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)
• Enrollment: 70
• Location: 1
• Arms: 3
• Duration (Months): 37.1
• Patients Per Site Per Month: 1.9

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 Disease	Intervention/Treatment	Phase
Peripheral Artery Disease; Type 2 Diabetes	Drug: Aspirin; Drug: Ticagrelor; Drug: Aspirin Placebo; Drug: Ticagrelor Placebo	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

Arm	Intervention/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

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029

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)

• Study Protocol and Statistical Analysis Plan - Jan 19, 2018

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: Peripheral Artery Disease; Type 2 Diabetes; Blood Viscosity; Ticagrelor; Aspirin
• Additional relevant MeSH terms: Peripheral Arterial Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Aspirin; Ticagrelor

Study Results

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.

Arm/Group Title	Aspirin/Ticagrelor Placebo	Aspirin/Ticagrelor	Aspirin Placebo/Ticagrelor
Arm/Group Description	aspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study team	aspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team	aspirin 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
STARTED	23	23	24
COMPLETED	22	21	21
NOT COMPLETED	1	2	3
Period Title: Period 1 Timeframe - Baseline to Week 4
STARTED	22	21	21
COMPLETED	19	20	21
NOT COMPLETED	3	1	0
Period Title: Period 1 Timeframe - Baseline to Week 4
STARTED	19	20	21
COMPLETED	18	18	21
NOT COMPLETED	1	2	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Two crossovers with all participants experiencing all 3 arms
Overall Participants	70
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

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

Outcome Measure Data

Analysis Population Description

data collected and included for any participants who return for any of their visits.

Arm/Group Title	Aspirin/Ticagrelor Placebo	Aspirin/Ticagrelor	Aspirin Placebo/Ticagrelor
Arm/Group Description	aspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study team	aspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team	aspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
Measure Participants	60	61	58
Mean (Standard Deviation) [5 s^-1 cPs]	1.045 (1.525)	-1.793 (1.835)	-1.759 (1.298)

2. Primary Outcome

Title	Mean Change in High Shear Blood Viscosity
Description	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

Outcome Measure Data

Analysis Population Description

data collected and included for any participants who return for any of their visits.

Arm/Group Title	Aspirin/Ticagrelor Placebo	Aspirin/Ticagrelor	Aspirin Placebo/Ticagrelor
Arm/Group Description	aspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study team	aspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team	aspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
Measure Participants	60	61	58
Mean (Standard Deviation) [300 s^-1 cPs]	0.165 (0.318)	-0.228 (0.469)	-0.231 (0.360)

3. Secondary Outcome

Title	Mean Change in Peripheral Arterial Blood Flow
Description	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

Outcome Measure Data

Analysis Population Description

data collected for participants who return for their visits.

Arm/Group Title	Aspirin/Ticagrelor Placebo	Aspirin/Ticagrelor	Aspirin Placebo/Ticagrelor
Arm/Group Description	aspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study team	aspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team	aspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
Measure Participants	60	61	58
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

Title	Mean Change in Microvascular Blood Flow Composite Score
Description	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

Outcome Measure Data

Analysis Population Description

data collected for participants who return for their visits.

Arm/Group Title	Aspirin/Ticagrelor Placebo	Aspirin/Ticagrelor	Aspirin Placebo/Ticagrelor
Arm/Group Description	aspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study team	aspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team	aspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
Measure Participants	60	61	58
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 Frame	16 weeks
Adverse Event Reporting Description	data collected for participants who return for any subsequent visits
Arm/Group Title	Aspirin/Ticagrelor Placebo		Aspirin/Ticagrelor		Aspirin Placebo/Ticagrelor
Arm/Group Description	aspirin 81 mg daily and ticagrelor placebo twice daily crossover order was never unblinded to PI and study team		aspirin 81 mg daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team		aspirin placebo daily and ticagrelor 90 mg twice daily crossover order was never unblinded to PI and study team
All Cause Mortality
	Aspirin/Ticagrelor Placebo		Aspirin/Ticagrelor		Aspirin Placebo/Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/70 (0%)		0/70 (0%)
Serious Adverse Events
	Aspirin/Ticagrelor Placebo		Aspirin/Ticagrelor		Aspirin Placebo/Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		1/70 (1.4%)		0/70 (0%)
Gastrointestinal disorders
GI Bleeding	0/70 (0%)		1/70 (1.4%)		0/70 (0%)
Other (Not Including Serious) Adverse Events
	Aspirin/Ticagrelor Placebo		Aspirin/Ticagrelor		Aspirin Placebo/Ticagrelor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/70 (0%)		1/70 (1.4%)
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	0/70 (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.