COVID-19 Clinical Care: Canadian Doctors Say That Early Usage Of Anticoagulants Like Heparin In Moderate COVID-19 Patients Reduces Mortality

COVID-19 Clinical Care: A new study undertaken by medical researchers from the St. Michael's Hospital, a treatment site of Unity Health Toronto and the University of Vermont Larner College of Medicine indicates that administering a full dose of a standard blood thinner early to moderately ill hospitalized patients with COVID-19 could halt the thrombo-inflammation process and reduce the risk of severe disease and death.

Typically the COVID-19 disease is marked by heightened inflammation and abnormal clotting in the blood vessels, particularly in the lungs, and is believed to contribute to progression to severe disease and death.
 
The drug heparin, besides having anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19.
 
It was found that early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death.
 
The study team randomly assigned moderately ill hospitalized ward patients admitted for COVID-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat.
 
Significantly at 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).
 
The study findings concluded in moderately ill ward patients with COVID-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.07.08.21259351v3
 
Dr Mary Cushman, M.D., M.Sc., study co-principal investigator and a professor of medicine at the University of Vermont's Larner College of Medicine told Thailand Medical News, “Heparin-a blood thinner given regularly at low dose to hospitalized patients, stops clots from forming and reduces inflammation. This study was designed to detect a difference in the primary outcome that included ICU transfer, mechanical ventilation or death.”
 
The Heparin-COVID-19 protocol for moderate patients is slowly gaining acceptance in many hospitals in the West.
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The clinical open-label randomized international multi-center RAPID Trial (also known as the RAPID COVID COAG—RAPID Trial) examined the benefits of administering a therapeutic full dose of heparin versus a prophylactic low dose to moderately ill patients admitted to hospital wards with COVID-19.
 
The main primary outcome was a composite of ICU admission, mechanical ventilation, or death up to 28 days. Safety outcomes included major bleeding. Primary outcome occurred in 37 of 228 patients (16.2%) with therapeutic full dose heparin, and 52 of 237 (21.9%) with low dose heparin (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.43-1.10; p=0.12). Four patients (1.8%) with therapeutic heparin died vs. 18 (7.6%) with prophylactic heparin (OR, 0.22; 95% CI, 0.07-0.65).
 
First author and co-principal investigator Dr Michelle Sholzberg, M.D.C.M., M.Sc., Head of Division of Hematology-Oncology, medical director of the Coagulation Laboratory at St. Michael's Hospital of Unity Health Toronto, and assistant professor at the University of Toronto added, "While we found that therapeutic heparin didn't statistically significantly lower incidence of the primary composite of death, mechanical ventilation or ICU admission compared with low dose heparin, the odds of all-cause death were significantly reduced by 78 percent with therapeutic heparin."
 
Co-principal investigator, Dr Peter Jüni, M.D.,  director of the Applied Health Research Centre (AHRC) at St. Michael's, and professor of medicine at the University of Toronto, said that the study team also presented a meta-analysis of randomized evidence (including data from a large multiplatform trial of ATTACC, ACTIV-4a and REMAP-CAP), which clearly indicated that therapeutic heparin is beneficial in moderately ill hospitalized COVID-19 patients. He adds that an additional meta-analysis presented in the preprint showed that therapeutic heparin is beneficial in moderately ill hospitalized patients but not in severely ill ICU patients.
 
An interesting aspect of the RAPID Trial was its funding mechanism, a sort of grassroots effort in which support was gathered via Defense Research Development Canada, St. Michael's Hospital Foundation, St. Joseph's Healthcare Foundation, participating institutional grants, and even a GoFundMe campaign, among other sources.
 
Dr Sholzberg added, "We called this trial 'The Little Engine that Could,' because of the sheer will of investigators around the world to conduct it. We believe that the findings of our trial and the multiplatform trial taken together should result in a change in clinical practice for moderately ill ward patients with COVID-19."
 
The study team however did caution that the trial has two major limitations:
 
Firstly, 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.
 
Secondly, the clinical trial had an open-label design, but all relevant outcomes were blindly adjudicated by an independent clinical events committee.
 
Also 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, it suggests a clinical benefit of therapeutic heparin in moderately ill ward patients with COVID-19 by reducing mortality.
 
Thailand Medical News covered another research in June 2020 that also extolled the possible merits of heparin in treating COVID-19. https://www.thailandmedical.news/news/covid-19-drugs-new-research-indicates-that-heparin-may-effectively-neutralize-sars-cov-2-coronavirus-that-causes-covid-19

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