title: Patients carrying CYP2C19 loss of function alleles have a reduced response to clopidogrel therapy and a greater risk of in-stent restenosis after endovascular treatment of lower extremity peripheral arterial disease.
abstract: OBJECTIVE
  This study evaluated the relationship between the cytochrome P450 (CYP) 2C19 genotype and the antiplatelet effect of clopidogrel therapy and investigated whether genotyping can predict the risk of ischemic events after endovascular treatment (ET) of lower extremity peripheral arterial disease.
  
  
  METHODS
  From January 2011 to July 2012, 120 consecutive patients with arteriosclerosis obliterans (TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease [TASC II] A-C) in the superficial femoral artery were included in a prospectively maintained database. Patients received 75 mg clopidogrel and 100 mg aspirin daily for at least 5 days before TaqMan (Life Technologies, Grand Island, NY) of CYP2C19 single-nucleotide polymorphisms and thromboelastography of the clopidogrel response. ET was subsequently performed, and follow-up evaluations, including duplex ultrasound imaging and ankle-brachial index assessment, were performed at 1, 3, 6, and 12 months after ET. During the follow-up, stent patency was assessed by ultrasound imaging, computed tomography angiography, or digital subtraction angiography.
  
  
  RESULTS
  A total of 74 ET procedures were performed. Fifty of the enrolled patients (41.7%) completed the follow-up examinations and were included in the analysis. The mean duration of follow-up was 9.8 ± 2.1 months (range, 1-30 months). Carriers of at least one CYP2C19 loss-of-function (LOF) allele had a diminished pharmacodynamic response to clopidogrel (51.6 ± 20.1 vs. 39.8 ± 15.2 for patients without and with LOF alleles, respectively; P = .022). Carriers of one LOF allele had an increased incidence of ischemic events compared with patients without any LOF alleles (59.0% vs. 20.8%, respectively; P = .008). This trend was even more evident in patients with two LOF alleles compared with patients with no LOF alleles (100% vs. 20.8% ischemic events; P = .002). The cumulative primary patency rate at 12 months was 56.0%, with significant differences between groups (73.1% vs. 34.6% in patients without and with LOF alleles, respectively; P = .0.006). CYP2C19 LOF carrier status was associated with an increased rate of primary end points (P = .007). On the basis of their adenosine diphosphate-induced platelet aggregation, patients with high platelet reactivity had a significantly higher risk of ischemic events (P = .012). CYP2C19 genotypic classification (adjusted hazard ratio, 2.688; 95% confidence interval, 1.366-5.288; P = .004) and history of smoking (adjusted hazard ratio, 2.430; 95% confidence interval, 1.024-5.765; P = .044) were independent risk factors for ischemic events.
  
  
  CONCLUSIONS
  CYP2C19 LOF alleles were associated with a diminished platelet response to clopidogrel treatment. Patients carrying CYP2C19 LOF alleles who are treated with clopidogrel may trend toward a poor prognosis after ET.
authors.affiliation: Department of Vascular Surgery, Zhongshan Hospital, Institute of Vascular Surgery, Fudan University, Shanghai, China.
authors.forename: Baolei
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Qiwen
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Department of Vascular Surgery, Zhongshan Hospital, Institute of Vascular Surgery, Fudan University, Shanghai, China.
authors.forename: Daqiao
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Vascular Surgery, Zhongshan Hospital, Institute of Vascular Surgery, Fudan University, Shanghai, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: guo.wei@zs-hospital.sh.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
mesh_terms: D000368:Aged; D000483:Alleles; D015901:Angiography, Digital Subtraction; D055109:Ankle Brachial Index; D001162:Arteriosclerosis Obliterans / Q000175:diagnosis / Q000235:genetics / Q000601:surgery*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D057510:Endovascular Procedures; D005260:Female; D005263:Femoral Artery / Q000601:surgery*; D005500:Follow-Up Studies; D005838:Genotype; D006083:Graft Occlusion, Vascular / Q000175:diagnosis / Q000235:genetics* / Q000517:prevention & control; D006801:Humans; D007866:Leg / Q000098:blood supply; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011475:Prosthesis Failure; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D018616:Ultrasonography, Doppler, Duplex
chemical_list: D010975:Platelet Aggregation Inhibitors; D004247:DNA; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine