Effect of Heparin and Tocilizumab in Patients with Severe COVID-19: The HEPMAB Randomized Clinical Trial
Authors: Ribeiro Lucas Trindade Cantú , Ribeiro Lucas Trindade Cantú , Landoni Giovanni , Quintão Vinícius Caldeira , de Lacerda Marcus Vinicius Guimaraes , Rizk Stephanie Itala , da Silva Costa Isabela Bispo Santos , de Almeida Andrade Fernanda Thereza , de Sant’Anna Melo Edielle , dos Santos Neto Nestor Cordeiro , de González Thalita Barbosa , Reis Laisse Barreto Ferreira , de Freitas Costa Valmir , Machado Theuran Inahja Vicente , da Costa Ribeiro Sabrina Corrêa , Vieira Alexandra Patricia Zilli , Natassja Huemer RN , Silva Fabricio , Lee Park Clarice , Fukushima Júlia Tizue , Junior Milton Henrique Guimarães , de Abreu Lima Cota Marcos , Kawahara Lucas Tokio , Barros Cecília Chie Sakaguchi , Muller Alicia , Nakada Leticia , de Paiva Pinto Bruno Fioravanti , Bergamin Fabrício Sanchez , Eduesley Santana Santos RN , dos Santos Figueira Fernando Augusto Marinho , de Paula Leonardo Jorge Cordeiro , Filho Roberto Kalil , Hajjar Ludhmila Abrahão 
Published: December 2023

Background

Clinical presentation of severe Coronavirus disease 2019 (COVID-19) is associated to an intense inflammatory response and thrombogenesis. The benefits of the association of interleukin-6 receptor blockade (tocilizumab) and therapeutic-dose anticoagulation remains unclear. We aimed to assess whether heparin and tocilizumab could effectively reduce inflammation and thrombogenesis in severe COVID-19 patients.

Methods

This is an open-label, multicenter, randomized, clinical trial, involving patients with severe COVID-19 infection. Eligible patients were randomly assigned in a 1:1:1:1 ratio to receive either therapeutic or prophylactic anticoagulation with heparin, with or without an intravenous single dose of tocilizumab. The participants in the study were assigned to one of the four distinct arms: 1) therapeutic anticoagulation; 2) prophylactic anticoagulation; 3) therapeutic anticoagulation plus a single intravenous dose of tocilizumab; and 4) prophylactic anticoagulation plus a single intravenous dose of tocilizumab. The primary outcome was clinical improvement at day 30, defined as a composite of hospital discharge and/or a reduction of at least 2 points of the modified ordinal scale of 7 points recommended by the World Health Organization.

Results

We enrolled 308 patients. Patients randomized to receive therapeutic anticoagulation more frequently had clinical improvement at day 30 when compared to the prophylactic anticoagulation patients [64/75 (85%) versus 51/80 (64%), odds ratio, 3.31; 95% confidence interval, 1.51; 7.26 P=0.003]. Major bleeding was more frequent in the therapeutic anticoagulation group (6.7%) and in the therapeutic anticoagulation plus tocilizumab group (5.0%), compared to the prophylactic anticoagulation group (P=0.02). All-cause mortality at day 30 was significantly lower in therapeutic anticoagulation group (9.3%), when compared to prophylactic anticoagulation group (28.7%), therapeutic anticoagulation plus tocilizumab group (21.5%) and prophylactic anticoagulation plus tocilizumab group (25.7%), P=0.02.

Conclusions

In this randomized clinical trial involving severe COVID-19 patients, therapeutic anticoagulation resulted in clinical improvement at 30 days. Even if therapeutic anticoagulation increased bleeding, it was associated with a reduced overall mortality. Tocilizumab did not provide additional benefits to heparin in COVID-19 patients.

Trial registration

Clinicaltrials.govNCT04600141. Registered October 22, 2020.https://www.clinicaltrials.gov/study/NCT04600141?term=NCT04600141&rank=1