Chronic Kidney Disease (CKD) Platelet Study

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.

• Ticagrelor 90mg (Drug), also known as Brilinta: Ticagrelor Pill
• Clopidogrel 75mg (Drug), also known as Plavix: Clopidogrel Pill and a matching placebo to conceal frequency
• Aspirin 81 mg (Drug), also known as baby aspirin: Aspirin Pill

Primary outcomes

• 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 outcomes

• Platelet Surface P-selectin Expression [2 weeks]: Platelet surface P-selectin expression was measured using flow cytometry before and after treatment.

Sex: All, ages: 18 Years to 91 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• ADP Induced Platelet Aggregation (Primary), Median, ohms: CKD-Ticagrelor 0 (0 to 2); CKD-Clopidogrel 6 (1 to 10.5); Control-ticagrelor 1 (0 to 3) (p 0.002)
• Platelet Surface P-selectin Expression (Secondary), Median, Fluorescence intensity: CKD-Ticagrelor 1002.5 (758.5 to 1149.5); CKD-Clopidogrel 1037.5 (848.5 to 1262.75); Control-ticagrelor 1052 (810 to 1279) (p 0.22)

Adverse events

Time frame: Adverse events reported during the 2 weeks of treatment from baseline visit to the final visit

Serious adverse events by term

Other adverse events by term

• Results publication: Jain N, Corken A, Arthur JM, Ware J, Arulprakash N, Dai J, Phadnis MA, Davis O, Rahmatallah Y, Mehta JL, Hedayati SS, Smyth S. Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease. Vascul Pharmacol. 2023 Feb;148:107143. doi: 10.1016/j.vph.2023.107143. Epub 2023 Jan 20. PMID 36682595
• Results publication: Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4. PMID 35224730

• Study Protocol and Statistical Analysis Plan (PDF, 2021-02-22)
• Informed Consent Form (PDF, 2020-07-23)

• Jain Nishank, MD, Principal investigator, University of Arkansas for Medical