Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization

Abstract

Background: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear.

Objective: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization.

Design: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087).

Setting: Done during 2021 to 2022 among 127 U.S. hospitals.

Participants: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation.

Intervention: 2.5 mg of apixaban versus placebo twice daily for 30 days.

Measurements: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding.

Results: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment.

Limitations: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity.

Conclusion: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive.

Primary funding source: National Institutes of Health.

Visual Abstract.. Thromboprophylaxis After COVID-19 Hospitalization.

Thromboembolism has been noted to be an important complication in hospitalized patients with COVID-19 from the beginning of the pandemic. A National Institutes of Health–sponsored, randomized, placebo-controlled trial was done to determine if extended thromboprophylaxis after hospital discharge would reduce deaths and thromboembolic events. The trial was done during 2021 to 2022, spanning the period when the Omicron and Delta variants were circulating and when there was a decreasing rate of hospitalization with COVID-19.

Figure 1.. CONSORT flow diagram.

A total of 1291 participants provided informed consent; 1217 were randomly assigned across 107 hospitals in the United States, with 610 and 607 participants randomly assigned to apixaban and placebo groups, respectively. CONSORT = Consolidated Standards of Reporting Trials.

Figure 2.. Primary composite efficacy end point within 90 days.

Kaplan–Meier curves of the primary composite efficacy end point within 90 d for participants randomly assigned to apixaban versus placebo (inset shows 30-d event curves). The 95% CIs are shown in the inset.

Appendix Figure 1.. Primary composite efficacy end point by prespecified subgroups.

BMI = body mass index; IMPROVE = International Medical Prevention Registry on Venous Thromboembolism; VTE = venous thromboembolism; WHO = World Health Organization.

Appendix Figure 2.. Primary composite efficacy end point within 90 days using modified intention-to-treat approach.