Cardiovascular and Thromboembolic Safety Signals Associated with Non-Steroidal Anti-Inflammatory Drugs Initiation: A Sequence Symmetry Analysis
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Background and aims
Non-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.
Methods
We 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).
Results
There 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.
Conclusions
Individual 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 Abstract
Key Question
Do individual NSAIDs show safety signals for cardiovascular or venous thromboembolic events in real-world data?
Key Finding
Initiation of several NSAIDs showed temporal safety signals for cardiovascular and venous thromboembolic events, with positive signals observed across multiple individual NSAIDs.
Take-home Message
Clinicians 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.
