Reviparin effective in reducing risk of death after heart attack

01/20/05

The drug reviparin (a low molecular weight heparin anticoagulant), when administered to patients with a heart attack, is effective in reducing the risk of death and the risk of a subsequent heart attack, according to a study in the January 26 issue of JAMA.

Approximately 15.5 million cardiovascular deaths occur every year, according to background information in the article. Of these, about half are likely to be due to acute myocardial infarction (MI, [heart attack]). Although reperfusion therapy (restoration of blood flow), aspirin, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors reduce the risk of death when used early in patients after a heart attack, the rate of death and illness remains high. No antithrombotic or newer antiplatelet drug has been shown to reduce the risk of death after a heart attack.

Salim Yusuf, D.Phil., F.R.C.P.C., of Hamilton General Hospital and McMaster University, Ontario, Hamilton, Canada, and colleagues evaluated the effects of reviparin on the composite outcome of death, heart attack, and stroke at 7 and 30 days. The randomized, double-blind, placebo-controlled trial (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation [CREATE]), included 15,570 patients with ST-segment elevation (a specific finding on the electrocardiogram ) or new left bundle-branch block (a slowing in the flow of electrical pulses that drive the heart beat). The patients presented within 12 hours of symptom onset at 341 hospitals in India and China from July 2001 through July 2004. Patients received reviparin (n = 7,780) or placebo (n = 7,790) subcutaneously twice daily for seven days.

The researchers found that the primary composite outcome was significantly reduced from 11.0 percent of patients in the placebo group to 9.6 percent in the reviparin group, a 13 percent lowered risk. These benefits persisted at 30 days (13.6 percent vs. 11.8 percent) patients, a 13 percent lowered risk; with significant reductions in the 30-day death rate (11.3 percent vs. 9.8 percent), 13 percent lower rate; and additional heart attack (2.6 percent vs. 2.0 percent), a 23 percent lower rate; and no significant differences in strokes (0.8 percent vs. 1.0 percent).

Reviparin treatment was significantly better when it was initiated very early after symptom onset at 7 days (less than 2 hours: 30 percent reduced risk; 30 of 1,000 events prevented; between 2 to 4 hours: 19 percent reduced risk; 21 of 1,000 events prevented; between 4 to 8 hours: 15 percent reduced risk; 16 of 1,000 events prevented; and greater than 8 hours: 6 percent increased risk. There was an increase in life-threatening bleeding at 7 days with reviparin and placebo (17 [0.2 percent] vs. 7 [0.1 percent], respectively); but the absolute excess was small (1 more event per 1,000) compared with the reductions in the primary outcome (18 fewer per 1,000) or mortality (15 fewer per 1,000).

"Reviparin is considerably less expensive than other antithrombotic agents, such as bivalirudin, … and can be given subcutaneously. Its use is relatively straightforward and can be used in both developed and developing countries. Therefore, the benefits of reviparin represents a moderate but important globally applicable advance in the management of patients with acute MI," the authors conclude.

(JAMA. 2005;293:427-436. Available post-embargo at JAMA.com)

Editor's Note: The study had no external funding. Reviparin and placebo were donated by Abbott Laboratories. Dr. Yusuf has received research grants and honoraria for lectures from Knoll and Abbott Laboratories.

Therapy With Glucose-Insulin-Potassium Infusion Not Beneficial for Treating Heart Attack

In a related study in this week's JAMA, a widely applicable, inexpensive therapy was found to have no effect on death rates when treating patients who had an acute ST-segment elevation myocardial infarction (STEMI), a heart attack with a specific finding on the electrocardiogram.

Shamir R. Mehta, M.D., M.Sc., of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, and colleagues evaluated the effects of high-dose glucose-insulin-potassium (GIK) infusion on patients with acute STEMI. GIK is a low-cost therapy that has been speculated to improve mortality in heart attack patients.

The study (a merger of CREATE and Estudios Cardiologicas Latin America Study Group, ECLA [CREATE-ECLA]) was conducted in 470 centers worldwide among 20,201 patients with STEMI who presented within 12 hours of symptom onset. The average age of patients was 58.6 years, and evidence-based therapies were commonly used. Patients were randomly assigned to receive GIK intravenous infusion for 24 hours plus usual care (n = 10,091) or to receive usual care alone (controls; n = 10,110).

The researchers found: "The CREATE-ECLA trial demonstrated that high-dose GIK solution given for 24 hours in patients presenting with acute STEMI has a neutral effect on mortality, cardiac arrest, and cardiogenic shock. The goal of our study was to reliably assess the effects of high-dose GIK in preventing mortality and major cardiovascular events in patients with STEMI. Given that there were more than 1,900 deaths in the study, it was well powered to detect even a moderate effect on mortality," the authors write. "The very high adherence to the protocol and the excellent 30-day follow-up (99.85 percent) provide confidence in the validity of our findings and suggest that it is very unlikely that the current regimen of high-dose GIK is of any material benefit in reducing mortality in patients with STEMI." (JAMA. 2005;293:437-446. Available post-embargo at JAMA.com)

Editor's Note: This study had no external funding. Aventis Pharma donated human insulin in India. Aventis Pharma had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

Editorial: Simple Principles of Clinical Trials Remain Powerful
In an accompanying editorial, Robert M. Califf, M.D., of Duke Clinical Research Institute, Durham, N.C., discusses the CREATE trials.

"What does [the CREATE-ECLA] trial show about GIK infusion? This 'generic' therapy has survived decades of clinical practice without a definitive test of its safety and effectiveness. The conceptual basis for its use is sound, and its rationale has been delineated in a variety of publications cited by the CREATE investigators. Unfortunately, regardless of its scientific rationale and the positive results of small studies, this definitive trial, combined with a previous overview that showed only a modest potential benefit, answers the question beyond reasonable doubt: there is no benefit of GIK therapy. Societal resources would be better spent on evaluating other approaches in clinical trials and using other therapies in practice."

"What does [the CREATE] trial show about reviparin? Antithrombotic therapy has become a mainstay of treatment of acute coronary syndromes (ACS), but the accrual of definitive evidence has been hampered by the fact that unfractionated heparin (UFH) became standard before the era of definitive clinical outcome trials," Dr. Califf writes. "CREATE advances the field by demonstrating that the recommendation for antithrombotic therapy can now be made with confidence that the evidence is not built like a house of cards on a series of neutral 'equivalence trials or small outcome trials. Given the modest advantage of low-molecular-weight heparin in general in the broader range of ACS, including non-ST elevation ACS, CREATE enhances the case for its preference over UFH." (JAMA. 2005;293:489-490. Available post-embargo at JAMA.com)

Editor's Note: Dr. Califf has received research contracts through Duke University from Sanofi and Aventis, makers of low-molecular-weight heparin.

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