title: Influence of smoking on the antiplatelet effect of clopidogrel differs according to clopidogrel dose: Insights from the GRAVITAS trial.
abstract: OBJECTIVE
  To examine the influence of smoking on the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI).
  
  
  BACKGROUND
  Certain studies suggest smokers may have enhanced clopidogrel-induced platelet inhibition compared to non-smokers after PCI. Whether this is affected by clopidogrel dose is unknown.
  
  
  METHODS
  In this study, we conducted an analysis of 5,429 patients in the Gauging Responsiveness With A VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Platelet reactivity was assessed 12-24 hr after PCI (baseline). Patients with high on-treatment platelet reactivity (OTR) (P2Y12 reaction units [PRU] ≥ 230) were randomized to clopidogrel 75 mg or 150 mg daily. Reactivity was subsequently assessed at 30-days, and 6-months. Patients were stratified by smoking status.
  
  
  RESULTS
  Smoking was independently associated with lower PRU (P = 0.001), and smokers were less likely to have high OTR (odds ratio 0.80, 95% confidence interval 0.68-0.94; P = 0.006) at baseline. Among patients assigned to clopidogrel 75 mg, smokers had lower PRU and were less likely to still have high OTR at 30-days (P < 0.001) and 6-months (P < 0.001). However, in patients assigned clopidogrel 150 mg, PRU and high OTR did not differ by smoking status at any time. Tests demonstrated an interaction between smoking and dose at 30 days (P = 0.007), and a trend at 6-months (P = 0.098).
  
  
  CONCLUSIONS
  Smokers treated with clopidogrel exhibit reduced platelet reactivity and are less likely to have persistent high OTR than non-smokers. This difference is mitigated by clopidogrel 150 mg, indicating non-smokers may require double-dose therapy to achieve a similar antiplatelet effect after PCI. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Reed
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: Department of Cardiology, Scripps Translational Science Institute, Scripps Clinic, La Jolla, California.
authors.forename: Jill
authors.initials: J
authors.lastname: Waalen
authors.forename: Paul S
authors.initials: PS
authors.lastname: Teirstein
authors.affiliation: Department of Medicine, Institut De Cardiologie De Montreal, Montreal, Quebec, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Tanguay
authors.affiliation: Department of Cardiology, Geisinger Clinic, Danville, Pennsylvania.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Berger
authors.affiliation: Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.affiliation: Department of Cardiology, Scripps Translational Science Institute, Scripps Clinic, La Jolla, California.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Price
mesh_terms: D000368:Aged; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D005260:Female; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000295:instrumentation; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010979:Platelet Function Tests; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects / Q000378:metabolism; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects* / Q000097:blood; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: clopidogrel resistance; platelet function; platelet reactivity