Coronary Artery Disease
Conditions
Keywords
Antiplatelet, Ticagrelor, Platelets, Thrombosis, Coronary artery disease
Brief summary
Acute coronary syndrome (ACS) patients treated with antiplatelet drugs who require coronary artery bypass grafting (CABG) surgery have to wait 5-7 days for the effects of the drugs to wean off. This treatment-devoid period leaves the patient vulnerable, therefore any means to shorten this period could be useful. The present study aims to investigate the possibility of reversing the antiplatelet effects of ticagrelor with the help of fresh donor platelets. Fresh platelets will be added to blood samples of treated patients in varying concentrations at specific timepoints to determine the time and amount of fresh platelets needed to normalize platelet reactivity in the treated samples.
Detailed description
The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for ACS patients requiring CABG surgery after treatment with dual antiplatelet therapy recommend delaying surgery for 5-7 days after discontinuation of therapy, to allow for the dissipation of its antiplatelet effects. This treatment-devoid waiting period puts the ACS patients at risk for further cardiovascular events. Any means to shorten this vulnerable period would be of critical value. One possibility to speed up the recovery of the inhibited platelets is to administer infusions of fresh platelets. In fact, platelet transfusions are frequently administered to patients during surgery who had received prior antiplatelet therapy. However, the degree to which these transfusions restore platelet function in the recipient subjects' blood and the time from dosing when they are most effective are unknown. The timing is critical in scenarios where urgent surgery is required because infusion of platelets too soon after antiplatelet dosing could render them useless by the residual drug in circulation. The aim of the present study is to investigate the restoration of platelet function of ticagrelor-treated subjects by adding donor platelets to their blood. The study would have 2 arms mimicking different clinical scenarios: 1. Clinical Scenario 1 - Patient given a loading dose (LD) of ticagrelor in the emergency room, requires surgery: A single LD of ticagrelor (180 mg) with aspirin (325 mg) will be given to study subjects and platelet testing will be performed after addition of fresh platelets to their blood ex vivo. Donor platelets will be added at 4-, 6-, 24- and 48-hours post-dose, to assess the time required for normalizing subject's platelet function after a LD of ticagrelor. 2. Clinical Scenario 2 - Patient on maintenance dosing (MD) of ticagrelor, requires surgery: Subjects will receive ticagrelor (90 mg twice daily) with aspirin (81 mg once daily) for 3-7 days. After the last dose, platelet testing will be performed after addition of fresh platelets to their blood ex vivo, at 4-, 6-, 24- and 48-hours post-dose to assess the time required for normalizing subject's platelet function after daily treatment with ticagrelor. Platelet testing will be carried out using the following methodologies: 1. Platelet Aggregation - VerifyNow P2Y12 assay. 2. Platelet Aggregation - Multiplate Analyzer.
Interventions
DRUGTicagrelor loading dose
Single loading dose of Ticagrelor 180 mg
DRUGAspirin loading dose
Single loading dose of Aspirin 325 mg
Ticagrelor 90 mg twice daily x 7 days
DRUGAspirin maintenance dose
Aspirin 81 mg once daily x 7 days
Sponsors
AstraZeneca
Icahn School of Medicine at Mount Sinai
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female volunteer between 18 and 75 years old. * History of stable (i.e. non-acute) cardiovascular disease or the presence of risk factors for cardiovascular disease (i.e. hypertension, diabetes, hyperlipidemia, high calcium score and abnormal findings on angiography or stress test).
Exclusion criteria
* Conditions associated with hemorrhagic risk, e.g., frequent epistaxis, gastrointestinal ulcer, hemorrhagic vascular lesions, recent surgery. * Allergy or hypersensitivity to aspirin or ticagrelor. * Loss of \>400 mL blood or blood donation within past 3 months. * Positive serology for hepatitis B (HBs Ag) or hepatitis C. * History of drug abuse or alcohol abuse. * Positive pregnancy test. * Evidence of unstable or acute cardiovascular disease (e.g., unstable angina, recent myocardial infarction, congestive heart failure). * History of clinically relevant pulmonary, hepatic, gastrointestinal, renal, metabolic, hematologic, neurologic, respiratory or psychiatric disease, bleeding, acute infectious disease or signs of acute illness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| P2Y12 Reaction Unit (PRU) | Baseline (pre-treatment), 4, 6, 24 and 48 hours post Loading dose/last Maintenance dose | Platelet function normalization using different concentrations (0%, 25%, 50%, and 75% supplementations) of fresh platelet within 48 hours of Ticagrelor Loading dose/last Maintenance dose, assessed using VerifyNow and expressed as P2Y12 Reaction Unit (PRU). The P2Y12 reaction unit (PRU) is an arbitrary unit of measure that represents the amount of platelet aggregation specific to the P2Y12 receptor. |
| Platelet Aggregation Using Multiplate Analyzer | Baseline (pre-treatment), 4, 6, 24, and 48 hours post Loading dose/last Maintenance dose | Platelet function normalization using different concentrations of fresh platelet within 48 hours of Ticagrelor Loading dose/last Maintenance dose, assessed using Multiplate Aggregometry (ADPtest), results expressed as Area Under Curve (U), where 1 U = 10 AU \* min. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients With Stable CVD DAPT loading dose (Ticagrelor (180 mg) + ASA (325 mg)); DAPT maintenance therapy (Ticagrelor (90 mg BID) + ASA (81 mg OD), for one week (in same patients) | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Patients With Stable CVD |
|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 7.9 |
| Alcohol Use Current | 9 Participants |
| Alcohol Use Never | 8 Participants |
| Alcohol Use Past | 3 Participants |
| BMI | 30.7 kg/m^2 STANDARD_DEVIATION 4.5 |
| Cholesterol level | 158.7 mg/dL STANDARD_DEVIATION 62 |
| Diabetic | 15 Participants |
| Diastolic blood pressure | 70.6 mm Hg STANDARD_DEVIATION 9 |
| HDL | 42.5 mg/dL STANDARD_DEVIATION 12.6 |
| Hypercholesterolemia | 19 Participants |
| Hypertension | 16 Participants |
| LDL level | 85.6 mg/dL STANDARD_DEVIATION 51.7 |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 13 Participants |
| Smoking History Current | 2 Participants |
| Smoking History Never | 10 Participants |
| Smoking History Past | 8 Participants |
| Systolic blood pressure | 127.2 mm Hg STANDARD_DEVIATION 17.5 |
| Triglycerides level | 165.4 mg/dL STANDARD_DEVIATION 91.4 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
P2Y12 Reaction Unit (PRU)
Platelet function normalization using different concentrations (0%, 25%, 50%, and 75% supplementations) of fresh platelet within 48 hours of Ticagrelor Loading dose/last Maintenance dose, assessed using VerifyNow and expressed as P2Y12 Reaction Unit (PRU). The P2Y12 reaction unit (PRU) is an arbitrary unit of measure that represents the amount of platelet aggregation specific to the P2Y12 receptor.
Time frame: Baseline (pre-treatment), 4, 6, 24 and 48 hours post Loading dose/last Maintenance dose
Population: Patients with stable CVD
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Loading Dose | P2Y12 Reaction Unit (PRU) | Post-dose 4 hours 0% | 39.1 PRU | Standard Deviation 25.9 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | Post-dose 24 hours 0% | 127.6 PRU | Standard Deviation 58.8 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | Post-dose 6 hours 0% | 25.9 PRU | Standard Deviation 28.9 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 24 hours 25% | 157.3 PRU | Standard Deviation 52.5 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 4 hours 50% | 100.3 PRU | Standard Deviation 49.6 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 24 hours 50% | 165.9 PRU | Standard Deviation 40.5 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 6 hours 25% | 55.3 PRU | Standard Deviation 50.2 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 24 hours 75% | 162.5 PRU | Standard Deviation 29.4 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 4 hours 25% | 69.6 PRU | Standard Deviation 35.6 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | Post-dose 48 hours 0% | 250.6 PRU | Standard Deviation 45.8 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 6 hours 50% | 67.8 PRU | Standard Deviation 53.8 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 48 hours 25% | 249.5 PRU | Standard Deviation 35.1 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 4 hours 75% | 98.6 PRU | Standard Deviation 54.4 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 48 hours 50% | 226.2 PRU | Standard Deviation 51.6 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 6 hours 75% | 71.2 PRU | Standard Deviation 42.8 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | 48 hours 75% | 204.2 PRU | Standard Deviation 45.9 |
| Loading Dose | P2Y12 Reaction Unit (PRU) | Baseline | 284.1 PRU | Standard Deviation 42.2 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 48 hours 75% | 203.9 PRU | Standard Deviation 41.5 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | Baseline | 284.1 PRU | Standard Deviation 42.2 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | Post-dose 4 hours 0% | 37.5 PRU | Standard Deviation 32.4 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 4 hours 25% | 72.2 PRU | Standard Deviation 38.5 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 4 hours 50% | 88.4 PRU | Standard Deviation 42.9 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 4 hours 75% | 85.9 PRU | Standard Deviation 49.4 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | Post-dose 6 hours 0% | 24.0 PRU | Standard Deviation 30.3 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 6 hours 25% | 46.0 PRU | Standard Deviation 37.3 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 6 hours 50% | 55.4 PRU | Standard Deviation 41.8 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 6 hours 75% | 67.7 PRU | Standard Deviation 45.3 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | Post-dose 24 hours 0% | 119.0 PRU | Standard Deviation 78 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 24 hours 25% | 147.6 PRU | Standard Deviation 65.2 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 24 hours 50% | 158.0 PRU | Standard Deviation 43.5 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 24 hours 75% | 154.0 PRU | Standard Deviation 51 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | Post-dose 48 hours 0% | 214.8 PRU | Standard Deviation 74 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 48 hours 25% | 219.7 PRU | Standard Deviation 52.2 |
| Maintenance Dose | P2Y12 Reaction Unit (PRU) | 48 hours 50% | 221.2 PRU | Standard Deviation 44.2 |
Primary
Platelet Aggregation Using Multiplate Analyzer
Platelet function normalization using different concentrations of fresh platelet within 48 hours of Ticagrelor Loading dose/last Maintenance dose, assessed using Multiplate Aggregometry (ADPtest), results expressed as Area Under Curve (U), where 1 U = 10 AU \* min.
Time frame: Baseline (pre-treatment), 4, 6, 24, and 48 hours post Loading dose/last Maintenance dose
Population: Patients with stable CVD
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | Post-dose 4 hours 0% | 13.6 10 AU * min | Standard Deviation 4.6 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | Post dose 24 hours 0% | 24.9 10 AU * min | Standard Deviation 14 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | Post-dose 6 hours 0% | 12.3 10 AU * min | Standard Deviation 5.9 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 24 hours 25% | 39.7 10 AU * min | Standard Deviation 18.1 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 4 hours 50% | 21.4 10 AU * min | Standard Deviation 7.7 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 24 hours 50% | 49.3 10 AU * min | Standard Deviation 17.9 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 6 hours 25% | 17.3 10 AU * min | Standard Deviation 6.1 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 24 hours 75% | 52.8 10 AU * min | Standard Deviation 22.7 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 4 hours 25% | 18.7 10 AU * min | Standard Deviation 5.2 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | Post-dose 48 hours 0% | 41.3 10 AU * min | Standard Deviation 17.7 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 6 hours 50% | 20.7 10 AU * min | Standard Deviation 6.5 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 48 hours 25% | 57.7 10 AU * min | Standard Deviation 17.6 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 4 hours 75% | 23.6 10 AU * min | Standard Deviation 8.4 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 48 hours 50% | 68.6 10 AU * min | Standard Deviation 20.4 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 6 hours 75% | 22.3 10 AU * min | Standard Deviation 7.5 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | 48 hours 75% | 72.8 10 AU * min | Standard Deviation 18.4 |
| Loading Dose | Platelet Aggregation Using Multiplate Analyzer | Baseline (pre-dose | 67.0 10 AU * min | Standard Deviation 14.3 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 48 hours 75% | 70.3 10 AU * min | Standard Deviation 23 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | Baseline (pre-dose | 67.0 10 AU * min | Standard Deviation 14.3 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | Post-dose 4 hours 0% | 15.7 10 AU * min | Standard Deviation 6.7 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 4 hours 25% | 20.9 10 AU * min | Standard Deviation 6.1 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 4 hours 50% | 22.1 10 AU * min | Standard Deviation 5.9 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 4 hours 75% | 24.2 10 AU * min | Standard Deviation 6.3 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | Post-dose 6 hours 0% | 13.4 10 AU * min | Standard Deviation 6 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 6 hours 25% | 16.5 10 AU * min | Standard Deviation 5.5 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 6 hours 50% | 18.9 10 AU * min | Standard Deviation 6.3 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 6 hours 75% | 20.4 10 AU * min | Standard Deviation 6.2 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | Post dose 24 hours 0% | 25.6 10 AU * min | Standard Deviation 15.6 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 24 hours 25% | 35.5 10 AU * min | Standard Deviation 15.1 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 24 hours 50% | 43.3 10 AU * min | Standard Deviation 16.7 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 24 hours 75% | 47.5 10 AU * min | Standard Deviation 18.2 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | Post-dose 48 hours 0% | 39.1 10 AU * min | Standard Deviation 21.3 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 48 hours 25% | 56.8 10 AU * min | Standard Deviation 19.5 |
| Maintenance Dose | Platelet Aggregation Using Multiplate Analyzer | 48 hours 50% | 63.8 10 AU * min | Standard Deviation 19.1 |