BackgroundSevere acute exacerbations of chronic obstructive pulmonary disease are key events that drive healthcare resource utilization (HCRU) and negatively impact patients’ quality of life. Research QuestionWhat is the real-world burden of COPD relative to patients’ medication history, specifically, exposure to short-acting beta agonists (SABA), antibiotics, and oral corticosteroids (OCS)? Study Design and MethodsA population-based retrospective cohort study was conducted of patients in Alberta, Canada identified as having COPD based on administrative healthcare data (April 1, 2011 to March 31, 2019). The risk of severe AECOPD over 90 days (COPD events resulting in hospitalization or emergency department [ED] visits) and COPD-specific HCRU were studied relative to prior-year SABA, antibiotic, and OCS history. ResultsThere were 188,969 patients identified with COPD (mean [SD] age: 68.8 [13.0] years). After controlling for age, sex, calendar year at index, comorbidities at index, and prior severe AECOPD, patients with frequent SABA, antibiotic, or OCS exposure in a given year had significantly higher 90-day risks of severe AECOPD in a positively associated relationship. Patients with the highest SABA exposure (6+ canisters in a given year) had twice the rate of severe AECOPD as patients with 1 SABA canister (incidence rate ratio [IRR]: 2.06, 95% CI: 2.01-2.11). The 90-day rates of severe AECOPD were 51% higher for patients with 6+ vs 1-2 antibiotic dispenses (IRR: 1.51, 95% CI: 1.48-1.55) and 3% higher for patients with 6+ vs 1-5 OCS burst-days (IRR: 1.03, 95% CI: 1.00–1.06). Mean annualized rates of hospitalization and ED visits were highest for patients dispensed 6+ (versus fewer) SABA canisters or antibiotics and patients with any OCS burst-days in a given year. InterpretationHistories of frequent or prolonged exposure to SABA, antibiotics, or OCS were associated with higher rates of severe AECOPD and HCRU.