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

European Heart Journal – Cardiovascular Pharmacotherapy (2016) 2, 108–118 doi:10.1093/ehjcvp/pvv054 REVIEW Morten Schmidt 1*, Morten Lamberts 2, Anne-Marie Schjerning Olsen 2, Emil Fosbøll 3, Alexander Niessner 4, Juan Tamargo 5, Giuseppe Rosano 6,7, Stefan Agewall 8,9, Juan Carlos Kaski 10, Keld Kjeldsen 11,12, Basil S. Lewis 13, and Christian Torp-Pedersen 14 1 Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus 8200, Denmark; 2Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; 3Department of Cardiology, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; 4Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria; 5Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid 28040, Spain; 6 IRCCS San Raffaele Roma, Roma, Italy; 7Cardiovascular and Cell Sciences Institute, St. George’s Hospital, London, UK; 8Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway; 9Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 10Division of Cardiac and Vascular Sciences, St. George’s, University of London, London, UK; 11 Copenhagen University Hospitals (Rigshospitalet and Holbæk Hospital), Copenhagen and Holbæk, Denmark; 12The Faculty of Medicine, Aalborg University, Aalborg, Denmark; 13 Lady Davis Carmel Medical Center, Ruth and Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Tel Aviv, Israel; and 14Department of Health, Science and Technology, Aalborg University, Aalborg, Denmark Received 14 May 2015; revised 19 August 2015; accepted 7 September 2015 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,6 – 8 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 least two major isoforms of the COX enzyme—COX-1 and COX-2.12 Both isoforms catalyse the conversion of the unsaturated fatty acid arachidonic acid into prostaglandin H2,12 which is further modified by tissuespecific isomerases into bioactive lipids (prostanoids). These prostanoids, including prostaglandins I2 (prostacyclin), D2, E2, F2a, and thromboxane A2, are mediators of a variety of biological effects.13 COX-1 is expressed constitutively in most tissues, e.g. myocardium, platelets, parietal cells, and kidney cells.12 It regulates normal cellular processes such as platelet aggregation, thrombosis, gastric cytoprotection, and kidney function. 12 COX-1 is stimulated by hormones or growth factors. In contrast, COX-2, usually undetectable in most tissues, is expressed in response to induction by The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Cardiovascular Pharmacotherapy or of the European Society of Cardiology. * Corresponding author. Tel: +45 8716 8063, Fax: +45 8716 8063, Email: & 2016 European Society of Cardiology. All rights reserved. This article is being published concurrently in the European Heart Journal (DOI: 10.1093/eurheartj/ehv505) and European Heart Journal – Cardiovascular Pharmacotherapy (DOI: 10.1093/ehjcvp/pvv054). Either citation can be used when citing this article. For permissions please email: . 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 109 Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs inflammatory cytokines and mitogens, e.g. atherogenesis, rheumatoid arthritis, ischemia, and neoplasms.12 Also, COX-2 is expressed in normal endothelial cells in response to shear stress.14 Inhibition of COX-2 is associated with suppression of prostacyclin, which protects the endothelial cells during shear stress,14 produces vasodilation, inhibits smooth muscle cell proliferation, and interacts with platelets antagonizing aggregation.13 Platelets contain only COX-1, which converts arachidonic acid to thromboxane A2—a potent proaggregatory and vasoconstrictive agent.13 The inhibition of the endogenous COX-1-mediated production of prostaglandins in the gastric mucosal cells increases the risk of gastrointestinal toxicity (dyspepsia, ulcers, bleeding, and perforation) and limits chronic use of NSAIDs.5 It was therefore expected that COX-2 selective NSAIDs would possess anti-inflammatory, analgesic, and antipyretic activity, without increasing the risk of gastrointestinal complications.12 This ‘COX-2 hypothesis’ provided the rationale for the developing of coxibs, which were first introduced into clinical practice in 1998.15 Selectivity for COX-2 represents a continuum, and coxibs can therefore be ranked based on their relative COX-2 vs. COX-1 selectivity as lumiracoxib . rofecoxib . etoricoxib . valdecoxib . parecoxib . celecoxib (Figure 2).15 Among the traditional NSAIDs, some are non-selective or relatively COX-1 selective, while others also have a preference for COX-2 (older COX-2 inhibitors).11 Importantly, there is an overlap in COX-2 selectivity between the older COX-2 inhibitors and coxibs when comparing the concentration of the drugs required to inhibit COX-1 and COX-2 activity (Figure 2).11 Thus, (...truncated)