DisCoVeRy: Remdesivir does not expose hospitalised patients with Covid-19 to an increased risk of cardiac effects

What is known?

At the start of the pandemic, there was an urgent need to find therapeutic options to treat patients with a moderate or severe form of Covid-19, i.e. hospitalised patients with respiratory symptoms requiring oxygen. The antiviral agent remdesivir was one of the first treatment options in the context of the rapid development of therapeutic strategies.

The DisCoVeRy clinical trial, initially launched in March 2020 by Inserm-PRC* in France and subsequently expanded to Europe through the EU-Response project (3) funded by the European Commission, was designed to evaluate several possible treatments for Covid-19. In this study, remdesivir, like the other antivirals tested (lopinavir/ritonavir, hydroxychloroquine, interferon, etc.), showed no clinical benefit in adult patients hospitalised and placed on supplemental oxygen compared with those receiving standard care alone (4).

Subsequently, studies on another population at risk of developing severe Covid (non-hospitalised, non-oxygen dependent population – Pinetree (5)) and a meta-analysis (Prospero (6)) demonstrated the efficacy of early remdesivir administration before the onset of severe Covid.

As with any newly authorised medicine, a large number of post-authorisation safety studies have been carried out. Several clinical cases and observational studies have warned of the occurrence of cardiac concerns at the start of treatment, in particular mild to moderate sinus bradycardia (arrhythmia corresponding to an abnormally slow heartbeat). The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) analysed this safety signal for sinus bradycardia. In June 2021, it concluded that a causal relationship between the use of the medicine and this adverse event was at least a ‘reasonable possibility’ with an undetermined frequency.

Post-hoc analysis of the DisCoVeRy study

Under those circumstances, a post-hoc analysis of the DisCoVeRy data was undertaken. In this study, participants had been allocated to ‘homogeneous’ groups, meaning that on inclusion they were not significantly different from each other on a number of key characteristics, such as co-morbidities.

The results of the analysis showed that, compared to the comparator group and regardless of severity, antiviral treatment was not associated with an increased risk of cardiac adverse events, including arrhythmias. Cardiac adverse events were reported in 46 of 410 patients receiving remdesivir and in 48 of 423 patients in the comparator group. The difference between the two groups was not significant. The incidence of arrhythmia, the most common cardiac disorder in both groups, was mainly associated with a favourable outcome, without the need to discontinue remdesivir. These results reflect the already well-documented cardiovascular complications associated with the disease itself. They also highlight the role of other risk factors, such as pre-existing co-morbidities and exposure in both groups to numerous drugs that can cause cardiac problems, particularly in intensive care.

Conclusion

The results of DisCoVeRy, a randomised controlled trial, complement existing data on the safe use of remdesivir in hospitalised patients with Covid-19. They are consistent with those of meta-analyses and other randomised controlled trials. New research, including meta-analyses with a larger sample size enabling sub-population analyses, is expected in the near future.

* Inserm Clinical Research Unit (Inserm-PRC)

** Analysis of experimental data after a study has been concluded and the data collected

References

(1) Terzić V (1,2), Miantezila Basilua J (1,2), Billard N (3), de Gastines L (1,2), Belhadi D (3,6), Fougerou-Leurent C (4), Peiffer-Smadja N (5,6), Mercier N (1,2), Delmas C (7), Ferrane A (7), Dechanet A (3), Poissy J (8), Espérou H (7), Ader F (9), Hites M (10), Andrejak C (11), Greil R (12), Paiva J-A (13), Staub T (14), Tacconelli E (15), Burdet C (3), Costagliola D (16), Mentré F (3,6), Yazdanpanah Y (3,5,17), Diallo A (1,2), and the DisCoVeRy study group. Cardiac adverse events and remdesivir in hospitalized patients with Coronavirus Disease 2019 (COVID-19): A post hoc safety analysis of the randomized DisCoVeRy trial. Clin Infect Dis 2024 Mar 29:ciae170.

1. Clinical Trial Safety and Public Health, ANRS|Emerging Infectious Diseases, Paris, France
2. Clinical Research Safety Department, INSERM, Paris, France
3. Department of Epidemiology, Biostatistics and Clinical Research, Hospital Bichat, APHP, Paris, France
4. Pharmacology Unit, University Hospital Rennes; CIC Inserm 1414, University Hospital Rennes, Rennes, France
5. Infectious Diseases Department, Hôpital Bichat – Claude-Bernard, APHP, Paris, France
6. Université Paris Cité, IAME, INSERM, Paris, France
7. Pôle de Recherche Clinique, INSERM, Paris, France
8. Université de Lille, Inserm U1285, CHU Lille, Pôle de réanimation, CNRS, UMR 8576 – UGSF – Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France
9. Département des Maladies infectieuses et tropicales, Hospices Civils de Lyon, F-69004, Lyon, and Centre International de Recherche en Infectiologie (CIRI), Inserm 1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ Lyon, F-69007, Lyon, France
10. Clinic of Infectious Diseases, Hôpital Universitaire de Bruxelles (HUB)-Erasme, Brussels, Belgium
11. Pulmonolgy Unit, University Hospital Amiens-Picardie, UR 4294 AGIR, Université Picardie Jules Verne, Amiens, France
12. IIIrd Medical Department, Paracelsus Medical University Salzburg; Salzburg Cancer Research Institute-Center for clinical Cancer and Immunology Trials (SCRI-CCCIT); Cancer Cluster Salzburg; Austrian Group for Medical Tumor Therapy (AGMT), Salzburg, Austria
13. Serviço de Medicina Intensiva, Centro Hospitalar Universitário São João, Porto, Portugal
14. Centre Hospitalier de Luxembourg, 4 Rue Ernest Barblé, L-1210 Luxembourg, Luxembourg
15. Infectious diseases, Dept. Diagnostic and Public Health, University of Verona, Verona, Italy
16. Sorbonne Université, INSERM, Institut Pierre Louis d’Épidémiologie et de Santé Publique (IPLESP), Paris, France
17. ANRS Emerging Infectious Diseases, Paris, France

(2) Gottlieb RL and Kalil AC. True DisCoVeRy of COVID-19 disease burden versus speculated antiviral cardiovascular risk requires a control group. Clin Infect Dis 2024 Mar 29:ciae172.

(3) https://cordis.europa.eu/project/id/101015736

Funded by the European Union (European Union’s Horizon 2020 research and innovation programme under grant agreement No 101015736), DisCoVeRy is now research axis 1 of the EU-RESPONSE project (European Research and Preparedness Network for Pandemics and Emerging Infectious Diseases), which brings together 22 partners (clinics, hospitals, universities, etc.) from 13 countries in the European Union, Norway, Switzerland, Luxembourg and Turkey.

(4) Ader F, et al. Final results of the DisCoVeRy trial of remdesivir for patients admitted to hospital with COVID-19. Lancet Infect Dis 2022;22(6):764-765.

(5) Gottlieb RL, et al. Early Remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med 2022;386(4):305-315.

(6) Amstutz A, et al. Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials. Lancet Respir Med 2023; 11(5):453-464.