Anticoagulant therapy with enoxaparin is an effective alternative to heparin therapy for patients with acute coronary syndromes

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Two new major studies suggest that anticoagulant therapy with enoxaparin is an effective alternative to heparin therapy for patients with acute coronary syndromes (ACS), according to articles in the July 7 issue of the Journal of the American Medical Association.

In the first study, investigators with the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa inhibitors (SYNERGY) trial compared the outcomes of patients treated with enoxaparin vs. unfractionated heparin. Although previous trials have demonstrated the superiority of enoxaparin compared with unfractionated heparin for patients with non-ST-elevation (a certain pattern on the electrocardiogram) ACS receiving medical therapy as their primary treatment strategy, the value of enoxaparin as the principal anticoagulant regimen for ACS has been debated.

The SYNERGY trial was a randomized, multicenter, international trial conducted between August 2001 and December 2003. A total of 10,027 high-risk patients with non-ST-elevation ACS to be treated with an intended early invasive strategy were recruited. Participants received either subcutaneous enoxaparin (n=4,993) or intravenous unfractionated heparin (n=4,985), administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician.

The primary efficacy outcome was the composite clinical end point of death or nonfatal myocardial infarction (MI, heart attack) during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke.

The researchers found that the primary end point of death or nonfatal MI by 30 days occurred in 14.0 percent of patients assigned to enoxaparin and 14.5 percent of patients assigned to unfractionated heparin. Enoxaparin was not superior to unfractionated heparin but fulfilled the noninferiority criteria. "No differences in ischemic events reported by the physician during percutaneous coronary intervention [PCI, i.e., a stent] were observed between enoxaparin and unfractionated heparin, including similar rates of abrupt closure, threatened abrupt closure, unsuccessful PCI, or emergency coronary artery bypass graft [CABG] surgery. Bleeding was modestly increased in patients assigned to enoxaparin...," the researchers write.

"In high-risk patients with an intended early invasive treatment strategy, enoxaparin and unfractionated heparin are safe and effective alternatives as the antithrombin regimen. Enoxaparin has the advantages of convenience (fixed dosing without need for monitoring or intravenous infusion) and a trend toward a lower rate of nonfatal MI with a modest excess of bleeding. As a first-line agent in the absence of changing antithrombin therapy during treatment, enoxaparin appears to be superior without an increased bleeding risk," the authors write.

In a related study, investigators with the A to Z trial assessed whether combining enoxaparin with the glycoprotein IIb/IIIa inhibitor tirofiban and aspirin is a suitable alternative to the current standard combination of unfractionated heparin with tirofiban and aspirin, in patients with non-ST-elevation ACS.

Participants in the international, randomized trial received either 1 mg/kg of enoxaparin every 12 hours (n = 2,026) and tirofiban and aspirin or intravenous unfractionated heparin (n = 1,961) and tirofiban and aspirin. Phase A of the A to Z trial was conducted between December 1999 and May 2002. The primary outcome measures were death, recurrent heart attack, or ischemia at 7 days, with the study designed to assess both superiority and noninferiority. Safety was based on measures of major and minor bleeding.

The authors write, "Analysis of the 3,987 patients randomized into phase A of the A to Z trial revealed a 1 percent absolute and 12 percent relative difference in favor of enoxaparin compared with unfractionated heparin for the prevention of the composite end point of death, MI, or refractory ischemia. This benefit did not meet criteria to declare superiority but fell well within specified bounds for noninferiority. We found a consistent but nonsignificant risk reduction of 10 percent to 15 percent with enoxaparin across various subpopulations and most subgroups. These risk reductions were of a larger magnitude for patients at higher risk, those who were being managed conservatively, and those who received no antithrombotic agent within 24 hours before randomization. These trends should be interpreted with caution in the absence of a finding of superiority; however, they are consistent with prior studies of glycoprotein IIb/IIIa inhibition with tirofiban and previous studies comparing enoxaparin with unfractionated heparin, which found greater relative efficacy among higher risk patients," the authors write.

"Because it is easier to use and modestly reduces recurrent ischemic events without an increase in the need for blood products, enoxaparin compares favorably with unfractionated heparin in patients with non-ST-segment elevation ACS who are receiving tirofiban and aspirin," the authors conclude.

In an accompanying editorial, Pranab Das, M.D., and David J. Moliterno, M.D., of the University of Kentucky, Lexington, write that these 2 new trials "advance the current understanding and potential future role of enoxaparin in the management of non-ST-segment elevation ACS."

The authors note, "Indeed, there is something for everyone. Had the 'A' portion of A to Z or SYNERGY shown enoxaparin to be superior to unfractionated heparin, as some had expected and many had hoped, commentators would be giving accolades instead of point-counterpoint perspectives."

"Both the A to Z and SYNERGY trials provide evidence that enoxaparin remains a reasonable alternative to unfractionated heparin in contemporary ACS treatment. Enoxaparin has several unique benefits and apparently few limitations. From SYNERGY, the numbers needed to treat with enoxaparin to prevent an occurrence of death or MI at 30 days and to produce a ... major bleeding event are 184 and 68, respectively. It will be interesting to see if these latest mega-trials affect the use of enoxaparin and the associated guidelines related to non-ST-segment elevation ACS," the authors conclude.

jama-archives.org

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