Vioxx Heart Risk Found to Be Early and Persistent

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Vioxx Heart Risk Found to Be Early and Persistent

By Peggy Peck, Managing Editor, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University

of Pennsylvania School of Medicine.

May 03, 2006

Also covered by: MSNBC



MedPage Today Action Points

Explain to interested patients that Vioxx (rofecoxib) is no longer

available. This study found no significantly increased risk for

Celebrex (celecoxib) users.

Explain to interested patients that current guidelines suggest that

all NSAIDs—except aspirin—may increase the risk of cardiovascular

events, so the drugs should be used at low doses for short periods.

Review

MONTREAL, May 3 — Vioxx (rofecoxib) attacks hearts early, not late,

and its hazardous effect is sustained for seven days after treatment

is stopped, according to researchers here.

The drug is now the centerpiece of hundreds of liability suits

against Merck, which voluntarily pulled the -2 inhibitor from the

market almost two years ago.

First-time Vioxx users had a 67% increase in the risk of a myocardial

infarction during the first six to 13 days of use Levéque, a

doctoral fellow at the Department of Epidemiology and Biostatistics

at McGill University, and colleagues, reported in an early online

release for the May 23 issue of the Journal of the Canadian Medical

Association.

Vioxx users had a 23% increase in risk of MI for seven days after

stopping treatment, but on day eight the risk returned to baseline

values, the investigators found.

Levéque and colleagues identified 113,927 people, mean age 75.2, who

had received at least one prescription for a non-steroidal anti-

inflammatory drug from January 1999 to December 2002. At baseline

this cohort included 30,274 people taking Vioxx and 44,885 who had

prescriptions for Celebrex (celecoxib). The entire cohort was

followed for average of 2.4 years, but the analysis was based on data

collection at one year.

At that point, there were 783 MIs among non-users, 239 MIs among

Vioxx users, and 287 MIs among Celebrex users. Sixty-five MIs

occurred in first-time Vioxx users and 57 in first-time Celebrex users.

The risk of MI was highest for first-time Vioxx users (adjusted rate

ratio 1.67, 95% CI, 1.21-2.30), with events occurring a median of

nine days after Vioxx treatment was started. The risk for first-time

Celebrex users was higher than that for non-users but not significant

(adjusted rate ratio 1.29; 95% CI 0.90-1.83).

While MI risk with Vioxx increased steadily over time, this increase

was not significant and the risk with Celebrex was stable, said

Levéque.

The finding appears to contradict two widely reported aspects of the

event risk associated with Vioxx: that risk is increased only with

long-term use and that increased risk is dose dependent.

Merck, the maker of Vioxx, voluntarily pulled the drug from the

market Sept. 30, 2004, when investigators with APPROVe (Adenomatous

Polyp Prevention on Vioxx), a cancer prevention trial, reported that

using the drug daily for more than 18 months increased the risk of

thrombotic events, including non-fatal MIs. Study patients were

taking 25 mg of Vioxx or placebo daily.

The company is defending itself in a series of malpractice cases

brought by patients who claim the drug caused their heart attacks.

While APPROVe suggested that the risk was triggered by long-term use,

Levéque said an earlier Vioxx trial—VIGOR Vioxx Gastrointestinal

Outcomes Research—had " early separation of the time-to-event

curves, " which are consistent with the observed risk in her analysis.

In the Canadian analysis, patients were " taking low doses of Vioxx

and still had significantly increased risk of early events, " she said.

Likewise, the most common Celebrex dose was low, 200 mg or less

daily, which prompted Levéque to be cautious about endorsing Celebrex

safety. " Compared to Vioxx, Celebrex appears to be relatively safe,

but more studies—at higher doses—are needed, " she said.

The authors suggested that the observed decrease in the risk of MI

over time, despite repeated exposure, " is presumably owing to the

depletion of susceptible people. More research is needed to identify

those most susceptible to cardiotoxicity mediated by -2 inhibitor

therapy " and to investigate whether an early risk is present for

Celebrex and in other populations.

The study was funded by the Canadian Institutes for Health Research.

Primary source: Canadian Medical Association Journal

Source reference:

Levesque L et al " Time variations in the risk of myocardial

infarction among elderly users of COX-2 inhibitors " CMAJ 2006; 174

(II) Online 1-8