By Duke Medicine News and Communications

DURHAM, NC – Tiny babies sometimes have big heart problems, but when that happens, doctors are often left scratching their heads over how much medication to give them.

"That's because 75 percent of the drugs we use in children have never been tested in kids, so often, we're working with a best-guess situation," says Dr. Jennifer Li, a pediatric cardiologist at Duke University Medical Center.

Li and colleagues from 22 research centers around the world are hoping to change that. They've just completed the first-ever study examining use of an anti-clotting drug called clopidogrel, also known as Plavix, in children under age two. "We were astonished at how little of the drug they needed to reap the same benefits as adults," says Li. "It was only about a fifth of the amount that we were expecting."

The study, known as the PICOLO Trial, will appear in the January 29 issue of the journal Circulation.

Clopidogrel, like aspirin, is useful in keeping platelets from sticking together and forming blood clots. Studies show it can reduce the risk of heart attack, stroke, or death in adults who are high risk for cardiovascular problems.

But children with heart disease can benefit from clopidogrel, too, says Li. It's just not been clear what the optimal dose should be.

"Just because a kid is one-eighth the size of an adult doesn't mean you give them one-eighth the amount of medicine," says Li, who is chief of cardiovascular research in the division of pediatric cardiology. "Kids are not just small adults. Their bodies are changing faster; they metabolize drugs differently; they are just biologically different."

Li recruited 92 participants for the study. All had heart disease that put them at high risk of developing life-threatening blood clots. Most had been diagnosed with hypoplastic left heart syndrome, a disorder involving a poorly performing, small ventricle that left them weak and blue in color. Others had problems with floppy or imperfect valves and one had Kawasaki disease, a condition that causes inflammation in coronary arteries. Many of the children were facing multiple surgeries to correct the defects and three-quarters of them had already had shunts implanted in their hearts to keep their blood flowing properly.

The patients were randomized into one of two groups: Some got clopidogrel, others, a placebo. Those in the treatment group were given one of four doses of clopidogrel, ranging from .01 to .20 milligrams per kilogram of weight over a period of one to four weeks.

Li notes that adults, with an average weight of 75 kilograms, are typically given 75 milligrams of clopidogrel per day to inhibit clot formation. When extrapolated, would predict an optimal dose of about one milligram per day for children under age two. But the study showed that the optimal dose for infants and toddlers up to 24 months was actually only .2 milligrams per day – about a fifth of that amount.

"It just goes to show you that you can't simply extrapolate from what you do in adults and apply it to children," says Li.

Li says using even optimal dosing with clopidogrel in children may involve some side effects. While there were no reports of serious bleeding, one patient did develop lower platelet counts, a condition investigators say may have been related to treatment.

Bristol-Myers Squibb and sanofi-aventis, the makers of Plavix, sponsored the study.

Co-authors from the Duke Clinical Research Institute include Eric Yow and Katherine Berezny.