Getting Answers Rapidly in the Time of COVID-19: The RAPID COVID COAG Trial

Study Title: Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care (RAPID COVID COAG)

ClinicalTrials.gov Identifier: NCT04362085

Sponsor: Unity Health Toronto

Accrual Goal: 462 participants

Participating Centers: Multiple sites in Canada, United States, Europe, and the Middle East

Study Design: This is a pragmatic multicenter open-label randomized trial in patients hospitalized with COVID-19 who have an elevated D-dimer on admission. Patients without suspected venous thromboembolism (VTE) will be randomized to therapeutic dose anticoagulation or standard care. The primary outcome is a composite measure of intensive care unit admission, noninvasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death (up to 28 days).

Patients are eligible for inclusion if they are admitted to an inpatient acute medical ward with a confirmed diagnosis of COVID-19–related illness. They must have an elevated D-dimer (at least 2 times the upper limit of normal, or above upper limit of normal with low oxygen saturation). Patients are excluded if they are admitted to the intensive care unit at the time of screening, if they are already on noninvasive or invasive mechanical ventilation, if they are at high bleeding risk (recent known bleeding, platelet count < 50, international normalized ratio > 1.8), or if they are already on therapeutic dose anticoagulation.

Rationale: Patients hospitalized with COVID-19–related illness have increased risk of VTE, with prevalence estimates of between five to 10 percent in medical inpatients and 15 to 25 percent in critically ill patients.¹  Early reports suggested that high D-dimer concentrations were prognostic for both VTE risk and mortality.^2,3  Autopsy reports from deceased patients have also demonstrated pulmonary microvascular thrombosis in patients.⁴  There has therefore been intense interest in establishing the optimal anticoagulant prophylaxis strategy for hospitalized patients. This must be counterbalanced by data suggesting that bleeding may also be a significant cause of morbidity in these patients.⁵ 

While there are ongoing studies examining the optimal anticoagulant intensity in COVID-19 medical inpatients, several recent guidelines from ASH and the International Society on Thrombosis and Haemostasis have recommended prophylactic intensity anticoagulation until full results are critically reviewed and available.^6,7 

In this study, the authors compare the efficacy and safety of therapeutic intensity versus standard care (prophylactic intensity anticoagulation) in patients with COVID-19 with an elevated D-dimer level on admission. Anticoagulation is continued for 28 days or until hospital discharge or death.

Comment: This study is notable for its pragmatic inclusion criteria and involvement of several international centers, which make its results generalizable to many hospitalized patients. The primary outcome (does therapeutic anticoagulation prevent escalation to critical care or impact mortality?) is simple for clinicians to understand and is clinically relevant. Limitations, however, include its broad inclusion criteria that may introduce heterogeneity in the interventions used in both the therapeutic and standard-care arms. Additionally, follow-up for clinical outcomes is only up to 28 days from randomization, and it remains unclear whether this will be long enough to capture VTE events, particularly if patients are admitted for prolonged periods.

The study results will also need to be interpreted considering recent interim results made available from the ATTACC/REMAP-CAP/ACTIV-4a multiplatform randomized controlled trial collaboration.⁸  In this study, patients with COVID-19 who were acutely or critically ill were randomized to therapeutic versus prophylactic-dose anticoagulation for up to 14 days. Unlike the RAPID COVID COAG study, the primary outcome was an ordinal measure of organ-free support days (composite of mortality, days without organ-sustaining therapies). This study used an “adaptive design” with prespecified thresholds for declaring superiority or futility of treatment arms. On January 21, 2021, this study stopped enrolment in the moderately ill (non–critically ill inpatients, n = 1,772) as the superiority boundary was reached, supporting the benefit of therapeutic anticoagulation while demonstrating a low major bleeding rate (<2%). Meanwhile, in the critically ill patients the prespecified futility boundary was reached, suggesting a lack of benefit with therapeutic anticoagulation while possibly increasing risk of major bleeding.

These results remain preliminary, and there is an urgent need for additional data from randomized, clinically relevant studies, including RAPID COVID COAG.⁹  Given the ongoing pandemic it is clear that these studies will have significant implications for the care of patients hospitalized with COVID-19.