The use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) is widespread to reduce the pain associated with osteoarthritis; however the side-effects of these drugs can be severe, sometimes leading to gastro-intestinal ulcer complications which account for around 7000 US and 1000 UK deaths each year. The development of Cyclo-oxygenase 2 (COX2)-selective inhibitors should reduce these ulcer complications, but evidence is limited, and the possibility that COX2 inhibitors increase cardiovascular events has been raised.
TARGET (The Therapeutic Arthritis Research and Gastrointestinal Event Trial) assessed gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with the NSAIDs naproxen and ibuprofen. 18325 osteoarthritis patients (aged 50 years or older) were randomised to receive either lumiracoxib (9156 patients), naproxen (4754 patients), or ibuprofen (4415 patients) for 1 year. The risk of ulcer complications was reduced among patients given lumiracoxib (0.25%) compared with patients using non-selective NSAIDs (1.09%); however this benefit did not apply for patients who were also taking aspirin.
TARGET also demonstrated that the incidence of non-fatal and silent myocardial infarction, stroke, or cardiovascular death, which was low in the population, did not differ significantly between treatment groups (lumiracoxib 0.65% vs NSAIDs 0.55%), or when analysed by aspirin use, age, sex, high cardiovascular risk, or cerebrovascular history. "The fact that we enrolled osteoarthritis patients in the study who already had high blood pressure or other risk factors for coronary heart disease was important," says Dr. Michael E Farkouh, lead author on the cardiovascular outcomes paper (New York University School of Medicine, USA).
Investigator Michael Doherty (University of Nottingham, UK) comments: "Lumiracoxib showed a three to four-fold reduction in ulcer complications compared with non-steroidal anti-inflammatory drugs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis".
The TARGET study is critically evaluated in an accompanying commentary by Eric J Topol and Gary W Falk (Cleveland Clinic Foundation, USA – see p 639). With regard to cardiovascular outcomes they comment: 'The overall low frequency of myocardial events is important to put in context. Patients in TARGET were 50 years or older and nearly all those with myocardial infarction, stroke, coronary artery bypass surgery, or congestive heart failure were excluded. Less than 2% of the patients had a previous myocardial infarction or a revascularisation procedure. Unfortunately, this trial, like all others in the clinical development of coxibs, purposefully excluded patients with known and significant pre-existing coronary artery disease'.
Topol and Falk also highlight concerns about lumiracoxib's liver toxicity and potential increase in heart attack if lumiracoxib is compared with naproxen alone: 'TARGET quantifies lumiracoxib's narrow benefit over two NSAIDs with a trade-off. For patients not taking aspirin, there is an absolute reduction of 0.72% in ulcer complications, with an excess of 2.0% of liver function test abnormalities. The putative benefit is further compromised if naproxen is the NSAID, with a 0.17% excess of myocardial infarction. For patients taking low-dose aspirin, it is hard to justify the coxib: there is no benefit in ulcer complication reduction, but the risk of myocardial infarction and hepatotoxicity persist.'
Contact: (Ulcer complications study) Professor Michael Doherty, c/o Emma Thorne University of Nottingham Press Office, UK; T) 44-115- 951-5793; emma.thorne@nottingham.ac.uk
(Cardiovascular outcomes study) Dr Michael E Farkouh, New York University School of Medicine, 530, First Avenue, New York, NY 10016, USA; (Pamela McDonnell, Public Affairs) 1-212-404-3555; Pamela.McDonnell@med.nyu.edu
(Commentary) The Cleveland Clinic : Media Relations, Michelle Bolek 1-216-444-0333 ; bolekm@ccf.org or Lisa Murphy, 1-216-444-7935 ; murphyl@ccf.org
Journal
The Lancet