Biotech Tracker News - Key Angiomax Data Published in JAMA
February 19, 2003.  Results of The Medicines Company’s (NASDAQ: MDCO) REPLACE-2 (The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2) trial of Angiomax were published in the February 19, 2003 issue of The Journal of the American Medical Association. Angiomax with provisional gpIIb/IIIa blockade met its objective of non-inferiority to heparin plus planned gpIIb/IIIa blockade during PCI with regard to suppression of acute ischemic end points. Angiomax administration was also associated with less bleeding. The high-profile publication essentially confirms our earlier view that Angiomax will expand its use as a heparin replacement in the setting of percutaneous coronary interventions (PCI).  Angiomax is a direct thrombin inhibitor associated with better efficacy and less bleeding complications than heparin during coronary balloon angioplasty. However, its effects had not been widely examined during a full array of PCI. REPLACE-2 was a randomized, double-blind, unfractionated heparin-controlled trial of 6,010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries. PCIs included stent, angioplasty, and atherectomy procedures. The study was designed to determine Angiomax’s efficacy and bleeding risk profile, with a provisional glycoprotein IIb/IIIa (gpIIb/IIIa) inhibitor, compared to heparin plus planned gpIIb/IIIa blockade. The study’s primary composite endpoint was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding. Its secondary composite endpoint was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization.  A gpIIb/IIIa blocker was administered to 7.2% of patients in the Angiomax group. The primary composite endpoint occurred among 9.2% of subjects in the Angiomax group versus 10.0% of subjects in the heparin group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; p = .32). The secondary composite endpoint occurred in 7.6% of subjects in the Angiomax group versus 7.1% of subjects in the heparin group (1.09; 0.90-1.32; p = .40). In-hospital major bleeding rates were significantly reduced by the administration of Angiomax (2.4% vs. 4.1%; p<.001).  Rigorously pre-specified statistical criteria for Angiomax’s noninferiority were satisfied for both endpoints. Non-inferiority endpoints are appropriate given the possibility of Angiomax’s appropriate cost-effectiveness profile, short duration of administration, and potential to reduce hemorrhagic complications. Angiomax with a provisional gpIIb/IIIa inhibitor was superior to heparin alone by an imputed comparison.  It is important to note that a statistically insignificant 0.5% excess of ischemic events (predominantly non–Q-wave myocardial infarction) was observed in the Angiomax group. Long-term follow-up (6 month and 1 year) is underway in the REPLACE-2 program. The follow-up is designed to assess the consequences of this disparity in early, peri-procedural ischemic events, as it has been noted that the literature is replete with examples of even larger differences in early infarction rates that have not consistently translated into detectable 1-year mortality differences. Formal health economic analyses of REPLACE-2 are also ongoing.  Dr. Elliott M. Antman addressed the global meaning of translating the results of REPLACE-2 into clinical practice with an emphasis on the degree to which Angiomax should replace unfractionated heparin in the PCI setting. Salient editorial points were:  Angiomax is an attractive anticoagulant in the PCI setting in patients with renal failure and in those with heparin-induced thrombocytopenia.  The attractiveness of Angiomax beyond these two settings is especially complicated by the fact that REPLACE-2 excluded patients with acute ST-elevation myocardial infarction, thus the trial results “cannot be extrapolated to guide dosing for primary PCI.”  More experience with Angiomax plus a gpIIb/IIIa inhibitor is needed to understand fully the combination’s safety profile.  Future use patterns will need to be judged in the context of the advent of novel anticoagulants that will become available to support PCI. Agents in development include Lovenox, other low molecular weight heparins, Arixtra, Exanta, other novel direct thrombin inhibitors, rNAPc2, and anti-tissue factor antibodies.
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