Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial

Abstract

Importance: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.

Objective: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19.

Design, setting, and participants: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.

Interventions: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.

Main outcomes and measures: The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis.

Results: Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients 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]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred 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).

Conclusions and relevance: Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization.

Trial registration: ClinicalTrials.gov Identifier: NCT04505774.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Berger reported receiving grants from the American Heart Association and AstraZeneca and receiving personal fees from Janssen, Amgen, and Amarin. Dr Kornblith reported receiving personal fees from Cerus Corp. Dr Gong reported receiving grants from the Agency for Healthcare Research and Quality and the US Centers for Disease Control and Prevention and receiving personal fees from Regeneron. Dr Reynolds reported receiving nonfinancial support from Abbott Vascular, Siemens, and BioTelemetry. Dr Cushman reported receiving personal fees from the National Institutes of Health. Dr McVerry reported receiving grants from Bayer Pharmaceuticals, the Translational Breast Cancer Research Consortium, and the UPMC Learning While Doing Program and receiving personal fees from Boehringer Ingelheim. Dr Lopes reported receiving grants from Boehringer Ingleheim, GlaxoSmithKline, Medtronic, Pfizer, Sanofi, and Bristol Myers Squibb and receiving personal fees from Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi. Dr Berry reported receiving grants from the PREPARE Network, the European Commission, the Global Coalition for Adaptive Research, and the University of Pittsburgh and being part owner of Berry Consultants, which received fees for the design and analysis of the ACTIV-4a trial. Dr Farkouh reported receiving grants from Amgen, Novartis, and Novo Nordisk. Dr Hade reported receiving grants from the National Institutes of Health. Dr Khatri reported receiving grants from Cerenovus; receiving personal fees from Basking Biosciences, Lumosa, Diamedica, and Bayer; and receiving royalties from UpToDate. Dr Kirwan reported receiving grants from Socar Research. Dr Baumann Kreuziger reported receiving personal fees from CSL Behring, Quercegen Pharmaceuticals, and the Vaccine Injury Compensation Program. Dr Lawler reported receiving grants from the Canadian Institutes for Health Research, the LifeArc Foundation, the Peter Munk Cardiac Centre, FastGrants (Thistledown Foundation), the Province of Ontario, Canada, the Ted Rogers Centre for Heart Research, the Heart and Stroke Foundation of Canada, and the National Institutes of Health; receiving personal fees from Novartis, Corrona Pharmacovigilance LLC, CorEvitas, and Brigham and Women’s Hospital; and receiving royalties from McGraw-Hill Publishing. Dr Lopez-Sendon Moreno reported receiving personal fees from Hoffman-La Roche and Novartis. Dr Lopez-Sendon reported receiving grants from Amgen, AstraZeneca, Bayer, Pfizer, Merk, Sanofi, and Boeringher Ingleheim and receiving personal fees from Menarini. Dr Quigley reported receiving grants from Pfizer. Dr Hochman reported receiving grants from Merck Sharp & Dohme, Omron Healthcare Inc, Amgen, Espero BioPharma, Sunovion Pharmaceuticals, AstraZeneca, Arbor Pharmaceuticals, the National Institutes of Health, Medtronic, Royal Philips NV (formerly Volcano Corporation), and Abbott Vascular Inc (formerly St Jude Medical Inc) and receiving financial donations from Arbor Pharmaceuticals LLC and AstraZeneca. Dr Neal reported receiving grants from the US Department of Defense, the National Institute of General Medical Sciences, Haemonetics, Instrumentation Laboratories, Accriva, and Janssen Pharmaceuticals and receiving personal fees from Janssen Pharmaceuticals, Haemonetics, and Haima Therapeutics. No other disclosures were reported.

Figures

Figure 1.. Eligibility, Randomization, and Follow-up in the ACTIV-4a Trial of P2Y12 Inhibitors in Non–Critically Ill Patients Hospitalized for COVID-19

ACTIV-4a indicates Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute. aRandomization was stratified by hospital site and severity of illness.

Figure 2.. Effect of Randomization to a P2Y12 Inhibitor on the Number of Days Not Requiring Respiratory or Cardiovascular Organ Support

The number of days not requiring respiratory or cardiovascular organ support (eg, oxygen via high-flow nasal cannula ≥20 L per minute, noninvasive or invasive mechanical ventilation, vasopressors, inotropes, or extracorporeal membrane oxygenation) as horizontally stacked proportions of patients in the 2 treatment groups, with the following possible outcomes: in-hospital death with or without organ support (dark red, the worst possible outcome, corresponding to a score of −1 on the ordinal scale); survival with organ support (red-to-blue gradient shading based on the number of days alive without organ support, corresponding to a score of 0-21 on the ordinal scale); and survival until hospital discharge without organ support (dark blue, the best possible outcome, corresponding to a score of 21 on the ordinal scale).

Figure 3.. Effect of Randomization to a P2Y12 Inhibitor on the Time to the Event for the Composite Outcome of Organ Support or Death in Non–Critically Ill Patients With COVID-19

Kaplan-Meier curve for the time to event of respiratory or cardiovascular organ support or death. All patients were followed up until death or 28 days. The time to organ support or death in patients assigned to a P2Y12 inhibitor vs usual care was not significantly different (26% vs 22%, respectively; adjusted hazard ratio, 1.19 [95% CI, 0.84-1.68], P = .34). The time to the event was compared post hoc using Cox regression.