Original Investigation 

Caring for the Critically Ill Patient

March 21, 2023

Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19

Ewan C. Goligher, Patrick R. Lawler, Thomas P. Jensen, et al

JAMA. Published online March 21, 2023. doi:10.1001/jama.2023.3651

Key Points

Question  What patient characteristics are associated with benefit or harm of therapeutic-dose heparin in patients hospitalized for moderate or severe COVID-19, and how do methods to analyze heterogeneity of treatment effect (HTE) in clinical trial populations compare?

Findings  In an exploratory analysis of a multiplatform randomized trial of therapeutic-dose heparin for early-pandemic patients with moderate or severe COVID-19, 3 approaches for testing HTE—conventional subgroup analysis, risk-based analysis, and effect-based analysis—were congruent in findings that therapeutic-dose heparin was more likely to be beneficial in patients who were less severely ill at presentation or who had lower body mass index, and more likely to be harmful in sicker patients and those with higher body mass index.

Meaning  Benefits and harms of therapeutic-dose heparin varied by hospitalized COVID-19 patient characteristics, illustrating the importance of considering HTE in the design and analysis of randomized clinical trials.

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