Early Identification of Cardiovascular Adverse Events Associated With Rofecoxib Using Real‐World Data From the UK : A Nested Case–Control and Case‐Crossover Study

BACKGROUND: Traditional pharmacovigilance systems have limitations in detecting common adverse drug reactions. We investigated whether real-world data (RWD) could have detected rofecoxib's cardiovascular adverse effects earlier using nested case-control (NCC) and case-crossover (CCO) designs. METHODS: We included adult rofecoxib users from the UK CPRD GOLD (1999-2004). In NCC design, cases of a first major adverse cardiovascular event (MACE) were matched with four controls on age, sex, practice and calendar time. Rofecoxib exposure was categorised as current (≤ 3 months), recent (3-6), or past use (> 6) in NCC, and assessed at the start of each 3-month interval in CCO design. Exposure odds in CCO were compared between a 3-month risk with four reference windows. Conditional logistic regression models estimated adjusted intensity ratio (aIR). To identify the shortest time necessary to detect the association, analyses were conducted in 1-, 2-, 3-, 4- and 5-years after the drug's market uptake. RESULTS: Three thousand two hundred and eighteen cases were matched to 10 745 controls (mean age 73.8 years, 66% female). In NCC, current rofecoxib use (42% of cases) was associated with an 18% higher risk of MACE (aIR 1.18, 95% CI 1.08-1.29) versus past use. The CCO (3210 risk and 12 737 reference windows) showed an 83% increased risk of MACE (aIR 1.83, 95% CI 1.53-2.18). First signal emerged after 2 years with CCO (aIR 3.94, 95% CI 1.88-8.25), and after 3 years with NCC design (aIR 1.46, 95% CI 1.18-1.81). CONCLUSION: Using RWD, cardiovascular adverse effects of rofecoxib could have been detected within 2 years of the market entry in the UK, well before traditional pharmacovigilance methods. This supports incorporating RWD analysis into routine drug safety monitoring.