The New England Journal of Medicine on Monday issued a rare correction on a influential 2005 study on the now-withdrawn painkiller Vioxx.
The correction involves a crucial point that was first reported a month ago: That cardiovascular risks linked to the controversial cox-2 inhibitor kick in at 4 months to 6 months of use, not after 18 months as was previously asserted in last year's article.
"This correction retracts the claim that there is an 18-month delay before patients experience an increased risk while taking Vioxx," said Dr. Steven Nissen, interim chairman of the department of cardiovascular medicine at the Cleveland Clinic, and the author of a related letter, also released Monday by the journal.
"What it says now is there is no delay in the risk," Nissen added.
The original article outlined the results of the APPROVe study, which was funded by Vioxx's maker, Merck & Co. Early data from the APPROVe trial prompted Merck -- in cooperation with the U.S. Food and Drug Administration -- to pull Vioxx from the market in September 2004.
However, until recently, Merck has contended that Vioxx-linked heart risks only arose in users after they had taken the cox-2 inhibitor drug for 18 months or more. Indeed, the original wording of the March 2005 APPROVe study echoed that contention, mentioning no risk to users before the 18-month point.
Monday's correction of the March 17, 2005 NEJM article, which is slated to appear in the journal's July 13 issue, changes all that.
Another Vioxx expert agreed that the change was long overdue.
The correction and accompanying articles published Monday "all demonstrate that there was never any data to support the 18-month duration of Vioxx exposure for risk of heart attack," said Dr. Eric Topol, professor of medicine and genetics at Case Western Reserve University in Cleveland.
"Four other trials (VIGOR, Study 090, ADVANTAGE and VICTOR) also all point out that the risk of heart attack begins in the early weeks of Vioxx exposure," noted Topol, who has been at the forefront of the movement to investigate the painkiller debacle. The Cleveland cardiologist has authored 16 articles on the topic over the past five years and has also testified before the FDA in its hearings on the safety of such drugs.
This latest chapter in the Vioxx saga began last month. On May 18, the Wall Street Journal reported that data submitted a week previously by Merck to the FDA showed that Vioxx began to adversely affect the cardiovascular system after only four months of use -- not the 18 months the company had asserted in the past.
The new data -- based on a one-year follow-up of APPROVe participants -- included a key graph tracking the number of "confirmed thrombotic [clotting] cardiovascular events," the WSJ reported. That graph showed that the number of dangerous events among Vioxx users began to outnumber those of people taking a placebo by four months of use.
While the number of cardiovascular events included in the new analysis was not large enough to show statistical significance, it does suggest a trend beginning at four months, experts said.
In contrast, a similar graph appearing in the study as it was originally published in the NEJM showed no such divergence between the two groups until the 18-month point.
In a letter published in the journal Monday, two of the APPROVe investigators said the discrepancy between the 2005 and 2006 data lies in the fact that the original analysis left out cardiovascular events occurring more than two weeks after participants stopped using Vioxx. When this data was included in the subsequent analysis, it suggested that risks could begin to rise within four to six months of use.
"Thus, the additional safety data were not available at the time our article was published [in March 2005] and have only been compiled for analysis in the past few months," wrote Dr. Robert S. Bresalier of the University of Texas M.D. Anderson Cancer Center in Houston, and Dr. John A. Baron of Dartmouth Medical School in Hanover, N.H.
"Clearly, an in-depth analysis of the extended experience of the patients in the APPROVe trial is indicated, and it is under way," the two investigators added.
The news came as no surprise to experts, who said the latest developments only confirmed their fears about the safety of the now-withdrawn painkiller.
Topol pointed to another study, published in April in the online edition of the Canadian Medical Journal.
In that study, researchers at McGill University, in Montreal, reviewed three years of data on Vioxx and found that 25 percent of users who suffered a heart attack did so within 14 days of taking their first dose of the drug. Topol said the Canadian study "further substantiated" the notion that the dangerous cardiovascular effects begin sooner rather than later.
Another cox-2 expert said the Vioxx saga holds lessons for users of the sole remaining cox-2 on the market -- Celebrex. A second cox-2 drug, Bextra, was pulled in early 2005 due to similar heart concerns.
"This is [medically] newsworthy only in that it may bring attention to clinicians and patients using the currently available cox-2 drug and, potentially, other cox-2 inhibitors in the future," said Dr. Mark Fendrick, a professor of internal medicine at the University of Michigan School of Medicine.
Fendrick has long advised that a combination of an NSAID painkiller, such as naproxen, plus a stomach-protecting drug such as Prilosec or Nexium, can provide similar levels of pain relief as any cox-2 medication -- without the cardiovascular risks.
"I would strongly recommend this older combination over celecoxib [Celebrex] in patients at risk for cardiac events," he said.
Since the drug's withdrawal, thousands of lawsuits from patients who claim Vioxx caused strokes or other cardiovascular events have been filed against Merck, and verdicts have gone both for and against the company. Last month, a Texas jury awarded $32 million to the family of a 71-year-old man; jurors said Vioxx caused his death after he had taken it for less than a month.
According to Nissen, the new data suggesting an earlier risk "window" for Vioxx may be important from a legal standpoint because the 18-month cut-off has, up till now, "constituted the principle legal defense" for the company.
Controversies linked to Vioxx-related data aren't new.
Last December, NEJM editors published a rare "Expression of Concern" letter aimed at Merck. That letter charged that another major study on VIGOR -- published in the journal in 2000 and subsequently used as strong argument for the safety of Vioxx -- was submitted to the journal after data on cardiovascular events among Vioxx trial participants was deleted by Merck, which funded the trial.
In a statement released at the time, Merck said it had "promptly and appropriately disclosed the results of the VIGOR study."
The correction involves a crucial point that was first reported a month ago: That cardiovascular risks linked to the controversial cox-2 inhibitor kick in at 4 months to 6 months of use, not after 18 months as was previously asserted in last year's article.
"This correction retracts the claim that there is an 18-month delay before patients experience an increased risk while taking Vioxx," said Dr. Steven Nissen, interim chairman of the department of cardiovascular medicine at the Cleveland Clinic, and the author of a related letter, also released Monday by the journal.
"What it says now is there is no delay in the risk," Nissen added.
The original article outlined the results of the APPROVe study, which was funded by Vioxx's maker, Merck & Co. Early data from the APPROVe trial prompted Merck -- in cooperation with the U.S. Food and Drug Administration -- to pull Vioxx from the market in September 2004.
However, until recently, Merck has contended that Vioxx-linked heart risks only arose in users after they had taken the cox-2 inhibitor drug for 18 months or more. Indeed, the original wording of the March 2005 APPROVe study echoed that contention, mentioning no risk to users before the 18-month point.
Monday's correction of the March 17, 2005 NEJM article, which is slated to appear in the journal's July 13 issue, changes all that.
Another Vioxx expert agreed that the change was long overdue.
The correction and accompanying articles published Monday "all demonstrate that there was never any data to support the 18-month duration of Vioxx exposure for risk of heart attack," said Dr. Eric Topol, professor of medicine and genetics at Case Western Reserve University in Cleveland.
"Four other trials (VIGOR, Study 090, ADVANTAGE and VICTOR) also all point out that the risk of heart attack begins in the early weeks of Vioxx exposure," noted Topol, who has been at the forefront of the movement to investigate the painkiller debacle. The Cleveland cardiologist has authored 16 articles on the topic over the past five years and has also testified before the FDA in its hearings on the safety of such drugs.
This latest chapter in the Vioxx saga began last month. On May 18, the Wall Street Journal reported that data submitted a week previously by Merck to the FDA showed that Vioxx began to adversely affect the cardiovascular system after only four months of use -- not the 18 months the company had asserted in the past.
The new data -- based on a one-year follow-up of APPROVe participants -- included a key graph tracking the number of "confirmed thrombotic [clotting] cardiovascular events," the WSJ reported. That graph showed that the number of dangerous events among Vioxx users began to outnumber those of people taking a placebo by four months of use.
While the number of cardiovascular events included in the new analysis was not large enough to show statistical significance, it does suggest a trend beginning at four months, experts said.
In contrast, a similar graph appearing in the study as it was originally published in the NEJM showed no such divergence between the two groups until the 18-month point.
In a letter published in the journal Monday, two of the APPROVe investigators said the discrepancy between the 2005 and 2006 data lies in the fact that the original analysis left out cardiovascular events occurring more than two weeks after participants stopped using Vioxx. When this data was included in the subsequent analysis, it suggested that risks could begin to rise within four to six months of use.
"Thus, the additional safety data were not available at the time our article was published [in March 2005] and have only been compiled for analysis in the past few months," wrote Dr. Robert S. Bresalier of the University of Texas M.D. Anderson Cancer Center in Houston, and Dr. John A. Baron of Dartmouth Medical School in Hanover, N.H.
"Clearly, an in-depth analysis of the extended experience of the patients in the APPROVe trial is indicated, and it is under way," the two investigators added.
The news came as no surprise to experts, who said the latest developments only confirmed their fears about the safety of the now-withdrawn painkiller.
Topol pointed to another study, published in April in the online edition of the Canadian Medical Journal.
In that study, researchers at McGill University, in Montreal, reviewed three years of data on Vioxx and found that 25 percent of users who suffered a heart attack did so within 14 days of taking their first dose of the drug. Topol said the Canadian study "further substantiated" the notion that the dangerous cardiovascular effects begin sooner rather than later.
Another cox-2 expert said the Vioxx saga holds lessons for users of the sole remaining cox-2 on the market -- Celebrex. A second cox-2 drug, Bextra, was pulled in early 2005 due to similar heart concerns.
"This is [medically] newsworthy only in that it may bring attention to clinicians and patients using the currently available cox-2 drug and, potentially, other cox-2 inhibitors in the future," said Dr. Mark Fendrick, a professor of internal medicine at the University of Michigan School of Medicine.
Fendrick has long advised that a combination of an NSAID painkiller, such as naproxen, plus a stomach-protecting drug such as Prilosec or Nexium, can provide similar levels of pain relief as any cox-2 medication -- without the cardiovascular risks.
"I would strongly recommend this older combination over celecoxib [Celebrex] in patients at risk for cardiac events," he said.
Since the drug's withdrawal, thousands of lawsuits from patients who claim Vioxx caused strokes or other cardiovascular events have been filed against Merck, and verdicts have gone both for and against the company. Last month, a Texas jury awarded $32 million to the family of a 71-year-old man; jurors said Vioxx caused his death after he had taken it for less than a month.
According to Nissen, the new data suggesting an earlier risk "window" for Vioxx may be important from a legal standpoint because the 18-month cut-off has, up till now, "constituted the principle legal defense" for the company.
Controversies linked to Vioxx-related data aren't new.
Last December, NEJM editors published a rare "Expression of Concern" letter aimed at Merck. That letter charged that another major study on VIGOR -- published in the journal in 2000 and subsequently used as strong argument for the safety of Vioxx -- was submitted to the journal after data on cardiovascular events among Vioxx trial participants was deleted by Merck, which funded the trial.
In a statement released at the time, Merck said it had "promptly and appropriately disclosed the results of the VIGOR study."
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