Does proton pump inhibitor (PPI) use increase the risk of cardiovascular events in persons without a prior history of cardiovascular disease? A recent study published by Shah et al in PLoS One suggests that they can.
Millions of prescriptions are written for these agents every year, primarily to treat common upper gastrointestinal ailments such as gastroesophageal reflux disease (GERD) and dyspepsia. Over-the-counter formulations also are ubiquitous and used widely without medical supervision. If, in fact, PPI therapy poses a danger to the general population, large scale public health education would be essential.
Authors of the present study, from Stanford University, performed data mining from two database sources, which included nearly 3 million patients. The baseline population was patients with GERD using acid suppressant agents who were matched with controls from the baseline population not prescribed PPI therapy. The mean follow-up time was slightly more than 2 years and the main outcome was acute myocardial infarction (AMI). The investigators also examined the association between PPI use and cardiovascular mortality, defined as death from AMI, stroke, heart failure, or aneurysm rupture.
The study revealed that patients with GERD who were receiving PPI therapy were 16% more likely to develop AMI. This association was noted regardless of type of PPI, suggesting a class effect. Interestingly, patients for whom H2-blockers were prescribed for symptoms of GERD showed no greater risk for AMI. There was also a more than 2-fold increase in cardiovascular mortality in patients taking PPIs, which persisted even after controlling for cardiovascular risk factors. The association between PPI and AMI also was consistent regardless of use of the antiplatelet agent clopidogrel. Of note, only 6% of the cohort population was taking clopidogrel.
A few years ago, several studies suggested that PPIs can adversely affect clopidogrel metabolism, therefore increasing risk of cardiovascular mortality. Many cardiologists either discontinued their patients’ PPI, switched them to an H2-blocker, or returned them to primary care providers to discuss alternative options for the treatment of reflux symptoms. Thankfully, a well-designed double-blinded randomized controlled trial comparing PPI and placebo among clopidogrel users did not find any difference in cardiovascular outcomes or death. In fact, patients on antiplatelet agents who were not taking a PPI were significantly more likely to develop an upper GI bleed from ulcers. Unfortunately, performing an RCT in this current scenario may be more of a challenge.
The current study has several notable limitations inherent in data mining studies. The study design was not intended to establish causality. As there was no control arm, there is a possibility that those who developed AMI were at higher risk for GERD (overweight, smoker, poor diet, etc). It also is possible that some may have been using a PPI to treat chest pain or angina and not heartburn specifically. We have seen other studies where an association was recognized between drug and disease, but then disproved in controlled studies, similar to the PPI-clopidogrel theory.
Even though the results are intriguing and this possible association deserves more attention with better designed studies in the future, the findings should not prompt patients to stop taking PPIs nor should providers not prescribe PPIs when indicated, ie, for treatment of reflux symptoms, dyspepsia, or for patients with a history of peptic ulcer disease. That said, it is advisable to prescribe PPIs at the lowest possible effective dose.
1. Shah NH, LePendu P, Bauer-Mehren A, et al. Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS One 2015 Jun 10;10(6).
2. Bhatt DL, Cryer BL, Contant CF et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010; 363:1909-1917.