Southern Medical Journal:
Special Sections: Letters to the Editor
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR
To the Editor:
Osteoarthritis (OA) is one of the leading causes of chronic disability in the elderly, predominantly because of involvement of the knee and hip joints. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used to reduce pain and inflammation and improve function in OA patients. We have been aware of side effects of NSAIDs including renal and gastrointestinal toxicity for years. Recently, a few studies1–3 have suggested that besides COX-2 inhibitors, some nonselective NSAIDs could also raise the relative risk of cardiovascular adverse events, such as acute myocardial infarction (MI). This warrants that we take a fresh look at NSAID use and their safety in the elderly.
A recent meta-analysis of 14 observational studies from population databases between January 1980 to June 2005 compared the risk of acute MI in NSAID users with that in non- or remote NSAID users.1 Nonselective NSAIDs as a class were found to be associated with an increased acute MI risk [relative AMI risk 1.19; 95% CI 1.08 to 1.31]. Similar findings were found with diclofenac [relative AMI risk 1.38; 95% CI 1.22 to 1.57] and ibuprofen [relative AMI risk 1.11; 95% CI 1.06 to 1.17]. However, this effect was not observed with naproxen [relative AMI risk 0.99; 95% CI 0.88 to 1.11].
In a population-based, nested case-control analysis by Hippisley-Cox and Coupland,2 the risk of acute MI was compared between patients taking COX-2 inhibitors and nonselective NSAIDs. Data was obtained from 367 general practices contributing to the UK QRESEARCH database between 2000 and 2004. Subjects included 9218 patients with a first ever diagnosis of acute MI during the four-year study period and 86,349 controls matched for age, calendar year, sex, and practice. Despite making adjustments for many potential confounders such as smoking status, comorbidities, use of statins, aspirin, and antidepressants, a significantly increased risk of acute MI was found to be associated with current use of diclofenac (1.55, 1.39–1.72); ibuprofen (1.24, 1.11–1.39) and rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09–1.61), compared with no use within the previous three years.
Gislason et al3 reported that selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with a previous MI. Of 71,515 patients hospitalized with first-time acute MI during 1995 to 2002, 58,432 (81.7%) were alive at discharge and were included in this study. All prescription claims for NSAIDs and COX-2 inhibitors after discharge were identified from nationwide Danish administrative registers. The risk of death and rehospitalization for acute MI was studied with the use of multivariable proportional hazards models and case-crossover analysis. It was found that 9,773 patients experienced rehospitalization for MI, and 16,573 died. They found an increased risk of death with any use of ibuprofen, diclofenac, other NSAIDs, rofecoxib and celecoxib. The hazard ratios and 95% confidence intervals for death were 2.80 (2.41–3.25 for rofecoxib), 2.57 (2.15–3.08 for celecoxib), 2.40 (2.09–2.80 for diclofenac), 1.50 (1.36–1.67 for ibuprofen), and 1.29 (1.16–1.43 for other NSAIDs). There were trends for increased risk of rehospitalization for acute MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs. The duration of treatment was similar with rofecoxib, celecoxib, and ibuprofen, at 37 to 40 days, but the duration of treatment was only 20 days for diclofenac and 83 days for other NSAIDs. A clear dose-related response in the increased risk of death for both coxibs and NSAIDs was seen, although a similar association was not found for risk of recurrent MI.
In a nutshell, we should be more cautious when prescribing NSAIDs to elderly patients with OA who have known cardiovascular disease or several risk factors for the same. Patients need to be involved in the decision-making process while being informed of the potential risks of NSAIDs and alternative choices. In the elderly, when NSAIDs are being used in patients with risk factors for cardiovascular disease, it would be prudent to limit their dose to the lower part of the effective range; eg, limiting diclofenac to 100 mg/d, ibuprofen to 1200 mg/d, and naproxen to 500 mg/d. This dose may further need to be adjusted based on the patient's creatinine clearance. Adding misoprostol or a proton pump inhibitor may reduce their GI side effects. However, in patients with known coronary artery disease or with a past history of stroke, even these doses could cause potential harm, and for now, it would be best to avoid NSAIDs in this particular group of patients, until more conclusive evidence becomes available.
Harinder Singh, MD
Department of Geriatrics
University of Arkansas for Medical Sciences
Little Rock, AR
1. Singh G, Wu O, Langhorne P, et al. Risk of acute myocardial infarction with non-selective non-steroidal anti-inflammatory drugs: a meta-analysis. Arthritis Res Ther 2006;8:R153.
2. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330:1366.
3. Gislason GH, Jacobsen S, Rasmussen JN, et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase inhibitors and nonselective nonsteroidal anti-inflammatory drugs after acute myocardial infarction. Circulation 2006;113:2906–2913.
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