title: Role of genetic factors on the effect of additional loading doses and two maintenance doses used to overcome clopidogrel hyporesponsiveness.
abstract: OBJECTIVE
  Additional loading doses and higher maintenance doses (MDs) have been used to overcome hyporesponsiveness of clopidogrel. We aimed to investigate whether genetic polymorphisms of two cytochromes (CYP2C19 and CYP2C9) and ABCB1 modify effect of such dose-adjustment strategy.
  
  
  METHODS
  We enrolled 118 patients undergoing elective or acute percutaneous coronary intervention (PCI) with drug eluting stent (DES). Platelet reactivity index (PRI) was measured using the vasodilator-stimulated phosphoprotein (VASP) index and a cut-off value of ≥ 60% was defined as hyporesponsiveness. Polymorphism of two cytochromes (CYP2C19, CYP2C9) and gene ABCB1 were determined. In patients hyporesponsive to the initial LD the dose-adjustment was performed using up to 3 additional 600 mg LDs in order to achieve PRI <60%, and both 150 mg and 75 mg MD were tested at the follow-up.
  
  
  RESULTS
  Patients with at least one CYP2C19*2 allele had higher baseline PRI after the initial LD (78.2 ± 13.1 vs. 65.3 ± 19.5, P=0.005). The PRI reduction with additional LD was significantly smaller in carriers of the CYP2C19*2 (25.2 ± 15.6 vs. 35.5 ± 16.8, P=0.025) and similar trend was observed with subsequent additional LDs. Both MDs were less effective in presence of CYP2C19*2. Target PRI was, however, more frequently achieved with higher MD even in presence of CYP2C19*2 (in 70.6% vs. 23.5% of hyporesponders, P=0.008). No such differences were observed for other polymorphisms.
  
  
  CONCLUSIONS
  In patients hyporesponsive to a routine clopidogrel doses the potency of additional LD and higher MD of clopidogrel is compromised by presence of CYP2C19*2 allele. The dose-adjustment strategy is not affected by ABCB1 C3435T or CYP2C9 genotypes.
authors: Latvian Centre of Cardiology, Paul Stradins Clinical University Hospital, Riga, Latvia; Latvian Research Institute of Cardiology, Riga, Latvia; Faculty of Medicine, University of Latvia, Riga, Latvia. Electronic address: gustavs.latkovskis@gmail.com.
authors: Gustavs
authors: G
authors: Latkovskis
authors: Faculty of Pharmacy, Riga Stradins University, Riga, Latvia.
authors: Inga
authors: I
authors: Urtane
authors: Latvian Centre of Cardiology, Paul Stradins Clinical University Hospital, Riga, Latvia.
authors: Agnese
authors: A
authors: Knipse
authors: Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors: Raitis
authors: R
authors: Peculis
authors: Cell Transplantation Centre, Paul Stradins Clinical University Hospital, Riga, Latvia.
authors: Inese
authors: I
authors: Cakstina
authors: Latvian Biomedical Research and Study Centre, Riga, Latvia.
authors: Janis
authors: J
authors: Klovins
authors: Latvian Centre of Cardiology, Paul Stradins Clinical University Hospital, Riga, Latvia; Latvian Research Institute of Cardiology, Riga, Latvia; Faculty of Medicine, University of Latvia, Riga, Latvia.
authors: Andrejs
authors: A
authors: Erglis
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D000483:Alleles; D015815:Cell Adhesion Molecules / Q000097:blood; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D005260:Female; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010597:Pharmacogenetics; D010750:Phosphoproteins / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D065729:Cytochrome P-450 CYP2C9; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: ABCB1; CYP2C19; CYP2C9; Clopidogrel resistance; VASP