Boston, MA - The PROTECT-TIMI-30 study, comparing eptifibatide plus either unfractionated heparin or enoxaparin vs bivalirudin alone in ACS patients undergoing PCI, appears to have favored bivalirudin.

The study, published in the June 20, 2006 issue of the Journal of the American College of Cardiology, was conducted by a group led by Dr C Michael Gibson (Brigham and Women's Hospital, Boston, MA).

The trial was sponsored by Millennium Pharmaceuticals (Cambridge, MA) and Schering-Plough Research Institute (Kenilworth, NJ). It randomized 857 ACS patients undergoing PCI into three treatment groups: bivalirudin monotherapy; eptifibatide plus unfractionated heparin; and eptifibatide plus enoxaparin. The primary aim was to show that coronary flow reserve after PCI was better with eptifibatide.

However, results showed that eptifibatide was associated with lower coronary flow reserve compared with bivalirudin, although the GP IIb/IIIa inhibitor did improve the secondary end points of myocardial perfusion and duration of ischemia after PCI. Ischemic events and biomarkers for myonecrosis, inflammation, and thrombin generation did not differ between agents.

The primary safety objective of the study was to show that bleeding with a GP IIb/IIIa inhibitor could be minimized by using reduced-bolus heparin or enoxaparin. But minor bleeding and transfusions were increased in the eptifibatide group, although TIMI major bleeding was not significantly different.

In an accompanying editorial, Dr John Bittl (Ocala Heart Institute, FL) asks whether the surprising results of the PROTECT-TIMI-30 trial are real observations or merely bad luck.

He points out that the main objective of any clinical trial is to answer the primary question. "In the PROTECT-TIMI-30 trial, the measurement of the primary end point supported the alternative hypothesis of bivalirudin superiority and rejected the null hypothesis as well as the primary hypothesis of eptifibatide superiority," he writes.

Noting that additional insights about treatment differences might be gleaned from the more than 30 secondary end points in the PROTECT-TIMI-30 trial, Bittl cautions that many secondary comparisons were made, raising the likelihood that some of these will give false positives.

He says the fact that there was no difference in the primary safety end point of TIMI major bleeding in the study is not surprising, as the occurrence of TIMI major bleeding is so infrequent after PCI that "it is not a discriminating end point to define treatment safety." He adds that end points in clinical trials should be clinically meaningful, such as transfusions, vessel repair, and retroperitoneal hemorrhage in the case of PCI trials. And he notes that in this study there was a 10-fold higher rate of transfusions in the eptifibatide-treated patients than in the bivalirudin group.

Bittl concludes: "The report of the PROTECT-TIMI-30 trial will likely have a polemic effect in clinical practice. Users of bivalirudin will defend their choice by pointing to reduced bleeding and the theoretical advantage of improved coronary flow reserve. Users of eptifibatide will emphasize the trends in secondary end points."

He adds that the forthcoming publication of the ACUITY trial, another industry-sponsored trial comparing bivalirudin with enoxaparin during PCI, "will generate more provisional results to challenge existing illusions about marginal superiority of one treatment over another." The ACUITY results, which were first presented earlier this year at the American College of Cardiology Scientific Sessions, also appeared to suggest that bivalirudin monotherapy was an attractive option for many patients.