Lots of talk, but very little data presented!
Press Release Source: The Medicines Company
The Medicines Company's REPLACE-2 Clinical Trial Meets Primary and Secondary Endpoints for Angiomax -bivalirudin-
Sunday November 17, 1:40 pm ET
The Cleveland Clinic presents results of landmark study at The American Heart Association's Scientific Sessions 2002 as a late-breaking presentation
CHICAGO--(BUSINESS WIRE)--Nov. 17, 2002-- The Medicines Company (Nasdaq: MDCO - News) announced today that all of the primary and secondary objectives for the landmark post-marketing REPLACE-2 clinical trial of Angiomax® (bivalirudin) were met.
These findings support further steps in the clinical transition from heparin to Angiomax as a foundation anticoagulant in coronary angioplasty. Associate Professor A. Michael Lincoff, M.D. of The Cleveland Clinic, the REPLACE-2 Principal Investigator, today presented results of the 6,002 patient, double-blind study in coronary angioplasty and stenting as a late breaking presentation at The American Heart Association's Scientific Sessions 2002.
The REPLACE-2 study was designed to evaluate whether patients in the trial receiving Angiomax plus provisional glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors would have outcomes that were better than, or "superior" to, a heparin historical control arm (based on heparin event rates from prior angioplasty trials). The REPLACE-2 study was also designed to evaluate whether patients in the randomized trial receiving Angiomax plus provisional GP IIb/IIIa inhibitors would have outcomes that were the same as, or "non-inferior" to, patients in the trial receiving heparin plus GP IIb/IIIa inhibitors.
The primary "quadruple" composite outcomes endpoint of death, myocardial infarction, urgent revascularization and major bleeding at 30-days was met:
Angiomax was superior to heparin alone
Angiomax was non-inferior to heparin plus GP IIb/IIIa inhibitor
The secondary "triple" composite outcomes endpoint of death, myocardial infarction and urgent revascularization at 30-days was met:
Angiomax was superior to heparin alone
Angiomax was non-inferior to heparin plus GP IIb/IIIa inhibitor
The Angiomax treatment group demonstrated a significant decrease in bleeding complications, as compared to heparin plus GP IIb/IIIa inhibitor.
The Angiomax treatment group demonstrated a significant decrease in thrombocytopenia, as compared to heparin plus GP IIb/IIIa inhibitor.
The provisional use rate of GP IIb/IIIa inhibitors in the Angiomax treatment group was 7.2%.
Based on REPLACE-2 dosing and administration data for each of the products used in the study and using wholesale drug acquisition costs, The Medicines Company estimates an average $448 per-patient difference in pharmacy acquisition cost in favor of the Angiomax regimen versus the heparin plus GP IIb/IIIa regimen.
Professor Eric Topol, M.D., Chairman of Cardiovascular Medicine at The Cleveland Clinic and Chairman of the REPLACE-2 study noted, "For the last ten years, we have been attempting to advance the field of interventional cardiology by performing a series of clinical trials investigating antiplatelet agents, antithrombin agents and new devices, including atherectomy and stents. This latest trial provides a newly validated approach using a backbone of more potent and safer anticoagulation."
Dr. Lincoff added, "REPLACE-2 is a large and robust trial demonstrating that the bivalirudin plus provisional IIb/IIIa blockade is superior to heparin and yields composite clinical outcomes that are similar to our current standard of care, while reducing the incidence of bleeding, transfusion and, potentially, cost associated with the current standard. We found this pattern of results throughout the data set and we are pleased to report this progress. We also need to thank the study management personnel as well as the investigators, their teams and the patients who participated in this trial. The speed and quality of the study were notable."
Led by Associate Professor Lincoff and Professor Topol, the study's investigators plan to submit more detailed REPLACE-2 results to a major medical journal for publication. In addition, because of the size and breadth of REPLACE-2, several subgroup analyses will be performed and results presented at cardiology conferences in early 2003. The study will also continue beyond these primary results to examine patient outcomes at six-months and one-year. Also, a detailed cost analysis study is underway to examine per-patient total hospital resource consumption for U.S. centers. The cost analysis should be completed in 2003.
Dave Stack, President and Chief Executive Officer of The Medicines Company noted, "We would like to thank Professor Topol and Dr. Lincoff for their leadership and inspiration during this trial. We also add our thanks to investigator participants. We believe that the REPLACE-2 data will lead to progressive replacement of heparin with Angiomax by doctors and pharmacists in coronary angioplasty and as a result improve patient care and cost effectiveness in this rapidly growing cath lab marketplace. REPLACE-2 clearly demonstrates that Angiomax belongs in the front line of any modern interventional cardiology practice."
The Medicines Company intends to submit a supplement for U.S. Food and Drug Administration review to update the product labeling to include REPLACE-2 data. Angiomax was approved in the U.S. for use in coronary angioplasty in December of 2000 and was launched in the U.S. in January of 2001. In addition, the REPLACE-2 trial results will be used as the basis for regulatory updates and submissions in international markets, including Europe.
Clive Meanwell, Executive Chairman of The Medicines Company added, "With these REPLACE-2 results, a pertinent set of questions about optimal angioplasty anticoagulation has been answered. The design and statistical methods of REPLACE-2 were well founded and validated by world experts, and the trial was conducted rigorously using the highest standards of good clinical practice. We believe that patients will benefit substantially from the Angiomax-based regimen in the modern practice of coronary angioplasty."
REPLACE-2 Design: REPLACE-2 was a 6,002 patient (intent to treat), randomized, double-blind trial conducted at 233 clinical sites in the United States, Canada, Western Europe and Israel. 77% of the patients were enrolled in the U.S. All patients in the heparin arm of the study received heparin plus a GP IIb/IIIa inhibitor (either Integrilin® or ReoPro®). Patients in the Angiomax arm received Angiomax alone with provisional use of Integrilin or ReoPro. Investigators based their decision to administer the provisional GP IIb/IIIa inhibitor on protocol-suggested clinical situations. It is important to note that the use of a provisional GP IIb/IIIa did not unblind the study drug, as the active drug or placebo was also prepared by the hospital pharmacist as described above. This means that the operator could request a provisional agent in either arm - in the heparin arm, patients were administered a placebo when provisional use of a GP IIb/IIIa was requested.
The trial was structured to mirror the practices of modern angioplasty care and ensure the validity of the trial data. Study drugs were prepared by each center's hospital pharmacy to blind the interventional cardiology team conducting the procedure. The Activated Clotting Time (ACT) measurement was also blinded to the operator.
The REPLACE-2 endpoints were modeled after previous large angioplasty trials to evaluate the anticoagulant regimens by combining event rates into triple or quadruple endpoints. The heparin-alone arm of the study was calculated using an average of the event rates from the EPISTENT and ESPRIT angioplasty trials.
About Angiomax: Angiomax is a small-molecule, reversible, direct thrombin inhibitor that has been shown in clinical trials to reduce the incidence of death, myocardial infarction, and the need for revascularization in patients undergoing balloon angioplasty, compared to heparin. In addition, Angiomax has been associated with a significant reduction in bleeding complications in this patient group. Reductions in these complications not only represent the opportunity for better patient care, but also the opportunity for cost-savings by institutions. Significant reductions in ischemic and bleeding complications remain evident in high-risk patients unlike outcomes in high-risk patients treated with heparin.
Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing Percutaneous Translumenal Coronary Angioplasty (PTCA). Angiomax is intended for use with aspirin. The most common (greater than 10%) adverse events for Angiomax in clinical trials comparing Angiomax and heparin were back pain, pain, nausea, headache, and hypotension. The incidence of these adverse events was comparable in both the Angiomax and heparin groups. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of Angiomax administration. Angiomax is contraindicated in patients with active major bleeding or hypersensitivity to Angiomax or its components. |
