Effect of intravenous almitrine on intubation or mortality in patients with COVID-19 acute hypoxemic respiratory failure: A multicentre, randomised, double-blind, placebo-controlled trial

Pierre Kalfon; Jean-François Payen; Alexandra Rousseau; Benjamin Chousterman; Marine Cachanado; Annick Tibi; Juliette Audibert; François Depret; Jean-Michel Constantin; Emmanuel Weiss; Francis Remerand; Yonathan Freund; Tabassome Simon; Bruno Riou

doi:10.1016/j.eclinm.2022.101663

Effect of intravenous almitrine on intubation or mortality in patients with COVID-19 acute hypoxemic respiratory failure: A multicentre, randomised, double-blind, placebo-controlled trial

EClinicalMedicine. 2022 Oct:52:101663. doi: 10.1016/j.eclinm.2022.101663. Epub 2022 Sep 21.

Authors

Affiliations

¹ Service de Réanimation polyvalente, Hôpital Louis Pasteur, Centre Hospitalier de Chartres, Le Coudray, France.
² Department of Anesthesiology and Intensive Care, Grenoble Alpes University Hospital, and Grenoble Alpes University, Grenoble Institut des Neurosciences, INSERM U1216, Grenoble, France.
³ Department of Clinical Pharmacology and Clinical Research Platform (URC-CRC-CRB), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Antoine, Paris, France.
⁴ Université Paris Cité, INSERM UMR 942, and AP-HP, Department of Anesthesiology and Critical Care, Groupe Hospitalier Saint-Louis-Lariboisière, Paris, France.
⁵ Université Paris Cité, and AP-HP, Agence Générale des Équipements et Produits de Santé, Département Essais Cliniques, Paris, France.
⁶ Université Paris Cité, and AP-HP, service d'Anesthésie-Réanimation-Centre de traitement des brûlés, Hôpital Saint Louis, Paris, France.
⁷ Sorbonne Université, GRC 29, and AP-HP, Department of Anesthesiology and Critical Care, Hôpital Pitié-Salpêtrière, Paris, France.
⁸ Université Paris Cité, and AP-HP, Department of Anesthesiology and Critical Care, Hôpital Beaujon, Paris, France.
⁹ Université de Tours and CHRU de Tours, Department of Anesthesiology and Critical Care, Hôpital Trousseau, Tours, France.
¹⁰ Sorbonne Université, INSERM UMRS 1166, IHU ICAN, and AP-HP, Department of Emergency Medicine, Hôpital Pitié-Salpêtrière, Paris, France.
¹¹ Sorbonne Université, France.

Abstract

Background: Severe hypoxemia in patients with COVID-19 pneumonia might result from hypoxic pulmonary vasoconstriction, contributing to ventilation/perfusion (V/Q) mismatch. Because almitrine improves V/Q, it might reduce the risk for mechanical ventilation (MV) in such patients. Our primary objective was to determine the effect of almitrine on the need for MV at day 7.

Methods: In a randomised double-blind placebo-controlled trial involving 15 ICUs, patients hospitalized for COVID-19 pneumonia and experiencing acute hypoxemic respiratory failure were randomly assigned to receive 5 days of intravenous low-dose (2 µg.kg^-1.min^-1) almitrine or placebo. The primary outcome was endotracheal intubation for MV or death within 7 days after randomisation. Secondary outcomes included in-hospital mortality, 28-day mortality, number of ventilator-free days, number of days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects. This trial was registered with ClinicalTrials.gov, NCT04357457.

Findings: Between September 3, 2020 and September 25, 2021 181 patients were enrolled and randomly assigned to almitrine (n=89) or placebo (n=92). 179 patients (excluding two who withdrew from the study) were included in the intention-to-treat analysis (mean age: 60·1 years; 34% women) and analyzed. On day 7, the primary endpoint occurred in 32 patients assigned to almitrine (36%) and in 37 patients assigned to placebo (41%), for a difference of -4·3% (95% confidence interval: -18·7% to 10·2%). Secondary outcomes (28-day mortality, in-hospital mortality, ventilator-free days at day 28, days in the ICU and the hospital, and treatment discontinuation for pre-specified adverse effects) did not differ between the two groups.

Interpretation: In patients with COVID-19 acute hypoxemic respiratory failure, low-dose almitrine failed in reducing the need for MV or death at day 7.

Funding: Programme Hospitalier de Recherche Clinique (PHRC COVID 2020) funded by the French Ministry of Health, Les Laboratoires Servier (Suresnes, France) providing the study drug free of charge.

Keywords: ARDS; Almitrine; COVID-19; Hypoxemia; Pneumonia.

Associated data

ClinicalTrials.gov/NCT04357457