Rofecoxib may cause heart attacks in first weeks of use

A small but significant number of elderly people who began taking rofecoxib (Vioxx) had heart attacks in the first two weeks, a study has found. Previously the risk was thought to occur only after 18 months of treatment.

The study was posted online ahead of publication on 2 May by the CMAJ, the journal of the Canadian Medical Association (http://www.cmaj.ca/, doi: 10.1503/cmaj.051 679).

“A small proportion of patients using rofecoxib for the first time had their first MI [myocardial infarction] shortly after starting the drug,” the paper says. The risk was highest in the first six to 13 days (median nine days) after they started treatment with the drug. The risk did not increase with length of treatment and returned to the baseline risk within eight to 30 days after treatment was stopped.

The risk of a heart attack was more acute than previously recognised, the authors write. “About one-quarter of current users of rofecoxib who had an MI experienced this event within a few weeks of receiving their first prescription.”

The researchers, from McGill University in Montreal and Queen's University in Kingston, Ontario, used information about people aged 66 years or older who had not previously had a heart attack and who were taking rofecoxib or celecoxib (Celebrex) for the first time.

The data were collected in Quebec province's computerised health database from January 1999 to June 2002. A time matched, nested case-control approach was used to analyse information on drug use and heart attacks, and the study compared current users and non-users of the two drugs in the year preceding the date of the heart attack.

Rofecoxib was taken off the market in September 2004. Celecoxib is still on the market but carries a black box warning from the US Food and Drug Administration. A risk of heart attack from use of celecoxib cannot be excluded, the researchers say. Other drugs in the class of cyclo-oxygenase-2 (COX 2) inhibitors also showed signs of early cardiovascular toxicity, they say.

The researchers looked at almost 114 000 people who had received a prescription for a non-steroidal anti-inflammatory drug. Their mean age was 75.2. The researchers found 239 rofecoxib users and 287 celecoxib users who had a first heart attack while taking the prescribed drug.

The risk of a first heart attack was higher among people who were prescribed rofecoxib for the first time than among matched controls who did not use prescribed non-steroidal anti-inflammatory drugs in the year preceding their heart attack (rate ratio 1.67 (95% confidence interval 1.21 to 2.30)), the investigators report.

First time users of celecoxib also had a slightly higher risk of heart attack, but the difference was not significant (rate ratio 1.29 (0.90 to 1.83)).

The investigators say that their study may not have been large enough to analyse the risk for users who continue to use COX 2 inhibitors beyond the first prescription. Also, only patients admitted to hospital were included in the database, meaning that cases involving silent heart attacks and sudden death may have been excluded. The investigators did not have information on smoking, obesity, physical activity, family history, socioeconomic status, or use of non-steroidal anti-inflammatory agents bought over the counter.

A spokesman for Merck, the makers of rofecoxib, said it was important to remember the Canadian study was an observational one. The company continues to believe that randomized clinical trials provide stronger evidence than observational studies about the efficacy and safety of medicines.