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Randomized Controlled Trial
. 2023 May 1;6(5):e2314428.
doi: 10.1001/jamanetworkopen.2023.14428.

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

Jeffrey S Berger  1 , Matthew D Neal  2 , Lucy Z Kornblith  3   4 , Michelle N Gong  5 , Harmony R Reynolds  6 , Mary Cushman  7 , Andrew D Althouse  8   9 , Patrick R Lawler  10 , Bryan J McVerry  11 , Keri S Kim  12 , Lisa Baumann Kreuziger  13 , Scott D Solomon  14 , Mikhail N Kosiborod  15 , Scott M Berry  16 , Grant V Bochicchio  17 , Marco Contoli  18 , Michael E Farkouh  10 , Joshua D Froess  8 , Sheetal Gandotra  19 , Yonatan Greenstein  20 , Erinn M Hade  21 , Nicholas Hanna  22 , Kristin Hudock  23 , Robert C Hyzy  24 , Fátima Ibáñez Estéllez  25 , Nicole Iovine  26 , Ashish K Khanna  27   28 , Pooja Khatri  23 , Bridget-Anne Kirwan  29 , Matthew E Kutcher  30 , Eric Leifer  31 , George Lim  32 , Renato D Lopes  33 , Jose L Lopez-Sendon  34 , James F Luther  8 , Lilia Nigro Maia  35 , John G Quigley  36 , Lana Wahid  37 , Jennifer G Wilson  38 , Ryan Zarychanski  39 , Andrei Kindzelski  31 , Mark W Geraci  11 , Judith S Hochman  6 ; ACTIV-4a Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Jeffrey S Berger et al. JAMA Netw Open. .

Abstract

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19.

Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.

Design, setting, and participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.

Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.

Main outcomes and measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis.

Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77).

Conclusions and relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.

Trial registration: ClinicalTrials.gov Identifier: NCT04505774.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Berger reported receiving grants from the National Heart, Lung, and Blood Institute and American Heart Association and personal fees from Jannssen and Amgen outside the submitted work. Dr Neal reported receiving personal fees from Haemonetics and Takeda, grants from Instrumentation Laboratories and Haemonetics, and serving on the advisory board for and having equity stake in Haima Therapeutics outside the submitted work. Dr Kornblith reported receiving consulting fees from Cerus, Gamma Diagnostics, and University of Maryland outside the submitted work. Dr Gong reported receiving grants from the National Institutes of Health and the Centers for Disease Control and Prevention outside the submitted work. Dr Reynolds reported receiving nonfinancial support from Siemens, Philips, and Abbott Vascular and grants from the National Heart, Lung, and Blood Institute outside the submitted work. Dr Lawler reported receiving grants from National Institutes of Health during the conduct of the study. Dr McVerry reported receiving grants from the University of Pittsburgh Medical Center Learning While Doing Program during the conduct of the study and grants from National Heart, Lung, and Blood Institute and Bayer and personal fees from Boehringer Ingelheim Inc and Synairgen Research outside the submitted work. Dr Kim reported serving on National Institutes of Health committees and receiving grants from Eisai outside the submitted work. Dr Baumann Kreuziger reported receiving grants from the National Institutes of Health during the conduct of the study and personal fees from the Health Resources and Services Administration Vaccine Injury Compensation Program outside the submitted work. Dr Solomon reported receiving grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Heart, Lung and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros for consulting outside the submitted work. Dr Kosiborod reported receiving grants from University of Pittsburgh during the conduct of the study and grants from Alnylam Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Esperion Therapeutics, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics and personal fees from 35Pharma outside the submitted work. Dr Berry reported being part owner of Berry Consultants, which received funding for the design and analysis of the trial. Dr Contoli reported receiving personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, and AlkAbello and grants from Chiesi and GlaxoSmithKline outside the submitted work. Dr Farkouh reported receiving grants from Amgen, AstraZeneca, Novartis, and Novo Nordisk and consultant fees from Otitopic outside the submitted work. Dr Khanna reported being a consultant for Edwards Lifesciences, Caretaker Medical, Retia Medical, Philips Research North America, GE Healthcare, Baxter, and Medtronic and being supported by an National Institutes of Health/ National Center for Advancing Translational Sciences KL2 award for a pilot trial of continuous hemodynamic and oxygenation monitoring on hospital wards. Dr Khatri reported receiving personal fees from Bayer, Basking, and Lumosa outside the submitted work and royalties from UpToDate for online publication. Dr Kirwan reported receiving grants from Socar Research SA during the conduct of the study. Dr Lopes reported receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi outside the submitted work. Dr Quigley reported receiving grants from National Institutes of Health during the conduct of the study. Dr Wilson receiving reported grants from the National Institutes of Health and the Centers for Disease Control and Prevention outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Eligibility, Randomization, and Follow-up in the ACTIV-4a Trial of P2Y12 Inhibitors in Critically Ill Patients With COVID-19
aCOVID-19 confirmed by positive test result, but reason for hospitalization was for an unrelated condition. bRandomization was stratified by site and by severity of illness. cFour hundred seventy-five included in the organ support–free days end point. dSix patients withdrew on day 1 or 2 after randomization and are excluded from the primary outcome analysis in accordance with the statistical analysis plan because they cannot be assigned a value for the 21-day analysis. However, these 6 patients are included in the safety analyses, so if these patients had any adverse events, they would be included. eFour hundred sixty-eight included in the organ support–free days end point.
Figure 2.
Figure 2.. Effect of Randomization to a P2Y12 Inhibitor on the Number of Days Not Requiring Respiratory or Cardiovascular Organ Support and Survival Through 90 Days in Critically Ill Patients With COVID-19
(A) Data are shown as the number of days not requiring respiratory or cardiovascular organ support (eg, oxygen via high-flow nasal cannula ≥20 L/min, 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). (B) Kaplan-Meier curve showing survival through 90 days in critically ill patients. The 90-day survival in patients assigned to a P2Y12 inhibitor vs usual care was not significantly different in both a bayesian piecewise exponential model (adjusted hazard ratio, 0.99; 95% CI, 0.77-1.27; posterior probability of superiority, 53%) and a frequentist Cox proportional hazards regression model (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77).
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