Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19
Authors: Goligher Ewan C. , Lawler Patrick R. , Jensen Thomas P. , Talisa Victor , Berry Lindsay R. , Lorenzi Elizabeth , McVerry Bryan J. , Chang Chung-Chou Ho , Leifer Eric , Bradbury Charlotte , Berger Jeffrey , Hunt Beverly J. , Castellucci Lana A. , Kornblith Lucy Z. , Gordon Anthony C. , McArthur Colin , Webb Steven , Hochman Judith , Neal Matthew D. , Zarychanski Ryan , Berry Scott , Angus Derek C. ,   REMAP-CAP, ATTACC, and ACTIV-4a Investigators, Aday Aaron , Ahuja Tania , Al-Beidh Farah , Angus Derek C. , Annane Djillali , Arabi Yaseen M. , Aryal Diptesh , Baumann Kreuziger Lisa , Beane Abigail , Berger Jeffrey S. , Berry Scott M. , Berry Lindsay R. , Bhimani Zahra , Bihari Shailesh , Billett Henny H. , Bond Lindsay , Bonten Marc , Bradbury Charlotte Ann , Brooks Maria M. , Brunkhorst Frank , Buxton Meredith , Buzgau Adrian , Carrier Marc , Castelucci Lana A. , Chekuri Sweta , Chen Jen-Ting , Cheng Allen C. , Chkhikvadze Tamta , Coiffard Benjamin , Contreras Aira , Costantini Todd W. , Cushman Mary , de Brouwer Sophie , Derde Lennie P.G. , Detry Michelle A. , Duggal Abhijit , Džavík Vladimir , Effron Mark B. , Eng Heather F. , Escobedo Jorge , Estcourt Lise J. , Everett Brendan M. , Farkough Micheal E. , Fergusson Dean A. , Fitzgerald Mark , Fowler Rob A. , Froess Joshua D. , Fu Zhuxuan , Galanaud Jean-Philippe , Galen Benjamin T. , Gandotra Sheetal , Girard Timothy D. , Godoy Lucus D. , Goligher Ewan C. , Gong Michelle Ng , Goodman Andrew L. , Goossens Herman , Gordon Anthony C. , Green Cameron , Greenstein Yonatan Y. , Gross Peter L. , Guerrero Raquel Morillo , Hamburg Naomi , Haniffa Rashan , Hanna George , Hanna Nicholas , Hedge Sheila M. , Hendrickson Carolyn M. , Higgins Alisa M. , Hindenburg Alexander A. , Hite Robert Duncan , Hochman Judith S. , Hope Aluko A. , Horowitz James M. , Horvat Christopher M. , Houston Brett  L. , Huang David T. , Hudock Kristin , Hunt Beverley J. , Husain Mansoor , Hyzy Robert C. , Iyer Vivek , Jacobson Jeff R. , Jayakumar Devachandran , Kahn Susan R. , Keller Norma M. , Khan Akram , Kim Yuri , Kim Keri S. , Kindzelski Andrei , King Andrew J. , Kirwan Bridget-Anne , Knudson M. Margaret , Kornblith Lucy Z. , Kornblith Aaron E. , Krishnan Vidya , Kumar Anand , Kutcher Matthew E. , Laffan Michael A. , Lamontagne Francois , Lawler Patrick R. , Le Gal Gregoire , Leeper Christine M. , Leifer Eric S. , Lewis Roger J. , Lim George , Lima Felipe Gallego , Linstrum Kelsey , Litton Edward , Lopez-Sendon Jose , Lopez-Sendon Moreno Jose Luis , Lorenzi Elizabeth , Lother Sylvain A. , Madrona Sebastian García , Malhotra Saurabh , Marcos Martin Miguel , Marshall John C. , Marten Nicole , Martinez Andrea Saud , Martinez Mary , Mateos Garcia Eduardo , Matthay Michael A. , Mavromichalis Stephanie , McArthur Colin J. , McAuley Daniel F. , McDonald Emily G. , McGlothlin Anna , McGuinness Shay P. , McQuilten Zoe K. , McVerry Bryan J. , Middeldorp Saskia , Montgomery Stephanie K. , Moore Steven C. , Mouncey Paul R. , Murthy Srinivas , Nair Girish B. , Nair Rahul , Neal Matthew D. , Nichol Alistair D. , Nicolau Jose C. , Nunez-Garcia Brenda , Pandey Ambarish , Park John J. , Park Pauline K. , Parke Rachael L. , Parker Jane C. , Parnia Sam , Paul Jonathan D. , Pompilio Mauricio , Prekker Matt , Quigley John G. , Reynolds Harmony R. , Rosenson Robert S. , Rost Natalia S. , Rowan Kathryn , Santos Mayler Olombrada , Santos Fernanda O. , Santos Marlene , Satterwhite Lewis , Saunders Christina T. , Schreiber Jake , Schutgens Roger E.G. , Seymour Christopher W. , Shankar Hari Manu , Sheehan John P. , Siegal Deborah M. , Silva Jr. Delcio Goncalves , Singhal Aneesh B. , Slutsky Arthur S. , Solvason Dayna , Stanworth Simon J. , Tritschler Tobias , Turgeon Alexis F. , Turner Anne M. , van Bentum-Puijk Wilma , van de Veerdonk Frank L. , van Diepen Sean , Vazquez Grande Gloria , Wahid Lana , Wareham Vanessa , Webb Steve A. , Wells Bryan , Widmer R. Jay , Wilson Jennifer G. , Yuriditsky Eugene , Zampieri Fernando , Zarychanski Ryan , Zhong Yongqi 
Published: March 2023

Importance

Randomized 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.

Objective

To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE.

Design, Setting, and Participants

Exploratory 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.

Exposures

Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis.

Main Outcomes and Measures

Organ 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.

Results

Baseline 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 &amp;lt;30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs &amp;gt;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 &amp;gt;1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR &amp;lt;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 Relevance

Among 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 Registration

ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589