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

JAMA. 2022 Jan 18;327(3):227-236. doi: 10.1001/jama.2021.23605.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • COVID-19 / blood
  • COVID-19 / mortality
  • COVID-19 Drug Treatment*
  • Clopidogrel / administration & dosage
  • Clopidogrel / adverse effects
  • Comorbidity
  • Extracorporeal Membrane Oxygenation / statistics & numerical data
  • Female
  • Hemorrhage / chemically induced
  • Heparin / administration & dosage*
  • Heparin / adverse effects
  • Hospital Mortality
  • Humans
  • Inpatients*
  • Male
  • Medical Futility
  • Middle Aged
  • Outcome Assessment, Health Care
  • Oxygen Inhalation Therapy / statistics & numerical data
  • Platelet Activation / drug effects
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / adverse effects
  • Purinergic P2Y Receptor Antagonists / administration & dosage*
  • Purinergic P2Y Receptor Antagonists / adverse effects
  • Receptors, Purinergic P2Y12
  • Respiration, Artificial / statistics & numerical data
  • Thrombosis / epidemiology
  • Ticagrelor / administration & dosage
  • Ticagrelor / adverse effects
  • Time Factors
  • Treatment Outcome

Substances

  • Anticoagulants
  • P2RY12 protein, human
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y12
  • Heparin
  • Clopidogrel
  • Ticagrelor

Associated data

  • ClinicalTrials.gov/NCT04505774