You are on shift in the fast track pod of your ED when you see a 55-year-old male that comes to you with shoulder pain. He’s been helping a friend with some yardwork and admits to succumbing to weekend warrior peer pressure. OK, simple enough. But wait…he has diabetes, hypertension, and coronary artery disease with two stents placed six years ago. Are we thinking twice about that NSAID prescription? New data suggests that NSAIDs carry an increased risk of out of hospital cardiac arrest.
What medication will you give your patient?
Meanwhile, Across the Pond…
A Danish study by Sondergaard, et al. in 2017 pooled data from 28,947 patients who had suffered an out of hospital cardiac arrest (OHCA) between 2001 – 2010 - 3,376 of which had used NSAIDs 30 days before cardiac arrest. The objective of this study was to evaluate the association between NSAID use and the risk of OHCA.
This study opted for a case-time-control design, in which “each individual serves as both case and their own control in two different time-periods”. The case period (30 days before cardiac arrest) precedes the outcome, while the control period precedes the case period. Therefore, in this study, exposure to NSAIDs 30 days prior to cardiac arrest serves as the case period, while the 30-day period prior to the case period serves as the control period. Additionally, there was a 30 day “washout period” between the case and control periods to “eliminate possible carry-over effects”. 
The choices of NSAID included: diclofenac, naproxen, ibuprofen, rofecoxib, celecoxib, and “other”. Given the known cardiovascular risks of the COX-2 inhibitors* , it is important to note that a majority of the NSAIDs were ibuprofen (51%) and diclofenac (21.8%). The study found a significantly increased risk of OHCA in the use of diclofenac and ibuprofen, with an odds ratio of 1.50 [95% confidence interval (CI) 1.23–1.82] for diclofenac and 1.31 [95% CI 1.14–1.51] for ibuprofen. Naproxen, celecoxib, and rofecoxib were not associated with an increased risk of OHCA (odds ratio of 1.29 for naproxen [95% CI 0.77–2.16], 1.13 for celecoxib [95% CI 0.74–1.70], and 1.28 for rofecoxib [95% CI 0.74–1.70]). This is an interesting finding in that the risk of OHCA in non-selective NSAIDs was higher. 
As described above, the short-term use of ibuprofen was noted to have an associated increase in risk of cardiac arrest. Naproxen, however, was noted to not have a statistically significant association with cardiac arrest. Previous studies have also noted increased risk of cardiovascular events with short-term ibuprofen use, and less risk with the use of naproxen. 
These studies could be game-changers, given the increasingly comorbid patient population that we all see. That being said, the major study cited above by Sondergaard is observational in nature, and since treatment allocation is not random, no conclusions on causality can be drawn, even though there seems to be an association. It’s a slow morning, so you had time to peruse the literature. You ultimately decide to discharge your patient with a prescription for naproxen and advise him to follow-up with his primary care physician.
*COX-2 inhibitors increase the risk of thrombotic cardiovascular events by increasing thromboxane production and reducing prostacyclin formation. 
Submitted by Sonya Naganathan, MD, PGY4
Faculty reviewed by Phil Chan, MD (@PhilChanEM)
1. Kathrine B. Sondergaard, 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, Volume 3, Issue 2, 1 April 2017, Pages 100-107.
2. Bing RJ, Lomnicka M. Why do cyclo‐oxygenase‐2 inhibitors cause cardiovascular events? J Am Coll Cardiol 2002; 39: 521–2.
3. Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, et al. (2013) Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382: 769–779. 10.1016/S0140-6736(13)60900-9.