For most heart patients, the blood thinner Plavix does its job preventing clogged vessels. But it doesn't work well in a significant minority -- yes, minority -- of patients, putting them at risk of suffering a heart attack or stroke. This was brought to light last month in stern warnings from the U.S. Food and Drug Administration about Plavix's failures, which sent shockwaves through doctors and patients alike.
Now scientists at UNC-Chapel Hill are hoping to add clarity. In a study launched this month, researchers are testing heart patients to see whether they carry the genetic trait that defines whether Plavix will be a good drug or ineffective, or something in between. For those whose genes indicate a problem, the doctors will double the Plavix dose to determine whether more is better.
"We want to make sure we put the right people on the medicine and know who responds and who doesn't," said Dr. Joseph Rossi, a UNC-CH cardiologist who is leading the study.
The information is vital, because Plavix is the frontline medicine used for people who have cardiovascular disease. About 3 million people in the United States are prescribed the drug, which works by keeping clot-forming platelets from becoming too sticky and blocking blood vessels. It'salso used to inhibit blood clots from forming around stents, which prop open narrowed or clogged vessels.
Marketed in the United States since 1997, Plavix is the No. 2 heart pill in the world, behind Lipitor, which lowers cholesterol. It reaps more than $8 billion a year in sales for Bristol-Myers Squibb and Sanofi-Aventis SA. But in recent years, reports have focused on people who take the drug and get little or no blood-thinning benefit. As many as 34 percent of patients have a poor response. The problem lies in a specific gene, said Dr. George A. "Rick" Stouffer, a UNC-CH cardiologist who is working with Rossi on the study. People who have inherited a certain gene variant from both parents don't produce an enzyme in the liver that activates Plavix's blood-thinning mechanism. Up to 4 percent of heart patients have this abnormality. Stouffer said they have almost no response to the drug, putting them at highest risk of suffering a heart attack or stroke despite taking a drug they hope is helping. Another 30 percent of people have a mix of genes -- one that metabolizes Plavix and another that doesn't. Inmany of these patients, the drug has limited effect. Doctors can check this by running a blood test that measures how sticky the platelets are. Albert Freund, 69, of Chapel Hill, is participating in the UNC-CH study and discovered Friday that he has the mix of genes. In his case, however, his single gene that enables him to metabolize Plavix triggers a rapid response to the drug, so he gets about as much benefit as the majority of people who are genetically inclined to do well on Plavix.
"I'm going to be 69 next week," Freund said, "and I feel 45." Rossi, who is Freund's doctor, said having the genetic information about patients is only part of the story, and Freund's case illustrates the complications. But the FDA warning about Plavix has heightened the need for routine genetic tests before patients begin taking the drug. Though expensive and potentially time-consuming, the genetic information is good at flagging a problem. But there are only iffy solutions. For some patients who would do poorly on Plavix, a competing drug can be prescribed, although it's not a good fit for older people. "That covers a lot of the waterfront," Stouffer said. Alternatively, some doctors have taken to doubling the dosage of Plavix, but without good research to know whether it's safe and effective. Rossi said that's what the UNC-CH study is hoping to discern. "It's been studied in small trials, but not with enough patients to prove it saves lives," he said. Rossi said 200 patients will be enrolled in the UNC-CH study in coming months. Patients who have the problematic genetic profile will be tested on a regular dose of Plavix and a double dose, and screened for how well they respond. Rossi and Stouffer said they hope to have results by early next year. "Because this is an area of ongoing research, we have an obligation to do good clinical studies to determine what the right course of action is," Rossi said.
