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Top Articles for 2005
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Merck's Withdrawal of Vioxx Calls the Cardiac Safety of COX-2 Inhibitors Into Question
Posted 11/03/2004
Victoria Porter
Introduction
Rofecoxib (Vioxx), a selective cyclooxygenase-2 (COX-2)-inhibiting nonsteroidal anti-inflammatory (NSAID) prescribed for the
treatment of arthritis and acute pain, was voluntarily withdrawn from the market by its manufacturer, Merck & Co., on September
30, 2004 due to an increased risk of cardiovascular events, mainly myocardial infarction (MI) and stroke.
The decision was made after a clinical study testing the prolonged use of the drug for prevention against colorectal polyps (the
Adenomatous Polyp Prevention on Vioxx [APPROVe] study) suggested that, overall, the risk of MI is doubled in patients on
rofecoxib compared with those taking placebo.[1-3]
Merck and the United States Food and Drug Administration (FDA) are now urging patients currently on Vioxx to discuss alternative
treatments with their healthcare providers. In response to the public health issue that has been brought to the fore after Merck's
withdrawal of the drug, the FDA intends to closely examine whether the cardiovascular risks posed by Vioxx are the result of a
class effect that may extend to other COX-2 inhibitors.
Rofecoxib has been on the market since 1999, and as a result of Merck's multibillion-dollar direct-to-consumer marketing and
physician-targeted ad campaigns, the drug has been prescribed to 1.3 million patients in the United States and 700,000 patients in
80 countries abroad.[2] Last year, annual sales totaled $5.6 billion.[2] The large marketing campaign and the significant number of
prescriptions of the drug have led some to contend that as many as 100,000 people may have suffered a cardiovascular event as a
result of taking rofecoxib.[4]
Criticisms also continue to surge from those who contend that the FDA failed to act quickly enough on earlier reports of the drug's
adverse events. In addition, critics have called into question the widespread healthcare implications of multibillion-dollar
marketing campaigns that make unsupported claims regarding a drug's safety and efficacy.
Mechanism of Action
COX-2 inhibitors block the action of an enzyme that many tissues throughout the body utilize to make prostanoids, compounds
that play a role in regulating an array of physiologic actions, such as inflammation, blood clotting, and protection of the stomach
lining from the destructive effects of digestive acids.[2]
Three coxibs – celecoxib (Celebrex; Pfizer), rofecoxib (Vioxx), and valdecoxib (Bextra; Pfizer) – have been approved for use by the
FDA[1]; a fourth, etoricoxib (Arcoxia, Merck), has been approved by the European regulatory authority and is currently under
consideration for FDA approval,[1] and a fifth, lumiracoxib (Prexige; Novartis), was recently approved in England and Mexico for
the treatment of acute and chronic pain and is also under marketing consideration by the FDA.[1,5]
Other pain relievers, such as aspirin, ibuprofen, and naproxen, block not only COX-2 but also COX-1, a related enzyme. COX-1
blocking action leads to irritation of the stomach lining. Therefore, the primary selling point that Merck emphasized in its marketing
of Vioxx was the fact that it inhibits COX-2 and its painful inflammatory products while having no effect on COX-1, thereby
producing fewer ulcers and other gastrointestinal problems. Researchers believe that Vioxx's claim to fame was the very same
thing that led to its downfall – its selective action on the COX-2 enzyme, although offering gastrointestinal protection, throws the
prostanoids involved in clotting out of balance.[2]
How Prolific is the Problem?
The results of the aforementioned APPROVe study, a study that included 2600 patients with colon polyps and no history of any
cardiovascular disease, reported that 3.5% of the patients assigned to rofecoxib suffered an MI or stroke, vs 1.9% of the patients
assigned to placebo (P < .001).[6]
Merck pointed to the fact that the phase 3 studies that provided the basis for FDA regulatory approval of Vioxx in 1998 did not
show an increased risk of cardiovascular events in patients taking rofecoxib compared with patients on non-naproxen NSAIDs or
compared with those taking placebo.[4]
The company, however, did notify the FDA of an elevated cardiac risk back in March 2000, after conducting the Vioxx
Gastrointestinal Outcomes Research (VIGOR) study,[7] which compared adverse effects between patients taking rofecoxib and
those taking naproxen. VIGOR demonstrated that the incidence of gastrointestinal toxicity was lower in patients taking rofecoxib
than in patients taking naproxen, but that the rofecoxib group had a higher risk of cardiovascular events than the naproxen group.
At the time of these findings, Merck believed it was not Vioxx that increased the risk, but rather, it was naproxen that protected
against it. It was also at this time when Merck announced it would begin long-term randomized clinical trials to further investigate
the cardiovascular safety profile of rofecoxib, which included the initiation of the APPROVe study.[4]
Eric J. Topol, MD, Cleveland Clinic Foundation (Cleveland, Ohio) believes the consequences are far and wide. "Given the finding
in the colon-polyp trial in low-risk patients without known cardiovascular disease – an excess of 16 myocardial infarctions or
strokes per 1000 patients – there may be tens of thousands of patients who have had major adverse events attributable to
rofecoxib," Dr. Topol wrote in a perspective published in the October 21st issue of The New England Journal of Medicine.[6]
An FDA safety official put the estimate lower, contending that 27,000 adverse events occurred among patients taking rofecoxib.
This number was based on an FDA-sponsored study of 1.4 million patients at Kaiser Permanente healthcare facilities. However,
figures cited by Dr. Topol, on the basis of his analyses of the APPROVe study and FDA safety data, are considerably higher –
he estimated that 30,000 to 100,000 people have experienced heart problems or strokes as a result of taking rofecoxib.[4]
Merck responded to Topol's article, describing his claims as "go[ing] beyond the data." In a 2-page statement, the company wrote
that "Dr. Topol neglects to mention the fact that Merck undertook three separate clinical studies designed, collectively, to assess
the cardiovascular safety of Vioxx versus placebo."
Is it a Class Effect?
In another perspective published in the same issue of NEJM, Garret A FitzGerald, MD, University of Pennsylvania, suggests that
clinical trials of all COX-2 inhibitors have shown signs of some increased cardiovascular risk.[1] He believes that it stands to
reason that depression of prostaglandin I2 formation, which occurs with the use of coxibs, would lead to elevated blood pressure
and accelerated atherogenesis, and would predispose patients taking COX-2 inhibitors to "an exaggerated thrombotic response
to the rupture of an atherosclerotic plaque."[1,4]
Right now, Merck's biggest focus is Vioxx; however, concerns have the potential to arise with the other COX-2 inhibitor the
company has developed, etoricoxib. Although a 1-year trial studying the effects of etoricoxib in 7000 people with osteoarthritis
demonstrated that rates of serious adverse events such as MI, stroke, and blood clots were no higher in the etoricoxib-treated
patients than in those receiving diclofenac, patients treated with etoricoxib did have a reportedly higher rate of hypertension
compared with the diclofenac group.[8]
Merck is not the only pharmaceutical manufacturer that will be under scrutiny in the aftermath of the Vioxx saga. Pfizer, in defense
of its own coxibs, Bextra and Celebrex (celecoxib), has been quick to respond to challenges that the use of all COX-2 inhibitors
poses a heightened risk of cardiac events. According to Pfizer, 3 long-term studies of Celebrex involving more than 6000 patients
have failed to show "any significant safety issues and are expected to continue to completion."[9] Pfizer believes its drug does
not pose the same cardiovascular risks as Vioxx does because their different chemical structures translate into different safety
profiles.[9]
To quell any lingering concerns, however, Pfizer announced on October 18th that it will sponsor a major clinical study to further i
nvestigate the effects of celecoxib in osteoarthritis patients at high risk for cardiac disease. This multicenter, randomized,
placebo-controlled trial is expected to begin in early 2005 and will be conducted over a period of at least 2 years. The aim of the
trial is to assess the effects of celecoxib on inflammation and cardiovascular events. It will enroll more than 4000 patients from
major hospitals and universities worldwide who have had a recent MI and also have a history of osteoarthritis. Pfizer reported that
rigorous monitoring of cardiovascular safety will be conducted by an independent data safety monitoring committee.[10]
Pfizer has also had to address the current status of its other widely marketed COX-2 inhibitor, Bextra. In mid-October, the company
issued a letter to healthcare professionals stating that the use of Bextra to manage postoperative pain in coronary artery bypass
graft surgery patients increased the risk of cardiovascular events. Pfizer reported, however, that the risk of cardiovascular events
was not increased in patients who underwent general surgery or in those patients treated with the drug for the management of
arthritis.
Merck and Pfizer are not the only targets; it is likely that other coxib manufacturers will also go under the regulatory microscope --
and not just by the FDA; the European Medicines Agency in London has also expressed the intention of reviewing safety data on
all drugs of this class.[4]
Safety Concerns — Did FDA Address Them Quickly Enough?
In both NEJM pieces, Drs. Topol and FitzGerald chastised the FDA for not acting promptly enough on earlier reports of adverse
events associated with the use of rofecoxib.
In his article, Dr. Topol criticized the FDA for waiting 2 years after receiving notification from Merck about possible cardiac risks
associated with rofecoxib before acting on the information. Although the FDA approved the drug in 1999, it wasn't until February
2001 that the FDA Arthritis Advisory Committee convened to discuss the cardiovascular risks that had been reported in Merck's
pre-approval studies. Dr. Topol noted an earlier analysis of all available data on rofecoxib and celecoxib that he and his colleagues
published in August 2001.[11] They found a disproportionately high number of MIs seen in patients taking rofecoxib, and
concluded at that time that patients with coexisting osteoarthritis and heart disease have the highest risk of cardiovascular events
and may represent the largest segment of the population for whom rofecoxib was being prescribed. They also strongly believed
that a trial specifically assessing cardiovascular risks associated with these agents, especially in patients with established
coronary artery disease, who often have osteoarthritis as a comorbidity, should have been conducted.
Referring back to this recommendation, Dr. Topol wrote: "The trial would have prospectively determined the incidence of
cardiovascular events, whose possible association with coxib treatment had not been anticipated in the early and pivotal trials of
these drugs. . . . Unfortunately, such a trial was never done.".[6]
Dr. Topol also pointed out that although the FDA has the authority to mandate that a trial be conducted, it never took the initiative
to do so. He noted that the responsibility for the consequences associated with a drug should be shared between the FDA and
Merck. "The senior executives at Merck and the leadership at the FDA share responsibility for not having taken appropriate action
and not recognizing that they are accountable for the public health," Dr. Topol wrote.
Meanwhile, the evidence of rofecoxib-associated risks of MI and other serious cardiovascular events continued to mount, as one
epidemiologic study after another – involving populations as large as 1.4 million patients – demonstrated these risks, Dr. Topol
noted. "Each time a study was presented or published, there was a predictable and repetitive response from Merck, which claimed
that the study was flawed and that only randomized, controlled trials were suitable for determining whether there was any risk," he
wrote.[6]
Commenting on the consequences of generalizing a study's findings to a larger population of patients, the editors of The Lancet
published an editorial in the October 9th issue pointed out that physicians must make themselves more aware of the preliminary
nature of the safety and efficacy data that are provided for newly licensed drugs. "For rofecoxib, the original safety data were
based on results from approximately 5000 patients. In comparison with the 2 million people receiving the drug until last week, this
is a very small number and helps to explain how an important side-effect could have been missed, and subsequent confidence in
the drug misplaced. For all newly licensed drugs, confidence about safety can only be provisional."[12]
Dr. Topol noted that it was really not until April 11, 2002, that the FDA took a significant action by instructing Merck to include
certain precautions about cardiovascular risks in its package insert. In addition, the Agency sponsored one of the large
epidemiologic studies performed in a cohort of Kaiser Permanente patients. However, he believes that neither Merck nor the FDA
"fulfilled its responsibilities to the public, noting that "the FDA's passive position of waiting for data to accrue is not acceptable.
" Emphasizing the magnitude of the problem, he wrote: "Considering the tens of millions of patients who were taking rofecoxib,
we are dealing with an enormous public health issue. Even a fraction of a percent excess in the rate of serious cardiovascular
events would translate into thousands of affected people."[6]
Dr. FitzGerald, too, admonished the FDA for not taking a more active role. "Only the FDA can provide unbiased and informed
guidance; it has a role to play beyond watchful waiting," he argued. "In the absence of such guidance, what should physicians
and their patients do?"[1]
Prior to the release of the APPROVe study findings, Dr. FitzGerald noted, the evidence from the VIGOR and Therapeutic Arthritis
Research and Gastrointestinal Event Trial (TARGET)[13] trials suggested that gastrointestinal benefit from coxibs outweighed the
evidence of cardiovascular risk. But the burden of proof was shifted after the APPROVe study results were released, he noted.
"We now have clear evidence of an increase in cardiovascular risk that revealed itself in a manner consistent with a mechanistic
explanation that extends to all the coxibs. It seems to be the time for the FDA urgently to adjust its guidance to patients and
doctors to reflect this new reality."[1]
Dr. FitzGerald believes that "it is essential to determine whether the cardiovascular risk is or is not a class effect. The burden of
proof now rests with those who claim that this is a problem for rofecoxib alone and does not extend to other coxibs. We must
remember that the absence of evidence is not evidence of absence."[1]
Rofecoxib's main selling point was that it was safer than its competitors because it was expected to cause fewer stomach ulcers
than many other painkillers. When the first COX-2 inhibitors came on the market in January 1999, they were aimed at a broad
group of consumers – those individuals who did not have effective pain relief from other available treatments. Arthritis sufferers
were deemed most likely to benefit from rofecoxib, since up to 25% have ulcers if they take NSAIDs regularly. Physicians believed
that elderly people and other patients taking blood thinners such as warfarin, in whom bleeding ulcers would be fatal, would
especially benefit. As a result of Merck's intensive marketing efforts, 52% of physicians were willing to write prescriptions for
COX-2 inhibitors if patients requested them and needed painkillers, according to the results of a 2001 survey of 2300 physicians'
prescribing practices.[2]
Although COX-2 inhibitors have lived up to their claim of producing fewer ulcers and other types of stomach irritation, Jerry Avorn, MD, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, and author of the book, Powerful Medicine: The Benefits, Risks, and Costs of Prescription Drugs, believes that the widespread use of rofecoxib by people who didn't need the modest amount of stomach protection it offered "has cost billions of dollars that could have been better used for other purposes in our health care system."[2]
Nevertheless, Merck believes its withdrawal of rofecoxib from the market demonstrates their conscientiousness in protecting the public health. "We are taking the action because we believe it serves the best interests of patients," said Raymond V Gilmartin, Merck's Chairman, President, and Chief Executive Officer. "Although we believe it would have been possible to continue to market Vioxx with labeling that would incorporate these new data, given the availability of alternative therapies, and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take."[14]
Conclusions
The aforementioned Lancet editorial nicely sums up the lessons we have learned from the Vioxx story: "Merck responded well to this latest piece of the rofecoxib jigsaw puzzle. However, the real picture of cardiovascular risk has been apparent for some time and Merck's vigorous defence of this drug in the past was clearly an error. If the dangers associated with rofecoxib were not proven, they were certainly possible, even probable, given the available data, and it should not have been left to a small trial in a novel application to reveal them."[12]
The Lancet editors went on to say that it is up to the FDA and other drug regulators to reassess the safety and efficacy thresholds required for the licensing of a new pharmaceutical product. "The Vioxx story is one of blindly aggressive marketing by Merck mixed with repeated episodes of complacency by drug regulators. . . . Without more vigilant drug regulation in the future, doctors will continue to be misled and patients' lives will continue to be endangered."[12]
Public Health Advisory
Meanwhile, the FDA has issued a public health advisory recommending that patients who were taking rofecoxib consult their physicians for an alternative prescription. In a written statement, FDA Commissioner Lester M Crawford opined that "Merck did the right thing by promptly reporting these findings to FDA and voluntarily withdrawing the product from the market. . . . Although the risk that an individual patient would have a heart attack or stroke related to Vioxx is very small, the study that was halted suggests that, overall, patients taking the drug chronically face twice the risk of a heart attack compared to patients receiving a placebo."[3]
Patients who have been advised to discontinue rofecoxib should be reassured by their physicians that there is no danger in stopping rofecoxib abruptly and that it does not need to be tapered, according to researchers. Investigators also reported that there is no reason to suspect any long-term or delayed effects in patients who have stopped taking the drug, because once the drug has been flushed out of the system, the affected enzyme molecules slowly regain their activity, and the new ones that are manufactured by cells are unaffected. "The toxicity should not be long-lasting," according to Emma A Meagher, MD, University of Pennsylvania School of Medicine. "It's contributing to thrombosis, which is an acute event."[15]
Patients and healthcare professionals may obtain further information from www.merck.com and www.vioxx.com, or by calling 1-888-368-4699.
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