Comparative Effectiveness And Safety Of P2Y12 Inhibitors In The Secondary Prophylaxis Of Acute Coronary Syndrome

Abstract

One of the major problems among patients suffering from coronary heart disease especially acute coronary syndrome (ACS) is recurrent cardiovascular events following revascularization. Therefore, treatment with P2Y12 receptor antagonists and aspirin, widely known as dual antiplatelet therapy (DAPT), is strongly recommended as secondary prophylaxis following revascularization. DAPT has been shown to be effective at reducing recurrent events and rehospitalization. However, it has also been shown to increase the risk of major bleeding events. Clopidogrel, a P2Y12 inhibitor, has been utilized for ACS management since its approval in 1997 with two additional P2Y12 agents approved by the US Food and Drug Administration in 2009 (prasugrel) and 2011 (ticagrelor). Compared with clopidogrel these newer agents have more potent and predictable antiplatelet aggregation profiles, attributed to consistent pharmacokinetics and dynamics. However, the evidence related to their safety and efficacy/effectiveness is inconsistent. Moreover, the evidence from the studies conducted in the US comes from electronic health records that may not be generalizable to a broader US population. In this dissertation, we sought to assess the comparative effectiveness and safety of different P2Y12 inhibitors in patients with ACS following revascularization with percutaneous coronary intervention (PCI) using commercial claims and encounters (CCAE) and Medicare Supplement (MDCR) data samples of the MarketScan database that may represent a broader US population In the first aim of this dissertation, we looked at the treatment patterns of different P2Y12 inhibitors among patients with coronary heart disease. Recommendations for antiplatelet treatment with P2Y12 agents after revascularization vary across types of revascularization i.e., fibrinolysis, PCI, or coronary artery bypass grafting, and across different clinical characteristics. Aim 1 examined patterns of P2Y12 inhibitor utilization across a number of important characteristics including high bleeding risk, history of stroke/trans-ischemic attack, and associated comorbidities. Our results show that in the year 2018, ticagrelor became the most prescribed drug among patients below age 65 years compared to clopidogrel and prasugrel. We also observed an increased utilization of ticagrelor among patients managed with PCI. However, regardless of age, clopidogrel was the most commonly used drug in patients revascularized using coronary artery bypass graft. Clopidogrel use was more common than other P2Y12 inhibitors in patients with higher comorbid indices, a history of stroke/trans ischemic attacks, and in patients with a high risk of bleeding. In the second and third aims, we assessed the effectiveness and safety of different P2Y12 inhibitors among ACS patients undergoing PCI respectively. Our results showed no difference in the primary effectiveness outcome, defined as any cardiovascular event at 30 days and 180 days observation between propensity score (PS) matched treatment cohorts in our combined CCAE and MDCR population. However, in the MDCR sample, we saw an 84% higher risk of hospitalization due to composite cardiovascular outcome in the female population associated with prasugrel compared to ticagrelor in 180 days outcome using a time to event analysis with Cox-regression hazard models. Additionally, in the CCAE sample, those who were managed with bare-metal stents (BMS) stent had a 43% lower risk of hospitalization due to composite cardiovascular outcome when prescribed prasugrel compared to ticagrelor at 180 days. We did not find any difference in hospitalizations due to composite major bleeding identified using the Cunningham algorithm in all of the PS matched comparisons across all the groups. However, we found a significant 44% increased risk of hospitalization because of major bleeding with prasugrel compared to ticagrelor at 180 days. This study provides useful information related to coronary heart disease management and insight into how newer agents are being utilized in a real-world US population. We show a significant increase in the use of ticagrelor in younger populations undergoing a PCI. Multiple predictors of P2Y12 inhibitor use were studied. Although antiplatelet prescription guidelines were generally followed, the use of prasugrel among patients with a history of stroke or transient ischemic attack was also observed which is contraindicated and may be worth additional investigation. Differences in the use of P2Y12 inhibitors across different patient clinical characteristics may have important policy implications and help to guide appropriate prescribing. Additionally, we observed that the female population benefited more from newer P2Y12 use in our study. Given the differential mechanism of sex on ACS prognosis, future studies are warranted to confirm this finding.