Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19. Goligher, E. C., Lawler, P. R., Jensen, T. P., Talisa, V., Berry, L. R., Lorenzi, E., McVerry, B. J., Chang, C. H., Leifer, E., Bradbury, C., Berger, J., Hunt, B. J., Castellucci, L. A., Kornblith, L. Z., Gordon, A. C., McArthur, C., Webb, S., Hochman, J., Neal, M. D., Zarychanski, R., Berry, S., Angus, D. C., REMAP-CAP, ATTACC,, Investigators, A., Aday, A., Ahuja, T., Al-Beidh, F., Angus, D. C., Annane, D., Arabi, Y. M., Aryal, D., Baumann Kreuziger, L., Beane, A., Berger, J. S., Berry, S. M., Berry, L. R., Bhimani, Z., Bihari, S., Billett, H. H., Bond, L., Bonten, M., Bradbury, C. A., Brooks, M. M., Brunkhorst, F., Buxton, M., Buzgau, A., Carrier, M., Castelucci, L. A., Chekuri, S., Chen, J., Cheng, A. C., Chkhikvadze, T., Coiffard, B., Contreras, A., Costantini, T. W., Cushman, M., De Brouwer, S., Derde, L. P., Detry, M. A., Duggal, A., Džavík, V., Effron, M. B., Eng, H. F., Escobedo, J., Estcourt, L. J., Everett, B. M., Farkough, M. E., Fergusson, D. A., Fitzgerald, M., Fowler, R. A., Froess, J. D., Fu, Z., Galanaud, J., Galen, B. T., Gandotra, S., Girard, T. D., Godoy, L. D., Goligher, E. C., Gong, M. N., Goodman, A. L., Goossens, H., Gordon, A. C., Green, C., Greenstein, Y. Y., Gross, P. L., Guerrero, R. M., Hamburg, N., Haniffa, R., Hanna, G., Hanna, N., Hedge, S. M., Hendrickson, C. M., Higgins, A. M., Hindenburg, A. A., Hite, R. D., Hochman, J. S., Hope, A. A., Horowitz, J. M., Horvat, C. M., Houston, B. L., Huang, D. T., Hudock, K., Hunt, B. J., Husain, M., Hyzy, R. C., Iyer, V., Jacobson, J. R., Jayakumar, D., Kahn, S. R., Keller, N. M., Khan, A., Kim, Y., Kim, K. S., Kindzelski, A., King, A. J., Kirwan, B., Knudson, M. M., Kornblith, L. Z., Kornblith, A. E., Krishnan, V., Kumar, A., Kutcher, M. E., Laffan, M. A., Lamontagne, F., Lawler, P. R., Le Gal, G., Leeper, C. M., Leifer, E. S., Lewis, R. J., Lim, G., Lima, F. G., Linstrum, K., Litton, E., Lopez-Sendon, J., Lopez-Sendon Moreno, J. L., Lorenzi, E., Lother, S. A., Madrona, S. G., Malhotra, S., Marcos Martin, M., Marshall, J. C., Marten, N., Martinez, A. S., Martinez, M., Mateos Garcia, E., Matthay, M. A., Mavromichalis, S., McArthur, C. J., McAuley, D. F., McDonald, E. G., McGlothlin, A., McGuinness, S. P., McQuilten, Z. K., McVerry, B. J., Middeldorp, S., Montgomery, S. K., Moore, S. C., Mouncey, P. R., Murthy, S., Nair, G. B., Nair, R., Neal, M. D., Nichol, A. D., Nicolau, J. C., Nunez-Garcia, B., Pandey, A., Park, J. J., Park, P. K., Parke, R. L., Parker, J. C., Parnia, S., Paul, J. D., Pompilio, M., Prekker, M., Quigley, J. G., Reynolds, H. R., Rosenson, R. S., Rost, N. S., Rowan, K., Santos, M. O., Santos, F. O., Santos, M., Satterwhite, L., Saunders, C. T., Schreiber, J., Schutgens, R. E., Seymour, C. W., Shankar Hari, M., Sheehan, J. P., Siegal, D. M., Silva Jr., D. G., Singhal, A. B., Slutsky, A. S., Solvason, D., Stanworth, S. J., Tritschler, T., Turgeon, A. F., Turner, A. M., Van Bentum-Puijk, W., Van De Veerdonk, F. L., Van Diepen, S., Vazquez Grande, G., Wahid, L., Wareham, V., Webb, S. A., Wells, B., Widmer, R. J., Wilson, J. G., Yuriditsky, E., Zampieri, F., Zarychanski, R., & Zhong, Y. JAMA, 329(13):1066, April, 2023.
Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19 [link]Paper  doi  abstract   bibtex   
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 <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 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
@article{goligher_heterogeneous_2023,
	title = {Heterogeneous {Treatment} {Effects} of {Therapeutic}-{Dose} {Heparin} in {Patients} {Hospitalized} for {COVID}-19},
	volume = {329},
	issn = {0098-7484},
	url = {https://jamanetwork.com/journals/jama/fullarticle/2802856},
	doi = {10.1001/jama.2023.3651},
	abstract = {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 \<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 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},
	language = {en},
	number = {13},
	urldate = {2024-05-30},
	journal = {JAMA},
	author = {Goligher, Ewan C. and Lawler, Patrick R. and Jensen, Thomas P. and Talisa, Victor and Berry, Lindsay R. and Lorenzi, Elizabeth and McVerry, Bryan J. and Chang, Chung-Chou Ho and Leifer, Eric and Bradbury, Charlotte and Berger, Jeffrey and Hunt, Beverly J. and Castellucci, Lana A. and Kornblith, Lucy Z. and Gordon, Anthony C. and McArthur, Colin and Webb, Steven and Hochman, Judith and Neal, Matthew D. and Zarychanski, Ryan and Berry, Scott and Angus, Derek C. and {REMAP-CAP, ATTACC, and ACTIV-4a Investigators} and Aday, Aaron and Ahuja, Tania and Al-Beidh, Farah and Angus, Derek C. and Annane, Djillali and Arabi, Yaseen M. and Aryal, Diptesh and Baumann Kreuziger, Lisa and Beane, Abigail and Berger, Jeffrey S. and Berry, Scott M. and Berry, Lindsay R. and Bhimani, Zahra and Bihari, Shailesh and Billett, Henny H. and Bond, Lindsay and Bonten, Marc and Bradbury, Charlotte Ann and Brooks, Maria M. and Brunkhorst, Frank and Buxton, Meredith and Buzgau, Adrian and Carrier, Marc and Castelucci, Lana A. and Chekuri, Sweta and Chen, Jen-Ting and Cheng, Allen C. and Chkhikvadze, Tamta and Coiffard, Benjamin and Contreras, Aira and Costantini, Todd W. and Cushman, Mary and De Brouwer, Sophie and Derde, Lennie P.G. and Detry, Michelle A. and Duggal, Abhijit and Džavík, Vladimir and Effron, Mark B. and Eng, Heather F. and Escobedo, Jorge and Estcourt, Lise J. and Everett, Brendan M. and Farkough, Micheal E. and Fergusson, Dean A. and Fitzgerald, Mark and Fowler, Rob A. and Froess, Joshua D. and Fu, Zhuxuan and Galanaud, Jean-Philippe and Galen, Benjamin T. and Gandotra, Sheetal and Girard, Timothy D. and Godoy, Lucus D. and Goligher, Ewan C. and Gong, Michelle Ng and Goodman, Andrew L. and Goossens, Herman and Gordon, Anthony C. and Green, Cameron and Greenstein, Yonatan Y. and Gross, Peter L. and Guerrero, Raquel Morillo and Hamburg, Naomi and Haniffa, Rashan and Hanna, George and Hanna, Nicholas and Hedge, Sheila M. and Hendrickson, Carolyn M. and Higgins, Alisa M. and Hindenburg, Alexander A. and Hite, Robert Duncan and Hochman, Judith S. and Hope, Aluko A. and Horowitz, James M. and Horvat, Christopher M. and Houston, Brett  L. and Huang, David T. and Hudock, Kristin and Hunt, Beverley J. and Husain, Mansoor and Hyzy, Robert C. and Iyer, Vivek and Jacobson, Jeff R. and Jayakumar, Devachandran and Kahn, Susan R. and Keller, Norma M. and Khan, Akram and Kim, Yuri and Kim, Keri S. and Kindzelski, Andrei and King, Andrew J. and Kirwan, Bridget-Anne and Knudson, M. Margaret and Kornblith, Lucy Z. and Kornblith, Aaron E. and Krishnan, Vidya and Kumar, Anand and Kutcher, Matthew E. and Laffan, Michael A. and Lamontagne, Francois and Lawler, Patrick R. and Le Gal, Gregoire and Leeper, Christine M. and Leifer, Eric S. and Lewis, Roger J. and Lim, George and Lima, Felipe Gallego and Linstrum, Kelsey and Litton, Edward and Lopez-Sendon, Jose and Lopez-Sendon Moreno, Jose Luis and Lorenzi, Elizabeth and Lother, Sylvain A. and Madrona, Sebastian García and Malhotra, Saurabh and Marcos Martin, Miguel and Marshall, John C. and Marten, Nicole and Martinez, Andrea Saud and Martinez, Mary and Mateos Garcia, Eduardo and Matthay, Michael A. and Mavromichalis, Stephanie and McArthur, Colin J. and McAuley, Daniel F. and McDonald, Emily G. and McGlothlin, Anna and McGuinness, Shay P. and McQuilten, Zoe K. and McVerry, Bryan J. and Middeldorp, Saskia and Montgomery, Stephanie K. and Moore, Steven C. and Mouncey, Paul R. and Murthy, Srinivas and Nair, Girish B. and Nair, Rahul and Neal, Matthew D. and Nichol, Alistair D. and Nicolau, Jose C. and Nunez-Garcia, Brenda and Pandey, Ambarish and Park, John J. and Park, Pauline K. and Parke, Rachael L. and Parker, Jane C. and Parnia, Sam and Paul, Jonathan D. and Pompilio, Mauricio and Prekker, Matt and Quigley, John G. and Reynolds, Harmony R. and Rosenson, Robert S. and Rost, Natalia S. and Rowan, Kathryn and Santos, Mayler Olombrada and Santos, Fernanda O. and Santos, Marlene and Satterwhite, Lewis and Saunders, Christina T. and Schreiber, Jake and Schutgens, Roger E.G. and Seymour, Christopher W. and Shankar Hari, Manu and Sheehan, John P. and Siegal, Deborah M. and Silva Jr., Delcio Goncalves and Singhal, Aneesh B. and Slutsky, Arthur S. and Solvason, Dayna and Stanworth, Simon J. and Tritschler, Tobias and Turgeon, Alexis F. and Turner, Anne M. and Van Bentum-Puijk, Wilma and Van De Veerdonk, Frank L. and Van Diepen, Sean and Vazquez Grande, Gloria and Wahid, Lana and Wareham, Vanessa and Webb, Steve A. and Wells, Bryan and Widmer, R. Jay and Wilson, Jennifer G. and Yuriditsky, Eugene and Zampieri, Fernando and Zarychanski, Ryan and Zhong, Yongqi},
	month = apr,
	year = {2023},
	pages = {1066},
}
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