Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study

Abstract

Background: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established.

Study design: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events.

Conclusions: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.

Figure 1

Coagulopathy and COVID-19 pathogenesis. Coagulopathy and diffuse pulmonary microthrombi have been documented in COVID-19. While coagulopathy is a known consequence of inflammatory changes, it is unclear if SARS-Co-V-2 independently affects hypercoagulability. Coagulopathy, along with viral endothelial injury, leads to diffuse pulmonary microthrombi which may potentiate pulmonary injury in addition to alveolar damage from SARS-Co-V-2 infection as well as macrothrombotic events. Factor Xa can also play a role in cell entry and infection by SARS-Co-V-2, and therefore viral propagation. Outpatient anticoagulation with rivaroxaban, a specific Factor Xa inhibitor, has the potential to prevent thromboembolic events as well as pulmonary microthrombi and progression of pulmonary insufficiency in COVID-19, reducing the need for hospitalization.

Figure 2

PREVENT-HD study design. EOS, End of study; EOT, end of treatment; IWI, Interactive Web Interface; OD, once daily; PCR,polymerase chain reaction; TC, telephone contact.

Figure 3

Data flow in PREVENT-HD. Study data are collected remotely by site staff. Key data flow in daily to weekly from the local hospital electronic medical records (EMR), through REDCap Cloud, to a parallel clinical database. Data from EMR can be used in real time to identify eligible subjects to consent remotely, and to monitor for outcome events in enrolled participants. Site staff conduct virtual follow-up visits by phone or telehealth and enter data from outside the hospital system into electronic case report forms. Participants do not need to leave home through the duration of the study.

Figure 4

Study start-up timeline in PREVENT-HD. To respond to the public health crisis presented by COVID-19, study start-up timelines for PREVENT-HD were accelerated. From first draft of the protocol to first participant enrolled required only 127 days. FDA, Food and Drug Administration; FPI, first participant in; IRB, Institutional Review Board; IND, Investigational New Drug; SA, site activation.