title: Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.
abstract: BACKGROUND
  Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel.
  
  
  RESULTS
  In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 micromol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P<0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved >50% IPA (98% versus 31%, P<0.0001) and >70% IPA (90% versus 16%, P<0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72-hour slope [% IPA/h] -1.04 versus -0.48, P<0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS).
  
  
  CONCLUSIONS
  Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation.
authors.affiliation: Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, 2401 W Belvedere Ave., Baltimore, MD 21215, USA. pgurbel@lifebridgehealth.org
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bliden
authors.forename: Kathleen
authors.initials: K
authors.lastname: Butler
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.forename: Tania
authors.initials: T
authors.lastname: Gesheff
authors.forename: Cheryl
authors.initials: C
authors.lastname: Wei
authors.forename: Renli
authors.initials: R
authors.lastname: Teng
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Antonino
authors.forename: Shankar B
authors.initials: SB
authors.lastname: Patil
authors.forename: Arun
authors.initials: A
authors.lastname: Karunakaran
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Kereiakes
authors.forename: Cordel
authors.initials: C
authors.lastname: Parris
authors.forename: Drew
authors.initials: D
authors.lastname: Purdy
authors.forename: Vance
authors.initials: V
authors.lastname: Wilson
authors.forename: Gary S
authors.initials: GS
authors.lastname: Ledley
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000368:Aged; D001241:Aspirin / Q000627:therapeutic use; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine; D001241:Aspirin