Reversal of the Anti-platelet Effects of Ticagrelor
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Study type: Interventional
Phase: Phase 4

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.
    

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).

        1. Single anti-platelet treatment group: (Ticagrelor 90mg bid) × 7 days

        2. Dual anti-platelet treatment group: (Ticagrelor 90mg bid + Aspirin 100mg daily) × 7 days

        3. Control group: No anti-platelet therapy

      Inclusion criteria:

        1. Healthy volunteers

        2. Participants aged >18 years old

      Exclusion criteria:

        1. Allergy or intolerance to aspirin or ticagrelor;

        2. Subjects at a high risk of bleeding (e.g. platelet count<100×10^9/L, history of peptic
           ulcer, hemoglobin<110g/L);

        3. Subjects with bronchial asthma or chronic obstructive pulmonary disease;

        4. Subjects with bradycardia (e.g. sick sinus syndrome, high-grade atrioventricular block,
           history of syncope with unproved uncorrelation with bradycardia);

        5. Smokers;

        6. Subjects with diabetes mellitus;

        7. Subjects planning to be pregnancy;

        8. Subjects with hepatic or renal dysfunction;

        9. 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:

        1. Before taking the agent:

             1. ADP-induced platelet aggregation: light transmittance aggregation (LTA) in response
                to 5μM ADP

             2. Arachidonic acid (AA)-induced platelet aggregation: LTA in response to 1mM AA

        2. After 7-day medication:

             1. ADP-induced platelet aggregation: LTA in response to 5μM ADP

             2. AA-induced platelet aggregation: LTA in response to 1mM AA

             3. ADP-induced platelet aggregation of mixed sample: LTA in response to 5μM ADP

             4. AA-induced platelet aggregation of mixed sample: LTA in response to 1mM AA

      Primary end points:

      1. 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:

      1. 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:

        1. Subjects with diagnosed coronary artery disease undergoing percutaneous coronary
           intervention (PCI);

        2. Subjects who have received dual anti-platelet therapy (ticagrelor 90mg bid + aspirin
           100mg daily) for 7 days;

      Exclusion Criteria:

        1. Subjects at a high risk of bleeding (e.g. platelet count<100×10^9/L, history of peptic
           ulcer, hemoglobin<110g/L);

        2. Subjects with anemia;

        3. Smokers

        4. Subjects planning to be pregnancy;

        5. Subjects with hepatic or renal dysfunction;

        6. 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

        1. Before mixture:

             1. ADP-induced platelet aggregation: light transmittance aggregation (LTA) in response
                to 5μM ADP

             2. Arachidonic acid (AA)-induced platelet aggregation: LTA in response to 1mM AA

        2. After mixture:

             1. ADP-induced platelet aggregation: LTA in response to 5μM ADP

             2. AA-induced platelet aggregation: LTA in response to 1mM AA

      Primary end points:

      1. 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:

      1. Relationship between function of platelet aggregation and the time of saving fresh
      platelet.

      Safety issue: No
    

Intervention name(s): Ticagrelor; Aspirin + Ticagrelor; Control; Aspirin + Ticagrelor
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): (Ticagrelor 90mg Bid) x 7days; (Aspirin 100mg daily + Ticagrelor 90mg Bid) x 7days; No Anti-platelet Therapy; Dual anti-platelet therapy (Aspirin 100mg daily + Ticagrelor 90mg Bid) after percutaneous coronary intervention (PCI)
Other intervention name(s): Brilinta; Brilinta; Brilinta
Intervention MeSH terms: Aspirin; Ticagrelor
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Ticagrelor; Aspirin; Peri-operative treatment