Natural History of Recurrent Acute Pancreatitis: Implications for Interventional Trial Design

BACKGROUND: Patients with acute pancreatitis (AP) often experience recurrent acute pancreatitis (RAP), increasing the risk of chronic pancreatitis (CP) and long-term complications. Progression along the AP-RAP-CP spectrum has been explored in epidemiological studies, but available data provide limited insight into recurrence dynamics within RAP itself. This information is crucial for the design of studies aiming to prevent RAP recurrence and disease progression. METHODS: In this nationwide cohort study, we included 45,338 Danish adults hospitalised with an incident episode of AP between January 1, 2000, and December 31, 2022, identified through national health registries. RAP was defined as recurrent hospitalisations for AP separated by ≥ 90 days. Competing risk models with pseudo-observations estimated cumulative incidence functions for RAP recurrence stratified by the number of prior AP episodes. Inter-episode intervals were estimated using Weibull models. RESULTS: During a median follow-up of 4.5 years, 6894 patients developed RAP, corresponding to a 15.2% risk (95% confidence interval, 14.9%-15.5%). The RAP recurrence risk increased with accumulating episodes. The 12-month cumulative incidence of RAP recurrence rose from 17% after one RAP episode to 46% after five episodes. Most recurrences occurred within 12 months, and inter-episode intervals shortened with increasing episode number. Weibull models demonstrated a wear-out pattern, with shape parameters increasing progressively across successive RAP episodes, indicating accelerating recurrence risk over time. CONCLUSIONS: RAP follows an accelerating course characterised by increasing recurrence risk. Risk-enriched trial designs targeting patients with more prior episodes may improve the feasibility and statistical efficiency of future interventional studies.