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COX-2 selective inhibitors: Adverse cardiovascular effects

Daniel H Solomon, MD, MPH
Section Editors
Daniel E Furst, MD
Christopher P Cannon, MD
Deputy Editors
Paul L Romain, MD
Gordon M Saperia, MD, FACC


The use of all nonsteroidal antiinflammatory drugs (NSAIDs), selective and nonselective, is associated with a range of potential adverse effects, including an increased risk of adverse cardiovascular effects. The risk of different events varies depending upon the clinical context, medication, and dose. Both cyclooxygenase (COX)-2 selective NSAIDs (coxibs) and nonselective NSAIDs may increase such risk.

The cardiovascular effects of coxibs and their implications for clinical use will be reviewed here. The cardiovascular effects of nonselective NSAIDs and overviews of the adverse effects of NSAID therapy are presented separately. (See "Nonselective NSAIDs: Adverse cardiovascular effects" and "Overview of selective COX-2 inhibitors", section on 'Toxicities and possible toxicities' and "Nonselective NSAIDs: Overview of adverse effects".)


Several factors appear to be related to the cardiovascular risks associated with coxibs and nonselective nonsteroidal antiinflammatory drugs (NSAIDs), including the degree of cyclooxygenase (COX)-2 selectivity [1]. Selective COX-2 inhibition is associated with reduced prostaglandin I2 (PGI2 or prostacyclin) production by vascular endothelium with little or no inhibition of potentially prothrombotic platelet thromboxane A2 production [2]. The relatively selective reduction in prostacyclin activity could predispose to endothelial injury [3].

However, some analyses have failed to show a clear relationship of increased cardiovascular risk with COX-2 selectivity, and other factors may be important, including effects on blood pressure, renal function, endothelial cells, and nitric oxide production [4].


The use of cyclooxygenase (COX)-2 selective nonsteroidal antiinflammatory drugs (NSAIDs) (coxibs) and most nonselective NSAIDs is associated with a very small increased risk of adverse cardiovascular events [4-14]. Coxibs, like nonselective NSAIDs, should be avoided whenever possible in patients at an elevated risk of cardiovascular disease (CVD) and in patients with established CVD, based upon the evidence that these drugs increase the risk of ischemic CVD, heart failure (HF), increased blood pressure, and cardiac arrhythmia. The absolute risk of ischemic cardiovascular events, such as myocardial infarction (MI), is low, but risk increases with higher doses, frequency of use, and established CVD [4,7,11,12,15,16]. A reasonable approach would be to first try acetaminophen or another non-NSAID analgesic; if needed, naproxen with gastrointestinal protection could be used next. Beyond that, there are insufficient data to recommend one agent over another; however, they should always be used at the lowest effective dose. (See "Nonselective NSAIDs: Adverse cardiovascular effects" and 'Ischemic cardiovascular disease' below and 'Heart failure and peripheral edema' below and 'Hypertension' below and 'Cardiac arrhythmia' below.)


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Literature review current through: Sep 2016. | This topic last updated: Jul 8, 2015.
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