Effect of P2Y12 Inhibitors on Organ Support–Free Survival in Critically Ill Patients Hospitalized for COVID-19
Authors: Berger Jeffrey S. , Neal Matthew D. , Kornblith Lucy Z. , Gong Michelle N. , Reynolds Harmony R. , Cushman Mary , Althouse Andrew D. , Lawler Patrick R. , McVerry Bryan J. , Kim Keri S. , Baumann Kreuziger Lisa , Solomon Scott D. , Kosiborod Mikhail N. , Berry Scott M. , Bochicchio Grant V. , Contoli Marco , Farkouh Michael E. , Froess Joshua D. , Gandotra Sheetal , Greenstein Yonatan , Hade Erinn M. , Hanna Nicholas , Hudock Kristin , Hyzy Robert C. , Ibáñez Estéllez Fátima , Iovine Nicole , Khanna Ashish K. , Khatri Pooja , Kirwan Bridget-Anne , Kutcher Matthew E. , Leifer Eric , Lim George , Lopes Renato D. , Lopez-Sendon Jose L. , Luther James F. , Nigro Maia Lilia , Quigley John G. , Wahid Lana , Wilson Jennifer G. , Zarychanski Ryan , Kindzelski Andrei , Geraci Mark W. , Hochman Judith S. ,   ACTIV-4a Investigators, Hochman Judith S. , Neal Matthew D. , Berger Jeffrey S. , Kosiborod Mikhail , Solomon Scott , Geraci Mark , Cushman Mary , Berry Scott , Farkouh Michael , Gong Michelle , Hudock Kristin , Kim Keri S. , Kornblith Lucy Z. , Lawler Patrick R. , Maggioni Aldo , Lopes Renato , Lopez-Sendon Jose , Kirwan Bridget-Anne , Kamel Hooman , Goligher Ewan , Zarychanski Ryan , Khatri Pooja , Leifer Eric , McVerry Bryan J. , Reynolds Harmony R. , Wilson Jennifer G. , Hade Erinn , Yu Cheng , Lowenstein Charles , Vardeny Orly , Berwanger Otavio , Althouse Andrew , Javaheri Ali , Kamel Hooman Kamel , Gagliardotto Aurea , Eisenberg Justine , Barnette Cheri , Bhatt Ankeet , Everett Brenden , Contreras Aira , Mavromichalis Stephanie , Iturrate Eduardo , Gilsenan Margaret , Naumova Anna , Roberts Arlene , Newman Jonathan , Levine Julia , Chang Michelle , Holden Alair , Wisniewski Stephen , Leeper Christine , Angus Derek , Martinez Mary , Schreiber Jake , Lundy-Wiggins Valena , Froess Joshua , Vadlamudi Ashita Sai , Sciurba Frank , Morris Alison , Music Edvin , de Brouwer Sophie , Perrin Emilie , Gombault Caroline , Bula Sandra , Nelson Michael , Daelemans Céline , Paraz Laurine , Detry Michelle , McGlothlin Anna , Quintana Melanie , Crawford Amy , Lorenzi Elizabeth , Berry Lindsay , Chen Jocelyn , Heath Anna , Sin Danielle , Diene Elhaji , Gwiszcz Ewelina , Hogan Isabelle , Ringwood Nancy , Fitzgerald Laura , Morin Haley , Kornblith Lucy , Nunez-Garcia Brenda , Kornblith Aaron , Hendrickson Carolyn , Lee Deanna , Nguyen Viet , Shelley India , Loar India , Baumann Kreuziger Lisa , Jones Stephanie , Quigley John G. , Atal Neha , McVerry Bryan , Huang David , Wunderly Renee , Buxton Meredith , Roberts Tracey , Linstrum Kelsey , McNamara Amanda , Weissman Alexandra , Barbee Dylan , Berryman Emily , Frasure Jamey , Sulken Amy , Beasley Kalli , Lalani Narlina , Mayberry Ashlea , Sheryl Windsor , Sindy Roche , Ianof Jéssica Natuline , Mazza Lilian , Morata Julia , Cafarella Carolina Martins , Suiama Mayra Akimi , de Lima Franco Daniele , Escobedo Jorge , Martinez Andrea , Ohara Pedro , Assis Douglas , Manzalini Chiara , Corsi Stefania , Campo Gianluca , Prieto Paula , Prieto Rocio , Wakeman Rebecca , Duncan Christopher J. , Savaram Srikar , Taylor Alexandra Marie , Renard Valerie J. , Dreyer Grace R. , Der Tatyana , Ko Emily R. , Stafford Neil , Archibald Andrea , Mohammed Oluwayemisi , Azuogalanya Nkiruka , Ortel Thomas L. , Moskowitz Ari , Mohammed  Amira , Hite R. Duncan , More Harshada , Tanzeem Hammad , Ernst Neil , Kuebel Dalton , Vargas Julia , Sihota Hena , Whitson Micah R. , Harris Donna S. , Jacobson Jeffrey R , Murillo Blasco María I. , Galiano Cuevas Francisco , Plump Michael , Cusson Bruce , Eaton Amelia , Harris Lynnette , Pickmans Mhorys , Reeves Jessica , Reeves Brandon , Shah Kinchit , Sura Tanmay , Wadhwani Hinna , Maves Ryan , Stallings Leonard , Nigro Maia Lilia , Prado Nadielly , Silva Junior Osvaldo , Jorge Cláudio , Costa Osana , Buka Mariana Buka , Frassatto Danielli , Dutra Paulo , da Silva Larissa , Alessio Nicolly , Pontana Thaise , Cordeiro Natalia , Souza Thiago , Mastro Jaqueline , Souza Jaqueline  , Pradela Cassia , Moreira Larissa , Pavon Guizela Pavon , Rodrigues Andreza , Centurione Anna ,   Silva Joelma , Andreoti Katia , Vectorazzo Renan ,   Silva Tamires Silva , Garcia Juliana , Demore Ana Paula , Papi Alberto , Ronzoni Luca , Lopez-Sendon Moreno Jose Luis , Echegaray Itziar Pozuelo , Ahsan Chowdhury , Kornblith Aaron E. , Hendrickson Carolyn M. , Worner Fernando , Pastor P , Morales JL , Peteiro Jesus , Vázquez Rita Galeiras , Sanchez-Andrade Bolaños José María , Khan Muhib A , Khan Malik MHS , Brooks Heather C , Prekker Matt , Ajani Zahra A. , Moisés Jorge , Osorio Jeisson , Aibar Jesús , Krishnan Vidya , Exline Matthew C , Schwartz Elizabeth L , Kutcher Matthew , Grenn Emily , Shaw Taylor , Barinas Simon , Guo Stephanie C. , Seto Todd B. , Satterwhite Lewis , Latorre Julius Gene , Deb Lena F. , Liang Conrad W , Audea Vanessa F , Puri Nitin K , Green Adam , Duggal Abhijit , Nair Girish B. , Dogra Sanjay , Schooler Jordan B , Moore Steven C , Kaatz Scott , Gaddh Manila , Atassi Bassel , Kapoor Rajat , Alonso A Alvaro , Hamel Alexander P. , Leitao Mauricio , Rogers Angela J. , Babudieri Sergio , Busch Johanna I , Patel Hemali , Kostis John , Shah Binita , Matthay Michael , Gropper Rachel M. , Agrawal Anika , Ashktorab Kimia , Joseph Bellal , Vintch Janine R E. , Yuchno David , Perdeneiras Jaeger Cristiano , dArminio Monforte Antonella , Garcia-Cortes Luis R , Herrera-Morales Blanca E , Gashi Eleonora , Sokol Seth , Simonelli Paul , Sherwin Robert , Ackerman Adam , Colovos Christos , de Matos Soeiro Alexandre , de Oliveira Antunes Murillo , Tibério Augusto Oliveira Costa , Echols Melvin R. , Sheehan John P. , Kumfer Kraig T. , Caramori Paulo , Casagrande Otávio Fachinetto , Carpio Carlos , Zamarrón Ester , Álvarez-Sala Rodolfo , Coppola Nicola , Russo Antonio , Berger Jeffrey , Tidswell Mark A. , Steingrub Jay S. , O'Mahony Shane , Huang David T. , Leandro Liporace Idelzuita , Pan Stephen , Shah Ravi J. , Khan Akram , Oh Minn , Lammi Matthew , Sanne Shane E , Costantini Todd , Berndtson Allison E. , Mateos Eduardo , Vallurupalli Srikanth , Ravula Srilakshmi , Bromberg Michael , Effron Mark B , Pishko Allyson M. , Cohen Alice , Horta Cynthia , Jaffe James 
Published: May 2023

Importance

Platelet activation is a potential therapeutic target in patients with COVID-19.

Objective

To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.

Design, Setting, and Participants

This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care–level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.

Intervention

Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor.

Main Outcomes and Measures

The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis.

Results

At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support–free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR &amp;gt; 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77).

Conclusions and Relevance

In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.

Trial Registration

ClinicalTrials.gov Identifier: NCT04505774