Genetic Predictors of Early Stent Thrombosis Identified

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A model that combines 3 gene variants involved in clopidogrel metabolism and platelet receptor function with 2 clinical factors—clopidogrel loading dose and use of proton pump inhibitors (PPI)—can increase the ability to predict risk for early stent thrombosis in patients undergoing percutaneous coronary intervention (PCI), according to results of a study published in the October 26, 2011, issue of the Journal of the American Medical Association.

Researchers led by Gilles Montalescot, MD, PhD, of the Pitié-Salpêtrière Hospital (Paris, France), retrospectively analyzed clinical and genetic factors associated with definite early stent thrombosis in 123 patients treated with PCI who also underwent genotyping. All patients were enrolled in ONASSIST (Online Assistance for Stent Thrombosis), a national French registry of patients who develop definite stent thrombosis, and each was matched with 2 controls (n = 246). The study was conducted in 10 French centers between January 2007 and May 2010.

Three Genotypes Stand Out

Patients with early stent thrombosis received significantly lower clopidogrel loading doses than controls and were more frequently receiving PPIs.

The researchers looked at 23 genetic variants in 15 genes. Carriage of the CYP2C19*2 loss-of-function allele was more frequent in cases than controls (48.8% vs. 27.4%), including a sevenfold higher prevalence of carriers of 2 copies of the loss-of-function allele (16.3% vs. 2.5%). Conversely, carriage of the CYP2C19*17 gain-of-function allele was significantly less frequent in cases than controls (20.4% vs. 32.7%).

In addition to the difference in CYP2C19 metabolic status, patients who developed stent thrombosis were more likely than controls to have ABCB1 3435 TT alleles and less frequently were carriers of the ITGB3 PLA2 polymorphism (table 1).

Table 1. Genetic Variants Involved in Stent Thrombosis

No significant interactions were identified between the genetic variants and independent clinical and angiographic factors. There also were no interactions between clopidogrel loading doses and CYP2C19, ABCB1, or ITGB3 polymorphisms (P = 0.46, P = 0.84, and P = 0.63 for interaction) or among the CYP2C19, ABCB1, and ITGB3 genetic variants.

Other genetic factors that have been shown in previous studies to interfere with clopidogrel pharmacology or to be linked with thrombotic disorders were not associated with stent thrombosis in the study.

In addition, multivariate logistic regression analysis identified multiple nongenetic independent predictors of early stent thrombosis:

• Acuteness of PCI (adjusted OR 3.05; 95% CI 1.54-6.07)
• Complex lesions (adjusted OR 2.33; 95% CI 1.40-3.89)
• LVEF less than 40% (adjusted OR 2.25; 95% CI 1.09-4.70)
• Diabetes (adjusted OR 1.82; 95% CI 1.02-3.24)
• Use of PPIs (adjusted OR 2.19; 95% CI 1.29-3.75)
• Higher clopidogrel loading doses (adjusted OR 0.73; 95% CI 0.57-0.93)

Of these, only clopidogrel loading dose and PPI use are potentially modifiable.

Combining Factors Strengthens Prediction

The accuracy of the clinical-only model was similar to that of a genetic-only model (area under the curve 0.73 vs. 0.68; P = 0.34). However, a combined clinical and genetic model increases the discriminatory power compared with the clinical-only model (area under the curve 0.78 vs. 0.73; P = 0.004). In fact, patients in the highest tertile of risk using the combined clinical and genetic model had a sevenfold increased risk of early stent thrombosis vs. patients in the lowest tertile (OR 7.63; 95% CI 4.18-13.91).

The study authors say these findings add to the understanding of the genetic profile of patients treated with clopidogrel who are at risk of early stent thrombosis.

“Altogether, clopidogrel dose, PPI use, and presence of CYP2C19 and ABCB1 genetic variants suggest that the level of P2Y12 antagonism achieved through clopidogrel active metabolite generation is the key factor influencing the risk of early stent thrombosis in patients receiving clopidogrel and adherent to treatment,” they write.

In an email communication with TCTMD, Dr. Montalescot said the study suggests that in addition to known risk factors for early stent thrombosis, genetic factors need to be looked at carefully.

“As they all are independently associated with the risk of [stent thrombosis], the combination of clinical, angiographic, and genetic factors becomes extremely powerful to predict the risk of [stent thrombosis] in a global score where all these variables are integrated,” he said.

Dr. Montalescot also said it will be important to replicate these findings in other patient groups.

“Our score for the risk of [stent thrombosis] needs to be prospectively evaluated in other PCI databases,” he said. “The next step then would be to use our score to tailor antiplatelet therapy in PCI patients and see the impact on outcome of such a strategy.”

The researchers stress that for now at least, the findings apply only to white individuals, who who comprised the majority of the cohort. The effects of different genes according to different ethnic groups may warrant separate studies, they add.

Already Outdated?

But in a telephone interview with TCTMD, Charles E. Chambers, MD, of Penn State Hershey Medical Center (Hershey, PA), pointed out that the authors themselves acknowledge that newer stents with less thrombogenic platforms accounted for less than 10% of the cases in the French database.

“These data are outdated because we have already moved to next-generation stents,” he said. “While this is a very well-done study and very interesting, I think it’s important to realize that these numbers may not be what we would be seeing now in practice.”

Dr. Chambers added that given the known impact of CYP2C19 on clopidogrel, it is not surprising that there may be other genes at play that also interfere with clopidogrel metabolism.

Study Details

Patients who developed early stent thrombosis were more likely than those who did not to be diabetic and to have impaired left ventricular function but less frequently had hypercholesterolemia. They also presented more frequently with complex lesions (ACC/AHA type C) and acute coronary syndromes in comparison with controls.

 

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Source:
Cayla G, Hulot J-S, O’Connor SA, et al. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA. 2011; 306:1765-1774.

 

 

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