Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non–Critically Ill Hospitalized Patients With COVID-19
Jeffrey S. Berger, Lucy Z. Kornblith, Michelle N. Gong, Harmony R. Reynolds, Mary Cushman, Yu Cheng, Bryan J. McVerry, Keri S. Kim, Renato D. Lopes, Bassel Atassi, Scott Berry, Grant Bochicchio, Murillo de Oliveira Antunes, Michael E. Farkouh, Yonatan Greenstein, Erinn M. Hade, Kristin Hudock, Robert Hyzy, Pooja Khatri, Andrei Kindzelski, Bridget-Anne Kirwan, Lisa Baumann Kreuziger, Patrick R. Lawler, Eric Leifer, Jose Lopez-Sendon Moreno, Jose Lopez-Sendon, James F. Luther, Lilia Nigro Maia, John Quigley, Robert Sherwin, Lana Wahid, Jennifer Wilson, Judith S. Hochman, Matthew D. Neal, ACTIV-4a Investigators, Jonathan Newman, Mark Geraci, Aldo Maggioni, Hooman Kamel, Ewan C. Goligher, Ryan Zarychanski, Brendan M. Everett, Sean van Diepen, Gregoire Le Gal, Deborah M. Siegal, Jean-Philippe Galanaud, Sheila Hegde, Yuri Kim, Natalia S. Rost, Aneesh B. Singhal, Aira Contreras, Stephanie Mavromichalis, Eduardo Iturrate, Margaret Gilsenan, Anna Naumova, Arlene Roberts, Julia Levine, Christine M. Leeper, Derek C. Angus, Mary Martinez, Jake Schreiber, Joshua Froess, Caroline E. Stehle, Ashita Sai Vadlamudi, Frank Sciurba, Alison Morris, Edvin Music, Sophie de Brouwer, Emilie Perrin, Caroline Gombault, Sandra Bula, Michael Nelson, Céline Daelemans, Laurine Paraz, Michelle A. Detry, Anna McGlothlin, Melanie Quintana, Amy Crawford, Danielle Sin, Elhaji Diene, Ewelina Gwiszcz, Isabelle Hogan, Alair Holden, Nancy Ringwood, Laura Fitzgerald, Haley Morin, Brenda Nunez-Garcia, Aaron E. Kornblith, Carolyn M. Hendrickson, Deanna Lee, Viet Nguyen, India Shelley, Shannon Broaddrick, Neha Atal, David T. Huang, Renee Wunderly, Meredith Buxton, Tracey Roberts, Kelsey Linstrum, Amanda McNamara
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.