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ATLANTA, March 15 - After fibrinolysis for ST-elevation myocardial infarction (STEMI), Lovenox (enoxaparin) reduces the 30-day incidence of death and non-fatal reinfarction by 17%, compared with unfractionated heparin, but at the cost of a 50% increase in major bleeding.

This was the bottom line of ExTRACT-TIMI 25, a study of 20,506 patients reported by Elliott M. Antman, M.D., of Brigham and Women's Hospital and Harvard Medical School, at the American College of Cardiology meeting here. The results were simultaneously published online by the New England Journal of Medicine.

"We found that there is a better anticoagulant strategy than the current strategy that is used around the world for managing patients who receive fibrinolytic therapy for ST-elevation myocardial infarction," Dr. Antman said.

He and international colleagues in the ExTRACT TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Thrombolysis in Myocardial Infarction) trial came to that conclusion by studying outcomes in patients with STEMI scheduled to undergo fibrinolysis. They were randomly assigned to Lovenox, a low-molecular-weight heparin, throughout the index hospitalization, or unfractionated heparin for at least 48 hours.

"We felt that it was a very important question to determine whether there was a better alternative to the current regiment of unfractionated heparin that is typically administered with a fibrinolytic drug," Dr. Antman said. "Guidelines on both sides of the Atlantic recommend administration of unfractionated heparin in concert with aspirin and a fibrinolytic drug."

For people younger than 75, Lovenox was given in a 30 mg intravenous bolus and subcutaneous injections at 1 mg/kg every 12 hours.

"For patients at least 75 years old, we tested a strategy that has never been test before," Dr. Antman said. "We eliminated the intravenous bolus and we gave them only 75% of the dose that had been given to younger patients. This was very important as we did not want our older patients to accumulate high levels of anti-Factor-Xa activity and run the risk of extensive bleeding."

As in most studies of its ilk, the primary efficacy endpoint was a composite of death or non-fatal recurrent MI in the first 30 days. A second endpoint included a composite of the first two events plus urgent revascularization. They also considered a net clinical benefit outcome, which balances benefit of therapy against the risk of bleeding and other adverse events.

The investigators found that the primary endpoint occurred in 12% of those on unfractionated heparin, compared with 9.9% of those on Lovenox.

"Our novel regimen of enoxaparin, which was a strategy that we used throughout the initial hospitalization for patients' heart attacks, reduced the risk of dying or having a second heart attack by 17%, which was highly statistically significant [P

Non-fatal re-infarctions occurred in 4.5% of patients assigned to unfractionated heparin, compared with 3.0% of those receiving enoxaparin (relative risk reduction 33%, P

There were deaths in 7.5% of patients who received unfractionated heparin and in 6.9% of those given Lovenox (P = 0.11). The composite of death, non-fatal reinfarction, or urgent revascularization occurred in 14.5 % of patients who assigned to unfractionated heparin, compared with 11.7 % of those in the Lovenox arm (P

In the safety analysis, the investigators found that major bleeding occurred in 1.4 % of patients on unfractionated heparin, compared with 2.1 % of those on Lovenox. The relative risk for major bleeding (including intracranial hemorrhage) on Lovenox was 1.53 (95% CI, 1.23-1.89, P

For the net clinical benefit measure, the composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage occurred in 12.2 % of patients given unfractionated heparin and 10.1 % of those given enoxaparin (P

"We found a number of extremely positive observations in our trial," Dr. Antman said. "The major secondary endpoint of our trial -- death, non-fatal MI or urgent re-vascularization -- was already statistically significantly lower at 48 hours, and was highly statistically significant at 30 days. And the major bleeding rates we observed in our trial were lower than had previously been reported with either of the antithrombin strategies that we tested."

The investigators calculated that for every 1,000 patients treated with the Lovenox strategy, versus the standard unfractionated heparin strategy, there would be 15 fewer non-fatal re-infarctions, seven fewer episodes of urgent revascularization, and six fewer deaths, at the cost of four more non-fatal bleeds, and no difference in intracranial hemorrhage.

But in a question and answer session at a media briefing in which the trial results were discussed, Salim Yusuf, M.D., of McMaster University in Hamilton, Ontario, commented that the 50% increase in major bleeding in patients taking Lovenox in the ExTRACT-TIMI 25 trial was a matter of concern.

"The overall rates of bleeding were 50% higher," Dr. Yusuf said. "The proportion of people who died after a bleed was 38% with enoxaparin and 31% with unfractionated heparin. That calculates to about 75 deaths associated with bleeding with enoxaparin, compared with about 33 or 35. To me that is a highly significant difference in fatal bleeds."

ExTRACT-TIMI 25 was supported by a research grant from Sanofi-Aventis.

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