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MEDICAL BIOLOGY: COXIBS AND CARDIOVASCULAR EVENTS

The following points are made by Eric J. Topol (J. Am. Med. Assoc. 2005 293:366):

1) Physicians, patients, and the general public are confronted with an acute confusional state regarding the cardiovascular safety of medicines for arthritis. Since September 30, 2004, the day that rofecoxib (Vioxx) was precipitously withdrawn, there has hardly been a day without significant news on the general topic of cyclooxygenase 2 (COX-2) inhibitors. On December 9, 2004, the US Food and Drug Administration (FDA) issued a black box warning for valdecoxib (Bextra) for life-threatening skin reactions and cardiovascular risk.[1] Just over a week later, on December 17, 2004, the National Cancer Institute announced the premature cessation of a trial of celecoxib (Celebrex) known as Adenoma Prevention with Celecoxib (APC) due to a significant excess of cardiovascular death, myocardial infarction (MI), and stroke.[2]

2) APC was a trial of 2026 patients, with randomization to 1 of 3 groups: placebo; celecoxib, 200 mg twice daily; or celecoxib, 400 mg twice daily. The patients, each of whom had an adenomatous polyp removed before enrollment, were followed up for a mean of 33 months (of a planned 60 months) while taking the study drug, with the primary objective of limiting the development of colorectal cancer. A significant excess of major cardiovascular events was demonstrated, with a dose-response effect (odds ratio, 2.5 for celecoxib 400-mg dose, and 3.4 at the 800-mg dose, vs placebo). The absolute excess of major cardiovascular events of 13/1000 patients at the 400-mg dose and 21/1000 patients at the 800-mg dose is similar in magnitude to the results of trials with rofecoxib and valdecoxib.[1,3] However, it is not possible to meaningfully interpret interdrug differences because the patient populations in the various trials were different; the drug doses, strength, and duration of therapy were different; and each of the drugs in the coxib class are distinct molecules with specific biological properties. While celecoxib is the least COX-2 selective in the class of 5 agents that have gone through pivotal trials,[4] lumiracoxib (Prexige) is the most selective. A trial of 18,325 patients, the largest in the field, demonstrated only modest (not statistically significant) excess of cardiovascular risk when lumiracoxib was compared with naproxen, but not when compared with ibuprofen.[5] There have not been any direct comparative (head-to-head) trials of one of the agents vs another, which is the only way to definitively establish likeness or difference between the drugs.

3) Notwithstanding these concerns, several epidemiologic studies have considered large populations of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors. In general, these studies found an increased cardiovascular hazard for rofecoxib, especially at higher doses, but not for celecoxib. Some studies therefore concluded that celecoxib did not carry any risk for MI or stroke. But in randomized trials, a signal for potential cardiovascular risk with celecoxib was present.

4) In the wake of the high density of new data on coxibs, several important issues now need to be confronted. First, is there any continuing role for coxibs? Only rofecoxib has been shown to reduce gastrointestinal complications compared with naproxen, but valdecoxib and celecoxib have never been definitively confirmed to protect against gastrointestinal complications. While coxib superiority over 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 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.

References (abridged):

1. US Food and Drug Administration. Bextra label updated with boxed warning concerning severe skin reactions and warning regarding cardiovascular risk. FDA Talk Paper. December 9, 2004. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html Accessed December 21, 2004.

2. US Department of Health and Human Services. NIH halts use of COX-2 inhibitor in large cancer prevention trial. NIH News. December 17, 2004. Available at: http://www.nih.gov/news/pr/dec2004/od-17.htm Accessed December 21, 2004.

3. Topol EJ. Failing the public health: rofecoxib, Merck, and the FDA. N Engl J Med. 2004;351:1707-1710

4. Topol EJ, Falk GW. A coxib a day won't keep the doctor away. Lancet. 2004;364:639-640

5. Farkouh ME, Kirshner H, Harrington RA. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomized controlled trial. Lancet. 2004;364:675-684

J. Am. Med. Assoc. http://www.jama.com

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MEDICAL BIOLOGY: COXIBS AND CARDIOVASCULAR DISEASE

Notes by ScienceWeek:

Drug-based management of pain is a central focus of the pharmaceutical industry, with annual revenues from the sale of such drugs in the many billions of dollars. During the past four or five decades, a wide-spectrum of pain-management drugs have been put on the market, some more commercially successful than others. Currently, the two most popular (and most profitable) pain-management drugs are Vioxx (Merck) and Celebrex (Pharmacia), but recent research suggests these drugs will soon be obsolete.

In the human body, the receptors for pain, called "nociceptors" or pain receptors, are free nerve endings -- endings not terminating on other neurons or muscle fibers or specialized sense receptors. Such free nerve endings are found in almost every tissue of the body. These free nerve endings may respond to any type of stimulus if the stimulus is strong enough to cause tissue damage. When stimuli for other sensations, such as touch, pressure, heat, and cold, reach a certain intensity, they provoke the sensation of pain as well as the relevant primary sensation. Excessive stimulation of most sensory receptors causes pain, but pain is also caused by excessive distension or dilation of a structure, prolonged muscular contractions, muscle spasms, inadequate blood flow to an organ, or the presence of certain specific chemical substances. For example, tissue injury releases certain chemical substances that stimulate pain receptors. In general, pain persists even after an initial tissue trauma occurs, since these substances linger and interact with free nerve endings.

Of these released chemical substances, the substances called "prostaglandins" are apparently of considerable importance in the physiology of pain. Prostaglandins are fatty acids secreted by cells, the prostaglandins having hormone-like actions in the immediate vicinity of the cells that release them. Once released, among other things, prostaglandins apparently increase the sensitivity of local pain receptors and so magnify the pain experienced as a result of tissue injury. This is a normal part of the so-called "inflammatory response", a general response of any tissue to injury.

In general, the term "inflammation" refers to a dynamic complex of cellular and chemical reactions occurring in affected blood vessels and adjacent tissues in response to an injury or abnormal stimulation of a tissue caused by physical, chemical, or biological agents. A primary stage of inflammation consists of dilation of blood vessels and increased permeability of these blood vessels, the process occurring within minutes after injury, and involving a number of released substances, including various prostaglandins. In turn, in addition to their apparent effects on pain receptors, prostaglandins stimulate the migration of immune system cells to the injured tissue.

Given that the release of prostaglandins increases the pain associated with tissue injury, the synthesis of prostaglandins by cells of injured tissue becomes a reasonable target for pain-management drugs. The enzyme known to be involved in the cellular synthesis of various prostaglandins is called cyclooxygenase, or COX, and there are two forms of this enzyme, COX-1 and COX-2. The so-called non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen (Advil and Motrin), naproxen (Aleve and Naprosyn), indomethacin (Indocin), and common aspirin, essentially achieve their pain management effects by inhibiting both COX-1 and COX-2. That would be perfect for pain-management, except for the fact that COX-1 apparently protects the lining of the stomach and intestines against damage by stomach acids, so that when COX-1 is inhibited, the lining is more likely to be damaged by stomach acids and form ulcers. It doesn't happen to everyone who uses these drugs, but it happens to enough people to make use of these drugs in high doses problematic.

Enter the two new drugs rofecoxib (Vioxx) and celecoxib (Celebrex). The reason for the excitement concerning these drugs (and the reason for their huge marketplace value) is simple: Both Vioxx and Celebrex act by inhibiting only COX-2. They have little or no effect on COX-1, and thus involve little or no risk of ulcers in the gastrointestinal tract. Celebrex is currently Pharmacia's top drug at $2.3 billion a year in sales, and until its recent withdrawal Vioxx was Merck's second-leading drug at $1.7 billion a year in sales.

The following points are made by Garret A. FitzGerald (New Engl. J. Med. 2004 351:1709):

1) The coxibs are a subclass of nonsteroidal antiinflammatory drugs (NSAIDs) designed to inhibit selectively cyclooxygenase-2 (COX-2).(1) Their development was based on the hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate inflammation, and that cyclooxygenase-1 (COX-1) was the source of the same prostaglandins in gastric epithelium, where they afford cytoprotection. Three coxibs -- celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib -- have been approved for use by the Food and Drug Administration (FDA); a fourth, etoricoxib, has been approved by the European regulatory authority, and it and a fifth, lumiracoxib, are currently under consideration for FDA approval.

2) Coxibs have been aggressively marketed directly to consumers in the US and have rapidly dominated the prescription-drug market for NSAIDs, accounting for worldwide sales of roughly $10 billion. Rofecoxib (Vioxx) has now been withdrawn from the market by Merck, following the premature cessation, by the data and safety monitoring board, of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, which was designed to determine the drug's effect on benign sporadic colonic adenomas. This action was taken because of a significant increase by a factor of 3.9 in the incidence of serious thromboembolic adverse events in the group receiving 25 mg of rofecoxib per day as compared with the placebo group. Blood pressure was elevated in patients in the rofecoxib group early in the course of the study, but the incidence of myocardial infarction and thrombotic stroke in the two groups began to diverge progressively after a year or more of treatment.

3) Coincident with the approval of rofecoxib and celecoxib in 1999, the author and a colleagues reported that both drugs suppressed the formation of prostaglandin I2 in healthy volunteers.(2) Prostaglandin I2 had previously been shown to be the predominant cyclooxygenase product in endothelium, inhibiting platelet aggregation, causing vasodilatation, and preventing the proliferation of vascular smooth-muscle cells in vitro. However, it was assumed that prostaglandin I2 was derived mainly from COX-1, the only cyclooxygenase species expressed constitutively in endothelial cells. This assumption later proved incorrect, since studies in mice and humans showed that COX-2 was the dominant source. The individual cardiovascular effects of prostaglandin I2 in vitro contrast with those of thromboxane A2, the major COX-1 product of platelets, which causes platelet aggregation, vasoconstriction, and vascular proliferation.

4) Whereas aspirin and traditional NSAIDs inhibit both thromboxane A2 and prostaglandin I2, the coxibs leave thromboxane A2 generation unaffected, reflecting the absence of COX-2 in platelets. Increasing laminar shear stress in vitro increases the expression of the gene for COX-2, leading our group to suggest that COX-2 might be hemodynamically induced in endothelial cells in vivo. If so, suppression of the COX-2-dependent formation of prostaglandin I2 by the coxibs might predispose patients to myocardial infarction or thrombotic stroke. Thus, a single mechanism, depression of prostaglandin I2 formation, might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque. The higher a patient's intrinsic risk of cardiovascular disease, the more likely it would be that such a hazard would manifest itself rapidly in the form of a clinical event.(3-5)

References:

1. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-442

2. FitzGerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003;2:879-890

3. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665-674

4. Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004;364:675-684

5. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002;360:1071-1073

New Engl. J. Med. http://www.nejm.org

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PUBLIC HEALTH: VIOXX, MERCK, AND THE FDA

The following points are made by Eric J. Topol (New Engl. J. Med. 2004 351:1707):

1) On May 21, 1999, the pharmaceutical company Merck was granted approval by the Food and Drug Administration (FDA) to market rofecoxib (Vioxx). On September 30, 2004, after more than 80 million patients had taken this medicine and annual sales had topped $2.5 billion, the company withdrew the drug because of an excess risk of myocardial infarctions and strokes. This represents the largest prescription-drug withdrawal in history, but had the many warning signs along the way been heeded, such a debacle could have been prevented.

2) Neither of the two major forces in this five-and-a-half-year affair -- neither Merck nor the FDA -- fulfilled its responsibilities to the public. The pivotal trial for rofecoxib involved 8076 patients with rheumatoid arthritis and demonstrated that this coxib had lower gastrointestinal toxicity than naproxen.(1) Even though the drug was approved in 1999 on the basis of data submitted to the FDA, the data were not submitted to a peer-reviewed journal until the following year and did not appear in print until November 23, 2000, one and a half years after commercial approval had been granted. The cardiovascular data reported in that article were incomplete, in part because of incomplete ascertainment: the design and execution of the trial had not anticipated that untoward cardiovascular events might occur.(1)

3) It was not until February 8, 2001, that the FDA Arthritis Advisory Committee met to discuss concern about the potential cardiovascular risks associated with rofecoxib. It remains unclear why the FDA waited two years after its review and approval of rofecoxib to conduct this meeting. The author and his colleagues reviewed the data from the meeting that were made publicly accessible and published an analysis of all the available data on rofecoxib and celecoxib on August 22, 2001.(2) The primary conclusion, based on the clear-cut excess number of myocardial infarctions associated with rofecoxib and the numerical, albeit not statistically significant, excess associated with celecoxib (Celebrex), was that "it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents."(2)

4) Such a trial needed to be conducted in patients with established coronary artery disease, who frequently have coexisting osteoarthritis requiring medication and have the highest risk of further cardiovascular events. Given the very high coincidence of coronary disease and arthritis, this group may represent the largest segment of the population for whom rofecoxib was prescribed. In light of the insight that arterial inflammation is the basis for myocardial infarction and stroke and the knowledge that coxibs reduce the production of biomarkers of inflammation such as C-reactive protein and improve endothelial function, such a trial would also have been quite attractive from the standpoint of potential benefit. 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.

5) Unfortunately, such a trial was never done. The FDA has the authority to mandate that a trial be conducted, but it never took the initiative. Instead of conducting such a trial at any point -- and especially after the FDA advisory committee meeting in 2001 -- Merck issued a relentless series of publications, beginning with a press release on May 22, 2001, entitled "Merck Reconfirms Favorable Cardiovascular Safety of Vioxx" and complemented by numerous papers in peer-reviewed medical literature by Merck employees and their consultants. The company sponsored countless continuing medical "education" symposiums at national meetings in an effort to debunk the concern about adverse cardiovascular effects. The message that was duly reinforced was that rofecoxib had no cardiovascular toxicity. Only by happenstance, in a trial involving 2600 patients with colon polyps who could not have been enrolled if they had had any cardiovascular disease, was it discovered that 3.5 percent of the patients assigned to rofecoxib had myocardial infarction or stroke, as compared with 1.9 percent of the patients assigned to placebo, necessitating premature cessation of the trial and the decision to discontinue treatment with rofecoxib.(3)

References:

1. 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.

2. Mukherjee DM, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-959

3. Topol EJ, Falk GW. A coxib a day won't keep the doctor away. Lancet 2004;364:639-640

New Engl. J. Med. http://www.nejm.org

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