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 10mg once daily or placebo for 35 days. The primary efficacy endpoint is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety endpoint 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 4000 participants to yield the required number of endpoint 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.

Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry

“…Three large randomized clinical trials to determine the benefit of therapeutic-intensity vs. prophylactic intensity heparin in critically ill COVID-19 patients were suspended at interim analysis for futility (NCT02735707, NCT04505774, and NCT04372589). There has been interest in the use of direct-acting oral anticoagulants (DOACs) to manage COVID-19 related coagulopathy, but optimal protocols for managing coagulopathy in COVID-19 patients have not yet been developed (Capell et al, 2021; Lopes et al, 2021). The most prominent risk of anticoagulants is bleeding, and notably direct oral anticoagulants, as well as nafamostat, have a reduced risk of intracranial hemorrhage and other bleeding events compared to vitamin K antagonists (Chen, Stecker, & B, 2020; Hellenbart, Faulkenberg, & Finks, 2017; Makino et al, 2016).…”

The COVID-19 Pandemic and the Need for an Integrated and Equitable Approach: An International Expert Consensus Paper

“…Early administration of antithrombotic agents such as low-molecular-weight heparin (LMWH), direct orally active factor Xa inhibitors (apixaban, rivaroxaban), or sulodexide to patients at risk of disease worsening reduces the risk of hospitalization, need for oxygen support, or even mortality. 112 113 114 115 116 117 Nevertheless, particularly for LMWHs, the optimal dose needs to be thoroughly evaluated. 118 The organization of the necessary framework for home-based medical care will be of major importance for the optimal administration of the forthcoming specific antiviral treatments which are currently under investigation or clinical development.…”

Outpatient Management of COVID-19 Disease: A Holistic Patient-Centered Proposal Based on the Greek Experience

“…High risk, according to this statement, may be estimated via IMPROVE and PADUA scores which include parameters such as obesity, older age, previous VTE, malignancy, thrombophilia, and acute illness/immobilization the past 7 days [ 47 ]. Various regimens for VTE prophylaxis in outpatients at risk with COVID-19 are currently under investigation in many clinical trials [ 59 , 60 ]. Another retrospective study including 715 out-patients, reported no major cardiovascular or thromboembolic event in this population [ 61 ].…”