title: Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial.
abstract: Concomitant use of proton-pump inhibitors (PPIs) has been implicated in diminished antiplatelet response to clopidogrel and an increased risk of ischemic events, but primarily among patients undergoing percutaneous coronary intervention. We sought to examine the potential influence of interactions between PPIs and clopidogrel versus prasugrel on platelet reactivity and clinical outcomes after acute coronary syndromes (ACS) in patients managed medically without revascularization.
  
  
  METHODS
  This analysis from the TRILOGY ACS trial focused upon the 7,243 ACS patients aged <75 years who were managed without revascularization, randomized to clopidogrel or prasugrel, and followed for a median of 17 months. Proton-pump inhibitor type and use were assessed at each study visit, and 2,049 of the patients in this cohort underwent serial platelet reactivity assessments.
  
  
  RESULTS
  Proton-pump inhibitor use (23%) was similar between the clopidogrel and prasugrel groups at baseline and throughout the study. Median on-treatment platelet reactivity values were consistently lower with prasugrel versus clopidogrel irrespective of PPI use. For the primary end point (composite of cardiovascular death, myocardial infarction [MI], or stroke), PPI use modified the unadjusted treatment effect of prasugrel versus clopidogrel (interaction P = .02). After adjusting for differences in baseline characteristics, this treatment effect modification was attenuated for the composite end point (interaction P = .06) but was significant for the MI component end point (interaction P = .01). Similarly, among patients on a PPI, the frequency of MI was significantly lower with prasugrel versus clopidogrel (hazard ratio = 0.61; 95% CI 0.42-0.88). These findings were similar by PPI type (omeprazole and pantoprazole).
  
  
  CONCLUSIONS
  Among ACS patients managed without revascularization, use of PPIs did not result in a differential antiplatelet response between prasugrel versus clopidogrel but was associated with a lower incidence of MI with prasugrel. These hypothesis-generating findings suggest that factors besides platelet reactivity may underlie the differential risk of MI observed by treatment assignment with PPI use.
authors.affiliation: Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil. Electronic address: corjnicolau@incor.usp.br.
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Nicolau
authors.affiliation: Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Durham, NC.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Roe
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Lokhnygina
authors.affiliation: Duke Clinical Research Institute, Durham, NC.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neely
authors.affiliation: Cardiovascular Division, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ramón
authors.initials: R
authors.lastname: Corbalán
authors.affiliation: Cardiology Department, Hospital Central "Dr Morones Prieto", San Luis Potosí, Mexico.
authors.forename: José L
authors.initials: JL
authors.lastname: Leiva-Pons
authors.affiliation: Department of Cardiology, Córdoba National University, Córdoba, Argentina.
authors.forename: Felipe
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Division of Cardiology, Department of Medicine, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.affiliation: Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands.
authors.forename: Freek W A
authors.initials: FW
authors.lastname: Verheugt
authors.affiliation: Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.affiliation: Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Harvey D
authors.initials: HD
authors.lastname: White
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.affiliation: Centre for Chronic Disease Control and Public Health Foundation of India, New Delhi, India.
authors.forename: Dorairaj
authors.initials: D
authors.lastname: Prabhakaran
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Durham, NC.
authors.forename: E Magnus
authors.initials: EM
authors.lastname: Ohman
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy*; D000368:Aged; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D017410:Practice Guidelines as Topic; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine