Looking for the Dosage

From the annual Scientific Sessions of the American Heart Association, Orlando

What’s the ideal dosage for a drug?

Clearly an important question, but one that often doesn’t get answered. When a new drug is in development, a few phase I and II studies  monitor safety and test drive a few dosages. Drugs for cardiovascular diseases usually run through these preliminary steps with surrogate end points.  The ultimate clinical goal for these agents is to cut the rate of myocardial infarctions, strokes, heart failure hospitalizations, or the biggest end point of all, death. But dose-ranging studies, to be at an affordable size, generally use end points like drops in blood pressure or serum cholesterol, or easy measures of atherosclerosis. Once the megatrial begins, the one that puts the new drug to the test of saving lives or major events in thousands of patients, the focus is invariably on a single dosage matched against placebo with a backdrop of optimized standard therapy.

The problem is, how can you be sure the dosage tested is really best for preventing the events you care about? The answer is you can’t.

That dilemma made two reports at the American Heart Association’s meeting last week stand out. One, the HEAAL study, compared the standard, 50 mg/day dosage of the angiotensin-receptor blocker losartan against a 150 mg/day regimen in a study with nearly 4,000 heart failure patients followed for a median of almost 5 years to see which worked best for preventing deaths and heart failure hospitalizations. The answer was that the 150 mg/day dosage cut these events by an absolute 3% without causing significantly more problematic side effects.

The second study,  J-CHF, compared three different daily dosages of the beta blocker carvedilol, 2.5, 5 , or 20 mg, also in patients with heart failure, and also looking for a difference in the rate of death or hospitalization for heart failure or another cardiovascular disease. This study, unfortunately, had an overly anxious safety-monitoring committee that bailed on the trial after only 364 patients had entered, too few to show which dosage worked best.

Dr. Marvin A. Konstam/photo by Mitchel Zoler

Experts who discussed these two studies at the meeting agreed on how important and unique the comparisons were.  In the case of losartan, “we felt that this was a major unanswered question,” said Dr. Marvin A. Konstam, a Tufts cardiologist in Boston and lead investigator for the HEAAL trial.

One reason why different doses of a drug aren’t often compared in big, clinical-end point trials: no drug maker wants to pay for such studies.  Once a drug dosage is approval by a regulatory agency like the  FDA, there isn’t much incentive to further pursue dosage; it probably won’t make much difference in sales.

The Japanese Heart Foundation, a group with no financial interest in carvedilol, sponsored the beta-blocker study. The losartan study was sponsored by Merck, the company that markets losartan (Cozaar). But last week, a spokeswoman for Merck noted that Cozaar comes off its patent in 2010, and the company’s main motivation for running the study was a request from the European regulatory agency.

So don’t expect to see more studies like these two coming along soon. Without them, the best dosage for many other drugs remains anyone’s guess.

—Mitchel Zoler  (on Twitter @mitchelzoler)

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Filed under Cardiovascular Medicine, Internal Medicine, Practice Trends, Primary care

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