ARDS; Alteplase; COVID-19; Severe hypoxemic respiratory failure; Thrombolysis
Abstract :
[en] [en] BACKGROUND: Pulmonary intravascular thrombus formation has been widely observed in patients with respiratory failure, for example, in patients with SARS-CoV-2 infection (COVID-19). The aim of this study was to evaluate the efficacy/safety of alteplase thrombolysis in COVID-19 severe hypoxemic respiratory failure. In this multicenter, open-label study, patients were randomized to receive alteplase (low- or high-dose) over 5 days plus standard of care (SOC), or SOC alone. The primary endpoint was time to clinical improvement (≥ 2-point decrease on WHO Clinical Progression Scale, or hospital discharge) up to Day 28. Secondary endpoints included all-cause mortality at Day 28, treatment failure at Day 28 and change in arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) ratio at Day 6 versus baseline.
RESULTS: Sixty-nine patients were randomized to alteplase (low- or high-dose) and 35 to SOC; 65% were on high-flow oxygen or non-invasive ventilation at baseline. Median time to clinical improvement was 25 days in the alteplase group and > 28 days (median not reached) in the SOC group. All-cause mortality was 8/69 (12%) versus 10/35 (29%) in the alteplase versus SOC groups, respectively (unadjusted risk difference [RD], - 17% [95% confidence interval (CI) - 34 to 0], p = 0.047; adjusted RD, - 16% [95% CI - 31 to 1], p = 0.058). The PaO2/FiO2 ratio (mean [standard deviation]) increased by + 30 (84) mmHg in the alteplase group and decreased by - 12 (59) mmHg in the SOC group (adjusted mean difference vs. SOC, p = 0.052). Differences were greater in patients receiving high-dose alteplase, and in those not receiving invasive ventilation. Eighteen patients (26.1%) in the alteplase group discontinued treatment due to adverse events. Major bleeding was more frequent with alteplase than with SOC (9 vs. 0 patients); no bleeding was fatal. The study closed early due to insufficient patient recruitment.
CONCLUSION: Alteplase was not associated with faster clinical recovery from COVID-19 severe hypoxemic respiratory failure. A numerical difference in survival and PaO2/FiO2 ratio was observed, particularly in patients not receiving invasive ventilation. These exploratory findings merit further investigation in larger patient cohorts that are adequately powered to confirm the hypotheses generated in this study regarding the impact of alteplase on treatment outcomes. Trial registration ClinicalTrials.gov: NCT04640194 (November 23, 2020); https://clinicaltrials.gov/study/NCT04640194 (early discontinuation due to insufficient patient recruitment).
Disciplines :
Anesthesia & intensive care
Author, co-author :
Landoni, Giovanni; Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy ; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
Chowdary, Pratima; Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK
Meziani, Ferhat; Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Strasbourg, France
Creteur, Jacques; Department of Intensive Care, ULB Hôpital Erasme, Brussels, Belgium
De Schryver, Nicolas; Intensive Care Unit, Clinique St-Pierre, Ottignies, Belgium
Motsch, Johann; Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
Henrichmoeller, Ingrid; Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany ; Fifth Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany
Pagès, Alain; Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany
Peter, Nuala; Boehringer Ingelheim, Biberach an Der Riss, Germany
Danays, Thierry; TDC, Aix en Provence, France
Weigand, Markus A; Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany. markus.weigand@med.uni-heidelberg.de
TRISTARDS Investigators
LAYIOS, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > > Service des soins intensifs
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