title: Is There an Ideal Level of Platelet P2Y12-Receptor Inhibition in Patients Undergoing Percutaneous Coronary Intervention?: "Window" Analysis From the ADAPT-DES Study (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents).
abstract: OBJECTIVE
  This study sought to determine whether there is an ideal level of platelet reactivity (PR) to optimize safety and efficacy within the large multicenter ADAPT-DES (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents) study of 8,582 patients receiving successful drug-eluting stent implantation.
  
  
  BACKGROUND
  Patients with high PR on clopidogrel have a greater incidence of adverse ischemic events after stent implantation, whereas low PR may increase bleeding. Due to limited sample size, previous studies have not been able to adjust for differences in baseline characteristics that may confound the relationship of PR and outcomes.
  
  
  METHODS
  In the ADAPT-DES study, routine platelet function testing (VerifyNow) was performed following clopidogrel loading. To characterize the independent association between PR and clinical events, patients were stratified into quintiles of P2Y12 reaction units (PRU).
  
  
  RESULTS
  The PRU medians of the 5 quintiles were 57, 130, 187, 244, and 317 (most to least inhibited). There was a monotonic association between successively higher PRU quintiles and stent thrombosis, whereas for clinically relevant bleeding, the greatest risk occurred in the lowest PRU quintile, with similar risks across the 4 higher quintiles. These relationships remained significant in fully adjusted multivariable analyses (adjusted hazard ratio [HR] for stent thrombosis in Q5 versus Q1: 2.32; 95% confidence interval [CI]: 1.17 to 4.59; p = 0.02; adjusted HR for clinically relevant bleeding in Q5 versus Q1: 0.61; 95% CI: 0.47 to 0.77; p < 0.001). However, there were no significant independent associations between the level of PRU and mortality.
  
  
  CONCLUSIONS
  In this large observational study, increasing PRU was associated with a monotonic increase in stent thrombosis, whereas bleeding risk was confined to the lowest PRU quintile, suggesting an optimal therapeutic window of platelet inhibition at moderately inhibited PRU. However, there was no demonstrable threshold effect for PRU and mortality in adjusted analyses, perhaps due to the offsetting impact of bleeding and ischemia across the spectrum of platelet inhibition. (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents [ADAPT-DES]; NCT00638794).
authors.affiliation: Division of Cardiology, Columbia University/NewYork-Presbyterian Hospital, New York, New York; Cardiovascular Research Foundation, New York, New York. Electronic address: akirtane@columbia.edu.
authors.forename: Ajay J
authors.initials: AJ
authors.lastname: Kirtane
authors.affiliation: Division of Cardiology, Columbia University/NewYork-Presbyterian Hospital, New York, New York.
authors.forename: Puja B
authors.initials: PB
authors.lastname: Parikh
authors.affiliation: LeBauer Cardiovascular Research Foundation/Moses Cone Hospital, Greensboro, North Carolina.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Stuckey
authors.affiliation: Cardiovascular Research Foundation, New York, New York.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Amper Kliniken AG, Dachau, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Witzenbichler
authors.affiliation: Division of Cardiology, Columbia University/NewYork-Presbyterian Hospital, New York, New York; Cardiovascular Research Foundation, New York, New York; Department of Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Giora
authors.initials: G
authors.lastname: Weisz
authors.affiliation: Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, North Carolina.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rinaldi
authors.affiliation: Department of Cardiology, Universitäts-Herzzentrum Freiburg Bad Krozingen, Bad Krozingen, Germany.
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Neumann
authors.affiliation: Wellmont CVA Heart Institute, Kingsport, Tennessee.
authors.forename: D Christopher
authors.initials: DC
authors.lastname: Metzger
authors.affiliation: Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, Minnesota; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Henry
authors.affiliation: Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania.
authors.forename: David A
authors.initials: DA
authors.lastname: Cox
authors.affiliation: Reid Heart Center, FirstHealth of the Carolinas, Pinehurst, North Carolina.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Duffy
authors.affiliation: LeBauer Cardiovascular Research Foundation/Moses Cone Hospital, Greensboro, North Carolina.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Brodie
authors.affiliation: Department of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Ernest L
authors.initials: EL
authors.lastname: Mazzaferri
authors.affiliation: Cardiovascular Research Foundation, New York, New York.
authors.forename: Rupa
authors.initials: R
authors.lastname: Parvataneni
authors.affiliation: Division of Cardiology, Columbia University/NewYork-Presbyterian Hospital, New York, New York; Cardiovascular Research Foundation, New York, New York.
authors.forename: Akiko
authors.initials: A
authors.lastname: Maehara
authors.affiliation: Division of Cardiology, Columbia University/NewYork-Presbyterian Hospital, New York, New York; Cardiovascular Research Foundation, New York, New York; Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Généreux
authors.affiliation: Cardiovascular Research Foundation, New York, New York; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Roxana
authors.initials: R
authors.lastname: Mehran
authors.affiliation: Division of Cardiology, Columbia University/NewYork-Presbyterian Hospital, New York, New York; Cardiovascular Research Foundation, New York, New York.
authors.forename: Gregg W
authors.initials: GW
authors.lastname: Stone
mesh_terms: D000368:Aged; D001241:Aspirin / Q000008:administration & dosage; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D003327:Coronary Disease / Q000097:blood / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D003328:Coronary Thrombosis / Q000209:etiology / Q000517:prevention & control; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D054855:Drug-Eluting Stents; D005260:Female; D005858:Germany; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000295:instrumentation* / Q000401:mortality; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010979:Platelet Function Tests; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011474:Prosthesis Design; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects*; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin
keywords: hemorrhage; platelets; stent(s); thrombosis