title: Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study.
abstract: OBJECTIVE
  CYP3A4-metabolized statins can influence the pharmacodynamic effect of clopidogrel. We sought to assess the impact of switching to a non-CYP3A4-metabolized statin on platelet function among patients receiving clopidogrel and atorvastatin with high on-treatment platelet reactivity (HPR).
  
  
  RESULTS
  Percutaneous coronary intervention (PCI)-treated patients (n= 50) with HPR [20 μM adenosine diphosphate (ADP)-induced maximal platelet aggregation (MPA) >50%] were enrolled during chronic administration of atorvastatin (10 mg/day) and clopidogrel (75 mg/day) (≥6 months). They were randomly assigned to a 15-day therapy with either rosuvastatin 10 mg/day (n= 25) or pravastatin 20 mg/day (n= 25). Platelet function was assessed before and after switching by conventional aggregometry and the VerifyNow P2Y12 assay. Genotyping was performed for CYP2C19*2/*3, CYP3A5*3, and ABCB1 C3435T alleles. The primary endpoint was the absolute change in 20 μM ADP-induced MPA. After switching, MPAs after stimuli with 20 and 5 μM ADP were decreased by 6.6% (95% confidence interval: 3.2-10.1%; P < 0.001), and 6.3% (95% confidence interval: 2.5-10.2%; P = 0.002), respectively. Fifty-two P2Y12 reaction units fell (95% confidence interval: 35-70; P < 0.001) and the prevalence of HPR decreased (24%; P < 0.001). Pharmacodynamic effects were similar after rosuvastatin and pravastatin therapy. In addition to smoking status, the combination of calcium channel blocker usage and ABCB1 C3435T genotype significantly affected the change of 20 μM ADP-induced MPA.
  
  
  CONCLUSIONS
  Among PCI-treated patients with HPR during co-administration of clopidogrel and atorvastatin, switching to a non-CYP3A4-metabolized statin can significantly decrease platelet reactivity and the prevalence of HPR. This switching effect appears similar irrespective of the type of non-CYP3A4-metabolized statin.
authors.affiliation: Division of Cardiology, Department of Internal Medicine,  Gyeongsang National University Hospital, Jinju,  Korea.
authors.forename: Yongwhi
authors.initials: Y
authors.lastname: Park
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Jeong
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.forename: Jong Hwa
authors.initials: JH
authors.lastname: Ahn
authors.forename: Tae Jung
authors.initials: TJ
authors.lastname: Kwon
authors.forename: Jeong Rang
authors.initials: JR
authors.lastname: Park
authors.forename: Seok-Jae
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Eun-Ha
authors.initials: EH
authors.lastname: Gho
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bliden
authors.forename: Choong Hwan
authors.initials: CH
authors.lastname: Kwak
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Hwang
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Kim
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001241:Aspirin / Q000627:therapeutic use; D000069059:Atorvastatin; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000502:physiology*; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D005464:Fluorobenzenes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005838:Genotype; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017035:Pravastatin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000244:Adenosine Diphosphate; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017035:Pravastatin; D013988:Ticlopidine; D001241:Aspirin