Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial
Authors: Sholzberg Michelle , Tang Grace H , Rahhal Hassan , AlHamzah Musaad , Kreuziger Lisa Baumann , Áinle Fionnuala Ní , Alomran Faris , Alayed Khalid , Alsheef Mohammed , AlSumait Fahad , Pompilio Carlos Eduardo , Sperlich Catherine , Tangri Sabrena , Tang Terence , Jaksa Peter , Suryanarayan Deepa , Almarshoodi Mozah , Castellucci Lana A , James Paula D , Lillicrap David , Carrier Marc , Beckett Andrew , Colovos Christos , Jayakar Jai , Arsenault Marie-Pier , Wu Cynthia , Doyon Karine , Andreou E Roseann , Dounaevskaia Vera , Tseng Eric K , Lim Gloria , Fralick Michael , Middeldorp Saskia , Lee Agnes Y Y , Zuo Fei , da Costa Bruno R , Thorpe Kevin E , Negri Elnara Márcia , Cushman Mary , Jüni Peter 
Published: October 2021

Abstract

Objective
To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards.

Design
Randomised controlled, adaptive, open label clinical trial.

Setting
28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US.

Participants
465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237).

Interventions
Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death.

Main outcome measures
The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated.

Results

The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m
2
. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69).

Conclusions
In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial.

Trial registration

ClinicalTrials.gov
NCT04362085
.