LOS ANGELES—The three randomized, double-blind clinical trials that comprise the multinational MEDAL program were primarily meant to examine thrombotic cardiovascular (CV) risks associated with etoricoxib (Arcoxia^R, Merck & Co.) compared with diclofenac (Voltaren®, Novartis). In today's issue of The Lancet, lead author Loren Laine, MD, and colleagues report gastrointestinal (GI) safety data from that trial.¹

"There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in more serious complicated events. The reduction in uncomplicated events with etoricoxib is maintained in patients treated with proton pump inhibitors (PPIs) and is also observed with regular low-dose aspirin use," writes Dr. Laine, of the division of gastrointestinal and liver diseases, department of medicine, at the Keck School of Medicine, University of Southern California, in Los Angeles.

Given the lack of difference in serious GI events, the clinical importance of this observation is less clear. In an accompanying editorial, Joost P. H. Drenth, MD, and Freek W. A. Verheugt, MD, write, "[W]e would need to treat 259 patients with etoricoxib to prevent one uncomplicated gastrointestinal event in one patient. So, although the effect might well be statistically significant, the effect is certainly not large and might not be clinically relevant. Furthermore, the clinical significance of an uncomplicated (small) peptic ulcer, if...complications do not occur, remains to be seen." Dr. Drenth is in the department of gastroenterology and hepatology, and Dr. Verheugt is in the department of cardiology at Radboud University Medical Centre, in Nijmegen, The Netherlands.

Prespecified analysis of combined data from three trials

This study was a preplanned secondary analysis of pooled data from three double-blind randomized comparisons of etoricoxib (at 60 or 90 mg/day) to diclofenac (at 150 mg/day) in 34,701 patients with osteoarthritis or rheumatoid arthritis. These trials, designed and sponsored by Merck, comprised the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study, the Etoricoxib vs Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) study, and the EDGE II study. The studies had similar entry criteria and treatment protocols and were designed to permit pooled intent-to-treat analysis.

The analysis covered upper GI clinical events (bleeding, perforation, obstruction, or ulcer) and complicated GI events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). The researchers also analyzed GI events in the subgroups of patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin.
 
They found:

• Significantly fewer upper GI clinical events with etoricoxib than with diclofenac (hazard ratio [HR] .69, 95% CI .57–.83, P = .0001).
  
• Significantly fewer uncomplicated GI events with etoricoxib than with diclofenac (HR .57, 95% CI .45–.74, P <.0001).
  
• No difference in the rates of complicated GI events with etoricoxib compared with diclofenac (HR .91, 95% CI .67–1.24, P = .561).

The researchers say that low-dose aspirin (<e;100 mg/day) "was strongly recommended for cardiovascular prophylaxis in patients with established cardiovascular, peripheral, arterial, or cerebrovascular disease" and for patients with diabetes. Use of PPIs or misoprostol "was also strongly recommended for patients at high risk of upper gastrointestinal clinical events" including patients over age 65 with a history of GI ulcer of hemorrhage or with concurrent use of corticosteroid, anticoagulant, or antiplatelet therapy. Low-dose aspirin was used during at least 10% of the 18-month study period by 37% of the etoricoxib patients and by 37% of the diclofenac patients. Of the entire patient group, 51% used anti-ulcer medications for at least 20% of the study period, and nearly all patients used PPIs (only 25 patients used misoprostol, so the subsequent analysis included only the PPI users). This high rate of PPI use might account for the low incidence of upper GI events, even in the diclofenac group, where rates were "at least 60% lower than rates with diclofenac or other traditional NSAIDs," the researchers suggest.

Study limitations also limit clinical relevance

Some cautions about this trial are warranted, however. "To attribute benefits to secondary outcomes in a trial can be problematic," Drs. Drenth and Verheugt warn. First, patients in these studies were allocated to groups according to CV risk factors, not according to upper GI risk factors, a possible source of bias. Second, patients taking PPIs or low-dose aspirin were not randomly allocated across group.

 "The statistical analysis, key to the results, was by employees from Merck Research Laboratories, and the company had influence over all aspects, including data analysis, safety monitoring, and reporting of the MEDAL program. This control might not necessarily affect the credibility of the results, but the demise of rofecoxib indicates that independent data analysis—done here by Frontier Science Foundation—is desirable," according to Drs. Drenth and Verheugt. They question "whether a COX-2 inhibitor such as etoricoxib, is safer than a PPI added to a standard nonsteroidal anti-inflammatory drug." They conclude that the Laine study does not answer that question but "merely generates the hypothesis, rather than answering it." Finally, they note that the PPI option would be less expensive and "potentially less cardiotoxic."

References

1. Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomized comparison. Lancet. 2007;369:465-473.
2. Drenth JPH, Verheugt FWA. Do COX-2 inhibitors give enough gastrointestinal protection? Lancet 2007;369:439-440.