No Benefit to Adding P2Y12 Inhibitor with Heparin for Moderate COVID-19

The addition of a P2Y12 inhibitor with a therapeutic dose of heparin did not improve outcomes among non-critically ill patients hospitalized for COVID-19 in a recent study.

Studies of anticoagulant therapies in moderately ill COVID-19 patients have yielded mixed results, and investigators have hypothesized whether adding antiplatelet therapies may improve outcomes.

In a study, published in JAMA, investigators led by Jeffrey S. Berger, MD, MS, of the New York University Grossman School of Medicine sought to test that possibility, evaluating the risks and benefits of adding a P2Y12 inhibitor to anticoagulant therapy. The results published recently were part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute (ACTIV-4a) study, which continues to enroll critically ill patients.

The open-label, international, multicenter, randomized, clinical trial included 562 non-critically ill patients hospitalized for COVID-19 between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain and the United States. They were randomized into two groups, with 293 receiving a therapeutic dose of heparin plus a P2Y12 inhibitor and 269 receiving the usual care of heparin only. The primary outcome was a composite that included in-hospital death and days free of respiratory or cardiovascular organ support up to Day 21.

“The results of this trial refute the hypothesis that a strategy of a P2Y12 inhibitor, when added to a therapeutic dose of heparin, would benefit non-critically ill patients hospitalized for COVID-19,” the authors wrote. “This hypothesis was based, in part, on studies that reported an association between increased platelet activity and severity of disease.”

Most patients (63%) in the P2Y12 inhibitor group received ticagrelor, and 37% received clopidogrel for 14 days or until hospital discharge with a median duration of 6 days (IQR, 4-8 days).

The study found no significant difference in the number of days alive and free of cardiovascular or respiratory organ support, with a median of 21 days (IQR, 20-21 days) in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25].

The posterior probability of futility was 96%.

The study also found no significant difference in the safety outcome, with major bleeding occurring in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15).

More research is needed to determine whether other platelet-mediated thromboinflammatory pathways may be better targets for therapeutics. The study also didn’t rule out the possibility that a P2Y12 inhibitor could be beneficial as a sole antithrombotic agent or with a longer treatment duration or at an earlier stage of illness.

Bart Spaetgens, MD, PhD; Magdolna Nagy, PhD; and Hugo ten Cate, MD, PhD, wrote in an associated editorial that “it seems quite ambitious to expect improvement on a composite outcome of in-hospital death and organ support–free days, which has a multifactorial origin that is not expected to be substantially driven by platelet reactivity; however, there is also no signal of benefit for thrombotic outcomes, suggesting little added antithrombotic effect with antiplatelet therapy.”

While the study found no benefits to P2Y12 inhibition, platelets may still be a therapeutic target for critically ill patients with COVID-19.

“Nevertheless, the results reported by Berger et al in this issue of JAMA demonstrate that in moderately ill hospitalized patients with COVID-19, additional P2Y12 inhibition did not improve outcome,” Spaetgens et al wrote. “Therefore, while awaiting the current trials, further studies should explore the role of other antiplatelet agents, which may potentially also target some of the pathogenic inflammatory pathways, and also may have a favorable risk-benefit ratio that provides protection without further compromising the individual patient’s bleeding risk.”