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

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.

Conflict of interest statement

PK received personal fees from General Electric Healthcare outside of the submitted work. JFP: Nothing to disclose. AR: Nothing to disclose. BC: Nothing to disclose. MC: Nothing to disclose. AT: Nothing to disclose. JA: Nothing to disclose. FD: personal fees from Sedana medical and Biomerieux; research grant from French Ministry of Health, European Society of Intensive Care Medicine, and Société Française d'Anesthésie Réanimation. JMC: personal fees and non-financial support from Drager, GE Healthcare, Sedana Medical, Baxter, and Amomed; personal fees from Fisher and Paykel Healthcare, Orion, Philips Medical, and Fresenius Medical Care; and nonfinancial support from LFB and Bird Corporation, outside of the submitted work. EW: personal fees from MSD, Akcea therapeutics, and LFB; nonfinancial support from LFB and Akcea therapeutics, outside of the submitted work. FR: Nothing to disclose. YF: Nothing to disclose. TS: research grants or contracts from AstraZeneca, Bayer, Boehringer, Daiichi-Sankyo, Eli-Lilly, GSK, Novartis, and Sanofi; personal fees from Servier, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board from Ablative solutions, Air Liquide, AstraZeneca, Sanofi, Novartis, and 4Living Biotech, outside of the submitted work. BR: Nothing to disclose.

© 2022 The Authors.

Figures

Figure 1

Flow of participants through the study.

Figure 2

The 28-day survival curves for patients not undergoing endotracheal intubation for mechanical ventilation or death in the almitrine (n=87) and placebo (n=91) groups after randomisation. P value refers to between-group difference (log rank test).