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

Sponsor
Icahn School of Medicine at Mount Sinai (Other)
Overall Status
Completed
CT.gov ID
NCT02325466
Collaborator
(none)
70
Enrollment
1
Location
3
Arms
37.1
Duration (Months)
1.9
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
70 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in Peripheral Artery Disease (PAD) Patients With Type 2 Diabetes (T2D)
Study Start Date :
Apr 1, 2015
Actual Primary Completion Date :
May 4, 2018
Actual Study Completion Date :
May 4, 2018

Arms and Interventions

ArmIntervention/Treatment
Placebo Comparator: Aspirin/Ticagrelor placebo

aspirin 81 mg daily and ticagrelor placebo twice daily

Drug: Aspirin
Aspirin 81mg
Other Names:
  • ASA
  • Drug: Ticagrelor Placebo
    Other Names:
  • Placebo
  • Active Comparator: Aspirin/Ticagrelor

    aspirin 81 mg daily and ticagrelor 90 mg twice daily

    Drug: Aspirin
    Aspirin 81mg
    Other Names:
  • ASA
  • Drug: Ticagrelor
    ticagrelor 90 mg

    Active Comparator: Aspirin Placebo/Ticagrelor

    aspirin placebo daily and ticagrelor 90 mg twice daily

    Drug: Ticagrelor
    ticagrelor 90 mg

    Drug: Aspirin Placebo
    Other Names:
  • Placebo
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    2. 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 Outcome Measures

    1. 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.

    2. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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)

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Icahn School of Medicine at Mount SinaiNew YorkNew YorkUnited States10029

    Sponsors and Collaborators

    • Icahn School of Medicine at Mount Sinai

    Investigators

    • Principal Investigator: Robert Rosenson, MD, Icahn School of Medicine at Mount Sinai

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Robert Rosenson, Professor Medicine, Cardiology, Icahn School of Medicine at Mount Sinai
    ClinicalTrials.gov Identifier:
    NCT02325466
    Other Study ID Numbers:
    • GCO 13-1925
    First Posted:
    Dec 25, 2014
    Last Update Posted:
    Mar 21, 2022
    Last Verified:
    Mar 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Robert Rosenson, Professor Medicine, Cardiology, Icahn School of Medicine at Mount Sinai
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment DetailsRecruitment 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.
    Pre-assignment Detail
    Arm/Group TitleAspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Arm/Group Descriptionaspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study teamaspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study teamaspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
    Period Title: Period 1 Timeframe - Baseline to Week 4
    STARTED232324
    COMPLETED222121
    NOT COMPLETED123
    Period Title: Period 1 Timeframe - Baseline to Week 4
    STARTED222121
    COMPLETED192021
    NOT COMPLETED310
    Period Title: Period 1 Timeframe - Baseline to Week 4
    STARTED192021
    COMPLETED181821
    NOT COMPLETED120

    Baseline Characteristics

    Arm/Group TitleAll Participants
    Arm/Group DescriptionTwo crossovers with all participants experiencing all 3 arms
    Overall Participants70
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    72
    (9)
    Sex: Female, Male (Count of Participants)
    Female
    34
    48.6%
    Male
    36
    51.4%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    41
    58.6%
    Not Hispanic or Latino
    29
    41.4%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    4
    5.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    22
    31.4%
    White
    23
    32.9%
    More than one race
    21
    30%
    Unknown or Not Reported
    0
    0%
    Hematocrit (percent of cells) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percent of cells]
    38.3
    (4.4)
    Fibrinogen (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    351
    (109)
    Fasting glucose (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    124
    (47)
    Hemoglobin A1c (percentage of hemoglobin) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage of hemoglobin]
    7.20
    (1.1)
    Blood viscosity 300 s^-1 (centipoises (cPs)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [centipoises (cPs)]
    4.0
    (0.6)
    Blood viscosity 5 s^-1 (cPs) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cPs]
    11.1
    (2.1)

    Outcome Measures

    1. Primary Outcome
    TitleMean Change in Low Shear Blood Viscosity
    DescriptionCompare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity from week 16 to baseline
    Time Framebaseline, week 16

    Outcome Measure Data

    Analysis Population Description
    data collected and included for any participants who return for any of their visits.
    Arm/Group TitleAspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Arm/Group Descriptionaspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study teamaspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study teamaspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
    Measure Participants606158
    Mean (Standard Deviation) [5 s^-1 cPs]
    1.045
    (1.525)
    -1.793
    (1.835)
    -1.759
    (1.298)
    2. Primary Outcome
    TitleMean Change in High Shear Blood Viscosity
    DescriptionCompare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity at week 16 to baseline
    Time Framebaseline and week 16

    Outcome Measure Data

    Analysis Population Description
    data collected and included for any participants who return for any of their visits.
    Arm/Group TitleAspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Arm/Group Descriptionaspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study teamaspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study teamaspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
    Measure Participants606158
    Mean (Standard Deviation) [300 s^-1 cPs]
    0.165
    (0.318)
    -0.228
    (0.469)
    -0.231
    (0.360)
    3. Secondary Outcome
    TitleMean Change in Peripheral Arterial Blood Flow
    DescriptionMeasure 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 Framebaseline and week 16

    Outcome Measure Data

    Analysis Population Description
    data collected for participants who return for their visits.
    Arm/Group TitleAspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Arm/Group Descriptionaspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study teamaspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study teamaspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
    Measure Participants606158
    ABI right side
    0.038
    (0.055)
    0.021
    (0.019)
    0.095
    (0.051)
    ABI left side
    0.015
    (0.067)
    0.032
    (0.038)
    0.075
    (0.029)
    TBI right side
    0.044
    (0.013)
    0.009
    (0.015)
    0.011
    (0.008)
    TBI left side
    0.004
    (0.022)
    -0.016
    (0.018)
    0.036
    (0.028)
    4. Secondary Outcome
    TitleMean Change in Microvascular Blood Flow Composite Score
    DescriptionMeasure 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 Framebaseline and week 16

    Outcome Measure Data

    Analysis Population Description
    data collected for participants who return for their visits.
    Arm/Group TitleAspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Arm/Group Descriptionaspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study teamaspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study teamaspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
    Measure Participants606158
    Right side
    -4.10
    (13.30)
    13.64
    (7.34)
    -5.23
    (7.76)
    Left side
    -5.60
    (11.86)
    24.76
    (8.36)
    -4.29
    (7.48)

    Adverse Events

    Time Frame16 weeks
    Adverse Event Reporting Description data collected for participants who return for any subsequent visits
    Arm/Group TitleAspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Arm/Group Descriptionaspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study teamaspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study teamaspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
    All Cause Mortality
    Aspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/70 (0%) 0/70 (0%) 0/70 (0%)
    Serious Adverse Events
    Aspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/70 (0%) 1/70 (1.4%) 0/70 (0%)
    Gastrointestinal disorders
    GI Bleeding0/70 (0%) 1/70 (1.4%) 0/70 (0%)
    Other (Not Including Serious) Adverse Events
    Aspirin/Ticagrelor PlaceboAspirin/TicagrelorAspirin Placebo/Ticagrelor
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/70 (0%) 0/70 (0%) 1/70 (1.4%)
    Respiratory, thoracic and mediastinal disorders
    Shortness of Breath0/70 (0%) 0/70 (0%) 1/70 (1.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Results Point of Contact

    Name/TitleDr. Robert S. Rosenson
    OrganizationIcahn School of Medicine at Mount Sinai
    Phone212-241-9101
    Emailrobert.rosenson@mssm.edu
    Responsible Party:
    Robert Rosenson, Professor Medicine, Cardiology, Icahn School of Medicine at Mount Sinai
    ClinicalTrials.gov Identifier:
    NCT02325466
    Other Study ID Numbers:
    • GCO 13-1925
    First Posted:
    Dec 25, 2014
    Last Update Posted:
    Mar 21, 2022
    Last Verified:
    Mar 1, 2022