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Multinational Etoricoxib and Diclofenac Arthritis Long-Term Study Program - MEDAL Program – Presented at AHA 2006
Description:
The goal of the MEDAL study program was to evaluate the risk of thrombotic cardiovascular events with etoricoxib, a highly selective cyclooxygenase-2 (COX-2) inhibitor, compared with the nonsteroidal anti-inflammatory drug (NSAID) diclofenac among patients with osteoarthritis and rheumatoid arthritis.
Hypothesis:
Etoricoxib will not be inferior to diclofenac for thrombotic cardiovascular events through 3 years of follow-up, defined as an upper boundary less than 1.30 for the 95% confidence interval (CI) of the hazard ratio (HR) in the per-protocol analysis.
Study Design
Study Design:
Patients Screened: 39,984
Patients Enrolled: 34,701
Mean Follow Up: 3 years
Mean Patient Age: Mean age, 63 years
Female: 74
Patient Populations:
Clinical diagnosis of osteoarthritis of the knee, hip, hand, or spine, or a clinical diagnosis of rheumatoid arthritis that satisfied at least four of seven of the American Rheumatism Association 1987 revised criteria; judgment of the investigator to need chronic treatment with an NSAID; and age ≥50 years
Exclusions:
History of MI, coronary artery bypass graft surgery, or percutaneous coronary intervention >6 months prior to enrollment
Primary Endpoints:
Composite of any thrombotic CV events, defined as sudden or unexplained death, MI, unstable angina pectoris, intracardiac thrombus, resuscitated cardiac arrest, thrombotic stroke, cerebrovascular thrombosis, transient ischemic attack, peripheral venous thrombosis, pulmonary embolism, and peripheral arterial thrombosis, evaluated for noninferiority
Secondary Endpoints:
Confirmed arterial events only; APTC (MI, stroke, vascular death)
Drug/Procedures Used:
Data were drawn from three randomized trials of etoricoxib (60 mg or 90 mg daily; n = 17,412) or diclofenac (150 mg daily; n = 17,289), the EDGE, EDGE II, and MEDAL studies. The EDGE trial (n = 7,111) enrolled patients with osteoarthritis, the EDGE II trial enrolled patients with rheumatoid arthritis (n = 4,086), and the MEDAL trial enrolled patients with osteoarthritis or rheumatoid arthritis (n = 23,504). Other study design elements were similar.
Principal Findings:
Mean duration of study drug exposure was 18 months. Indication for therapy was osteoarthritis in 72% of patients and rheumatoid arthritis in 28%. Diabetes was present in 11% of patients, hypertension in 47%, and established atherosclerotic cardiovascular (CV) disease in 12%. Approximately one-third of patients had ≥2 CV risk factors or established CV atherosclerotic disease.
The primary endpoint of thrombotic CV events occurred in 320 patients in the etoricoxib group (1.24 events per 1,000 patient-years) and 323 patients in the diclofenac group (1.24 events per 1,000 patient-years; HR 0.95, 95% CI 0.81-1.11), meeting the prespecified criteria for noninferiority. The secondary endpoint of arterial thrombotic events was also noninferior between the etoricoxib and diclofenac groups (1.05 vs. 1.10 events per 1,000 patient-years, respectively; HR 0.96, 95% CI 0.81-1.13), as did the Anti-Platelet Trialists’ Collaboration (APTC) endpoint of myocardial infarction (MI), stroke, or vascular death (0.84 vs. 0.87 events per 1,000 patient-years; HR 0.96, 95% CI 0.79-1.16).
Congestive heart failure trended higher with the etoricoxib 90 mg group compared with diclofenac (0.4% vs. 0.2%), but did not differ with the etoricoxib 60 mg group compared with diclofenac (0.3% vs. 0.2%). Likewise, discontinuation due to edema occurred significantly more frequently with etoricoxib 90 mg than diclofenac (1.2% vs. 0.6%), but there was no difference between etoricoxib 60 mg and diclofenac (0.8% vs. 0.7%). Discontinuations due to hypertension occurred significantly more frequently with both doses of etoricoxib compared with diclofenac (2.4% for 90 mg vs. 1.2%; 2.2% for 60 mg vs. 1.6%).
Confirmed upper gastrointestinal (GI) events, which include perforations, ulcers, and bleeds, occurred less frequently in the etoricoxib group compared with the diclofenac group (0.67 vs. 0.97 events per 1,000 patient-years; HR 0.69, 95% CI 0.57-0.83), driven by a reduction in ulcers with no difference in perforations, obstructions, or major bleeds.
Interpretation:
Among patients with osteoarthritis and rheumatoid arthritis, etoricoxib, a highly selective COX-2 inhibitor, was noninferior to the NSAID diclofenac for the risk of thrombotic CV events through 3 years.
COX-2 inhibitors have been shown to have an increased risk of vascular events compared with placebo. Additionally, data from the VIGOR trial demonstrated an increased risk of CV events associated with the COX-2 inhibitor rofecoxib compared with the NSAID naproxen, one of several studies that led to a Food and Drug Administration warning for all NSAIDs, both COX-2 selective and traditional. Traditional NSAIDs inhibit both COX-1 and COX-2 receptors. Diclofenac appears to have less COX-1 inhibition than other traditional NSAIDs such as naproxen, but more than the selective COX-2 inhibitors such as etoricoxib and celecoxib.
Chronic pain management for patients with arthritis presents complex choices for physicians and patients alike. Balancing the need for pain and inflammation relief with the risk of upper GI complications and thrombotic CV events is complex. In the present study, etoricoxib was associated with lower rates of upper GI events and demonstrated noninferiority with respect to thrombotic CV events. However, discontinuation due hypertension was higher with etoricoxib and discontinuation due to edema was higher with the 90 mg dose of etoricoxib.
While the present study addressed the risk of thrombotic CV events between etoricoxib and diclofenac, several questions remain to be addressed for the class of NSAIDs. One of these questions includes whether naproxen at a variety of doses is either cardioprotective or associated with a risk of events over placebo. Finally, data from the MEDAL program cannot be extrapolated to other COX-2 selective or traditional NSAIDs.
References:
Cannon CP, 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: 1771-81.
Presented by Dr. Christopher P. Cannon at the American Heart Association Annual Scientific Sessions, Chicago, IL, November 2006.
Keywords: Myocardial Infarction, Stroke, Diclofenac, Follow-Up Studies, Cyclooxygenase 2 Inhibitors, Risk Factors, Blood Platelets, Pyrazoles, Edema, Pyridines, Pain Management, Sulfones, Numismatics, Ulcer, Naproxen, Lactones, Heart Failure, Osteoarthritis, Confidence Intervals, Hypertension, Diabetes Mellitus, Sulfonamides
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