Experts debate "house of coxibs"

Allison Gandey

December 29, 2004

Dec 29, 2004

Cleveland, OH - The deliberations over cyclooxygenase-2 inhibitors rage on in an early-release article in the Journal of the American Medical Association and this week's issue of the New England Journal of Medicine, where experts debate the value of coxibs, the conduct of Merck & Co, and the role of the US Food and Drug Administration.

With the considerably higher cost, marginal efficacy, and known cardiovascular risks of the remaining agents on the market, valdecoxib and celecoxib, it would seem prudent, at the least, to avoid using these agents as first-line therapy.

In an editorial published in JAMA, Dr Eric Topol (Cleveland Clinic Foundation, OH and editor-in-chief of www.jointandbone.org's sibling website, www.theheart.org) writes there has hardly been a day without significant news on COX-2 inhibitors since rofecoxib (Vioxx, Merck) was withdrawn from the market [ 1 ]. "In the wake of the high density of new data on coxibs, several important issues now need to be confronted," he writes. "First, is there any continuing role for coxibs?"

Topol points out that only rofecoxib has been shown to reduce gastrointestinal complications compared with naproxen, but valdecoxib (Bextra, Pfizer) and celecoxib (Celebrex, Pfizer) have never been definitively confirmed to protect against gastrointestinal complications. "Importantly, there have not been any direct comparative (head-to-head) trials of 1 of the agents vs another, which is the only way to definitively establish likeness or difference between the drugs," he writes.

Topol notes that while coxib superiority over nonsteroidal anti-inflammatory drugs (NSAIDs) for relief of arthritic pain has not been shown, many individual patients report pain relief with a coxib but not an NSAID. "With the considerably higher cost, marginal efficacy, and known cardiovascular [CV] risks of the remaining agents on the market, valdecoxib and celecoxib, it would seem prudent, at the least, to avoid using these agents as first-line therapy," he argues.

From the outset, the coxib class of medicines seemed destined for potential collapse.

"There are major concerns about how an entire drug class has gone awry with respect to unleashing significant cardiovascular hazard," Topol writes. "From the outset, the coxib class of medicines seemed destined for potential collapse. These drugs were mass-marketed from the moment they were commercially available in the new world of direct-to-consumer advertising, with unrealistic expectations about pain relief, marked gastrointestinal protection, and safety." Topol argues that rather than a sufficient waiting period after approval to firmly establish safety in the large, representative real-world population, "the unbridled promotion exacerbated the public-health problem."

Topol points out that in recent weeks, there has been considerable speculation on how the FDA can be bolstered to preempt a coxiblike problem in the future. "An independent drug safety agency or center that compartmentalizes the vital functions of approval and surveillance seems to be gathering broad support," he writes. "[P]roviding more authority to the FDA to shape and require the execution of vital trials is perhaps the most important lesson from the coxibs."


Merck responds

Replying to another article by Topol, this 1 published in the October 21, 2004 issue of the New England Journal of Medicine and previously reported by rheuma wire [ 2 ], Drs Peter Kim and Alise Reicin (Merck Research Laboratories, West Point, PA) write in a letter, "Merck has been proactive and conscientious in evaluating the cardiovascular profile of rofecoxib; Dr Topol's remarks to the contrary in his Perspective article are false" [ 3 ].

Kim and Reicin argue that Topol's description of the drug's time line "obfuscates the facts." They explain that the FDA approved Vioxx in May 1999 and the clinical data then existing did not suggest an adverse cardiovascular effect. "Nevertheless, because the literature suggested a hypothetical possibility of both cardioprotective and prothrombotic effects of COX-2 inhibitors, Merck initiated adjudication of cardiovascular events by an external expert panel at the end of 1998 (before the Vioxx Gastrointestinal Outcomes Research [VIGOR] trial began) for future studies of Merck's COX-2 inhibitors."

Kim and Reicin point out that Merck learned the preliminary VIGOR results in March 2000, which showed more cardiovascular events over a period of 1 year in patients receiving Vioxx than in those receiving naproxen [ 4 ]. They explain that the company promptly disclosed this finding to the FDA, other regulators, and the media.

Merck has been proactive and conscientious in evaluating the cardiovascular profile of rofecoxib; Dr Topol's remarks to the contrary in his Perspective article are false.

"Dr Topol neglects to mention that beginning in 2000, Merck undertook 3 prospective, randomized, placebo-controlled trials of Vioxx in more than 24 000 patients with or without known cardiovascular disease," they write, adding that after deliberations with numerous consultants, Merck finalized a protocol in 2002, which prespecified the analysis of adjudicated cardiovascular-event data from these studies as a hypothesis-testing end point. Two of these studies, Adenomatous Polyp Prevention on Vioxx (APPROVE), with approximately 2600 patients, and Vioxx in Colorectal Therapy, Definition of Optimal Regimen (VICTOR), a study of 7000 patients with a history of colon cancer, had already begun, and the third, a study of 15 000 patients at risk for prostate cancer, was initiated after consultation with regulatory agencies.

Kim and Reicin argue that before the results of the APPROVE study were available, completed and ongoing randomized trials involving more than 28 000 patients with more than 14 000 patient-years of exposure showed an incidence of cardiovascular events among patients taking Vioxx that was similar to the incidence among those taking placebo and those taking NSAIDs other than naproxen. "Because naproxen inhibits platelet aggregation in similar fashion to low-dose aspirin, we concluded that the VIGOR results were most likely due to the effects of naproxen."

Kim and Reicin note that the APPROVE study began 9 months after the FDA approved Vioxx and 1 month before the results of the VIGOR study were known. Because the study was designed to examine the effects of long-term use of rofecoxib on gastric polyps, they were able to detect an increase in cardiovascular risk that began after 18 months of continuous Vioxx therapy, they explain. "At that time, September 2004, Merck moved promptly and voluntarily to remove Vioxx from the market. The record, in short, is one of careful analysis at every stage, a continued commitment to research, and prompt and decisive action in response to clinical-study results."


The FDA responds

"Dr Topol shows a lack of understanding of the FDA's regulatory authority," write Drs Lourdes Villalba and James Witter (Food and Drug Administration, Rockville, MD) [ 5 ]. "The FDA cannot 'mandate' postmarketing clinical trials. Dr Topol also fails to appreciate the successful efforts by the FDA to negotiate ongoing evaluation of cardiovascular safety in several multiyear clinical trials, 1 of which helped to resolve the cardiovascular questions first noted in the postmarketing VIGOR study."

Dr Topol shows a lack of understanding of the FDA's regulatory authority. The FDA cannot 'mandate' postmarketing clinical trials.

Villalba and Witter note that the FDA convened an advisory committee (on February 8, 2001) to review the data from VIGOR. "The study showed a 50% decreased risk of gastroduodenal perforations, symptomatic ulcers, and bleeding with Vioxx (50 mg daily), but twice the risk of cardiovascular thrombotic events (mostly myocardial infarctions [MIs], with no differences in strokes or cardiovascular deaths), as compared with naproxen," they write, explaining that the study had several limitations that hampered the generalization of these findings.

"After careful review," the doctors write, "the expert panel (which included cardiologists) recommended that the label for Vioxx should include the unquestionable gastrointestinal advantage as well as the negative cardiovascular safety information."

Villalba and Witter argue that the finding of an increased risk of MIs and strokes in Merck's APPROVE study was unexpected, but not an accident. "The FDA worked vigorously with Merck to inform the public of the potential cardiovascular risks associated with Vioxx and to ensure adequate ascertainment and analyses of these cardiovascular events in Merck's prevention trials."


Topol replies

"In response to Drs Kim and Reicin," Topol writes, "I believe that many vital steps were not taken to evaluate the cardiovascular safety of rofecoxib properly" [ 6 ]. He points out that in 2000, along with the VIGOR trial, a second trial conducted by Merck, known as Study 090, also showed a significant excess of heart attacks and strokes among patients taking rofecoxib, as compared with controls [ 7 ]. "Together with the results of the VIGOR trial, there was indeed replication in an independent, randomized, controlled trial of an excess of the cardinal cardiovascular end point of death, heart attack, and stroke."

Topol shows that 1.3% of patients in the rofecoxib group of the 2 trials and 0.6% of patients from the control group experienced death, MI, or stroke (odds ratio 2.1, 95% CI 1.4-3.3, p=0.001).

Cardiovascular events and deaths in 2 trials of rofecoxib


Outcome
VIGOR
  Study 090
 
  Rofecoxib
Control
Rofecoxib
Control
Patients, n
4047
4029
390
588
Death, n
22
15
0
0
MI, n
20
4
3
1
Stroke, n
11
9
2
0
Total, n (%)
53 (1.3)
28 (0.7)
5 (1.3)
1 (0.2)



To download table as a slide, click on logo at the bottom of the page



Topol notes that not only was Study 090 never published and available solely through a subsequent FDA memorandum, but the data presented in the VIGOR article also suffered from errors of omission, along with erroneous information and lack of completeness. "In the VIGOR article," Topol writes, "the actual deaths were not reported, but it is stated in the article in 3 places that the overall mortality rate was similar in the 2 groups. The heart-attack rate for rofecoxib was erroneous. More than half of the thrombotic events are not presented in the VIGOR article but appear in the FDA report." Topol says the updated cardiovascular-event data from VIGOR were submitted to the FDA on October 13, 2000—six weeks before the VIGOR study was published.

Not only was Study 090 never published and available solely through a subsequent FDA memorandum, but the data presented in the VIGOR article also suffered from errors of omission, along with erroneous information and lack of completeness.

"Drs Villalba and Witter are incorrect in suggesting that the FDA cannot influence postmarketing clinical trials that a sponsor performs," Topol argues, noting that their claim that the 50% decreased risk of gastroduodenal perforations outweighed the cardiovascular risk in the VIGOR trial is not substantiated by the data. "There were no differences in the rate of perforation (0.1% in both the rofecoxib and naproxen groups). It is hard to imagine that the small protection from gastric or duodenal ulcers in the VIGOR trial is an acceptable trade-off as compared with twice the incidence of death, heart attacks, and strokes."

Topol charges that it took 14 months after the expert FDA panel convened—from February 2001 to April 2002—to minimally change the cardiovascular safety information for rofecoxib in the package insert. "After their cumulative meta-analysis, Juni et al correctly stated, 'Our findings indicate that rofecoxib should have been withdrawn several years earlier' "[ 8 ].



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Sources

  1. Topol EJ. Arthritis medicines and cardiovascular events—"house of coxibs." JAMA 2005; DOI: 10.1001/jama.293.3.366. Available at: http://jama.ama-assn.org/.

  2. Topol EJ. Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004;351:1707-1709.

  3. Kim PS and Reicin AS. Rofecoxib, Merck, and the FDA. N Engl J Med 2004; 351:2875-2876.

  4. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343:1520-1528.

  5. Villalba L and Witter J. Rofecoxib, Merck, and the FDA. N Engl J Med 2004; 351:2876.

  6. Topol EJ. Rofecoxib, Merck, and the FDA. N Engl J Med 2004; 351:2877-2878.

  7. Food and Drug Administration. Memorandum. February 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf.

  8. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: Cumulative meta-analysis. Lancet 2004; 364:2021-2029.


 

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