Proton pump inhibitors (PPIs) are used to suppress gastric acid secretion [1] and are widely prescribed for gastroesophageal reflux disease (GERD) and peptic ulcer disease [1]. PPIs are generally considered a well-tolerated and safe class of drugs, but as the use of PPIs continues to increase, and even overuse of PPIs, many concerns about the appropriateness of their use have arisen. Several studies have linked PPIs use to higher risks of adverse health outcomes [[2], [3], [4]], including diabetes [5], chronic kidney disease [6], dementia [7], pneumonia [8], and gastric cancer [9].

Initial concerns regarding PPI-related increased risks of cardiovascular disease (CVD) in patients with prior CVD events focused on interactions with the antiplatelet agent clopidogrel [4,10,11]. Several studies have indicated the independent association of PPIs use with higher CVD risks in participants with prevalent CVD [[12], [13], [14], [15]]. Nevertheless, a few studies have explored the associations of PPIs use with CVD outcomes in general populations [[16], [17], [18], [19]], and the findings have been inconsistent. For example, two population-based studies reported that PPIs use could increase the risk of incident stroke [16,18]. In contrast, the results from a prospective cohort suggested a null association between PPIs use and the risk of stroke after adjusting for indications for PPIs use among women [17]. However, a recent randomized controlled trial reported that PPIs were associated with a modest but nonsignificant higher risks of CVD outcomes (HR 1.04; 95% CI 0.93 to 1.15) [20]. Although randomized controlled trials generate the best evidence for the effects of interventions, this trial was limited by a relatively short follow-up time (median of 3.01 years) [21,22]. In addition, the performance of PPIs in randomized controlled trials is assessed under ideal and controlled circumstances, and their findings are difficult to generalize to larger, more inclusive populations because of their well-known limitations. Therefore, the association between PPIs use and the risk of CVD outcomes needs to be evaluated in real-life settings of large-scale cohort studies. Furthermore, a detailed quantitative analysis of the specific incident CVD events, such as heart failure, atrial fibrillation, and venous thromboembolism, potentially attributable to PPIs use, is not available. There is only limited evidence [16] examining how potential modifiable factors (e.g., obesity, smoking, and alcohol use) affect the association of PPIs use with CVD outcomes.

Given the major public health implications of widespread PPIs use, a better understanding of the potential CVD risks associated with PPIs use is needed [1,2]. Therefore, we sought to examine the associations of regular PPIs use with the risks of CVD outcomes (incidence of CVD, coronary heart disease [CHD], stroke, heart failure, atrial fibrillation, and venous thromboembolism) in a prospective cohort study of nearly half a million UK adults. Furthermore, we explored the potential effect modification by several risk factors for CVD outcomes.