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
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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 .
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SciScore for 10.1101/2021.07.08.21259351: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Authorized research ethics committees approved the trial at all participating sites.
Consent: Written informed consent was obtained from all participants or their legal representatives.Sex as a biological variable not detected. Randomization Trial Design and Oversight: The RAPID trial was an investigator-initiated, parallel, pragmatic, adaptive multi-center, open-label randomized controlled trial conducted at 28 sites in 6 countries. Blinding An independent event-adjudication committee, which consisted of clinicians who were unaware of the treatment assignments, adjudicated the components of the primary outcome, bleeding and thrombotic events. Power Analysis Statistical Analysis: We estimated … SciScore for 10.1101/2021.07.08.21259351: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Authorized research ethics committees approved the trial at all participating sites.
Consent: Written informed consent was obtained from all participants or their legal representatives.Sex as a biological variable not detected. Randomization Trial Design and Oversight: The RAPID trial was an investigator-initiated, parallel, pragmatic, adaptive multi-center, open-label randomized controlled trial conducted at 28 sites in 6 countries. Blinding An independent event-adjudication committee, which consisted of clinicians who were unaware of the treatment assignments, adjudicated the components of the primary outcome, bleeding and thrombotic events. Power Analysis Statistical Analysis: We estimated that 231 patients per group would provide 90% power to detect a 15% absolute risk difference, from 50% in the control group to 35% in the experimental group, at a two-sided alpha level of 0.048 accounting for two planned interim analyses at 25% and 75% of the originally planned sample size. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our trial has two major limitations. First, RAPID had an adaptive design. The protocol prespecified that the sample size would be increased if the conditional power at 75% of the original sample size was between 60 and 80%.21 However, the conditional power was below 60%, therefore the sample size was not increased, thus RAPID remained underpowered. Second, the trial had an open-label design, but all relevant outcomes were blindly adjudicated by an independent clinical events committee. The RAPID trial did not find a significant reduction in the primary composite outcome of death, mechanical ventilation or ICU admission with therapeutic heparin. However, in conjunction with the multiplatform trial,19 it suggests a clinical benefit of therapeutic heparin in moderately ill ward patients with Covid-19. Support: Funded by Task 54, Defence Research Development Canada, Department of National Defence, Ottawa, Canada; St. Michael’s Hospital Foundation, Toronto, Canada; St. Joseph’s Health Centre Foundation, Toronto, Canada; 2020 TD Community Health Solutions Fund – COVID-19 Research Grant; Michael Garron Hospital, Toronto, Canada; The Ottawa Hospital Foundation COVID-19 Emergency Response Fund, Ottawa, Canada; International Network of Venous Thromboembolism Clinical Research Networks (INVENT) Kickstarter Award; Science Foundation Ireland, Enterprise Ireland, IDA Ireland COVID-19 Rapid Response Funding Call 20/COV/0157; SEAMO (Southeastern Ontario Academic Medical Organization) COVID-1...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04362085 Active, not recruiting Coagulopathy of COVID-19: A Pragmatic Randomized Controlled … NCT04444700 Active, not recruiting A Pragmatic Randomized Controlled Trial of Therapeutic Antic… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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