Merck Stands Behind Cardiovascular Safety Profile of Vioxx (Rofecoxib)

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Merck Stands Behind Cardiovascular Safety Profile of Vioxx

(Rofecoxib)

UPPER GWYNEDD, PA -- August 22, 2001 -- In response to an

article published in this week's Journal of the American

Medical Association containing data from selected previously

released studies of Vioxx® (rofecoxib) and Pharmacia's

Celebrex, Merck & Co., Inc. today said the Company stands

behind the overall and cardiovascular safety profile and the

favorable gastrointestinal (GI) profile of Vioxx.

Merck believes Vioxx is an appropriate and efficacious

therapy for the relief of the signs and symptoms of

osteoarthritis and the management of acute pain in adults.

Merck concurs with statements made in the article by

Mukherjee et al that selective " COX-2 inhibitors show less

propensity for gastrointestinal toxicity " than non-selective

non-steroidal anti-inflammatory drugs (NSAIDs) and that

" aspirin and naproxen show greater potential for

gastrointestinal toxicity but have a cardioprotective

effect. " Merck also agrees with the authors' statement that

their analysis " has several significant limitations. "

The authors say more data are needed on the cardiovascular

profile of COX-2 inhibitors. However, Merck believes that

extensive cardiovascular data already exist on Vioxx and

that these data -- which were not incorporated into the

authors' analysis -- suggest that there is no increase in

the risk of cardiovascular events as a result of treatment

with Vioxx.

These cardiovascular data are from a meta-analysis of data

from 19 controlled clinical studies with Vioxx involving

more than 28,000 patients and showed the relative risks of

serious cardiovascular events were similar with Vioxx and

placebo, and with Vioxx and the widely prescribed NSAIDs

ibuprofen, diclofenac and nabumetone. This analysis was

presented in February at the FDA Advisory Committee meeting

and in Europe in June at the annual meeting of the European

League Against Rheumatism.

Patient safety is of paramount importance to Merck. As is

the case with all of our products, Merck is interested in

helping to answer important questions that could help

further the scientific understanding of Vioxx and other

medicines that selectively inhibit COX-2. We routinely

review data from completed studies and clinical use of our

products, and consistent with this approach, we will

continue to evaluate data from ongoing studies with Vioxx

and relevant emerging studies on COX-2 inhibitors to enhance

our understanding of these medicines and assess the

potential value of future trials.

Merck's gastrointestinal (GI) outcomes study of over 8,000

patients, called VIGOR (Vioxx Gastrointestinal Outcomes

Research study), was a GI study that was not designed to

show differences in cardiovascular effects. In the study,

however, significantly fewer heart attacks were observed in

patients taking naproxen 1,000 mg (0.1 percent) compared to

patients taking Vioxx 50 mg (0.5 percent) -- a dose two

times the highest chronic dose approved for osteoarthritis.

This is the first time this result has been observed. This

finding is consistent with the ability of naproxen to

inhibit platelet aggregation in a manner similar to aspirin.

The authors of the JAMA article also acknowledged this

potential cardioprotective benefit of naproxen. Aspirin is

indicated to prevent second cardiac events in patients with

a history of heart attack, stroke or other cardiac events,

but was not taken by patients in VIGOR. There was no

difference in cardiovascular mortality between the two

groups. In VIGOR, there was no correlation between renal

effects and cardiovascular events.

In VIGOR, Vioxx 50 mg significantly reduced serious GI side

effects by half compared to a commonly used dose of naproxen

(1,000 mg) in rheumatoid arthritis patients. Vioxx is not

indicated for rheumatoid arthritis.

The results of the study were first released in March 2000.

Since that time, the data have been widely reported,

published in The New England Journal of Medicine and

discussed extensively by an FDA Advisory Committee.

Vioxx is a once-a-day NSAID that selectively inhibits COX-2.

For several decades, the prescribing information for NSAIDs

such as ibuprofen has contained language that states that

NSAID medications should be used with caution in patients

with fluid retention, hypertension or heart failure. The

prescribing information for both Vioxx and Celebrex, which

are NSAIDs, contains similar language.

The authors of the JAMA article concede that their analysis

" has several significant limitations. " These limitations

included:

· The analysis looked only at three of the many available

studies of Vioxx and one study of Celebrex.

· The authors borrowed a " placebo " arm for their analysis

from four older, separate aspirin studies that did not

involve Vioxx or Celebrex, and compared data from that

" placebo " group to data from separate studies of Vioxx or

Celebrex. It is widely understood that an essential

component in determining the validity of such an analysis is

the similarity of the studies being compared.

· Specifically, none of the aspirin studies used by the

authors to estimate the " placebo " rate of cardiovascular

events included patients with rheumatoid arthritis. The

authors acknowledge this limitation in their article because

rheumatoid arthritis is a disease that may increase one's

risk of cardiovascular events.

Therefore, to compare a group of patients taking Vioxx for

rheumatoid arthritis with a " placebo " group of patients who

do not have rheumatoid arthritis is inappropriate and

misleading because one would expect a higher rate of

cardiovascular events in the rheumatoid arthritis group,

regardless of any medications. In fact, two of the aspirin

studies cited by the authors involved healthy male

physicians (Physicians' Health Study and Doctors' Study) who

likely had lower risk for cardiovascular events than those

studied in the COX-2 inhibitor studies cited in the article.

Based on the authors' analyses and the data from Merck's

large-scale placebo-controlled clinical trials, Merck does

not believe the authors' conclusions in the article are

scientifically supported by the totality of the data

available.

In rare cases, serious stomach problems, such as bleeding,

can occur without warning symptoms. People who have had an

allergic reaction, such as asthma, to Vioxx, aspirin, or

other arthritis medicines should not take Vioxx. People who

have had liver or kidney problems, or are pregnant, should

tell their doctors. Also, Vioxx should not be used by women

in late pregnancy. Vioxx is not a substitute for aspirin for

cardiovascular prophylaxis. Vioxx does not interfere with

the effects of low-dose aspirin on platelets.

Common side effects reported in osteoarthritis clinical

trials with Vioxx were upper-respiratory infection,

diarrhea, nausea and high blood pressure. Vioxx was approved

by the Food and Drug Administration in May 1999 for the

management of osteoarthritis and the relief of acute pain.

More than 40 million prescriptions have been written for

Vioxx in the United States since its introduction.

Merck & Co., Inc. is a leading research-driven

pharmaceutical products and services company. Merck

discovers, develops, manufactures and markets a broad range

of innovative products to improve human and animal health,

directly and through its joint ventures. Merck-Medco Managed

Care manages pharmacy benefits for employers, insurers, and

other plan sponsors, encouraging the appropriate use of

medicines and providing disease management programs. Through

these complementary capabilities, Merck works to improve

quality of life and contain overall health-care costs.

Vioxx® is the Merck registered trademark for rofecoxib.

SOURCE: Merck & Co., Inc.

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