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Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology

Morten Schmidt, Morten Lamberts, Anne-Marie Schjerning Olsen, Emil Fosbøll, Alexander Niessner, Juan Tamargo, Giuseppe Rosano, Stefan Agewall, Juan Carlos Kaski, Keld Kjeldsen, Basil S. Lewis, Christian Torp-Pedersen
DOI: http://dx.doi.org/10.1093/eurheartj/ehv505 ehv505 First published online: 16 March 2016

Introduction

Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have been used in clinical practice for more than a century and are among the most widely used drugs worldwide for the treatment of pain, fever, and inflammation.1,2 For decades, it has been known that many of these drugs can cause fluid retention and elevate blood pressure,3 thus increasing cardiovascular risk particularly in heart failure patients.4 However, the main worry in relation to the use of these agents has been gastrointestinal bleeding.5

Newer selective COX-2 inhibitors (coxibs) were developed as NSAIDs with reduced gastrointestinal toxicity, but retained analgesic and anti-inflammatory properties. Coxibs were tested in accordance to modern drug development regulations with large numbers of patients included in clinical trials. These trials demonstrated that rofecoxib,68 celecoxib,9 valdecoxib,10 and parecoxib10 increased the risk of cardiovascular complications. As a result, coxibs currently have very limited indications for use. Paradoxically, an older and relatively selective COX-2 inhibitor, diclofenac,11 continues to be one of the most widely used drugs worldwide and is in most countries sold over the counter.1 Mixed COX-1/COX-2 inhibitors such as ibuprofen and naproxen are also used widely and, without solid evidence, assumed to be safe. Given the current uncertainty regarding the safety of this class of agents and the rapidly accumulating data on their cardiovascular risks, this review summarizes the current evidence from randomized and observational studies on the cardiovascular safety of non-aspirin NSAIDs and presents a position for their use.

Mechanisms

Non-steroidal anti-inflammatory drugs exhibit their anti-inflammatory effect by inhibiting COX, which is the rate-limiting enzyme in prostaglandin synthesis (Figure 1).12 There are at …

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