High Doses of Heart Medicine Raise Risk of Death, Study Finds

Patients taking high doses of one of the heart drugs known as calcium channel blockers had nearly triple the death rate of others with heart disease, a new study shows.

In a separate study published last week, the same drug was linked to a 60% increase in heart attack risk.

The latest study deals with older versions of nifedipine, sold in generic form and under the brand names Procardia and Adalat. These older versions must be taken three or four times per day. Newer, once-a-day versions--marketed as Procardia XL or Adalat CC--were not studied.

The American Heart Assn. and the National Institutes of Health both issued warnings to coincide with publication of the latest study today in Circulation, a journal published by the heart association.

The heart association cautioned that patients should not stop taking the older drugs because a sudden stop can itself can cause medical problems. Instead, patients were advised to consult their doctors about possible alternatives.

The NIH warned doctors against routine use of the older versions of nifedipine, saying they “should be used with great caution, if at all, especially at higher doses.”

Calcium channel blockers have been used to treat heart attacks and chest pain, but they are now most widely used to treat high blood pressure.

Researchers are divided over the implications of the two studies. Some agree with the drugs’ makers that newer, more widely used versions of the medicines are safer. Others say the studies raise questions about the safety of all calcium channel blockers.

The study was a mathematical analysis of 16 previously published studies of patients who took the older versions for heart attacks or chest pain, known as angina.

The study found that patients taking the highest doses of nifedipine had nearly three times the death rate of patients given a placebo--six deaths per 100 people, compared with about two deaths per 100.

At lower doses, the risk dropped sharply. The average increase in risk for all patients taking older versions of nifedipine was 16%.

An estimated 6 million Americans take calcium channel blockers, said the study’s authors, Dr. Curt Furberg of the Bowman Gray School of Medicine and Dr. Bruce Psaty of the University of Washington in Seattle.

Furberg said that fewer than 10% of them are taking the older versions. But he said the findings raise questions about the safety of other calcium channel blockers and of the newer, once-a-day versions of nifedipine.

“If you have a toxic substance and put it into a long-release, it’s still a toxic substance,” he said. “We have proven alternatives that are much more effective and cheaper.”

Makers of the drugs vigorously disputed Furberg’s assertions.

“There is a much lower incidence of side effects with the newer agents,” said John F. Niblack, head of research and development at Pfizer, which makes Procardia and Procardia XL. “And there’s good long-term evidence that they are excellent for the treatment of hypertension and angina and that they are very safe.”

Dr. Steven Jungerwirth, medical director for heart disease research at Bayer, which makes Adalat and Adalat CC, said nifedipine “is extremely well-tolerated and very safe and very effective in lowering blood pressure.”

The NIH took the middle ground, saying it is unclear whether the concerns raised in the studies should extend to other calcium channel blockers. The government has begun a study to provide definitive evidence on the question.

The drug makers also criticized the study on technical grounds, saying it was based on biased data. Furberg distributed a written rebuttal to that charge.

In March, Psaty and Furberg found, in a study of people with high blood pressure, that calcium channel blockers were associated with a 60% increase in the risk of heart attacks. The highest doses tripled the risk.

That study, which was presented at an American Heart Assn. meeting, prompted thousands of patients to call their doctors for advice.