Therapeutic-dose of heparin does not improve outcomes in critically ill COVID-19 patients

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Literature - The REMAP-CAP, ACTIV-4a, and ATTACC Investigators, et al. - NEJM 2021, doi:10.1056/NEJMoa2103417

Introduction and methods

Low-molecular-weight heparins have anti-inflammatory effects and may also have antiviral effects [1,2]. Increased risk of thrombosis has been reported in patients with COVID-19. Therefore, anticoagulation strategies with higher dose anticoagulation have been included in guidance statements for management of COVID-19 patients, especially for those who are critically ill [3,4].

Effectiveness and safety of therapeutic-dose anticoagulation to improve outcomes in COVID-19 patients are undefined.

This was an international, adaptive, multiplatform, randomized, controlled trial to assess the effect of an initial strategy of therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin on in-hospital survival and duration of intensive care unit (ICU)-level CV or respiratory organ support in patients with COVID-19 who were critically ill.

The platforms of the 3 trials REMAP-CAP, ACTIV-4a and ATTACC harmonized protocols and analysis plans to accelerate generation of evidence and maximize external validity of results. All 3 platforms enrolled patients who were hospitalized for severe COVID-19. Severe COVID-19 was defined as COVID-19 leading to receipt of ICU-level respiratory or CV organ support in an ICU. Patients were randomized to receive therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin or to receive usual-care pharmacologic thromboprophylaxis in an open-label fashion. Primary outcome was organ support-free days, assessed on a ordinal scale combining in-hospital death (value of -1) and number of days free of CV or respiratory organ support up to day 21 among patients who survived to hospital discharge.

Randomization started at April 2020 and enrolment discontinued in Dec 2020 after an interim analysis showed futility. This analysis showed results of the primary analysis involving 1098 patients with severe confirmed COVID-19.

Main results

  • Median value for organ support-free days was 1 (IQR -1 to 16) in patients randomized to therapeutic-dose anticoagulation, and median value was 4 (IQR -1 to 16) in patients assigned to usual-care pharmacologic thromboprophylaxis (OR 0.82, 95%CI: 0.67-1.03).
  • 62.7% Of patients in the therapeutic-dose anticoagulation group and 64.5% in the usual-care thromboprophylaxis group survived to hospital discharge (OR 0.84, 95%ICI: 0.64-1.11).
  • There were fewer patients with major thrombotic events in the group randomized to therapeutic-dose anticoagulation than in the group with usual-care pharmacologic thromboprophylaxis (6.4% vs. 10.4%), but the incidence of secondary efficacy outcome of major thrombotic events or death was similar in the two groups (40.1% and 41.1%, respectively).
  • Major bleeding event occurred in 3.8% of patients in the therapeutic-dose anticoagulation group and in 2.3% of those assigned to the usual-care thromboprophylaxis group.


In patients with COVID-19 who were critically ill, initial strategy of therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin was not associated with greater number of days free of CV or respiratory organ support, and also not with increased survival to hospital discharge when compared to usual-care pharmacologic thromboprophylaxis.

These results refute the hypothesis that a routine therapeutic-dose anticoagulation strategy benefits patients with severe COVID-19.

Editorial comment

In his editorial commentary, Hugo ten Cate lists several explanations for the different findings between critically ill patients and those with moderate illness. In the critically ill patients, therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin was not associated with improved outcomes and In the moderately ill patients, therapeutic-dose heparin of LMWH increased the probability of survival until hospital discharge with a reduced need for organ support, but at the cost of more bleeding than with thromboprohylaxis (1.9% vs. 0.9%). He wondered what conclusions to draw from these mixed data.

First, these findings do not support the use of therapeutic-dose heparin or LMWH in critically ill patients. Second, which dose of thromboprophylatic drugs should be given to moderate ill patients with COVID-19 remains an important question.

Ten Cate ends by writing: “In spite of the signals of benefit of anticoagulation in noncritically ill patients with Covid-19, physicians must deal with the key issues regarding the lack of insight into the mechanisms by which heparin or LMWH does (or does not) provide protection and the question of whether the individual patient’s bleeding risk outweighs the benefit. As the late Ed Salzman concluded in the early days of clinical research with LMWH: a promising innovation in antithrombotic treatment, but the jury is still out.”


1. Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: do heparins have direct anti-inflammatory effects? Thromb Haemost 2017;117:437-44.

2. Hippensteel JA, LaRiviere WB, Colbert JF, Langouët-Astrié CJ, Schmidt EP. Heparin as a therapy for COVID-19: current evidence and future possibilities. Am J Physiol Lung Cell Mol Physiol 2020;319:L211-L217.

3. National Institute for Health and Care Excellence. (2020). COVID-19 rapid guideline: reducing the risk of venous thromboembolism in over 16s with COVID-19. NICE guideline 186. November 20, 2020.

4. Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol 2020;76:1815-26

Find this article online at N Eng J MedFind the editorial comment at N Eng J Med

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