Coronary Artery Disease, Type-2 Diabetes Mellitus
Conditions
Keywords
Antiplatelet, Ticagrelor, Clopidogrel, Thrombosis, Diabetes, Coronary Artery Disease
Brief summary
The purpose of this study is to determine whether treatment with ticagrelor + aspirin is more effective than treatment with clopidogrel + aspirin in patients with type-2 diabetes. Both treatments will be given (separately) to all subjects as a one-time loading dose (i.e. higher than a normal daily dose), followed by daily dose for the next 5 to 7 days. Effectiveness of treatment will be measured with specialized blood tests before the loading dose, at two time-points after the loading dose, and once after the last daily dose.
Detailed description
The rising prevalence of diabetes mellitus and its associated cardiovascular complications present a major burden to healthcare providers worldwide. Cardiovascular mortality is much higher among subjects with Type 2 Diabetes Mellitus (T2DM). Increased platelet reactivity is considered a potential link between the two diseases. Thus, given the higher blood thrombogenicity of T2DM with CAD, the availability of more potent antiplatelet drugs should be associated with improvements in the prevention of cardiovascular events in the diabetic populations. Ticagrelor has been shown to possess a faster onset of action and more potency than clopidogrel. Furthermore, the PLATO has shown that these characteristics results in a significant reduction in Cardiovascular events and even death as compared with Clopidogrel. We plan to compare the antithrombotic activity of ticagrelor versus clopidogrel in T2DM patients using a cross-over study design. Each participant will be randomly assigned to receive ticagrelor/clopidogrel + aspirin as a loading dose followed by 5-7 days of daily maintenance dosing. After a washout period of 1-2 weeks, each participant will receive the second treatment (clopidogrel/ticagrelor + aspirin) again as a loading dose followed by 5-7 days of daily dosing. Platelet function will be tested at pre-treatment baseline, two post-dose time-points on the day of loading dose, and one time-point after the last maintenance dose on day 5-7. Platelet testing will be carried out using the following methodologies: 1. Badimon Perfusion Chamber: an ex-vivo model of thrombosis that has been extensively utilized for evaluation of antithrombotic or prothrombotic effects under various pathological states. The model involves native blood perfusing over a thrombogenic substrate, triggering thrombus formation that can be measured by planimetry. 2. Platelet Aggregation - Multiplate Analyzer. 3. Platelet Aggregation - VerifyNow P2Y12 assay. 4. Vasodilator-Stimulated Phosphoprotein (VASP).
Interventions
Single loading doses of Ticagrelor (180 mg) and ASA (325 mg), followed by daily dosing for 5-7 days (ticagrelor 90 mg twice daily + ASA 81 mg once daily).
Single loading doses of Clopidogrel (600 mg) and ASA (325 mg), followed by daily dosing for 5-7 days (clopidogrel 75 mg + ASA 81 mg once daily).
Sponsors
AstraZeneca
Juan J Badimon
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with type-2 diabetes being treated with oral or parenteral hypoglycemic therapy or both. * Have not had thienopyridine therapy for at least 30 days before the study. * Are of legal age (at least 18 years of age but less than 75 years of age) and competent mental condition to provide written informed consent. * For women of child-bearing potential only test negative for pregnancy at the time of enrollment.
Exclusion criteria
* Have a defined need for thienopyridine therapy. * Subjects within ≤30 days of coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). * Known glycosylated hemoglobin (HbA1c) ≥10 mg/dL within last 3 months prior to study entry. * Have received fibrinolytic therapy \<48 hours prior to randomization. * Have active internal bleeding or history of bleeding diathesis. * Have clinical findings that are, in the judgment of the investigator, associated with an increased risk of bleeding. * Have history of ischemic or hemorrhagic stroke, transient ischemic attack (TIA) or intracranial neoplasm, arteriovenous malformation, or aneurysm. * Have an International Normalized Ratio (INR) known to be \>1.5 within 1 week of study entry. * Have a known platelet count of \<100,000/mm3 within 1 week of study entry. * Have known anemia (hemoglobin \[Hgb\] \<10 gm/dL) within 1 week of study entry. * Are receiving or will receive oral anticoagulation or other antiplatelet therapy (other than ASA) that cannot be safely discontinued for the duration of the trial. * Are receiving daily treatment with non-steroidal anti-inflammatory drugs (NSAIDS) that cannot be discontinued. * Have a concomitant medical illness that in the opinion of the investigator may interfere with or prevent completion in this study. * Have known severe hepatic dysfunction (e.g., cirrhosis or portal hypertension). * Have a history of intolerance or allergy to ASA or approved thienopyridines (ticlopidine or clopidogrel).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Thrombus Formation | up to 7 days | Thrombus formation in Badimon Perfusion Chamber high-shear) (ex vivo model of thrombosis). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity | up to 7 days | Platelet reactivity by Multiplate Analyzer |
| P2Y12 Reaction Unit (PRU) | up to 7 days | Platelet reactivity by measuring P2Y12 Reaction Unit using Accumetrics VerifyNow |
| Platelet Reactivity Index (PRI) | up to 7 days | Platelet reactivity index by Vasodilator-Stimulated Phosphoprotein phosphorylation (VASP) assay. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Type 2 Diabetic Patients All participants receive both Ticagrelor and Clopidogrel (each with aspirin) in a cross-over design. Treatment sequence (Tica-Clop OR Clop-Tica) was randomly assigned and with a 2-week washout period in between (i.e., Tica/Clop (5-7 days), Washout (14 days), and Clop/Tica (5-7 days)). | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Type 2 Diabetic Patients |
|---|---|
| Age, Continuous | 57.2 years STANDARD_DEVIATION 8.3 |
| Body Mass Index (BMI) | 30.9 kg/m^2 STANDARD_DEVIATION 4.5 |
| Diabetes, type-2 | 20 Participants |
| Hypercholesterolemia | 19 Participants |
| Hypertension | 17 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
| Smoking | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Thrombus Formation
Thrombus formation in Badimon Perfusion Chamber high-shear) (ex vivo model of thrombosis).
Time frame: up to 7 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor + Aspirin | Thrombus Formation | 2 hour post loading dose | 66.9 percentage of baseline size | Standard Error 8 |
| Ticagrelor + Aspirin | Thrombus Formation | 6 hours post loading dose | 59.9 percentage of baseline size | Standard Error 8 |
| Ticagrelor + Aspirin | Thrombus Formation | 5-7 days of maintenance dose | 68.9 percentage of baseline size | Standard Error 8.3 |
| Clopidogrel + Aspirin | Thrombus Formation | 2 hour post loading dose | 84.4 percentage of baseline size | Standard Error 6.4 |
| Clopidogrel + Aspirin | Thrombus Formation | 6 hours post loading dose | 79.8 percentage of baseline size | Standard Error 6.4 |
| Clopidogrel + Aspirin | Thrombus Formation | 5-7 days of maintenance dose | 82.6 percentage of baseline size | Standard Error 6.5 |
Secondary
P2Y12 Reaction Unit (PRU)
Platelet reactivity by measuring P2Y12 Reaction Unit using Accumetrics VerifyNow
Time frame: up to 7 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor + Aspirin | P2Y12 Reaction Unit (PRU) | 2 hour post-loading dose | 14.8 percentage of baseline PRU | Standard Error 7.2 |
| Ticagrelor + Aspirin | P2Y12 Reaction Unit (PRU) | 6 hour post-loading dose | 8.2 percentage of baseline PRU | Standard Error 7.5 |
| Ticagrelor + Aspirin | P2Y12 Reaction Unit (PRU) | 5-7 days of maintenance dosing | 14.5 percentage of baseline PRU | Standard Error 7.5 |
| Clopidogrel + Aspirin | P2Y12 Reaction Unit (PRU) | 2 hour post-loading dose | 77.8 percentage of baseline PRU | Standard Error 11.8 |
| Clopidogrel + Aspirin | P2Y12 Reaction Unit (PRU) | 6 hour post-loading dose | 66.8 percentage of baseline PRU | Standard Error 11.9 |
| Clopidogrel + Aspirin | P2Y12 Reaction Unit (PRU) | 5-7 days of maintenance dosing | 62.7 percentage of baseline PRU | Standard Error 11.8 |
Secondary
Platelet Reactivity
Platelet reactivity by Multiplate Analyzer
Time frame: up to 7 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor + Aspirin | Platelet Reactivity | 2 hour post-loading dose | 20.5 percentage of baseline Unit | Standard Error 7.4 |
| Ticagrelor + Aspirin | Platelet Reactivity | 6 hour post-loading dose | 20.6 percentage of baseline Unit | Standard Error 7.5 |
| Ticagrelor + Aspirin | Platelet Reactivity | 5-7 days of maintenance dosing | 24.2 percentage of baseline Unit | Standard Error 7.7 |
| Clopidogrel + Aspirin | Platelet Reactivity | 2 hour post-loading dose | 54.5 percentage of baseline Unit | Standard Error 14.4 |
| Clopidogrel + Aspirin | Platelet Reactivity | 6 hour post-loading dose | 43.6 percentage of baseline Unit | Standard Error 14.6 |
| Clopidogrel + Aspirin | Platelet Reactivity | 5-7 days of maintenance dosing | 45.5 percentage of baseline Unit | Standard Error 14.4 |
Secondary
Platelet Reactivity Index (PRI)
Platelet reactivity index by Vasodilator-Stimulated Phosphoprotein phosphorylation (VASP) assay.
Time frame: up to 7 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor + Aspirin | Platelet Reactivity Index (PRI) | 2 hour post-loading dose | 21.8 percentage of baseline PRI | Standard Error 2.5 |
| Ticagrelor + Aspirin | Platelet Reactivity Index (PRI) | 6 hour post-loading dose | 17.8 percentage of baseline PRI | Standard Error 2.5 |
| Ticagrelor + Aspirin | Platelet Reactivity Index (PRI) | 5-7 days of maintenance dosing | 17.2 percentage of baseline PRI | Standard Error 2.5 |
| Clopidogrel + Aspirin | Platelet Reactivity Index (PRI) | 2 hour post-loading dose | 85.8 percentage of baseline PRI | Standard Error 3.3 |
| Clopidogrel + Aspirin | Platelet Reactivity Index (PRI) | 6 hour post-loading dose | 82.5 percentage of baseline PRI | Standard Error 3.4 |
| Clopidogrel + Aspirin | Platelet Reactivity Index (PRI) | 5-7 days of maintenance dosing | 68.4 percentage of baseline PRI | Standard Error 3.4 |