Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics worldwide. In 2013, over 100 million prescriptions were written for NSAIDs in the United States,[1] and many are available over the counter.

NSAIDs exert their effect by nonselective inhibition of both cyclooxygenase (COX)-1 and COX-2 isoenzymes. COX-1 is produced constantly in the tissues, whereas COX-2 is induced mainly during inflammation. Selective COX-2 inhibitors (coxibs) were developed to reduce the gastrointestinal ulceration and bleeding related to COX-1 inhibition. COX-2 inhibitors have analgesic and anti-inflammatory efficacy similar to that of nonselective COX inhibitors.

Although aspirin has been shown to be beneficial for secondary prevention of cardiovascular events,[2] the cardiovascular safety of other NSAIDs is a concern and is the focus of the present review.

Cardiovascular Risk of Selective COX-2 Inhibitors

In the early 2000s, concerns about cardiovascular side effects from COX-2 inhibitors were noted, namely with rofecoxib and valdecoxib.[3-5] In a meta-analysis of 138 randomized trials, COX-2 inhibitors were associated with a significant increase in the risk for myocardial infarction (MI) (risk ratio [RR], 1.86; 95% confidence interval [CI], 1.33-2.59; P =.0003) and vascular events (RR, 1.42; 95% CI, 1.13-1.78; P = .003) compared with placebo.[6]

In September 2004, the manufacturer voluntarily withdrew rofecoxib from the market. In late 2004, the US Food and Drug Administration (FDA) declared a "black box" warning for valdecoxib, stating that it is contraindicated in patients undergoing coronary artery bypass surgery. At the same time, the FDA also issued a public health advisory regarding the use of COX-2 inhibitors that advised physicians to weigh the benefits vs risks of using valdecoxib and celecoxib. This statement considered patients who are at high risk for gastrointestinal bleeding, are intolerant of nonselective NSAIDs, or are not doing well on nonselective NSAIDs to be appropriate candidates for COX-2 inhibitors.[7]

Animal studies suggest that the adverse cardiovascular effects observed with COX-2 inhibitors are due to enhanced endothelial thrombosis (as a result of reduction in prostacyclin synthesis), sodium and water retention, and loss of the protective effects of COX-2 upregulation in the setting of MI, resulting in larger infarction size and thinning of the left ventricular wall in the infarct zone.[8]

Cardiovascular Risk of Nonselective NSAIDs

Concerns about the cardiovascular side effects with COX-2 inhibitors has led to an increase in the use of nonselective NSAIDs during the past few years.[9] Examples of these agents include ibuprofen and naproxen.

Earlier meta-analyses of observational studies and randomized trials considered naproxen and ibuprofen as possible "safer agents."[6,10] Multiple studies had consistently shown an increased risk for cardiovascular events with diclofenac, but mixed findings for naproxen and ibuprofen.[11,12] Subsequently, data accrued linking naproxen and ibuprofen with an increased risk for cardiovascular events. In a network meta-analysis,[13] ibuprofen was associated with the highest risk for stroke among the different types of NSAIDs assessed.

The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was a randomized trial designed to evaluate the effect of naproxen vs celecoxib and vs placebo on cognitive function in elderly persons. It was prematurely terminated after the Adenoma Prevention with Celecoxib trial reported increased cardiovascular risks with celecoxib.[14] As it happened, ADAPT did not show an increased risk for cardiovascular events for celecoxib, but there was possible evidence of cardiovascular and cerebrovascular hazard with naproxen compared with placebo.[15] A 2007 American Heart Association Scientific Statement on NSAIDs noted limitations of the ADAPT study and suggested that naproxen remained the preferred choice.[16]



In patients with recent or remote history of MI, the data shows an increased risk for cardiovascular events with both COX-2 inhibitors and nonselective NSAIDs. The use of COX-2 inhibitors or nonselective NSAIDs is contraindicated in patients with acute MI. In patients with stable ischemic heart disease, caution with these agents is warranted.

The ongoing PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen Or Naproxen) trial, the first study of patients with high cardiovascular risk but without acute coronary syndrome who are receiving long-term treatment with a selective COX-2 inhibitor or traditional NSAIDs (ibuprofen or naproxen), will provide more information in the future.[28]

Meanwhile, the FDA recommendation for the lowest dosage for the shortest duration prevails. For patients with acute MI, coronary artery disease, or risk factors for cardiovascular disease, the American College of Cardiology/American Heart Association recommends a stepped approach as outlined in the Figure below, with COX-2 selective agents reserved as last-line management of intolerable pain.[29]