Authors
Gurbel PA, Bliden KP, Butler K, et al.
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.
References
Circulation 2009;120:2577-85
Background
Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist.
Purpose
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.
Design
Multicenter, randomized, double-blind, double-dummy, parallel-group 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 Platelet function testing was performed at various time points
Exclusion Criteria
Acute coronary syndrome within 12 months of screening Any indication (e.g. atrial fibrillation, prosthetic heart valve, or coronary stent) for antithrombotic therapy (e.g. warfarin, clopidogrel, or aspirin dose other than 75 to 100 mg/d during the study period) Congestive heart failure; left ventricular ejection fraction <35% Forced expiratory volume in the first second (FEV1) or forced vital capacity (FVC) below the lower limits of normal Bleeding diathesis or severe pulmonary disease Pregnancy Current smoking Concomitant therapy with moderate or strong cytochrome P450 3A inhibitor substrates, or strong cytochromeP4503A inducers Platelet count <100 000/mm3; hemoglobin <10 g/dL Hemoglobin A1c >10% History of drug addiction or alcohol abuse in the past 2 years Need for nonsteroidal antiinflammatory drugs (NSAIDs) Creatinine clearance (CrCl) <30 mL/min
Follow-Up
6 weeks
Treatment Regimen
All patients received aspirin and were randomized to ticagrelor, clopidogrel or placebo
Results
Primary Endpoints: Greater IPA (20 µmol/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/hr] -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).
Summary
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.
Implications
The study provides important insight into the onset and offset of platelet inhibition with ticagrelor. The study does not have any immediate clinical implications.
Related Figures
None.