Vascular and Upper Gastrointestinal Effects of Non-Steroidal Anti-Inflammatory Drugs: Meta-Analyses of Individual Participant Data From Randomised Trials

Study Questions:

Do nonsteroidal anti-inflammatory drugs (NSAIDS) including COX-2 inhibitors increase the risk for cardiovascular outcomes among patients at increased risk of vascular disease?


This meta-analysis included trials identified through Medline and EMBASE searches up to January 2009. Additional trials were identified through clinical trial registers, and inquiry among collaborators and pharmaceutical companies. For the present analyses, trials with results available prior to January 2011, were eligible if they were properly randomized, of at least 4 weeks’ duration, and involved a comparison of an NSAID versus placebo (or open control) or one NSAID regimen versus another NSAID regimen, and no other systematic differences in drug treatment between treatment arms were planned. The main outcomes were major vascular events (nonfatal myocardial infarction, nonfatal stroke, or vascular death); major coronary events (nonfatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed).


A total of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years) were included in this meta-analysis. In trials providing individual participant data, the mean age at randomization was 61 years, about two-thirds were female, and 79% were white. Few patients had a history of atherosclerosis (9%), of diabetes (9%), or of upper gastrointestinal peptic ulcer (7%). Major vascular events were increased by approximately one third by COX-2 inhibitors (rate ratio [RR], 1.37; 95% confidence interval [CI], 1.14-1.66; p = 0.0009) or diclofenac (RR, 1.41; 1.12-1.78; p = 0.0036), chiefly due to an increase in major coronary events (COX-2 inhibitors: RR, 1.76; 1.31-2.37; p = 0.0001; diclofenac: RR, 1.70; 1.19-2.41; p = 0.0032). Ibuprofen also significantly increased major coronary events (RR, 2.22; 1.10-4.48; p = 0.0253), but not major vascular events (RR, 1.44; 0.89-2.33). Compared with placebo, of 1,000 patients allocated to COX-2 inhibitors or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (RR, 0.93; 95% CI, 0.69-1.27). Vascular death was increased significantly by COX-2 inhibitors (RR, 1.58; 1.00-2.49; p = 0.0103) and diclofenac (RR, 1.65; 0.95-2.85; p = 0.0187), nonsignificantly by ibuprofen (RR, 1.90; 0.56-6.41; p = 0.17), but not by naproxen (RR, 1.08; 0.48-2.47; p = 0.80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (COX-2 inhibitors: RR, 1.81; 1.17-2.81; p = 0.0070; diclofenac: RR, 1.89; 95% CI, 1.16-3.09; p = 0.0106; ibuprofen: RR, 3.97; 2.22-7.10; p < 0.0001; and naproxen: RR, 4.22; 2.71-6.56; p < 0.0001).


The investigators concluded that the vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to COX-2 inhibitors, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted.


This meta-analysis provides detailed information regarding the use of anti-inflammatory drugs and risk for vascular events. Many patients at risk for vascular events have concomitant conditions such as arthritis; hence, the frequent use of anti-inflammatory agents. Clinicians can provide information based on this meta-analysis regarding the risks and benefits of anti-inflammatory agents to their patients.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Stroke, Diclofenac, Myocardial Infarction, Atherosclerosis, Cyclooxygenase 2 Inhibitors, Ibuprofen, Naproxen, Heart Failure, Cardiovascular Diseases, Peptic Ulcer, Risk Assessment, Diabetes Mellitus

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