Strengths and Limitations
death, critically ill
DISEASE, CRITICALLY ILL
This study has several strengths. Despite the challenges of enrolling critically ill patients hospitalized for COVID-19 in clinical trials, participating sites recruited nearly 1000 high-risk patients and achieved high levels of adherence and follow-up, thereby ensuring that our hypotheses were rigorously tested. We tested therapies in the context of usual care, including the use of corticosteroids and remdesivir and over the course of several waves of the pandemic during which patients were likely exposed to different SARS-CoV-2 viral variants.This study also has several limitations. First, the trial was open label, so ascertainment, performance, and reporting biases and the differential use of other therapies was possible. However, the primary outcome of organ support–free days and death was chosen to reduce bias given that these are ascertained directly from the medical record. We also found no evidence of differential use of heparin dosing according to treatment allocation (prophylactic-dose heparin was used in >90% of trial participants in both groups). Second, the assessment of P2Y12 inhibitors in critically ill patients occurred during approximately 16 months during which different SARS-CoV-2 viral variants emerged, potentially conferring different susceptibility to interventions. Although variants differed over time and therapies for COVID-19 evolved during the trial, we found no evidence of time-dependent effects of treatments evaluated in the trial. Third, many patients in the P2Y12 inhibitor group received clopidogrel. It is possible that the effect of P2Y12 inhibitors on critically ill patients with COVID-19 varies according to the type of P2Y12 inhibitor used. However, there was no evidence of a meaningful difference in the treatment effect according to hospital site proclivity for use of clopidogrel or ticagrelor. We tested treatment during 14 days or at hospital discharge, whichever came first. We therefore cannot assess the potential effect of longer durations of therapy on 90-day outcomes. Fourth, the ACTIV-4a trial was stopped early because of a marked decrease in the rate of enrollment of critically ill patients over time, and as such no definitive conclusion was demonstrated for the a priori defined end points. Despite these limitations, these trial results contribute meaningful findings to the body of literature indicating that antiplatelet therapy in patients hospitalized for COVID-19 does not have a compelling benefit, regardless of disease severity.