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

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 .

The Pathobiological Basis for Thrombotic Complications in COVID-19: a Review of the Literature

“…Randomized controlled trials done in the outpatient setting on patients with symptomatic COVID-19 infection did not show a reduction in rate of a composite clinical outcome (which includes all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes) when treated with aspirin or apixaban compared to placebo [ 94 ]. Studies done on moderately ill patients with COVID-19 admitted to hospital wards showed a decrease in the odds of death at 28 days with therapeutic heparin in comparison with prophylactic heparin [ 95 ]. This study showed no difference in their primary outcome, a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to ICU [ 95 ].…”

“…Studies done on moderately ill patients with COVID-19 admitted to hospital wards showed a decrease in the odds of death at 28 days with therapeutic heparin in comparison with prophylactic heparin [ 95 ]. This study showed no difference in their primary outcome, a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to ICU [ 95 ]. In a randomized controlled trial evaluating hospitalized but non-critically ill COVID-19 patients, those treated with therapeutic dose of heparin were shown to have an increased probability of survival to hospital discharge as well as a decreased probability of using organ support machinery compared to patients receiving usual care thromboprophylaxis [ 96 ].…”

Anticoagulant therapy for COVID-19: What we have learned and what are the unanswered questions?

“…[14] Finally, the results of the RAPID trial in moderately-ill patients with elevated Dd did not show benefit of therapeutic heparin (mostly LMWH) versus prophylactic heparin to reduce the composite primary outcome of death, need for invasive/non-invasive mechanical ventilation, and admission to an ICU, but it significantly reduced the secondary outcome of death by 78% (0.22, 0.07 to 0.65; P = 0.006). [15] We await the publication of additional trials as well as prospective meta-analyses from the WHO and INVENT networks on the topic which should add clarity, but the totality of data showing benefit of therapeutic anticoagulation for moderate-severity COVID-19 pneumonitis in high risk subgroups with elevated Dd.…”

Impaired glucose regulation, SARS-CoV-2 infections and adverse COVID-19 outcomes

“… [30] Similarly statins such as simvastatin and lovastatin were found to be most effective in severe SARS-CoV-2 infection exerting its influence via cytotoxic T lymphocytes and regulatory T cell induction. [31] As the literature assessing the effect of medications targeting dysglycemia, hypertension, thrombosis, [32] and hypercholesterolemia on SARS-CoV-2 infection and severity tends to suggest modest protection against infection and mortality, future studies will be enhanced by accounting for medications to avoid negative confounding towards the null (eg, weaker associations due to the protective effect of medications being more common among patients with vs. without diabetes). The need for more robust consideration of several additional important factors including socio-demographic (access to care, income, education, isolation), behavioral (diet, activity), ( Figure 2 ) and biological (d-dimer, blood pressure, renal function) was also largely lacking in published studies limiting interpretation and conclusions.…”