WiCKDonASA: Whole Blood Platelet Aggregation in Chronic Kidney Disease Patients on Aspirin Study

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01768637
• Collaborator: American Heart Association (Other)
• Enrollment: 48
• Location: 1
• Arms: 2
• Actual Duration (Months): 17
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

Higher coronary in-stent thromboses and bleeding complications on anti-platelet agents are more common in Chronic Kidney Disease vs. non-Chronic Kidney Disease patients. Poor inhibition of platelet aggregation by anti-platelet agents predicts future cardiovascular events. Clinical practice guidelines are ambiguous about the use of these agents in Chronic Kidney Disease due to lack of controlled studies. The investigators hypothesize that patients with Chronic Kidney Disease compared with non-Chronic Kidney Disease have reduced platelet aggregation and poor platelet inhibitory response to aspirin. The aims are to 1) define the range of whole blood platelet aggregation in stages 3-5 Chronic Kidney Disease patients; 2) investigate whether patients with stages 4-5 Chronic Kidney Disease vs. non-Chronic Kidney Disease have lower platelet aggregation or impaired von Willebrand Factor activity; and 3) compare inhibition of platelet aggregation from baseline after 2 weeks of aspirin therapy and another 2 weeks of clopidogrel therapy added to aspirin in Chronic Kidney Disease vs. non-Chronic Kidney Disease patients. Accomplishing these aims will provide pilot data to power future studies of targeted anti-platelet agent treatments in Chronic Kidney Disease in order to improve cardiovascular outcomes.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease	Drug: Aspirin; Drug: Clopidogrel	Phase 1

Detailed Description

Patients will be consented for the study and asked to initial on the consent form to state whether they agree for the genetic testing. After signing informed consent, complete medical history and medication list will be obtained and verified with the electronic medical record. After meeting all inclusion and exclusion criteria during the screening visit, those patients on aspirin for primary prevention of cardiovascular events will be asked to stop it for 2 weeks prior to blood collection for baseline data. Normal controls will be chosen after frequency matching for decade of age, gender, diabetes mellitus and interval of body mass index (5 kg/m2). Dietary supplements (Vitamin E and fish oil) known to affect platelet function will be assessed and patients on those will be asked to discontinue these. Participants with also be asked to not eat foods known to affect platelet function (coffee, chocolate, grapes, and alcohol) 48 hours prior to sample collection on visit 1. An interviewer-administered assessment of diet and exercise with a modified 24-hour dietary recall and the Stanford 7-day Physical activity Recall will be performed to ensure dietary consistency which may affect platelet aggregability on visit 1. Blood will be drawn via venopuncture for laboratory studies (whole blood platelet aggregation, von Willebrand Factor antigen levels and activity). Participants will be administered aspirin 81 mg for 2 weeks and asked to return in 2 weeks. On visit 2, whole blood platelet aggregation will be re-measured and questionnaires filled out. Two oral swabs will be taken from those participants who consented for genetic testing and samples will be stored at Dallas Veterans Affairs Medical Center for short term until shipped to Diagnostics Laboratory for genetic testing of clopidogrel cytochrome P450 polymorphisms. All participants will be administered clopidogrel 75 mg daily on top of aspirin 81 mg for 2 weeks and asked to return in 2 weeks. On visit 3, whole blood platelet aggregation will be re-measured and questionnaires filled out. At the completion of the study, participants will be placed back on their original antiplatelet agent if applicable and referred back to the primary care provider.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Whole Blood Platelet Aggregation in Chronic Kidney Disease Patients on Aspirin
• Actual Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Chronic Kidney Disease Patients with pre-dialysis stages 4-5 Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily.	Drug: Aspirin; Aspirin 81 mg by mouth daily; Other Names: ASA ; Drug: Clopidogrel; Clopidogrel 75 mg by mouth once daily; Other Names: Plavix
Active Comparator: Normal controls Patients without Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily.	Drug: Aspirin; Aspirin 81 mg by mouth daily; Other Names: ASA ; Drug: Clopidogrel; Clopidogrel 75 mg by mouth once daily; Other Names: Plavix

Outcome Measures

Primary Outcome Measures

1. Whole Blood Platelet Aggregation to 0.5 Millimoles Arachidonic Acid [2 weeks]

   Citrated whole blood was used to measure platelet aggregation induced by agonist (arachidonic acid at 5 mM concentration) using impedance whole blood platelet aggregometry via a Chrono-log aggregometer. Values at baseline (visit 1) was compared between groups with post treatment values (visit 2) after 2 weeks of aspirin treatment

Secondary Outcome Measures

1. Whole Blood Platelet Aggregation to 2 µg/mL Collagen [2 weeks]

   Citrated whole blood was used to measure platelet aggregation induced by agonist (collagen at 2mM concentration) using impedance whole blood platelet aggregometry via a Chrono-log aggregometer. Values at baseline (visit 1) was compared between groups with post treatment values (visit 2) after 2 weeks of aspirin treatment

2. Whole Blood Platelet Aggregation to 20 µg/mL Adenosine Diphosphate [4 weeks]

   Citrated whole blood was used to measure platelet aggregation induced by agonist (adenosine diphosphate at 20mM concentration) using impedance whole blood platelet aggregometry via a Chrono-log aggregometer. Values at baseline (visit 1) and on aspirin (visit 2) was compared between groups with post treatment values (visit 3) after 2 weeks of aspirin and clopidogrel treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male or female >21 years

Cases:

Chronic kidney disease stages 4-5, with estimated glomerular filtration rate of <30

Controls:

estimated glomerular filtration rate of >90, urinary albumin to creatinine ratio <30 and no other kidney damage

Exclusion Criteria:

• End-stage renal disease (peritoneal dialysis and hemodialysis)

• Kidney transplant or any other transplant patient

• Recent hospitalizations <3 months

• Acute coronary or cerebrovascular event in the last 12 months

• Surgery in the last 3 months

• Blood dyscrasias or active bleeding

• Gastro-intestinal bleeding in the last 6 months

• Concomitant use of other anti-platelet agent or antithrombotic drugs

• Recent treatment (<30 days) with a glycoprotein antagonist or proton pump inhibitor

• Hematocrit <25% or white blood cell count >20,000 or platelet count <50,000

• Any active malignancy or liver disease

• No current diagnosis of depression, not on any antidepressant medications,

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-8856

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• American Heart Association

Investigators

• Principal Investigator: Susan Hedayati, MD, University of Texas Southwestern Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT01768637
• Other Study ID Numbers: 12CRP11830004
• First Posted: Jan 15, 2013
• Last Update Posted: Apr 19, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by University of Texas Southwestern Medical Center: Chronic kidney disease; Platelet function; aspirin; antiplatelet agent
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Aspirin; Clopidogrel

Study Results

Participant Flow

Recruitment Details	Participants were recruited from December 10, 2012 to January 31, 2014 from outpatient clinics at Parkland hospital, Dallas Veterans Affairs hospital and University of Texas Southwestern Medical Center, Dallas, TX, USA.
Pre-assignment Detail	From 1,545 participants screened from outpatient clinics, 196 eligible patients were approached for enrollment, 128 refused and 48 signed consent.

Arm/Group Title	Chronic Kidney Disease	Normal Controls
Arm/Group Description	Patients with pre-dialysis stages 4-5 Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily	Patients without Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily
Period Title: Overall Study
STARTED	29	19
Completed Visit 1	28	16
Completed Visit 2	26	13
COMPLETED	26	12
NOT COMPLETED	3	7

Baseline Characteristics

Arm/Group Title	Chronic Kidney Disease	Normal Controls	Total
Arm/Group Description	Patients with pre-dialysis stages 4-5 Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily	Patients without Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily	Total of all reporting groups
Overall Participants	28	16	44
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52 (10)	49 (11)	51 (11)
Sex: Female, Male (Count of Participants)
Female	12 42.9%	8 50%	20 45.5%
Male	16 57.1%	8 50%	24 54.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 28.6%	4 25%	12 27.3%
Not Hispanic or Latino	20 71.4%	12 75%	32 72.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	15 53.6%	4 25%	19 43.2%
White	13 46.4%	12 75%	25 56.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.0 (5.5)	29.8 (4.9)	31.2 (5.3)
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	13 46.4%	7 43.8%	20 45.5%
Proton pump inhibitor use (Count of Participants)
Count of Participants [Participants]	1 3.6%	1 6.3%	2 4.5%
Beta blocker use (Count of Participants)
Count of Participants [Participants]	21 75%	0 0%	21 47.7%
Statin use (Count of Participants)
Count of Participants [Participants]	19 67.9%	5 31.3%	24 54.5%
Angiotensin converting enzyme inhibitor or angiotensin receptor blocker use (Count of Participants)
Count of Participants [Participants]	12 42.9%	5 31.3%	17 38.6%
Allopurinol use (Count of Participants)
Count of Participants [Participants]	6 21.4%	0 0%	6 13.6%
Baseline use of aspirin (Count of Participants)
Count of Participants [Participants]	12 42.9%	4 25%	16 36.4%
estimated glomerular filtration rate (eGFR) (ml/min/1.73m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73m^2]	17 (7)	101 (15)	47.2 (42.3)
Urine albumin to creatinine ratio (mg/g) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/g]	1282	5	87
Hemoglobin (g/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/dl]	11.2 (1.7)	14.4 (1.7)	12.5 (2.3)
Hematocrit (percent of red blood cells in blood) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent of red blood cells in blood]	33.9 (5.1)	42.6 (4.2)	36.9 (6.4)
Platelet count (K per microL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [K per microL]	232 (55)	217 (55)	227 (54.7)
Glycosylated hemoglobin (percent of glycated hemoglobin in blood) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent of glycated hemoglobin in blood]	6.8 (0.4)	6.4 (0.4)	6.4 (1.3)

Outcome Measures

1. Primary Outcome

Title	Whole Blood Platelet Aggregation to 0.5 Millimoles Arachidonic Acid
Description	Citrated whole blood was used to measure platelet aggregation induced by agonist (arachidonic acid at 5 mM concentration) using impedance whole blood platelet aggregometry via a Chrono-log aggregometer. Values at baseline (visit 1) was compared between groups with post treatment values (visit 2) after 2 weeks of aspirin treatment
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chronic Kidney Disease	Normal Controls
Arm/Group Description	Patients with pre-dialysis stages 4-5 Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily	Patients without Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily
Measure Participants	28	16
Baseline	21.0	18.0
visit 2	0	0

2. Secondary Outcome

Title	Whole Blood Platelet Aggregation to 2 µg/mL Collagen
Description	Citrated whole blood was used to measure platelet aggregation induced by agonist (collagen at 2mM concentration) using impedance whole blood platelet aggregometry via a Chrono-log aggregometer. Values at baseline (visit 1) was compared between groups with post treatment values (visit 2) after 2 weeks of aspirin treatment
Time Frame	2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chronic Kidney Disease	Normal Controls
Arm/Group Description	Patients with pre-dialysis stages 4-5 Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily	Patients without Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily
Measure Participants	28	16
Baseline	28.5	25.0
visit 2	19.5	19.0

3. Secondary Outcome

Title	Whole Blood Platelet Aggregation to 20 µg/mL Adenosine Diphosphate
Description	Citrated whole blood was used to measure platelet aggregation induced by agonist (adenosine diphosphate at 20mM concentration) using impedance whole blood platelet aggregometry via a Chrono-log aggregometer. Values at baseline (visit 1) and on aspirin (visit 2) was compared between groups with post treatment values (visit 3) after 2 weeks of aspirin and clopidogrel treatment
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chronic Kidney Disease	Normal Controls
Arm/Group Description	Patients with pre-dialysis stages 4-5 Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily	Patients without Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily
Measure Participants	28	16
Baseline	13.5	9.0
visit 2	11.0	10.0
visit 3	8.0	3.0

Adverse Events

Time Frame	Adverse events were collected throughout the period of the study visits for an average of 4 weeks.
Adverse Event Reporting Description	not different
Arm/Group Title	Chronic Kidney Disease		Normal Controls
Arm/Group Description	Patients with pre-dialysis stages 4-5 Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily		Patients without Chronic Kidney Disease will receive open-label aspirin 81 mg once daily for 2 weeks, then 2 weeks of aspirin 81 mg plus clopidogrel 75 mg once daily. Aspirin: Aspirin 81 mg by mouth daily Clopidogrel: Clopidogrel 75 mg by mouth once daily
All Cause Mortality
	Chronic Kidney Disease		Normal Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/16 (0%)
Serious Adverse Events
	Chronic Kidney Disease		Normal Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Chronic Kidney Disease		Normal Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/28 (17.9%)		9/16 (56.3%)
Blood and lymphatic system disorders
Brusing or nose bleed	5/28 (17.9%)	5	9/16 (56.3%)	9

Limitations/Caveats

Limited by residual confounding due to small sample size and lack of randomization ex vivo measurement of platelet function which may be different from in vivo function Sub-optimal reproducibility of platelet assays

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.