No change in organ support-free days with P2Y12i in non-critically ill COVID-19 patients

ACTIV-4a: P2Y12 Inhibitors in Noncritically Ill Hospitalized Patients with COVID-19

News - Nov. 17, 2021

Presented at the American Heart Association’s Scientific Sessions 2021 by: Jeffrey Berger, MD - New York, NY, USA

Introduction and methods

Aim of the study

Thrombosis and inflammation play a role in the risk of death and complications in patients with COVID-19. In the multiplatform RCT was shown that therapeutic-dose heparin increased days alive and free of organ support in non-critically ill patients with COVID-19. Nonetheless, ~25% of patients on therapeutic-dose heparin died or received intensive care level support, demonstrating the need for additional therapies in this cohort. Increased platelet production, size, immaturity, hyperreactivity and changed platelet transcriptome contribute to disease severity in COVID-19.

Study design

The Active Inpatients Anti-Thrombotic Study (ACTIV-4a) enrolled hospitalized patients with COVID-19. At enrollment, patients were prospectively stratified into critically ill and non-critically ill. Here, data of non-critically ill patients were reported. Enrichment criteria were: D-dimer ≥2-fold site determined ULN; age 60-84 years; or if less than 60 years, presence of 1 risk enhancers.

It was an open-label study in a 1:1 ratio stratified by site and severity of illness. In this part of the trial, patients were randomized to P2Y12 inhibitor plus standard of care anticoagulation (usual care) or to no P2Y12 inhibitor plus usual care. Duration of P2Y12 inhibitor treatment was 14 days or until hospital discharge.

Enrollment was discontinued in this group after the criterion for futility was met. 562 Participants were at that time randomized.

Primary outcome

The primary endpoint was 21 day organ support free days. Key secondary endpoints was the composite endpoint of major thrombotic events or death, and the primary safety endpoint was ISTH major bleed.

Main results

  • Ticagrelor was used in 63% and clopidogrel in 37% of patients. Median duration of study drug treatment was 6 (IQR 4-8) days and median duration of length of stay was 6 (IQR 4-9) days. 87% Of participants randomized to P2Y12i and 88% randomized to usual care received therapeutic-dose heparin at the end of day 1.
  • There was no difference in organ support-free days between the two arms (adjustedOR:0.83, 95%CI:0.55-1.25, probability for futility was 96.2%.
  • There was no effect of P2Y12i on the composite of death or organ support compared to placebo (adjusted HR 1.19, 95%CI:0.84-1.68).
  • Major thrombotic event or in-hospital death, major bleeding, major bleeding or in-hospital death were not different between the 2 arms.


Use of P2Y12 inhibitors did not results in an increase of organ support-free days or days alive in non-critically hospitalized patients with COVID-19. There was a low rate of major bleeding (~1% absolute risk increase).

Jeffrey Berger noted that testing of P2Y12 inhibitor in critically ill patients is ongoing. Moreover, two other studies will start soon, one testing the effect of a P-selectin inhibitor and one testing the effect of an SGLT2 inhibitor.


The discussant Erin Bohula, MD(Brigham and Women’s Hospital, Boston, MA, USA) said that this study enrolled a generally low risk population, demonstrated by the short hospitalizations, low rates of major thrombotic complications and low rates of major bleeding.

The neutral effects may be caused because the effect of a P2Y12 inhibitor was evaluated in the presence of full-dose anticoagulation. Also, the duration of the intervention was limited with a longer observation time. And was the endpoint in this study modifiable by P2Y12 inhibitors? Or should the investigators have chosen a different endpoint?

- Our reporting is based on the information provided at the American Heart Association’s Scientific Sessions 2021 -

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