Cardiovascular Risks of NSAIDs
July 30, 2009 4 minutes read
Cardiovascular Risks of NSAIDs
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP
Synopsis: When using an NSAID, a physician must weigh the anticipated therapeutic benefits and assess the potential risks from both the cardiovascular and gastrointestinal perspectives, and the final therapeutic decision should be individualized.
Source: Farkouh ME, Greenberg BP. An evidence-based review of the cardiovascular risks of nonsteroidal anti-inflammatory drugs. Am J Cardiol 2009;103:1227-1237.
More than 17 million Americans use various nonsteroidal anti-inflammatory drugs (NSAIDs) on a daily basis to reduce inflammation and provide relief of acute and chronic pain associated with a wide range of medical conditions, making this class of drugs one of the most commonly used classes of drugs in the United States. Cyclooxygenase-2 (COX-2)-specific inhibitors were developed because of their anti-inflammatory properties and because they did not have the adverse gastrointestinal effects frequently seen with COX-1 inhibitors.1-3
Serious adverse CV events have been reported with NSAID use; in fact, 5%-7% of all hospital admissions are related to the adverse effect of these drugs. However, definitive evidence regarding the precise CV risk associated with these drugs as a class and individually has been lacking. Therefore, Farkouh and Greenberg reviewed the key clinical trials, meta-analyses of clinical trials, and epidemiologic studies on the subject of the CV safety of NSAIDs and identified the key variables that defined the CV risk of the various NSAIDs. They reviewed a total of 8 active-controlled and placebo-controlled trials, 5 epidemiologic studies, and 5 meta-analyses, in addition to 7 other unclassified studies. Many of the toxic effects of the NSAIDs are related to their main mode of action, the inhibition of prostaglandin synthesis. The review revealed that the association of CV risk with the use of NSAIDs was related to 5 key variables (i.e., COX-2 selectivity, dose responsivity, plasma half-life, blood pressure, and interaction with aspirin) that determined the extent of CV toxicity.
Commentary
After reviewing all of the studies concerned with the side effects of the nonselective NSAIDs, they concluded that naproxen (Naprosyn®) was associated with a lower CV risk than rofecoxib and lumiracoxib; however, the drug exhibited a higher potential for producing increased gastrointestinal symptoms compared to the other agents.2 There was no apparent diminution of the cardioprotective effect of aspirin when used concomitantly. Ibuprofen demonstrated a risk comparable to that of celecoxib (Celebrex®) and it tended to exhibit slightly more risk than naproxen in the aspirin interaction studies, suggesting that the concomitant use of ibuprofen interfered with the possible protective effects of aspirin. This potentially clinically relevant interaction between ibuprofen and aspirin has been observed when ibuprofen is administered before aspirin and has been described as "aspirin resistance." Some clinicians have therefore suggested that NSAIDs other than ibuprofen be used in patients taking aspirin for cardioprotection.4 Diclofenac demonstrated risk comparable to celecoxib but no interaction with aspirin.
Celecoxib is the only COX-2-specific NSAID currently available for sale in the United States. Clinical trial evidence suggests that celecoxib use may result in an elevated risk for thromboembolic CV events especially at higher doses (i.e., 400 mg twice daily);5 however, it should be clearly recognized that the CV risk appears to be significantly less than with other COX-2-specific NSAIDs, especially when the drug is used only once daily or in low doses. Rofecoxib (Vioxx®) demonstrated a significantly increased CV risk, which led to its withdrawal from the U.S. market.6 For a variety of research and technical reasons, 3 other COX-2-specific inhibitors (lumiracoxib, valdecoxib, and etoricixib) have not been approved for marketing in the U.S. at this time.
In summary, simple analgesics such as aspirin or acetaminophen (Tylenol®) should always be used as initial or ongoing pharmacotherapy for relief of acute or chronic neuromuscular pain syndromes. If an NSAID is deemed to be necessary from a clinical point of view in patients for whom there appears to be no appropriate alternatives, it would appear to be safe to use naproxen or celecoxib for a limited time and at low dosage, although both of these agents may have a higher CV risk potential than do the simple analgesics. Finally, it should be recognized that the risk of gastrointestinal toxicity may be increased in patients with a prior history of a gastrointestinal event (i.e., ulcer, hemorrhage, etc.), in patients older than age 60, when a high dose of a NSAID is used, or if the patient is currently taking glucocorticoids and/or anticoagulants.
References
1. Baron JA, et al. Cardiovascular events associated with rofecoxib: Final analysis of the APPROVe trial. Lancet 2008;372:1756-1764.
2. Mukherjee D, et al. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286:954-959.
3. Strand V, et al. Are COX-2 inhibitors preferable to non-selective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking low-dose aspirin? Lancet 2007;370:2138-2151.
4. Solomon DH, et al. The cardiovascular system in rheumatic disease: The newest "extraarticular" manifestation? J Rheumatol 2005;32:1415-1417.
5. Solomon SD, et al; APC and PreSAP Trial Investigators. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 2006;114:1028-1035.
6. FDA. FDA issues public health advisory on Vioxx as its manufacturer voluntarily withdraws the product. Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106274.htm. Accessed June 30, 2009.
When using an NSAID, a physician must weigh the anticipated therapeutic benefits and assess the potential risks from both the cardiovascular and gastrointestinal perspectives, and the final therapeutic decision should be individualized.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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