Non-Steroidal Anti-Inflammatory Drugs May Increase Risk of Cardiac Arrest

Written by Angeline A. De Leon, Staff Writer. A case-time-control study of 28,947 patients with out of hospital cardiac arrest demonstrated an association between short-term treatment with non-selective NSAIDs and an increased early risk of cardiac arrest.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) refer to a class of drugs which aim to reduce pain and fever and help with inflammation. Readily available over the counter, common brands include Advil, Motrin, and Aleve and are widely used to treat various chronic health conditions such as arthritis. Over the years, research studies have reported a potential link between increased cardiovascular risk and the use of NSAIDs, particularly a newer class of NSAIDs called cyclooxygenase-2 (selective COX-2) inhibitors which are designed to avoid upset stomach ^1,2. Both randomized trials and observational studies have shown evidence associating COX-2 inhibitors with adverse cardiovascular events such as myocardial infarction, stroke, and heart failure ^3,4, and meta-analyses report similar findings regarding the use of ibuprofen, citing more than a 30% increased risk of an adverse coronary event with the use of ibuprofen vs. placebo ⁵. Currently, little is known regarding the potential pro-arrhythmic effects (induction of abnormal heartbeat) of NSAIDs, but some findings indicate that NSAIDs can result in cardiac death related to myocardial infarction ⁶. In a 2017 study ⁷ published in the European Heart Journal, researchers in Copenhagen investigated whether the use of NSAIDs may be associated with out-of-hospital cardiac arrest (OHCA).

In a nationwide case-time-control study, 28,947 patients with OHCA during 2001-10 (aged 10 years and older) were identified from the national Danish Cardiac Arrest Registry. NSAIDs prescriptions were categorized as non-selective NSAIDS (diclofenac, naproxen, ibuprofen), COX-2 selective inhibitors (rofecoxib, celecoxib), or other. Exposure to NSAIDs 30 days prior to cardiac arrest (case period) was assessed and compared with exposure to NSAIDs in a preceding 30-day period where the patient did not experience an event (control period), and case and control periods were separated by a 30-day washout period. Risk of OHCA associated with NSAIDs use was computed by matching each individual case to four controls based on age and sex (to account for variation in drug utilization over time).

Analyses revealed that of 28,947 OHCA patients, 3,376 were treated with an NSAID up to 30 days prior to OHCA. Mostly commonly used NSAIDs were found to be ibuprofen and diclofenac (accounting for 51% and 21.8% of total NSAID use, respectively). Use of any NSAID was associated with a significantly increased risk of cardiac arrest (Odds Ratio = 1.31, 95% Confidence Interval: 1.17-1.46). Increased risk for OHCA was also associated with non-selective NSAIDs (OR = 1.32, 95% CI: 1.18-1.48), but not COX-2 selective inhibitors. Use of diclofenac (OR = 1.50, 95% CI: 1.23-1.82) and ibuprofen (OR = 1.31, 95% CI: 1.14-1.51) was independently associated with increased risk of OHCA as well.

Based on findings in a nationwide cohort of OHCA patients, researchers conclude that short-term treatment with non-selective NSAIDs is directly linked to higher early risk of cardiac arrest. In particular, results appear to be driven by prescription use of ibuprofen and diclofenac. Evidence of the potentially devastating effects associated with NSAIDs prompts consideration of the cost vs. benefits of implementing NSAIDs in standard treatments.

This study is observational with no randomized treatment allocation and reports only associations; it does not prove causation.

Source: Sondergaard KB, Weeke P, Wissenberg M, et al. Non-steroidal non-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. European Heart Journal-Cardiovascular Pharmacotherapy. 2017; 3: 100-107. DOI: 10.1093/ehjvcp/pvw041.

Copyright © 2018 European Society of Cardiology

Posted March 16, 2018.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity.

References:

1. Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. The Lancet. 2008;372(9651):1756-1764.
2. Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Elsevier; 2013.
3. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. The Lancet. 2005;365(9458):475-481.
4. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. New England Journal of Medicine. 2005;352(11):1071-1080.
5. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. Bmj. 2011;342:c7086.
6. Molony DA. Rofecoxib increases renal events and arrhythmia, but a COX-2-inhibitor class effect does not exist. ACP journal club. 2007;146(1):25-25.
7. Sondergaard KB, Weeke P, Wissenberg M, et al. Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: a nationwide case–time–control study. European Heart Journal–Cardiovascular Pharmacotherapy. 2016;3(2):100-107.