Valdecoxib Withdrawal Leaves Pain Relief Treatment Gap

Abstract

On September 30, 2004, Merck & Co. announced it was recalling Vioxx (rofecoxib), a drug that selectively inhibits one form of prostaglandin endoperoxide synthase, commonly known as cyclooxygenase-2 (COX-2). This prescription nonsteroidal anti-inflammatory drug (NSAID) received FDA approval in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms. It was later approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children. The recall followed news from a large clinical trial in which long-term use of the drug (18 months or more) doubled participants’ risk of heart attack and stroke. While describing this risk as “small” to any particular patient, the FDA said, “We think Merck is doing the right thing.”The Vioxx decision sparked questions about the safety of all selective COX-2 inhibitors, including Bextra (valdecoxib) and Celebrex (celecoxib) manufactured by Pfizer Inc. But 6 months later, after concluding that the risks of Bextra outweigh its benefits, the federal agency added to a series of controversial news headlines by requesting that Pfizer voluntarily withdraw Bextra. This decision came after an FDA advisory panel in February recommended that the FDA allow Bextra and Celebrex to remain on the market, though most experts agreed the drugs presented potentially fatal cardiovascular risks. “In fact, the panel concluded there were significant risks with these drugs and that they should only be used as second-line agents, after conventional NSAIDS first, with or without gastric cytoprotection,” says Dr. Bernard Levin, Professor of Medicine and Vice President for Cancer prevention at the University of Texas M.D. Anderson Cancer Center. Levin, who was present at the panel’s presentation, says, “the vote was very tight and concerns were expressed about Bextra.” He adds that the ‘flavor’ of the panel’s recommendations, compared with news reports, “was much more conservative.”In addition to these risks, Bextra also was linked to the deadly skin disease, Stevens-Johnson syndrome. While disagreeing with the FDA’s request, Pfizer, Inc. announced on April 7 that it would suspend sales of the drug pending further discussions with the agency.With the FDA’s Bextra ruling, Celebrex became the only COX-2 inhibitor available, but the agency asked Pfizer to revise the drug’s label (package insert) to include a boxed warning highlighting the potential for increased risk of cardiovascular events “and the well-described, serious, potential life-threatening gastrointestinal bleeding associated with their use.” In addition, manufacturers of nonprescription (over-the-counter) NSAIDs were asked to revise their labeling to provide more specific information about the potential cardiovascular and GI risks of their individual products and to remind patients of the limited dose and duration of treatment of these products in accordance with the package instructions. Until Vioxx and Bextra were withdrawn, the combined yearly sales of COX-2 inhibitors exceeded $5 billion.Emergence of the idea in the late 1980s that selective COX-2 inhibitors might effectively relieve pain without the major side effect of GI bleeding associated with NSAIDs led a number of pharmaceutical companies to move from basic science to new drug development. But “the actual proof of enhanced safety turned out to be more elusive,” writes Dr. Jeffrey M. Drazen, Editor-in-Chief of The New England Journal of Medicine and Distinguished Parker B. Francis Professor of Medicine, Harvard Medical School. In an editorial in the journal, Drazen noted that when the first 2 drugs in this class were approved by the Food and Drug Administration in 1999, the lack of evidence of a clear benefit with respect to gastrointestinal safety prevented the manufacturers from making the very claim that had been the reason for developing these agents in the first place. Drazen points to results of 2 large studies of the drugs that were published in 2000. “In the Celecoxib Long-Term Arthritis Safety Study (CLASS), the apparent gastrointestinal protective effect of celecoxib noted at the 6-month analysis had evaporated at the 12-month analysis. Some have speculated that this lack of a demonstrable benefit might have been due to the fact that patients were allowed to continue the use of low-dose aspirin.” In contrast, he added, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study prohibited the use of low-dose aspirin and demonstrated a reduced incidence of gastrointestinal lesions after long-term use of rofecoxib, compared with naproxen.According to Levin, a characteristic of the early studies was lack of placebo controls, thus rendering it difficult to clearly determine the differential nature of side effects, of which there were many. “It’s only when they started doing placebo controls that these effects, particularly cardiovascular, became obvious,” he says. Thus, as Drazen notes, the VIGOR study showed a higher incidence of myocardial infarction in the rofecoxib group than in the control group treated with naproxen. “But because the study lacked a placebo group, it was unclear whether the effect was due to an increased cardiovascular risk with rofecoxib or a protective effect of naproxen, or whether this was merely a chance finding.”Still, as some critics have stated, the CLASS and VIGOR trials did show an increased risk of myocardial infarction. But “rather than consider this finding a major danger signal, the manufacturers designed trials to show efficacy for other indications and enhanced the cardiovascular safety monitoring in these subsequent trials,” writes Drazen. For example, efficacy trials were launched that were designed to investigate the prevention of recurrent colon polyps and the management of postoperative pain. “And when they started doing placebo-controlled trials for the prevention of polyps, the cardiovascular problems began to emerge as a serious issue,” Levin says. In September 2004, Merck withdrew Vioxx from the market because its recurrent polyp prevention trial showed increased cardiovascular toxicity.“Keep in mind that these drugs (selective Cox-2 inhibitors) were intended originally for short-term administration,” says Levin, adding that the early trials were for 6 months, or 1 year. “Now, you were looking at 2.5–3 years of administration.” The cardiovascular data of the colon polyp trial, as well as the cardiovascular data from a National Cancer Institute trial on celecoxib appear in The New England Journal of Medicine, March 17, 2005. Also reported in that issue of the journal are the cardiovascular toxicity data from a trial of another COX-2 inhibitor, valdecoxib (and its intravenous prodrug, parecoxib). This latter trial examined pain relief in patients recovering from coronary-artery bypass surgery. It showed an increased incidence of cardiovascular end points at 30 days among patients who had received a total of only 10 days of COX-2 inhibition.For Levin, the trials raise several practical questions. “The point is that the number of actual (cardiovascular) events is very small, particularly with celecoxib. The question arises that if you exclude everyone with some sort of cardiovascular history—previous MI, stroke, atherosclerotic cardiovascular disease—could you reduce the risk substantially not to warrant any danger? The question is raised as to how well must side effects be managed. For example, if you give a drug that causes high blood pressure, which some of these agents do, were these patients adequately and aggressively managed for this condition? We don’t know that. There’s no way of knowing that from the trials, but in practice what does that mean? How much do you have to be on top of those issues to make this a safer (class of) drug?”“It ultimately gets down to risk and benefit,” Levin says, noting that the “gray areas” between high cardiovascular risk versus low benefit and low cardiovascular risk versus high benefit (pain relief, better mobility, improved quality of life) are the most problematic. “In these gray areas, patients should discuss the situation with their physician. Some may need to be followed more closely than others and must report side effects clearly.”See The New England Journal of Medicine 2005;352:(March 17)no. 11. On September 30, 2004, Merck & Co. announced it was recalling Vioxx (rofecoxib), a drug that selectively inhibits one form of prostaglandin endoperoxide synthase, commonly known as cyclooxygenase-2 (COX-2). This prescription nonsteroidal anti-inflammatory drug (NSAID) received FDA approval in May 1999 for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain in adults, and for the treatment of menstrual symptoms. It was later approved for the relief of the signs and symptoms of rheumatoid arthritis in adults and children. The recall followed news from a large clinical trial in which long-term use of the drug (18 months or more) doubled participants’ risk of heart attack and stroke. While describing this risk as “small” to any particular patient, the FDA said, “We think Merck is doing the right thing.” The Vioxx decision sparked questions about the safety of all selective COX-2 inhibitors, including Bextra (valdecoxib) and Celebrex (celecoxib) manufactured by Pfizer Inc. But 6 months later, after concluding that the risks of Bextra outweigh its benefits, the federal agency added to a series of controversial news headlines by requesting that Pfizer voluntarily withdraw Bextra. This decision came after an FDA advisory panel in February recommended that the FDA allow Bextra and Celebrex to remain on the market, though most experts agreed the drugs presented potentially fatal cardiovascular risks. “In fact, the panel concluded there were significant risks with these drugs and that they should only be used as second-line agents, after conventional NSAIDS first, with or without gastric cytoprotection,” says Dr. Bernard Levin, Professor of Medicine and Vice President for Cancer prevention at the University of Texas M.D. Anderson Cancer Center. Levin, who was present at the panel’s presentation, says, “the vote was very tight and concerns were expressed about Bextra.” He adds that the ‘flavor’ of the panel’s recommendations, compared with news reports, “was much more conservative.” In addition to these risks, Bextra also was linked to the deadly skin disease, Stevens-Johnson syndrome. While disagreeing with the FDA’s request, Pfizer, Inc. announced on April 7 that it would suspend sales of the drug pending further discussions with the agency. With the FDA’s Bextra ruling, Celebrex became the only COX-2 inhibitor available, but the agency asked Pfizer to revise the drug’s label (package insert) to include a boxed warning highlighting the potential for increased risk of cardiovascular events “and the well-described, serious, potential life-threatening gastrointestinal bleeding associated with their use.” In addition, manufacturers of nonprescription (over-the-counter) NSAIDs were asked to revise their labeling to provide more specific information about the potential cardiovascular and GI risks of their individual products and to remind patients of the limited dose and duration of treatment of these products in accordance with the package instructions. Until Vioxx and Bextra were withdrawn, the combined yearly sales of COX-2 inhibitors exceeded $5 billion. Emergence of the idea in the late 1980s that selective COX-2 inhibitors might effectively relieve pain without the major side effect of GI bleeding associated with NSAIDs led a number of pharmaceutical companies to move from basic science to new drug development. But “the actual proof of enhanced safety turned out to be more elusive,” writes Dr. Jeffrey M. Drazen, Editor-in-Chief of The New England Journal of Medicine and Distinguished Parker B. Francis Professor of Medicine, Harvard Medical School. In an editorial in the journal, Drazen noted that when the first 2 drugs in this class were approved by the Food and Drug Administration in 1999, the lack of evidence of a clear benefit with respect to gastrointestinal safety prevented the manufacturers from making the very claim that had been the reason for developing these agents in the first place. Drazen points to results of 2 large studies of the drugs that were published in 2000. “In the Celecoxib Long-Term Arthritis Safety Study (CLASS), the apparent gastrointestinal protective effect of celecoxib noted at the 6-month analysis had evaporated at the 12-month analysis. Some have speculated that this lack of a demonstrable benefit might have been due to the fact that patients were allowed to continue the use of low-dose aspirin.” In contrast, he added, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study prohibited the use of low-dose aspirin and demonstrated a reduced incidence of gastrointestinal lesions after long-term use of rofecoxib, compared with naproxen. According to Levin, a characteristic of the early studies was lack of placebo controls, thus rendering it difficult to clearly determine the differential nature of side effects, of which there were many. “It’s only when they started doing placebo controls that these effects, particularly cardiovascular, became obvious,” he says. Thus, as Drazen notes, the VIGOR study showed a higher incidence of myocardial infarction in the rofecoxib group than in the control group treated with naproxen. “But because the study lacked a placebo group, it was unclear whether the effect was due to an increased cardiovascular risk with rofecoxib or a protective effect of naproxen, or whether this was merely a chance finding.” Still, as some critics have stated, the CLASS and VIGOR trials did show an increased risk of myocardial infarction. But “rather than consider this finding a major danger signal, the manufacturers designed trials to show efficacy for other indications and enhanced the cardiovascular safety monitoring in these subsequent trials,” writes Drazen. For example, efficacy trials were launched that were designed to investigate the prevention of recurrent colon polyps and the management of postoperative pain. “And when they started doing placebo-controlled trials for the prevention of polyps, the cardiovascular problems began to emerge as a serious issue,” Levin says. In September 2004, Merck withdrew Vioxx from the market because its recurrent polyp prevention trial showed increased cardiovascular toxicity. “Keep in mind that these drugs (selective Cox-2 inhibitors) were intended originally for short-term administration,” says Levin, adding that the early trials were for 6 months, or 1 year. “Now, you were looking at 2.5–3 years of administration.” The cardiovascular data of the colon polyp trial, as well as the cardiovascular data from a National Cancer Institute trial on celecoxib appear in The New England Journal of Medicine, March 17, 2005. Also reported in that issue of the journal are the cardiovascular toxicity data from a trial of another COX-2 inhibitor, valdecoxib (and its intravenous prodrug, parecoxib). This latter trial examined pain relief in patients recovering from coronary-artery bypass surgery. It showed an increased incidence of cardiovascular end points at 30 days among patients who had received a total of only 10 days of COX-2 inhibition. For Levin, the trials raise several practical questions. “The point is that the number of actual (cardiovascular) events is very small, particularly with celecoxib. The question arises that if you exclude everyone with some sort of cardiovascular history—previous MI, stroke, atherosclerotic cardiovascular disease—could you reduce the risk substantially not to warrant any danger? The question is raised as to how well must side effects be managed. For example, if you give a drug that causes high blood pressure, which some of these agents do, were these patients adequately and aggressively managed for this condition? We don’t know that. There’s no way of knowing that from the trials, but in practice what does that mean? How much do you have to be on top of those issues to make this a safer (class of) drug?” “It ultimately gets down to risk and benefit,” Levin says, noting that the “gray areas” between high cardiovascular risk versus low benefit and low cardiovascular risk versus high benefit (pain relief, better mobility, improved quality of life) are the most problematic. “In these gray areas, patients should discuss the situation with their physician. Some may need to be followed more closely than others and must report side effects clearly.” See The New England Journal of Medicine 2005;352:(March 17)no. 11.