In a multicenter, double-blind, double-dummy, parallel-group study, patients with acute ST-segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either enoxaparin sodium injection or unfractionated heparin.

Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an intravenous bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The intravenous infusion was to be given for at least 48 hours. The enoxaparin sodium injection dosing strategy was adjusted according to the patient's age and renal function. For patients younger than 75 years of age, enoxaparin sodium injection was given as a single 30 mg intravenous bolus plus a 1 mg/kg subcutaneous dose followed by a subcutaneous injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the intravenous bolus was not given and the subcutaneous dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The subcutaneous injections of enoxaparin sodium injection were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated heparin was 54 hours.

When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin sodium injection, the PCI was to be performed on enoxaparin sodium injection (no switch) using the regimen established in previous studies, i.e., no additional dosing, if the last subcutaneous administration was less than 8 hours before balloon inflation, intravenous bolus of 0.3 mg/kg enoxaparin if the last subcutaneous administration was more than 8 hours before balloon inflation.

All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase.

Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male. Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%.

The primary efficacy endpoint was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year.

The rate of the primary efficacy endpoint (death or myocardial re-infarction) was 9.9% in the enoxaparin sodium injection group, and 12% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003) (see Table 25).

Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals.

The beneficial effect of enoxaparin sodium injection on the primary endpoint was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1); however, it is necessary to interpret such subgroup analyses with caution.

Figure 1: Relative Risks of and Absolute Event Rates for the Primary Endpoint at 30 Days in Various Subgroups*

*The primary efficacy endpoint was the composite of death from any cause or myocardial re-infarction in the first 30 days. The overall treatment effect of enoxaparin sodium injection as compared to the unfractionated heparin (UFH) is shown at the bottom of the figure. For each subgroup, the circle is proportional to the number and represents the point estimate of the treatment effect and the horizontal lines represent the 95% confidence intervals. Fibrin-specific fibrinolytic agents included alteplase, tenecteplase, and reteplase. Time to treatment indicates the time from the onset of symptoms to the administration of study drug (median: 3.2 hours).

The beneficial effect of enoxaparin sodium injection on the primary endpoint observed during the first 30 days was maintained over a 12 month follow-up period (see Figure 2).

Figure 2: Kaplan-Meier Plot - Death or Myocardial Re-infarction at 30 Days - ITT Population

There is a trend in favor of enoxaparin sodium injection during the first 48 hours, but most of the treatment difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in Figure 2), an effect that is more striking when comparing the event rates just prior to and just subsequent to actual times of discontinuation. These results provide evidence that UFH was effective and that it would be better if used longer than 48 hours. There is a similar increase in endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued too soon in this study.

The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30 days were 2.1% in the enoxaparin sodium injection group and 1.4% in the unfractionated heparin group. The rates of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group and 0.7% in the unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin sodium injection group (10.1%) as compared to the heparin group (12.2%).