Vioxx Injury

Vioxx Injury


Vioxx has been removed from the market in all countries because it has been associated with heart attacks, stroke, cardiovascular injuries and other serious side effects. According to Merck, about 2 million people worldwide are currently taking Vioxx, and a total of 105 million people have taken it since it came on the market in 1999. Vioxx safety concerns include the increased incidence of blood clots tied to strokes and heart attacks found in multiple Vioxx clinical studies. Other serious ...MORE


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Rofecoxib
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Rofecoxib
Systematic (IUPAC) name
4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one
Identifiers
CAS number 162011-90-7
ATC code M01AH02
PubChem 5090
DrugBank APRD00151
Chemical data
Formula C17H14O4S
Mol. mass 314.357 g/mol
Pharmacokinetic data
Bioavailability 93%
Protein binding 87%
Metabolism hepatic
Half life 17 hours
Excretion biliary/renal
Therapeutic considerations
Pregnancy cat. C (Australia)

Legal status withdrawn

Routes oral
Rofecoxib (IPA: [rofəˈkɒksɪb]) is a nonsteroidal anti-inflammatory drug (NSAID) developed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was approved as safe and effective by the Food and Drug Administration (FDA) on May 20, 1999 and was subsequently marketed under the brand name Vioxx, Ceoxx and Ceeoxx.

Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.

On September 30, 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[1]

Rofecoxib was available on prescription as tablets and as an oral suspension.

Contents [hide]
1 The COX enzyme
2 Adverse drug reactions
3 Withdrawal from the market
3.1 VIGOR study
3.1.1 NEJM controversy
3.2 Alzheimer's studies
3.3 APPROVe study
3.4 Other studies
3.5 Withdrawal
3.6 Litigation
3.6.1 Political impact of Vioxx litigation in America
3.7 Other COX-2 inhibitors
4 Miscellaneous
5 Negative cardiovascular effects in the majority of NSAIDS
6 References
7 External links



[edit] The COX enzyme
In the early 1990s, scientists discovered that the COX enzyme had two forms, now called COX-1 and COX-2. COX-1 mediated the synthesis of prostaglandins responsible for protection of the stomach lining, while COX-2 mediated the synthesis of prostaglandins responsible for pain and inflammation. By creating “selective” NSAIDs that inhibit COX-2, but not COX-1, scientists hypothesized they could offer the same pain relief as traditional NSAIDs, but with greatly reduced risk of fatal or debilitating peptic ulcers.

Rofecoxib is a selective COX-2 inhibitor or coxib (CycloOXygenase-2 InhiBitors). Others include Pfizer’s celecoxib (Celebrex) and valdecoxib (Bextra). Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. (Bombardier et al., 2000).


[edit] Adverse drug reactions
Main article: Non-steroidal anti-inflammatory drug

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs. Rofecoxib, however, does appear to increase the risk of adverse cardiovascular events (see below).

The chief mechanism proposed to explain rofecoxib's cardiotoxicity is the suppression of prostaglandin, an anti-clotting agent in the blood (Fitzgerald, 2004). COX-2 plays a role in the production of prostaglandin. Because Vioxx inhibits the COX-2 enzyme, prostaglandin production can decrease in endothelial cells and lead to an inefficiency in declumping and vasorelaxtion. Merck, however, argues that there was no effect on prostaglandin production in blood vessels in animal testing.[1] Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionised under physiological conditions. (Reddy & Corey, 2005)

Vioxx has also been associated with cardiovascular disease, renal (kidney) disease, and heart arrhythmia.


[edit] Withdrawal from the market

[edit] VIGOR study
The VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. (Bombardier et al., 2000), had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups. Nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was accounted for by the patients at higher risk of heart attack: those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary artery bypass). (Bombardier et al., 2000)

Merck's scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks "is primarily due to" this protective effect (Targum, 2001). Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference (Michaels 2005), and some outside scientists warned Merck that this claim was implausible before VIGOR was published [2]. No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin (Karha and Topol, 2004; Solomon et al., 2002). Though Dr. Topol's 2004 paper criticized Merck's naproxen hypothesis, he himself co-authored a 2001 JAMA article stating "because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib." (Mukherjee, Nissen and Topol, 2001.)

The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001, which led to the introduction, in April 2002, of warnings on Vioxx labelling concerning the increased risk of cardiovascular events (heart attack and stroke).


[edit] NEJM controversy
Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA was not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that this data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data (Curfman et al, 2006a). They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.[3]

The editors charged that "more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article." This additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the "aspirin not indicated" group) and the editors noted that the omission "resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups." The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication. (Curfman et al., 2006b, Supplementary Material).

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the "omitted" table was printed in the text of the article. The authors stood by the original article. (Bombardier et al., 2006).

NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks). (Curfman et al., 2006b).

Some scientists have accused the NEJM editorial board of making unfounded accusations.[4], [5] Others have applauded the editorial. Renowned research cardiologist Eric Topol [6], a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up" [7]. Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying "this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies" [8].

On May 15, 2006, the Wall Street Journal reported that a late night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that "the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine's own role in aiding Vioxx sales."[2]

"Internal emails show the New England Journal's expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article." The Journal stated that NEJM's "ambiguous" language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; "the New England Journal says it didn't attempt to have these mistakes corrected."[2]


[edit] Alzheimer's studies
In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer's disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to rofecoxib (Konstam et al., 2001). Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib's safety.


[edit] APPROVe study
In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations. (Bresalier et al., 2005)

In sum, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.


[edit] Other studies
Pre-approval Phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that "study 090," a pre-approval trial, showed a 3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another [NSAID]), and an 8-fold increase in heart attacks and strokes combined compared to both control groups [9] [10]. Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib's cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes.

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005).

Furthermore, a more recent study of 114 randomized trial comprised of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia. COX-2 Inhibitor Drug Review of adverse renal and arrhythmia risk, in JAMA 2006


[edit] Withdrawal
Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.

In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.

On November 5 the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Juni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004).

In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib's benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen[11] -- though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.


[edit] Litigation
As of March 2006, there had been over 10,000 cases and 190 class actions filed against Merck over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck's warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.[12]

On August 19, 2005, a jury in Texas voted 10-2 to hold Merck liable for the death of Robert Ernst, a 59-year old man who allegedly died of a rofecoxib-induced heart attack. The plaintiffs' lead attorney was Mark Lanier. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award will almost certainly be capped at no more than USD$26.1 million because of punitive damages limits under Texas law.[13] As of March 2006, the plaintiff had yet to ask the court to enter a judgment on the verdict; Merck has stated that it will appeal.

On November 3, 2005, Merck won the second case Humeston v. Merck, a personal injury case, in Atlantic City, New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston's injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk.[14]

The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005 in Houston, Texas. The trial ended in a hung jury and a mistrial was declared on December 12, 2005. According to the Wall Street Journal, the jury hung by an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, Louisiana, where the Vioxx multi-district litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study.

On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastiointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding.

In January 2006, Garza v. Merck began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The punitive amount will be reduced to under $1 Million.

On April 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr McDarby $4.5 million in compensatory damages based on Merck's failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial.

Merck has reserved $970 million to pay for its Vioxx-related legal expenses through 2007.





[edit] Political impact of Vioxx litigation in America
The recall and litigation over rofecoxib has provoked debate over drug safety in the United States. Some argue that the U.S. Food and Drug Administration does not do enough to monitor product safety and that the rofecoxib withdrawal is an argument against tort reform. It has also been argued that litigation is an imperfect means of regulation that would overdeter companies for complying with FDA requirements, and that large awards like that in Ernst would inhibit research and development.


[edit] Other COX-2 inhibitors
It is currently unknown whether the increased risk of adverse cardiovascular events is common to all COX-2 inhibitors. Recent studies have demonstrated the increased risk of cardiovascular events associated with the use of celecoxib (Celebrex), valdecoxib (Bextra) and parecoxib (Dynastat). (Solomon et al., 2005; Nussmeier et al., 2005)

Newer and more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), are currently (circa 2005) undergoing Phase III/IV clinical trials. It is likely that these trials will be extended in order to supply additional evidence of cardiovascular safety.

A recent systematic review of 114 clinical trials, published in JAMA 2006, evaluated the adverse renal (kidney) and arrhythmia risks of celecoxib, valdecoxib, parecoxib, lumiracoxib, and etoricoxib. COX-2 Inhibitor Drug Review of adverse renal and arrhythmia risk, in JAMA 2006

Regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors (EMEA 2005):

Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease
Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking
Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment

[edit] Miscellaneous
Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.[15]

[edit] Negative cardiovascular effects in the majority of NSAIDS
Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with the majority of NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older "trusted" nsaids such as ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet properties.


[edit] References
^ E.g. Reuters. "Merck Sees Slightly Higher 2007 Earnings", New York Times, 2006-12-07, p. A1.
^ a b David Armstrong. "How the New England Journal Missed Warning Signs on Vioxx", Wall Street Journal, 2006-05-15, p. A1.
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al.. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343(21): 1520-8. PMID 11087881
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352(11): 1092-102. PMID 15713943
Curfman GD, Morrissey S, and Drazen JM. Expression of Concern Reaffirmed. N Engl J Med 2006; published online February 22. PMID 16495386
EMEA (2005) European Medicines Agency, "European Medicines Agency concludes action on COX-2 inhibitors," press release, June 27, 2005. Link
FDA (2005). "Summary minutes for the February 16, 17 and 18, 2005, Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee." Published on the internet, March 2005. Link
Fitzgerald GA, Coxibs and Cardiovascular Disease, N Engl J Med 2004;351(17): 1709-1711. PMID 15470192.
Grassley CE (15 Oct 2004). Grassley questions Merck about communication with the FDA on Vioxx. Press Release.
Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M (2004). Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet (published online)
Karha J and Topol EJ. The sad story of Vioxx, and what we should learn from it Cleve Clin J Med 2004; 71(12):933-939. PMID 15641522
M. A. Konstam et al., “Cardiovascular Thrombotic Events in Controlled, Clinical Trials of Rofecoxib,” Circulation 104 (2001): 2280–2288
Michaels, D. (June 2005) DOUBT Is Their Product, Scientific American, 292 (6).
Merck & Co., (5 Nov 2004). Response to Article by Juni et al. Published in The Lancet on Nov. 5. Press Release.
Merck & Co (30 Sep 2004) Merck Announces Voluntary Worldwide Withdrawal of VIOXX. Press release [16].
D. M. Mukherjee, S. E. Nissen, and E. J. Topol, “Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors,” Journal of the American Medical Association 186 (2001): 954–959.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352(11):1081-91. PMID 15713945
Okie, S (2005) "Raising the safety bar--the FDA's coxib meeting." N Engl J Med. 2005 Mar 31;352(13):1283-5. PMID 15800221.
Leleti Rajender Reddy, Corey EJ. Facile air oxidation of the conjugate base of rofecoxib (Vioxx™), a possible contributor to chronic human toxicity Tetrahedron Lett 2005, 46: 927. [17]
Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002;162:1099-104
Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352(11):1071-80. PMID 15713944
Swan SK et al., Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet. Annals of Int Med 2000; 133:1–9
Targum, SL. (1 Feb. 2001) Review of cardiovascular safety database. FDA memorandum. [18]
Wolfe, MM et al, Gastrointestinal Toxicity of Nonsteroidal Anti-anflamattory Drugs, New England Journal of Medicine. 1999; 340; 1888-98.


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COX-2 selective inhibitor is a form of Non-steroidal anti-inflammatory drug (NSAID) that directly targets COX-2, an enzyme responsible for inflammation and pain. Selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. Cox-2-selectivity does not seem to affect other adverse-effects of NSAIDs (most notably an increased risk of renal failure), and some results have aroused the suspicion that there might be an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane. Rofecoxib was taken off the market in 2004 because of these concerns.

Contents [hide]
1 Research history
2 Adverse-effects and withdrawal of Vioxx
3 Early COX-2 inhibiting drugs
4 Comparative studies
5 Combinations of drugs
6 Risks and adverse effects
7 Considerations for prescription
8 Future of Cox 2 Inhibitors a treatment for neuroblastomas
9 References
10 External links



[edit] Research history
The COX2 enzyme was discovered in 1998 by Daniel Simmons, a Brigham Young University researcher formerly of Harvard University. Dr. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced, he had his notebook notarized as proof of his discovery. Subsequently, Monsanto, the research firm with whom Dr. Simmons had contracted, fraudulently broke contract and refused to give Dr. Simmons any royalties and profits from his discovery. A lawsuit is currently in progress by Dr. Simmons against the drug developers. [1]

In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as "good prostaglandins" and "bad prostaglandins", according to the structure of a particular enzyme involved in their synthesis, cyclooxygenase.

Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-1, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain.

The existing nonsteroidal antiinflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin is equipotent at inhibiting COX-2 and COX-1 enzymes in vitro and ibuprofen demonstrates a sevenfold greater inhibition of COX-1, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam (Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications.

A search for COX-2-specific inhibitors resulted in promising candidates such as valdecoxib, celecoxib, and rofecoxib (marketed under the brand names Bextra, Celebrex, and Vioxx respectively). Valdecoxib and rofecoxib are about 300 times more potent at inhibiting COX-2, than COX-1, suggesting the possibility of relief from pain and inflammation, without gastrointestinal irritation, and promising to be a boon for those who had experienced such adverse effects previously or had comorbidities that could lead to such complications. Celecoxib is approximately 30 times more potent at inhibiting COX-2 than COX-1.

Although individual reactions to particular NSAIDs vary, in general the efficacy of COX-2 inhibitors has proved similar to that of other NSAIDs, as expected since both classes of drug inhibit the desired target, the action of COX-2 prostaglandins. The drugs's effectiveness is similar to that of traditional NSAIDs such as ibuprofen, diclofenac, or naproxen.


[edit] Adverse-effects and withdrawal of Vioxx
On September 27, 2004 Vioxx (Rofecoxib) was withdrawn voluntarily from the market, due to an increased risk of myocardial infarction and stroke. At present it is unclear whether this adverse effect pertains also to other drugs of this group or is specific for Vioxx.

Beasley Allen Law Firm is spearheading the review of over 31,000 claims against the manufacturers of Bextra, Celebrex and Vioxx.


[edit] Early COX-2 inhibiting drugs
Celebrex and Vioxx were introduced in 1999 and rapidly became the most frequently prescribed new drugs in the United States. By October 2000, their US sales exceeded 100 million prescriptions per year for $3 billion, and were still rising, sales of Celebrex alone reaching $3.1 billion in 2001. A Spanish study found that between January 2000 and June 2001, 7% of NSAID prescriptions and 29% of NSAID expenditures were for COX-II inhibitors. Over the period of the study, COX-II inhibitors rose from 10.03% of total NSAIDs prescribed by specialty physicians to 29.79%, and from 1.52% to 10.78% of NSAIDs prescribed by primary care physicians (98.23% of NSAIDs and 94.61% of COX-II inhibitors were prescribed by primary care physicians). For specialty physicians, rofecoxib and celecoxib were third and fifth most frequently prescribed NSAIDs but first and second in cost, respectively; for primary care physicians they were ninth and twelfth most frequently prescribed NSAIDs and first and fourth in cost.

The cause of the rapid widespread acceptance of Celebrex and Vioxx by physicians was the publication of two large trials in JAMA, the Celecoxib Long-term Arthritis Safety Study (CLASS) study, and the Vioxx Gastrointestinal Outcomes Research (VIGOR) study. Both publications concluded that COX-II specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. In the CLASS trial comparing Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for osteoarthritis or rheumatoid arthritis for six months, Celebrex was significantly associated with fewer upper gastrointestinal complications (0.44% vs. 1.27%, P=0.04), with no significant difference in incidence of cardiovascular events in patients not taking aspirin for cardiovascular prophylaxis. In the VIGOR trial testing Vioxx 50 mg/day versus naproxen for rheumatoid arthritis, Vioxx reduced the risk of symptomatic ulcers and clinical upper gastrointestinal events (perforations, obstructions and bleeding) by 54%, to 1.4% from 3%, the risk of complicated upper gastrointestinal events (complicated perforations, obstructions and bleeding in the upper gastrointestinal tract) by 57%, and the risk of bleeding from anywhere in the gastrointestinal tract by 62%. An enormous marketing effort capitalized on these publications; Vioxx was the most heavily advertised prescription drug in 2000, and Celebrex the seventh, according to IMS Health.


[edit] Comparative studies
In a metaanalysis of eight osteoarthritis studies, the incidence of withdrawal because of adverse gastrointestinal events was 3.5% for Vioxx, compared to 4.8% for ibuprofen, diclofenac, or nabumetone (Relafen). Endoscopic studies of patients receiving Celebrex 50-400 mg twice daily for 12-24 weeks found rates of upper gastrointestinal complications similar to placebo and significantly lower than naproxen 500 mg twice daily and ibuprofen 800 mg three times daily, but not statistically significantly different from patients receiving diclofenac 75 mg twice daily.11 The analysis found that Vioxx provided significant gastrointestinal benefits in patients both at high risk and at low risk of developing gastrointestinal problems; patients at low risk still had 88% fewer gastrointestinal problems with Vioxx.

The results of the CLASS study were confirmed by the Successive Celecoxib Efficacy and Safety Studies (SUCCESS) study, which examined the effectiveness and safety of celecoxib 200 mg and 400 mg daily and how well it was tolerated by patients in terms of adverse effects, compared with the most common NSAID regimens in the countries studied (diclofenac 100 mg daily and naproxen 1000 mg daily). SUCCESS showed that celecoxib was as effective as the conventional NSAIDs in controlling the pain of arthritis, and caused fewer gastrointestinal ulcers or ulcer complications (such as perforations or bleeding) and fewer upper gastrointestinal adverse effects, e.g. 29% less chance of having nausea and 22% less chance of abdominal pain. In addition, hospitalization rates for upper gastrointestinal problems were 2 to 4 times lower with celecoxib, and because there were fewer adverse effects, there was 23% less chance of a celecoxib patient stopping treatment. The study also found that there was no real advantage to taking a bigger dose of celecoxib: the 200 mg dose was found to be just as effective as the 400 mg dose.

The VIGOR study was followed by the Assessment of Difference between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness (ADVANTAGE) study, which showed that 9.1% of people taking Vioxx received a gastro-protective medicine compared with 11.2% of people taking naproxen, a reduction of 19%. In addition, after 3 months, 5.9% of people stopped taking Vioxx compared with 8.1% who stopped taking naproxen, a reduction of 27%. ADVANTAGE was the first study comparing the gastrointestinal tolerability of Vioxx and naproxen in a group that included patients taking low-dose aspirin for cardiovascular reasons. This was followed by the Experience with Vioxx in Arthritis (EVA) survey of 5,986 Belgian physicians and 74,192 people with osteoarthritis, which found that, after 12.5 or 25 mg of Vioxx once daily for 30 days, 80% of the patients wished to continue treatment with Vioxx and more than 80% of doctors said they would continue prescribing Vioxx. The preference to continue taking Vioxx was especially strong in people who previously treated with older NSAIDs.

In a six week long study comparing Vioxx 25 mg once daily, Vioxx 12.5 mg once daily, Celebrex 200 mg once daily, and paracetamol 1,000 mg four times daily for osteoarthritis of the knee, higher dose Vioxx was found to be superior to the other three treatments for reduction of nocturnal pain, and superior to Celebrex and acetaminophen for reduction of resting pain. At six weeks, 60% of high dose Vioxx patients reported a good or excellent response, compared to 46% of Celebrex patients and 39% of paracetamol patients. Low dose Vioxx was not found to be statistically significant from Celebrex at this dose. Similar results were found for early response to therapy.

However, when the Food and Drug Administration (FDA) later presented more complete data from the CLASS and VIGOR trials on its web site, the results were less certain. The CLASS trial was revealed to also have twelve and fifteen month time points which had not been discussed in the JAMA publication; in this segment of the trial, the number of ulcer-related complications for Celebrex caught up to the control NSAID group. Similarly, the complete VIGOR study data revealed that in fact, when all adverse events, not just gastrointestinal, were tabulated, the patients receiving VIOXX had suffered (barely) significantly higher incidence of adverse events overall than the control NSAID group. In particular, the risk of serious cardiovascular thrombotic events, e.g. myocardial infarction, was 1.7% in the VIOXX patients versus 0.7% in the control group, and there were significantly more withdrawals in the Vioxx group for causes including hypertension, edema, hepatotoxicity, heart failure, or pathological laboratory findings. The mean increases in systolic and diastolic blood pressure in the Vioxx group were 4.6 mmHg and 1.7 mmHg respectively, compared to 1.0 and 0.1 mmHg in the control NSAID group. An estimated 43,000,000 Americans, nearly one out of six, suffers from arthritis. However, 42% (18 million) of these also suffer from hypertension. Therefore, the promise of better patient outcomes and lowered medical costs from use of COX-2 inhibitors may not be as great as previously hoped. Questions remain regarding the relative safety and cost effectiveness of this new class. While endoscopic evidence of gastrointestinal damage is frequently seen in studies of nonspecific NSAIDs, the actual incidence of clinically evident symptoms and patient discomfort is much lower; furthermore, in cases of short-term therapy, any such damage generally reverses itself quickly after termination of the drug.


[edit] Combinations of drugs
A model comparing the theoretical relative frequency of gastrointestinal adverse effects and cost effectiveness of celecoxib, nonspecific NSAIDs alone, NSAIDs plus a proton pump inhibitor, NSAIDs plus an H2 receptor antagonist, NSAIDs plus misoprostol, and diclofenac/misoprostol, found the lowest probability of adverse gastrointestinal events for celecoxib, followed by NSAIDs plus a proton pump inhibitor, NSAIDs plus an H2 receptor antagonist, NSAID plus misoprostol, diclofenac/misoprostol, and NSAID alone. In total cost, including drug plus treatment of any gastrointestinal effects, the lowest cost treatment was celecoxib, followed by NSAIDs alone and diclofenac/misoprostol, with the other NSAID plus gastrointestinal protection regimens being much more costly. Similarly, a model of cost effectiveness of rofecoxib and celecoxib compared to high-dose acetaminophen or ibuprofen, with and without misoprostol, in patients with osteoarthritis of the knee found that acetaminophen had the lowest cost for average patients. For those not responding to paracetamol, ibuprofen was the most cost effective treatment by a large margin, but for those who did not respond to acetaminophen and had a high risk of gastrointestinal damage, rofecoxib was the most cost effective treatment.


[edit] Risks and adverse effects
This cardiovascular risk of COX-2 specific inhibitors is not surprising since prostaglandins are involved in regulation of blood pressure by the kidneys. Therefore, cardiovascular effects of NSAIDs prescribed for arthritis pain and inflammation need to be considered when choosing the appropriate medication for each patient. A French study of osteoarthritis patients over 65 years of age determined that, compared to Celebrex (200 mg once daily), patients taking Vioxx (25 mg once daily) suffered a two-fold increase in clinically significant edema and 60% more frequent increases in systolic blood pressure greater than 20 mmHg, as early as the second week of treatment. This has significant implications, since it has been estimated that every 2 mmHg increase in blood pressure raises the risk of stroke by two thirds and the risk of myocardial infarction by one third, suggesting that Celebrex may be a better choice for hypertensive patients or those at risk for edema. In addition, COX-2 inhibitors lack some of the platelet inhibiting properties of aspirin and other nonspecific NSAIDs and may, directly or indirectly, lead to increased risk of thrombosis, particularly in high risk patients where low dose aspirin therapy is warranted. On the other hand, this property makes them a better choice for perisurgical pain management, where inhibition of blood clotting would be problematic.

There are other differences between Celebrex and Vioxx that influence prescribing practices. Patients with known sensitivity to sulfa drugs are likely to be sensitive to Celebrex as well, due to similarity in structure. Vioxx has a more rapid onset and is approved for acute pain as well as osteoarthritis, while Celebrex is approved for rheumatoid arthritis as well as osteoarthritis.3


[edit] Considerations for prescription
A key assumption made in early COX-2 cost-effectiveness studies was lower cost due to a reduction in coprescription of agents used to protect the gastrointestinal tract from traditional NSAIDs. However, if gastroprotective agents continue to be coprescribed along with COX-2 inhibitors, there would seem to be no advantage to the use of these higher cost NSAIDs. Similarly, in patients who take aspirin for cardiovascular benefit, with its attendant gastrointestinal irritation, prescription of COX-2 inhibitors to avoid gastrointestinal irritation would seem to offer no advantage. This was confirmed by the CLASS study, which found significantly lower incidence of upper gastrointestinal complications alone and combined with symptomatic ulcers in patients taking Celebrex 400 mg twice daily, compared to ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily; but this freedom from gastrointestinal complications was lost in patients taking concurrent low dose aspirin.


[edit] Future of Cox 2 Inhibitors a treatment for neuroblastomas
Recent studies have shown that small tumors of the sympathetic nervous system (neuroblastoma) have abnormal levels of COX-2 expressed (Johnsen et al). These studies report that and overexpression of the COX-2 enzyme has an adverse effect on the tumor suppressor, p53. p53 is an apoptosis transcription factor normally found in the cytosol, when cellular DNA is damaged beyond repair, p53 is transported to the nucleus where is promotes p53 mediated cell suicide (apoptosis) (Lau et al, 2006). Two of the metabolites of COX-2, prostaglandin A2 (PGA2) and A1 (PGA1), when present in high quantities binds to p53 in the cytosol and inhibits its ability to cross into the nucleus. This essentially sequesters p53 in the cytosol and prevents apoptosis (Lau et al, 2006). coxibs such as CELEBREX® (celecoxib), by selectively inhibiting the overexpressed COX-2, allow p53 to work properly. Functional p53 allows DNA damaged neuroblastoma cells to commit suicide through apoptosis, halting tumor growth. COX-2 up-regulation has also been linked to the phosphorylation and activation of the E3 ubiquitin ligase HDM2, a protein that mediates p53 ligation and tagged destruction, through ubiquitination (Lau et al, 2006). The mechanism for this neuroblastoma HDM2 hyperactivity is unknown. Studies have shown that COX-2 inhibitors block the phosphorilation of HDM2 preventing its activation (Figure 6B). In vitro, the use of COX-2 inhibitors such as CELEBREX® (celecoxib) lowers the level of active HDM2 found in neuroblastoma cells. The exact process of how COX-2 inhibitors block HDM2 phosphorilation is unknown, but this mediated reduction in active HDM2 concentration level restores the cellular p53 levels. After treatment with CELEBREX® (celecoxib), the restored p53 function allows DNA damaged neuroblastoma cells to commit suicide through apoptosis reducing the size of growth of the tumor (Lau et al, 2006).


[edit] References
"Understanding NSAIDs: from aspirin to COX-2"; Gary A. Green; Clin Cornerstone 3(5):50-59, 2001.
"COX-2 inhibitors: A CLASS act of just VIGORously promoted"; Samir Malhotra, N. Shafiz, P. Pandhi; Medscape General Medicine 6(1), 2004.
"At what care level are cyclo-oxygenase-2 inhibitors prescribed?"; Montero, Fernandez MJ, Rodriguez, Alcala FJ, Valles Fernandez N, Lopez de Castro, F, Esteban, Tudela M, Cordero, Garcia B; Aten Primaria 2002 Oct 30:363-7.
"You and A: Arthritis drugs. Pain and confusion"; Francesca Lunzer Kritz; Washington Post; Sept. 4, 2001; HE01.
"Vioxx (rofecoxib) reduces night-time osteoarthritis pain better than celecoxib or acetaminophen"; European League Against Rheumatism (EULAR) conference proceedings.
"Will the promise of the COX-II selective NSAIDs come to fruition?"; Drug Ther Perspect 17(11); 6-10, 2001.
"Economic evaluation of celecoxib, a new cyclo-oxygenase-2 specific inhibitor, in Switzerland"; JV Chancellor, E. Hunsche, E. de Cruz, F. P. Sarasin; Pharmacoeconomics 2001; 19 Suppl 1:59-75.
"The cost-effectiveness of acetaminophen, NSAIDs, and selective COX-2 inhibitors in the treatment of symptomatic knee osteoarthritis"; C. C. Kamath, H. M. Kremers, D. J. Vanness, W. M. O'Fallon, R. L Cabanela, S. E. Gabriel; Value Health 2003, Mar-Apr;6 (2); 144-57.
"Osteoarthritis drug Celebrex (celecoxib) less likely to cause increased blood pressure than Vioxx (rofecoxib)"; European League Against Rheumatism (EULAR) conference proceedings.
"Will the promise of the COX-II selective NSAIDs come to fruition?"; Drug Ther Perspect 17(11); 6-10, 2001.
Johnsen, John and Magnus,Lindskog and Frida,Ponthan1, Ingvild,Pettersen, Lotta,Elfman, Abiel,Orrego, Baldur Sveinbjörnsson,Per,Kogner. "Cyclooxygenase-2 Is Expressed in Neuroblastoma, and Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis and Inhibit Tumor Growth In vivo." American Association for Cancer Research 64, 7210-721515 Oct 2004 September 2006
Lau, L and M. Hansford, L.Cheng, M.Hang and S.Baruchel, D.Kaplan and M.Irwin. "Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma." Oncogene doi: 10.1038/ sj.onc.120998118 Sep 2006 Sep 2006