Longitudinal trajectories unravel the complex interplay of medication, cardiovascular events, chronic kidney disease, and mortality.

Proton pump inhibitors (PPIs) are widely used to treat acid-related disorders, yet concerns persist regarding their association with adverse cardiovascular (CVAE), renal outcomes, and all-cause mortality. We leveraged real-world longitudinal data from the Stockholm CREAtinine Measurements (SCREAM) project to investigate trajectories linking PPI use with chronic kidney disease (CKD), CVAE, and all-cause mortality using a process mining approach. We identified 294,734 new users of PPIs or H2 blockers (H2Bs) with a baseline eGFR ≥ 60 mL/min/1.73 m² and followed them for up to 15 years using a process-mining approach to discover disease trajectories. The association of PPI and CVAE is not significant after accounting for death as a competing event. However, PPI use is significantly associated with a higher subdistribution hazard of CKD and all-cause mortality compared to H2B. Our findings indicate that CKD may act as a mediator in the trajectory PPI→CKD→CVAE, underscore the importance of monitoring renal function in long-term PPI users, and emphasise the need for future prospective trials to clarify cardiovascular risks.