Vioxx studies question timing of heart attack risk.

In lawsuits against Merck & Co. for injuries caused by its now-withdrawn painkiller Vioxx, the company has maintained that the drug causes increased risk of heart attack and stroke only after the patient takes it for 18 months. Two recent studies cast doubt on that assertion.

A study by McGill University Health Centre in Montreal, Canada, found that heart attacks can occur in the first two weeks of Vioxx use. (Linda E. Levesque et al., Time Variations in the Risk of Myocardial Infarction Among Elderly Users of COX-2 Inhibitors, Canadian Med. Ass'n J., May 23, 2006, available at www.cmaj.ca/cgi/rapidpdf/cmaj.051679v1.)

The researchers used data from a previous population-based study of more than 110,000 Quebec residents who were 66 or older and taking nonsteroidal anti-inflammatory drugs (NSAIDs). That study found that Vioxx increased the risk of heart attack, and the new study looked at the timing of that risk.

A quarter of patients who suffered a heart attack while taking Vioxx did so within the first two weeks of taking it. After the first few weeks, risk decreased, the study found.

"The additional cardiovascular risk from Vioxx actually decreased with longer duration of use, suggesting that the period of highest susceptibility for most people taking Vioxx may occur earlier than previously believed," study author Linda Levesque said in a written statement.

The study showed that "short-term use of rofecoxib [Vioxx] is not without risk, and that risk of [myocardial infarction] is not restricted to continuous users nor accentuated with longer-term use," the authors noted.

Merck withdrew Vioxx from the market in 2004 after a three-year study (called Adenomatous Polyp Prevention on Vioxx, or APPROVe) of about 2,600 people found that Vioxx users had a greater risk of thrombotic cardiovascular events such as heart attack and stroke than those taking a placebo, beginning after 18 months of treatment.

On May 11, Merck announced that an APPROVe follow-up study of the fourth year--after patients stopped taking Vioxx--did not show a statistically significant difference in risk between those who had been taking Vioxx and those who had been taking a placebo. But critics say that although the numbers may be too small to be statistically significant, Merck's announcement was misleading.

Also, some have interpreted a graph in the APPROVe follow-up study as suggesting increased risk after only four months of use. (Heather Won Tesoriero & Ron Winslow, New Merck Data Suggest Risks from Vioxx Begin Earlier in Use, Wall St. J., May 18, 2006, at A2.)

Then, on May 30, Merck announced an error in a statistical method used in the APPROVe study (involving "linear time" rather than "logarithm of time")--but said it did not change the study results.

"It is becoming more clear that Merck's argument about the 18-month minimum time period before the heart attacks are seen is spurious," said Ellen Relkin, a New York City lawyer and first vice chair of ATLA's Section on Toxic, Environmental, and Pharmaceutical Torts.

Both the McGill University study and the APPROVe study suggest risk, said W. Mark Lanier, a Houston lawyer who last year won the first verdict against Merck for a Vioxx plaintiff. The McGill study may be more powerful statistically because "it examined enough people in an early usage of the drug to get a clear reading of whether or not the drug causes heart problems early," he said. "The APPROVe study did not have enough enrolled in the early stages to give a read of whether or not Vioxx causes early heart attacks."

The McGill study authors wrote that their findings "emphasize the need for early and proactive monitoring of adverse effects in the event that other COX-2 inhibitors are approved or even reintroduced." They added that "more research is needed to identify those most susceptible to cardiotoxicity mediated by COX-2 inhibitor therapy."

Relkin noted that "the APPROVe data on the increased risk long after drug use suggests that there is more than one biological mechanism at play" and "makes a good case for the need for medical monitoring." She added that a New Jersey lawsuit seeking medical monitoring was dismissed but is now on appeal. (Sinclair v. Merck & Co., Inc., No. ATL-L-3771-04-MT, 2005 WL 1278364 (N.J. Super. Ct. May 19, 2005).)

Will these studies change the landscape of Vioxx cases? Of the six cases that have gone to trial, Merck has won haft. Lanier noted that one plaintiff who had used Vioxx for seven months won his case; one who used it for a month lost; and one who used it for three weeks lost, after the case initially resulted in a hung jury.

After the McGill study, "you are going to see more short-term cases filed, but these are still very hard to win," Lanier said. "The study makes winning one a bit easier, but the jury is out on whether there will be a greater number of short-term victories."

Relkin noted, "As a result of these studies, some law firms are reassessing their selection criteria, and some are going back to look at cases they previously rejected and determining if they ought to be reconsidered."

She added, "Now, since Merck is claiming it will not settle and will try each case, the science is evolving and emerging--and not in the way Merck had hoped."