Abstract & Commentary
Commentary by Theodore Chan, MD, FACEP, Associate Professor of Clinical Medicine; Medical Director, Department of Emergency Medicine, University of California San Diego Medical Center, San Diego. Dr. Chan is on the Editorial Board of Emergency Medicine Alert.
Source: CREATE Trial Group Investigators: Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA 2005;293:427-435.
In this large, randomized, double-blind, international clinical trial, investigators sought to evaluate the effect of reviparin (a LMWH similar to enoxaparin) on mortality, reinfarction, recurrent ischemia, stroke, and bleeding at seven and 30 days after STEMI. More than 15,000 STEMI patients at 341 centers in China and India were randomized to receive either a weight-based dose of reviparin (3436 6871 IU every 12 hours) or placebo injection. Patients were eligible if they presented within 12 hours of symptoms (with ST-segment elevation or new left bundle-branch block on electrocardiogram) with no contraindications to heparin. Subsequent care was left to the discretion of the clinicians and included standard ACS and reperfusion therapies as indicated.
There was a significant improvement in the primary outcome composite measure of death, reinfarction, and stroke at seven days following STEMI (9.6% vs 11.0%, p = 0.005, hazard ratio = 0.87, for the reviparin and placebo groups respectively). This beneficial advantage was maintained at 30 days following STEMI as well (11.8% vs 13.6%, p = 0.001, hazards ratio = 0.87, respectively). This improvement was seen for patients who underwent emergent fibrinolytic therapy (approximately 73% of patients) or alternatively direct percutaneous coronary intervention (6.1%). Moreover, the benefit was greatest in patients who received reviparin early. The relative risk reduction was 30% for patients treated within 2 hours, 20% for 2 to 4 hours, 15% for 4 to 8 hours, and negligible when started 8 or more hours after presentation.
The incidence of major or life-threatening bleeding was higher in the reviparin group, particularly in the first seven days (0.9% vs 0.4%, p < 0.001, respectively). As a result, the investigators performed a benefit and risk balance analysis, utilizing a composite endpoint of death, reinfarction, strokes, and life-threatening bleeding, which still demonstrated benefit for the reviparin group at 7 days (9.8% vs 11.1%, p = 0.01, hazards ratio = 0.88) and at 30 days (12.0% vs 13.7%, p = 0.002, hazards ratio = 0.87, respectively).
These data suggest that for every 1000 patients treated with reviparin, 17 fewer major adverse outcomes would be prevented. The authors conclude that, for patients with STEMI (or new left bundle-branch block with presentations consistent with ACS), reviparin reduces mortality and re-infarction without a substantially increased risk of stroke; although it carries a slight increase in risk of major bleeding over placebo, the benefit clearly outweighs the risk of therapy.
Commentary
This study (also known as the CREATE trial Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation) is the largest, randomized, double-blind clinical trial assessing the utility of heparin in the treatment of STEMI. As such, its findings of significant benefit of the LMWH reviparin over placebo are important. However, the question remains as to whether these findings are applicable to STEMI treatment in the United States.
First, while it’s true that definitive evidence of mortality benefit for UFH in ACS is limited, heparins have become standard therapy for ACS.1 Whether reviparin has additional benefit over UFH in the setting of STEMI is not answered by this study.
Second, this study was conducted in China and India where there are differences in the treatment of ACS. For example, while use of standard therapies in this study, such as aspirin, were high (97%), the fibrinolytic therapy (occurring in 73% of cases) was primarily streptokinase and urokinase, as opposed to tissue plasminogen activator, which is used more commonly in the United States. What effect these differences may have had on the beneficial outcome seen with reviparin remains unknown.
Finally, while similar to enoxaparin as an LMWH agent, reviparin is not used widely in this country.
Whether the benefits reported in this study are specific to reviparin, or are generalizable to other LMWH agents, remains unknown. There is, however, one large trial with enoxaparin (TIMI 25) underway that should provide additional information in the future.2
References
1. Collins R, et al. Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: Systematic overview of randomised trials. BMJ 1996; 313:652.
2. Antman EM, et al. The EXTRACT-TIMI 25 Investigators: Enoxaparin vs unfractionated heparin as antithrombin therapy in patients receiving fibrinolysis for STEMI. Am Heart J (in press).
In this large, randomized, double-blind, international clinical trial, investigators sought to evaluate the effect of reviparin (a LMWH similar to enoxaparin) on mortality, reinfarction, recurrent ischemia, stroke, and bleeding at seven and 30 days after STEMI.
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