JAMA: 3 genes, 2 Plavix-related factors linked to early stent thrombosis
Researchers in France identified three genes and two clopidogrel-related factors that were independently associated with early stent thrombosis. The study published in the Oct. 26 issue of the Journal of the American Medical Association provides a better understanding of the genetic profile of at-risk patents, but future studies will be needed to validate its prognostic accuracy, the authors wrote.
Early stent thrombosis is a serious complication of coronary stenting, but its rarity makes it a difficult condition to study. Guillaume Cayla, MD, PhD, of the Institute of Cardiology at Pitie-Salpetriere Hospital in Paris, and colleagues overcame that limitation by using the Online Assistance for Stent Thrombosis (ONASSIST) project, a national registry that includes 10 centers that performed nearly 18,500 PCI procedures between January 2007 and May 2010.
From that data set they identified 123 patients who were receiving dual-antiplatelet therapy and who experienced an angiographically documented stent thrombosis 30 days or less after the procedure. That group was matched with a control group that consisted of a 246 stent thrombosis-free patients. The researchers then obtained genomic DNA samples from both cohorts.
Their goal was to perform a case-control study to test clinical factors as well as genetic factors associated with early stent thrombosis. For the genetic component, they tested 23 genetic variants that are believed to adversely affect clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) absorption and metabolism. They used a multivariable logistic regression analysis to identify independent variables associated with early stent thrombosis. The researchers built a clinical-only model based on baseline demographic, clinical and angiographic characteristics. A genetic-only model included predicted metabolic status and genetic variants.
They identified three genotypes, CYP2C19, ABCB1 and ITGB3, that were related to clopidogrel metabolism and platelet function and that were significant determinants of early stent thrombosis. Nongenetic independent correlates were acuteness of the PCI, complex lesions, left ventricular function of less than 40 percent, diabetes mellitus, use of proton pump inhibitors (PPIs) and higher clopidogrel loading doses.
They found that the risk of early stent thrombosis increased according to the number of risk alleles in the patient. Additionally, a combined clinical and genetic risk model improved risk stratification for stent thrombosis. They found using the combined model that patients in the highest tertile of risk had a seven-fold increased risk of early stent thrombosis compared with patients in the lowest tertile.
“Our multicenter study suggests that a combination of three genotypes related to clopidogrel metabolism and platelet function (CYP2C19, ABCB1 and ITGB3) is an independent risk factor for early stent thrombosis beyond clinical and angiographic factors,” Cayla and colleagues wrote. “We also identified two potentially modifiable factors of early stent thrombosis: clopidogrel loading and clopidogrel interaction with PPIs.”
The authors noted that their study had a limited sample size and omitted the most severe cases, that is, cases in which the patient died soon after stent thrombosis. They did not evaluate stent malapposition or underexpansion, which are associated with stent thrombosis. Also, their patient population were predominantly Caucasians and may not be representative of all patient groups.
They recommended that validation studies be conducted to determine if their combined clinical-genetic risk stratification model improved the prognosis for patients undergoing PCI.
Early stent thrombosis is a serious complication of coronary stenting, but its rarity makes it a difficult condition to study. Guillaume Cayla, MD, PhD, of the Institute of Cardiology at Pitie-Salpetriere Hospital in Paris, and colleagues overcame that limitation by using the Online Assistance for Stent Thrombosis (ONASSIST) project, a national registry that includes 10 centers that performed nearly 18,500 PCI procedures between January 2007 and May 2010.
From that data set they identified 123 patients who were receiving dual-antiplatelet therapy and who experienced an angiographically documented stent thrombosis 30 days or less after the procedure. That group was matched with a control group that consisted of a 246 stent thrombosis-free patients. The researchers then obtained genomic DNA samples from both cohorts.
Their goal was to perform a case-control study to test clinical factors as well as genetic factors associated with early stent thrombosis. For the genetic component, they tested 23 genetic variants that are believed to adversely affect clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) absorption and metabolism. They used a multivariable logistic regression analysis to identify independent variables associated with early stent thrombosis. The researchers built a clinical-only model based on baseline demographic, clinical and angiographic characteristics. A genetic-only model included predicted metabolic status and genetic variants.
They identified three genotypes, CYP2C19, ABCB1 and ITGB3, that were related to clopidogrel metabolism and platelet function and that were significant determinants of early stent thrombosis. Nongenetic independent correlates were acuteness of the PCI, complex lesions, left ventricular function of less than 40 percent, diabetes mellitus, use of proton pump inhibitors (PPIs) and higher clopidogrel loading doses.
They found that the risk of early stent thrombosis increased according to the number of risk alleles in the patient. Additionally, a combined clinical and genetic risk model improved risk stratification for stent thrombosis. They found using the combined model that patients in the highest tertile of risk had a seven-fold increased risk of early stent thrombosis compared with patients in the lowest tertile.
“Our multicenter study suggests that a combination of three genotypes related to clopidogrel metabolism and platelet function (CYP2C19, ABCB1 and ITGB3) is an independent risk factor for early stent thrombosis beyond clinical and angiographic factors,” Cayla and colleagues wrote. “We also identified two potentially modifiable factors of early stent thrombosis: clopidogrel loading and clopidogrel interaction with PPIs.”
The authors noted that their study had a limited sample size and omitted the most severe cases, that is, cases in which the patient died soon after stent thrombosis. They did not evaluate stent malapposition or underexpansion, which are associated with stent thrombosis. Also, their patient population were predominantly Caucasians and may not be representative of all patient groups.
They recommended that validation studies be conducted to determine if their combined clinical-genetic risk stratification model improved the prognosis for patients undergoing PCI.