Peripheral Artery Disease, Type 2 Diabetes
Conditions
Keywords
Peripheral Artery Disease, Type 2 Diabetes, Blood Viscosity, Ticagrelor, Aspirin
Brief summary
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
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.
Interventions
Sponsors
Icahn School of Medicine at Mount Sinai
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Low Shear Blood Viscosity | baseline, week 16 | Compare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity from week 16 to baseline |
| Mean Change in High Shear Blood Viscosity | baseline and week 16 | Compare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity at week 16 to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Peripheral Arterial Blood Flow | baseline and week 16 | 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. |
| Mean Change in Microvascular Blood Flow Composite Score | baseline and week 16 | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment from April 2015 to April 2018. Study participants were recruited from the outpatient cardiology practice and the Cardiac Catheterization database at the Mount Sinai Hospital, New York, NY, USA.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Two crossovers with all participants experiencing all 3 arms | 70 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 3rd Crossover - Week 10 to Week 16 | Adverse Event | 1 | 0 | 0 |
| 3rd Crossover - Week 10 to Week 16 | Protocol Violation | 0 | 1 | 0 |
| 3rd Crossover - Week 10 to Week 16 | urgent vascularization | 0 | 1 | 0 |
| Period 1 Timeframe - Baseline to Week 4 | Adverse Event | 0 | 0 | 1 |
| Period 1 Timeframe - Baseline to Week 4 | urgent vascularization | 1 | 0 | 2 |
| Period 1 Timeframe - Baseline to Week 4 | Withdrawal by Subject | 0 | 2 | 0 |
| Period 2 - Timeframe Week 4 to Week 10 | Protocol Violation | 1 | 0 | 0 |
| Period 2 - Timeframe Week 4 to Week 10 | urgent vascularization | 1 | 0 | 0 |
| Period 2 - Timeframe Week 4 to Week 10 | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 9 |
| Blood viscosity 300 s^-1 | 4.0 centipoises (cPs) STANDARD_DEVIATION 0.6 |
| Blood viscosity 5 s^-1 | 11.1 cPs STANDARD_DEVIATION 2.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 41 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Fasting glucose | 124 mg/dL STANDARD_DEVIATION 47 |
| Fibrinogen | 351 mg/dL STANDARD_DEVIATION 109 |
| Hematocrit | 38.3 percent of cells STANDARD_DEVIATION 4.4 |
| Hemoglobin A1c | 7.20 percentage of hemoglobin STANDARD_DEVIATION 1.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants |
| Race (NIH/OMB) More than one race | 21 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 70 | 0 / 70 |
| other Total, other adverse events | 0 / 70 | 0 / 70 | 1 / 70 |
| serious Total, serious adverse events | 0 / 70 | 1 / 70 | 0 / 70 |
Outcome results
Primary
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
Time frame: baseline and week 16
Population: data collected and included for any participants who return for any of their visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin/Ticagrelor Placebo | Mean Change in High Shear Blood Viscosity | 0.165 300 s^-1 cPs | Standard Deviation 0.318 |
| Aspirin/Ticagrelor | Mean Change in High Shear Blood Viscosity | -0.228 300 s^-1 cPs | Standard Deviation 0.469 |
| Aspirin Placebo/Ticagrelor | Mean Change in High Shear Blood Viscosity | -0.231 300 s^-1 cPs | Standard Deviation 0.36 |
Primary
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
Time frame: baseline, week 16
Population: data collected and included for any participants who return for any of their visits.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin/Ticagrelor Placebo | Mean Change in Low Shear Blood Viscosity | 1.045 5 s^-1 cPs | Standard Deviation 1.525 |
| Aspirin/Ticagrelor | Mean Change in Low Shear Blood Viscosity | -1.793 5 s^-1 cPs | Standard Deviation 1.835 |
| Aspirin Placebo/Ticagrelor | Mean Change in Low Shear Blood Viscosity | -1.759 5 s^-1 cPs | Standard Deviation 1.298 |
Secondary
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.
Time frame: baseline and week 16
Population: data collected for participants who return for their visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aspirin/Ticagrelor Placebo | Mean Change in Microvascular Blood Flow Composite Score | Right side | -4.10 score on a scale | Standard Deviation 13.3 |
| Aspirin/Ticagrelor Placebo | Mean Change in Microvascular Blood Flow Composite Score | Left side | -5.60 score on a scale | Standard Deviation 11.86 |
| Aspirin/Ticagrelor | Mean Change in Microvascular Blood Flow Composite Score | Right side | 13.64 score on a scale | Standard Deviation 7.34 |
| Aspirin/Ticagrelor | Mean Change in Microvascular Blood Flow Composite Score | Left side | 24.76 score on a scale | Standard Deviation 8.36 |
| Aspirin Placebo/Ticagrelor | Mean Change in Microvascular Blood Flow Composite Score | Right side | -5.23 score on a scale | Standard Deviation 7.76 |
| Aspirin Placebo/Ticagrelor | Mean Change in Microvascular Blood Flow Composite Score | Left side | -4.29 score on a scale | Standard Deviation 7.48 |
Secondary
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.
Time frame: baseline and week 16
Population: data collected for participants who return for their visits.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aspirin/Ticagrelor Placebo | Mean Change in Peripheral Arterial Blood Flow | ABI right side | 0.038 index | Standard Deviation 0.055 |
| Aspirin/Ticagrelor Placebo | Mean Change in Peripheral Arterial Blood Flow | ABI left side | 0.015 index | Standard Deviation 0.067 |
| Aspirin/Ticagrelor Placebo | Mean Change in Peripheral Arterial Blood Flow | TBI right side | 0.044 index | Standard Deviation 0.013 |
| Aspirin/Ticagrelor Placebo | Mean Change in Peripheral Arterial Blood Flow | TBI left side | 0.004 index | Standard Deviation 0.022 |
| Aspirin/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | TBI left side | -0.016 index | Standard Deviation 0.018 |
| Aspirin/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | ABI right side | 0.021 index | Standard Deviation 0.019 |
| Aspirin/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | TBI right side | 0.009 index | Standard Deviation 0.015 |
| Aspirin/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | ABI left side | 0.032 index | Standard Deviation 0.038 |
| Aspirin Placebo/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | TBI left side | 0.036 index | Standard Deviation 0.028 |
| Aspirin Placebo/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | ABI left side | 0.075 index | Standard Deviation 0.029 |
| Aspirin Placebo/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | TBI right side | 0.011 index | Standard Deviation 0.008 |
| Aspirin Placebo/Ticagrelor | Mean Change in Peripheral Arterial Blood Flow | ABI right side | 0.095 index | Standard Deviation 0.051 |