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The strategy of keeping some high-risk COVID-19 survivors on extended thromboprophylaxis after hospital discharge is now backed by randomized data.
People at high risk for venous thromboembolism (VTE) but low bleeding risk fared better taking prophylactic-dose rivaroxaban (Xarelto) for 35 days starting at hospital discharge than peers getting no post-discharge anticoagulation, according to the MICHELLE trialists led by vascular surgeon Eduardo Ramacciotti, MD, of Brazil’s Science Valley Research Institute in São Paulo.
The composite efficacy outcome — comprising symptomatic or fatal VTE, asymptomatic VTE on imaging, symptomatic arterial thromboembolism, and cardiovascular death at day 35 — reached 3.14% with rivaroxaban and 9.43% with no anticoagulation (RR 0.33, 95% CI 0.13-0.90), with the difference driven by excess pulmonary embolisms in the control group.
Moreover, rivaroxaban’s benefit after COVID hospitalization was not offset by bleeding. Neither study arm experienced any major bleeding, Ramacciotti’s group showed in The Lancet.
Results of MICHELLE were consistent across all prespecified subgroups.
Despite thrombotic complications being commonplace in hospitalized COVID-19 patients — and an independent predictor of poor outcome — this is only the first positive randomized trial to inform the use of thromboprophylaxis post-hospital discharge, suggested hematologists Charlotte Bradbury, MBBCh, PhD, of University of Bristol in England, and Zoe McQuilten, MBBS, PhD, of Monash University in Melbourne, Australia.
The findings are in contrast with those from the ACTION trial, reported in the spring, which found extended therapeutic-dose rivaroxaban (20 mg daily) continued through day 30 to be no better than standard in-hospital prophylactic-dose heparin alone for anticoagulation in COVID-19 patients.
“These results are encouraging, but in view of the small size of this trial, clinicians are likely to wait for results from other ongoing trials … evaluating post-discharge thromboprophylaxis before changing standard practice and guideline recommendations,” Bradbury and McQuilten wrote in their accompanying editorial.
Pending trials on extended thromboprophylaxis after COVID-19 recovery include a study at one Mexican center; the XACT trial being conducted in Austin, Texas; the larger ACTIV-4c trial across the U.S.; and HEAL-COVID from the U.K.
The open-label MICHELLE trial was conducted at 14 centers in Brazil. From October 2020 to June 2021 investigators screened 997 patients and randomized 320 to receive either rivaroxaban 10 mg/day or no anticoagulation for 35 days. Excluded from the trial were patients with risk factors for bleeding (e.g., thrombocytopenia, severe renal failure).
The randomized cohort averaged 57.1 years of age, and 40% were women. An IMPROVE VTE score of 4 or greater was calculated for 38% of individuals, the rest having scores of 2-3 atop elevated D-dimer levels.
Participants had received standard heparin thromboprophylaxis during COVID hospitalization. Over half had stayed in the ICU during that hospitalization.
Secondary outcomes in MICHELLE favored the rivaroxaban group as well:
- Symptomatic and fatal VTE: 0.63% vs 5.03% with no extended anticoagulation (RR 0.13, 95% CI 0.02-0.99)
- Symptomatic VTE and all-cause mortality: 2.52% vs 5.66% (RR 0.44, 95% CI 0.14-1.41)
- Symptomatic VTE, myocardial infarction, stroke, or cardiovascular death: 0.63% vs 5.66% (RR 0.11, 95% CI 0.01-0.87)
The oral anticoagulant was associated with allergic reactions in 1% of patients.
Ramacciotti’s team acknowledged the study’s small sample and the potential for bias arising from the open-label design.
Additionally, the authors noted imbalances in the proportion of rivaroxaban and control arms undergoing CT pulmonary angiograms (73% vs 57%) and bilateral lower limb venous Doppler ultrasounds (85% vs 75%) to evaluate asymptomatic VTE on day 35, “decreasing the risk of reporting bias and making the results of MICHELLE even more conservative,” the authors asserted.
Reasons for missing imaging evaluations “included fear of returning to the hospital in the middle of the pandemic, increased creatinine levels, and reported allergy to media contrast,” they noted.
Créditos: Comité científico Covid