MEDAL Program Showed Arthritis Patients Taking ARCOXIA(R) (etoricoxib) Experienced Significantly Fewer Upper Gastrointestinal Events Compared to Diclofenac.
WHITEHOUSE STATION, N.J. -- The results from a pre-specified upper gastrointestinal safety analysis of the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-Term) Program comparing the investigational selective COX-2 inhibitor ARCOXIA([R]) (etoricoxib) and diclofenac, the most widely prescribed non-steroidal anti-inflammatory drug (NSAID) in the world, were published in the February 10, 2007 issue of The Lancet.
The results showed that overall upper gastrointestinal (GI) events (bleeding, perforation, obstruction or ulcer) were significantly less common with ARCOXIA compared to diclofenac in a broad patient population. These results were maintained in patients taking proton pump inhibitors (PPIs) for GI protection and in patients taking low dose aspirin regularly for cardiovascular protection. Upper GI clinical events were significantly lower with ARCOXIA (0.67 per 100 patient years, 95 percent CI: 0.57-0.77) than with diclofenac (0.97 per 100 patient years, 95 percent CI: 0.85-1.10); RR (relative risk): 0.69; 95 percent CI 0.57, 0.83. However, there was no significant difference in the rates of complicated upper GI events (perforations, obstructions and significant bleeding) between ARCOXIA and diclofenac (0.30 vs. 0.32 per 100 patient years), respectively.
"These results demonstrate significantly fewer upper GI clinical events with etoricoxib as compared to diclofenac," said Loren Laine, M.D., MEDAL steering committee co-chair and professor of Gastrointestinal & Liver Diseases, Department of Medicine, University of Southern California. "The significant difference in overall upper GI clinical events demonstrated between etoricoxib and diclofenac was driven by uncomplicated symptomatic ulcers, which, although not life-threatening, have clinical impact because they require further medical follow-up and therapy." Professor Laine stated that the difference in the results between complicated and uncomplicated events could potentially relate to diclofenac's lack of anti-platelet effect.
In the MEDAL Program, arthritis patients who had GI risk factors were encouraged to use PPIs and those with cardiovascular risk factors were encouraged to use low-dose aspirin to simulate real-world practice. The MEDAL Program provides the first comparison of a selective COX-2 inhibitor and a traditional NSAID to assess the effect of concomitant GI co-therapy with PPI's on long-term risk of upper GI clinical events and upper GI symptoms, and is the largest comparison of these agents in low-dose aspirin users. Therefore, subgroup analyses related to concomitant use of PPI co-therapy and/or low-dose aspirin use were conducted.
"The results of the subgroup analyses furthermore indicate that the reduction in uncomplicated upper GI events with etoricoxib is maintained in PPI users and in patients taking low-dose aspirin regularly," said Professor Laine.
Upper GI clinical event characteristics
In the MEDAL Program, potential upper GI clinical events included bleeding, perforation, obstruction or ulcer. The subset of complicated events included those with perforation, obstruction and complicated bleeding. Uncomplicated events included uncomplicated bleeding and uncomplicated ulcer. Patients with both a complicated and uncomplicated event were counted in the overall clinical event patient group and the complicated event patient group, but not the uncomplicated event patient subgroup.
Concomitant low-dose aspirin (<100 mg/day) was used during at least 10 percent of the study by 6,454 (37 percent) in the ARCOXIA group and 6,367 (37 percent) in the diclofenac group. Among this group, aspirin was used during at least 75 percent of the study period in 5,745 (89 percent) of patients taking ARCOXIA and 5,673 (89 percent) of patients taking diclofenac. Concomitant PPIs were used in at least 20 percent of the study consecutively (or 30 consecutive days) by 8,434 (48 percent) of ARCOXIA patients and 8,447 (49 percent) of diclofenac patients. Among this group, PPIs were used during at least 75 percent of the study period in 6,951 (82 percent) of patients taking ARCOXIA and 6,911 (82 percent) of patients taking diclofenac.
Upper GI clinical events in the intent-to-treat population
In the pre-specified pooled intent-to-treat analysis of three-double-blind randomized comparisons of ARCOXIA (60 mg or 90 mg daily) and diclofenac (150 mg daily) in 34,701 patients with osteoarthritis or rheumatoid arthritis, upper GI clinical events were significantly lower with ARCOXIA (0.67 per 100 patient years, 95 percent CI: 0.57-0.77) than with diclofenac (0.97 per 100 patient years, 95 percent CI: 0.85-1.10); RR 0.69; 95 percent CI 0.57, 0.83. The rates of uncomplicated upper GI events were significantly lower with ARCOXIA (0.37 per 100 patient years, 95 percent CI: 0.28-0.43) versus diclofenac (0.65 per 100 patient years, 95 percent CI: 0.54-0.74); RR 0.57; 95 percent CI 0.45, 0.74. However, there was no significant difference in the rates of complicated upper GI events (perforations, obstructions and significant bleeding) between ARCOXIA and diclofenac (0.30 vs. 0.32 per 100 patient years), respectively.
Upper GI clinical events sub-group analyses related to concomitant use of low-dose aspirin and/or PPI
No significant treatment-by-subgroup interactions were seen related to regular low-dose aspirin use (eN75 percent of the study period) among patients taking ARCOXIA compared to diclofenac (1.14 per 100 patient years vs. 1.46 per 100 patient years, respectively) or PPI use (eN75 percent of the study period) (0.56 per 100 patient years vs. 0.91 per 100 patient years, respectively). These results indicate that the treatment effect for ARCOXIA versus diclofenac was consistent both with and without low-dose aspirin and with and without PPI. When more liberal definitions of concomitant aspirin use (eN 10 percent of study) and PPI use (eN 20 percent of study consecutively, or 30 consecutive days) were assessed, no differences were seen in the results of the PPI use analyses. However, for the aspirin use analyses, the treatment-by-subgroup interactions were significant for overall upper gastrointestinal clinical events (aspirin: RR 0.83, 95 percent CI: 0.65-1.07 versus no aspirin: 0.52, 0.38-0.71; p=0.021) and for uncomplicated events (aspirin: 0.73, 0.52-1.03 versus no aspirin: 0.43, 0.30-0.63; p=0.043), indicating that the magnitude of the decrease in overall and uncomplicated events with ARCOXIA versus diclofenac was smaller in patients taking low-dose aspirin for at least 10 percent of the study period than in those without aspirin use.
Upper GI symptoms analysis
Dyspepsia, defined as pain or discomfort in the upper abdomen (including epigastric or stomach) or nausea, is the most common side effect for which patients discontinue NSAID therapy. Among patients taking NSAIDs regularly, dyspepsia is reported weekly in up to ~30 percent of patients and daily in up to ~15 percent. The results from the analysis found a significant decrease in discontinuations due to dyspepsia with ARCOXIA when compared with diclofenac (327 (1.88 percent), 1.25 per 100 patient-years vs. 424 (2.45 percent), 1.69 per 100 patient-years; RR=0.75 (0.65 - 0.87). The decrease was similar in patients taking PPIs and did not change significantly whether the patients took concomitant low-dose aspirin or not.
About the MEDAL program
Conducted at 1,380 sites in 46 countries, the MEDAL Program was a prospectively designed clinical program combining thrombotic CV safety data from three trials: the MEDAL study (largest component), the Etoricoxib vs. Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) study, and the EDGE II study. The MEDAL Program is the only arthritis study with thrombotic CV safety as its primary endpoint and represents the largest amount of CV data available comparing a selective COX-2 inhibitor versus a traditional NSAID. The primary objective of the MEDAL Program was to perform a non-inferiority analysis of confirmed thrombotic (blood-clotting) CV events following daily treatment with ARCOXIA (60 mg or 90 mg) daily or diclofenac (150 mg daily) in osteoarthritis (OA) and rheumatoid arthritis (RA) patient populations. The intent of the study was not to assess absolute risk; this would have required a placebo group, which would be unethical in a long-term arthritis study.
The study enrolled patients with OA or RA who were at least 50 years of age and had a clinical diagnosis of OA of the knee, hip, hand or spine, or a clinical diagnosis of RA that satisfied at least four of the seven of the American Rheumatism Association 1987 revised criteria, and in the judgment of the investigator, would require chronic therapy with an NSAID. These patients were not candidates for acetaminophen as first-line therapy due to the severity of their symptoms. Patients with a history of myocardial infarction, coronary artery bypass graft surgery or percutaneous coronary intervention more than 6 months preceding enrollment were allowed to participate. Of the 34,701 patients enrolled, 37 percent were taking low-dose aspirin and 50 percent were taking a gastroprotective agent. The average duration of therapy was 18 months.
An independent confirmation of the analyses of the MEDAL Program made public today was performed by the Frontier Science Foundation of Madison, WI, USA.
ARCOXIA is Merck's investigational selective COX-2 inhibitor for arthritis and pain. ARCOXIA has been under review by the FDA as an investigational selective COX-2 inhibitor since the original NDA was submitted in December 2003 and is currently available in 62 countries in Europe, Latin America, the Asia-Pacific region and Middle East/Northern Africa. The Company has submitted a response to the "approvable" letters on the New Drug Applications for ARCOXIA issued by the U.S. Food and Drug Administration. According to current FDA policy for this type of submission, the review is targeted to be approximately six months (end of April 2007).
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.
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|Date:||Feb 8, 2007|
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