PPIs unlikely linked to increased stroke risk in patients taking antithrombotics

Researchers at the University of Hong Kong (HKU) have found that the risk of ischaemic stroke is not increased in patients on proton-pump inhibitor (PPI) monotherapy, but is increased in those coprescribed with antithrombotic drugs, possibly due to their underlying higher risk profiles.

The modified self-controlled case series (SCCS) study included 18,170 patients with incident ischaemic stroke from 2003 to 2014, identified from the Hospital Authority’s Clinical Data Analysis and Reporting System (CDARS) database. Of the whole study population, 8,170 patients (at cohort entry: mean age, 71.1 years; male, 52 percent) had a history of PPI exposure, while 10,000 did not. Pantoprazole and esomeprazole were the most prescribed PPIs. The median PPI prescription period was 55 days, with a fixed observation period of 12.0 years for all participants in the PPI-exposed cohort.  The exposure window was predefined as days 1–30, 31–60, 61–90, and 91 to the end of prescription, from the initiation of PPI prescription. All other periods were referent windows. [Pharmacoepidemiol Drug Saf 2025;34:e70219]

The primary analysis found no increased risk of ischaemic stroke vs the referent windows, except a marginal increase during days 61–90 (incidence rate ratio [IRR], 1.55; 95 percent confidence interval [CI], 1.00–2.42) and days 91 to end of prescription (IRR, 1.51; 95 percent CI, 1.14–2.00). In the stratified analysis, an increased risk of stroke in all risk periods vs referent windows was found in patients prescribed PPIs concurrently with antithrombotic drugs (n=5,595), but not among those on PPI monotherapy (n=2,575).

“This is the first study adopting a modified SCCS design investigating drug safety outside the context of COVID-19 vaccine research, with adequate adjustments when assumptions are violated,” wrote the authors.

“Modified SCCS should be considered when both assumptions of event-dependent exposure and event-dependent observation periods are likely to be violated,” they explained. The SCCS design sets an observation period for each participant and then compares the risk of ischaemic stroke during the predefined exposure period (periods following PPI prescription) with the referent window (all other periods except the exposure window). By using each individual as their own control, SCCS inherently controls time-invariant confounding factors such as sex and genetic factors. Unlike a standard SCCS that includes individuals with both events and exposure, the modified SCCS included those with ischaemic stroke without PPI use history during the observation period. [Stat Med 2022;41:1735-1750]

Debate around conflicting evidence of incident ischaemic stroke risk associated with PPI use provided impetus for the study. Previous studies reporting an increased risk of ischaemic stroke after PPI use may be influenced by residual confounding. [Circ Cardiovasc Qual Outcomes 2015;8:47-55; Am J Gastroenterol 2017;112:1084-1093; J Int Med 2018;283:268-281; Gastroenterology 2018;154:1290-1297.e1] In addition, PPI users could be commonly coprescribed with antithrombotic drugs for primary prevention of ischaemic stroke, and are thus at high risk of developing ischaemic stroke at baseline. The stratified modified SCCS finding of higher risk of ischaemic stroke among PPI users coprescribed with antithrombotic drugs vs those receiving PPI monotherapy affirmed this explanation. [J Am Coll Cardiol 2023;82:1538-1557; Open Heart 2015;2: e000248]

“While the current analysis focused on ischaemic stroke, future studies with a larger sample size could investigate the risk of haemorrhagic stroke associated with PPIs to further understand their potential pathways of thrombotic and bleeding risks,” noted the authors.