Abstract
BackgroundAlthough randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. We evaluated the association between regular use of PPIs and incident stroke and identified population groups at high net risk.MethodsThis is a prospective analysis of 492,479 participants free of stroke from the UK biobank. Incident stroke was identified through linkage to hospital admission and death registries using the International Classification of Diseases (ICD)-10 codes (I60, I61, I63, and I64). We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, prevalent comorbidities, concomitant use of medications, and indications of PPIs. We assessed the risk differences (RDs) according to the baseline Framingham Stroke Risk Score. In the meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (from 1988 to 1 June 2020) for randomized trials comparing PPIs with other interventions, placebo, or no treatment on stroke risk. Results were combined using a fix-effect meta-analysis (Mantel-Haenszel method).ResultsWe documented 5182 incident strokes over 3,935,030 person-years of follow-up. Regular PPI users had a 16% higher risk of stroke than non-users (HR 1.16, 95% CI 1.06 to 1.27). The estimated effect was similar to our meta-analysis of nine RCTs (case/participants 371/26,642; RR 1.22, 95% CI 1.00 to 1.50; quality of evidence: moderate). The absolute effect of PPI use on stroke increased with the baseline Framingham Stroke Risk Score, with an RD of 1.34‰, 3.32‰, 4.83‰, and 6.28‰ over 5 years for the lowest, quartile 2, quartile 3, and the highest quartile, respectively.ConclusionsRegular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk. Physicians should therefore exercise caution when prescribing PPIs. An assessment of the underlying stoke risk is recommended for individualized use of PPIs.
Highlights
Randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed
The estimated effect was similar to our meta-analysis of nine RCTs
Regular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk
Summary
Randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. A number of studies have investigated PPI use and risk of stroke [9,10,11,12,13,14], the relationship remained unclear. The existing evidence showing an association between PPIs and stroke were observational studies. Randomized controlled trials (RCTs) may provide the highest level of evidence; current RCTs were underpowered to detect the effect of PPIs on stroke, many trials have demonstrated an association towards increased risk [17,18,19]. There have been no secondary studies conducted to combine these RCTs. Lastly, the investigation of subgroups at the high absolute risk of stroke among PPI users is still lacking. It has been shown that the absolute effects (often presented with risk difference [RD]) of interventions tended to increase with the baseline risk [20]
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