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Vioxx Market Withdrawal Information
VIGOR Study
The VIGOR study, published in 2000, had indicated a significant 4-fold increased
risk of acute myocardial infarction (heart attack) in rofecoxib patients when
compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span
of the study. There was no significant difference in the mortality from
cardiovascular events between the two groups. Nor was there any significant
difference in the rate of myocardial infarction between the rofecoxib and
naproxen treatment groups in patients without high cardiovascular risk.
The
difference in overall risk was accounted for by the patients meeting the
criteria for low-dose aspirin prophylaxis of secondary cardiovascular events
(previous myocardial infarction, angina, cerebrovascular accident, transient
ischemic attack, angioplasty, or coronary bypass), but who were excluded from
taking low-dose aspirin in the initial design study. Once this risk was noted,
Merck notified investigators in other rofecoxib studies to modify allow
high-risk patients to take low-dose aspirin. (Bombardier et al., 2000)
Merck's scientists interpreted the finding as a protective effect of naproxen in
reducing the risk of MI in high cardiovascular risk patients by 80 percent
(which some commentators have noted would make naproxen three times as effective
as aspirin). The results of the VIGOR study were submitted to the United States
Food and Drug Administration (FDA) in February 2001, which led to the
introduction, in April 2002, of warnings on Vioxx labeling concerning the
increased risk of cardiovascular events (heart attack and stroke).
In sum, the VIGOR study suggested that medium-term use of rofecoxib resulted in
nearly four-times the risk of suffering a heart attack or stroke in patients
already at high risk of adverse cardiovascular events compared to patients
receiving a placebo. There was no difference in risk for patients with normal
cardiovascular risk.
APPROVe Study
In 2001, Merck commenced the APPROVe (Adenomatous Polyp Prevention on Vioxx)
study, a three year trial with the primary aim of evaluating the efficacy of
rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been
approved for this indication, and it was hoped to add this to the indications
for rofecoxib as well. An additional aim of the study was to further evaluate
the cardiovascular safety of rofecoxib.
The APPROVe study was terminated early when the preliminary data from the study
showed an increased relative risk of adverse thrombotic cardiovascular events
(including heart attack and stroke), beginning after 18 months of rofecoxib
therapy. In patients taking rofecoxib, versus placebo, the relative risk of
these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100
patient years). The results from the first 18 months of the APPROVe study did
not show an increased relative risk of adverse cardiovascular events. (Bresalier
et al., 2005) Previous Phase III clinical trials had also not shown this trend.
(Swan, 2004)
In sum, the APPROVe study suggested that long-term use of
rofecoxib resulted
in nearly twice the risk of suffering a heart attack or stroke compared to
patients receiving a placebo.
Vioxx Withdrawal
Merck publicly announced the withdrawal of the drug from the market worldwide on
September 30, 2004.
In addition to its own studies, on September 23, 2004 Merck apparently received
information about new research by the FDA that supported previous findings of
increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA
analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks,
30 to 40 percent of which were probably fatal, in the five years the drug was on
the market.
On November 5 the medical journal The Lancet published a meta-analysis of the
available studies on the safety of rofecoxib (Jüni et al., 2004). The authors
concluded that, owing to the known cardiovascular risk, rofecoxib should have
been withdrawn several years earlier. The Lancet published an editorial which
condemned both Merck and the FDA for the continued availability of rofecoxib
from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et
al. meta-analysis (Merck & Co., 2004).
Other COX-2 Inhibitors
It is currently unknown whether the increased risk of adverse cardiovascular
events is common to all COX-2 inhibitors. Recent studies have demonstrated the
increased risk of cardiovascular events associated with the use of celecoxib,
valdecoxib and parecoxib. (Solomon et al., 2005; Nussmeier et al., 2005)
Newer and more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and
lumiracoxib (Prexige), are currently undergoing Phase III/IV clinical trials. It
is likely that these trials will be extended in order to supply additional
evidence of cardiovascular safety.
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