Balancing Risks and Benefits: Cardiovascular Safety of NSAIDs

Schmidt M, Lamberts M, Olsen AM, et al.
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. Eur Heart J 2016;37:1015-1023.

The following are key points from a review on the cardiovascular safety of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs):

  1. There are at least two major isoforms of the cyclooxygenase (COX) enzyme: COX-1 and COX-2. Both isoforms catalyze the conversion of the unsaturated fatty acid into prostaglandin H2, which is further modified by tissue-specific isomerases into bioactive lipids (prostanoids). COX-1 is expressed constitutively in most tissues and regulates normal cellular processes such as platelet aggregation or thrombosis. COX-2 is usually undetectable in most tissues and is expressed in response to induction by inflammatory cytokines. Platelets contain only COX-1, which converts arachidonic acid to thromboxane A2, a potent pro-aggregatory and vasoconstrictive agent.
  2. The inhibition of the endogenous COX-1-mediated production of prostaglandins in the gastric mucosal cells increases the risk of gastrointestinal toxicity. It was expected, consequently, that COX-2 selective NSAIDS would possess anti-inflammatory, analgesic, and antipyretic activity, without increasing the risk of gastrointestinal complications.
  3. Even before the approval of coxibs, it was anticipated that they could constitute a cardiovascular hazard because the selective COX-2 inhibition would shift the prothrombotic balance on the endothelial surface and favor thrombosis by inhibiting the generation of COX-2-derived vascular prostacyclin while not affecting the COX-1-mediated generation of thromboxane A2.
  4. The publication of the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial in 2004 led to withdrawal of rofecoxib from the market. This trial showed that the use of rofecoxib was associated with an increase in thrombotic events. The ACP (Adenoma Prevention with Celecoxib) study showed similarly increased vascular risks associated with Celecoxib use.
  5. A meta-analysis of 138 randomized trials comparing the effect of coxibs and traditional NSAIDs on the risk of vascular events demonstrated that coxibs (relative risk, 1.42; 95% confidence interval, 1.13-1.78), as well as high-dose diclofenac (1.63, 1.12-2.37) and ibuprofen (1.51, 0.96-2.37), were associated with a higher risk of vascular events, mainly myocardial infarction (1.86, 1.33-2.59), whereas high-dose naproxen was not (0.92, 0.67-1.26). (Reference: Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenate-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomized trials. BMJ 2006;332:1302-8.)
  6. Naproxen appears to have the least harmful cardiovascular risk profile, also in patients with myocardial infarction or heart failure. There is evidence that the vascular risks of diclofenac are comparable to those of coxibs.
  7. There may be an association between NSAID use and development of atrial fibrillation. Subgroups of patients with a particularly high risk of developing atrial fibrillation after initiating NSAID therapy are those with heart failure and chronic kidney disease.
  8. Balancing risks and benefits: Some patients may accept a minor absolute risk increase of serious cardiovascular events in order to improve their quality of life.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure

Keywords: Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Atrial Fibrillation, Cyclooxygenase 1, Cyclooxygenase 2 Inhibitors, Diclofenac, Drug Therapy, Heart Failure, Ibuprofen, Myocardial Infarction, Naproxen, Platelet Aggregation, Primary Prevention, Prostaglandin H2, Prostaglandins, Quality of Life, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Thrombosis, Thromboxane A2

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