Introduction: Proton pump inhibitors (PPIs) have been associated with an increased risk of cerebrovascular events, cognitive decline, and dementia in observational studies. These associations may be due to residual confounding. We conducted an MRI and cognitive sub-study a large randomized controlled trial to examine the potential link between PPI and cognitive or functional decline as well as covert vascular lesions detected by MRI imaging.
Methods: Centers in the Cardiovascular Outcomes for People Using Anticoagulant Strategies (COMPASS) trial consented participants without contraindications to MRI to brain imaging at baseline and study end. We obtained T1-weighted, T2-weighted, fluid-attenuated inversion recovery, and T2*-weighted images in all patients with parameters consistent with consensus guidelines for imaging manifestations of small vessel disease. Participants also completed Standard Assessment of Global- Activities in the Elderly [SAGE], the Digit Symbol Substitution [DSS] test, and a Montreal Cognitive Assessment [MoCA] at baseline and study end. Participants not taking PPI at baseline were randomized to pantoprazole 40mg or identical placebo. Images were read by trained readers blinded to treatment assignment. Imaging endpoints were new covert infarcts or cerebral microbleeds determined by comparing baseline and end study MRI images. We compared the mean end study MoCA, SAGE and DSS scores between the groups as well as the proportion with a 1.5 standard deviation (SD) decline in cognitive score at two years compared to group baseline. All primary analyses were intention to treat with a per protocol (participants that complied with PPI or placebo) conducted as secondary analyses. As multiple outcomes were being assessed a p value of <0.01 was taken to be statistically significant.
Results: Baseline characteristics were similar between the two groups (Table 1). Participants were followed up for a mean of 2 years (0.7 standard deviation). 509 PPI and 501 placebo participants had a readable MRI at baseline and study end. There was no difference in the proportion of participants with incident covert infarcts (PPI 3%, placebo 3.6%) or cerebral microbleeds (PPI 6.8%, placebo 6.5%) between the groups (Table 2). There was also no difference in mean end-study MoCA, SAGE or DSS scores and proportion declining > 1.5 SD between the two groups (Table 2). Per protocol analyses gave similar results for all outcomes (data not shown).
Conclusions: Pantoprazole was not associated with an increase in covert vascular lesions or worsened cognitive or functional decline in a population with stable atherosclerotic disease.

Table 1. Baseline characteristics

Table 2. Outcomes of the PPI component of the COMPASS MIND sub-study

John Eikelboom

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