Optimizing Clinical Trial Protocols Using EHR-Derived Heterogeneous Treatment Effects

• URL: http://arxiv.org/abs/2607.16934v1
• Date: Sat, 18 Jul 2026 19:06:47 GMT
• Title: Optimizing Clinical Trial Protocols Using EHR-Derived Heterogeneous Treatment Effects
• Abstract summary: We emulate the DAPA-HF trial using electronic health records from the Mayo Clinic Cloud.<n>In this study, we investigate whether HTE-guided stratification can identify patient subgroups with distinct treatment responses to dapagliflozin.
• Score: 6.268930167932179
• License: http://arxiv.org/licenses/nonexclusive-distrib/1.0/
• Abstract: Traditional randomized trials often obscure clinically meaningful heterogeneity in treatment response by focusing on average effects. Leveraging real-world data to emulate clinical trials and estimate heterogeneous treatment effects (HTEs) offers a promising path toward more precise and efficient trial design. In this study, we emulate the DAPA-HF trial using electronic health records from the Mayo Clinic Cloud (MCC) to investigate whether HTE-guided stratification can identify patient subgroups with distinct treatment responses to dapagliflozin versus placebo in patients with heart failure with reduced ejection fraction. All-cause mortality was evaluated using Cox proportional hazards models, with HTEs estimated using a Meta-S learner and subgroups defined using a decision tree-based thresholding approach. In the overall cohort of the emulation, no significant treatment difference was observed (HR, 1.681; 95% CI, 0.828-3.413; p = 0.1507). However, compared with the overall emulated cohort, in which dapagliflozin showed no statistically significant survival benefit, HTE-driven stratification identified subgroups with significant and directionally distinct treatment effects. The beneficial (low-HTE) subgroup showed a significant survival benefit from dapagliflozin (HR = 0.203, 95% CI, 0.087-0.476, p = 0.0002), whereas the harmful (high-HTE) subgroup showed a significant harmful association with markedly increased mortality risk (HR = 6.680, 95% CI, 2.759-16.171, p < 0.0001). These findings indicate that HTE-guided stratification can uncover clinically meaningful beneficial and harmful treatment-effect patterns that are masked in the full-cohort emulation.

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