Clinical question: What is the longer-term (180-day) mortality effect of common therapies on critically ill patients with COVID-19?
Background: Most randomized clinical trials for patients with COVID-19 focus on short-term outcomes such as 28-day mortality or organ failure. Trials evaluating longer-term outcomes of therapeutic interventions are needed.
Study design: Randomized adaptive-platform trial
Setting: International multicenter trial (197 sites in 14 countries)
Synopsis: 4,869 critically ill patients were enrolled from March 2020 through June 2021. Patients were randomized to one of six treatment arms (immune modulation, convalescent plasma, antiplatelet [subdivided into aspirin, P2Y12 inhibitor, or no antiplatelet], therapeutic anticoagulation, antivirals, and corticosteroids). The primary outcome was 180-day mortality calculated with adjusted hazard ratios (aHR). Futility was defined as the probability there was not more than 20% relative improvement in outcome. Harm was defined as the probability that the adjusted HR was >1. Secondary analyses included 90-day mortality, health-related quality of life, and disability at 180 days.
Criteria for high probability of benefit were met by IL-6 receptor antagonists (>99.9% probability) and antiplatelet treatment (95% probability). Futility criteria were met by therapeutic anticoagulation, convalescent plasma, and lopinavir-ritonavir while hydroxychloroquine had a high probability of harm (96.6% probability). Results of secondary outcomes were consistent with the 180-day mortality analysis. Limitations include missing data from some sites on disability and health care quality of life scores. Additionally, the trial was run while prior variants of COVID-19 were prevalent and prior to widespread vaccination. Finally, while the trial suggested a high probability of benefit from antiplatelet agents compared to the remaining interventions, it is notable that the credible interval for the aHR included the value 1, and other trials evaluating antiplatelet agents in patients hospitalized with COVID-19 produced mixed results. Overall, these results suggest previously reported initial effects are consistent through six months.
Bottom line: This randomized, adaptive-platform, clinical trial of critically ill patients with COVID-19 demonstrated a high probability that IL-6 receptor antagonists and antiplatelet agents improved six-month survival while therapeutic anticoagulation, convalescent plasma, and antiviral therapy with lopinavir-ritonavir did not improve long-term outcomes. Hydroxychloroquine produced a high probability of causing harm.
Citation: Writing Committee for the REMAP-CAP Investigators; Higgins AM, et al. Long-term (180-Day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial. JAMA. 2023;329(1):39-51.
Dr. Hamilton
Dr. Doyle
Drs. Hamilton and Doyle are clinical assistant professors at The Ohio State University Wexner Medical Center in Columbus, Ohio