Which Non-Steroidal Anti-Inflammatory Drug (NSAID) is the Safest?

One of the most commonly used category of medications worldwide is NSAIDs, but their long-term use is limited by serious gastrointestinal side effects. NSAIDs inhibit cyclo-oxygenase (COX). Analgesic/anti-inflammatory effects result from inhibition of COX-2 while gastrointestinal side effects arise from the inhibition of COX-1.


Medical Exam Review - Safest NSAIDs - COX-1, COX-2


There have been many studies looking at NSAIDs and their vascular events, coronary events, stroke, heart failure, and upper gastrointestinal complications; this post will review the largest meta-analysis to date reviewing the different types of NSAIDs and their above effects.


What they did:

• Meta-analysis 280 Trials comparing NSAIDs versus Placebo (124,513 Participants)

• Meta-analysis 474 Trials comparing one NSAID versus another NSAID (229,296 Participants)


Primary Outcomes:

• Major Vascular Events (Non-fatal myocardial infarction, non-fatal stroke, or vascular death)

• Major Coronary Events (Non-fatal myocardial infarction or coronary death)

• Stroke

• Mortality

• Heart Failure

• Upper Gastrointestinal complications (Perforation, obstruction, or bleed)


Results: Review of Safest NSAIDs



• Cannot definitively conclude if NSAID use immediately increases vascular risk

• Most studies in the analysis are less than 1 year, and not followed out past that time

• Low dose (220mg) naproxen was not reviewed or studied in this meta-analysis



• The vascular risks of high-dose diclofenac and high dose ibuprofen are similar to coxibs


In my opinion, how this affects your practice:

• All NSAIDS almost double the risk of Heart Failure

• All NSAIDs increase the risk of upper gastrointestinal bleeding

• High dose naproxen is associated with less vascular and coronary events compared to other NSAIDs



1. Coxib and Traditional NSAID Trialists’ (CNT) Collaboration. Vascular and Upper Gastrointestinal Effects of Non-Steroidal Anti-Inflammatory Drugs: Meta-Analyses of Individual Participant Data from Randomized Trials. Lancet 2013 May; EPub: 1 -11. PMID: 2372639



Dr. Salim R. Rezaie is a physician at the University of Texas Health Science Center at San Antonio. He is double board-certified in Emergency Medicine and Internal Medicine.

About Salim Rezaie

Dr. Rezaie completed his medical school training at Texas A&M Health Science Center, and followed that up with a combined Emergency Medicine/Internal Medicine residency at East Carolina University in Greenville, NC. Currently, he is an attending on the faculty of UTHSCSA in San Antonio, TX, where he focuses on medical education, social media as a tool for education (FOAMed), and building the bridges between internal medicine, critical care, and emergency medicine. Feel free to contact him on Twitter (@srrezaie) (@UTHSCSAPearls) about anything EM/IM! Salim Rezaie

Got something to add?

Please log In or register for a free account to write a comment.