Prof Juan Carlos Kaski, St George's University, London, UK

The debate continues as to the potential for proton pump inhibitor (PPI) drugs to impair cardiovascular outcomes. While some studies have suggested that PPI agents can harm patients with coronary artery disease (CAD) [1-4], particularly those receiving treatment with the antiplatelet drug clopidogrel [5], other prospective studies have not shown PPIs to be associated with an increased risk of cardiovascular death, MI, or stroke [6, 7]. The FDA has contributed to the debate by issuing a warning –in 2009- regarding the possible pharmacological interaction between clopidogrel and PPI drugs [8]. In a very recent study [9] on ‘Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population’, Nigam H. Shah and colleagues from Stanford University, explored the potential risk posed by the administration of PPIs in the general population using a novel pharmacovigilance derived methodology i.e. the “data-mining” approach.

Their conclusions, based on the analysis of more than “16 million clinical documents on 2.9 million individuals” have re-ignited the debate, as they have identified a small albeit significant increased risk of cardiovascular events in subjects receiving treatment with PPIs. Indeed, the authors report that “gastroesophageal reflux disease patients exposed to PPIs have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction. 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”. Of interest, the reported increase in cardiovascular risk was not linked to the use of clopidogrel and it was also found that H2 blockers, an alternative treatment for gastroesophageal reflux, “were not associated with increased cardiovascular risk”.  The authors’ conclusions regarding an association between PPI exposure and risk for acute myocardial infarction in the general population are discussed herewith by cardiovascular experts Prof AH and Prof J H.


  1. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA: the journal of the American Medical Association, 2009. 301(9): p. 937–44. doi: 10.1001/jama.2009.261. pmid:19258584
  2. Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH Sørensen R Abildstrøm SZ, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Annals of internal medicine, 2010. 153(6): p. 378–86. doi: 10.7326/0003-4819-153-6-201009210-00005. pmid:20855802
  3. Charlot M, Grove EL, Hansen PR, Olesen JB, Ahlehoff O, Selmer C, et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study. BMJ, 2011. 342: p. d2690. doi: 10.1136/bmj.d2690. pmid:21562004
  4. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. Journal of the American College of Cardiology, 2008. 51(3): p. 256–60. doi: 10.1016/j.jacc.2007.06.064. pmid:18206732
  5. Dunn SP, Steinhub, SR, Bauer D, Charnigo RJ, Berger PB, Topol EJ. Impact of proton pump inhibitor therapy on the efficacy of clopidogrel in the CAPRIE and CREDO trials. J Am Heart Assoc, 2013. 2(1): p. e004564. doi: 10.1161/JAHA.112.004564. pmid:23525436
Cardio Debate Expert Comments

If drugs, like Proton Pump Inhibitors (PPIs), are widely used, rare but potentially serious adverse effects become highly relevant, when considering the tens of millions of patients who take PPIs worldwide. Recognizing some of these harms, the US Food and Drug Administration (FDA) and Health Canada have issued safety advisories regarding the use of PPIs related to Clostridium difficile, fracture risk and profound hypomagenesemia. The research article of Nigam H. Shah it’s an uptodate review that goes well beyond the old debate on PPI and Clopidogrel, and sheds a new light on what is becoming a bedside clinical experience also for the cardiologist. I would like to stress the increased risk of severe hypomagnesemia (OR 3.79, 95% CI 2.99–4.82; NNH = 73), particularly in patients who have taken PPIs for more than five years[1], for the well known serious adverse events, including arrhythmias.

The FDA has recommended that at­risk cardiac patients requiring ongoing PPI use have their magnesium level verified periodically[2]. The key messages are: prolonged and profound inhibition of gastric acidity is not without consequences especially for the majority of our patients: those with chronic comorbidities, and that no drug is harmless.


  1. M. W. Hess;J. G. J. Hoenderop;R. J. M. Bindels; J. P. H. Drenth. Systematic Review: Hypomagnesaemia Induced by Proton Pump Inhibition Aliment Pharmacol Ther. 2012;36(5):405­413.
  2. FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs) Available at: