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ExTRACT-TIMI 25:Enoxaparin vs UF heparin for STEMI

Acute Coronary Syndromes (ACS)


Presenter Report: Morrow, David  (USA)

The low molecular weight heparin enoxaparin (ENOX) was compared to unfractionated heparin (UFH) as adjunctive anticoagulant therapy in patients treated with fibrinolysis for ST elevation myocardial infarction(STEMI).

The ENOX strategy consisted of treatment for the duration of the index hospitalization, while UFH was given as per guidelines recommendations for 48 hours unless there was an ongoing need for anticoagulation. As previously reported (NEJM 354: 1477, 2006), among the 20,479 subjects in the intent to treat (ITT) population,through 30 days the primary endpoint of death or nonfatal MI occurred in 9.9% of the ENOX group and 12.0% of the UFH group ( RR 0.83; 0.77-0.90; P<0.001); the main secondary endpoint of death, nonfatal MI, or urgent revascularization occurred in 11.7% of the ENOX group and 14.5% of the UFH group (RR 0.81; 0.75-0.87; P<0.001); major bleeding occurred in 2.1% of the ENOX group and 1.4% of the UFH group (RR 1.53; 1.23-1.89; P <0.001). Net clinical benefit (death, nonfatal MI, or nonfatal disabling stroke) favored ENOX over UFH –10.1% versus 12.3% (RR 0.82; 0.76-0.89; P<0.001)

To assess the long-term impact of the benefits and risks of ENOX seen at one month, we analyzed the outcomes at one year after randomization using Kaplan-Meier methodology. One year followup data were available on 99% of the ITT population.

Results at One Year
Endpoint ENOX (%) UFH (%) HR 95 CI P value
Death/MI 15.8 17.0 0.92 0.86-0.98 < 0.01
MI (nonfatal) 5.7 6.7 0.82 0.73-0.92 <0.001
Disabling Stroke 1.1 1.2 0.97 0.75-1.26 0.81
Death/MI/Nonfatal Disabling Stroke 16.0 17.3 0.91 0.85-0.98 0.007
Death 10.5 10.6 0.98 0.90-1.07 0.72

The ENOX strategy showed a consistent benefit over the UFH strategy with respect to the primary endpoint of death or nonfatal MI at one year across major prespecified subgroups.
Among patients who sustained a major bleed but survived to 30 days, there was no difference between the ENOX and UFH groups with respect to mortality or reinfarction after 30 days and up to 1 year.


The benefits of the strategy of ENOX over UFH in significantly reducing the rate of Death/MI by 30 days in STEMI patients treated with fibrinolysis persisted through one year. The 1-yr benefit of the ENOX strategy is accomplished through a reduction in the rate of nonfatal reMI. Although through 30 days the rate of major bleeding was significantly higher with ENOX, net clinical benefit was significantly in favor of ENOX both early (30 days) and late (one year) after treatment.

Discussant Report :
Wallentin, Lars (Sweden)

Several small and intermediately sized trials have indicated a reduction in the rate of new ischemic events with low molecular weight heparin enoxaparin (ENOX) in stead of unfractionated heparin (UFH) as adjuvant anticoagulant treatment of ST-elevation myocardial infarction (STEMI).

This report presents the one year follow up of the Extract trial which randomized 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive ENOX throughout the index hospitalization or unfractionated heparin (UFH) for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction (MI) through 30 days. The long-term follow-up was performed by telephone interviews after 6 and 12 months on the occurrence of death, MI or disabling stroke. There was however no adjudication of these end-points. The long-term follow-up was 99 % complete with information on 10153 and 10122 patients in the respective enoxaparin and unfractionated heparin groups.

The results showed that there remained a significant 1.2 % absolute and 8 % relative reduction (p=0.01) in the composite primary outcome event of death and myocardial infarction. In comparison to the 2.1% absolute and 17 % relative reduction at 30 days around half of the early benefit was lost during the follow-up period. The sustained reduction in event rate was driven by a sustained reduction in reinfarction while there was no difference in mortality after 30 days or after one year. Nor was there any difference in disabling stroke. During the initial treatment there was a 0.7% absolute increase in severe bleeds in the ENOX group which however was not associated with any complications during long-term follow-up.

This study has several strengths. It is the largest prospective randomized trial of Enox vs UFH as an adjuvant to fibrinolysis in STEMI. It focuses on evaluating one mode of reperfusion treatment and provides information on the effects of ENOX vs UFH in combination with all types of fibrinolytic agents. It is adequately powered for getting reliable signals on the effects on all the hard end-points death/MI/stroke. The design compares the test treatment to the currently recommended treatment with UFH infusion. The study now provides a very impressive documentation on short as well as long term effects. The results are clear and therefore have important clinical implications. Finally, the study also indicates new directions for research on further improvements based on the consistent pattern of raised event rates in this patient group after cessation of anticoagulant treatment – initially at cessation of UFH after 48 hours and later after cessation of ENOX at 8 days.


The ENOX strategy to support fibrinolysis is better than that of UFH because of the early superiority in reducing death/MI, and around half of this benefit remains after 1 year. There is, however, no difference in survival and a slight increase in severe bleeding during treatment, which however does not translate into any difference in long-term outcome or disabling stroke. The results also indicate a need for evaluation of prolonged treatment with oral antithrombotics after cessation of parenteral anticoagulation. Enoxaparin can currently be recommended as a standard anticoagulant treatment in STEMI in combination with all fibrinolytic agents and at primary PCI




Clinical Trial Update I

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.