The Long-term Risk for Myocardial Infarction or Stroke After Proton Pump Inhibitor Therapy (2008–2018)

Michael Nolde; Nayeon Ahn; Tobias Dreischulte; Ina-Maria Rückert-Eheberg; Florian Güntner; Alexander Günter; Roman Gerlach; Martin Tauscher; Ute Amann; Jakob Linseisen; Christa Meisinger; Sebastian-Edgar Baumeister


Aliment Pharmacol Ther. 2021;54(8):1033-1040. 

In This Article

Abstract and Introduction


Background: Proton pump inhibitors (PPIs) are well tolerated in the short term but have recently been associated with increased long-term cardiovascular risk in observational studies.

Aims: To evaluate long-term risks of myocardial infarction (MI) and ischaemic stroke (IS) associated with PPI vs H2-receptor antagonist (H2RA) therapy in adults without pre-existing cardiovascular or cerebrovascular disease

Methods: Using administrative claims data (2008–2018), we emulated a target trial comparing MI and IS risks in new users of PPIs vs H2RAs. Treatment was identified using dispensed prescriptions. MI and IS were defined using hospital discharge codes. Inverse probability weighting was used to adjust for confounding, and Cox models to estimate hazard ratios (HRs). Survival curves were estimated using weighted Kaplan-Meier estimators.

Results: We identified 1 143 948 new users of PPIs and 36 229 new users of H2RAs who were free of prevalent cardiovascular or cerebrovascular disease. The mean follow-up time was 6.2 years for PPI initiators and 5.3 years for H2RA initiators. After 10 years, the HRs for MI and IS were 0.96 (95% confidence interval (CI): 0.80–1.16) and 0.98 (95% CI: 0.89–1.08), respectively.

Conclusions: This analysis of claims data of a large German health insurer did not provide evidence that PPI therapy increased the risk of MI or IS in the first decade after treatment initiation.


Proton pump inhibitors (PPIs) are widely used to treat disorders characterized by excessive gastric acid production.[1] For more than a decade, PPIs have also been sold over-the-counter and are often consumed without medical supervision. The long-term risk of PPI intake has received considerable attention in recent years, with large and well-controlled cohort studies linking PPI use to an increased risk of myocardial infarction (MI), ischaemic stroke (IS)[2–6] and cardiovascular death.[7] The elevated risk was associated with PPI use but not with the use of H2-receptor antagonists (H2RAs), the most commonly used alternative class of medications to treat acid-related gastrointestinal conditions.[8] A potential mechanism to explain an increased long-term cardiovascular risk is that intake of PPIs inhibits the enzyme dimethylarginine dimethylaminohydrolase and might thereby impair endothelial nitric oxide production and vascular endothelial function. This pathway has been established ex vivo, in mice[9] and was recently observed in humans.[10]

In contrast, a large randomized controlled trial with 3 years of follow-up found no increased risk for MI or IS in patients with stable cardiovascular disease and peripheral artery disease.[11] Similarly, a large analysis of administrative claims data found no increased risk for a first MI during PPI intake of up to 3 years,[12] and an analysis of 68 514 women enrolled in the Nurses' Health Study found no increased risk for primary IS in prevalent users of PPIs.[13]

However, if PPI intake was to cause vascular damage and therefore increase the risk for cardiovascular disease, an observational window of more than 3 years might be necessary, especially for patients without pre-existing cardiovascular conditions. We conceptualized an emulation of a target trial[14] to examine the long-term effect of PPI vs H2RA therapy on the risk of MI and IS in a general population without prior cardiovascular events.