Routinely administering eptifibatide before angiography confers no survival benefit in patients with non-ST-segment elevation acute coronary syndromes, nor does early use reduce the number of subsequent heart attacks, compared with the use of eptifibatide after angiography, a large randomized controlled trial has concluded.
Further, early eptifibatide use, compared with delayed use, also carries a significantly increased risk for major bleeding, Dr. L. Kristin Newby said at a press teleconference during the annual meeting of the American College of Cardiology.
Guidelines in North America and Europe vary in their recommendations regarding early versus delayed provisional treatment with eptifibatide and other glycoprotein IIb/IIIa inhibitors, said Dr. Newby of Duke University Medical Center, Durham, N.C. Treatment decisions are usually guided by clinician preference or hospital policy. But the results of the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial may be strong enough to warrant a recommendation by the American College of Cardiology, she said. “I believe the guidelines committee will have to carefully consider these findings.”
EARLY ACS included 9,492 patients who had acute coronary syndrome without ST-segment elevation and were scheduled for an invasive intervention. Patients were assigned to one of two eptifibatide regimens. Early use consisted of two boluses of eptifibatide (180 mcg/kg of body weight each) given 10 minutes apart at least 12 hours before angiography and followed by a standard infusion. Delayed provisional use consisted of a matching placebo infusion with provisional use of eptifibatide after angiography.
The primary end points were a composite of all-cause mortality, heart attack, and recurrent ischemia requiring urgent revascularization, or a thrombotic complication during percutaneous coronary intervention within 96 hours. The secondary end point was a composite of death or heart attack within 30 days (N. Engl. J. Med. 2009; Mar. 30 [doi 10.1056/NEJMoa0901316
The patients' median age was 67 years. The median time from presentation of symptoms to randomization was almost 6 hours. Almost all (98%) underwent coronary angiography, and 59% later underwent PCI.
Compared with delayed administration, early administration of eptifibatide was not associated with any significant reduction in the composite primary end point (10.0% vs. 9.3%, respectively), or in the secondary end points of death or heart attack at 30 days (12.3% vs. 11.2%).
There were no significant differences between the groups in death from any cause; in the combination of death, heart attack, or urgent revascularization; or in any of the individual end points.
When bleeding severity was rated according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria, there was significantly more moderate bleeding in the early-administration group than in the delayed-administration group (6.8% vs. 4.3%; odds ratio, 1.6). When both severe and moderate bleeding were considered, the early strategy also carried a significantly increased risk (5.1% vs. 2.7%; OR, 1.9). Patients in the early administration group also required significantly more transfusions of packed red cells (8.6% vs. 6.7%; OR, 1.3). Dr. Newby said the EARLY ACS investigators are reviewing their data to identify subgroups of patients who have a low risk of bleeding and might benefit from early eptifibatide. “So far, we've seen no statistically significant interactions in our subgroup analyses, but we have seen some hints that patients who are troponin positive might get some benefit.”
Dr. Marc Cohen, professor of cardiology at Mount Sinai School of Medicine, New York, said, “I think it is fair to say that certain subgroups within the study may have diluted an otherwise important benefit from being observed. Specifically, the subgroup that was troponin negative—a group that we know from the year of the flood is not benefited with glycoprotein IIb/IIIa inhibitors—was not benefited in the EARLY-ACS trial and may have pulled the point estimate toward the neutral zone.
“In summary, I have to acknowledge that routine upstream administration of eptifibatide in high-risk, unstable angina or NSTEMI patients is not supported. I feel that several protocol-related variables may have contributed to a dilution of a beneficial effect,” he said.
The study was funded by Schering-Plough Corp. and Millennium Pharmaceuticals. Dr. Newby disclosed receiving grant support from Schering-Plough, and some of her coinvestigators disclosed that they receive some financial support from Schering-Plough.
Dr. Cohen said that he had no conflicts to disclose in regard to this study.