Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial

Blog Written by – Dr Jose Chacko

Question: In patients hospitalized with COVID-19, does prophylaxis with rivaroxaban 10 mg/day for 35 days after discharge improve clinical outcomes, including major and fatal thromboembolic events?

Setting, population, design: 14 hospitals in Brazil. This is a 1:1 randomized controlled trial. Thromboprophylaxis with rivaroxaban 10 mg/day or no anticoagulation for 35 days post discharge. Open label study, in permuted blocks of variable size, using a central, concealed, web-based, automated randomization system.

Included

1. Patients who were hospitalized with COVID-19 for at least 3 days. Patients who required ICU care were also included. Received standard thromboprophylaxis with unfractionated heparin, enoxaparin, or fondaparinux during hospital stay.
2. Increased risk for VTE: IMPROVE score of 2–3 with D-dimer more than 500 ng/ml or an IMPROVE score of 4 or more (regardless of the D-dimer level)

Excluded

1. Suspected or confirmed thrombotic event

Pre-study doppler or CT-angiogram was not carried out.

Interventions

Rivaroxaban was continued for 35 days.

Follow-up at day 7: telephonic or at the clinic

Follow-up at day 35: at clinic or hospital. Lower limb venous doppler and CT pulmonary angiogram was carried out.

Statistical analysis

Assumed a reduction in the composite primary outcome (symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism detected by bilateral lower limb venous Doppler ultrasound and CT pulmonary angiogram, symptomatic arterial thrombo-embolism and cardiovascular death at day 35) from 15% to 5% (relative risk reduction of 67%, absolute risk reduction by 10%). For 80% power and significance level of 0.05, 282 patients were required; a sample size of 320 patients was chosen, assuming a dropout rate of 10%.

The sample size was calculated assuming 80% power, at a significance level of 0·05, of a primary efficacy endpoint occurrence of 15% in the standard of care group (control group) and 5% in the treatment group, with a relative risk reduction of 67%.

997 screened —> 677 excluded —> 320 randomized —>  159 analyzed on intention to treat analysis ( 1 dropout from each group)

Patients were well-matched at baseline (Riva vs. control)

Age:  57·8 (14·8) vs. 56·4 (15·6) years

The median duration of hospitalization: 8 days

ICU admission: 54% vs. 50%

Anticoagulation during hospital stay: enoxaparin: 86%; unfractionated heparin: 14%

Primary composite outcome (Rivaroxaban vs. control)

• Symptomatic or fatal venous thromboembolism
• Asymptomatic venous thromboembolism (LL doppler or CT angio)
• Symptomatic arterial thrombo-embolism (MI, stroke, and limb ischemia, CV death)

5/159 (3.14%) vs. 15/159 (9.43%) RR: 0.33 (0.13–0.90) P: 0.02

Components of the primary composite outcome 

Secondary outcomes

Primary safety outcome: No major bleeding occurred in either group

Secondary safety outcomes:

Clinically relevant non-major bleeding

Other bleeding

Combination of major, CRNM, and other bleeding

Comments

Composite primary outcome

The number of events in the individual components of the primary outcome was small (fatal pulmonary embolism: 0 vs. 3; symptomatic pulmonary embolism 1 vs. 2)

None of the individual components of the primary composite outcome was significantly different

Fragility index for the composite primary outcome of 1

Summary – 

Due to the limitations of this trial, there is no sufficient evidence to change the current practices to commence extended thromboprophylaxis in patients with COVID 19.