Intermediate dose heparin thromboprophylaxis among critically ill patients with COVID-19: a randomized clinical trial.
Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) Investigators ., Bradbury CA., McVerry BJ., Lawler PR., Angus DC., Annane D., Arabi YM., Aryal D., Au C., Beane A., Berry SM., Berry LR., Best-Lane J., Bihari S., Bonten M., Brunkhorst F., Burrell A., Buxton M., Carrier M., Cecconi M., Cheng AC., Cove M., Derde LPG., Detry MA., Estcourt LJ., Fergusson DA., Fitzgerald M., Fowler RA., Goligher EC., Green C., Haniffa R., Harrison DA., Hays LMC., Higgins AM., Hills T., Horvat CM., Huang DT., Hunt BJ., Ichihara N., Jayakumar D., Keattch S., Kumar A., Laffan MA., Lamontagne F., Leeper CM., Lewis RJ., Lorenzi E., Lother SA., Marshall JC., McArthur CJ., McAuley DF., McGlothlin A., McGuinness SP., McQuilten ZK., Middeldorp S., Morpeth S., Mouncey PR., Murthy S., Neal MD., Nichol AD., Parke RL., Parker JC., Peters S., Reyes LF., Rowan K., Saito H., Santos M., Saunders CT., Schutgens REG., Seymour CW., Hari MS., Singh V., Stanworth SJ., Turgeon AF., Turner AM., van de Veerdonk FL., Gordon AC., Webb SA., Zarychanski R.
BACKGROUND: The optimal thromboprophylaxis among critically ill adults with COVID-19 is uncertain. OBJECTIVES: To determine the effectiveness and safety of intermediate-dose heparin compared with standard low-dose thromboprophylaxis. METHODS: In an ongoing adaptive platform trial (randomized embedded multifactorial adaptive platform for community-acquired pneumonia), critically ill patients with COVID-19 were randomized to intermediate-dose heparin or standard low-dose thromboprophylaxis. Interventions were continued in hospital for up to 14 days. The primary endpoint was organ support-free days (OSFDs), an ordinal outcome combining in-hospital survival and the number of days free of intensive care unit-based respiratory or cardiovascular organ support through 21 days. The primary analysis was an adjusted Bayesian hierarchical cumulative logistic model. An odds ratio (OR) > 1.0 represents an improved outcome with intermediate-dose heparin. RESULTS: Between April 27, 2021 and November 25, 2023, 1255 critically ill adults with COVID-19 were enrolled from 78 sites in 15 countries, of whom 1254 completed follow-up (n = 572 intermediate-dose, n = 682 low-dose). Enrollment was terminated prior to reaching a prespecified statistical trigger due to declining case numbers and slow recruitment. Median age was 59 years, and 36.7% were female (n = 461/1255). The probability that intermediate-dose heparin improved OSFDs was 73.5% (OR, 1.06; 95% credible interval, 0.87, 1.30), which did not meet the prespecified superiority threshold of 99%. Hospital survival was 77.1% (441/572) and 76.7% (523/682) in the intermediate- and low-dose heparin groups, respectively (median adjusted OR, 1.14; 95% credible interval, 0.86, 1.52). Major bleeding occurred in 10 of 572 (1.7%) and 14 of 682 (2.1%) patients receiving intermediate and standard low doses, respectively. CONCLUSION: Intermediate-dose heparin did not improve OSFDs or survival compared with standard thromboprophylaxis in critically ill patients with COVID-19. (ClinicalTrials.gov number: CT02735707).