Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19
Author:
Goligher Ewan C.1234, Lawler Patrick R.12356, Jensen Thomas P.7, Talisa Victor8, Berry Lindsay R.7, Lorenzi Elizabeth7, McVerry Bryan J.910, Chang Chung-Chou Ho10, Leifer Eric11, Bradbury Charlotte12, Berger Jeffrey13, Hunt Beverly J.14, Castellucci Lana A.1516, Kornblith Lucy Z.1718, Gordon Anthony C.19, McArthur Colin202122, Webb Steven2023, Hochman Judith13, Neal Matthew D.924, Zarychanski Ryan2526, Berry Scott7, Angus Derek C.8927, Aday Aaron28, Ahuja Tania28, Al-Beidh Farah28, Angus Derek C.28, Annane Djillali28, Arabi Yaseen M.28, Aryal Diptesh28, Baumann Kreuziger Lisa28, Beane Abigail28, Berger Jeffrey S.28, Berry Scott M.28, Berry Lindsay R.28, Bhimani Zahra28, Bihari Shailesh28, Billett Henny H.28, Bond Lindsay28, Bonten Marc28, Bradbury Charlotte Ann28, Brooks Maria M.28, Brunkhorst Frank28, Buxton Meredith28, Buzgau Adrian28, Carrier Marc28, Castelucci Lana A.28, Chekuri Sweta28, Chen Jen-Ting28, Cheng Allen C.28, Chkhikvadze Tamta28, Coiffard Benjamin28, Contreras Aira28, Costantini Todd W.28, Cushman Mary28, de Brouwer Sophie28, Derde Lennie P.G.28, Detry Michelle A.28, Duggal Abhijit28, Džavík Vladimir28, Effron Mark B.28, Eng Heather F.28, Escobedo Jorge28, Estcourt Lise J.28, Everett Brendan M.28, Farkough Micheal E.28, Fergusson Dean A.28, Fitzgerald Mark28, Fowler Rob A.28, Froess Joshua D.28, Fu Zhuxuan28, Galanaud Jean-Philippe28, Galen Benjamin T.28, Gandotra Sheetal28, Girard Timothy D.28, Godoy Lucus D.28, Goligher Ewan C.28, Gong Michelle Ng28, Goodman Andrew L.28, Goossens Herman28, Gordon Anthony C.28, Green Cameron28, Greenstein Yonatan Y.28, Gross Peter L.28, Guerrero Raquel Morillo28, Hamburg Naomi28, Haniffa Rashan28, Hanna George28, Hanna Nicholas28, Hedge Sheila M.28, Hendrickson Carolyn M.28, Higgins Alisa M.28, Hindenburg Alexander A.28, Hite Robert Duncan28, Hochman Judith S.28, Hope Aluko A.28, Horowitz James M.28, Horvat Christopher M.28, Houston Brett L.28, Huang David T.28, Hudock Kristin28, Hunt Beverley J.28, Husain Mansoor28, Hyzy Robert C.28, Iyer Vivek28, Jacobson Jeff R.28, Jayakumar Devachandran28, Kahn Susan R.28, Keller Norma M.28, Khan Akram28, Kim Yuri28, Kim Keri S.28, Kindzelski Andrei28, King Andrew J.28, Kirwan Bridget-Anne28, Knudson M. Margaret28, Kornblith Lucy Z.28, Kornblith Aaron E.28, Krishnan Vidya28, Kumar Anand28, Kutcher Matthew E.28, Laffan Michael A.28, Lamontagne Francois28, Lawler Patrick R.28, Le Gal Gregoire28, Leeper Christine M.28, Leifer Eric S.28, Lewis Roger J.28, Lim George28, Lima Felipe Gallego28, Linstrum Kelsey28, Litton Edward28, Lopez-Sendon Jose28, Lopez-Sendon Moreno Jose Luis28, Lorenzi Elizabeth28, Lother Sylvain A.28, Madrona Sebastian García28, Malhotra Saurabh28, Marcos Martin Miguel28, Marshall John C.28, Marten Nicole28, Martinez Andrea Saud28, Martinez Mary28, Mateos Garcia Eduardo28, Matthay Michael A.28, Mavromichalis Stephanie28, McArthur Colin J.28, McAuley Daniel F.28, McDonald Emily G.28, McGlothlin Anna28, McGuinness Shay P.28, McQuilten Zoe K.28, McVerry Bryan J.28, Middeldorp Saskia28, Montgomery Stephanie K.28, Moore Steven C.28, Mouncey Paul R.28, Murthy Srinivas28, Nair Girish B.28, Nair Rahul28, Neal Matthew D.28, Nichol Alistair D.28, Nicolau Jose C.28, Nunez-Garcia Brenda28, Pandey Ambarish28, Park John J.28, Park Pauline K.28, Parke Rachael L.28, Parker Jane C.28, Parnia Sam28, Paul Jonathan D.28, Pompilio Mauricio28, Prekker Matt28, Quigley John G.28, Reynolds Harmony R.28, Rosenson Robert S.28, Rost Natalia S.28, Rowan Kathryn28, Santos Mayler Olombrada28, Santos Fernanda O.28, Santos Marlene28, Satterwhite Lewis28, Saunders Christina T.28, Schreiber Jake28, Schutgens Roger E.G.28, Seymour Christopher W.28, Shankar Hari Manu28, Sheehan John P.28, Siegal Deborah M.28, Silva Jr. Delcio Goncalves28, Singhal Aneesh B.28, Slutsky Arthur S.28, Solvason Dayna28, Stanworth Simon J.28, Tritschler Tobias28, Turgeon Alexis F.28, Turner Anne M.28, van Bentum-Puijk Wilma28, van de Veerdonk Frank L.28, van Diepen Sean28, Vazquez Grande Gloria28, Wahid Lana28, Wareham Vanessa28, Webb Steve A.28, Wells Bryan28, Widmer R. Jay28, Wilson Jennifer G.28, Yuriditsky Eugene28, Zampieri Fernando28, Zarychanski Ryan28, Zhong Yongqi28,
Affiliation:
1. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada 2. Department of Medicine, Division of Respirology, University Health Network, Toronto, Ontario, Canada 3. Toronto General Hospital Research Institute, Toronto, Ontario, Canada 4. Department of Physiology, University of Toronto, Toronto, Ontario, Canada 5. Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada 6. McGill University Health Centre, Montreal, Quebec, Canada 7. Berry Consultants, Austin, Texas 8. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 9. University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 10. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 11. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 12. University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England 13. NYU Grossman School of Medicine, New York, New York 14. Kings Healthcare Partners, London, England 15. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada 16. Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada 17. Zuckerberg San Francisco General Hospital, San Francisco, California 18. University of California, San Francisco 19. Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England 20. Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia 21. Auckland City Hospital, Auckland, New Zealand 22. Medical Research Institute of New Zealand, Wellington, New Zealand 23. St John of God Subiaco Hospital, Subiaco, Western Australia, Australia 24. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 25. CancerCare Manitoba, Winnipeg, Canada 26. University of Manitoba, Winnipeg, Canada 27. Senior Editor, JAMA 28. for the REMAP-CAP, ATTACC, and ACTIV-4a Investigators
Abstract
ImportanceRandomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making.ObjectiveTo evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE.Design, Setting, and ParticipantsExploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial.ExposuresParticipants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis.Main Outcomes and MeasuresOrgan support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival.ResultsBaseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline.Conclusions and RelevanceAmong patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs.Trial RegistrationClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589
Publisher
American Medical Association (AMA)
Cited by
47 articles.
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