Can Predictive Modeling Inform the Selection of Time Zero for Target Trial Emulations? An Empirical Study of Atorvastatin Initiation in Medicare Beneficiaries

ABSTRACT Purpose When emulating trials of medication initiation using real-world data, there may be ambiguity regarding the most suitable time zero event for the research question of interest. The time zero event must be strongly associated with the clinical indication for treatment, confer a reasonably high probability of actual treatment initiation, and be measurable with sufficient temporal precision in the source data. When it is uncertain whether a candidate event will satisfy these three conditions simultaneously, empirical identification of predictors of medication initiation can provide valuable guidance. The objective of this study was to empirically identify predictors of incident atorvastatin initiation to inform the definition of time zero for future target trial emulations. Methods A retrospective cohort study was conducted using Medicare claims data from January 1, 2018 – December 31, 2019 (study period). The study population included beneficiaries: age ≥ 65 years with ≥ 12 months of continuous enrollment and no statin medication for ≥ 12 months as of the study period start date. The index date was the date of the first pharmacy dispensing claim for a newly initiated medication during the study period, and classified as atorvastatin or non-atorvastatin (non-atorvastatin initiators randomly sampled at 10%). Candidate predictor variables were ascertained within 6 months pre-index and included demographics, comorbidities, healthcare utilization, and pharmacotherapy. A prespecified eight-step procedure was used to identify significant, independent predictors of incident atorvastatin initiation (vs initiating a medication other than atorvastatin). Results The study cohort comprised 117,069 incident atorvastatin initiators and 393,083 non-atorvastatin initiators. The strongest predictors of atorvastatin initiation were having an inpatient admission for cerebral infarction (OR 11.29, 95% CI 10.47-12.17) and myocardial infarction (OR 6.56, 95% CI 5.92–7.27). For example, a White male with a recent hospitalization for cerebral infarction had a predicted probability of atorvastatin initiation of 69% (95% CI 68-70). Conclusion The empirically identified predictors of atorvastatin initiation among statin naïve Medicare beneficiaries align with ACC/AHA guidelines recommending prompt statin therapy for secondary prevention. These predictors satisfy the three key requirements for a valid time zero event and should mitigate channeling bias and residual confounding in future target trial emulations. KEY POINTS Findings : Acute myocardial infarction and cerebral infarction recorded during an inpatient admission were the strongest predictors of incident atorvastatin initiation among statin-naïve Medicare beneficiaries age 65 years and older. Clinical Context: These findings align with current American College of Cardiology/American Heart Association guidelines that recommend prompt statin therapy for secondary prevention after these acute cardiovascular events. Implications for Future Research: Anchoring the time zero event to an inpatient admission for myocardial/cerebral infarction satisfies the three key requirements for a valid time zero event when studying medication initiation: it is strongly associated with the clinical indication for treatment, carries a high probability of actual statin initiation, and can be identified with sufficient temporal precision in administrative data. This approach should reduce channeling bias, selection bias (e.g., immortal time bias) and residual confounding in future target trial emulations. Broader Significance: The study provides an empirically derived, high-probability time zero event that can strengthen future target trial emulations using real-world data to assess the safety of commonly used medicines in older adults, a population often underrepresented in randomized trials to obtain regulatory approval. PLAIN LANGUAGE SUMMARY This study aimed to identify a clear starting point for future research on the safety of atorvastatin in older adults. Using Medicare claims data from 2018–2019, researchers examined more than 1.3 million beneficiaries age 65 and older who had not previously taken statins in the last year. They developed a predictive model to determine which patient characteristics were most strongly linked to starting atorvastatin. The strongest predictors were a recent hospital admission for heart attack (myocardial infarction) or stroke (cerebral infarction). These events were associated with a much higher chance of promptly receiving atorvastatin, which aligns with American College of Cardiology and American Heart Association guidelines recommending statin therapy soon after such events for secondary prevention. By using hospital discharge after these acute events as the starting point for future studies, researchers can create comparisons that reduce bias and allow more reliable estimates of atorvastatin’s effects on potential harms in this vulnerable elderly population.