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Abstract
Background: The risk of secondary cardiovascular events associated with proton pump inhibitor (PPI) use and their interaction with thienopyridine antiplatelets such as clopidogrel is well established. Recent evidence from in-vitro and animal studies suggests PPIs may impact cardiovascular disease (CVD) irrespective of antiplatelet use. However, whether PPI use is associated with primary cardiovascular events in humans remains uncertain. Methods: Systematic searches were conducted in the MEDLINE and EMBASE databases from their inception to September 2022. Inclusion criteria included studies that examined participants free from cardiovascular disease at baseline who were followed over time to assess any of the following outcomes according to PPI use: incident myocardial infarction (MI), incident ischemic stroke (IS), or CVD mortality. Hazard ratios (HR) and their 95% confidence intervals (CI) were abstracted, combined estimates and heterogeneity (I 2 ) were calculated using the random-effects model in RevMan 5.4 software. Results: A total of 15 observational studies met the inclusion criteria, 2,272,479 participants were studied for MI, 2,689,943 for IS, and 1,591,428 for CVD mortality. The mean age of participants ranged from 49.3 to 82.2 years. Compared to non-use, PPI use was associated with 30% higher risk of incident MI (HR: 1.30, 95%CI: 1.10-1.53, I 2 =91%) and 15% higher risk of CVD mortality (HR: 1.15, 95%CI: 1.05-1.26, I 2 =56%). However, there was no statistically significant association with incident IS (HR: 1.05, 95%CI: 0.91-1.22, I 2 =96%). Conclusion: The meta-analysis results from published studies suggests PPI use is associated with higher risk of incident MI and CVD mortality. However, these findings should be interpreted with caution given the considerable heterogeneity among published studies and the possibility of residual confounding. More studies are needed to address these limitations and determine the validity of these associations.
Published Version
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