Rivaroxaban for Prevention of Thrombotic Events, Hospitalization, and Death in Outpatients With COVID-19: A Randomized Clinical Trial

Abstract

Background: COVID-19 (coronavirus disease 2019) is associated with heightened risks of venous and arterial thrombosis and hospitalization due to respiratory failure. To assess whether prophylactic anticoagulation can safely reduce the frequency of venous and arterial thrombosis, hospitalization, and death in nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor, we conducted the PREVENT-HD double-blind, placebo-controlled randomized trial (A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic COVID-19] Infection).

Methods: PREVENT-HD was conducted between August 2020 and April 2022 at 14 US integrated health care delivery networks. A virtual trial design used remote informed consent and clinical monitoring and facilitated data collection through electronic health record integration with a cloud-based research platform. Nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor were enrolled and randomly assigned to either 10 mg of oral rivaroxaban or placebo daily for 35 days. The primary efficacy outcome was time to first occurrence of a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic arterial embolism, hospitalization, or death through day 35. The principal safety end point was International Society on Thrombosis and Hemostasis critical-site or fatal bleeding. The last study visit was on day 49.

Results: The study was terminated prematurely because of enrollment challenges and a lower-than-expected blinded pooled event rate. A total of 1284 patients underwent randomization with complete accrual of primary events through May 2022. No patients were lost to follow-up. The primary efficacy outcome occurred in 22 of 641 in the rivaroxaban group and 19 of 643 in the placebo group (3.4% versus 3.0%; hazard ratio, 1.16 [95% CI, 0.63-2.15]; P=0.63). No patient in either group experienced critical-site or fatal bleeding. One patient receiving rivaroxaban had a major bleed.

Conclusions: The study was terminated prematurely after enrollment of 32% of planned accrual because of recruitment challenges and lower-than-expected event rate. Rivaroxaban prescribed for 35 days in nonhospitalized patients with symptomatic COVID-19 at risk for thrombosis did not appear to reduce a composite end point of venous and arterial thrombotic events, hospitalization, and death.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT04508023.

Keywords: COVID-19; pre-exposure prophylaxis; prevention and control; rivaroxaban; thrombosis; venous thromboembolism.

Conflict of interest statement

Disclosures Dr Piazza has received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corp, as well as consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific Corp, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. Dr Spyropoulos has received research support from Boehringer Ingelheim and Janssen and consulting fees from Janssen, Bristol-Meyer Squibb/Pfizer Alliance, Sanofi, Alexion, Boehringer Ingelheim, Bayer, and Roche Diagnostics. Drs Hsia and Bonaca receive salary support from Colorado Prevention Center, a nonprofit academic research organization affiliated with the University of Colorado that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, Anthos, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol-Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, NovoNordisk, Pfizer, PhaseBio, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group. Dr Hsia also reports owning AstraZeneca stock. Dr Goldin reports research support and consulting honoraria from Janssen. Dr Towner receives research grant support paid to his institution from Pfizer, Moderna, Gilead, ViiV, GSK, Janssen, and Merck. Dr Go has received research grants through his institution from Bristol-Myers Squibb/Pfizer Alliance, Janssen, Novartis, National Heart, Lung and Blood Institute, National Institute of Diabetes, Digestive and Kidney Diseases, and the Patient Centered Outcomes Research Institute. Dr Bull receives consulting fees from United Therapeutics, Liquidia, and Bayer. Dr Bonaca receives support from the American Heart Association Strategically Focused Research Network under awards 18SFRN3390085 (Brigham and Women’s Hospital–Dartmouth-Hitchcock Strategically Focused Research Network Center) and 18SFRN33960262 (Brigham and Women’s Hospital–Dartmouth-Hitchcock Clinical Project). Dr Bonaca also reports stock in Medtronic and Pfizer. Drs Weng, Lipardi, and Barnathan are employees of Janssen Research and Development.

Figures

Figure 1.

Trial screening, randomization, and follow-up.

Figure 2.

Kaplan-Meier plot of time to the first occurrence of the primary efficacy outcome of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic arterial embolization, hospitalization, or death in the intention-to-treat (A) and safety (B) populations. Primary efficacy events accrued at a higher rate in the earlier period of follow-up, with almost all the events occurring before 25 days after randomization. Randomization date is considered day 1, and follow-up time is relative to the randomization date. P value (2 sided) for rivaroxaban vs placebo is from the log-rank test, stratified by the time from a positive COVID-19 test to randomization (at 1–5 days and at 6–14 days), with treatment as the only covariate. HR indicates hazard ratio.