Cardiovascular and Thromboembolic Safety Signals Associated with Non-Steroidal Anti-Inflammatory Drugs Initiation: A Sequence Symmetry Analysis

Background and aimsNon-steroidal anti-inflammatory drugs (NSAIDs) are widely used, yet real-world evidence on cardiovascular (CV) and venous thromboembolic (VTE) risks for individual agents is limited. We aimed to identify CV and VTE safety signals associated with NSAID initiation. MethodsWe conducted a sequence symmetry analysis including patients aged 18+ with one year of prior observation initiating NSAIDs between 2013 to 2023 using CPRD GOLD. Patients had a CV [myocardial infarction (MI), arrythmia, heart failure, haemorrhagic/ischemic stroke] or VTE [deep vein thrombosis (DVT), pulmonary embolism (PE)] within {+/-}180 days of NSAID initiation. Adjusted sequence ratios (ASR) with 95% confidence intervals were calculated. Analyses were stratified by sex, age (18-65 and 65+), proton pump inhibitor use and different initiation windows (90 and 365 days). ResultsThere were 19,383 patients with an NSAID prescription and CV or VTE event (median age 66 [IQR 54 - 76] years, 54% male). Naproxen showed positive signals across all CV/VTE events, with highest ASR shown for PE (ASR 3.03 [95% CI 2.63-3.51]). Ibuprofen showed signals across six events, with PE the highest (ASR 2.2 [1.88-2.59]). Diclofenac and etoricoxib showed positive signals for five events with MI (ASR 3.30 [2.42-4.57]) and stroke (3.68 [2.14-6.62]) being the highest. Celecoxib and meloxicam showed positive signals across four events, with heart failure (2.15 [1.17-4.11]) and PE (2.66 [1.30-5.82]) the highest. Stratification analysis mostly aligned with the main analysis. ConclusionsIndividual NSAIDs showed variable CV and VTE signals, likely reflecting prescribing patterns and use. These findings suggest class-wide CV/VTE risks underscoring careful individual assessment when initiating therapy. Structured Graphical AbstractO_ST_ABSKey QuestionC_ST_ABSDo individual NSAIDs show safety signals for cardiovascular or venous thromboembolic events in real-world data? Key FindingInitiation of several NSAIDs showed temporal safety signals for cardiovascular and venous thromboembolic events, with positive signals observed across multiple individual NSAIDs. Take-home MessageClinicians should balance the risks and benefits of individual NSAIDs, supporting a more personalised approach to prescribing and highlighting the need for further evaluation of identified safety signals.