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

Eduardo Ramacciotti, Leandro Barile Agati, Daniela Calderaro, Valéria Cristina Resende Aguiar, Alex C Spyropoulos, Caroline Candida Carvalho de Oliveira, Jessica Lins Dos Santos, Giuliano Giova Volpiani, Marcone Lima Sobreira, Edwaldo Edner Joviliano, Milton Sérgio Bohatch Júnior, Benedito Antônio Lopes da Fonseca, Maurício Serra Ribeiro, Cesar Dusilek, Kengi Itinose, Suzanna Maria Viana Sanches, Karine de Almeida Araujo Ramos, Nara Franzin de Moraes, Paulo Fernando Guimarães Morando Marzocchi Tierno, André Luiz Malavasi Longo de Oliveira, Adriano Tachibana, Rodrigo Caruso Chate, Marcus Vinícius Barbosa Santos, Bruno Bezerra de Menezes Cavalcante, Ricardo Cesar Rocha Moreira, Chiann Chang, Alfonso Tafur, Jawed Fareed, Renato D Lopes, MICHELLE investigators, Tania Benevenuto Caltabiano, Breno Hattori, Marcello da Silva Jardim, Igor Marinho, Ivan Silva Marinho, Liane Mara Melo Batista, Lucas Rivabem, Carlos Alberto Kenji Nakashima, Ana Carla Gois Franco, Renata Fernanda de Oliveira Pereira, Giana Caroline Strack Neves, Izara de Castro E Souza, Bruno Moraes Ribas, Flavia Ramos Tristão, Marcus Vinicius Barbosa Santos, Eduardo Ramacciotti, Leandro Barile Agati, Daniela Calderaro, Valéria Cristina Resende Aguiar, Alex C Spyropoulos, Caroline Candida Carvalho de Oliveira, Jessica Lins Dos Santos, Giuliano Giova Volpiani, Marcone Lima Sobreira, Edwaldo Edner Joviliano, Milton Sérgio Bohatch Júnior, Benedito Antônio Lopes da Fonseca, Maurício Serra Ribeiro, Cesar Dusilek, Kengi Itinose, Suzanna Maria Viana Sanches, Karine de Almeida Araujo Ramos, Nara Franzin de Moraes, Paulo Fernando Guimarães Morando Marzocchi Tierno, André Luiz Malavasi Longo de Oliveira, Adriano Tachibana, Rodrigo Caruso Chate, Marcus Vinícius Barbosa Santos, Bruno Bezerra de Menezes Cavalcante, Ricardo Cesar Rocha Moreira, Chiann Chang, Alfonso Tafur, Jawed Fareed, Renato D Lopes, MICHELLE investigators, Tania Benevenuto Caltabiano, Breno Hattori, Marcello da Silva Jardim, Igor Marinho, Ivan Silva Marinho, Liane Mara Melo Batista, Lucas Rivabem, Carlos Alberto Kenji Nakashima, Ana Carla Gois Franco, Renata Fernanda de Oliveira Pereira, Giana Caroline Strack Neves, Izara de Castro E Souza, Bruno Moraes Ribas, Flavia Ramos Tristão, Marcus Vinicius Barbosa Santos

Abstract

Background: Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown.

Methods: In this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2-3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684.

Findings: From Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2-3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12-0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group.

Interpretation: In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis.

Funding: Bayer.

Conflict of interest statement

Declaration of interests ER reports grants and consulting fees from Bayer and Pfizer; grants from the Brazilian Ministry of Science and Technology; and personal fees from Aspen Pharma, Biomm Pharma, and Daiichi Sankyo, outside of the submitted work. LBA reports grants from Bayer, Pfizer, and the Brazilian Ministry of Science and Technology. DC reports personal fees from Bayer, Janssen, Daiichi Sankyo, and Pfizer; and grants from Stago. ACS reports consulting fees from Janssen Research & Development, Bayer, Portola, Boehringer Ingelheim, Bristol Myers Squibb, and ATLAS group; and grants from Janssen and Boehringer Ingelheim. MLS reports personal fees from Bayer, Pfizer, and Sanofi. EEJ reports consulting and personal fees form Bayer. CD reports consulting and personal fees from Bayer, Novartis, and Daiichi Sankyo. SMVS reports personal fees from Bayer. RCC reports personal fees from Boehringer Ingelheim and AstraZeneca. ATaf reports personal fees from Janssen and Recovery Force and grants from Bio Tap, Idorsia, Bristol Myers Squibb, Novo Nordisk, Janssen, and Doasense. RDL reports grants and personal fees from Bristol Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC, and Sanofi; and personal fees from Amgen, Bayer, and Boehringer Ingelheim, outside of the submitted work. All other authors declare no competing interests.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile IMPROVE VTE=International Medical Prevention Registry on Venous Thromboembolism venous thromboembolism
Figure 2
Figure 2
Primary efficacy and safety outcomes The primary endpoint 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 (myocardial infarction, non-haemorrhagic stroke, and major adverse limb event), and cardiovascular death at day 35.
Figure 3
Figure 3
Subgroup analysis IMPROVE VTE=International Medical Prevention Registry on Venous Thromboembolism venous thromboembolism. ULN=upper limit of normal.

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Source: PubMed

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