The use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) is widespread to reduce the pain associated with osteoarthritis. However, these can lead to gastrointestinal ulcer complications, accounting for around 7000 deaths each year in the United States and 1000 deaths in the United Kingdom.
The development of cyclo-oxygenase 2 (COX2)-selective inhibitors should reduce these ulcer complications, but evidence is limited.
In this study, doctors from the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) assessed gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with the NSAIDs naproxen and ibuprofen.
The team randomized 18325 osteoarthritis patients (aged ≥50 years) to receive either lumiracoxib (n = 9156), naproxen (n = 4754), or ibuprofen (n = 4415) for1 year.
The doctors found that the risk of ulcer complications was reduced in patients given lumiracoxib, compared with patients using NSAIDs. However, this benefit did not apply for patients who were also taking aspirin.
The team found 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.
"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 Farkouh from the New York University School of Medicine, USA.
Dr Michael Doherty, from the University of Nottingham, England, commented, "Lumiracoxib showed a 3 to 4-fold reduction in ulcer complications compared with NSAIDs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis".
|The risk of ulcer complications was reduced in patients given lumiracoxib.|
The TARGET study is critically evaluated in an accompanying commentary by Drs Eric Topol and Gary Falk from the Cleveland Clinic Foundation, USA. 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 revascularization 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."
Drs 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 2 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."