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P2Y12 inhibitors did not improve outcomes for non-critically ill patients hospitalized with COVID-19, an ACTIV-4a platform trial showed.

Patients randomized to receive a potent antiplatelet, typically atop therapeutic anticoagulation with heparin, actually had numerically fewer organ support-free days through day 21 than those who received usual care without a P2Y12 inhibitor (adjusted OR 0.83, 95% CI 0.55-1.25), reported Jeffrey Berger, MD, of NYU Grossman School of Medicine in New York City, during the virtual American Heart Association meeting.

In a Bayesian analysis, there was a 96% chance of futility and an 81% likelihood that P2Y12 inhibitors were worse than placebo, which prompted early termination of that portion of the trial after enrollment of 562 patients.

And for the composite of death or need for organ support, the P2Y12 inhibitor also trended in the wrong direction (26% vs 22%; HR 1.19, 95% CI 0.84-1.68).

"The data that you've seen does not support the use of these agents in context, but it will be important to address the similar question in higher-risk populations," said study discussant Amy Towfighi, MD, of the University of Southern California in Los Angeles, at the late-breaking clinical trial session.

The trial included a population with confirmed SARS-CoV-2 with at least one higher-risk criterion -- elevated D-dimer, ages 60 to 84, need for more than 2 L/min oxygen, hypertension, diabetes, impaired kidney function, cardiovascular disease, or obesity -- but was still a fairly low-risk group, she noted.

"On everyone's mind is the fact that most of these patients were on heparin, and certainly we've seen recently that more is less when it comes to anticoagulation," noted session moderator Stephen Wiviott, MD, of Brigham and Women's Hospital in Boston. He questioned whether the findings might have been different if the P2Y12 trial had been done before therapeutic anticoagulation was established as part of standard of care.

ACTIV-4a, together with the REMAP-CAP and ATTACC multi-platform trials, had shown a relative 27% increase in organ support-free days in patients with moderate COVID-19 given therapeutic-dose levels of heparin, but no advantage in . Thus, nearly 90% of patients in both arms of the P2Y12 portion of ACTIV-4a received therapeutic-dose heparin.

"These are all great and important questions, but I think we have to remember we were in the middle of a pandemic. We felt strongly that we needed to use the best standard of care. We needed to answer questions in an expedited manner because of what we're all seeing now. Unfortunately, this is still here and we still need to find our best strategies," Berger responded. "While it would be interesting to investigate P2Y12 inhibitors versus a therapeutic heparin strategy, unfortunately we're not at liberty. We have to go in that order."

The open-label trial randomized patients to 14 days of treatment or until hospital discharge, with ticagrelor (Brilinta) being the preferred P2Y12 inhibitor, which was used by 63% in the active treatment group. Other P2Y12 inhibitors were allowed, but clinicians opted only for clopidogrel (Plavix) for the remainder (90% of whom got a loading dose as recommended in the protocol).

The median duration of use was 6 days, the same as the hospital length of stay after randomization.

Among the secondary endpoints, major thrombotic events or in-hospital death occurred more often in those on a P2Y12 inhibitor (OR 1.42, 95% CI 0.64-3.13), and major bleeding was increased more than threefold (2.0% vs 0.7% with standard care).

The P2Y12 trial is ongoing for critically ill patients, defined as those needing high-flow oxygen, mechanical ventilation, vasopressors, inotropes, or extracorporeal membrane oxygenation support. Two other portions of ACTIV-4a testing the P-selectin inhibitor crizanlizumab (Adakveo) and SGLT2 inhibitors against standard of care are set to start for hospitalized COVID-19 patients.

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