Bivalirudin has been investigated as a replacement for heparin in a broad spectru of cardiovascular disease. Two smaller studies suggested it was more or at least as effective, with reduced bleeding, as compared to heparin plus GP IIb/IIIa inhibitors. ¡°If proven, this implied that bivalirudin may allow a more selective use of the GP IIb/IIIa inhibitors, which would exploit advantages with regard to cost, bleeding and ease of use¡±, Dr. Lincoff said. For REPLACE-II, researchers questioned whether bivalirudin monotherapy with GP IIb/IIIa inhibitors on a provisional basis would be equivalent or not inferior to the gold standard with regard to ischemic complications, he explained. Researchers enrolled 6,010 patients between October 2001 and August 2002. Patients were randomized to receive low-molecular, weight-adjusted heparin at a dose of 65 units/kg with Abciximab (ReoPro, Lilly) or eptifibatide (Integrellin, Millennium), or to bivalirudin only during the PCI. Patients in the latter group received a bolus of 0.75 mg/kg and an infusion of .75 mg/kg-hr. They could receive Abciximab or eptifibatide in a blinded fashion in the event of an ischemic complication. Dr. Lincoff said ischemic complications occurred in 7.2% of patients in the bivalirudin group.

The primary endpoint was a 30-day composite endpoint, consisting of death, MI, urgent revascularization and major bleeds. There was no significant difference between the treatment arms in basline characteristics, and the study showed noninferiority of bivalirudin compared with the heparin regimedn. The rate of MI was slightly higher with bivalirudin. ¡°The slight difference in the rates of MI was of some concern and controversy given that periprocedural MIs are associated with later mortality¡±, Dr. Lincoff added. Patients in the bivalirudin group experienced a 41% reduction in major bleeds compared with patients in the heparin group.

A prespecified secondary endpoint was a follow-up lat six months for death, MI and revascularization rates. ¡°We wanted to determine if the differences seen at the earlier endpoint translated to a late deficit, particularly for mortality¡±, Dr. Lincoff said. ¡°This was a concern with the slight trend for MI seen at 30 days.¡± He added that a one-year follow-up of mortality is planned, and the Scripps researchers hope to present that information in November at the American Heart Association meeting. Data were available at six months for 98.2% of patients. The rates of death, MI and revascularization were not significantly different between the treatment arms. There was a slight trend in favor of bivalirudin for reduction in death rates. In the bivalirudin arm, there were 28 deaths, seven of which occurred in the first 31 days. In the heparin arm, there were 40 deaths, 12 of which occurred in the first 31 days. ¡°The important thing is the difference between the treatment arms was not significant¡±, Dr. Lincoff said. ¡°We need and look forward to the one=year follow-up to see if these trends continue or if there are changes. ¡°It is reassuring that there is no evidence of excess risk of death in the bivalirudin group despite the appearance of a slight but not significant increase in the rate of Mi early on¡±, he said. There was also a slight trend in favor of the heparin regimen for reduction in the rates of IM and revascularization. Almost all MIs occurred in the first 30days, actually within hours of the procedure, Dr. Lincoff said. He and his colleagues looked at the subset of patients with diabetes. Of these 1,624 patients, there was a slight trend for a reduction in mortality with bivalirudin, even though patients with diabetes are traditionally at an elevated risk for mortality over long-term follow-up, he explained. ¡°There was no suggestion that substituting bivalirudin for heparin had an adverse effect on mortality¡±, Dr. Lincoff said. He added that the rate of total vessel revascularization was higher for patients with diabetes than for patients without diabetes, but that the difference was not significant.