WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck & Co., Inc. announced today that results are being presented from the largest and longest arthritis study program ever undertaken, the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-Term) Program, showing that the investigational selective COX-2 inhibitor ARCOXIA® (etoricoxib) demonstrated similar rates of confirmed thrombotic cardiovascular (CV) events compared to diclofenac, the most widely prescribed non-steroidal anti-inflammatory drug (NSAID) in the world. The primary data from the MEDAL Program are being presented today in three scientific forums: a late-breaking oral session at the American Heart Association 2006 Scientific Sessions, a late-breaking poster session at the American College of Rheumatology 2006 Scientific Meeting, and an online publication in The Lancet.
In the pre-specified “per protocol” analysis(1) of the primary endpoint, the relative risk of confirmed thrombotic CV events between ARCOXIA and diclofenac was 0.95 (95 percent CI: 0.81, 1.11). In the MEDAL Program, the confirmed rates of upper gastrointestinal (GI) clinical events, which include perforations, ulcers, bleeding and obstructions, 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). However, there was no significant difference in the rates of confirmed, complicated upper GI clinical events, which include perforations, obstructions and major bleeding, between ARCOXIA and diclofenac (0.30 vs. 0.32 per 100 patient years).
ARCOXIA has been under review by the U.S. Food and Drug Administration (FDA) since the original New Drug Application (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.
“Having a better understanding of how the risks and benefits of available treatments compare provides us with information to help manage our patients,” said Christopher Cannon, M.D., MEDAL Steering Committee Co-chair and a cardiologist in the TIMI Study Group at Brigham and Women’s Hospital. “Treatment options are important particularly in treating pain which is idiosyncratic in nature. Not every patient responds to pain treatment in the same way.”
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: MEDAL (largest component), EDGE and EDGE II. The MEDAL Program is the only arthritis study with thrombotic CV safety as its primary endpoint and represents the largest amount of CV data with a selective COX-2 inhibitor vs. 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 of 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 that were equal to or greater than 50 years of age and if they 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 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 (paracetamol) 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 six months preceding enrollment were allowed to participate. Of the 34,701 patients enrolled, 35 percent were taking low-dose aspirin and 50 percent were taking a gastroprotective agent. The average duration that each patient was on 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.
Thrombotic cardiovascular safety findings
The MEDAL Program results indicate the rate of confirmed thrombotic CV events was similar between ARCOXIA and diclofenac. The primary results are expressed as a relative risk, which is a ratio of risk on one treatment compared to the other treatment. Expressing results as a relative risk helps us to understand how close the event rates in the two treatments are to each other; if the event rates are identical, the relative risk equals 1.0.
In the primary pre-specified “per protocol” analysis(1) of the primary endpoint, the relative risk of confirmed thrombotic CV events between ARCOXIA and diclofenac was 0.95 (95 percent CI: 0.81, 1.11). Among the 34,701 patients enrolled in the MEDAL Program, 17,412 patients received ARCOXIA and 17,289 patients received diclofenac. In the primary analysis, 320 patients on ARCOXIA (1.24 events per 100 patient years) and 323 patients on diclofenac (1.30 events per 100 patient years) had thrombotic CV events, meeting the pre-specified criterion of non-inferiority. In the “intent-to-treat” analysis(2) (to end of studies), the relative risk of confirmed thrombotic CV events between ARCOXIA and diclofenac was 1.05 (95 percent CI: 0.93, 1.19), consistent with the primary per-protocol analysis.
Confirmatory analyses of the primary endpoint results, including results of analyses of individual events forming the composite primary endpoint and other secondary CV endpoints were all consistent with the primary endpoint results. The relative risk for ARCOXIA vs. diclofenac for certain thrombotic CV events (cardiac, cerebrovascular, peripheral) that were part of the composite endpoint also showed no evidence of a difference between the treatment groups. The most common thrombotic CV events were heart attacks, with rates per 100 patient years of 0.43 for ARCOXIA and 0.49 for diclofenac (non-fatal and fatal events) in the primary analysis. Similarly, fatal thrombotic CV events occurred at a rate of 0.17 per 100 patient years in each group. The relative risks for the secondary CV endpoints of thrombotic arterial CV events and APTC (Antiplatelet Trialists’ Collaboration) events were 0.96 for each, similar to the primary endpoint results.
In addition, the relative thrombotic CV risk of ARCOXIA vs. diclofenac did not differ across any of the subgroups analyzed, including patients with different degrees of CV risk, on different doses of ARCOXIA (60 mg or 90 mg), or by disease (OA vs. RA).
All-cause mortality rates were 0.48 and 0.50 per 100 patient years for ARCOXIA and diclofenac in an analysis which included all patients on study therapy or within 14 days of discontinuing study therapy.
Gastrointestinal safety findings
In the MEDAL Program the rate of confirmed upper GI clinical events, which include perforations, ulcers, bleeding and obstructions, was 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). The relative risk of confirmed upper GI events between ARCOXIA and diclofenac was 0.69 (95 percent CI: 0.57, 0.83). Of note, this result was achieved with 50 percent of patients in the MEDAL Program on gastroprotective agents (predominately proton pump inhibitors) and 35 percent on low-dose aspirin. However, there was no significant difference in the rates of confirmed, complicated upper GI clinical events, which include perforations, obstructions and significant bleeding, between ARCOXIA and diclofenac (0.30 vs. 0.32 per 100 patient years).
Other safety findings
In the MEDAL study, the largest component study of the MEDAL Program, the incidence of discontinuations due to hypertension-related adverse events was less than 3 percent for any treatment group; however, both ARCOXIA 60 mg and 90 mg demonstrated significantly higher rates of discontinuations for these events than diclofenac. In OA patients randomized to ARCOXIA 60 mg or diclofenac, 146 out of 6,769 patients on ARCOXIA (2.16 percent) discontinued due to hypertension-related adverse events, compared to 109 out of 6,700 patients on diclofenac (1.63 percent). In OA patients randomized to ARCOXIA 90 mg or diclofenac, 55 out of 2,171 patients on ARCOXIA (2.53 percent) discontinued due to hypertension-related adverse events, compared to 24 out of 2,162 patients on diclofenac (1.11 percent). In RA patients randomized to ARCOXIA 90 mg or diclofenac, 69 out of 2,841 patients on ARCOXIA (2.43 percent) discontinued due to hypertension-related adverse events, compared to 46 out of 2,855 patients on diclofenac (1.61 percent).
Rates of congestive heart failure were low in both the ARCOXIA and diclofenac treatment groups. A numerically higher rate of congestive heart failure compared with diclofenac was seen only with the ARCOXIA 90 mg dose, and not with the 60 mg dose. Specifically, 15 out of 2,171 OA patients on ARCOXIA 90 mg (0.69 percent) experienced congestive heart failure, compared to 7 out of 2,162 OA patients on diclofenac (0.32 percent); additionally, 18 out of 2,841 RA patients on ARCOXIA 90 mg (0.63 percent) experienced congestive heart failure, compared to 9 out of 2,855 RA patients on diclofenac (0.32 percent). For those patients in the study taking 60 mg ARCOXIA, 19 out of 6,769 OA patients (0.28 percent) experienced congestive heart failure, compared to 14 out of 6,700 OA patients on diclofenac (0.21 percent).
The incidence of discontinuations due to edema-related adverse events was significantly higher only for ARCOXIA 90 mg compared to diclofenac, and not with the 60 mg dose. In the MEDAL study, 41 out of 2,171 OA patients on ARCOXIA 90 mg (1.89 percent) were discontinued due to edema-related adverse events, compared to 17 out of 2,162 OA patients on diclofenac (0.79 percent); moreover, 28 out of 2,841 RA patients on ARCOXIA 90 mg (0.99 percent) discontinued due to edema-related adverse events compared to 16 out of 2,855 RA patients on diclofenac (0.56 percent). For those patients in the study taking 60 mg ARCOXIA, 56 out of 6,769 OA patients (0.83 percent) were discontinued due to edema-related adverse events, compared to 49 out of 6,700 OA patients on diclofenac (0.73 percent).
Results on hypertension, edema and congestive heart failure for the EDGE and EDGE II studies were consistent with the results of the MEDAL study.
About arthritis
According to the Arthritis Foundation, an estimated 46 million Americans, or one in five adults, suffer from some form of arthritis. Arthritis is one of the most prevalent chronic health problems.
About ARCOXIA
ARCOXIA is Merck & Co., Inc.'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 NDAs for ARCOXIA issued by the FDA. According to current FDA policy for this type of submission, the review is targeted to be approximately six months (end of April 2007).
About Merck
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.
Forward-looking statement
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.
(1) In the per-protocol analysis, only those events that occur in patients while they are on study treatment or within 14 days thereafter are analyzed: patients who took study medication less than 75% or took non-study NSAIDs more than 10% of time while on study medication were excluded from the analysis (approximately 4% of total MEDAL Program population).
(2) In an intent-to-treat analysis (to end of studies), patients are followed to the end of their respective study, no matter when they stopped study medication and no matter what other medications they took after stopping their study medication, and those events which occur are analyzed.
ARCOXIA® is a registered trademark of Merck & Co., Inc.
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