From the AGA Journals

VIDEO: No short-term link found between PPIs, myocardial infarction


Key clinical point: Starting a PPI did not appear to increase the short-term risk of MI.

Major finding: Over a median follow-up time of 2-3 months, the estimated risk of first-ever MI did not statistically differ between initiators of PPIs and initiators of histamine2-receptor antagonists.

Data source: Analyses of commercial and Medicare Supplemental Insurance claims for more than 5 million patients from 2001-2014.

Disclosures: The researchers received no grant support for this study. Ms. Landi disclosed a student fellowship from UCB Biosciences.

Source: Landi SN et al. Gastroenterology. 2017 Nov 6. doi: 10.1053/j.gastro.2017.10.042.

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Results reassuring

In the late 2000s, several large epidemiologic studies suggested that proton pump inhibitors (PPIs) increase the risk for MI in users of clopidogrel. There was a proposed mechanism: PPIs competitively inhibit cytochrome P450 isoenzymes, which blocked clopidogrel activation and, ex vivo, increased platelet aggregation. It sounded scary – but fortunately, some reassuring data quickly emerged. In 2007, the COGENT trial randomized patients with cardiovascular disease to a PPI/clopidogrel versus a placebo/clopidogrel combination pill. After 3 years of follow-up, there was no difference in rates of death or cardiovascular events. In the glaring light of this randomized controlled trial data, earlier studies didn’t look so convincing.

So why won’t the PPI/MI issue die? In part because COGENT was a relatively small study. It included 3,761 patients, but the main result depended on 109 cardiovascular events. Naysayers have argued that perhaps if COGENT had been a bigger study, the result would have been different.

Dr. Daniel E. Freedberg

In this context, the epidemiologic study by Suzanne Landi and her associates provides further reassurance that PPIs do not cause MI. Two insurance cohorts comprising over 5 million patients were used to compare PPI users with histamine2-receptor antagonist users after adjusting for baseline differences between the two groups. The large size of the dataset allowed the authors to make precise estimates; we can say with confidence that there was no clinically relevant PPI/MI risk in these data.

Can we forget about PPIs and MI? These days, my patients worry more about dementia or chronic kidney disease. But the PPI/MI story is worth remembering. Large epidemiologic studies are sometimes contradicted by subsequent studies and need to be evaluated in context.

Daniel E. Freedberg, MD, MS, is an assistant professor of medicine at the Columbia University Medical Center, New York. He has consulted for Pfizer.



Starting a prescription proton pump inhibitor (PPI) conferred no short-term increase in risk for myocardial infarction in a large retrospective insurance claims study.


Over a median follow-up of 2-3 months, estimated weighted risks of first-ever MI were low and similar regardless of whether patients started PPIs or histamine2 receptor antagonists (H2RAs), reported Suzanne N. Landi of the University of North Carolina at Chapel Hill, and her associates. “Contrary to prior literature, our analyses do not indicate increased risk of MI in PPI initiators compared to histamine2-receptor antagonist initiators,” they wrote in the March issue of Gastroenterology.

Epidemiologic studies have produced mixed findings on PPI use and MI risk. Animal models and ex vivo studies of human tissue indicate that PPIs might harm coronary vessels by increasing plasma levels of asymmetrical dimethylarginine, which counteracts the vasoprotective activity of endothelial nitrous oxide synthase, the investigators noted. To further assess PPIs and risk of MI while minimizing potential confounding, they studied new users of either prescription PPIs or an active comparator, prescription H2RAs. The dataset included administrative claims for more than 5 million patients with no MI history who were enrolled in commercial insurance plans or Medicare Supplemental Insurance plans. The study data spanned from 2001 to 2014, and patients were followed from their initial antacid prescription until they either developed a first-ever MI, stopped their medication, or left their insurance plan. Median follow-up times were 60 days in patients with commercial insurance and 96 days in patients with Medicare Supplemental Insurance, which employers provide for individuals who are at least 65 years old.

After controlling for numerous measurable clinical and demographic confounders, the estimated 12-month risk of MI was about 2 cases per 1,000 commercially insured patients and about 8 cases per 1,000 Medicare Supplemental Insurance enrollees. The estimated 12-month risk of MI did not significantly differ between users of PPIs and H2RAs, regardless of whether they were enrolled in commercial insurance plans (weighted risk difference per 1,000 users, –0.08; 95% confidence interval, –0.51 to 0.36) or Medicare Supplemental Insurance (weighted risk difference per 1,000 users, –0.45; 95% CI, –1.53 to 0.58) plans.

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