A VIOXX<unk>  sample blister pack. In addition to the reduced incidence of gastric ulceration,<unk>  exhibits no effect on bleeding time or platelet aggregation, even at supra-therapeutic doses. Aside from these features,<unk>  exhibits a similar adverse effect profile to other NSAIDs. Heart and blood vessels VIGOR study and publishing controversy The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., compared the efficacy and adverse effect profiles of a supra-therapeutic dose of<unk>  (50 mg/day) vs. a common dose of naproxen (500 mg/BID), had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in<unk>  patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over a mean duration of 9-months. The elevated risk began during the second month on<unk> . 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<unk>  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). 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. The Martin Report excused senior management by stating they believed they were victims of Pfizer's alleged manipulation of test results to promote their product as a safer alternative. 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. 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). Months after the preliminary version of VIGOR was published in the New England Journal of Medicine in November 2000, 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 NEJMs "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." Investigations revealed that Merck had several years worth of information suggesting an elevated risk of cardiac events, and Vice President Edward Scolnick took much of the blame for the suppression of this information. The FDA reviewers were aware of the potential for cardiovascular risk in 1999and it was argued that Merck had manipulated their EKG tests one week after the external review board provided their consultation to specifically exclude high risk factors from the trial subjects to avoid finding effect then predated the changes to their trials to almost three months earlier. Alzheimer's disease In 2000 and 2001, Merck conducted several studies of<unk>  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<unk>  to a placebo rather than to another pain reliever. These studies found an elevated death rate among<unk>  patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to<unk> . Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of<unk> 's safety. 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<unk>  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<unk>  as well. An additional aim of the study was to further evaluate the cardiovascular safety of<unk> . 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<unk>  therapy. In patients taking<unk> , versus placebo, the relative risk of
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