User:Oceanflynn/sandbox/VIGOR study and controversy

VIGOR study and controversy refers to the Vioxx Gastrointestinal Outcomes Research (VIGOR) conducted by Dr. Clair Bombardier as lead along with Merck scientists, L. Laine and A. Reicin A and nine other scientists whose 2000 published results were subsequently placed under caution by the The New England Journal of Medicine and became a lightning rod on research ethics. Others include Merck's etoricoxib (Arcoxia), 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 (Vioxx) and naproxen (Aleve). The VIGOR trial was later proven to have been based on faulty data and Vioxx was eventually withdrawn from the market. VIGOR trial,1 was a trial in which over 8000 patients were randomized to receive either naproxen or rofecoxib (Vioxx), a Cox-2 inhibitor that Merck hoped would have fewer gastrointestinal side effects."

VIGOR, "a large clinical trial that ended in 2000 also showed that Vioxx was much riskier than naproxen, an older painkiller sold under the name Aleve."

VIGOR
The Phase III parallel-group, double-blind study began with the first patient in on January 6, 1999 and the last patient out on March 17, 2000. The study was undertaken in 301 multinational sites with a total of 7000 patients, with approximately 3500 from the U.S. Researchers studied the relative risk of confirmed PUB (Perforation, Ulcers, Bleeding) in patients taking MK-0966 50 mg. By November 1999 there was concern "excess deaths and cardiovascular adverse experiences in Group A." Some "members expressed belief that the effect might be "due to cardioprotective effects of Treatment B." At the time, "no cardiovascular analysis plan was in place for VIGOR or VIOXX." "29% of patients did not complete this trial. The most common reason for discontinuation was the occurrence of a clinical adverse experience." "there were still about twice as many adverse events (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, and sudden or unexplained death, cerebrovascular events included stroke (ischemic and hemorrhagic) and transient ischemic attack. Also considered for adjudication were venous thrombosis and pulmonary embolism.) in the rofecoxib group than in the naproxen group." "conclude that naproxen, with a 51% risk reduction compared to rofecoxib, would be the preferred drug." "The VIGOR study was a large study with a longer drug exposure and follow-up than the two smaller studies (085 and 090). The cardiovascular thrombotic event rates, while not high, were significantly different between the two groups; most striking were the myocardial infarction event rates. Thus, to this Medical Reviewer, there are more cardiovascular thrombotic events in the rofecoxib group than in the naproxen group; the time-to-event curves are different, favoring naproxen. This Medical Reviewer is concluding that there is an increased risk of cardiovascular thrombotic events, particularly myocardial infarction, in the rofecoxib group compared with the naproxen group. More difficult is the question of a safety signal for rofecoxib. As there is no placebo group, it will be difficult to assess the CV thrombotic risk with rofecoxib use compared with no therapy at all."

Cardiovascular safety of COXIBS and NSAIDs
Bombardier and her research team compared the efficacy and adverse effect profiles of rofecoxib and naproxen. Their study 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 by the patients at higher risk of heart attack, i.e. 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).

According to Merck's internal documents, Merck’s scientists were concerned that Vioxx increased the risks of heart attacks and strokes by 2000 or 2001.

In February 2001 in a FDA Memorandum there was a review of the "cardiovascular safety of rofecoxib (MK-0966) 50 mg daily in patients with rheumatoid arthritis." This memorandum noted that on October 13, 2000, Merck "submitted a safety update which included 11 additional patients referred for adjudication of cardiovascular serious adverse experiences after February 10, 2000, the prespecified cut-off date in the original safety report." It was noted that Merck was claiming that rofecoxib (Vioxx) reduced gatro-intestinal (GI) bleeding GI bleeding and ulcers. for 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. Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference, and some outside scientists warned Merck that this claim was implausible before VIGOR was published. 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. 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. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)." This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

By 2002 an article in The Lancet reported serious concerns "of increased deaths associated with COXIBs and in particular, rofecoxib. This concern once again highlighted the risk of cardiovascular complications that were known with NSAIDs, now extending to COXIBs. An increased risk of acute myocardial infarction has been long associated with the use of NSAIDs, such as naproxen and diclofenac, particularly in high-risk patients over the age of 50 years." They concluded that the protective effect of naproxen against acute myocardial infarction risk interpreted from the VIGOR study was false and they they recommended that in the "[A]bsence of a protective effect of naproxen or other NANSAIDs on risk of coronary heart disease suggests that these drugs should not be used for cardioprotection."

The "first signs of concern regarding the cardiovascular safety of COXIBs arose because of the unanticipated but significantly higher incidence of cardiovascular thrombotic events with rofecoxib compared to naproxen in the VIGOR study." In this study, patients taking rofecoxib 50 mg had a five-fold increased risk of MI compared with naproxen 1 000 mg.

APPROVe
Based on the conclusions of the APPROVe study Merck voluntarily withdrew its product rofecoxib (Vioxx) worldwide on September 30, 2004 because Vioxx doubled the risk of heart attack and strokes in patients taking the medication longer than 18 months. Merck's decision was based on three-year data from a prospective, randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial.

The Adenomatous Polyp Prevention on Vioxx (APPROVe) study involving 2586 patients, which evaluated the incidence of adenomatous polyps in patients treated with rofecoxib 25 mg compared with placebo, showed a two-fold increase in myocardial infarctions and ischemic cerebrovascular events risk with rofecoxib.

Other selective COXIBs
In 2008 similar observations were reported for other more selective COXIBs.

By 2008 two new studies had been published suggesting that data in the VIGOR study had been manipulated in favor of rofecoxib and drugmaker Merck and Co. "was slow to disclose adverse events associated with the painkiller, and used academic researchers to enhance the credibility of scientific studies largely written by Merck employees."

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 were 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 these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data. 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.

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." These 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 statistically 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.

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 were printed in the text of the article. The authors stood by the original article.

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).

Some scientists have accused the NEJM editorial board of making unfounded accusations. Others have applauded the editorial. Renowned research cardiologist Eric Topol, a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up". 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".

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 Medicines own role in aiding Vioxx sales."

"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."

On January 1, 1999 the The Vioxx gastrointestinal outcomes research (VIGOR) trial began "aiming to show whether Vioxx causes fewer ulcers and other gastrointestinal problems than the standard arthritis treatment naproxen."

Both publications concluded that COX-2 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.

The VIGOR trial results were published in 2000 in the New England Journal of Medicine Bombardier and her research team claimed that there was "an increase in myocardial infarction in the patients given rofecoxib (0.4%) compared with those given naproxen (0.1%)" and "patients given naproxen experienced 121 side effects compared with 56 in the patients taking rofecoxib," a "marvellous result for Merck" which "contributed to huge sales of rofecoxib." Merck's scientists incorrectly 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. In September 2001, the United States Food and Drug Administration (FDA) sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)." This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke). By 2005 The New England Journal of Medicine published an editorial accusing the Bombardier et al. of deliberately withholding data.

Dr. Claire Bombardier, a University of Toronto rheumatologist, had claimed that the VIGOR trial testing resulted in 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.

In September 2004 Merck withdrew "Vioxx from the market after a clinical trial proved that it increased the risks of heart attacks and strokes."

On December 8, 2005 The New England Journal of Medicine claimed that "Merck deleted dangers linked to Vioxx, including three heart attack deaths among users, in its analysis of the VIGOR study."

In 2005 Merck was fighting lawsuits regarding Vioxx in civil trails. In their first case in August 2005 a jury in Angleton, Texas found for the plaintiff, "Carol Ernst, whose husband, Robert, had died after taking Vioxx for less than a year." Merck had to pay $253.5 million. However Merck won most cases by using the strategy of blaming the victims, by exposing exposed individual weaknesses such as inability to prove "they had taken the drug, and others were overweight, smoked, or had other risk factors for heart attacks."

In 2006 the Journal of the Royal Society of Medicine argued that the New England Journal of Medicine should have responded more vigorously and in a more timely fashion to the article they published by Bombardier in 2000 about the results of VIGOR trial,1 "which was the making of Merck's drug rofecoxib (Vioxx)." It was at the center of a dispute about the ethics of medical journals.

In November 2007 under pressure from New Orleans Judge Eldon E. Fallon of Federal District Court, who oversaw federal lawsuits from his court in New Orleans convinced plaintiffs and Merck to accept a settlement with Merck agreeing "to pay $4.85 billion to settle 27,000 lawsuits by people who claim they or their family members suffered injury or died after taking the drug." By 2007 there were 20 Vioxx civil trials from New Jersey to California which cost Merck $600 million a year which amounted to "more than $1.2 billion on Vioxx-related legal fees."

Rofecoxib
Vioxx, Ceoxx, and Ceeoxx