Extended thromboprophylaxis with NOAC after hospitalization for COVID-19 improves outcomes
The MICHELLE trial shows that extended post-discharge thromboprophylaxis with the NOAC rivaroxaban for 35 days improved clinical outcomes compared to no anticoagulation in patients with high risk of thromboembolism who were hospitalized due to COVID-19.
Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalization for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trialLiterature - Ramacciotti E, Agati, LB, Calderaro D et al., - Lancet 2022; 399:50-59, https://doi.org/10.1016/ S0140-6736(21)02392-8
Introduction and methods
Background
Use of prophylactic parenteral anticoagulants during hospitalization for COVID-19 is recommended, with consensus on the role of in-hospital heparin as primary thromboprophylaxis [1-3]. It is unclear what to do beyond the hospital stay and whether extended venous thromboembolism prophylaxis after hospitalization due to COVID-19 lowers venous thromboembolism, arterial thromboembolism or all-cause death [4-6].
This study investigated whether prophylaxis with rivaroxaban 10 mg/day for 35 days after discharge improved clinical outcomes in patients hospitalized with COVID-19.
Study design
The MICHELLE trial was an open-label, multicenter, randomized, controlled trial with blinded adjudication of outcomes in patient discharged after hospitalization for COVID-19, conducted in Brazil. Patients had to have an increased risk for venous thromboembolism (an elevated modified IMPROVE VTE score of 2-3 with a D-dimer >500 ng/mL or a score of ≥4. 320 Patients were randomized in a 1:1 ratio to rivaroxaban 10 mg/day or no anticoagulation for 35 days. At day 35, bilateral lower limb venous Doppler ultrasound and CT pulmonary angiograms were performed. Median hospitalization time was 8 days (IQR 6-12) and 52% of patients were in the ICU.
Primary outcomes
Primary efficacy outcome was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism detected by bilateral lower limb venous Doppler ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism (MI, non-hemorrhagic stroke and major adverse limb event) and CV death at day 35.
Primary safety outcome was major bleeding, defined according to the ISTH criteria.
Main results
Primary outcomes
- A primary efficacy outcome event occurred in 3.14% of patients in the rivaroxaban group and 9.43% in the control group (RR 0.33, 95%CI: 0.13-0.90, P=0.0293).
- This primary outcome was mainly driven by pulmonary embolism in the control group.
- There were no ISTH-defined major bleeding events in either group.
- Results were consistent across prespecified subgroups with no signs of heterogeneity.
Secondary outcomes
- Symptomatic and fatal venous thromboembolism occurred in 1 patient in the rivaroxaban group and in 8 in the control group (RR 0.13, 95%CI:0.02-0.99, P=0.0487).
- Symptomatic venous thromboembolism and all-cause mortality occurred in 4 patients in the rivaroxaban group and 9 in the control group (RR 0.44, 95%CI:0.14-1.41, P=0.1696).
- The composite of symptomatic venous thromboembolism, MI, stroke or CV death occurred in 1 patient in the rivaroxaban group and in 9 patients in the control group (RR 0.11, 95%CI:0.01-0.98, P=0.0360).
- Clinically relevant non-major bleeding occurred in 2 patients in the rivaroxaban group and in 2 in the control group. The combination of major, clinically relevant non-major, and other bleeding occurred in 4 patients receiving rivaroxaban and in 3 allocated to no anticoagulation.
Conclusion
This open-label, multicenter, randomized, controlled trial of patients who were hospitalized with confirmed COVID-19 showed that extended post-discharge thromboprophylaxis with rivaroxaban for 35 days reduced the risk of the composite of venous or arterial thromboembolism or CV death compared to no anticoagulation. There was no increase in major bleeding in the rivaroxaban group.
The authors state that use of extended prophylaxis with rivaroxaban can be an attractive strategy in patients with creatinine clearance >30 mL/min who were hospitalized with COVID-19 and had an IMPROVE VTE score 2-3 plus increased D-dimer levels or an score of ≥4.
References
1. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18: 1859–65.
2 Goligher EC, Bradbury CA, McVerry BJ, et al. Therapeutic anticoagulation with heparin in critically ill patients with COVID-19. N Engl J Med 2021; 385: 777–89.
3 Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet 2021; 397: 2253–63.
4. Gerotziafas GT, Catalano M, Colgan MP, et al. Guidance for the management of patients with vascular disease or cardiovascular risk factors and COVID-19: position paper from VAS-European Independent Foundation in Angiology/Vascular Medicine. Thromb Haemost 2020; 120: 1597-628.
5. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest 2020; 158: 1143–63.
6. Tritschler T, Mathieu ME, Skeith L, et al. Anticoagulant interventions in hospitalized patients with COVID-19: a scoping review of randomized controlled trials and call for international collaboration. J Thromb Haemost 2020; 18: 2958–67