Adverse effects of nonsteroidal anti-inflammatory drugs on the cardiovascular system

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very effective medications, but their use is associated with a broad spectrum of adverse reactions involving the liver, kidney, cardiovascular (CV) system, skin, and gut. As a consequence, this class of drugs represents a leading cause of drug-related morbidity, especially in the elderly and in patients with comorbidities. Most adverse effects are related to the inhibition of cyclooxygenase (COX) isoenzymes, which is systemic and neither site nor organ specific. Gastrointestinal (GI) undesirable effects are the most common, but-in the last decade-those concerning the CV system have been increasingly appreciated. Patients with cardiovascular disease (CVD) and comorbidities for which NSAIDs may provide symptomatic relief (e.g., osteoarthritis, OA, rheumatoid arthritis, RA) tend to be older, which places them at greater risk of harm. For these reasons, the use of NSAIDs in patients with CVD is a significant public health concern. An understanding of the risks associated with NSAIDs is critical for clinicians across the different practice settings. Meta-analyses of randomized clinical trials (RCTs) and observational studies have shown that COX-2 selective and nonselective NSAIDs are associated with an increased risk of atherothrombotic events (particularly acute myocardial infarction, AMI), with no significant difference in the incidence of vascular events between selective and nonselective agents (with the exception of naproxen). The risk of cardiotoxicity depends on dose, duration, and frequency of drug administration. Available data show that the risk of stroke conferred by NSAIDs is much smaller, if any, than the risk of AMI. Use of both subclasses of NSAIDs can lead to the development of congestive heart failure (CHF) in susceptible individuals and also increase the risk of dysrhythmia (atrial fibrillation, AF, and flutter), particularly in presence of CHF and chronic kidney disease. Both COX-2 selective and nonselective compounds have been associated with renal and renovascular adverse events, a finding consistent with the important role of constitutively expressed COX-2 in sustaining the physiological production of vasodilator and natriuretic prostanoids in the kidney. NSAIDs elevate blood pressure (BP) in hypertensive population and antagonize the BP lowering effect of antihypertensive medications (with exception of calcium channel blockers). In addition, fluid and electrolyte disturbances are common, especially in patients with underlying renal disease, CHF, and hepatic insufficiency. The risk of pharmacokinetic and pharmacodynamic drug interactions with NSAIDs is high. However, while nonselective compounds interfere with the anti-aggregant activity of low-dose aspirin (ASA), COX-2 selective agents do not. It should be emphasized that the intrinsic patient’s CV risk factors are of paramount importance. Indeed, the lower the risk factors, the lower the propensity for NSAIDs to cause CV adverse events. Drugs are indeed only one of the several concomitant risk factors and are not likely the most important. Anti-inflammatory therapy should therefore be tailored to the individual patient after careful evaluation of his/her risk factors and, ultimately, of the benefit-to-risk ratio.