Charlotte A Bradbury1, Patrick R Lawler2,3, Simon J Stanworth4,5, Bryan J McVerry6, Zoe McQuilten7,8, Alisa M Higgins7, Paul R Mouncey9, Farah Al-Beidh10, Kathryn M Rowan9, Lindsay R Berry11, Elizabeth Lorenzi11, Ryan Zarychanski12, Yaseen M Arabi13, Djillali Annane14,15, Abi Beane4, Wilma van Bentum-Puijk16, Zahra Bhimani17, Shailesh Bihari18, Marc J M Bonten16, Frank M Brunkhorst19, Adrian Buzgau7, Meredith Buxton20, Marc Carrier21,22, Allen C Cheng7,23, Matthew Cove24, Michelle A Detry11, Lise J Estcourt5, Mark Fitzgerald11, Timothy D Girard6, Ewan C Goligher2,3, Herman Goossens25, Rashan Haniffa26,27, Thomas Hills28, David T Huang6, Christopher M Horvat29, Beverley J Hunt30, Nao Ichihara31, Francois Lamontagne32, Helen L Leavis16, Kelsey M Linstrum6, Edward Litton33,34, John C Marshall17, Daniel F McAuley35,36, Anna McGlothlin11, Shay P McGuinness7,37, Saskia Middeldorp38, Stephanie K Montgomery6, Susan C Morpeth39, Srinivas Murthy40, Matthew D Neal6, Alistair D Nichol7,41, Rachael L Parke37,42, Jane C Parker7, Luis F Reyes43,44, Hiroki Saito45, Marlene S Santos17, Christina T Saunders11, Ary Serpa-Neto7,46, Christopher W Seymour6, Manu Shankar-Hari47,48, Vanessa Singh7, Timo Tolppa27, Alexis F Turgeon49,50, Anne M Turner28, Frank L van de Veerdonk38, Cameron Green7, Roger J Lewis11,51, Derek C Angus6, Colin J McArthur37, Scott Berry11, Lennie P G Derde16, Steve A Webb7,52, Anthony C Gordon10,53. 1. University of Bristol, Bristol, England. 2. Peter Munk Cardiac Centre at University Health Network, Toronto, Ontario, Canada. 3. University of Toronto, Toronto, Ontario, Canada. 4. University of Oxford, Oxford, England. 5. NHS Blood and Transplant, Oxford, England. 6. University of Pittsburgh, Pittsburgh, Pennsylvania. 7. Monash University, Melbourne, Victoria, Australia. 8. Monash Health, Melbourne, Victoria, Australia. 9. Intensive Care National Audit and Research Centre (ICNARC), London, England. 10. Imperial College London, London, England. 11. Berry Consultants, Austin, Texas. 12. University of Manitoba, Winnipeg, Canada. 13. King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 14. Hospital Raymond Poincaré (Assistance Publique Hôpitaux de Paris), Garches, France. 15. Université Versailles SQY-Université Paris Saclay, Montigny-le-Bretonneux, France. 16. University Medical Center Utrecht, Utrecht, the Netherlands. 17. St Michael's Hospital Unity Health, Toronto, Ontario, Canada. 18. Flinders University, Bedford Park, South Australia, Australia. 19. Jena University Hospital, Jena, Germany. 20. Global Coalition for Adaptive Research, Los Angeles, California. 21. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 22. Institut du Savoir Montfort, Ottawa, Ontario, Canada. 23. Alfred Health, Melbourne, Victoria, Australia. 24. Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 25. University of Antwerp, Wilrijk, Belgium. 26. University of Oxford, Bangkok, Thailand. 27. National Intensive Care Surveillance (NICST), Colombo, Sri Lanka. 28. Medical Research Institute of New Zealand (MRINZ), Wellington, New Zealand. 29. UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. 30. Kings Healthcare Partners, London, England. 31. The University of Tokyo, Tokyo, Japan. 32. Université de Sherbrooke, Sherbrooke, Québec, Canada. 33. Fiona Stanley Hospital, Perth, Western Australia, Australia. 34. University of Western Australia, Perth, Australia. 35. Queen's University Belfast, Belfast, Northern Ireland. 36. Royal Victoria Hospital, Belfast, Northern Ireland. 37. Auckland City Hospital, Auckland, New Zealand. 38. Radboud University Medical Center, Nijmegen, the Netherlands. 39. Middlemore Hospital, Auckland, New Zealand. 40. University of British Columbia, Vancouver, Canada. 41. University College Dublin, Dublin, Ireland. 42. University of Auckland, Auckland, New Zealand. 43. Universidad de La Sabana, Chia, Colombia. 44. Clinica Universidad de La Sabana, Chia, Colombia. 45. St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Japan. 46. Hospital Israelita Albert Einstein, Sao Paulo, Brazil. 47. King's College London, London, England. 48. Guy's and St Thomas' NHS Foundation Trust, London, England. 49. Université Laval, Québec City, Québec, Canada. 50. CHU de Québec-Université Laval Research Center, Québec City, Québec, Canada. 51. Harbor-UCLA Medical Center, Torrance, California. 52. St John of God Hospital, Subiaco, Western Australia, Australia. 53. Imperial College Healthcare NHS Trust, St Mary's Hospital, London, England.
Abstract
Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
Authors: Zsuzsanna Varga; Andreas J Flammer; Peter Steiger; Martina Haberecker; Rea Andermatt; Annelies S Zinkernagel; Mandeep R Mehra; Reto A Schuepbach; Frank Ruschitzka; Holger Moch Journal: Lancet Date: 2020-04-21 Impact factor: 79.321
Authors: Akshay Shah; Killian Donovan; Anna McHugh; Manish Pandey; Louise Aaron; Charlotte A Bradbury; Simon J Stanworth; Raza Alikhan; Stephen Von Kier; Keith Maher; Nicola Curry; Susan Shapiro; Matthew J Rowland; Matt Thomas; Richard Mason; Matthew Holland; Tom Holmes; Michael Ware; Stefan Gurney; Stuart R McKechnie Journal: Crit Care Date: 2020-09-18 Impact factor: 9.097
Authors: Anthony C Gordon; Paul R Mouncey; Farah Al-Beidh; Kathryn M Rowan; Alistair D Nichol; Yaseen M Arabi; Djillali Annane; Abi Beane; Wilma van Bentum-Puijk; Lindsay R Berry; Zahra Bhimani; Marc J M Bonten; Charlotte A Bradbury; Frank M Brunkhorst; Adrian Buzgau; Allen C Cheng; Michelle A Detry; Eamon J Duffy; Lise J Estcourt; Mark Fitzgerald; Herman Goossens; Rashan Haniffa; Alisa M Higgins; Thomas E Hills; Christopher M Horvat; Francois Lamontagne; Patrick R Lawler; Helen L Leavis; Kelsey M Linstrum; Edward Litton; Elizabeth Lorenzi; John C Marshall; Florian B Mayr; Daniel F McAuley; Anna McGlothlin; Shay P McGuinness; Bryan J McVerry; Stephanie K Montgomery; Susan C Morpeth; Srinivas Murthy; Katrina Orr; Rachael L Parke; Jane C Parker; Asad E Patanwala; Ville Pettilä; Emma Rademaker; Marlene S Santos; Christina T Saunders; Christopher W Seymour; Manu Shankar-Hari; Wendy I Sligl; Alexis F Turgeon; Anne M Turner; Frank L van de Veerdonk; Ryan Zarychanski; Cameron Green; Roger J Lewis; Derek C Angus; Colin J McArthur; Scott Berry; Steve A Webb; Lennie P G Derde Journal: N Engl J Med Date: 2021-02-25 Impact factor: 91.245
Authors: Michelle Sholzberg; Grace H Tang; Hassan Rahhal; Musaad AlHamzah; Lisa Baumann Kreuziger; Fionnuala Ní Áinle; Faris Alomran; Khalid Alayed; Mohammed Alsheef; Fahad AlSumait; Carlos Eduardo Pompilio; Catherine Sperlich; Sabrena Tangri; Terence Tang; Peter Jaksa; Deepa Suryanarayan; Mozah Almarshoodi; Lana A Castellucci; Paula D James; David Lillicrap; Marc Carrier; Andrew Beckett; Christos Colovos; Jai Jayakar; Marie-Pier Arsenault; Cynthia Wu; Karine Doyon; E Roseann Andreou; Vera Dounaevskaia; Eric K Tseng; Gloria Lim; Michael Fralick; Saskia Middeldorp; Agnes Y Y Lee; Fei Zuo; Bruno R da Costa; Kevin E Thorpe; Elnara Márcia Negri; Mary Cushman; Peter Jüni Journal: BMJ Date: 2021-10-14
Authors: Derek C Angus; Scott Berry; Roger J Lewis; Farah Al-Beidh; Yaseen Arabi; Wilma van Bentum-Puijk; Zahra Bhimani; Marc Bonten; Kristine Broglio; Frank Brunkhorst; Allen C Cheng; Jean-Daniel Chiche; Menno De Jong; Michelle Detry; Herman Goossens; Anthony Gordon; Cameron Green; Alisa M Higgins; Sebastiaan J Hullegie; Peter Kruger; Francois Lamontagne; Edward Litton; John Marshall; Anna McGlothlin; Shay McGuinness; Paul Mouncey; Srinivas Murthy; Alistair Nichol; Genevieve K O'Neill; Rachael Parke; Jane Parker; Gernot Rohde; Kathryn Rowan; Anne Turner; Paul Young; Lennie Derde; Colin McArthur; Steven A Webb Journal: Ann Am Thorac Soc Date: 2020-07
Authors: Dominic Wichmann; Jan-Peter Sperhake; Marc Lütgehetmann; Stefan Steurer; Carolin Edler; Axel Heinemann; Fabian Heinrich; Herbert Mushumba; Inga Kniep; Ann Sophie Schröder; Christoph Burdelski; Geraldine de Heer; Axel Nierhaus; Daniel Frings; Susanne Pfefferle; Heinrich Becker; Hanns Bredereke-Wiedling; Andreas de Weerth; Hans-Richard Paschen; Sara Sheikhzadeh-Eggers; Axel Stang; Stefan Schmiedel; Carsten Bokemeyer; Marylyn M Addo; Martin Aepfelbacher; Klaus Püschel; Stefan Kluge Journal: Ann Intern Med Date: 2020-05-06 Impact factor: 25.391
Authors: F A Klok; M J H A Kruip; N J M van der Meer; M S Arbous; D A M P J Gommers; K M Kant; F H J Kaptein; J van Paassen; M A M Stals; M V Huisman; H Endeman Journal: Thromb Res Date: 2020-04-10 Impact factor: 3.944
Authors: Ewan C Goligher; Charlotte A Bradbury; Bryan J McVerry; Patrick R Lawler; Jeffrey S Berger; Michelle N Gong; Marc Carrier; Harmony R Reynolds; Anand Kumar; Alexis F Turgeon; Lucy Z Kornblith; Susan R Kahn; John C Marshall; Keri S Kim; Brett L Houston; Lennie P G Derde; Mary Cushman; Tobias Tritschler; Derek C Angus; Lucas C Godoy; Zoe McQuilten; Bridget-Anne Kirwan; Michael E Farkouh; Maria M Brooks; Roger J Lewis; Lindsay R Berry; Elizabeth Lorenzi; Anthony C Gordon; Tania Ahuja; Farah Al-Beidh; Djillali Annane; Yaseen M Arabi; Diptesh Aryal; Lisa Baumann Kreuziger; Abi Beane; Zahra Bhimani; Shailesh Bihari; Henny H Billett; Lindsay Bond; Marc Bonten; Frank Brunkhorst; Meredith Buxton; Adrian Buzgau; Lana A Castellucci; Sweta Chekuri; Jen-Ting Chen; Allen C Cheng; Tamta Chkhikvadze; Benjamin Coiffard; Aira Contreras; Todd W Costantini; Sophie de Brouwer; Michelle A Detry; Abhijit Duggal; Vladimír Džavík; Mark B Effron; Heather F Eng; Jorge Escobedo; Lise J Estcourt; Brendan M Everett; Dean A Fergusson; Mark Fitzgerald; Robert A Fowler; Joshua D Froess; Zhuxuan Fu; Jean P Galanaud; Benjamin T Galen; Sheetal Gandotra; Timothy D Girard; Andrew L Goodman; Herman Goossens; Cameron Green; Yonatan Y Greenstein; Peter L Gross; Rashan Haniffa; Sheila M Hegde; Carolyn M Hendrickson; Alisa M Higgins; Alexander A Hindenburg; Aluko A Hope; James M Horowitz; Christopher M Horvat; David T Huang; Kristin Hudock; Beverley J Hunt; Mansoor Husain; Robert C Hyzy; Jeffrey R Jacobson; Devachandran Jayakumar; Norma M Keller; Akram Khan; Yuri Kim; Andrei Kindzelski; Andrew J King; M Margaret Knudson; Aaron E Kornblith; Matthew E Kutcher; Michael A Laffan; Francois Lamontagne; Grégoire Le Gal; Christine M Leeper; Eric S Leifer; George Lim; Felipe Gallego Lima; Kelsey Linstrum; Edward Litton; Jose Lopez-Sendon; Sylvain A Lother; Nicole Marten; Andréa Saud Marinez; Mary Martinez; Eduardo Mateos Garcia; Stavroula Mavromichalis; Daniel F McAuley; Emily G McDonald; Anna McGlothlin; Shay P McGuinness; Saskia Middeldorp; Stephanie K Montgomery; Paul R Mouncey; Srinivas Murthy; Girish B Nair; Rahul Nair; Alistair D Nichol; Jose C Nicolau; Brenda Nunez-Garcia; John J Park; Pauline K Park; Rachael L Parke; Jane C Parker; Sam Parnia; Jonathan D Paul; Mauricio Pompilio; John G Quigley; Robert S Rosenson; Natalia S Rost; Kathryn Rowan; Fernanda O Santos; Marlene Santos; Mayler O Santos; Lewis Satterwhite; Christina T Saunders; Jake Schreiber; Roger E G Schutgens; Christopher W Seymour; Deborah M Siegal; Delcio G Silva; Aneesh B Singhal; Arthur S Slutsky; Dayna Solvason; Simon J Stanworth; Anne M Turner; Wilma van Bentum-Puijk; Frank L van de Veerdonk; Sean van Diepen; Gloria Vazquez-Grande; Lana Wahid; Vanessa Wareham; R Jay Widmer; Jennifer G Wilson; Eugene Yuriditsky; Yongqi Zhong; Scott M Berry; Colin J McArthur; Matthew D Neal; Judith S Hochman; Steven A Webb; Ryan Zarychanski Journal: N Engl J Med Date: 2021-08-04 Impact factor: 176.079
Authors: Sam Schulman; Michelle Sholzberg; Alex C Spyropoulos; Ryan Zarychanski; Helaine E Resnick; Charlotte A Bradbury; Lisa Broxmeyer; Jean Marie Connors; Anna Falanga; Toshiaki Iba; Scott Kaatz; Jerrold H Levy; Saskia Middeldorp; Tracy Minichiello; Eduardo Ramacciotti; Charles Marc Samama; Jecko Thachil Journal: J Thromb Haemost Date: 2022-07-29 Impact factor: 16.036
Authors: Edward M Conway; Nigel Mackman; Ronald Q Warren; Alisa S Wolberg; Laurent O Mosnier; Robert A Campbell; Lisa E Gralinski; Matthew T Rondina; Frank L van de Veerdonk; Karin M Hoffmeister; John H Griffin; Diane Nugent; Kyung Moon; James H Morrissey Journal: Nat Rev Immunol Date: 2022-08-05 Impact factor: 108.555
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