Authors of a pivotal Canadian-led study involving the once popular painkiller Vioxx are now being accused of withholding evidence about the drug's heart risks by editors of the prestigious New England Journal of Medicine.
The VIGOR study, headed by Claire Bombardier, director of rheumatology at the University of Toronto, and funded by Vioxx-maker Merck & Co., was first published by the journal in November of 2000.
The study's touted result was that Vioxx caused fewer gastrointestinal problems than the older anti-inflammatory drug naproxen. While the study also reported the painkiller may increase the risk of cardiovascular events, it played them down in light of its benefits and Vioxx went on to become a blockbuster drug.
But in an "expression of concern" published on-line yesterday, journal executive editor Gregory Curfman and colleagues said the VIGOR study understated the risk of heart attacks attributed to Vioxx and that "certain calculations and conclusions" were both incorrect and misleading.
Merck disputes the finding.
In the on-line editorial, the editors wrote that court documents connected to a Vioxx lawsuit that were obtained in November revealed a memo dated July 5, 2000. The memo shows at least two of the authors, whom it does not name, knew before the study was published that there had been three more heart attacks among patients taking Vioxx than had been reported.
But Dr. Curfman, executive editor of the journal, told The Canadian Press in an interview that the two were employees of Merck & Co.
The editors wrote: "Until the end of November, 2005, we believed that these were late events that were not known to the authors in time to be included in the article." They went on to note the authors appeared to have had the information "at least two weeks before" they submitted revisions and 4½ months before publication of the article.
"Given this memorandum, it appears that there was ample time to include the data on these three additional (heart attacks) in the article."
If those data had been included, the editors feel the heart safety of the drug could have been viewed differently. What is more, the editors wrote, "We determined from a computer diskette that some of these data were deleted from the VIGOR manuscript two days before it was initially submitted to the Journal on May 18, 2000."
"Taken together, these inaccuracies and deletions call into question the integrity of the data on adverse cardiovascular events in this article," Dr. Curfman and colleagues wrote. "We have asked the authors to submit a correction to the Journal."
The journal report does not specifically identify which authors it believes withheld data from the 2000 VIGOR article. But since Dr. Bombardier was the lead author, hers, as is customary when citing medical-journal reports, is the main name mentioned.
Dr. Bombardier, who holds a Canada Research Chair in her field and who has been a Merck consultant on Vioxx since 1997, said in an e-mail to The Globe and Mail last night: "I believe that the VIGOR paper appropriately disclosed the data as per the pre-specified plan of analysis."
Dr. Bombardier also noted that the authors had not been informed of the journal's intention to post the editorial until noon yesterday.
"The authors of the paper will be preparing a response to the editorial but given the very short notice from the NEJM we have not had the time to finalize it yet."
In response, Merck said in a statement posted on its website, the study "fairly and accurately described the results of the study as of the pre-specified cutoff for analysis."
It said the additional heart attacks referred to in the editorial involve events that were reported after the cut-off date and that they did not "materially change any of the conclusions in the article."
Merck pulled Vioxx off the market in October of 2004 after finding the drug doubled the risk of heart attack and stroke. The company has since faced numerous legal proceedings, including U.S. Senate hearings and liability lawsuits.
While this may be the most public and serious criticisms the VIGOR trial has faced, it is certainly not the first.
The study has been widely criticized since 2001 after Merck submitted all its data from the VIGOR trial to the U.S. Food and Drug Administration to improve the stomach-safety profile on the Vioxx label.
It was then that doctors began criticizing the published version of the study for leaving out such details as the number of people who suffered from blood clots, strokes, hypertension and heart failure.
In a Globe and Mail investigation of the Vioxx file published last February, Dr. Bombardier said no information had been deliberately left out of the journal article. "It's always easy with the eyes of retrospect," she said.
"What we've learned from that is that we needed to look at the totality [of the outcomes and adverse events] not just what was statistically significant."
She defended VIGOR as the first trial to bring the drug's heart risks to light and also suggested some safety data were excluded because of the "limited space constraints of a peer-reviewed journal."
Dr. Curfman told The Globe at that time that the journal reported everything it had and did not know whether the authors had any other data. But that changed, yesterday's release explained, after plaintiff attorneys involved in Vioxx litigation subpoenaed Dr. Curfman to give testimony on Nov. 21 about the events leading up to the publication of the VIGOR trial.
During that process, Dr. Curfman discovered the July, 2000, memo, which the journal said also "contained other data on cardiovascular adverse events that we believe would have been relevant to the article."