Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Xuerong Wen

Abstract

Over 1 million individuals in the United States experienced a coronary event during 2019. Following an acute coronary syndrome, patients are initiated on dual antiplatelet therapy consisting of aspirin plus a P2Y12 agent to reduce the risk of subsequent ischemic events. In this dissertation we use the three-manuscript format to address some areas of unmet research related to this therapeutic area. Each manuscript has an abstract, introduction, methods, results, discussion, limitations, and conclusion section.

Manuscript 1: We examined the performance of several different causal modeling approaches to real-world data with the objective of addressing selection bias in the presence of differential treatment nonadherence in comparative effectiveness research. We compared the treatment effect estimates of ticagrelor versus clopidogrel following an acute coronary syndrome by applying several analytical approaches, each with different levels of adjustment for confounding and treatment nonadherence, to the previously published “PLATO” randomized control trial where there was negligible differences in protocol adherence among treatment groups. We found that applying a time-dependent exposure model adequately adjusted for the imbalance in rate of therapy switching and produced an effect estimate congruent to the PLATO trial.

Manuscript 2: Our objective was to conduct a comparative effectiveness and safety analysis of ticagrelor and prasugrel in patients who underwent percutaneous coronary intervention after being hospitalized for an acute coronary syndrome. We implemented marginal structural models and inverse probability censoring weighting to adjust for post-treatment selection bias caused by imbalance in treatment switching and insurance disenrollment between comparison groups. We found that implementing a time- dependent exposure and censor-weighted model, to adjust for the censoring imbalances observed in the real-world data cohort, derived results consistent with the recently published ISAR-REACT 5 trial. We also found that applying traditional approaches derived results that were consistent with previously published observational studies but contrary to the RCT.

Manuscript 3: Our objective was to compare the direct health system costs and healthcare resource utilization associated with escalating to either ticagrelor or prasugrel following initial clopidogrel treatment due to an acute coronary syndrome. Median per-member per-month all-cause and cardiovascular-related charges and healthcare utilization were evaluated for each patient following escalation. Propensity-score 1:1 greedy matching was used to adjust for confounders. Generalized linear models were used to derive an effect estimate of treatment escalation on outcomes. We found that patients who escalate antiplatelet therapy from clopidogrel to ticagrelor experienced lower total all-cause costs and cardiovascular-related costs when compared to those that escalated to prasugrel.

Available for download on Sunday, November 15, 2020

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