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Neutral effect of P2Y12 inhibitors in non-critical COVID-19 hospitalisations

Presented by
Prof. Jeffrey Berger, New York University Langone, USA
AHA 2021
Treatment with P2Y12 inhibitors for non-critically ill hospitalised patients with COVID-19 was not associated with a reduced number of organ support-free days or deaths in the phase 4 ACTIV-4A trial. The incidence of major bleeding events was low. P2Y12 inhibitors are currently being evaluated in critically ill hospitalised patients with COVID-19 [1].

Prof. Jeffrey Berger (New York University Langone, NY, USA) highlighted that approximately 1 out of 4 non-critically ill hospitalised patients with COVID-19 treated with therapeutic-dose heparin dies or needs intensive care level support, demonstrating a clear need for additional therapies in this population. In addition, there is evidence that platelets are associated with thrombotic events, organ failure, and death in patients with COVID-19 [2–4]. Thus, the randomised, open-label ACTIV-4A trial (NCT04505774) investigated the efficacy and safety of P2Y12 inhibitors in non-critically ill hospitalised patients with COVID-19. The study randomised 576 patients 1:1 to P2Y12 inhibitors in addition to usual standard-of-care anticoagulation or standard-of-care anticoagulation alone, before the futility criterion was met. Participants in the experimental condition received either ticagrelor (60 mg twice daily) or clopidogrel (300 mg load, followed by 75 mg once daily). The primary endpoint was 21-day organ support-free days.

Participants in the P2Y12 inhibitor condition showed numerically, but not significantly, lower rates of 21-day organ support-free days than patients in the control condition (OR 0.83). The calculated probabilities of futility and inferiority of additional P2Y12 treatment were 96.2% and 81.4%, respectively. The results were consistent across pre-defined subgroups. In addition, there was a numerically higher proportion of participants with major thrombotic events or in-hospital deaths in the P2Y12 inhibitor arm (6.1%) than in the standard-of-care arm (4.5%). The key safety endpoint analysis showed low major bleeding rates in participants treated with P2Y12 inhibitors (2.0%) and in those treated with usual care (0.7%).

Notably, there was a relatively long off-treatment period, due to the median 6-day treatment period and the 21-day endpoint. Moreover, participants received full-dose anticoagulation background therapies. This could explain why there was no (added) benefit observed for P2Y12 inhibition in these patients. The evaluation of P2Y12 inhibitors in critically ill hospitalised patients with COVID-19 is ongoing.


    1. Berger JS, et al. P2Y12 Inhibitors in Non-Critically Ill Hospitalized Patients with COVID-19: A Randomized Clinical Trial. LBS07, AHA 2021 Scientific Sessions, 13–15 November.
    2. Manne BK, et al. Blood. 2020;136(11):1317–1329.
    3. Barrett TJ, et al. Science Advances. 2021;7(37).
    4. Barrett TJ, et al. J Throb Hemost. 2021.


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