Use of Negative Control Outcomes to Assess Cohort Comparability Among Evolocumab Initiators: A Real-World Database Study

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Background: Real-world selection of lipid-lowering therapies (LLT) is often affected by patient prognosis, leading to residual bias in comparing treatment effects. We used negative control outcomes (NCOs) to assess the comparability in a traditional active comparator design (evolocumab vs other LLT initiators) and in a study design between patients treated and non-treated after evolocumab initiation. Methods: Using Tianjin Regional Healthcare Database, an electronic health records (EHR) database in China, we identified patients who initiated evolocumab and patients who initiated other LLT from 2018 to 2023. Within the evolocumab cohort, we further defined patients who filled the second prescription of evolocumab as "treated" and patients who did not as "non-treated" after evolocumab initiation. We evaluated residual confounding by calculating hazard ratios (HR) to compare the one-year risk of NCOs in the domains of frailty and health-seeking behavior in the two designs after applying inverse probability of treatment weighting (IPTW). Results: 14,978 evolocumab initiators (5708 patients treated and 9270 patients non-treated), and 658,255 other LLT initiators were identified. Compared to other LLT initiators, evolocumab initiators showed a lower risk of fracture in domain of frailty (HR 0.75, 95% CI 0.56-1.00), and a higher risk of visual test in domain of health-seeking behavior (HR 2.41, 95% CI 1.31-4.47). Between patients treated and non-treated after evolocumab initiation, no association was identified in domain of frailty: fracture (HR 1.02, 95% CI 0.81-1.54) and incident cancers excluding nonmelanoma skin cancers (HR 1.01, 95% CI 0.81-1.28), whereas event numbers were insufficient for evaluating NCOs in the health-seeking behavior domain. Conclusion: Comparing evolocumab to other LLTs may result in biased estimates, while the treated and non-treated evolocumab initiators are more comparable in the measured confounding and the NCO domain of frailty. This study provides important insights for consideration when designing a comparative study in China.

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