March 14, 2006. Lisa Nainggolan

The new regimen of enoxaparin involves lower doses in elderly patients and those with renal dysfunction, and this translated into a reduction in bleeding compared with previous trials of enoxaparin in thrombolysis patients. However, it was still associated with an increase in major bleeding compared with UFH in this study.

Enoxaparin did not reduce mortality alone in EXTRACT-TIMI 25, but it did reduce the primary end point of death or nonfatal recurrent MI and was associated with a net clinical benefit when the efficacy and bleeding results were combined.

"It is our judgment that despite the increase in episodes of major bleeding, the early and sustained reduction in ischemic events and the balance of efficacy and safety . . . demonstrate the advantage of the regimen of enoxaparin over 48 hours of UFH as the adjunctive antithrombin regimen to support fibrinolysis," Antman and colleagues state.

The results of EXTRACT will undoubtedly be compared with those of the OASIS-6 study, also reported today at a late-breaking session at the meeting.

OASIS-6 is comparing another strategy of prolonged antithrombin therapy—this time with the factor Xa inhibitor fondaparinux—with 48 hours of UFH therapy in all patients with STEMI, including those undergoing primary PCI, those receiving no reperfusion therapy, and those undergoing thrombolysis.

The results of the subgroup of patients with STEMI who receive thrombolysis in OASIS-6 will thus be the most interesting to compare with the EXTRACT findings.

In the paper, Antman and colleagues explain that thrombolysis is the most common method of reperfusion worldwide for patients with STEMI, and contemporary guidelines recommend the routine administration of UFH for 48 hours, along with the thrombolytic agent and aspirin. But the use of UFH requires frequent monitoring to adjust the infusion rate to maintain a therapeutic range of anticoagulation.

LMWHs such as enoxaparin provide a reliable level of anticoagulation without the need for therapeutic monitoring and offer the advantage of subcutaneous administration.

In the study, 20 506 patients with STEMI who were scheduled to undergo fibrinolysis were randomized to receive enoxaparin (until hospital discharge or for a maximum of eight days, whichever came first) or UFH heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent MI through 30 days.

The dose of enoxaparin was reduced accordingly for those aged 75 years or older (they were given three quarters of the normal dose and the bolus was omitted) and in those who had clinically significant impairment in renal function (enoxaparin was given once a day, rather than twice).

The primary end point was significantly reduced in those patients who received enoxaparin—this was primarily driven by a 33% reduction in the rate of nonfatal MI in the enoxaparin group, as there was no significant difference in mortality between the two arms. A significant 26% reduction in urgent revascularization was also seen with the low-molecular-weight heparin.

"Our results suggest that a strategy of administering enoxaparin throughout the index hospitalization is superior to the current strategy of administering UFH for 48 hours as adjunctive therapy for patients with STEMI who undergo pharmacologic reperfusion with a fibrinolytic agent," say Antman and colleagues

Three factors may have contributed to the effects observed, they add. First, the superior antithrombotic effect of enoxaparin "may be explained, in part, by its greater ratio of anti-factor Xa to anti-factor IIa activity," they note. Second, a longer duration of treatment with enoxaparin may have helped, and finally, a possible rebound increase in thrombotic events after the discontinuation of UFH could have contributed.

However, they note, "We are unable to determine definitively the relative contributions of each of these factors to the results observed."

Major bleeding was significantly increased with enoxaparin, by 53%, but there was no significant increase in the rate of intracranial hemorrhage with the low-molecular-weight heparin (0.8% vs 0.7% with UFH; p=0.14), the investigators note.

"For every 1000 patients treated with the enoxaparin strategy, there would be 15 fewer nonfatal reinfarctions, seven fewer episodes of urgent revascularization, and six fewer deaths, at the cost of four additional episodes of nonfatal major bleeding (with no increase in the number of nonfatal intracranial hemorrhages)," they conclude.

1. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006; DOI: 10.1056/NEJMoao6o898. Available at: http://www.nejm.org.