CardioExchange Archive

Although there is broad consensus in the medical community that primary PCI is the best treatment for MI patients when it can be delivered promptly, there is no agreement about the best accompanying drug regimen, which usually entails a combination of antiplatelet and antithrombotic drugs. The role of one antithrombotic, bivalirudin (Angiomax, The Medicines Company) has been particularly uncertain because it is far more expensive than its alternative, unfractionated heparin.

HEAT-PPCI was designed to help settle this problem. The investigators ran a large, practical clinical trial that automatically randomized all primary PCI patients at the Liverpool Heart and Chest Hospital in the U.K. The results of the trial, which were the subject of considerable debate when they were presented at the American College of Cardiology meeting earlier this year, have now been published in the Lancet, along with two editorials that address the controversies engendered by the trial.

A total of 1,829 patients were randomized in the HEAT-PPCI trial to either heparin or bivalirudin. The results did not demonstrate any advantage for bivalirudin. There was a significant increase in the primary efficacy outcome — a composite of death, stroke, reinfarction, or unplanned target lesion revascularization — in the bivalirudin group compared with the heparin group (8.7% versus 5.7%, RR 1.52, CI 1.09-2.13, p=0.01). There was no significant difference in the incidence of major bleeding (3.5% versus 3.1%, p=0.59). The use of bailout GP IIb/IIIa inhibitors was similar in both groups: 13% for bivalirudin and 15% for heparin.

The authors conclude that their trial “suggests that the use of heparin, rather than bivalirudin confers significant advantage in the avoidance of major adverse events. This finding might provide an opportunity, rare in modern health care, to provide improved outcomes at much reduced cost. In our centre, routine use of heparin (rather than bivalirudin, which costs about 400 times as much) would reduce immediate drug costs in our annual 1000 PPCI cases by £500 000.”

In an accompanying editorial, Peter Berger and James Blankenship say that the difference in findings between HEAT-PPCI and earlier trials can be explained by several factors, including the lower use of GP IIb/IIIa inhibitor in conjunction with heparin in HEAT-PPCI, the use of higher doses of heparin in previous studies, and the greater use of radial access in HEAT-PPCI. The trial, they write, “provides strong evidence that bivalirudin alone compared with 70 U/kg of heparin alone (with infrequent bailout use of GP IIb/IIIA inhibitors in both arms), with radial access for STEMI percutaneous coronary intervention, seems to be inferior to heparin as administered in this trial. Even if heparin alone had produced statistically similar outcomes to bivalirudin, it would have been a win for heparin. A drug that costs less than a 400th of another that has similar efficacy and safety ought be used preferentially.”

In a second editorial, David Shaw dismisses the intense criticism from some prominent critics of the trial’s ethics based on the fact that trial participants did not provide informed consent until after they had been randomized. Instead, he writes, “HEAT-PPCI is not only an impressive achievement in medical research, but also in ethical study design. Far from being unethical, the study sets a high standard for consent in pragmatic trials.”

Delayed consent “was preferable to attempting to obtain consent from potentially incompetent patients needing extremely urgent cardiac treatment… The use of delayed consent is particularly appropriate in pragmatic comparative effectiveness trials where the two drugs under investigation are both used for licensed indications in conditions of equipoise. In routine clinical care, it would be perfectly normal for a doctor to choose either heparin or bilvalirudin without involvement of the patient in the decision.”

The results of the trial also “mean that resources will not be wasted on bivalirudin, a more expensive and less effective treatment than heparin.” Shaw observes: “Unsurprisingly, much of the opposition to HEAT-PPCI has come from doctors with close industry ties.”