Canadian researchers say older people who took the
pain reliever Vioxx for the first time had an elevated risk of an initial heart attack within two weeks of taking the drug.
The study's results, which contain a number of caveats, clash with Merck's assertion that Vioxx-takers had a heightened risk of cardiovascular problems after taking the drug for more than 18 months.
"A small proportion of patients using rofecoxib for the first time had their first myocardial infarction shortly after starting the drug," researchers say in an online version of the
Canadian Medical Association Journal
published Tuesday. Rofecoxib is the generic name for Vioxx. Myocardial infarction is the scientific term for a heart attack.
Merck questioned their methodology of searching past medical records -- an observational study -- rather than conducting a randomized clinical trial.
"While we have not seen the results of the specific study, it is important to remember that this is an observational study," the company said. "Merck & Co. continues to believe that randomized clinical trials provide stronger evidence than observational studies about the efficacy and safety of medicines."
Merck removed Vioxx from the market in September 2004, citing the results from a company-sponsored clinical trial that showed the drug could lead to heart injuries after being taken for more than a year and a half.
Before Merck pulled the drug, "the data from placebo-controlled clinical studies demonstrated no increased risk for Vioxx compared to placebo," the company said.
In the past, Merck has
criticized observational studies. Merck used this argument in August 2004, when it disputed the findings of a Food and Drug Administration study that said Vioxx users had a higher heart-attack risk than users of Celebrex, a
drug that's still on the market. Vioxx and Celebrex are called COX-2 inhibitors.
The Canadian researchers say first-time users of Celebrex experienced a slightly higher but statistically insignificant increase in their risk for a first heart attack.
The FDA now requires a black box warning, its strongest alert,
on Celebrex and other prescription pain relievers to alert patients about the increased risk of cardiovascular problems.
The risk of a first heart attack among people 66 years old and older was highest among first-time users of Vioxx within six to 13 days of taking the drug, Canadian researchers say. The median was nine days.
These findings were considered statistically significant by the researchers at McGill University in Montreal and Queen's University in Kingston, Ontario. Among so-called prevalent Vioxx users, there was no statistically significant increase in risk. The researchers define a prevalent user as someone who had at least more than one prescription for the drug.
In fact, they say the risk of heart attacks among elderly Vioxx users "appears to decrease over time, despite repeated exposure, presumably owing to the depletion of susceptible people."
The Canadian study will no doubt provide ammunition to attorneys who are representing plaintiffs suing Merck for personal injury or monetary losses related to Vioxx. The company is defending itself against 11,500 personal injury lawsuits and 190 class-action suits.
The next trial starts in early June in New Jersey. A trial in California is set for later next month.
Researchers in the Canadian study used a computerized database of public health records from the province of Quebec between January 1999 and June 2002, assessing nearly 114,000 people. They found 3,708 Vioxx users who met the study's guidelines, as well as 5,598 Celebrex users and 16,680 people who didn't use the drugs. The average age was just over 78.
They found 239 current Vioxx users who had a heart attack, including 65 who took the drug for the first time. They found 287 current Celebrex users who had a heart attack, including 57 first-time users of the drug. The placebo group had 793 heart-attack patients.
The key figure is the heart-attack rate. The control-group's ratio is expressed as 1.00. The ratio for first-time Vioxx users is 1.67, which researchers say is statistically significant. However, they say prevalent Vioxx users had a 1.17 ratio, which is statistically insignificant.
The heart-attack ratio for first-time Celebrex users is 1.29, which researchers say is statistically insignificant. The 0.97 risk ratio for prevalent Celebrex users also is statistically insignificant.
"Although we cannot directly compare our results to those of randomized trials, particularly in view of the older age of our study group, we nonetheless demonstrate the presence of an early risk" of acute heart attack for Vioxx, the researchers say.
Even though the results "provide no conclusive evidence of an increased risk" of heart attacks for Celebrex users, they say "further definitive studies are required."
The researchers note that their work has some limitations. For example, they lacked information about patients' personal health habits, such as smoking, obesity, physical activity and their family history, and their socioeconomic status. These factors can affect one's risk of having a heart attack, but they say "several investigators have demonstrated that, in the context of assessing the risk of
heart attack, unmeasured risk factors result in no or negligible bias."
In addition, they were unable to determine the patients' use of over-the-counter pain relievers such as ibuprofen. But they said "this source of bias is likely to be negligible ... thus leading to an underestimation of the true risk." They cited a previous study they conducted as the source for this assertion.
By early Wednesday afternoon, Merck's stock was off 28 cents to $34.20.