News from the American Heart Association's Scientific Sessions 2005

Warfarin remains standard therapy to prevent thrombotic events in AF, Arrhythmias and Conduction Disturbances Dallas—Warfarin (Coumadin) remains the treatment of choice to prevent thrombotic events in patients with atrial fibrillation (AF), at least in patients with previous exposure to oral anticoagulation. In a study in which oral anticoagulation was compared with an antiplatelet combination of clopidogrel (Plavix) and aspirin in patients with AF, anticoagulated patients had nearly half the rate of events as those treated with antiplatelet therapy, said Stuart J. Connolly, MD, lead investigator of a study known as Atrial Fibrillation Clopidogrel Trial with Irb­e­sartan for Prevention of Vascular Events-W (ACTIVE-W).

The advantage with warfarin was apparent only when patients had their international normalized ratio (INR) maintained within the normal range, said Dr Connolly, speaking to attendees at the American Heart Association’s Scientific Sessions 2005.

ACTIVE-W included 6,706 patients with AF and at least 1 additional risk factor for stroke. They were randomly assigned to standard care with oral anticoagulant therapy, usually warfarin at a dosage to maintain an INR of 2.0 to 3.0, or antiplatelet therapy with clopidogrel, 75 mg/day, and aspirin, 75 to 100 mg/day.

At the time of enrollment, more than three-fourths of the patients assigned to either treatment had previous exposure to oral anticoagulant therapy. “This was more of a trial of switching therapies rather than de novo treatment,” said Dr Connolly, director of the division of cardiology at McMaster University in Hamilton, Ontario, Canada.

The trial was designed to show noninferiority of the clopidogrel/aspirin regimen compared with the oral anticoagulant regimen. The study was terminated early when the study’s Data Safety and Monitoring Board alerted the steering committee to a difference in efficacy in favor of oral anticoagulation over anti­platelet therapy.

The annual risk of achieving the primary end point of stroke, myocardial infarction, embolism, and vascular death was 3.93% in the patients assigned to oral anticoagulation compared with 5.64% in those assigned to the anti­platelet regimen, representing a 47% reduction (P = .002) in the anticoagulant group compared with the clopidogrel-aspirin group.

Rates of bleeding overall were similar in the 2 groups. The treatment effects were different between patients who had been on warfarin at baseline and those who were not, especially with respect to bleeding risk. Patients as­signed to clopidogrel/aspirin had a 36% excess risk of major bleeding if they had previous exposure to warfarin, whereas among the patients without prior warfarin exposure, the risk of a major bleed was 37% lower in the clopidogrel-aspirin group versus the oral anticoagulation group.

Dr Connolly noted that control of INR was poorer in those patients assigned to oral anticoagulation who were not on it at study entry. “Good control of INR is important to determining the effects of oral anticoagulation and clopidogrel/aspirin,” he said. “There was little benefit (to oral anticoagulation) in centers where INR control was not maintained.”

Jonathan Halperin, MD, from Mount Sinai Medical Center, New York, said that maintaining an INR in the normal range is “no easy feat”; nevertheless, the re­sults of the study were convincing in favor of warfarin over antiplatelet therapy. Previous studies have shown a 30% to 40% reduction in stroke risk with oral anticoagulation when it has been compared with antiplatelet therapy, much like Dr Connolly’s study, he said. How­ever, those with INR values outside the therapeutic range more than 35% of the time did no better with warfarin than patients taking clopidogrel/aspirin, he said.

Interpreting the results into clinical practice requires consideration of whether patients are starting therapy or have already been stable on oral anticoagulants, said Dr Halperin, professor of medicine, Mt. Sinai School of Medicine, and director of clinical cardiology, Mt. Sinai Medical Center, New York.

“The data from ACTIVE-W make it clear that starters face greater odds of adverse outcomes with anticoagulation and stand to gain more from alternative therapy than switchers or those continuing oral anticoagulation,” said Dr Halperin.

Central blood pressure may be better predictor of risk than brachial blood pressure hypertension Dallas—Drugs that lower brachial blood pressure to the same degree can have different effects on central blood pressure, and evidence exists that central blood pressure is a better predictor of cardiovascular risk than brachial blood pressure, said presenters at the American Heart As­sociation’s Scientific Sessions 2005.

Although most studies in which the efficacy of blood-pressure—lowering drugs is examined have assumed that blood pressure in the arm represents blood pressure elsewhere in the body, “brachial blood pressure is an imperfect surrogate for the effects of blood-pressure–lowering drugs on central aortic pressures,” said Bryan Williams, MD. “Moreover, central pressure appears to be an important determinant of clinical outcomes.”

Dr Williams was lead investigator of the Conduit Artery Function Evaluation (CAFÉ), a substudy of the Anglo-Scandi­navian Cardiac Outcomes Trial (ASCOT). In CAFÉ, 2,199 patients had their brachial blood pressures measured and had central aortic pressures derived by using a noninvasive computer program that ex­amines the shape of the pulse wave at the wrist. The shape of the pulse wave is influenced by antihypertensive drugs, he said.

Central pressure is a measure of the strength of a reflected wave of pressure that meets an outgoing pulse of pressure produced by the next heartbeat. This summed pressure is not measured by the traditional brachial blood pressure, explained Dr Williams, professor of medicine, department of cardiovascular sciences, University of Leicester, UK.

The larger ASCOT study compared the effects of 2 antihypertensive regimens—a regimen of amlodipine (Nor­vasc) and perindopril (Aceon) versus atenolol (Tenormin) and a thiazide diuretic in 19,257 patients with hypertension—and found significant reductions in adverse cardiovascular and renal outcomes and death in the patients as­signed to amlodipine-perindopril compared with atenolol-diuretic.

Brachial pressures differed little between the treatment groups in CAFÉ, but trial-averaged values for central aortic pressures and hemodynamic values were lower in the amlodipine-perindopril group. Central aortic systolic blood pressure was 4.3 mm Hg and the central aortic pulse pressure was 3.0 mm Hg lower with the amlodipine-perindopril regimen compared with the beta blocker-thiazide diuretic regimen. Typically, a 3- to 4-mm Hg decline in brachial blood pressure would be expected to reduce the incidence of stroke by about 25%, said Dr Williams. In ASCOT, amlodipine-perindopril was associated with a 27% reduction in stroke.

A prespecified secondary analysis that compared the incidence of clinical events between the 2 treatment groups found a reduction in the composite end point of cardiovascular events, revascularization procedures, and renal impairment in the group randomly as­signed to amlodipine-perindopril, al­though this analysis of CAFÉ lacked the power to produce statistically meaningful differences. After adjusting for other variables, only central pulse pressure was a significant determinant of total cardiovascular and renal end points, he said.

“These findings provide a novel mech­anism to explain the different clinical outcomes between the 2 blood pressure treatment arms in ASCOT and potentially other blood-pressure—lowering treatment trials,” he said. They may also have significant implications for treatment guidelines.

Technology to measure central blood pressure “should be incorporated into blood-pressure—lowering trials so that we gain as much information as possible about what the drugs are doing,” Dr Williams added.

Clinical benefit of lowering LDL may not extend to ultra-low levels Lipid Disorders Dallas—High-dose atorvastatin (Lipitor) is not significantly better than moderate doses of simvastatin (Zocor) in preventing second coronary events, said Terje R. Pedersen, MD, at the American Heart Association’s Scientific Sessions 2005. He presented the results of a study known as Incremental Decrease in Clinical End­points Through Aggressive Lipid Low­ering (IDEAL). The results may signal a threshold level of low-density lipoprotein (LDL) cholesterol beyond which further reduction produces little clinical benefit.

Atorvastatin, 80 mg/day, was compared with simvastatin, 20 to 40 mg/day, in 8,888 patients with stable coronary heart disease (CHD). The regimen of simvastatin used in IDEAL was one established by the Scandinavian Simvastatin Survival Study to provide significant clinical benefits compared with placebo, said Dr Pedersen.

At study entry, LDL cholesterol was a mean of 122 mg/dL, which was reduced to a mean of 81 mg/dL in the group assigned to atorvastatin and 104 mg/dL in those assigned to simvastatin.

The primary end point was a composite of myocardial infarction, CHD death, or cardiac arrest with resuscitation, the rate of which was not significantly different between the 2 treatment groups.

The group assigned to atorvastatin had 11% fewer such events over the 5-year course of the study, but this reduction failed to achieve statistical significance.

Several secondary end points did favor atorvastatin, however. Patients as&shy;signed to high-dose atorvastatin had a 13% reduction in major cardiovascular events (P = .02), a 16% reduction in any CHD event (P < .001), and a 16% reduction in any cardiovascular event (P < .001).

The study offered reassurance that high doses of HMG-CoA reductase in&shy;hibitors (statins) are safe, said Dr Pedersen, professor of medicine, Ulleval University Hospital, and director of the Center for Preventive Medicine, Oslo, Norway. In the Treat to New Targets study, high-dose atorvastatin was associated with a trend toward an increase in noncardiovascular mortality compared with moderate-dose pravastatin. In IDEAL, there was a trend toward fewer noncardiovascular deaths in the atorvastatin group. “The two trials taken together show that high-dose atorvastatin is not detrimental in any way,” said Dr Pedersen.

With the new safety evidence and previous evidence showing an efficacy advantage, Dr Pedersen said that he expects that more clinicians will use high-dose statins in their practice.

High-dose statin therapy probably failed to significantly reduce the incidence of death because mortality in patients with acute coronary syndromes has been reduced dramatically by the widespread use of revascularization procedures, he said. The mortality rate in IDEAL was only 1% per year, he noted, calling it “outstanding.” He added, “It will be hard for any particular drug to demonstrate further reductions in cardiovascular mortality.”

Steven Nissen, MD, medical director of the Cleveland Clinic Cardiovascular Co&shy;or&shy;din&shy;ating Center, reached a similar conclusion. “We’re reaching the limits of what LDL reduction can achieve. What you see in the clinical trials is that lower levels of cholesterol provide some benefit…but it’s not always statistically significant,” he said. “I tell my patients that we’ll lower your cholesterol as low as we can get it without producing adverse effects.”

Addition of an agent that increases high-density lipoprotein cholesterol may be more advantageous than driving LDL cholesterol to ultra-low levels, believes Allen J. Taylor, MD, director, cardiology service, Walter Reed Army Medical Center, Washington, DC.

“An LDL cholesterol-lowering strategy is a starting point, but overall a partial therapy approach. Clinicians have been waiting for the story on ultra-low LDL cholesterol to unfold,” he said. “The belief was that we just needed to get LDL cholesterol low enough, and that would finally give us the answer that would control CHD risk. In the end, it’s a single risk factor in a multifactorial disease.”

Insulin sensitizer reduces coronary risk in high-risk type 2 diabetes diabetes Dallas—Evidence suggests that the insulin-sensitizing agent pioglitazone (Actos) can reduce the risk of cardiac events in patients with type 2 diabetes with a previous myocardial infarction (MI). The findings come from an exploratory analysis of the Pro&shy;spec&shy;tive Pioglitazone Clinical Trial In Macro&shy;vascular Events Study (Pro&shy;ACTIVE), the results of which were announced at the American Heart Association’s Sci&shy;entific Ses&shy;sions 2005.

The findings presented here were a subgroup analysis of the 5,238 pa&shy;tients in the main PROactive study, in which patients with type 2 diabetes and ma&shy;cro&shy;vascular disease were randomly as&shy;signed to pioglitazone, 45 mg/day, or placebo on top of conventional therapy with antidiabetic, lipid-modifying, and antihypertensive medications. Pa&shy;tients were followed for nearly 3 years.

In the overall study, pioglitazone was associated with a 10% reduction in the primary end point—a composite of 7 different macrovascular events (all-cause mor&shy;t&shy;ality, non-fatal MI, stroke, major leg amputation above the ankle, acute coronary syndrome [ACS], cardiac intervention including coronary artery bypass graft surgery or percutaneous coronary intervention, or leg revascularization)&mdash;but this reduction failed to reach statistical significance. Pioglita&shy;zone significantly re&shy;duced the combined risk of death, MI, and stroke by 16% (P = .027). These data were reported last summer at the 41st annual meeting of the European Associa&shy;tion for the Study of Diabetes in Athens, Greece.

The secondary analysis reported here included 2,445 patients from PROactive who had a previous MI, 63% of whom were on HMG-CoA reductase inhibitor (statin) therapy. Pioglitazone was associated with a 28% reduction (P = .045) in the incidence of a second MI and a 37% reduction (P = .035) in the occurrence of ACS. Furthermore, there was a 19% reduction (P = .034) in the risk of a cardiac composite end point composed of nonfatal MI, coronary revascularization, ACS, and cardiac death.

“This is the first drug in diabetes which has been shown…to decrease mortality, MI, and ACS,” said Er&shy;land Erdmann, MD, lead investigator of the study and a professor of medicine at the University of Koeln in Germany. “I think it is of utmost importance that this drug lowers all of the cardiovascular risks, especially in those patients who have the most serious prognosis.”

According to Dr Erdmann, pio&shy;glitazone attacks multiple cardiovascular risk factors, and its effects include an increase in high-density lipoprotein cholesterol and decreases in triglycerides, glycosylated hemoglobin values, blood glucose, C-reactive protein, and blood pressure. Some evidence suggests that it may also have beneficial effects on arterial wall function. The improvements in lipid values appear to be unique to pioglitazone among the insulin sensitizers, he added.

FDA

Spotlight

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Although there was a higher incidence of heart failure with pioglitazone treatment, heart failure deaths were no more frequent in the pioglitazone-treated patients, leading Dr Erdmann to speculate that some of the heart failure attributed to pioglitazone was actually edema.

Pioglitazone treatment of 1,000 pa&shy;tients with type 2 diabetes and a history of MI would prevent 22 recurrent MIs and 23 cases of ACS over 3 years, Dr Erdmann said.

The selection of the primary end point in the main PROactive study has been criticized because it included both coronary disease and peripheral disease. “Many who pursue mech&shy;anisms of atherosclerosis would point out that peripheral vascular disease and coronary disease, including the response to therapy, are not the same,” commented Jorge Plutzky, MD, director, Vascular Disease Pre&shy;vention Pro&shy;gram, Brigham and Wom&shy;en’s Hos&shy;pital, Boston.