Credit: Robert Boston
Washington University
New research helps explain the higher risk of death observed among some patients taking the anticoagulant clopidogrel after a heart attack.
Researchers identified genetic variants that increased the risk of dying in the year following a first heart attack, but they appeared to do so for different reasons depending on a patient’s race.
Two DNA variants common in African Americans were associated with an increased risk of both bleeding and death.
And in Caucasians, a different variant was linked to additional heart attacks and a higher risk of death.
The variations influence the way patients metabolize clopidogrel and can alter its effectiveness.
These findings were published in Circulation: Cardiovascular Genetics.
“The research is provocative,” said the study’s first author Sharon Cresci, MD, of the Washington University School of Medicine in St Louis.
“Knowing about potential genetic differences based on race can help physicians tailor drugs to patients based on their genetic makeup.”
Clopidogrel is metabolized in the liver, where it is turned into its active form via a group of enzymes called cytochrome P450 (CYP). Although clopidogrel is effective in many patients, earlier studies showed that some patients metabolize the drug better than others.
Indeed, in 2010, the US Food and Drug Administration added a black box warning to labels of clopidogrel after research (which primarily involved Caucasians) showed that people with a particular CYP genetic variant metabolized the drug poorly, which reduced the amount of the drug circulating in the blood. These patients had a higher risk of heart attack and stroke.
Additional studies showed that other CYP gene variants are linked to the rapid metabolism of clopidogrel, and patients with those variants had a higher risk of bleeding. But it has not been clear, until now, that the effects of these particular gene variations can vary by race.
To uncover this finding, Dr Cresci and her colleagues analyzed CYP variants among 2062 Caucasians and 670 African Americans who suffered heart attacks. Nearly 80% of the Caucasians and 65% of the African Americans were prescribed clopidogrel.
The patients were enrolled in a major study known as TRIUMPH (Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health), which was conducted from 2005 to 2008 at 24 US hospitals.
Among patients taking clopidogrel, the 1-year mortality rate for African Americans was 7.2%, compared with 3.6% for Caucasians.
Caucasians who carried the CYP2C19*2 variant, which has been linked to poor metabolism of the drug, had a higher rate of repeat heart attacks and death. However, among African Americans treated with clopidogrel, the CYP2C19*2 variant was not associated with a higher rate of death.
African Americans had higher rates of bleeding and death if they carried either of 2 other variants: CYP1A2*1C or CYP2C19*17, the latter of which has been associated with the rapid metabolism of clopidogrel. Among Caucasians on clopidogrel, neither variant increased the risk of death.
“This is very novel information that begs for more research,” said study author Richard G. Bach, MD, also of Washington University.
Although genetic testing is available to identify CYP variants in a patient’s DNA, these tests are not widely used by cardiologists. Results of the current study suggest this practice may need to be reconsidered.
“This research is an important addition to the field because previous studies looking at CYP gene variants and their effects on risks of repeat heart attacks, bleeding, and death have included predominantly Caucasian patients of European ancestry,” Dr Cresci noted. “There is almost no data, until now, about these variants in African Americans.”
Research examining how genetic variants alter the effectiveness of clopidogrel remains somewhat controversial, Dr Bach said. Many physicians feel that before they can tailor therapy for heart attack patients, more data is needed to prove a clear link between genetic variants and negative health consequences and that tailoring therapy will improve patients’ outcomes, he explained.
His hope is that additional research would provide more definitive conclusions to help physicians choose the best medications for patients after a heart attack and, ultimately, “to reduce the too-high rate of death and disability for patients after a heart attack,” Dr Bach said.
Dr Cresci agreed, adding, “By focusing on genetic differences, we may be able to individualize therapies after heart attacks and achieve the best treatment for each patient.”
