Vioxx® (rofecoxib) significantly reduced the risk of serious gastrointestinal side effects by 50 percent compared to the non-steroidal anti-inflammatory drug (NSAID) naproxen and significantly reduced the risk of the most serious of these GI side effects by 60 percent, according to a study(A) published for the first time in this week's The New England Journal of Medicine. Merck has submitted the data from this study to the Food and Drug Administration to seek changes to the
prescribing information for Vioxx.
The study, called VIGOR (Vioxx Gastrointestinal Outcomes Research),
compared Vioxx 50 mg once daily -- a dose two to four times higher than the
daily dose used for osteoarthritis -- to naproxen 500 mg twice daily
(prescription strength) in rheumatoid arthritis patients. Vioxx is not
approved to treat rheumatoid arthritis; Vioxx is approved by the FDA to treat
osteoarthritis and acute pain.
More than 8,000 patients participated in the study, with 4,047 taking
Vioxx and 4,029 taking naproxen. The analysis published today evaluated
patient results throughout the duration of the study; most patients remained
in the study more than nine months, and some patients participated as long as
13 months. Vioxx achieved the primary endpoint and all secondary endpoints of
the study. The results are:
- Vioxx reduced the risk of symptomatic ulcers and
complicated GI events (ulcers, perforations, obstructions and bleeding in
the upper GI tract) by 50 percent (p less than 0.001) compared to
naproxen. The rate of these events was 4.5 percent per year among
naproxen patients compared to 2.1 percent per year among patients taking
- Secondary endpoint: Vioxx reduced the risk of the most serious, or
complicated, GI events (perforations, obstructions and bleeding in the
upper GI tract) by 60 percent (p=0.005) compared to naproxen. The rate
of these events was 1.4 percent per year among patients taking naproxen
compared to 0.6 percent per year among patients taking Vioxx(B).
- Vioxx also reduced the risk of gastrointestinal bleeding by 60 percent
(p less than 0.001). The rate of bleeding was 3.0 percent per year among
patients taking naproxen compared to 1.2 percent per year among patients
Reductions in risk seen in patients with and without known risk factors
for GI side effects
The authors also assessed whether Vioxx reduced serious GI events in
patients with individual risk factors such as older age, prior history of a GI
side effect, use of steroids and H. pylori(C) presence. In this study, Vioxx
reduced the risk of serious GI side effects in patients considered to be at
higher risk because they had one of these risk factors. Vioxx also reduced
the risk of GI side effects in patients considered to be at lower risk because
they did not have any of these individual risk factors.
"Although NSAIDs are among the most commonly used medications in the
world, they can be associated with serious gastrointestinal toxicity," said
Dr. Loren Laine, Professor of Medicine, University of Southern California, and
an author of the study. "It has been estimated that more than 100,000
patients are hospitalized and 16,500 die each year in the United States as a
result of NSAID-associated gastrointestinal side effects. This study was
undertaken to assess whether Vioxx, at a dose twice as high as the maximum
approved dose for chronic use, decreased the risk of these serious GI side
Although not designed as an efficacy study, patients and physicians were
also asked to evaluate the effect of therapy on the symptoms of rheumatoid
arthritis. Physicians' and patients' evaluations of the efficacy of the
medicines were similar, and the rates of discontinuation due to lack of
efficacy were low in both treatment groups (6.3 percent among patients taking
Vioxx and 6.5 percent among patients taking naproxen).
Overall, Vioxx was well tolerated in this study. The most common reasons
for discontinuation from the study were dyspepsia, abdominal pain, upper
abdominal pain, nausea and heartburn. There were significantly fewer
discontinuations for these side effects among patients taking Vioxx compared
to patients taking naproxen.
As previously reported, significantly fewer heart attacks were seen in
patients taking naproxen (0.1 percent) compared to the group taking Vioxx (0.4
percent) in this study, which is consistent with naproxen's ability to block
platelet aggregation by inhibiting COX-1. This effect on platelet aggregation
is similar to low-dose aspirin, which is used to prevent second cardiac events
in patients with a history of heart attack, stroke or other cardiac events.
In this study, there was no difference in cardiovascular mortality or the
incidence of strokes between the groups treated with Vioxx or naproxen.
Patients taking low-dose aspirin did not participate in VIGOR.
Vioxx does not block platelet aggregation and should not be used as a
substitute for aspirin to prevent cardiac events. Vioxx does not interfere
with the ability of low-dose aspirin to block platelet aggregation.
Administration of low-dose aspirin with Vioxx may result in an increased rate
of GI ulcers or other complications compared to use of Vioxx alone.
In the paper, the authors write that non-selective NSAIDs inhibit two
related enzymes: COX-1, the enzyme that helps maintain the stomach lining,
and COX-2, the enzyme that triggers pain and inflammation. The analgesic and
anti-inflammatory effects of NSAIDs are believed to be caused by the
inhibition of COX-2, while the GI side effects of NSAIDs -- which range from
upset stomach to ulcers and internal bleeding -- are attributed to the
inhibition of COX-1. At therapeutic doses, Vioxx selectively inhibits COX-2
without inhibiting COX-1. Naproxen is a widely used NSAID that inhibits both
COX-1 and COX-2.
- (A) Bombardier, C. et al. Comparison of Upper Gastrointestinal Toxicity
of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis, The New
England Journal of Medicine, Volume 343, Number 21.
- (B) Because patients participated in the study for varying lengths of
time, these rates reflect events per 100 patient years.
- (C) Heliobacter pylori are bacteria associated with ulcers.
Get the full prescribing information for Vioxx in the October 31st issue of Vidyya.