Merck Disagrees with Conclusions of Observational Analysis Presented at Int' Medical Meeting

Main Category: Cardiovascular / Cardiology
Article Date: 27 Aug 2004 - 11:00 PST

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Merck Stands Behind the Efficacy, Overall Safety and Cardiovascular Safety of VIOXX

Merck strongly disagrees with the conclusions of an observational analysis by Graham et al, presented at an international medical meeting1 this week, which evaluated the rate of cardiovascular events in patients taking COX-2 specific inhibitors VIOXX® (rofecoxib) and Celebrex® (celecoxib) and in patients taking non-selective NSAIDs. This analysis is a retrospective database analysis - not a clinical trial. Observational analyses have limitations, often conflict with each other, and must be interpreted within the context of data from large, randomized, controlled clinical trials. Randomized, controlled clinical trials are the gold standard to evaluate safety and efficacy. It is important to note that, although the analysis was funded by the Food and Drug Administration (FDA) under contract with Kaiser Permanente, the conclusions presented by the authors do not necessarily reflect the views of the FDA.

VIOXX has been extensively studied; more than 24,000 patients have been treated with VIOXX in randomized, controlled clinical trials. Two randomized, placebo-controlled studies (n=2,142) discussed in the labeling for VIOXX showed no significant difference in the rate of serious cardiovascular thrombotic events in patients taking VIOXX vs. placebo. The gastrointestinal (GI) outcomes study known as VIGOR showed a higher incidence of serious cardiovascular thrombotic events in patients receiving VIOXX 50 mg compared to patients treated with naproxen.

"This retrospective analysis is based only on a database review. Observational analyses do not have the rigor of randomized, controlled clinical trials. The robust clinical trial data available support the safety of VIOXX. Based on all of the data that are available from our clinical trials, Merck stands behind the efficacy and safety, including cardiovascular safety, of VIOXX," said Peter S. Kim, PhD., president, Merck Research Laboratories. "Nothing is more important to Merck than the safety of our medicines. We believe that the prescribing information for VIOXX accurately and appropriately reflects the efficacy and safety of VIOXX. Merck is also conducting large prospective clinical trials that, when added to the extensive data from clinical trials that are already available, will provide an even more comprehensive picture of the cardiovascular safety profile of VIOXX."

Merck discusses findings and limitations of this analysis

Observational analyses have inherent limitations and often yield conflicting results. With respect to this analysis, press reports have not focused on other findings: the researchers found that there was no statistically significant increase in risk for patients taking VIOXX 12.5 mg and 25 mg compared to patients not taking an NSAID. Also, the finding of a statistically significant increase for Vioxx 50 mg was based on 10 cases of acute myocardial infarction (AMI) or sudden cardiac death (SCD) versus eight events in the control group. Moreover, while some press reports have cited other observational analyses that seem to support the conclusions of this analysis, they do not cite other observational analyses that do not support the authors conclusions, including a different observational analysis presented at this medical meeting.

Results from recent large, controlled clinical studies with VIOXX

In VIGOR, VIOXX 50 mg once daily significantly reduced the risk of serious GI side effects by more than half compared to the NSAID naproxen (500 mg twice daily) in patients with rheumatoid arthritis. The study also showed a statistically significant higher incidence of serious cardiovascular thrombotic events in patients receiving VIOXX 50 mg once daily - a dose two-times the highest recommended chronic dose - compared to patients treated with naproxen 500 mg twice daily. A total of 45 serious cardiovascular thrombotic events occurred among 4,047 patients taking VIOXX compared to 19 among 4,029 taking naproxen. This was largely due to a difference in the incidence of non-fatal heart attacks: 18 for VIOXX and four for naproxen. The number of cardiovascular thrombotic deaths was similar in patients treated with VIOXX (n=7) compared to naproxen (n=6).

The U.S. prescribing information for VIOXX also includes data from a placebo-controlled database derived from two studies with a total of 2,142 elderly patients (mean age 75; VIOXX n=1,067, placebo n=1,075). The median exposure in these studies was approximately 14 months. The number of patients with a serious cardiovascular thrombotic event was 21 for patients treated with VIOXX 25 mg once daily vs. 35 for patients receiving placebo. In these same two placebo-controlled studies, mortality due to cardiovascular thrombotic events was eight vs. three for VIOXX vs. placebo, respectively. The significance of the cardiovascular findings from these three studies (VIGOR and the placebo-controlled studies) is unknown. Prospective studies with VIOXX to compare the incidence of serious cardiovascular events to NSAID comparators or placebo have not been completed.

Because of its lack of platelet effects, VIOXX is not a substitute for aspirin to prevent cardiovascular events. Caution should be exercised when VIOXX is used in patients with a medical history of ischemic heart disease, which includes patients with a history of angina or heart attack.

Merck believes that VIOXX is an appropriate and efficacious therapy for the relief of the signs and symptoms of osteoarthritis (12.5 mg or 25 mg once daily) and adult rheumatoid arthritis (25 mg once daily) and for the management of acute pain and primary dysmenorrhea (50 mg once daily) and the acute treatment of migraine (25 mg or 50 mg), as outlined in the prescribing information for VIOXX.

The recommended starting dose of VIOXX for the treatment of osteoarthritis is 12.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 25 mg once daily. For rheumatoid arthritis, the recommended dose is 25 mg once daily. The maximum daily dose for osteoarthritis and rheumatoid arthritis is 25 mg once daily. VIOXX 50 mg once daily is the recommended dose for acute pain and menstrual pain. The chronic use of VIOXX 50 mg is not recommended; use of VIOXX 50 mg for more than five days in the management of acute pain has not been studied. For the acute treatment of migraine attacks, the recommended starting dose for VIOXX is 25 mg once daily. Some patients may receive additional benefit with 50 mg as compared to 25 mg. The maximum recommended daily dose is 50 mg.

Important information about VIOXX

People with allergic reactions, such as asthma, to aspirin or other arthritis medicines should not take VIOXX. In rare cases, serious stomach problems, such as bleeding, can occur without warning. Patients should inform their physicians if they have liver or kidney disease, or a history of angina (chest pain), heart attack or a blocked artery in their heart. VIOXX cannot take the place of aspirin for the prevention of heart attack or stroke. VIOXX should not be used by women in late pregnancy.

Commonly reported side effects in clinical trials with VIOXX included upper-respiratory infections, diarrhea, nausea and high blood pressure.

VIOXX is the first COX-2 specific inhibitor that is proven to reduce the risk of developing clinically important GI side effects in patients with or without risk factors for such GI side effects compared to the NSAID naproxen. In VIGOR, VIOXX 50 mg significantly reduced serious GI side effects, including perforations, obstructions, ulcers and bleeds, by 54 percent compared to a commonly used dose of naproxen (1,000 mg) in rheumatoid arthritis patients. The GI safety benefit compared to naproxen, as shown in VIGOR, appears as a modification to the GI Warning section of the prescribing information, a section included in the prescribing information for all NSAIDs.

About VIOXX

VIOXX was first approved in the United States in 1999 for the relief of the signs and symptoms of osteoarthritis, management of acute pain in adults and treatment of menstrual pain. Since its introduction, more than 91 million prescriptions have been written in the United States.2

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical products company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health, directly or through its joint ventures.

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 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, 2003, and in its periodic reports on Form 10-Q and Form 8-K (if any), which the company incorporates by reference.

The full prescribing information and patient package insert for VIOXX® are attached. The full prescribing information is also available by calling 1-800-546-8173 and the patient package insert is available by calling 1-800-344-7833.

VIOXXâis a registered trademark of Merck & Co., Inc.
Celebrexâis a registered trademark of Pfizer, Inc.

1 20th International Conference on Pharmacoepidemiology & Therapeutic Risk Management in Bordeaux, Francefrom Aug. 22-25, 2004 .

2 IMS Health, National Prescription Audit Plus ä. Based on total dispensed prescriptions for the period May 1999 through November 2003.

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