REVERSAL: Reversal of the Anti-platelet Effects of Ticagrelor

Sponsor

The First Affiliated Hospital with Nanjing Medical University (Other)

Overall Status

Completed

CT.gov ID

NCT02383771

Collaborator

National Natural Science Foundation of China (Other)

Enrollment

Location

Arms

21.1

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the proportion of untreated donor platelets required to fully reverse the platelet inhibitory effects of ticagrelor and aspirin in healthy persons and patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) and receiving ticagrelor.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Ticagrelor Drug: Aspirin + Ticagrelor Drug: Control Drug: Aspirin + Ticagrelor	Phase 4

Detailed Description

Reversal of the Anti-platelet Effects of Ticagrelor: REVERSAL study

The fatality of stent thrombosis (ST) in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) is approximately 50% and clopidogrel is an important anti-platelet drug for prevention of ST. CAD patients implanted with stent including bare metal stent (BMS) and drug eluting stent (DES) are recommended to receive dual anti-platelet treatment (DAPT), i.e. clopidogrel along with aspirin, for at least one year to reduce the incidence of ST by up-to-date guidelines. However, due to the variability of anti-platelet effect of clopidogrel, regular dose (75 mg daily) of clopidogrel administered cannot achieve enough inhibition of platelet aggregation in 20-30% of total patients, which is named as clopidogrel low responsiveness (CLR), and the morbidity of thrombosis (including) in CAD patients is still 10%.

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is a more potent adenosine diphosphate (ADP) receptor antagonist with faster onset and more significantly higher inhibition of platelet aggregation compared with clopidogrel and directly acts on P2Y12-ADP receptor in platelets without process of hepatic metabolism. In the PLATO study, ticagrelor plus reduced the remarkable incidence of cardiovascular events in patients with acute coronary syndrome (ACS) without significant higher incidence of major bleeding events compared with clopidogrel plus aspirin. Surprisingly, the incidence of death due to cardiovascular causes and the total fatality was decreased in patients with ticagrelor plus aspirin compared with those with clopidogrel plus aspirin. The results suggested the more benefit brought by ticagrelor, highlighting the wide use of it in the future.

Due to the potent anti-platelet effect of ticagrelor, more bleeding events may occur. Additionally, when facing the need for cardiac or non-cardiac operation, occurrence of life-threatening bleeding event or necessity of emergency operation, doctors may be confused of the treatment for the patients taking ticagrelor, of which the half-life period is 8-9 hours and it suggests the importance of studying the reversal of the anti-platelet effects of ticagrelor.

The primary objective of this study is to investigate the proportion of untreated donor platelets required to fully reverse the platelet inhibitory effects of aspirin and ticagrelor in healthy persons and patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) and receiving ticagrelor.

Study Population:

The investigators design two cohort studies, and plan to enroll 32 healthy volunteers in cohort 1 and 16 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) and receiving dual anti-platelet therapy (ticagrelor 90mg bid + aspirin 100mg daily) for 7 days

Cohort 1:

Randomization:

A total of 32 healthy volunteers are planned to be enrolled and will be randomly divided into three groups: single anti-platelet treatment group (A group, 8 of 32), dual anti-platelet treatment group (B group, 8 of 32) and control group (C group, 16 of 32).

Single anti-platelet treatment group: (Ticagrelor 90mg bid) × 7 days
Dual anti-platelet treatment group: (Ticagrelor 90mg bid + Aspirin 100mg daily) × 7 days
Control group: No anti-platelet therapy

Inclusion criteria:

Healthy volunteers
Participants aged >18 years old

Exclusion criteria:

Allergy or intolerance to aspirin or ticagrelor;
Subjects at a high risk of bleeding (e.g. platelet count<100×10^9/L, history of peptic ulcer, hemoglobin<110g/L);
Subjects with bronchial asthma or chronic obstructive pulmonary disease;
Subjects with bradycardia (e.g. sick sinus syndrome, high-grade atrioventricular block, history of syncope with unproved uncorrelation with bradycardia);
Smokers;
Subjects with diabetes mellitus;
Subjects planning to be pregnancy;
Subjects with hepatic or renal dysfunction;
Subjects who have taken other anti-platelet drugs, non-steroidal anti-inflammatory drugs or proton pump inhibitors before scanning or need to take them during study period.

Blood collection and sample preparation

Venous blood samples are collected by venipuncture into two 4.5-mL draw BD vacutainer tubes containing 0.105M buffered sodium citrate (3.2%) at 08.00 hours in the morning before taking the agent and after the last dose of the study drug. Platelet-rich plasma (PRP) from subjects in A group is mixed with increasing proportions of that in C group, with one untreated subject serving as the control for one treated subject. The proportion of control platelets mixed with inhibited platelets is calculated based on platelet numbers, starting at 10% and increasing by 10% increments. So as the PRP in B group.

Test:

Before taking the agent:
ADP-induced platelet aggregation: light transmittance aggregation (LTA) in response to 5μM ADP
Arachidonic acid (AA)-induced platelet aggregation: LTA in response to 1mM AA
After 7-day medication:
ADP-induced platelet aggregation: LTA in response to 5μM ADP
AA-induced platelet aggregation: LTA in response to 1mM AA
ADP-induced platelet aggregation of mixed sample: LTA in response to 5μM ADP
AA-induced platelet aggregation of mixed sample: LTA in response to 1mM AA

Primary end points:

Reversal of the platelet inhibitory effects of antiplatelet therapy Proportion of untreated donor platelets required to fully reverse the platelet inhibitory effects of antiplatelet therapy in healthy volunteers

Secondary end points:

Inhibition of platelet aggregation (IPA) in response to 5μM ADP determined by light transmittance aggregometer (LTA) after 7-day ticagrelor administration

Safety issue: No

Cohort 2:

A total of 16 patients with diagnosed coronary artery disease who have undergone percutaneous coronary intervention (PCI) and have received dual anti-platelet therapy (ticagrelor 90mg bid

aspirin 100mg daily) for 7 days is planned to be enrolled.

Inclusion Criteria:

Subjects with diagnosed coronary artery disease undergoing percutaneous coronary intervention (PCI);
Subjects who have received dual anti-platelet therapy (ticagrelor 90mg bid + aspirin 100mg daily) for 7 days;

Exclusion Criteria:

Subjects at a high risk of bleeding (e.g. platelet count<100×10^9/L, history of peptic ulcer, hemoglobin<110g/L);
Subjects with anemia;
Smokers
Subjects planning to be pregnancy;
Subjects with hepatic or renal dysfunction;
Subjects who have taken other anti-platelet drugs, non-steroidal anti-inflammatory drugs or proton pump inhibitors before scanning or need to take them during study period.

Sample test for fresh platelet saved in blood bank

Function of platelet aggregation, platelet count, pH value and metabolic products (including PO2, PCO2, blood glucose, lactate, bicarbonate, sodium, potassium and chloride) are measured in fresh platelet sample preserved in blood bank for 1, 2, 3, 4, and 5 days respectively.

Blood collection and sample preparation for patients

Venous blood samples are collected by venipuncture into two 4.5-mL draw BD vacutainer tubes containing 0.105M buffered sodium citrate (3.2%) at 08.00 hours in the morning after taking the medicine. Platelet-rich plasma (PRP) from participants is mixed with increasing proportions of that extracted from fresh platelet sample reserved in blood bank for one day as the control for each treated subject. The proportion of control platelets mixed with inhibited platelets is calculated based on platelet numbers, starting at 10% and increasing by 10% increments. So as the PRP mixed with fresh platelet sample preserved for four days.

Test for sample from patients

Before mixture:
ADP-induced platelet aggregation: light transmittance aggregation (LTA) in response to 5μM ADP
Arachidonic acid (AA)-induced platelet aggregation: LTA in response to 1mM AA
After mixture:
ADP-induced platelet aggregation: LTA in response to 5μM ADP
AA-induced platelet aggregation: LTA in response to 1mM AA

Primary end points:

Reversal of the platelet inhibitory effects of antiplatelet therapy Proportion of untreated donor platelets required to fully reverse the platelet inhibitory effects of antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) and receiving ticagrelor

Secondary end points:

Relationship between function of platelet aggregation and the time of saving fresh platelet.

Safety issue: No

Study Design

Study Type:

Interventional

Actual Enrollment :

64 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Investigator)

Primary Purpose:

Treatment

Official Title:

Reversal of the Anti-platelet Effects of Ticagrelor in Healthy Persons and Patients With Coronary Artery Disease

Study Start Date :

Mar 1, 2015

Actual Primary Completion Date :

Nov 1, 2016

Actual Study Completion Date :

Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Anti-platelet Treatment Ticagrelor	Drug: Ticagrelor (Ticagrelor 90mg Bid) x 7days Other Names: Brilinta
Experimental: Dual Anti-platelet Treatment Aspirin + Ticagrelor	Drug: Aspirin + Ticagrelor (Aspirin 100mg daily + Ticagrelor 90mg Bid) x 7days Other Names: Brilinta
Sham Comparator: Control No Drug	Drug: Control No Anti-platelet Therapy
Other: CAD undergoing PCI Patients with coronary artery disease undergoing percutaneous coronary intervention and receiving dual anti-platelet therapy (ticagrelor 90mg bid + aspirin 100mg daily)	Drug: Aspirin + Ticagrelor Dual anti-platelet therapy (Aspirin 100mg daily + Ticagrelor 90mg Bid) after percutaneous coronary intervention (PCI) Other Names: Brilinta

Outcome Measures

Primary Outcome Measures

Reversal of the platelet inhibitory effects of antiplatelet therapy in healthy volunteers [7 days after randomization]
Proportion of untreated donor platelets required to fully reverse the platelet inhibitory effects of antiplatelet therapy
Reversal of the platelet inhibitory effects of antiplatelet therapy in patients [7 days after percutaneous coronary intervention]
Reversal of the platelet inhibitory effects of antiplatelet therapy Proportion of untreated donor platelets required to fully reverse the platelet inhibitory effects of antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) and receiving ticagrelor

Secondary Outcome Measures

Inhibition of platelet aggregation in response to AA or ADP [7 days after randomization]
Inhibition of platelet aggregation (IPA) in response to 5μM ADP determined by light transmittance aggregometer (LTA) after 7-day ticagrelor administration
Change of ADP-induced platelet aggregation in platelets saved in blood bank due to the saving time [5 days after fresh platelet collected and stored in blood bank]
How the ADP-induced platelet aggregation in platelets saved in blood bank changes due to the saving time

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Cohort 1:

Inclusion Criteria:

Healthy volunteers;
Subjects aged >18 years old;

Exclusion Criteria:

Allergy or intolerance to aspirin or ticagrelor;
Subjects at a high risk of bleeding (e.g. platelet count<100×10^9/L, history of peptic ulcer, hemoglobin<110g/L);
Subjects with anemia;
Subjects with bronchial asthma or chronic obstructive pulmonary disease;
Subjects with bradycardia (e.g. sick sinus syndrome, high-grade atrioventricular block, history of syncope with unproved uncorrelation with bradycardia);
Smokers;
Subjects with diabetes mellitus;
Subjects planning to be pregnancy;
Subjects with hepatic or renal dysfunction;
Subjects who have taken other anti-platelet drugs, non-steroidal anti-inflammatory drugs or proton pump inhibitors before scanning or need to take them during study period.

Cohort 2:

Inclusion Criteria:

Subjects with diagnosed coronary artery disease undergoing percutaneous coronary intervention (PCI);
Subjects who have received dual anti-platelet therapy (ticagrelor 90mg bid + aspirin 100mg daily) for 7 days;

Exclusion Criteria:

Subjects at a high risk of bleeding (e.g. platelet count<100×10^9/L, history of peptic ulcer, hemoglobin<110g/L);
Subjects with anemia;
Smokers
Subjects planning to be pregnancy;
Subjects with hepatic or renal dysfunction;
Subjects who have taken other anti-platelet drugs, non-steroidal anti-inflammatory drugs or proton pump inhibitors before scanning or need to take them during study period.