(A-253) Determining Cardiovascular Safety Signals of Non-Steroidal Anti-Inflammatory Drugs: A Sequence Symmetry Study

Background: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are associated with many adverse drug effects, particularly cardiovascular (CVD) events such as myocardial infarction (MI) and stroke. Signal detection methods using real-world data could provide valuable insights into CVD risks for different NSAIDs.

Objectives: To detect CVD adverse event signals associated with different NSAIDs.

Methods: Sequence symmetry analysis was performed using primary care data from the United Kingdom (CPRD GOLD) between 2013 and 2023. Patients aged 18+ with at least 365 days of prior observation prescribed each NSAID and each CVD event (MI, arrhythmia, deep vein thrombosis (DVT), heart failure, pulmonary embolism (PE), ischemic and haemorrhagic stroke) were included. A 365-day washout window and 180-day exposure gap was applied. Patients prescribed NSAIDs and had a cardiovascular event on the same day were excluded. Positive (amiodarone to levothyroxine) and negative controls (amiodarone to allopurinol) were included to validate results. Adjusted sequence ratios (aSRs) with 95% CIs were calculated with aSR > 1 indicating a positive adverse event signal.

Results: The positive control showed an aSR of 4.30 (95% CI 3.52 - 5.29), and the negative control showed no signals. Naproxen showed positive signals across all CVD events, including PE (3.03 [2.63 - 3.51]) and acute MI (2.34 [2.08, 2.63]. Meloxicam, etoricoxib and celecoxib showed signals for four of seven CVD events, with MI being common for all three (1.80 [1.07-3.09], 2.27 [1.40 - 3.76] and 1.88 [1.02 - 3.55] respectively). Etoricoxib also exhibited positive signals for ischemic stroke (3.84 [2.11 - 7.43]) and PE (2.69 [1.47, 5.15]), and celecoxib showed a positive signal for DVT (1.93 [1.14 - 3.34]). Ibuprofen and diclofenac showed signals across multiple CVD events, including DVT (1.47 [1.36–1.59] and 1.20 [1.06–1.37], respectively) and PE (1.43 [1.30 - 1.57] and 1.26 [1.12 - 1.44], respectively). Indomethacin signaled for ischemic stroke (1.90 [1.04–3.61]), while ketoprofen and etodolac showed signals for arrhythmia (1.28 [1.05, 1.56] and 1.74 [1.02, 3.05], respectively). Aspirin showed negative signals for all CVD events except PE (1.08 [0.96, 1.22]). Other NSAIDs (e.g. piroxicam, salicylates, mefenamate, ketorolac) had no significant signals for CVD events.

Conclusions: CVD safety signals varied among NSAIDs. Naproxen, meloxicam, COX-2 inhibitors (etoricoxib, celecoxib), ibuprofen, and diclofenac showed positive signals, while aspirin showed negative signals, reflecting its preventative use. These findings underscore the need for further research on NSAID-associated CVD risks.