Efficacy and Safety of Low-dose Ticagrelor

Phase 2

Completed

Conditions: Coronary Artery Disease

Interventions: Drug: ticagrelor
Drug: clopidogrel

Registration Number: NCT03381742

Lead Sponsor: First Affiliated Hospital of Harbin Medical University

Brief Summary: Guideline recommendations on the use of dual antiplatelet therapy have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for ACS patients. Recent study found that ticagrelor 90mg twice a day orally could significantly reduce the occurrence of clopidogrel resistance and adverse cardiovascular events. The previous studies have reported that half-dose ticagrelor had the similar inhibitory effect on platelet aggregation as the standard-dose ticagrelor, which was significantly stronger than that in the clopidogrel group. One-quarter standard-dose ticagrelor provided greater degree of platelet inhibition than standard dose clopidogrel in Chinese patients with stable CAD. But large-scale clinical trials are still needed to confirm the effects of low-dose ticagrelor on platelet function in Chinese patients with coronary heart disease.

Detailed Description: Dual Antiplatelet Therapy (DAPT) with aspirin and P2Y12 receptor inhibitor remains a cornerstone in the secondary prevention of coronary artery disease (CAD). Clopidogrel is one of the most commonly used antithrombotic agent that inhibits the platelet P2Y(12) adenosine diphosphate (ADP) receptor.

Ticagrelor is an oral, reversibly-binding, direct-acting P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Guideline recommendations on the use of dual antiplatelet therapy have been formulated that ticagrelor 90 mg twice daily plus aspirin in preference to clopidogrel 75mg daily plus aspirin for ACS patients. Recent study found that ticagrelor 90mg twice a day orally could significantly reduce the occurrence of clopidogrel resistance and adverse cardiovascular events. The previous studies have reported that half-dose ticagrelor had the similar inhibitory effect on platelet aggregation as the standard-dose ticagrelor, which was significantly stronger than that in the clopidogrel group. One-quarter standard-dose ticagrelor provided greater degree of platelet inhibition than standard dose clopidogrel in Chinese patients with stable CAD. But large-scale clinical trials are still needed to confirm the effects of low-dose ticagrelor on platelet function in Chinese patients with coronary heart disease.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3043

Inclusion Criteria

Patients with coronary artery disease

Exclusion Criteria

younger than 18 years of age;
anti-platelet therapy with clopidogrel or ticagrelor for less than 5 days;
previous or current treatment with any other potentially confounding drugs.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ticagrelor 90mg bidpo.	ticagrelor	To observe the efficacy and safety of ticagrelor 90mg bidpo. in patients with coronary artery disease.
ticagrelor 45mg bidpo.	ticagrelor	To observe the efficacy and safety of ticagrelor 45mg bidpo. in patients with coronary artery disease.
ticagrelor 90mg qdpo.	ticagrelor	To observe the efficacy and safety of ticagrelor 90mg qdpo. in patients with coronary artery disease.
clopidogrel 75mg qdpo.	clopidogrel	To observe the efficacy and safety of clopidogrel 75mg qdpo. in patients with coronary artery disease.

Primary Outcome Measures

Name	Time	Method
ADP-induced Inhibition of Platelet Aggregation	up to 5 days	The venous blood samples for platelet function test were drawn after an overnight fast, at 12 hours post-last study-drug dose for subjects receiving twice-daily administrations, and at 24 hours post-last study-drug dose for subjects treated with once-daily regimens. The blood was collected in an evacuated vacuum tube containing 3.2% trisodium citrate and lithium heparin. Then the samples were processed within two hours of blood draw according to standard operating procedure. The physical properties of samples were analyzed using Thromboelastography (TEG) Hemostasis Analyzer (CFMS LEPU-8800, Lepu Medical Technology Co., Ltd, Beijing, China) and automated analytical software. TEG test used four channels to detect the effects of anti-platelet therapy via the arachidonic acid (AA) and ADP pathways. TEG test results were expressed in terms of ADP-induced inhibition of platelet aggregation (IPA, range 0% - 100%), with higher values indicating greater platelet inhibition.
Number of Participants With Bleeding (Major or Minor Bleeding)	up to 5 days	Major bleeding was defined as type ≥ 3 and minor bleeding as types 1 and 2, in accordance to the Bleeding Academic Research Consortium classification. (Mehran R et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449.)

Secondary Outcome Measures

Name	Time	Method
Number of Participants With High On-Treatment Platelet Reactivity (HTPR)	up to 5 days	HTPR was defined as IPA ≤ 30% and MA ≥ 47 mm.
Number of Participants With New-onset Dyspnea	up to 5 days	New-onset dyspnea in patients without previous history of dyspnea
Number of Participants With Cardiovascular Event (Cardiovascular Death, New-onset Myocardial Infarction, or Stroke)	up to 5 days	Cardiovascular death was defined as sudden cardiac death, fatal myocardial infarction, death due to heart failure, or death due to other cardiovascular causes. Stroke was defined as the focal loss of neurologic function caused by an ischemic or a hemorrhagic event with residual symptoms lasting at least 24 hours or eventually leading to death.
ADP-induced Platelet-fibrin Clot Strength (MA)	up to 5 days	The physical properties of samples were analyzed using Thromboelastography (TEG) Hemostasis Analyzer (CFMS LEPU-8800, Lepu Medical Technology Co., Ltd, Beijing, China) and automated analytical software. TEG test used four channels to detect the effects of anti-platelet therapy via the arachidonic acid (AA) and ADP pathways. TEG test results were expressed in terms of ADP-induced platelet-fibrin clot strength (MA). A MA\>47mm was shown to have a high predictive value for 3-year post-PCI ischemic events during dual antiplatelet therapy. Moreover, ROC curve and quartile analysis suggested MA\<31 mm as a predictive value for post-PCI bleeding events (J Am Coll Cardiol. 2013;62(24):2261-73. doi: 10.1016/j.jacc.2013.07.101.).