ORLANDO, Fla.--Results from a large randomized clinical trial released Nov. 13 at the American Heart Association’s 2011 scientific conference showed abciximab plus unfractionated heparin, as compared with bivalirudin, increased the risk of bleeding in non–STEMI (NSTEMI) patients undergoing PCI, findings that may put the issue of what anti-thrombotic therapy to use in the cath lab to rest. The results were simultaneously published online in the New England Journal of Medicine.

In a news conference unveiling clinical trial results, Adnan Kastrati, MD, of Deutsches Herzzentrum in Munich, Germany, said the ISAR-REACT 4 trial was designed to determine whether abciximab (ReoPro, Eli Lilly/Centocor) combined with unfractionated heparin compared with bivalirudin (Angiomax, The Medicines Company) improves outcomes for patients with NSTEMI undergoing PCI. Abciximab is a glycoprotein IIb/IIIa inhibitor while bivalirudin is a direct thrombin inhibitor.

The ACUITY study found that in patients with moderate to severe acute coronary syndromes, the rates of ischemia and bleeding were similar between bivalirudin and heparin, and that bivalirudin alone showed similar rates of ischemia and significantly lower rates of bleeding (NEJM 2006:355;21[2213-2216]). But the ACUITY study authors acknowledged a number of design limitations, including being an open-label trial that potentially introduced bias. The ISAR-REACT offered a more rigorous, multicenter, double-blind, double-dummy randomized clinical trial.

ISAR-REACT included 1,721 patients enrolled from six centers. The study included patients between the ages of 19 and 80 years old who had unstable angina within the preceding 48 hours, elevated levels of troponin or CK MB, and coronary stenosis requiring PCI. Patients with STEMI within 48 hour of symptom onset, cardiogenic shock, active bleeding, a planned staged PCI within 30 days and impaired renal function were excluded. Patients were randomized to recieve abciximab plus unfractionated heparin (861 patients) or bivalirudin (860 patients).

The primary end point was a composite of death, large recurrent MI, urgent target-vessel revascularization, or major bleeding within 30 days after randomization. Two secondary end points were a composite efficacy end point of death, any recurrent MI, or urgent target-vessel revascularization and a safety end point of major bleeding within 30 days after randomization.

There was no statistically significant difference in the primary endpoint, Kastrati said, nor in an analysis of various subsets. While there was no difference statistically in efficacy, the study did found a significantly significant difference in major bleeding, with a relative risk of 4.6 percent in the abciximab group compared with a 2.6 percent relative risk in the bivalirudin group.

“This means the risk increased by 84 percent with abciximab, and the difference was significant,” Kastrati said.

“Abciximab and unfractionated heparin, as compared with bivalirudin, failed to reduce the rate of the primary endpoint and increased the risk of bleeding among patients with NSTEMI undergoing PCI,” he concluded. He added that the ISAR-REACT results in conjunction with other findings on the use of bivalirudin in these patients may make bivalirudin the preferred drug.

In a follow-up discussion, Deepak L. Bhatt, MD, PhD, chief of cardiology at the VA Boston Healthcare System and director of the Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital in Boston, pointed out that the results dealing with the primary endpoint--death, a large MI, major bleeding--showed event rates and event curves that “were virtually superimposable.” He reiterated that in the secondary safety endpoint, major bleeding, there was a significant reduction in risk associated with bivalirudin.

“Practically speaking, this trial was done in a very rigorous manner,” Bhatt said, citing the design and a strict use of definitions of terms. Advantages of bivalirudin compared abciximab and unfractionated heparin included less major bleeding, similar efficacy plus the bonuses of shorter duration of infusion and likely lower costs, he said.

“Coupled with data from HORIZON-AMI, which showed a significantly lower mortality of bivalirudin than with heparin plus glycoprotein IIb/IIIa inhibitors, these data from ISAR-REACTsupport the use of bivalirudin during PCI across the full spectrum of acute coronary syndromes, and in my opinion will  probably serve as the final chapter in the story of what the preferred anticoagulant is for percutaneous coronary intervention.”

Speaking with Cardiovacular Business after the presentation, Bhatt said ACUITY was well-designed but as an open-label trial it was vulnerable to bias that led some physicians to question the results. With supporting evidence of ISAR-REACT, physicians may see more clear advantages to using bivalirudin, which also has a shorter plasma half-life.

 He added that a finding in the HORIZONS-AMI trial that associated bivalirudin with an increased rate of stent thrombosis also may have contributed to a slowing in its acceptance by physicians, but the mortality benefits outweigh that risk.