Results of two new randomized clinical studies confirm that Lovenox (enoxaparin sodium injection) is an effective and safe antithrombotic agent in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) undergoing an invasive management strategy, a release from Aventis said.

In addition, a systematic overview of six clinical trials involving approximately 22,000 patients with NSTE ACS showed that overall, Lovenox is superior to un-fractionated heparin (UFH) in preventing nonfatal myocardial infarction (MI) and the composite of death or nonfatal MI regardless of management strategy, with similar safety.

Results of the SYNERGY trial, the "A" phase of the A-to-Z (Aggrastat to Zocor) trial, and the systematic overview were published in the July 7 issue of the Journal of the American Medical Association.

"The results of SYNERGY, A-to-Z and the systematic overview confirm the benefit of enoxaparin across the spectrum of high- and low-risk ACS patients intended for aggressive or conservative management strategies," said Kenneth W. Mahaffey, associate professor of medicine, Duke Clinical Research Institute at Duke University Medical Centre, Durham, NC, and one of the lead authors of both the SYNERGY study and the systematic overview. "The benefits appear to be enhanced in patients who receive enoxaparin as their initial therapy," he added.

SYNERGY was a prospective, randomized, open-label study of Lovenox versus UFH in more than 10,000 high-risk patients presenting with NSTE ACS and treated with an early invasive strategy. All patients enrolled in the study received treatment with aspirin and either Lovenox or UFH. Clopidogrel and platelet glycoprotein IIb/IIIa inhibitors were administered at the treating physician's discretion. Lovenox was established to be at least as effective as UFH in reducing the incidence of death or nonfatal MI at 30 days, the primary endpoint (14.0 per cent vs. 14.5 per cent, p=0.396).

Bleeding was modestly increased in patients assigned to Lovenox, with a statistically non-significant excess in GUSTO severe events (2.7 per cent vs. 2.2 per cent, p=0.084), although TIMI major bleeding was significantly higher in patients treated with Lovenox (9.1 per cent vs. 7.6 per cent, p= 0.008). The majority of the bleeding excess resulted from coronary bypass artery graft (CABG)-related events. No significant differences in transfusion, intracranial haemorrhage or thrombocytopenia were observed. Importantly, with greater than 90 percent of patients undergoing coronary angiography and 47 percent undergoing percutaneous coronary intervention, no increase was observed in ischemic complications at the time of procedure, including thrombus formation, abrupt closure, stroke or need for urgent CABG.

A series of comprehensive secondary analyses was conducted to remove the confounding influence of pre-randomization antithrombin therapy or postrandomization "crossovers" to alternate antithrombin therapy. Lovenox appeared to have a relative advantage with no excess of bleeding in these analyses. In patients who did not receive antithrombin therapy prior to randomization, Lovenox was associated with a 16 percent relative risk reduction in death and nonfatal MI at 30 days compared with UFH (12.6 per cent vs. 14.8 per cent, p= 0.116). Inpatients who did not receive prior antithrombin therapy or who were randomized to the same antithrombin therapy as they were prior to randomization, Lovenox resulted in a statistically significant 18 percent relative reduction in death or nonfatal MI compared to patients who received UFH (13.3 per cent vs. 15.9 per cent, p=0.039). Bleeding events in these two groups of patients were similar.

The A phase of the 4,000- patient A-to-Z study was designed as an open-label comparison of the efficacy and safety of Lovenox and UFH when administered concomitantly with tirofiban (Aggrastat), a platelet glycoprotein IIb/IIIa inhibitor, and aspirin. Approximately 55 per cent of patients in each arm were recommended for an early invasive treatment strategy, and by 48 hours, approximately 42.5 per cent in the Lovenox arm and 43.8 per cent in the UFH arm had undergone cardiac catheterization.

At 7 days, the primary endpoint (death, myocardial infarction or refractory ischemia) occurred in 8.4 percent of patients receiving Lovenox and 9.4 percent of patients receiving UFH in the intention-to-treat population (p=0.16). Patients treated with Lovenox who received no antithrombotic agent within 24 hours before randomization also experienced a trend toward risk reduction (8.1 per cent vs. 10.2 per cent), though not statistically significant.

Combined rates of clinically significant bleeding (TIMI major or minor bleeding) in the as-treated population were 3.0 per cent in the Lovenox arm vs. 2.2 percent in the UFH arm (p=0.134). There was no difference in major bleeding rates between Lovenox and UFH for any individuals who underwent early intervention, but there was a significant increase in reports of "any bleed" in Lovenox-treated patients, driven primarily by investigator-identified minor bleeding episodes.

"Recent studies have demonstrated that enoxaparin is an effective and safe alternative to unfractionated heparin in patients with unstable angina or non-ST-segment elevation myocardial infarction, though these efficacy and safety results were less robust than the significant reductions in death and myocardial infarction seen in earlier large clinical trials," said Dr. Mahaffey. He added, "To investigate whether the treatment effect of enoxaparin has changed as strategies have evolved to include concomitant antiplatelet agents and more aggressive invasive treatment, we undertook a systematic overview of the ESSENCE, TIMI 11B, ACUTE II, INTERACT, SYNERGY and A-to-Z trials examining enoxaparin versus UFH in ACS."

Investigators conducted an analysis of data from these six clinical trials comparing Lovenox® to UFH in the treatment of approximately 22,000 patients with NSTE ACS. The systematic evaluation was performed for the endpoints of death and nonfatal MI, transfusion, and major bleeding in the overall trial populations and in the subpopulation receiving no antithrombin therapy prior to randomization.

In patients treated with Lovenox, there was a significant reduction in the composite of death or MI, which translates into a relative risk reduction of 8.2 percent. There was no difference in mortality at 30 days in the intention-to-treat populations. Among patients who did not receive any antithrombin therapy prior to randomization, there was a trend toward a decrease in mortality in favour of Lovenox (2.8 per cent in the Lovenox arm vs. 3.2 per cent in UFH arm). A statistically significant 14.6 percent relative risk reduction in the combined endpoint of death and MI was observed in patients in the group treated with Lovenox. The treatment effect was consistent across trials with varying protocol designs over the past eight years of NSTE ACS trial experience.

The primary safety analysis examined endpoints occurring through day 7 after randomization. No significant difference was detected in transfusion or major bleeding in the overall safety population or in the population receiving no antithrombin therapy prior to randomization. In the analyses of both the overall safety populations of all six trials and the overall safety population of trials assessing CABG-related bleeding, no significant difference was detected in in-hospital blood transfusion or major bleeding. A modest but statistically significant increase in major bleeding during hospitalization was detected in the analysis of patients who did not receive antithrombin therapy prior to randomization, but no difference in blood transfusion was noted.