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. 2015 Jun 10;10(6):e0124653.
doi: 10.1371/journal.pone.0124653. eCollection 2015.

Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population

Free PMC article

Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population

Nigam H Shah et al. PLoS One. .
Free PMC article


Background and aims: Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.

Methods: Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.

Results: In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.

Conclusions: Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.

Conflict of interest statement

Competing Interests: PL, ABM, SVI, and NHS are inventors on technology disclosures and/or patents, name: Methods for Ontology based Analytics and numbers: US13/273,038, US13/420,402, US13/424,375, and US13/424,376, owned by Stanford University, that enable the use of clinical text for data-mining. JPC and YTG are inventors on patents titled: Dimethylarginine Dimethylaminohydrolase Inhibitors and Methods of Use Thereof and number: US13/766,336, owned by Stanford University, that protect the use of agents that therapeutically modulate the DDAH/NOS pathway. YTG and JPC are also founders of Altitude Pharma, Inc., a biotechnology Company that is developing PPI-based products for airway diseases. Apixio, Inc. partly funded this study. JM is an employee of Practice Fusion, Inc., which owns inventions by JM. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.


Fig 1
Fig 1. PPI use is associated with an increased risk for MI, regardless of age or clopidogrel use.
No association is identified for H2 Blocker use: In the fig, the dotted red line represents the reference point indicating no elevated risk for myocardial infarction (MI). The odds ratio and 95% confidence interval for each exposure are indicated by a blue dot and blue line, respectively, which are also represented numerically to the right of each fig. The size of the dot is proportional to the exposure size of each group (see Table 1). Fig A, derived from STRIDE (N = 70,477), shows that PPIs have a class-level effect for MI in the general population of patients with GERD. By comparison, H2 blockers, an alternate treatment, have no association. Fig B breaks down the associations for each PPI individually. Figs C and D use stratification to show that the signals are corroborated in two independent datasets (STRIDE and Practice Fusion) and are robust in important subgroups. Fig C shows that, for the STRIDE dataset, when patients on clopidogrel are excluded, the associations are unchanged. Also, in lower-risk age groups for MI, the associations are still present. Similar trends are seen in these subgroups in the Practice Fusion (PF) dataset (N = 227,438) shown in Fig D.
Fig 2
Fig 2. Survival plot from the prospectively followed GenePAD study confirms that PPI use is associated adverse outcome.
The Kaplan–Meier curves in the fig show the survival probability from cardiovascular mortality according to PPI usage over an 8 years follow-up period in the ongoing Genetic Determinants of Peripheral Artery Disease (GenePAD) study. PPI usage is associated with a 2.22 fold (CI 1.19–4.16) increased risk of cardiovascular mortality, relative to controls in unadjusted Cox proportional hazards models.
Fig 3
Fig 3. Cumulative risk and exposure plots reveal that pharmacovigilance algorithms could have flagged lansoprazole for monitoring as early as the year 2000.
The x-axis is calendar year; the y-axis on the left is the unadjusted odds ratio; the y-axis on the right is the number of patients exposed. The solid red line is the point estimate of the odds ratio. The dotted red lines are the confidence intervals. The blue line is the number of patients exposed. Vertical lines mark the earliest detected signal—the year when the lower bound on the 95% confidence interval rises above 1.0. Signal detection algorithms on clinical notes would have flagged lansoprazole for monitoring as early as the year 2000.

Comment in

  • Proton Pump Inhibitors and Myocardial Infarction.
    Freedberg DE, Yang YX, Abrams JA. Freedberg DE, et al. Gastroenterology. 2015 Oct;149(4):830-3. doi: 10.1053/j.gastro.2015.08.002. Epub 2015 Aug 12. Gastroenterology. 2015. PMID: 26277262 No abstract available.
  • Is Proton Pump Inhibitor Use Associated With Risk of Myocardial Infarction?
    Chan JL, El-Serag HB. Chan JL, et al. Gastroenterology. 2016 Feb;150(2):526-7. doi: 10.1053/j.gastro.2015.12.016. Epub 2015 Dec 21. Gastroenterology. 2016. PMID: 26718176 No abstract available.
  • Reply.
    Shah NH, Cooke JP, Leeper NJ. Shah NH, et al. Gastroenterology. 2016 Feb;150(2):528. doi: 10.1053/j.gastro.2015.12.017. Epub 2015 Dec 22. Gastroenterology. 2016. PMID: 26721609 No abstract available.

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