Sehested TS, Fosbøl EL, Hansen PW, Charlot MG, Torp-Pedersen C, Gislason GH
Circulation. 2016; 134:A18462.


Use of proton pump inhibitors has been linked with endothelial dysfunction and increased risk of myocardial infarction.


We hypothesize that use of proton pump inhibitors (PPIs) increases the risk of ischemic stroke.


Using nationwide Danish registries, we performed a retrospective cohort study. We identified all individuals above 30 years, who had an elective gastroscopy between 1997 and 2012. Patients were excluded due to prior cardiovascular disease at baseline. Association between PPI exposure and risk of first-time ischemic stroke was analyzed in a time-dependent multivariable-adjusted Poisson regression model.


A total of 244,679 individuals were included in the study (mean age was 57.0 years). Approximately 44% filed a prescription for a PPI. In comparison with nonusers, PPI users were older and had more comorbidities, including atrial fibrillation at baseline (3.4 vs. 3.8%). During follow-up, there were 9,489 (3.9%) events of first-time stroke. Time-dependent PPI exposure was associated with stroke with an incidence rate ratio (IRR) of 1.21 (95% CI 1.16-1.27; P-value <0.0001) adjusted for age, sex, atrial fibrillation, hypertension, diabetes, heart failure, peptic ulcer, cancer, chronic kidney disease and NSAID use. Histamine H2 receptor antagonists demonstrated no association with stroke risk with an IRR of 0.99 (95% CI 0.83-1.21; P-value 0.99). We observed a dose-response relationship between PPI use and associated increased risk of ischemic stroke (Figure).


In this nationwide cohort of patients undergoing gastroscopy, we found an association between use of PPIs and increased risk of first-time ischemic stroke and a positive dose-response relationship between PPI dose and stroke risk. Considering the wide use of proton pump inhibitors worldwide, our study further questions the cardiovascular safety of these drugs and further studies are warranted.

Link to open access article: Sehested TS, et al; Circulation. 2016; 134:A18462.

PPI risks, Sehested