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Part 2: Vioxx Withdrawal Prompts Reevaluation of COX-2 Inhibitor Safety In a statement on Oct. 1, Pfizer concluded that based on long-term clinical trials in more than 6,000 patients, celecoxib did not increase the risk of myocardial infarction or stroke in patients with arthritis and pain, even at higher-than- recommended doses. Pfizer vice president Mitch Gandelman went on to suggest that the company would investigate whether celecoxib might reduce cardiovascular risk, according to a New York Times story on Oct. 4. In support of this hypothesis, he mentioned two small- scale university studies but acknowledged that the evidence was "scant and inconclusive." As of press time, Mr. Gandelman and Pfizer representatives had not returned Medscape's calls requesting comments. Safety of Valdecoxib Pfizer's drug valdecoxib (Bextra) is also "under a cloud because another FDA physician reviewing the data on that drug concluded there may be an increased cardiovascular risk," said Dr. Wolfe, who is also an adjunct professor of internal medicine at Case Western Reserve University in Cleveland, Ohio. "I think it is very likely that the effect of increasing cardiovascular risk is a class effect." According to agency files obtained in a lawsuit by Public Citizen, an unredacted review by the FDA Medical Officer recommended nonapproval for valdecoxib for acute pain, citing the Coronary Artery Bypass Graft (CABG) Surgery study 035. Even though the entire study population received prophylactic low-dose aspirin, this trial showed an excess of serious cardiovascular thromboembolic adverse events including death in association with the use of valdecoxib, 40 mg twice daily, when added to ad lib parenteral narcotic analgesia. In other databases, including formal safety Trials 47 and 62, valdecoxib at doses higher than 20 mg per day was associated with a greater incidence of edema and hypertension than were ibuprofen, naproxen, and diclofenac. Safety of Lumiracoxib In the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) comparing lumiracoxib with naproxen or ibuprofen, serious gastrointestinal events were significantly lower in the lumiracoxib group, but only in patients not taking aspirin. Although the trial lacked power to detect a difference in the rates of cardiovascular events in nonaspirin users, there was a nonsignificant increase in the lumiracoxib group (0.26 vs 0.18 per 100 patient-years; hazard ratio, 1.47). The conundrum over COX-2 inhibitors may have a chilling effect on drugs awaiting approval, which is justified if increased cardiovascular risk is a class effect, but unfortunate if the risk is exclusive to rofecoxib. The FDA and other regulatory agencies might ask for greater quantities and longer duration of safety data before approval. Although lumiracoxib is already approved in the U.K., the FDA rejected Novartis's application last year, requesting more efficacy data. In a trial of 18,000 patients, lumiracoxib reduced the risk of gastrointestinal adverse effects without increasing the risk of myocardial infarction compared with ibuprofen and naproxen. However, in a commentary in the Aug. 21 issue of The Lancet, Eric J. Topol, MD, from the Cleveland Clinic Foundation in Ohio, noted that the trial excluded many people with coronary artery disease and demonstrated potential problems with liver toxicity. Risk-Benefit Data After analyzing benefit-to-risk ratio, some experts have concluded that even a small increase in cardiovascular risk for the coxibs may not justify their use, given limited evidence of greater efficacy or lower gastrointestinal toxicity than other NSAIDs. In a recent cost-effectiveness analysis by Rachel Elliott, BPharm, MRPharmS, PhD, nonselective NSAIDs plus proton-pump inhibitors or misoprostol were more cost- effective than COX-2 inhibitors for preventing severe gastrointestinal bleeding, according to Dr. Chen. "One has to wonder, what is the point of taking [coxibs], if they don't have any advantage in terms of gastrointestinal toxicity over the older NSAIDs," Dr. Wolfe said. "They are no more effective than the older NSAIDs. Unlike the older NSAIDs, there is some concern about increased cardiovascular risk." Dr. Chen and colleagues conducted a systematic review (J Clin Pharm Ther., June 2004;29[3]:215-229) of the analgesic efficacy and tolerability of COX-2 inhibitors for postoperative pain control in 18 randomized controlled trials enrolling a total of 2,783 patients. Relief of orthopaedic pain was no different with rofecoxib 50 mg or naproxen 550 mg. Although the adverse effects of single-dose COX-2 inhibitors were generally mild and less than nonselective NSAIDs, there was no significant difference. Overall, the investigators concluded that the analgesic efficacy and tolerability of single-dose COX-2 inhibitors were better than for opioid-containing analgesics and similar to nonselective NSAIDs, but they recommended further studies to examine the efficacy and tolerability of COX-2 inhibitors. "Since the launch of COX-2 inhibitors, debates over their benefits (ie, decreasing severe gastrointestinal adverse events) and therapeutic roles is still going on. The trade-off between their risk and benefit is still not clear," Dr. Chen said. "The 'class effect' of cardiovascular diseases is one of the concerns with other COX-2 inhibitors.... We need more head-to-head comparisons, long-term follow-up, and patient-centered resources use data to answer these questions." According to Dr. Wolfe, the COX-2 enzyme has important functions throughout the body, including bone healing, repair of tendon rupture, circulation to the heart, and other protective and restorative roles, especially in emergency situations. "The body needs to be able to produce [the COX-2 enzyme] and use it as part of the healing process," Dr. Wolfe said. "By inhibiting it as the COX-2 inhibitors do, more so than the older NSAIDs, you're asking for trouble.... I think the safe way to go is really not to use any of the drugs in this class, even the ones left after Vioxx is coming off the market." In response to physicians who argue that the coxibs may be more effective in a subgroup of patients refractory to other drugs, Dr. Wolfe counters that trials and clinical experience with older NSAIDs may not have adequately tested a range of doses that might be equivalent in terms of pain relief to doses that are being used for the coxibs. "I don't think there's really any evidence at all from the standpoint of effectiveness in pain relief in treating rheumatoid arthritis or osteoarthritis that these COX-2 inhibitors are working on people who have never responded to the other [NSAIDs]," Dr. Wolfe said. His group is considering whether the evidence suggests that the FDA should issue a box warning for other coxibs, or even remove them from the market. Since the withdrawal of rofecoxib, class action lawsuits have emerged in Canada and in the U.S., and both Merck and the FDA have been criticized for their handling of the situation. In an early-release perspective in the New England Journal of Medicine, Dr. Topol suggests that the debacle could have been prevented had many early warning signs been heeded, and that neither Merck nor the FDA fulfilled their responsibilities to the public. Based on all the available data on rofecoxib and celecoxib available as of Aug. 22, 2001, Dr. Topol and colleagues concluded that there was a clear-cut excess number of myocardial infarctions associated with rofecoxib, and an increase with celecoxib not meeting statistical significance, mandating a trial specifically to assess cardiovascular risk and benefit of these agents in patients with established coronary artery disease. Long-term Issues Whether the damage from rofecoxib to the COX-2 class is over is still unclear. Dr. FitzGerald advocates long-term follow-up of patients in the APPROVe study to ascertain long-term risk. "Many effects may wear off very quickly, but if the drug induced hardening of the arteries, that would take longer to dissipate," Dr. FitzGerald said. "The best people to advise us now are the FDA. They are an unbiased source and they have access to more information than any investigator or any individual company. The question is whether they should offer a warning to patients at high cardiovascular risk concerning all members of the class until we have more information and whether they can give us guidance on duration of therapy in other patients." Dr. Topol calls for a full congressional review of the rofecoxib situation, claiming that Merck valued sales over safety, and that the FDA's passive position of waiting for data to accrue was not acceptable. Merck issued a response calling Dr. Topol's commentary "flawed in many important respects" and detailing the history of Merck's interaction with the FDA over rofecoxib. After the VIGOR study, Dr. Wolfe suggested that the FDA could have forced Merck to at minimum put a box warning on rofecoxib and recommend that it should be used as a last-choice drug. "My guess is that if the FDA had forced the company to do that, the drug would not have been used anywhere near as much, and even though it ultimately came off the market last week, the number of people damaged would have been reduced enormously," he said. Editor's Note: Dr. FitzGerald reports having received consulting fees from NiCox and Merck and research support from Merck. N Engl J Med. Published online Oct. 6, 2004. Reviewed by Gary D. Vogin, MD Laurie Barclay, MD Freelance writer for Medscape Medical News Medscape Medical News is edited by Deborah Flapan, assistant managing editor of news at Medscape. Send press releases and comments to [log in to unmask] SOURCE: Medscape Medical News http://www.medscape.com/viewarticle/490979 * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn