised 2,440 patients about to undergo coronary stenting. They were randomized to either conventional antiplatelet therapy, or to flexible antiplatelet treatment guided by platelet-function monitoring.

The patients were a mean of 63 years old; about 80% were men. About a quarter (27%) presented with an acute coronary syndrome without ST-segment elevation.

At the time of stenting, patients in the monitoring group underwent platelet function measuring for both aspirin and P2Y12 inhibitors. (The P2Y12 inhibitors clopidogrel and prasugrel, both thienopyridines, were used in the study.) These assays were repeated 2-4 weeks after stenting, and drug therapy was adjusted according to the results.

If the initial assay indicated aspirin reactivity, these patients received an aspirin bolus before stenting. If reactivity with clopidogrel was detected, the patient received either glycoprotein IIb/IIIa inhibitors and a loading dose of at least 600 mg clopidogrel, or a loading dose of 60 mg prasugrel, followed by a daily maintenance dose of 150 mg clopidogrel or 10 mg prasugrel.

At the 2- to 4-week follow-up visit, patients who showed high platelet reactivity with clopidogrel were switched to 10 mg prasugrel or had a 75-mg increase in their daily clopidogrel.

If, during treatment, patients had low platelet reactivity with thienopyridine, they were switched to daily clopidogrel at 75 mg if they were already getting 10 mg prasugrel or 150 mg clopidogrel.

Patients in the standard therapy group received the stents without any platelet function tests. The use of GP IIb/IIIa inhibitors was left up to the treating physicians.

Before stenting, 34% of the monitoring group had high clopidogrel platelet reactivity; 80% of those received the clopidogrel bolus and 3% the additional prasugrel. High aspirin reactivity was seen in 8%; of those, 85% had the additional aspirin dose.

At the follow-up visit, 16% of the monitoring group showed high platelet reactivity to thienopyridine; 43% of those then received an increase in their maintenance clopidogrel dose. A total of 4% of the monitoring group showed aspirin reactivity at the follow-up visit; 46% of these received an increase in their maintenance dose.

At 1 year after stenting, the primary composite end point had occurred in 35% of the monitoring group and 31% of the standard therapy group, a nonsignificant difference. There were no significant between-group differences when the component end points were individually examined. Bleeding rates were less than 5% and similar in both groups.

The study was largely sponsored by Allies in Cardiovascular Trials Initiatives and Organized Networks, and included funding from Sanofi-Aventis, Cordis, Medtronic, and Boston Scientific.

Dr. Montalescot disclosed that he is a consultant with Atrium, Bayer, and Bristol-Myers Squibb. Several of the coauthors reported financial relationships with multiple pharmaceutical and device companies.

Adjusting antiplatelet therapy on the basis of platelet function doesn’t confer any significant clinical benefits over a course of standard antiplatelet therapy for patients undergoing coronary stenting.

By the end of 1 year, about a third of patients in each group had died or experienced a heart attack, stent thrombosis, cerebrovascular accident, or urgent revascularization, Dr. Gilles Montalescot and his colleagues reported simultaneously at the annual scientific sessions of the American Heart Association and in the Nov. 4 issue of the New England Journal of Medicine (2012 [doi:10.1056/NEJMoa12099979]).

"We observed no hint of improvement in ischemic outcomes and no better safety outcomes with a strategy of monitoring and drug adjustment as compared with a conventional strategy," wrote Dr. Montalescot of the University Pierre and Marie Curie, Paris, and his co-investigators in the ARCTIC trial (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy vs. a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption vs. Continuation 1 Year After Stenting).

ARCTIC comprised 2,440 patients about to undergo coronary stenting. They were randomized to either conventional antiplatelet therapy, or to flexible antiplatelet treatment guided by platelet-function monitoring.

The patients were a mean of 63 years old; about 80% were men. About a quarter (27%) presented with an acute coronary syndrome without ST-segment elevation.

At the time of stenting, patients in the monitoring group underwent platelet function measuring for both aspirin and P2Y12 inhibitors. (The P2Y12 inhibitors clopidogrel and prasugrel, both thienopyridines, were used in the study.) These assays were repeated 2-4 weeks after stenting, and drug therapy was adjusted according to the results.

If the initial assay indicated aspirin reactivity, these patients received an aspirin bolus before stenting. If reactivity with clopidogrel was detected, the patient received either glycoprotein IIb/IIIa inhibitors and a loading dose of at least 600 mg clopidogrel, or a loading dose of 60 mg prasugrel, followed by a daily maintenance dose of 150 mg clopidogrel or 10 mg prasugrel.

At the 2- to 4-week follow-up visit, patients who showed high platelet reactivity with clopidogrel were switched to 10 mg prasugrel or had a 75-mg increase in their daily clopidogrel.

If, during treatment, patients had low platelet reactivity with thienopyridine, they were switched to daily clopidogrel at 75 mg if they were already getting 10 mg prasugrel or 150 mg clopidogrel.

Patients in the standard therapy group received the stents without any platelet function tests. The use of GP IIb/IIIa inhibitors was left up to the treating physicians.

Before stenting, 34% of the monitoring group had high clopidogrel platelet reactivity; 80% of those received the clopidogrel bolus and 3% the additional prasugrel. High aspirin reactivity was seen in 8%; of those, 85% had the additional aspirin dose.

At the follow-up visit, 16% of the monitoring group showed high platelet reactivity to thienopyridine; 43% of those then received an increase in their maintenance clopidogrel dose. A total of 4% of the monitoring group showed aspirin reactivity at the follow-up visit; 46% of these received an increase in their maintenance dose.

At 1 year after stenting, the primary composite end point had occurred in 35% of the monitoring group and 31% of the standard therapy group, a nonsignificant difference. There were no significant between-group differences when the component end points were individually examined. Bleeding rates were less than 5% and similar in both groups.

The study was largely sponsored by Allies in Cardiovascular Trials Initiatives and Organized Networks, and included funding from Sanofi-Aventis, Cordis, Medtronic, and Boston Scientific.

Dr. Montalescot disclosed that he is a consultant with Atrium, Bayer, and Bristol-Myers Squibb. Several of the coauthors reported financial relationships with multiple pharmaceutical and device companies.

Adjusting antiplatelet therapy on the basis of platelet function doesn’t confer any significant clinical benefits over a course of standard antiplatelet therapy for patients undergoing coronary stenting.

By the end of 1 year, about a third of patients in each group had died or experienced a heart attack, stent thrombosis, cerebrovascular accident, or urgent revascularization, Dr. Gilles Montalescot and his colleagues reported simultaneously at the annual scientific sessions of the American Heart Association and in the Nov. 4 issue of the New England Journal of Medicine (2012 [doi:10.1056/NEJMoa12099979]).

"We observed no hint of improvement in ischemic outcomes and no better safety outcomes with a strategy of monitoring and drug adjustment as compared with a conventional strategy," wrote Dr. Montalescot of the University Pierre and Marie Curie, Paris, and his co-investigators in the ARCTIC trial (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy vs. a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption vs. Continuation 1 Year After Stenting).

ARCTIC comprised 2,440 patients about to undergo coronary stenting. They were randomized to either conventional antiplatelet therapy, or to flexible antiplatelet treatment guided by platelet-function monitoring.

The patients were a mean of 63 years old; about 80% were men. About a quarter (27%) presented with an acute coronary syndrome without ST-segment elevation.

At the time of stenting, patients in the monitoring group underwent platelet function measuring for both aspirin and P2Y12 inhibitors. (The P2Y12 inhibitors clopidogrel and prasugrel, both thienopyridines, were used in the study.) These assays were repeated 2-4 weeks after stenting, and drug therapy was adjusted according to the results.

If the initial assay indicated aspirin reactivity, these patients received an aspirin bolus before stenting. If reactivity with clopidogrel was detected, the patient received either glycoprotein IIb/IIIa inhibitors and a loading dose of at least 600 mg clopidogrel, or a loading dose of 60 mg prasugrel, followed by a daily maintenance dose of 150 mg clopidogrel or 10 mg prasugrel.

At the 2- to 4-week follow-up visit, patients who showed high platelet reactivity with clopidogrel were switched to 10 mg prasugrel or had a 75-mg increase in their daily clopidogrel.

If, during treatment, patients had low platelet reactivity with thienopyridine, they were switched to daily clopidogrel at 75 mg if they were already getting 10 mg prasugrel or 150 mg clopidogrel.

Patients in the standard therapy group received the stents without any platelet function tests. The use of GP IIb/IIIa inhibitors was left up to the treating physicians.

Before stenting, 34% of the monitoring group had high clopidogrel platelet reactivity; 80% of those received the clopidogrel bolus and 3% the additional prasugrel. High aspirin reactivity was seen in 8%; of those, 85% had the additional aspirin dose.

At the follow-up visit, 16% of the monitoring group showed high platelet reactivity to thienopyridine; 43% of those then received an increase in their maintenance clopidogrel dose. A total of 4% of the monitoring group showed aspirin reactivity at the follow-up visit; 46% of these received an increase in their maintenance dose.

At 1 year after stenting, the primary composite end point had occurred in 35% of the monitoring group and 31% of the standard therapy group, a nonsignificant difference. There were no significant between-group differences when the component end points were individually examined. Bleeding rates were less than 5% and similar in both groups.

The study was largely sponsored by Allies in Cardiovascular Trials Initiatives and Organized Networks, and included funding from Sanofi-Aventis, Cordis, Medtronic, and Boston Scientific.

Dr. Montalescot disclosed that he is a consultant with Atrium, Bayer, and Bristol-Myers Squibb. Several of the coauthors reported financial relationships with multiple pharmaceutical and device companies.

A 100-mg daily dose of aspirin reduced by one-third the rate of recurrent major vascular events for patients who had one acute unprovoked venous thromboembolism and were switched from anticoagulant therapy to either aspirin or placebo after 3 months of anticoagulant therapy.*

Patients with one episode of unprovoked VTE often discontinue anticoagulant therapy due to inconvenience and the risk of bleeding, said Dr. Timothy A. Brighton of the University of Sydney, Australia, and his colleagues. For those patients, 100 mg of aspirin per day appears to be a safe alternative.

Dr. Brighton and his colleagues reported the findings based on combined data from the ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) study and the WARFASA (Warfarin and Aspirin) study. The findings of ASPIRE were simultaneously published in the New England Journal of Medicine and presented at the annual meeting of the American Heart Association in Los Angeles. The findings of WARFASA were previously published in the same journal.

ASPIRE examined the effect of a 100-mg daily dose of aspirin in patients who had a history of a first-ever unprovoked VTE and had completed initial anticoagulation therapy. The study population included 822 adults who were randomized to a placebo or aspirin at 56 sites in five countries from May 2003 and August 2011. Roughly half of the patients were men; 56% had a proximal deep-vein thrombosis as an index event; 29% had a pulmonary embolism as an index event, and 14% had both conditions as an index event (N. Engl. J. Med. 2012 Nov. 4 [doi: 10.1056/NEJMoa1210384]).

Overall, VTE recurred in 57 patients (14%) in the aspirin group, compared with 73 patients (18%) in the placebo group (rates of 5% and 7% per year, respectively, a nonsignificant difference).

However, the rates of two secondary composite outcomes were significantly reduced in patients who took aspirin compared with those on placebo, the researchers noted. The rate of a composite outcome including VTE, myocardial infarction, stroke, or cardiovascular death was reduced by 34% in aspirin patients (5% per year for aspirin vs. 8% per year for placebo).

The rate of a composite outcome including VTE, myocardial infarction, stroke, major bleeding, or death from any cause was reduce by 33% in aspirin patients (6% per year for aspirin vs. 9% per year for placebo).

No significant differences in serious adverse events or in the rates of major or clinically relevant nonmajor bleeding were observed between the aspirin and placebo groups, the researchers noted.

The findings were limited by the low number of patients in the study, however. The ASPIRE data alone were not adequately powered to show a significant reduction in the recurrence of VTE.

To address the issue, researchers combined the ASPIRE data with data from a similar population of 402 patients in the WARFASA (Warfarin and Aspirin) study (N. Engl. J. Med. 2012; 366:1959-67). In this multicenter, double-blind study, patients with first-ever unprovoked venous thromboembolism completed 6-18 months of oral anticoagulant treatment and were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years.

VTE recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 – 0.93). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups.

Using the combined data from both studies, the researchers found “a highly significant reduction of 32% in the rate of recurrence of venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess of bleeding.”

Therefore, the combined results of the two studies support the use of low-dose aspirin to prevent both recurrent VTE and major vascular events in patients who have had a first episode of unprovoked VTE, the researchers said.

Lead author Dr. Brighton disclosed serving as a consultant for Pfizer, GlaxoSmithKline, and other companies. The study was supported by grants from the National Health and Medical Research Council (Australia), the Health Research Council (New Zealand), the National Heart Foundation of Australia, Bayer HealthCare (Germany), and the Australasian Society of Haematology and Thrombosis

* This story was updated on 11/7/12.

A 100-mg daily dose of aspirin reduced by one-third the rate of recurrent major vascular events for patients who had one acute unprovoked venous thromboembolism and were switched from anticoagulant therapy to either aspirin or placebo after 3 months of anticoagulant therapy.*

Patients with one episode of unprovoked VTE often discontinue anticoagulant therapy due to inconvenience and the risk of bleeding, said Dr. Timothy A. Brighton of the University of Sydney, Australia, and his colleagues. For those patients, 100 mg of aspirin per day appears to be a safe alternative.

Dr. Brighton and his colleagues reported the findings based on combined data from the ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) study and the WARFASA (Warfarin and Aspirin) study. The findings of ASPIRE were simultaneously published in the New England Journal of Medicine and presented at the annual meeting of the American Heart Association in Los Angeles. The findings of WARFASA were previously published in the same journal.

ASPIRE examined the effect of a 100-mg daily dose of aspirin in patients who had a history of a first-ever unprovoked VTE and had completed initial anticoagulation therapy. The study population included 822 adults who were randomized to a placebo or aspirin at 56 sites in five countries from May 2003 and August 2011. Roughly half of the patients were men; 56% had a proximal deep-vein thrombosis as an index event; 29% had a pulmonary embolism as an index event, and 14% had both conditions as an index event (N. Engl. J. Med. 2012 Nov. 4 [doi: 10.1056/NEJMoa1210384]).

Overall, VTE recurred in 57 patients (14%) in the aspirin group, compared with 73 patients (18%) in the placebo group (rates of 5% and 7% per year, respectively, a nonsignificant difference).

However, the rates of two secondary composite outcomes were significantly reduced in patients who took aspirin compared with those on placebo, the researchers noted. The rate of a composite outcome including VTE, myocardial infarction, stroke, or cardiovascular death was reduced by 34% in aspirin patients (5% per year for aspirin vs. 8% per year for placebo).

The rate of a composite outcome including VTE, myocardial infarction, stroke, major bleeding, or death from any cause was reduce by 33% in aspirin patients (6% per year for aspirin vs. 9% per year for placebo).

No significant differences in serious adverse events or in the rates of major or clinically relevant nonmajor bleeding were observed between the aspirin and placebo groups, the researchers noted.

The findings were limited by the low number of patients in the study, however. The ASPIRE data alone were not adequately powered to show a significant reduction in the recurrence of VTE.

To address the issue, researchers combined the ASPIRE data with data from a similar population of 402 patients in the WARFASA (Warfarin and Aspirin) study (N. Engl. J. Med. 2012; 366:1959-67). In this multicenter, double-blind study, patients with first-ever unprovoked venous thromboembolism completed 6-18 months of oral anticoagulant treatment and were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years.

VTE recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 – 0.93). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups.

Using the combined data from both studies, the researchers found “a highly significant reduction of 32% in the rate of recurrence of venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess of bleeding.”

Therefore, the combined results of the two studies support the use of low-dose aspirin to prevent both recurrent VTE and major vascular events in patients who have had a first episode of unprovoked VTE, the researchers said.

Lead author Dr. Brighton disclosed serving as a consultant for Pfizer, GlaxoSmithKline, and other companies. The study was supported by grants from the National Health and Medical Research Council (Australia), the Health Research Council (New Zealand), the National Heart Foundation of Australia, Bayer HealthCare (Germany), and the Australasian Society of Haematology and Thrombosis

* This story was updated on 11/7/12.

A 100-mg daily dose of aspirin reduced by one-third the rate of recurrent major vascular events for patients who had one acute unprovoked venous thromboembolism and were switched from anticoagulant therapy to either aspirin or placebo after 3 months of anticoagulant therapy.*

Patients with one episode of unprovoked VTE often discontinue anticoagulant therapy due to inconvenience and the risk of bleeding, said Dr. Timothy A. Brighton of the University of Sydney, Australia, and his colleagues. For those patients, 100 mg of aspirin per day appears to be a safe alternative.

Dr. Brighton and his colleagues reported the findings based on combined data from the ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) study and the WARFASA (Warfarin and Aspirin) study. The findings of ASPIRE were simultaneously published in the New England Journal of Medicine and presented at the annual meeting of the American Heart Association in Los Angeles. The findings of WARFASA were previously published in the same journal.

ASPIRE examined the effect of a 100-mg daily dose of aspirin in patients who had a history of a first-ever unprovoked VTE and had completed initial anticoagulation therapy. The study population included 822 adults who were randomized to a placebo or aspirin at 56 sites in five countries from May 2003 and August 2011. Roughly half of the patients were men; 56% had a proximal deep-vein thrombosis as an index event; 29% had a pulmonary embolism as an index event, and 14% had both conditions as an index event (N. Engl. J. Med. 2012 Nov. 4 [doi: 10.1056/NEJMoa1210384]).

Overall, VTE recurred in 57 patients (14%) in the aspirin group, compared with 73 patients (18%) in the placebo group (rates of 5% and 7% per year, respectively, a nonsignificant difference).

However, the rates of two secondary composite outcomes were significantly reduced in patients who took aspirin compared with those on placebo, the researchers noted. The rate of a composite outcome including VTE, myocardial infarction, stroke, or cardiovascular death was reduced by 34% in aspirin patients (5% per year for aspirin vs. 8% per year for placebo).

The rate of a composite outcome including VTE, myocardial infarction, stroke, major bleeding, or death from any cause was reduce by 33% in aspirin patients (6% per year for aspirin vs. 9% per year for placebo).

No significant differences in serious adverse events or in the rates of major or clinically relevant nonmajor bleeding were observed between the aspirin and placebo groups, the researchers noted.

The findings were limited by the low number of patients in the study, however. The ASPIRE data alone were not adequately powered to show a significant reduction in the recurrence of VTE.

To address the issue, researchers combined the ASPIRE data with data from a similar population of 402 patients in the WARFASA (Warfarin and Aspirin) study (N. Engl. J. Med. 2012; 366:1959-67). In this multicenter, double-blind study, patients with first-ever unprovoked venous thromboembolism completed 6-18 months of oral anticoagulant treatment and were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years.

VTE recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 – 0.93). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups.

Using the combined data from both studies, the researchers found “a highly significant reduction of 32% in the rate of recurrence of venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess of bleeding.”

Therefore, the combined results of the two studies support the use of low-dose aspirin to prevent both recurrent VTE and major vascular events in patients who have had a first episode of unprovoked VTE, the researchers said.

Lead author Dr. Brighton disclosed serving as a consultant for Pfizer, GlaxoSmithKline, and other companies. The study was supported by grants from the National Health and Medical Research Council (Australia), the Health Research Council (New Zealand), the National Heart Foundation of Australia, Bayer HealthCare (Germany), and the Australasian Society of Haematology and Thrombosis

* This story was updated on 11/7/12.