Low Molecular Weight Heparin (Reviparin) in Preventing Mortality, Reinfarction, and Strokes in Over 15,500 Patients With ST Elevation Acute Myocardial Infarction - CREATE ELCA - Reviparin

Description:

The goal of the trial was to evaluate treatment with the low molecular weight heparin reviparin compared with placebo in patients with acute myocardial infarction (MI).

Hypothesis:

Treatment with the low molecular weight heparin reviparin will be associated with a reduction in mortality compared with placebo.

Study Design

Study Design:

Patients Enrolled: 15,570
Mean Follow Up: 30 days
Mean Patient Age: Mean age 59 years
Female: 23

Patient Populations:

ST-segment elevation MI or new left bundle branch block, presentation within 12 hours of symptom onset, without contraindications to heparin

Primary Endpoints:

Death, MI, or stroke at seven days; and coprimary endpoint death, MI, stroke, or recurrent ischemia at seven days

Secondary Endpoints:

Death, MI, or stroke at 30 days; coprimary endpoint death, MI, stroke, or recurrent ischemia at 30 days; and individual components of composite endpoint

Drug/Procedures Used:

Patients were randomized to reviparin (n=7,780) given subcutaneously for seven days, or placebo (n=7,790). Dosing was based on patient weight, with 3,436 IU given every 12 hours if <50 kg, 5,153 IU given every 12 hours if 5-750 kg, and 6,871 IU given every 12 hours if >75 kg.

The trial was a factorial design, and patients were also randomized to glucose, insulin, and potassium (GIK) infusion or control; the GIK data are reported separately. Patients also received usual therapy for treatment of MI, including aspirin and reperfusion therapy. Enrollment was conducted exclusively in India and China.

Concomitant Medications:

Aspirin (97%), thienopyridine (55%), thrombolytic therapy (73%), and primary percutaneous coronary intervention (PCI) (6%)

Principal Findings:

The majority of patients were treated with a reperfusion regimen of thrombolytic therapy (73%), with the most frequently used streptokinase (49%) and urokinase (23%). An additional 6% underwent primary PCI. Open-label unfractionated heparin or low molecular weight heparin was used in 9.6% of the reviparin group and 11.0% of the placebo group. Median time from symptom onset to treatment was 4.9 hours in the reviparin group and 4.8 hours in the placebo group.

The primary endpoint of death, MI, or stroke at seven days was significantly lower in the reviparin group (9.6% vs. 11.0%, hazard ratio [HR] 0.87, p=0.0048). The coprimary endpoint (primary expanded to include recurrent ischemia) at seven days was also lower in the reviparin group (11.1% vs. 12.6%, HR 0.87, p=0.0039).

Mortality by seven days occurred less frequently in the reviparin group (8.0% vs. 8.9%, HR 0.89, p=0.0357), as did reinfarction (1.6% vs. 2.1%, HR 0.75, p=0.018). There was no significant difference in stroke at seven days (0.8% vs. 0.6%, p=0.26). Results were maintained at 30 days for the primary endpoint (11.8% vs. 13.6%, HR 0.87, p=0.0014), the coprimary endpoint (13.8% vs. 15.6%, HR 0.88, p=0.0016), death (HR 0.87, p=0.0045), and MI (HR 0.77, p=0.013). Life-threatening or major bleeding at seven days was significantly higher in the reviparin group compared with placebo (0.9% vs. 0.4%, p<0.001), as was life-threatening bleeding alone (0.7% vs. 0.3%, p<0.001).

Interpretation:

Among patients with acute MI, treatment with the low molecular weight heparin reviparin was associated with a reduction in the primary composite endpoint at seven days as well as a reduction in death and MI compared with placebo.

The present study is the first large-scale randomized trial to show a significant reduction in mortality with an antithrombotic therapy on top of aspirin and, in the majority of patients, reperfusion therapy in the setting of acute MI. There was no evidence of a rebound effect of a drop in efficacy after the reviparin was discontinued at day seven, with the efficacy benefit maintained through 30 days. Despite the reduction in mortality and reinfarction, it should be noted that there was a small, but significant increase in life-threatening and major bleeding in the reviparin arm.

The study was conducted exclusively in India and China, and differences in practice patterns may limit generalizability to Western countries. For example, the predominant fibrinolytic therapies used were streptokinase (49%) and urokinase (23%), and only 6% of patients were treated with primary PCI. This contrasts with Western practice patterns, where more fibrin-specific therapy and more primary PCI is used. Despite these differences, other similarities were noted, including a high use of thienopyridine therapy. The ongoing, international EXTRACT trial of enoxaparin in ST elevation MI will also provide additional information on mortality with use of a low molecular weight heparin.

References:

The 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;293:427-436.

Presented by Salim D. Yusuf at the American Heart Association Scientific Sessions, November 2004, New Orleans, LA.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, EP Basic Science, Lipid Metabolism, Novel Agents

Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Insulin, Urokinase-Type Plasminogen Activator, Heparin, Low-Molecular-Weight, Heparin, Fibrinolytic Agents, Glucose, Thienopyridines, Potassium, China, Streptokinase, Enoxaparin, India, Bundle-Branch Block, Hemorrhage


< Back to Listings