Spotlight on gastric acid suppressants

Two recent studies focused on the potential risks of gastric acid suppression with proton-pump inhibitors (PPIs) and histamine H2-receptor antagonists. Use of these medications may be associated with an increased risk of recurrent Clostridium difficile infection and of first-time ischemic stroke, the studies found.

To determine the association between the medications and recurrent C. difficile infection, researchers conducted a systematic review and meta-analysis of 16 studies. From 1991 to 2013, the studies (15 observational studies, one post hoc analysis) evaluated the occurrence of recurrent C. difficile infection in a total of 7,703 infected patients in both inpatient and outpatient settings.

Results were published online on March 27 by JAMA Internal Medicine.

About 52% (4,038 patients) were using gastric acid suppressants (PPIs and/or H2 blockers). Nearly 20% of the total study population (1,525 patients) developed recurrent C. difficile infection, defined in the studies as recurrent infection within 30, 56, 60, or 90 days after symptom resolution.

Among patients using gastric acid suppressants, the rate of recurrent infection was 22.1%, compared with 17.3% among those who did not use the medications, an odds ratio (OR) for recurrent C. difficile infection of 1.52 (95% CI, 1.20 to 1.94; P<0.001). This remained significant after adjustment for potential confounders, such as age and comorbidities (OR, 1.38; 95% CI, 1.08 to 1.76; P=0.02).

The researchers found significant differences when they compared studies of PPIs only and those of PPIs and/or H2 blockers reported together. C. difficile recurrence risk was significantly increased in studies of PPIs only (OR, 1.66; 95% CI, 1.18 to 2.34; P=0.004) but not in those of both PPIs and/or H2 blockers (OR, 1.37; 95% CI, 0.95 to 1.99; P=0.09).

The authors noted limitations of the analysis, such as substantial heterogeneity across studies and how most of the studies did not mention the dosage and duration of gastric acid suppression therapy. An accompanying editor's note stated that randomized clinical trials are needed to produce an unbiased assessment without the risk of unmeasured confounding. “In the meantime, these findings support a strategy of withholding gastric acid suppression therapy in the setting of active or recent C difficile infection,” the editorialists wrote.

Another study, published on April 11 by the American Journal of Gastroenterology, found that PPI use is associated with an increased risk of first-time ischemic stroke in the general population.

Using data from Taiwanese patients who were or were not prescribed PPIs between 2002 and 2012, researchers matched 198,148 PPI use periods to 198,148 nonuse control periods. The primary outcome was hospitalization for a primary diagnosis of ischemic stroke during the follow-up period (120 days after PPI prescription initiation).

There were 292 events (0.147%) during PPI use periods, compared to 217 (0.109%) during nonuse control periods. Compared to nonusers, PPI users had a hazard ratio of 1.36 for ischemic stroke (95% CI, 1.14 to 1.62, P=0.001). In subgroup analyses, this risk was more prominent in those younger than 60 years old (P=0.043 for interaction), but several other variables (i.e., gender, history of myocardial infarction, diabetes mellitus, hypertension, use of antiplatelet agents or NSAIDs, or type of PPIs) did not significantly influence risk.

The authors noted limitations of the study, such as its retrospective observational design, the potential for unmeasured confounders and coding inaccuracies, and the possibility that patients obtained nonprescription PPIs. “Rather than providing practical implications, the findings should better be viewed as providing some clues for hypothesis generation, and further studies are needed to verify our findings,” they wrote, adding that the associated stroke risk is modest compared to the benefits of PPIs in acid-related gastrointestinal disorders.