Chronic Kidney Diseases, Heart Attack, Stroke, Ischemic
Conditions
Keywords
P2Y12 inhibitors, Platelet aggregation, ticagrelor, clopidogrel, chronic kidney disease
Brief summary
This study evaluates how aspirin, clopidogrel and ticagrelor work in people with chronic kidney disease (CKD) compared to people with normal kidneys. In the first part of the study, half of CKD participants will be randomly assigned to ticagrelor and aspirin, while the other half will be assigned to clopidogrel and aspirin in a blinded fashion. The treatment duration will be two weeks. After recruiting CKD participants the investigator will recruit controls with normal kidney function that will receive only ticagrelor and aspirin for two weeks.
Detailed description
It is known that people with chronic kidney disease (CKD) are at higher risk to have heart and blood vessel problems like heart attack and stroke compared to people that do not have kidney problems. Aspirin, clopidogrel and ticagrelor prevent blood clots building up in the vessels. If a blood clot is present in one vessel, it could stop oxygen carrying blood to get to a specific organ, and that could cause problems like heart attack or stroke. There is very little knowledge about the way this group of medicines works in people with chronic kidney disease as well as it works in individuals with normal kidney function.
Interventions
DRUGTicagrelor 90mg
Ticagrelor Pill
DRUGClopidogrel 75mg
Clopidogrel Pill and a matching placebo to conceal frequency
DRUGAspirin 81 mg
Aspirin Pill
Sponsors
American Society of Nephrology
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
CKD participants will be randomly assigned into one of the 2 study groups: ticagrelor (90 mg) one pill in the morning and one pill in the evening, or, clopidogrel (75 mg) one pill in the morning + placebo one pill in the evening. Placebo looks like the study drug but has no medicine in it. Neither participant nor the study personnel will know about allocation. The study drugs will look the same, except aspirin pill which will be dispensed to everyone in an open label manner. There is no masking for control with normal kidney function. Participants will be asked to take open label ticagrelor, 90 mg twice daily (one pill in the morning and one pill in the evening) and aspirin 81 mg/day.
Intervention model description
CKD participants will be double-blind randomized in these two arms: Arm 1 - Ticagrelor, 90 mg twice daily (one pill in the morning and one pill in the evening) + Aspirin 81 mg/day. Ticagrelor is the test treatment. Arm 2 - Clopidogrel, 75 mg/day in the morning and a matching placebo in the evening + Aspirin 81 mg/day. Clopidogrel is the reference treatment. Arm 3: Control with normal kidney function will be recruited after matching for age and diabetes status to the Arm 1 participants. Participants will be asked to take Ticagrelor, 90 mg twice daily (one pill in the morning and one pill in the evening) and aspirin 81 mg/day. Open label treatment. All participants are required to take the oral treatment for a total of two weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 91 Years
Healthy volunteers
Yes
Inclusion criteria
1. Males and females, aged 18-91 years 2. Ability to understand and sign informed consent after the nature of the study has been fully explained 3. CKD participants: Non-dialysis CKD patients: Presence of CKD with an estimated GFR of \<30 mL/min/1.73 m2 for a period of ≥3 months, as defined by the National Kidney Foundation (NKF) and determined with the CKD-EPI creatinine-based formula 4. Controls with normal kidney function: participants with an estimated GFR \>90 mL/min/1.73 m2 as determined by the CKD-EPI creatinine-based formula and a urine albumin-to-creatinine ratio \<30 mg/g as defined by the National Kidney Foundation
Exclusion criteria
* No healthcare power of attorney to sign informed consent * Unwillingness or inability to participate in the protocol or comply with any of its components. * Subjects unable or unwilling to stop taking: * Aspirin and other antithrombotic agents, like cilostazol, ranolazine, aggrenox, prasugrel, warfarin, xarelto, pradaxa, eliquis. * Glycoprotein IIb/IIIa antagonist (abciximab-ReoPro, eptifibatide-Integrilin, tirofiban-Aggrastal) * NSAIDs and PPIs * Fish oil, Vitamin E and herbal supplements * Acute kidney injury superimposed on CKD * Kidney transplant or any other solid organ transplant recipient * End-stage kidney disease on maintenance dialysis (peritoneal or hemodialysis) * Nephrotic syndrome defined as nephrotic range proteinuria, hypoalbuminemia, hyperlipidemia and generalized edema * Recent hospitalization or surgery \<3 months * Acute coronary or cerebrovascular event in the last 12 months * Blood dyscrasias, active bleeding, or bleeding diathesis * Gastrointestinal bleeding in the last 6 months * Recent treatment (\<30 days) with a glycoprotein IIb/IIIa antagonist (Integrelin). * Hematocrit \<25%, white blood cell count \>20,000/μL, or platelet count \<50,000/μL * Any active malignancy or liver disease. * Pregnancy * Positive urine pregnancy test in a woman of childbearing potential prior to study entry. A female of childbearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). * Patients must not be nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ADP Induced Platelet Aggregation | 2 weeks | We will use summary statistics to describe the distribution of the data. Post-treatment ADP-induced WBPA value in ohms (Ω) will be the primary outcome variable. We will use an analysis of covariance (ANCOVA) model to compare the treatment effects of ticagrelor vs. clopidogrel in CKD patients because this approach has higher statistical power than other methods to analyze drug effects. T |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Surface P-selectin Expression | 2 weeks | Platelet surface P-selectin expression was measured using flow cytometry before and after treatment. |
Countries
United States
Participant flow
Recruitment details
CKD recruitment. 50 patients signed consent and were randomized. Of those randomized, 1 received kidney transplant and 1 allergic reaction to clopidogrel and did not complete the study visits. 48 patients completed study visits. Non-CKD control recruitment: 26 signed consent and completed study visits.
Pre-assignment details
Goal 48 CKD who complete visits; we ended up consenting and randomizing 50 CKD patients. Enrolled 26 to achieve goal. actual enrollment 50+26 = 76
Participants by arm
| Arm | Count |
|---|---|
| Experimental: CKD-Ticagrelor Ticagrelor 90mg Twice daily (double blind, random assignment) + aspirin 81 mg/d | 25 |
| Active Comparator: CKD-Clopidogrel Clpidogrel 75 mg/day in the morning and a matching placebo in the evening to conceal frequency (double blind, random assignment) aspirin 81 mg/d | 23 |
| Non-CKD Control Arm - Active Comparator: Control-ticagrelor Open label ticagrelor, 90 mg twice daily + aspirin 81 mg/d in subjects without CKD | 26 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Kidney Transplant | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Experimental: CKD-Ticagrelor | Non-CKD Control Arm - Active Comparator: Control-ticagrelor | Active Comparator: CKD-Clopidogrel |
|---|---|---|---|---|
| Age, Continuous | 52.2 years STANDARD_DEVIATION 15.1 | 55.2 years STANDARD_DEVIATION 11.5 | 48.0 years STANDARD_DEVIATION 15.2 | 52.2 years STANDARD_DEVIATION 15.1 |
| Baseline use of aspirin, n (%) | 20 Participants | 10 Participants | 3 Participants | 7 Participants |
| Body mass index | 33.5 kg/m^2 STANDARD_DEVIATION 8.8 | 34.5 kg/m^2 STANDARD_DEVIATION 8.6 | 31.2 kg/m^2 STANDARD_DEVIATION 7 | 32.5 kg/m^2 STANDARD_DEVIATION 9.1 |
| Diabetes mellitus, n (%) | 31 Participants | 17 Participants | 0 Participants | 14 Participants |
| eGFR | 16.5 mL/min/1.73 m^2 STANDARD_DEVIATION 6 | 16.7 mL/min/1.73 m^2 STANDARD_DEVIATION 6.5 | 89.6 mL/min/1.73 m^2 STANDARD_DEVIATION 13.2 | 16.4 mL/min/1.73 m^2 STANDARD_DEVIATION 5.7 |
| Hemoglobin | 13.5 g/dl STANDARD_DEVIATION 1.3 | 11.1 g/dl STANDARD_DEVIATION 1.8 | 13.5 g/dl STANDARD_DEVIATION 1.3 | 11.1 g/dl STANDARD_DEVIATION 1.9 |
| Percent of Hemoglobin A1c | 6.9 percentage of hemoglobin STANDARD_DEVIATION 1.6 | 6.9 percentage of hemoglobin STANDARD_DEVIATION 1.6 | 5.3 percentage of hemoglobin STANDARD_DEVIATION 0.4 | 7.0 percentage of hemoglobin STANDARD_DEVIATION 1.9 |
| Platelet count | 236.7 1000 cells per µL STANDARD_DEVIATION 61.5 | 243.07 1000 cells per µL STANDARD_DEVIATION 71.1 | 266.5 1000 cells per µL STANDARD_DEVIATION 57.9 | 229.9 1000 cells per µL STANDARD_DEVIATION 49.7 |
| Race/Ethnicity, Customized African American | 29 participants | 13 participants | 3 participants | 13 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 41 participants | 11 participants | 21 participants | 9 participants |
| Race/Ethnicity, Customized Hispanics | 3 participants | 1 participants | 2 participants | 0 participants |
| Serum creatinine | 4.2 mg/dl STANDARD_DEVIATION 1.9 | 4.2 mg/dl STANDARD_DEVIATION 1.9 | 0.9 mg/dl STANDARD_DEVIATION 0.1 | 4.3 mg/dl STANDARD_DEVIATION 1.8 |
| Sex: Female, Male Female | 42 Participants | 13 Participants | 16 Participants | 13 Participants |
| Sex: Female, Male Male | 32 Participants | 12 Participants | 10 Participants | 10 Participants |
| Statin use, n (%) | 33 Participants | 15 Participants | 4 Participants | 14 Participants |
| Urine albumin-to-creatinine ratio | 1,229.4 mg/g of creatinine | 1,039.0 mg/g of creatinine | 0 mg/g of creatinine | 2,400.0 mg/g of creatinine |
| White blood cell count | 7.6 1000 cells per µL STANDARD_DEVIATION 2.4 | 7.7 1000 cells per µL STANDARD_DEVIATION 2.4 | 6.2 1000 cells per µL STANDARD_DEVIATION 1.6 | 7.5 1000 cells per µL STANDARD_DEVIATION 2.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 23 | 0 / 26 |
| other Total, other adverse events | 14 / 25 | 11 / 23 | 13 / 26 |
| serious Total, serious adverse events | 1 / 25 | 0 / 23 | 0 / 26 |
Outcome results
Primary
ADP Induced Platelet Aggregation
We will use summary statistics to describe the distribution of the data. Post-treatment ADP-induced WBPA value in ohms (Ω) will be the primary outcome variable. We will use an analysis of covariance (ANCOVA) model to compare the treatment effects of ticagrelor vs. clopidogrel in CKD patients because this approach has higher statistical power than other methods to analyze drug effects. T
Time frame: 2 weeks
Population: CKD groups were analyzed between randomized arms using ANCOVA. CK-ticagrelor arm was compared to control ticagrelor arm using Wilcoxon rank sum test.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CKD-Ticagrelor | ADP Induced Platelet Aggregation | 0 ohms |
| CKD-Clopidogrel | ADP Induced Platelet Aggregation | 6 ohms |
| Control-ticagrelor | ADP Induced Platelet Aggregation | 1 ohms |
Comparison: mean changes in values were compared by Wilcoxon rank sum test adjusted for multiple comparisons (Bonferonni method) between CKD-ticagrelor arm, and the non-CKD controlsp-value: 0.18Wilcoxon (Mann-Whitney)
p-value: 0.002ANCOVA
Secondary
Platelet Surface P-selectin Expression
Platelet surface P-selectin expression was measured using flow cytometry before and after treatment.
Time frame: 2 weeks
Population: CKD groups were analyzed between randomized arms using ANCOVA. CK-ticagrelor arm was compared to control ticagrelor arm using Wilcoxon rank sum test.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CKD-Ticagrelor | Platelet Surface P-selectin Expression | 1002.5 Fluorescence intensity |
| CKD-Clopidogrel | Platelet Surface P-selectin Expression | 1037.5 Fluorescence intensity |
| Control-ticagrelor | Platelet Surface P-selectin Expression | 1052 Fluorescence intensity |
Comparison: CKD groups randomized were compared for post treatment values.p-value: 0.22ANCOVA