Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in Peripheral Artery Disease Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The hypothesis being that both aspirin-ticagrelor and ticagrelor monotherapy will be superior to aspirin monotherapy in the reduction of whole blood viscosity at the end of each 4 week treatment period. Study participants will be randomized into 3 groups, and each group will receive each of 3 treatments in the cross-over study. At the end of each individual 4 week treatment period the investigators will determine whether there are differences in low and high shear rate dependent viscosity and investigate the effect of the treatment on peripheral arterial blood flow using pulse volume recordings, ankle brachial index and toe pressures. Subjects will be eligible if they have ankle-brachial index less than or equal to 0.85, or if a patient's blood vessels are calcified, patients will have toe-brachial index less than or equal to 0.6 performed using continuous-wave Doppler.

Detailed Description
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Ticagrelor has been shown to significantly reduce the rate of cardiovascular disease (CVD) events and death compared with clopidogrel in patients having prior acute coronary syndrome. A number of outcome studies have demonstrated the risk of major CVD events increased with blood viscosity. Stroke patients and those with stroke risk factors were shown to have chronically elevated blood viscosity relative to healthy controls. Based on prior observations, the rationale for this study is to demonstrate that both aspirin-ticagrelor and ticagrelor monotherapy will be superior to aspirin monotherapy in the reduction of whole blood viscosity at the end of each 4 week treatment period. The primary objectives for this study is to: (1) Compare the effect of aspirin-ticagrelor with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) shear rates at the end of each 4-week treatment period; and (2) to compare the effect of ticagrelor mono-therapy with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) at the end of each 4-week treatment. The secondary objectives for this study include: (1) a determination as to whether there are differences in low and high shear rate dependent viscosity with treatment by ticagrelor alone and combination aspirin-ticagrelor. Additionally, investigated will be the effect of the treatment on peripheral arterial blood flow using pulse volume recordings, ankle brachial index, and toe pressures. The general approach to evaluation of drug efficacy will be through blood samples collected with a standard venipuncture for viscosity testing. Blood viscosity will be measured using an automated scanning capillary tube viscometer across a physiologic range of shear rates of 1-1000 s-1 in increments of 0.1 s-1. Blood viscosity levels at 5 s-1 will be reported as low-shear viscosity, and blood viscosity measurements at 300 s-1 will be reported as high-shear viscosity. Additionally, pulse volume recordings will be simultaneously obtained at the level of the ankle, metatarsal and toe bilaterally according to standard protocol, and Continuous-wave Doppler will be used to determine ankle-brachial indices or toe-brachial indices, and flow velocity profiles.

Official Title
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Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in Peripheral Artery Disease (PAD) Patients With Type 2 Diabetes (T2D)

Conditions
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Peripheral Artery Disease, Type 2 Diabetes

Intervention / Treatment
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* Drug: Aspirin
* Drug: Ticagrelor
* Drug: Aspirin Placebo
* Drug: Ticagrelor Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male aged ≥ 35 years Type 2 diabetes mellitus Symptomatic PAD Ankle-brachial index ≤ 0.85 or calcified blood vessels with toe-brachial index ≤ 0.6 and/or abnormal post-exercise ankle-brachial index Prior surgical or percutaneous intervention of the peripheral arteries ≥12 months previously with a residual stenoses of ≥50% in a non-dilated artery. Exclusion Criteria: Subject is pregnant or breast-feeding Planned revascularization or amputation Known bleeding disorder History of intracranial hemorrhag3 Considered at risk of hemorrhagic events Hypersensitivity or allergic reactions to aspirin Concomitant use of anticoagulants such as warfarin, dabigatran, factor Xa inhibitors or antiplatelet drugs such as clopidogrel, dipyridamole and sulfapyridine Subject has a condition or circumstance which would prevent them from adhering to treatment regimens Subject has active infection Subject has an anemia Subject has given blood or received a blood transfusion at any point during the study Subject has polycythemia vera or any hyperviscosity syndrome Subjects with Waldenstrom's macroglobulinemia who have an increased risk of hyperviscosity syndrome Subject has history of severe liver disease, obstructive liver disease such as primary biliary cirrhosis or end-stage renal disease (eGFR <30 mL/min/m2) Family members or employees of the investigator or study centers involved in the study Subject has poor diabetes or hypertension control (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Aspirin/Ticagrelor placebo<br>aspirin 81 mg daily and ticagrelor placebo twice daily | Drug: Aspirin<br>* Aspirin 81mg<br>* Other names: ASA;Drug: Ticagrelor Placebo<br> <br> * Other names: Placebo;|
| Active Comparator: Aspirin/Ticagrelor<br>aspirin 81 mg daily and ticagrelor 90 mg twice daily | Drug: Aspirin<br>* Aspirin 81mg<br>* Other names: ASA;Drug: Ticagrelor<br>* ticagrelor 90 mg<br>|
| Active Comparator: Aspirin Placebo/Ticagrelor<br>aspirin placebo daily and ticagrelor 90 mg twice daily | Drug: Ticagrelor<br>* ticagrelor 90 mg<br>Drug: Aspirin Placebo<br> <br> * Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Low Shear Blood Viscosity | Compare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity from week 16 to baseline | baseline, week 16 | 
| Mean Change in High Shear Blood Viscosity | Compare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity at week 16 to baseline | baseline and week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Peripheral Arterial Blood Flow | Measure of treatment effect using pulse volume recordings of the ankle, great toe and brachial artery to calculate the ankle brachial index (ABI) and toe brachial index (TBI) at week 16 compared to baseline. ABI and TBI are taken in order to determine the existence and severity of peripheral arterial disease. ABI - The normal range for the ankle-brachial index is between 0.90 and 1.30. ABI <0.90 is abnormal: 0.41 to 0.90 indicates mild to moderate peripheral artery disease; 0.40 and lower indicates severe disease. The lower the index, the higher the chances of leg pain while exercising or limb-threatening low blood flow. TBI ≥ 0.7 is normal, TBI < 0.7 is abnormal. | baseline and week 16 | 
| Mean Change in Microvascular Blood Flow Composite Score | Measure of treatment effect using pulse volume recordings of the ankle, great toe and brachial artery to calculate the ankle brachial index and toe pressures composite score at week 16 from baseline. Composite score obtained by adding all the measurements and averaged. The score was tested by the Laser Doppler Flowmetry (LDF). Minimum score is 0 which mean no blood flow detected and there is no maximum value of the score, and higher score mean better blood flow. | baseline and week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral Artery Disease, Type 2 Diabetes, Blood Viscosity, Ticagrelor, Aspirin