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

doi:10.1016/j.eclinm.2022.101663

. 2022 Oct:52:101663.

doi: 10.1016/j.eclinm.2022.101663. Epub 2022 Sep 21.

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

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.

PMID: 36157895
PMCID: PMC9489996
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

Pierre Kalfon et al. EClinicalMedicine. 2022 Oct.

. 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.

PMID: 36157895
PMCID: PMC9489996
DOI: 10.1016/j.eclinm.2022.101663

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.

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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.

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).

See this image and copyright information in PMC

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References

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1. COVID-19 Lombardy ICU Network. Grasselli G, Greco M, Zanella A, et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern. Med. 2020;180:1345–1355. - PMC - PubMed
1. IMProving Emergency Care (IMPEC) FHU Collaborators Group. Bouzid D., Visseaux B, Kassasseya C, et al. Comparison of patients infected with Delta versus Omicron COVID-19 variants presenting to Paris emergency departments : a retrospective cohort study. Ann Intern Med. 2022;175:831–837. - PMC - PubMed
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[1] Kandel N, Chungong S, Omaar A, Xing J. Health security capacities in the context of COVID-19 outbreak: an analysis of international health regulations annual report data from 182 countries. Lancet. 2020;395:1047–1053. - PMC - PubMed

[2] Kandel N, Chungong S, Omaar A, Xing J. Health security capacities in the context of COVID-19 outbreak: an analysis of international health regulations annual report data from 182 countries. Lancet. 2020;395:1047–1053. - PMC - PubMed

[3] COVID-19 Lombardy ICU Network. Grasselli G, Greco M, Zanella A, et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern. Med. 2020;180:1345–1355. - PMC - PubMed

[4] COVID-19 Lombardy ICU Network. Grasselli G, Greco M, Zanella A, et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern. Med. 2020;180:1345–1355. - PMC - PubMed

[5] IMProving Emergency Care (IMPEC) FHU Collaborators Group. Bouzid D., Visseaux B, Kassasseya C, et al. Comparison of patients infected with Delta versus Omicron COVID-19 variants presenting to Paris emergency departments : a retrospective cohort study. Ann Intern Med. 2022;175:831–837. - PMC - PubMed

[6] IMProving Emergency Care (IMPEC) FHU Collaborators Group. Bouzid D., Visseaux B, Kassasseya C, et al. Comparison of patients infected with Delta versus Omicron COVID-19 variants presenting to Paris emergency departments : a retrospective cohort study. Ann Intern Med. 2022;175:831–837. - PMC - PubMed

[7] COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study. Intensive Care Med. 2021;47:60–73. - PMC - PubMed

[8] COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study. Intensive Care Med. 2021;47:60–73. - PMC - PubMed

[9] Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med. 2020;46:1105–1108. - PMC - PubMed

[10] Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med. 2020;46:1105–1108. - PMC - PubMed

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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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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