Merck Wrote Drug Studies for Doctors
By STEPHANIE SAUL
16 april 2008--The drug maker Merck drafted dozens of research studies for a best-selling drug, then lined up prestigious doctors to put their names on the reports before publication, according to an article to be published Wednesday in a leading medical journal.
The article, based on documents unearthed in lawsuits over the pain drug Vioxx, provides a rare, detailed look in the industry practice of ghostwriting medical research studies that are then published in academic journals.
The article cited one draft of a Vioxx research study that was still in want of a big-name researcher, identifying the lead writer only as “External author?”
Vioxx was a best-selling drug before Merck took it off the market in 2004 over evidence linking it to heart attacks. Last fall, the company agreed to a $4.85 billion settlement to resolve tens of thousands of lawsuits filed by former Vioxx patients or their families.
The lead author of Wednesday’s article, Dr. Joseph S. Ross of the Mount Sinai School of Medicine in New York, said a close look at the Merck documents raised broad questions about the validity of much of the drug industry’s published research, because the ghostwriting practice appears to be widespread.
“It almost calls into question all legitimate research that’s been conducted by the pharmaceutical industry with the academic physician,” said Dr. Ross, whose article, written with colleagues, was published Wednesday in JAMA, The Journal of the American Medical Association. and posted Tuesday on the journal’s Web site.
Merck acknowledged on Tuesday that it sometimes hired outside medical writers to draft research reports before handing them over to the doctors whose names eventually appear on the publication. But the company disputed the article’s conclusion that the authors do little of the actual research or analysis.
The final work is the product of the doctor and “accurately reflects his or her opinion,” said a Merck lawyer, James C. Fitzpatrick.
And at least one of the doctors whose published research was questioned in Wednesday’s article, Dr. Steven H. Ferris, a New York University psychiatry professor, said the notion that the article bearing his name was ghostwritten was “simply false.” He said it was “egregious” that Dr. Ross and his colleagues had done no research besides mining the Merck documents and reading the published journal articles.
In an editorial, JAMA said the analysis showed that Merck had apparently manipulated dozens of publications to promote Vioxx.
“It is clear that at least some of the authors played little direct roles in the study or review, yet still allowed themselves to be named as authors,” the editorial said.
The editorial called upon medical journal editors to require each author to report his or her specific contributions to articles. “Journal editors also bear some of the responsibility for enabling companies to manipulate publications,” the editorial said.
JAMA itself published one of the Vioxx studies that was cited in Dr. Ross’s article.
In that case, in 2002, a Merck scientist was listed as the lead author. But Dr. Catherine D. DeAngelis, JAMA’s editor, said in a telephone interview on Tuesday that, even so, it was dishonest because the authors did not fully disclose the role of a ghostwriter.
“I consider that being scammed,” Dr. DeAngelis said. “But is that as serious as allowing someone to have a review article written by a for-profit company and solicited and paid for by a for-profit company and asking you to put your name on it after it was all done?”
Although the role of pharmaceutical companies in influencing medical journal articles has been questioned before, the Merck documents provided the most comprehensive look at the practice yet, according to one of the study’s four authors, Dr. David S. Egilman, a clinical associate medical professor at Brown University.
In the Vioxx lawsuits, millions of Merck documents were supplied to plaintiffs. Those documents were available to Dr. Egilman and Dr. Ross because they had served as consultants to plaintiffs’ lawyers in some of those suits.
Combing through the documents, Dr. Ross and his colleagues unearthed internal Merck e-mail messages and documents about 96 journal publications, which included review articles and reports of clinical studies. While the Ross team said it was not necessarily raising questions about all 96 articles, it said that in many cases there was scant evidence that the recruited authors made substantive contributions.
One paper involved a study of Vioxx as a possible deterrent to Alzheimer’s progression.
The draft of the paper, dated August 2003, identified the lead writer as “External author?” But when it was published in 2005 in the journal Neuropsychopharmacology, the lead author was listed as Dr. Leon J. Thal, a well-known Alzheimer’s researcher at the University of California, San Diego. Dr. Thal was killed in an airplane crash last year.
The second author listed on the published Alzheimer’s paper, whose name had not been on the draft, was Dr. Ferris, the New York University professor. Dr. Ferris, reached by telephone Tuesday, said he had played an active role in the research and he was substantially involved in helping shape the final draft.
“It’s simply false that we didn’t contribute to the final publication,” Dr. Ferris said.
A third author, also not named on the initial draft, was Dr. Louis Kirby, currently the medical director for the company Provista Life Sciences. In an e-mail message on Tuesday, Dr. Kirby said that as a clinical investigator for the study he had enrolled more patients, 109, than any of the other researchers. He also said he made revisions to the final document.
“The fact that the draft was written by a Merck employee for later discussion by all the authors does not in and of itself constitute ghostwriting,” Dr. Kirby’s e-mail message said.
The current editor of the journal Neuropsychopharmacology, Dr. James H. Meador-Woodruff, the chairman of psychiatry at the University of Alabama, Birmingham, said he was not the editor in 2005 but planned to investigate the accusations. “Currently, we have in place prohibitions against this,” Dr. Meador-Woodruff said.
Showing posts with label vioxx. Show all posts
Showing posts with label vioxx. Show all posts
Thursday, April 17, 2008
Wednesday, April 16, 2008
Rofecoxib (Vioxx) Studies on Mortality Were Controlled by Drug Company
By Peggy Peck
NEW YORK, 15 april 2008 -- Ongoing litigation about rofecoxib (Vioxx) has provided confirmation that Merck employees or hired ghostwriters were the true authors of manuscripts about the drug published as the work of academic researchers.That finding was published in the April 16 issue of the Journal of the American Medical Association along with a second study -- also mined from a paper flood uncovered by lawyers -- that suggests Merck manipulated data to hide an increased mortality risk with rofecoxib.Bruce M. Psaty, M.D., Ph.D., and Richard A. Kronmal, Ph.D., of the University of Washington in Seattle, said Merck told the FDA that an intention-to-treat analysis of data from three trials designed to assess the effects of rofecoxib on the occurrence or progression of Alzheimer's disease revealed an increased mortality risk with the drug.
But Merck, according to Drs. Psaty and Kronmal, told the FDA there was no increased mortality, a conclusion the company reached by using an on-treatment rather than intention-to-treat analysis.
As early as Dec. 5, 2001, the FDA raised the question of mortality risk in a letter to Merck that asked "about the ethics of continuing study 078 [an Alzheimer's disease study] based on the excess mortality seen in study 091 [another Alzheimer's disease trial]."
Merck, in its response, reiterated the mortality data derived from the on-treatment analysis, adding that the difference between rofecoxib and placebo represented "small numeric differences … most consistent with chance fluctuations." Merck said, too, that the study had no data safety monitoring board and the company had not supplied the mortality data to institutional review boards at the study sites because the company "does not believe that a safety issue has been identified."
Rofecoxib was not removed from the market until Sept. 30, 2004, when the data safety monitoring board of a colorectal cancer trial reported an increased risk of cardiovascular events associated with long-term, high-dose rofecoxib use.
The two JAMA papers not only call into question the integrity of the drug company, but also of the researchers, who posed as authors for money or prestige, or both, and the integrity of JAMA itself.
Catherine D. DeAngelis, M.D., JAMA's editor-in-chief, and Phil B. Fontanarosa, M.D., M.B.A., the executive deputy editor, took themselves as well as industry and academia to task in an editorial, writing that even though the two studies document the actions of a single company, "the manipulation of study results, authors, editors, and reviewers is not the sole purview of one company."
Joseph S. Ross, M.D., M.H.S., of Mount Sinai School of Medicine in New York, and colleagues turned up 250 documents by searching court documents for these words: clinical trial, author, authorship, review, manuscript, and publication. The court documents were part of the legal files compiled for two New Jersey Vioxx trials.
The search uncovered a Merck publications status report, which revealed that 24 of the early clinical trials of rofecoxib -- which were eventually published as 20 manuscripts when some of the trial protocols were combined for publication -- had a Merck employee "designated within the report as author of the first draft of the manuscript."
When those 20 trials were matched with published papers, Dr. Ross discovered that in 16 cases the listed first author was "an external academically affiliated investigator."
A Merck employee, who was designated as author in the company's internal document, was listed as an author -- usually the final author -- in 14 of the studies.
Dr. Ross and colleagues included examples of communications between Merck and medical publishing companies that were hired to write manuscripts that were then shopped around to academic researchers as Merck sought high-profile authors.
In one case -- which was especially embarrassing for the JAMA editors -- Grace E. Johnson, Pharm.D., a senior editor at Scientific Therapeutics Information, Inc., sent Merck a first draft of "A Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Study to Evaluate the Safety and Efficacy of Rofecoxib 25 mg and Celecoxib 200 mg in Patients with Osteoarthritis of the Knee and Hip," which she said had been prepared for submission to JAMA Express.
Drs. DeAngelis and Fontanarosa wrote that the study "was, indeed, published in JAMA (in January 2002), but not as an Express (online publication) article." They added that when the paper was published, "it was disclosed that Merck sponsored the trial; that three of the five authors (including the first and corresponding author) were employees of Merck; and that the other two authors (who were identified as co-principal investigators) disclosed receiving funding from Merck."
But there was no disclosure that the paper was written by Scientific Therapeutics Information, Inc.
In their editorial, the JAMA editors proposed an 11-point plan of action to clean up medical publishing.
Those recommendations include:
Requiring that all clinical trials be prospectively listed in registries accepted by the International Committee of Medical Journal Editors prior to patient enrollment, and the names of the principal investigators included in that registration.
Require that all authors report their specific contribution to the manuscript, and also require the listing by name of all individuals who "do not qualify for authorship" but who had a role in the manuscript development.
Journals should seriously consider funding sources and authors' disclosed financial conflicts of interest and financial relationship when deciding whether to publish a study or review.
Academic investigators who are not in the employ of trial sponsors should be responsible for collecting and monitoring data and preparing the manuscript reporting study results.
All journals "must require a statistical analysis of clinical trial data conducted by a statistician who is not an employee of a for-profit company" (JAMA already does this).
An author who fails to disclose financial relationships or other conflicts of interest should be punished by both his or her academic institution and by the journal, which should consider banning the author from publishing in the journal.
Peer reviewers who leak confidential information about studies under review should likewise be punished by their institutions and by the journals.
Any editor who knowingly allows (or is party to allowing) for-profit companies to manipulate the journal "must be relieved of the editorship."
Continuing medical education providers "should not condone or tolerate for-profit companies having any input into the content of educational materials or providing funding or sponsorship for medical education programs.
And finally, the JAMA editors recommended this sweeping rule: "Individual physicians must be free of financial influence of pharmaceutical and medical device companies including serving on speaker's bureaus or accepting gifts."
Dr. Psaty reported that he testified at a Senate hearing titled "FDA, Merck, and Vioxx: Putting Patients First," Dr. Kronmal said that he was retained by plaintiff attorneys in Merck litigation from 2005 to 2007. There was no funding organization or sponsor for the Psaty/Kronmal paper.
Primary source: Journal of the American Medical AssociationSource reference:Ross JS, et al "Guest authorship and ghostwriting in publications related to rofecoxib: A case study of industry documents from rofecoxib litigation" JAMA 2008; 299: 1800-1812. Additional source: Journal of the American Medical AssociationSource reference: Psaty BM, Kronmal RA "Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: A case study based on documents from rofecoxib litigation" JAMA 2008; 299: 1813-1817. Additional source: Journal of the American Medical AssociationSource reference: DeAngelis CD, Fontanarosa PB "Impugning the integrity of medical science: The adverse effects of industry influence" JAMA 2008; 299: 1833-35
By Peggy Peck
NEW YORK, 15 april 2008 -- Ongoing litigation about rofecoxib (Vioxx) has provided confirmation that Merck employees or hired ghostwriters were the true authors of manuscripts about the drug published as the work of academic researchers.That finding was published in the April 16 issue of the Journal of the American Medical Association along with a second study -- also mined from a paper flood uncovered by lawyers -- that suggests Merck manipulated data to hide an increased mortality risk with rofecoxib.Bruce M. Psaty, M.D., Ph.D., and Richard A. Kronmal, Ph.D., of the University of Washington in Seattle, said Merck told the FDA that an intention-to-treat analysis of data from three trials designed to assess the effects of rofecoxib on the occurrence or progression of Alzheimer's disease revealed an increased mortality risk with the drug.
But Merck, according to Drs. Psaty and Kronmal, told the FDA there was no increased mortality, a conclusion the company reached by using an on-treatment rather than intention-to-treat analysis.
As early as Dec. 5, 2001, the FDA raised the question of mortality risk in a letter to Merck that asked "about the ethics of continuing study 078 [an Alzheimer's disease study] based on the excess mortality seen in study 091 [another Alzheimer's disease trial]."
Merck, in its response, reiterated the mortality data derived from the on-treatment analysis, adding that the difference between rofecoxib and placebo represented "small numeric differences … most consistent with chance fluctuations." Merck said, too, that the study had no data safety monitoring board and the company had not supplied the mortality data to institutional review boards at the study sites because the company "does not believe that a safety issue has been identified."
Rofecoxib was not removed from the market until Sept. 30, 2004, when the data safety monitoring board of a colorectal cancer trial reported an increased risk of cardiovascular events associated with long-term, high-dose rofecoxib use.
The two JAMA papers not only call into question the integrity of the drug company, but also of the researchers, who posed as authors for money or prestige, or both, and the integrity of JAMA itself.
Catherine D. DeAngelis, M.D., JAMA's editor-in-chief, and Phil B. Fontanarosa, M.D., M.B.A., the executive deputy editor, took themselves as well as industry and academia to task in an editorial, writing that even though the two studies document the actions of a single company, "the manipulation of study results, authors, editors, and reviewers is not the sole purview of one company."
Joseph S. Ross, M.D., M.H.S., of Mount Sinai School of Medicine in New York, and colleagues turned up 250 documents by searching court documents for these words: clinical trial, author, authorship, review, manuscript, and publication. The court documents were part of the legal files compiled for two New Jersey Vioxx trials.
The search uncovered a Merck publications status report, which revealed that 24 of the early clinical trials of rofecoxib -- which were eventually published as 20 manuscripts when some of the trial protocols were combined for publication -- had a Merck employee "designated within the report as author of the first draft of the manuscript."
When those 20 trials were matched with published papers, Dr. Ross discovered that in 16 cases the listed first author was "an external academically affiliated investigator."
A Merck employee, who was designated as author in the company's internal document, was listed as an author -- usually the final author -- in 14 of the studies.
Dr. Ross and colleagues included examples of communications between Merck and medical publishing companies that were hired to write manuscripts that were then shopped around to academic researchers as Merck sought high-profile authors.
In one case -- which was especially embarrassing for the JAMA editors -- Grace E. Johnson, Pharm.D., a senior editor at Scientific Therapeutics Information, Inc., sent Merck a first draft of "A Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Study to Evaluate the Safety and Efficacy of Rofecoxib 25 mg and Celecoxib 200 mg in Patients with Osteoarthritis of the Knee and Hip," which she said had been prepared for submission to JAMA Express.
Drs. DeAngelis and Fontanarosa wrote that the study "was, indeed, published in JAMA (in January 2002), but not as an Express (online publication) article." They added that when the paper was published, "it was disclosed that Merck sponsored the trial; that three of the five authors (including the first and corresponding author) were employees of Merck; and that the other two authors (who were identified as co-principal investigators) disclosed receiving funding from Merck."
But there was no disclosure that the paper was written by Scientific Therapeutics Information, Inc.
In their editorial, the JAMA editors proposed an 11-point plan of action to clean up medical publishing.
Those recommendations include:
Requiring that all clinical trials be prospectively listed in registries accepted by the International Committee of Medical Journal Editors prior to patient enrollment, and the names of the principal investigators included in that registration.
Require that all authors report their specific contribution to the manuscript, and also require the listing by name of all individuals who "do not qualify for authorship" but who had a role in the manuscript development.
Journals should seriously consider funding sources and authors' disclosed financial conflicts of interest and financial relationship when deciding whether to publish a study or review.
Academic investigators who are not in the employ of trial sponsors should be responsible for collecting and monitoring data and preparing the manuscript reporting study results.
All journals "must require a statistical analysis of clinical trial data conducted by a statistician who is not an employee of a for-profit company" (JAMA already does this).
An author who fails to disclose financial relationships or other conflicts of interest should be punished by both his or her academic institution and by the journal, which should consider banning the author from publishing in the journal.
Peer reviewers who leak confidential information about studies under review should likewise be punished by their institutions and by the journals.
Any editor who knowingly allows (or is party to allowing) for-profit companies to manipulate the journal "must be relieved of the editorship."
Continuing medical education providers "should not condone or tolerate for-profit companies having any input into the content of educational materials or providing funding or sponsorship for medical education programs.
And finally, the JAMA editors recommended this sweeping rule: "Individual physicians must be free of financial influence of pharmaceutical and medical device companies including serving on speaker's bureaus or accepting gifts."
Dr. Psaty reported that he testified at a Senate hearing titled "FDA, Merck, and Vioxx: Putting Patients First," Dr. Kronmal said that he was retained by plaintiff attorneys in Merck litigation from 2005 to 2007. There was no funding organization or sponsor for the Psaty/Kronmal paper.
Primary source: Journal of the American Medical AssociationSource reference:Ross JS, et al "Guest authorship and ghostwriting in publications related to rofecoxib: A case study of industry documents from rofecoxib litigation" JAMA 2008; 299: 1800-1812. Additional source: Journal of the American Medical AssociationSource reference: Psaty BM, Kronmal RA "Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: A case study based on documents from rofecoxib litigation" JAMA 2008; 299: 1813-1817. Additional source: Journal of the American Medical AssociationSource reference: DeAngelis CD, Fontanarosa PB "Impugning the integrity of medical science: The adverse effects of industry influence" JAMA 2008; 299: 1833-35
Friday, July 27, 2007
Vioxx Trouble Started Early and Stayed Late
OXFORD, England, July 26 -- The cardiovascular risk of rofecoxib (Vioxx), the now-withdrawn Cox-2 inhibitor, increased from the start of treatment rather than after an 18-month delay, found researchers here.
The findings support a long-standing claim of rofecoxib critics, a claim that was disputed by Merck on the basis of the drug-maker's analysis of the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial.
When the trial was published in the New England Journal of Medicine in 2005 after the drug's withdrawal in September 2004, Kaplan-Meier curves suggested that the risk was entirely accounted for by patients who took the drug for 18 or more months, a threshold that the company and its lawyers embrace.
Even after the statistical analysis was admitted to be in error and revised in May 2006 to demonstrate a chance that risk began earlier in treatment, the company held the line that there was no evidence to support harm before 18 months.
Now in an analysis of a large colorectal cancer prevention trial, a 2.66-fold excess risk was seen within eight months of rofecoxib treatment (P=0.04) or sooner, found David J. Kerr, M.D., of the University of Oxford here, and colleagues.
Half of all events occurred among patients treated for less than 12 months, they reported in the July 26 issue of the New England Journal of Medicine.
And, the results may implicate other Cox-2 inhibitors as well, commented Elliott M. Antman, M.D., of Brigham and Women's Hospital and Harvard, acting as a spokesperson for the American Heart Association.
"Based on our understanding of the biology there's no reason to believe that other Cox-2 inhibitors would have a longer period to harm," he said, though he noted that other drugs in the class may have less cardiovascular risk than rofecoxib.
"We should not feel safe saying we don't need to worry until 18 months have elapsed," he added.
It was true at the time that there was no evidence to support earlier harm of rofecoxib and not much information to support or refute that claim, commented Steven E. Nissen, M.D., of the Cleveland Clinic, who was one of the early rofecoxib critics.
So to clarify the duration of drug exposure responsible for increased cardiovascular risk, Dr. Kerr and colleagues analyzed outcomes in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial.
This trial began like APPROVe, attempting to prevent colorectal cancer with rofecoxib treatment. However, when the drug was withdrawn from the market, the researchers halted treatment and continued to follow patients for two years after the trial closed.
Before September 2004, 2,434 patients at 151 hospitals in Britain who had undergone potentially curative surgery for colorectal cancer were randomized to 25-mg rofecoxib daily or placebo.
Patients in the rofecoxib group had slightly greater baseline cardiovascular risk than the placebo group based on predefined risk factors, but the only significant difference was a higher prevalence of diabetes (8.7% versus 5.6%, P=0.003).
Treatment continued for a median 7.4 months in the rofecoxib group and 8.2 months in the placebo group before the trial was closed and treatment discontinued. A third of all patients received assigned medication for at least a year.
The researchers found 16 confirmed cardiovascular thrombotic events in 15 patients receiving rofecoxib during or within 14 days after the treatment period versus seven events in six patients in the placebo group.
The relative risk of a cardiovascular thrombotic event was 2.66-fold higher with rofecoxib than placebo (95% confidence interval 1.03 to 6.86, P=0.04). Adjustment for cardiovascular risk factors attenuated the association, but the point estimate remained similar (RR 2.41, 95% CI 0.93 to 6.26, P=0.07).
Eight of the events were cardiac, three were peripheral vascular, and five were cerebrovascular in the rofecoxib group. In the placebo group, there were four, one, and one of these events, respectively, and two hemorrhagic events as well. Three of events overall occurred in conjunction with other non-steroidal anti-inflammatory drugs.
Moreover, Kaplan-Meier plots showed that the curves started to separate almost from day one, Dr. Nissen noted.
"The risk begins almost immediately and just gets progressively greater over time," he said.
An additional 14 adjudicated events were added from study closure to 24 months of follow-up for a total of 21 events in the rofecoxib group and 14 in the placebo group.
The relative risk of cardiovascular thrombotic events over the entire period from the beginning of treatment out to 24 months after trial closure was 1.50-fold higher with rofecoxib than placebo (95% CI 0.76 to 2.94, P=0.24).
Death from cardiovascular causes did not differ significantly between groups (five in the rofecoxib group versus seven in the placebo group).
But, the lack of significance for longer-term risk was not reassuring, Dr. Antman said.
"The trends here are all consistent with a signal of harm," he said. "Whether or not it's statistically significant has more to do with sample size."
Furthermore, other studies have suggested residual risk remains after rofecoxib is discontinued, Dr. Nissen said.
"It's important to know about the time to onset of risk because there are other drugs being developed in the class," Dr. Nissen noted. "If new drugs come along that have this problem, we need to recognize that they can cause trouble fairly quickly."
Merck commented that the "limited data from prematurely terminated studies such as ...VICTOR need to be interpreted with caution, and that assessments of cardiovascular risk with Vioxx must take into account the large amount of randomized, placebo-controlled clinical trial data from the Vioxx research and development program."
The study was sponsored by the University of Oxford and an educational study grant from Merck.
Dr. Kerr and another researcher reported receiving grant support from Cancer Research UK. One researcher also reported receiving consulting fees from Merck and Johnson & Johnson, while another reported serving as an advisor to Merck and to Novartis and as a consultant to lawyers representing Merck. Drs. Antman and Nissen reported no relevant conflicts of interest. Additional source: New England Journal of MedicineSource reference: Kerr DJ, et al "Rofecoxib and Cardiovascular Adverse Events in Adjuvant Treatment of Colorectal Cancer" N Engl J Med 2007;357:360-369.
OXFORD, England, July 26 -- The cardiovascular risk of rofecoxib (Vioxx), the now-withdrawn Cox-2 inhibitor, increased from the start of treatment rather than after an 18-month delay, found researchers here.
The findings support a long-standing claim of rofecoxib critics, a claim that was disputed by Merck on the basis of the drug-maker's analysis of the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial.
When the trial was published in the New England Journal of Medicine in 2005 after the drug's withdrawal in September 2004, Kaplan-Meier curves suggested that the risk was entirely accounted for by patients who took the drug for 18 or more months, a threshold that the company and its lawyers embrace.
Even after the statistical analysis was admitted to be in error and revised in May 2006 to demonstrate a chance that risk began earlier in treatment, the company held the line that there was no evidence to support harm before 18 months.
Now in an analysis of a large colorectal cancer prevention trial, a 2.66-fold excess risk was seen within eight months of rofecoxib treatment (P=0.04) or sooner, found David J. Kerr, M.D., of the University of Oxford here, and colleagues.
Half of all events occurred among patients treated for less than 12 months, they reported in the July 26 issue of the New England Journal of Medicine.
And, the results may implicate other Cox-2 inhibitors as well, commented Elliott M. Antman, M.D., of Brigham and Women's Hospital and Harvard, acting as a spokesperson for the American Heart Association.
"Based on our understanding of the biology there's no reason to believe that other Cox-2 inhibitors would have a longer period to harm," he said, though he noted that other drugs in the class may have less cardiovascular risk than rofecoxib.
"We should not feel safe saying we don't need to worry until 18 months have elapsed," he added.
It was true at the time that there was no evidence to support earlier harm of rofecoxib and not much information to support or refute that claim, commented Steven E. Nissen, M.D., of the Cleveland Clinic, who was one of the early rofecoxib critics.
So to clarify the duration of drug exposure responsible for increased cardiovascular risk, Dr. Kerr and colleagues analyzed outcomes in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial.
This trial began like APPROVe, attempting to prevent colorectal cancer with rofecoxib treatment. However, when the drug was withdrawn from the market, the researchers halted treatment and continued to follow patients for two years after the trial closed.
Before September 2004, 2,434 patients at 151 hospitals in Britain who had undergone potentially curative surgery for colorectal cancer were randomized to 25-mg rofecoxib daily or placebo.
Patients in the rofecoxib group had slightly greater baseline cardiovascular risk than the placebo group based on predefined risk factors, but the only significant difference was a higher prevalence of diabetes (8.7% versus 5.6%, P=0.003).
Treatment continued for a median 7.4 months in the rofecoxib group and 8.2 months in the placebo group before the trial was closed and treatment discontinued. A third of all patients received assigned medication for at least a year.
The researchers found 16 confirmed cardiovascular thrombotic events in 15 patients receiving rofecoxib during or within 14 days after the treatment period versus seven events in six patients in the placebo group.
The relative risk of a cardiovascular thrombotic event was 2.66-fold higher with rofecoxib than placebo (95% confidence interval 1.03 to 6.86, P=0.04). Adjustment for cardiovascular risk factors attenuated the association, but the point estimate remained similar (RR 2.41, 95% CI 0.93 to 6.26, P=0.07).
Eight of the events were cardiac, three were peripheral vascular, and five were cerebrovascular in the rofecoxib group. In the placebo group, there were four, one, and one of these events, respectively, and two hemorrhagic events as well. Three of events overall occurred in conjunction with other non-steroidal anti-inflammatory drugs.
Moreover, Kaplan-Meier plots showed that the curves started to separate almost from day one, Dr. Nissen noted.
"The risk begins almost immediately and just gets progressively greater over time," he said.
An additional 14 adjudicated events were added from study closure to 24 months of follow-up for a total of 21 events in the rofecoxib group and 14 in the placebo group.
The relative risk of cardiovascular thrombotic events over the entire period from the beginning of treatment out to 24 months after trial closure was 1.50-fold higher with rofecoxib than placebo (95% CI 0.76 to 2.94, P=0.24).
Death from cardiovascular causes did not differ significantly between groups (five in the rofecoxib group versus seven in the placebo group).
But, the lack of significance for longer-term risk was not reassuring, Dr. Antman said.
"The trends here are all consistent with a signal of harm," he said. "Whether or not it's statistically significant has more to do with sample size."
Furthermore, other studies have suggested residual risk remains after rofecoxib is discontinued, Dr. Nissen said.
"It's important to know about the time to onset of risk because there are other drugs being developed in the class," Dr. Nissen noted. "If new drugs come along that have this problem, we need to recognize that they can cause trouble fairly quickly."
Merck commented that the "limited data from prematurely terminated studies such as ...VICTOR need to be interpreted with caution, and that assessments of cardiovascular risk with Vioxx must take into account the large amount of randomized, placebo-controlled clinical trial data from the Vioxx research and development program."
The study was sponsored by the University of Oxford and an educational study grant from Merck.
Dr. Kerr and another researcher reported receiving grant support from Cancer Research UK. One researcher also reported receiving consulting fees from Merck and Johnson & Johnson, while another reported serving as an advisor to Merck and to Novartis and as a consultant to lawyers representing Merck. Drs. Antman and Nissen reported no relevant conflicts of interest. Additional source: New England Journal of MedicineSource reference: Kerr DJ, et al "Rofecoxib and Cardiovascular Adverse Events in Adjuvant Treatment of Colorectal Cancer" N Engl J Med 2007;357:360-369.
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