Stroke Outcomes With Proton Pump Inhibitors, Thienopyridines

Study Questions:

What is the association of concomitant use of proton pump inhibitors (PPI) and thienopyridines with adverse cerebrovascular outcomes?


The investigators conducted a systematic review and meta-analysis of randomized controlled trials and cohort studies from inception to July 2017, reporting the following outcomes among patients treated with thienopyridine and PPI versus thienopyridine alone: 1) ischemic stroke, 2) combined ischemic or hemorrhagic stroke, 3) composite outcome of stroke, myocardial infarction (MI), and cardiovascular (CV) death, 4) MI, 5) all-cause mortality, and 6) major or minor bleeding events. After the unadjusted analyses of risk ratios, they performed additional analyses of studies reporting hazard ratios adjusted for potential confounders.


The authors identified 22 studies (12 randomized controlled trials and 10 cohort studies) comprising 131,714 patients. Concomitant use of PPI with thienopyridines was associated with increased risk of ischemic stroke (risk ratio, 1.74; 95% confidence interval [CI], 1.41-2.16; p < 0.001), composite stroke/MI/CV death (risk ratio, 1.14; 95% CI, 1.01-1.29; p = 0.04), and MI (risk ratio, 1.19; 95% CI, 1.00-1.40; p = 0.05). Likewise, in adjusted analyses concomitant use of PPI with thienopyridines was again associated with an increased risk of stroke (hazard ratios adjusted, 1.30; 95% CI, 1.04-1.61; p = 0.02), composite stroke/MI/CV death (hazard ratios adjusted, 1.23; 95% CI, 1.03-1.47; p = 0.02), but not with MI (hazard ratios adjusted, 1.19; 95% CI, 0.93-1.52; p = 0.16).


The authors concluded that co-prescription of PPI and thienopyridines increases the risk of incident ischemic strokes and composite stroke/MI/CV death.


This study reports that concomitant use of PPI was associated with an increased risk of ischemic stroke, composite stroke/MI/CV death, and MI in crude analyses, which persisted for stroke and composite stroke/MI/CV death in adjusted analyses. In addition, a subgroup analysis demonstrated increased risk of both cerebrovascular and CV outcomes among patients on thienopyridines treated with PPIs. These findings support current guidelines for PPI prescription, and highlight the need for pharmacovigilance, particularly in patients treated with thienopyridines. In general, clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and gastrointestinal risks.

Clinical Topics: Prevention

Keywords: Hemorrhage, Myocardial Infarction, Myocardial Ischemia, Outcome Assessment (Health Care), Pharmacovigilance, Primary Prevention, Proton Pump Inhibitors, Pyridines, Risk Assessment, Stroke, Thienopyridines, Vascular Diseases

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