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Goligher EC, Bradbury CA, McVerry BJ, et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4. (Original study)
Abstract

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.

METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.

RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.

CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).

Ratings
Discipline Area Score
Intensivist/Critical Care 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Infectious Disease 6 / 7
Emergency Medicine 6 / 7
Comments from MORE raters

Emergency Medicine rater

This RCT provides essential information pertaining to anticoagulation in critically ill Covid-19 patients. It is an open-label trial that randomized 1098 critically patients with Covid-19 to receive therapeutic- vs prophylactic-dosed heparin. Severe Covid-19 was defined by receipt of ICU-level respiratory or cardiovascular organ support. The trial was stopped when prespecified criterion for futility was met. Therapeutic-dose heparin was not associated with greater survival to discharge or greater number of days free of cardiovascular/respiratory organ support compared with prophylactic doses. There are several limitations, including the risk for bias with an open-label design. A significant number of patients were admitted in the UK, with intermediate-dose anticoagulation used for prophylaxis. These results suggest that for those without another indication for anticoagulation, prophylactic dose heparin is recommended. Treatment-dose heparin does not improve outcomes.

Infectious Disease rater

This is a very important and necessary trial. However, this particular type of design and the final sample size may be not enough for a definitive conclusion. A multicenter blinded randomized trial in ICU-ventilated patients with three arms: standard prophylactic dose, standard anticoagulant dose and intermediate dose may be more useful.

Intensivist/Critical Care rater

Important information, albeit a bit confusing with the entirely different results in the critical care vs non-critical care population. Regardless, these are important data to suggest that we should not be rushing to empirically fully anticoagulate these patients simply because we are concerned about clotting.

Internal Medicine rater

Looks like no benefit and modest harm for full anticoagulation in critically ill COVID.
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