Cardiovascular Safety Of Non-steroidal Anti-inflammatory Drugs Research Articles

Cardiovascular effects and safety of (non-aspirin) NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective, widely used analgesics. For the past 2 decades, considerable attention has been focused on their cardiovascular safety. After early studies indicating an association between NSAID use and increased risks of heart failure and elevated blood pressure, subsequent studies found a link between NSAID use and an increased risk of thrombotic events. Selective cyclooxygenase 2 (COX2) inhibitors (also known as coxibs) have been associated with the greatest risk of adverse vascular effects but concern also relates to non-selective NSAIDs, especially those with strong COX2 inhibition such as diclofenac. Although NSAID use is discouraged in patients with cardiovascular disease, pain-relief medication is often required and, in the absence of analgesics that are at least as effective but safer, NSAIDs are frequently prescribed. Furthermore, non-prescription use of NSAIDs, even among people with underlying cardiovascular risks, is largely unsupervised and varies widely between countries. As concern mounts about the disadvantages of alternatives to NSAIDs (such as opioids) for pain management, the use of NSAIDs is likely to rise. Given that the pharmaceutical development pipeline lacks new analgesics, health-care professionals, patients and medicine regulatory authorities are focused on optimizing the safe use of NSAIDs. In this Review, we summarize the current evidence on the cardiovascular safety of NSAIDs and present an approach for their use in the context of holistic pain management.

Cardiovascular safety of non-steroidal anti-inflammatory drugs in chronic inflammatory rheumatic diseases.

Rheumatic diseases (RD), such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, vasculitis, gout are associated with increase in cardiovascular morbidity and mortality. The main causes of increased cardiovascular risk are inflammatory heart and vascular lesions, accelerated progression of atherosclerosis and side effects of drug therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in clinical practice and are on the list of the most prescribed medications. It is known that NSAIDs have a negative effect on the cardiovascular system (CVS). However NSAIDs may decrease the intensity of inflammation, which is an independent risk risk factor for CVS pathology. Therefore in patients with RD it is theoretically possible to reduce the severity of cardiovascular side effects when using NSAIDs. The article discusses the issues of NSAID's cardiovascular safety, the molecular mechanisms underlying the negative effect of them on CVS, critically evaluated the results of main studies concerning the cardiovascular safety of NSAIDs in chronic inflammatory diseases.

Coxibs Refocus Attention on the Cardiovascular Risks of Non-Aspirin NSAIDs.

Non-steroidal anti-inflammatory drugs (NSAIDs) were differentiated from steroidal anti-inflammatory medicines to help clinicians who needed to use anti-inflammatory agents that were safer than steroids. With market entry of rofecoxib in 1999, NSAIDs were then further classified into traditional NSAIDs and cyclooxygenase (COX)-2 inhibitors (coxibs), the latter posing potentially fewer gastrointestinal risks. In 2005, rofecoxib was withdrawn from the market because of concerns about the risk of heart attack and stroke with long-term use, and clinical practice began focusing more on the cardiovascular versus gastrointestinal safety of coxibs. Since then, many coxibs have remained unapproved by the US FDA or have been removed from the market. This article explains how coxibs refocused attention on the cardiovascular safety of NSAIDs and the general implications of that. COX-2 activity/specificity is one factor associated with increased cardiovascular risks; however, these risks cannot be attributed to coxibs alone. The traditional NSAIDs (i.e., meloxicam, etodolac, and nabumetone) have significant COX-2 specificity, but naproxen and ibuprofen have less specificity. All NSAIDs, whether traditional or a coxib, pose some cardiovascular risks. It is possible that clinicians continue to focus more on decreasing the immediate gastric risks than preventing the later cardiovascular risks. The cardiovascular risks posed by NSAIDs should not be disregarded for the sake of achieving gastrointestinal benefits. Current recommendations suggest NSAIDs should be considered a single class of non-aspirin NSAIDs. Preferred NSAIDs are ibuprofen and naproxen. Coxibs are preferred in patients with low cardiovascular risk and high gastrointestinal risk who are intolerant to anti-dyspepsia therapy.

Clinical shorts

Cardiovascular safety of NSAIDs: Debate about the cardiovascular safety of cyclooxygenase-2 (COX-2) inhibitors has spread to traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Researchers conducted a network meta-analysis of all large-scale randomized controlled trials comparing any NSAID

Abstract 2274: Effect of myeloperoxidase inhibitor resorcinol on colon tumorigenesis in APCmin/+ mice

Abstract Beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer progression are well accepted. Nevertheless, NSAIDs have had only a minor impact in primary or secondary prevention - even in high risk populations - for at least two reasons. First, NSAIDs are contra-indicated in some high risk conditions, such as colitis-associated colorectal cancer, because of their corrosive actions in the gut. Second, publicity about the cardiovascular safety of NSAIDs has thwarted their potential in primary or secondary prevention of sporadic polyps. Thus, we sought to identify molecular targets and agents that might work in these situations. Myeloperoxidase (MPOx) from neutrophils is distantly related to the cyclooxygenase (COX) enzymes. MPOx and its relative, eosinophil peroxidase (EPOx) constitute part of the innate immune process in the normal gut, and the pathology of colitis. Hypochlorite generated by MPOx oxidizes amino acids (serine, threonine) and polyunsaturated fatty acids (arachidonic acid). Several of these oxidative by-products generated by MPOx - hypochlorite are non-prostaglandin E2 (PGE2) mediators that enhance β-catenin signaling. Thus, we hypothesized that MPOx and its by-products may promote intestinal malignancy, comparable to the actions of COX and PGE2. Using APCmin/+ mice we tested the effect of resorcinol, an irreversible MPOx inhibitor, under two experimental conditions: 1) colorectal and intestinal tumor promotion accompanying inflammation induced with dextran sodium sulfate (DSS); and 2) tumor formation in the normal intestine, without colitis, but with basal “inflammation” (para-inflamation) due to commensal bacteria in the gut. For APCmin/+ mice with DSS induced inflammation, 1.25mg/kg intraperitoneal (IP) resorcinol caused a 30% reduction in colorectal adenoma numbers, and a 40% reduction in average adenoma size (p<0.05). Small intestinal polyp numbers were also reduced by 20%. Surprisingly, in APCmin/+ mice without DSS-induced colitis, but with basal “inflammation” of the normal gut, resorcinol 1.25mg/kg IP caused a modest, but detectable increase in adenoma formation. To reconcile these results we hypothesize that anti-inflammatory effects dominate the high intensity inflammation in the DSS colitis-APCmin/+ mouse, and manifest as reduced colitis-associated tumor formation. Conversely, we hypothesize that anti-inflammatory action in the lesser basal “inflammation” of normal APCmin/+ mice suppresses innate immune surveillance and elimination processes, which spares aberrant crypt foci. Alternatively, oxidation of resorcinol in the gut of normal APCmin/+ mice may be generating tumor promoting quinine metabolites. We are breeding an MPOx null-APCmin/+ mouse to help distinguish between these two alternatives. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2274.

Cardiovascular risk associated with nonsteroidal anti-inflammatory drugs

Since the introduction of selective cyclooxygenase-2 inhibitors (coxibs), there has been an ongoing discussion about the cardiovascular (CV) safety of coxibs and the traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Available data about the CV safety of NSAIDs come mostly from meta-analyses and a few clinical trials. Current evidence suggests that NSAIDs may increase the risk of CV events. Naproxen might be associated with lower risk, but available data are not conclusive. Recent recommendations on the treatment of patients with NSAIDs favor the use of naproxen in patients with increased CV risk. Therefore, this review focuses on data about naproxen and examines CV risk with ibuprofen and non-naproxen NSAIDs. In addition, data about CV safety of paracetamol (acetaminophen) are presented.