Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme

• cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials; however prior to the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs)
  • the MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac
• trial design:
  • a prespecified pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily).
  • primary hypothesis stated that etoricoxib is not inferior to diclofenac, defined as an upper boundary of less than 1·30 for the 95% CI of the hazard ratio for thrombotic cardiovascular events in the per-protocol analysis
  • ntention-to-treat analyses were also done to assess consistency of results
• study results:
  • 34 701 patients (24 913 with osteoarthritis and 9 787 with rheumatoid arthritis) were enrolled to MEDAL
  • average treatment duration was 18 months
  • 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1·24 and 1·30 per 100 patient-years and a hazard ratio of 0·95 (95% CI 0·81-1·11) for etoricoxib compared with diclofenac
  • gastrointestinal clinical events
    • rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac (0·67 vs 0·97 per 100 patient-years; hazard ratio 0·69 [0·57-0·83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0·30) and diclofenac (0·32)
  • congestive heart failure, oedema, hypertension, renal dysfunction
    • a higher rate of congestive heart failure was seen with etoricoxib 90 mg than with diclofenac, but the difference was not significant; no difference was seen with etoricoxib 60 mg
    • discontinuations because of oedema were significantly more frequent with 90 mg of etoricoxib than with diclofenac, but rates were similar for 60 mg of etoricoxib and diclofenac
    • discontinuations because of hypertension were more frequent with both doses of etoricoxib than with diclofenac
    • no difference in the incidence of discontinuation due to renal dysfunction
  • efficacy in arthritis
    • etoricoxib and diclofenac showed similar efficacy for treatment of arthritis
• in conclusion:
  • annual incidence of thrombotic cardiovascular events in the overall MEDAL programme population was about 1·25%, and the absolute difference in event rates between treatments was less than one patient per 1000 treated for a year (-0·07 events per 100 patient years; 95% CI -0·26 to 0·13)
    • therefore based on 95% CI for this difference in the primary analysis, etoricoxib could be associated with at most an increase of 1·3 events (or a decrease of 2·6 events) per 1000 patients treated for a year compared with diclofenac
  • the authors concluded that rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs

Study limitations:

• the study did not include a placebo group - however long-term placebo-controlled trials in arthritic patients are not possible because many patients in the placebo group would have breakthrough symptoms on placebo, and thus would require some type of anti-inflammatory treatment
  • this non-use of a placebo group means that the absolute cardiovascular risks associated with etoricoxib and diclofenac cannot be ascertained from this trial
• results observed with these two drugs cannot necessarily be extrapolated to other COX-2 selective or traditional NSAIDs

Reference:

1. Cannon PC et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006;368:1771-1781.