Warning on drug taken by millions for heart disease

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A warning has been issued about a widely prescribed heart drug shown to cause a death rate among users that is nearly three times that of nonusers. The drug is nifedipine, taken by millions of Americans for hypertension and the heart-related pain of angina. Its mortality risk has been identified only among those who were taking high doses of a short-acting form of the drug, which is sold under the brand names of Procardia and Adalat. The warning came from the National Heart, Lung and Blood Institute after the results of 16 studies were combined for a meta-analysis. Most of the 8,350 study participants had had a heart attack.

Nifedipine is one of ten in a drug class, known as calcium channel blockers, which has long been a source of concern. Calcium channel blockers were approved as safe and effective in the treatment of angina, but they are primarily prescribed for hypertension. While these drugs do relieve angina and lower blood pressure, they have not been subjected to long-term trials to prove that they reduce the rate of stroke and heart attack, two main reasons for life-long use (see HealthFacts, December 1992).

Drug trials for FDA approval are short-term, lasting only a few months at best. Information on long-term effects is not available until clinical trials follow people who are taking the new drug or a placebo over the course of many years.

Such clinical trials, 16 in all, formed the basis for the new meta-analysis by Curt D. Furberg, M.D., Ph.D., and colleagues at the Bowman Gray School of Medicine, Winston-Salem, North Carolina. These represent all the studies of nifedipine for which mortality statistics are available (Circulation, 1 September 1995). Results showed a 6% death rate among people given a high dose (80 mg a day or more), as compared with a 2-3% death rate among those who remained un-treated or were taking a placebo. No increase in death was shown among those taking less than 50 mg/daily or less, but a slight increase was shown among those taking 60 mg / daily. Though the higher death rate was found only in moderate- to high-dose nifedipine, Dr. Furberg and colleagues noted that other calcium channel blockers "may have similar adverse effects, in particular those of the dihydropyridine type [e.g., Cardene, DynaCirc, Plendil, Norvasc]."

The new warning about high-dose nifedipine came with the caution that people should not stop taking this drug without calling their doctor. Furthermore, it does not extend to all calcium channel blockers, though the conclusion by Dr. Fur-berg and colleagues indicates a discussion with the doctor is advisable for anyone taking one of these drugs. Some experts are calling for further research to evaluate the newer longer acting calcium channel blockers.

The meta-analysis follows a study of people under treatment for hypertension (JAMA, 23/30 August 1995). The rate of heart attack was 60% higher among people treated with certain short-acting calcium channel blockers, compared with those treated with diuretics alone. The excessive risk was found among people taking three different short-acting drugs (verapmil, ditiazem, and nifediapine).

"There is no reason to prescribe short-acting drugs for any one. The manufacturer ought to take off them off the market," said Michael H. Alderman, M.D., chairman of the department of epidemiology and social medicine at Albert Einstein College of Medicine, Bronx, New York, and president elect of the American Society of Hypertension, in a telephone interview.

Until calcium channel blockers began to come on the market, people with hypertension were treated primarily with diuretics and beta-blockers (e.g., Inderal). These older drugs are no longer under patent and are thus available in the less expensive generic form. Most importantly, unlike the calcium channel blockers, the older drug classes have been proven to reduce the rate of heart attack and stroke.

Calcium channel blockers tend to be more expensive because many of them remain under patent. Their overuse is the result of the manufacturers' promotional activities aimed at doctors and more recently, direct-to-consumer advertising (Cardizem CD, see HealthFacts, February 1993). For years, the Joint National Committee on the Detection, Evaluation and Treat of High Blood Pressure has recommended that diuretics or beta blockers should be the first drugs prescribed for hypertension. Calcium channel blockers are to be prescribed only when the older drugs fail to lower blood pressure.

Yet Dr. Alderman contends that the largest use of calcium channel blockers is inappropriate. They are prescribed primarily as first-line treatment to people with hypertension and no history of heart attacks. "The tragedy is that the calcium channel blockers have been around for 15 years, and we don't have any outcome data to support their continued use: Are they better than, worse than, or same as the older drugs? Why don't we know?"

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