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The results of the controversial HEAT-PPCI trial have been published along with two commentaries supporting both the main findings and the ethics of the delayed consent strategy used in the study.

As presented earlier this year at the American College of Cardiology meeting, the trial showed that using low-cost heparin versus the more-expensive bivalirudin (Angiomax) improved 28-day outcomes in patients undergoing emergency angiography for suspected ST-segment elevation myocardial infarction (STEMI), according to , of the Liverpool Heart and Chest Hospital in England, and colleagues.

The rate of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularization was 8.7% in the bivalirudin group and 5.7% in heparin group (RR 1.52, 95% CI 1.09-2.13), with no difference in the rate of major bleeding (3.5% versus 3.1%, P=0.59), the researchers reported online in .

"Bivalirudin with selective glycoprotein IIb/IIa inhibitor use has emerged as first-line therapy in the performance of primary percutaneous coronary intervention. Our study builds on this evidence base and suggests that the use of heparin rather than bivalirudin confers significant advantage in the avoidance of major adverse events," they wrote. "This finding might provide an opportunity, rare in modern healthcare, to provide improved outcomes at much reduced cost."

HEAT-PPCI randomized patients being considered for primary PCI at the Liverpool Heart and Chest Hospital to receive heparin administered as a 70-U/kg bolus before the procedure or bivalirudin administered as a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour during the procedure. Glycoprotein IIb/IIIa inhibitors were used for bailout only.

The final analysis included 1,812 patients. PCI was performed in 83% of those in the bivalirudin group and 82% of those in the heparin group. Glycoprotein IIb/IIIa inhibitors -- used for bailout only -- were administered in 13% of patients in the bivalirudin group and 15% of those in the heparin group.

The trial came under attack when it was presented on two fronts: clinical results and ethics. But upon publication, it was bolstered by two supportive commentaries.

, and , of the Geisinger Health System in Danville, Pa., discussed the clinical implications of the findings, and pointed out four important aspects of the trial:

• Use of glycoprotein IIb/IIIa inhibitors was not required in the study.
• The dose of heparin used was lower than in most previous trials in which heparin was used as monotherapy.
• Radial access was used in a high proportion of patients (81%).
• The new antiplatelets prasugrel and ticagrelor were used in about 90% of patients.

Although they also acknowledged the limitations -- the open-label, single-center design, the fact that unmasked investigators performed follow-up, and the relatively low percentage of patients who underwent PCI (82%) -- they concluded that "HEAT-PPCI was an exciting, well-done trial for which the trial team should be congratulated."

"Most of the criticism has been based on inappropriate comparisons with trials that required use of a glycoprotein IIb/IIIa inhibitor with heparin, or that administered much larger doses of heparin," they wrote. "HEAT-PPCI provides strong evidence that bivalirudin alone compared with 70 U/kg of heparin alone (with infrequent bailout use of glycoprotein 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," they continued. "A drug that costs less than a 400th of another that has similar efficacy and safety ought be used preferentially."

But beyond the clinical issues, the consent strategy used in the trial was heavily criticized. With full approval of the necessary regulatory authorities, the researchers did not seek consent -- from surviving patients or the "appropriate representatives -- until after the patient left the catheterization laboratory. The approach resulted in enrollment of 97% of eligible patients.

In his commentary, , of the University of Basel's Institute for Biomedical Ethics in Switzerland, defended the ethics of delayed consent as used in the trial, stating, "Far from being unethical, the study sets a high standard for consent in pragmatic trials."

"In this context, this strategy was preferable to attempting to obtain consent from potentially incompetent patients needing extremely urgent cardiac treatment. Delayed consent is recognized as an acceptable method of respecting patients' autonomy in emergency research in the Declaration of Helsinki," he wrote. "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."

He went on to say that it would have been unethical to do the study any other way, adding that "HEAT-PPCI has blazed a trail for future research of this type."

From the American Heart Association: