Alteplase in COVID-19 severe hypoxemic respiratory failure: the TRISTARDS multicenter randomized trial
Authors: Landoni Giovanni , Chowdary Pratima , Meziani Ferhat , Creteur Jacques , De Schryver Nicolas , Motsch Johann , Henrichmoeller Ingrid , Pagès Alain , Peter Nuala , Danays Thierry , Weigand Markus A. ,   the TRISTARDS Investigators, Zoufaly Alexander , Seitz Tamara , Pawelka Erich , Neuhold Stephanie , Höpler Wolfgang , Rumpf Benedikt , Totschnig David , Likar Rudolf , Koestenverger Markus , Neuwersch-Sommeregger Stefan , Creteur Jacques , Ego Amedee , Moreau Anthony , Grimaldi David , Annoni Filippo , Gorham Julie , Halenarova Katarina , Pletschette Zoe , Brasseur Alexandre , Taccone Fabio , Nobile Leda , Lheureux Olivier , Snacken Morgane , Dehout Charles , De Schryver Nicolas , Vinetti Marco , Serck Nicolas , Dugernier Thierry , Layios Nathalie , Parzibut Gilles , Boldo Rodrigo , dos Santos Vanessa Santos , Nunes Cristine Erdmann , Diehl Jean-Luc , Aissaoui N , Augy J , Guerot E , Hauw-Berlemont C , Hermann B , Peron N , Santi F , Langlais J , Troger A , Chekhrit K , Poissy Julien , Caplan M , El Kalioubie A , Favory R , Gaudet A , Goutay J , Preau S , Rouze A , Mariller Laure , Mira Jean-Paul , Hamou Z Ait , Ghanem S Ben , Bertrix M , Charpentier J , Creutin T , Jozwiak M , Laghlam D , Peju E , Pene F , Vigneron C , Meziani Ferhat , Demisselle J , Helms J , Jandeaux L , Kummerlen C , Merdji H , Monnier A , Rahmani H , Studer A , Cunat S , Hakkari Ouafa , Monnet Xavier , Adda I , Anguel N , Ayed S , Fosse Q , Guerin L , Osman D , Pavot A , Pham T , Carpentier C , Denormandie P , Lai C , Fourreau Alain , Monchi Mehran , Ellrodt O , Jochmans S , Mazerand S , Rolin N , Serbource-Goguel J , Soulier P , Sy O , Benane Nourdine , Mourvillier Bruno , Cousson J , Goury A , Passouant O , Thery G , Castex Cédric , Lascarrou Jean-Baptiste , Roquilly A , Canet E , Garret C , Lemarie J , Martin M , Reignier J , Seguin A , Zambon O , Lamouche Wilquin P , Agbakou M , Decamps P , Desmedt L , Blonz G , Hourmant Y , Grillot N , Rouhani A , Bouras M , Mahe P.-J. , Latte D. Demeure Dit , Bourdiol A , Benkalfate N , Carpentier M , Guillotin F , Benguerfi S , Motsch Johann , Zimmermann Johannes , Al Halabi Karam , Altvater Marc , Decker Sebastian , Fiedler Mascha , Knebel Phillip , Maichle Barbara , Weigand Markus , Welte Tobias , Drick Nora , Pink Isabelle , Schmidt Julius Johannes , Bercker Sven , Simon Philipp , Fichtner Falk , Hempel Gunther , Kliem Peter , Kluba Karsten , Laudi Sven , Müller Sarah , Oesemann Rene , Roedel Michael , Schering Stefan , Schulz Sebastian , Seeber Christian , Ullmann Hannah , Ziganshyna Svitlana , Jahn Nora , Boerge Bastian , Keller Maren , Irlbeck Michael , Frank Sandra , Hoffmann Ursula , Huseynov Aydin , Britsch Simone , Ishar-Singh Gill , Jabbour Claude , Stieglitz Sven , Guelker Jan-Erik , Cecconi Maurizio , Greco Massimiliano , Monti Giacomo , Azzolini Maria Luisa , Righetti Beatrice , Diaz Francisco Marquez , Girón Sofía Elizabeth , de La Cruz Alejandra Aviles , Ibarra Ana Elena Ramírez , Romo Paola Hernández , García Marián Serna , Castillo Andrés García , Spronk Peter , Kuindersma Marnix , Blans Michiel , Leeuwen Henk , Peters Marco , Rengers Els , Hoiting Oscar , Filimonov Viktor Borisovich , Peshenniokva Maria , Kravchenko Olga , Karev Yuri , Filimonova Anastasiia , Avdeev Sergey Nikolaevich , Chikina Svetlana , Gneusheva Tatiana , Merzhoeva Zamira , Nekludova Galina , Protsenko Denis Nikolaevich , Tyurin Igor , Matyushkov Nikita , Lisun Tatiana Valerievna V. , Boyarkov Aleksandr , Bobkova Svetlana , Klinov Alexey , Schukarev Dmitry , Smolin Nikolay , Ferrer Ricard , Nuvials Xavier , Contreras Sofia , Cortés Alejandro , Lora Mariel Rojas , Sierra Rafael , Alarbe Samer , Fernandez Ana , Contreras Mario , Freire María Dolores , Revuelto Jaume , Celaya Mikel , Marín Judith , Parrilla Francisco , Perez Purificación , Muñoz Rosana , Diaz Emilio , Mora Cristina , de Haro Candelaria , Moglia Edgard 
Published: November 2024

Abstract
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).