Investigating the Risk of Adverse Cardiovascular Events Associated with Concomitant Treatment of Clopidogrel and Protein Pump Inhibitors

Abstract

Proton pump inhibitors (PPIs) are commonly coadministered with clopidogrel, an antiplatelet agent, to patients with acute coronary syndrome (ACS). Mechanistic studies suggest that PPIs have the potential to competitively inhibit the bioactivation of clopidogrel and may attenuate its antiplatelet action in the body. The clinical implications of this drug-drug interaction have been extensively studied; however reported findings are inconsistent. More recently, several studies have questioned whether PPIs are associated with adverse cardiovascular events independent of clopidogrel. Given that PPIs and clopidogrel are widely used, it is critical to better understand the clinical impact of the concomitant treatment with both drugs. This thesis includes four studies that investigate the clinical effects of the drug-drug interaction between clopidogrel and PPIs. Chapter 2, a systematic review and meta-analysis, summarizes findings from 118 studies. Findings do not provide strong evidence for an association between adverse cardiovascular events and the use of PPIs when used alone, in combination with clopidogrel, or in combination with other antiplatelets. Chapters 3, 4, and 5 present analyses of real-world data comprised of electronic medical records. Results of these analyses demonstrate 1) that the concomitant use of clopidogrel and PPIs among inpatients was consistent with clinical guidelines suggested by the FDA (Chapter 3); 2) a lack of association between PPI use vs nonuse and four adverse cardiovascular outcomes among clopidogrel users (Chapter 4); and 3) a lack of association between PPI use vs nonuse and adverse cardiovascular outcomes among prasugrel users or ticagrelor users (Chapter 5). Collectively, our findings do not provide evidence of an elevated risk of adverse cardiovascular outcomes with the combined use of PPIs and clopidogrel. Although pharmacodynamic and pharmacokinetic studies have demonstrated an interaction between these two drugs, our findings support the opinion that the biological interaction does not translate into adverse clinical events among patients with acute coronary syndrome.