The Effect of Salicylate on Platelet Function in CKD (Chronic Kidney Disease) Patients Treated With Aranesp (EPOASA)

The Effect of Low-dose Salicylate Treatment on Platelet Function in Patients With Renal Failure Treated With Darbepoetin Alfa

The aim of the study is to

1. To determine whether treatment with Erythropoiesis-stimulating agents (in the form of Aranesp®) affects platelet function, and how.
2. To determine whether salicylate treatment changes the effect of EPO (erythropoietin) on platelet function.

Study Overview

• Status: Recruiting
• Conditions: Erythropoietin Adverse Reaction
• Intervention / Treatment: Drug: Acetylsalicylic acid

Detailed Description

Background:

It is well known that treatment with EPO increases the risk of thrombotic complications in patients with chronic kidney disease, including cerebral thrombosis. The requited level of Hgb for sufficient treatment has therefore been set at a relatively low level (6.8-7.3 mM). One obvious potential cause of this problem is the increased thrombocytosis and platelet activation caused by EPO treatment. An old investigation has shown that low-dose acetyl salicylic acid (ASA) treatment can remove this effect. This investigation has not been performed using modern methods to investigate platelet function, and the possible prophylaxis of EPO-induced thrombosis has since received little interest.

Investigators of current study therefore propose to repeat this investigation using advanced methods for assessing thrombocyte function, as a preliminary, exploratory investigation prior to a later randomized controlled study.

Pre-treatment Washout (4 weeks, 6 weeks if treated with Mircera))

Patients who are not treated with ESA do not receive any treatment. Patients treated with ESA stop their treatment for 4 weeks. Patients treated with Mircera ® stop treatment for 6 weeks.

Patients must not take ASA as an analgesic during the whole period of the project.

At the end of the pre-treatment period, the Standard package (blood samples) is assessed.

EPO Treatment (4 weeks) The patient is treated with darbepoetin alfa (Aranesp) in equipotent doses compared to previous therapy.

After 2 weeks the Hgb is measured, and the EPO dosis adjusted if necessary at the discretion of the responsible physician.

After 4 weeks, the Standard package is assessed. If the Hgb is >8,0 mM or is rising rapidly (>1,2mM per month), the EPO dose is reduced at the discretion of the responsible physician.

EPO + ASA Treatment Aranesp treatment is supplemented with ASA (Hjertemagnyl ® 75 mg x 1 daily). After 4 weeks the Standard package is assessed.

If the patient develops gastrointestinal symptoms (abdominal pain, nausea or heartburn), and is not already being treated with pantoprazole or other PPI (proton pump inhibitors), treatment is supplemented with pantoprazole 40 mg x 1 daily.

ASA treatment withdrawal - e.g. in regard to surgery - results in discontinuation of participation in the study.

Post-treatment Washout Both Aranesp and Hjertemagnyl treatment is stopped. After 4 weeks the Standard package and is assessed.

Termination The indication for, and dose of ESA and ASA is prescribed at the discretion of the responsible physician.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mette KOefoed, md; Phone Number: 0045 93576330; Email: mkof@regionsjaelland.dk
• Study Contact Backup: Name: Rikke Borg, md, phd; Email: rbor@regionsjaelland.dk

Study Locations

• Denmark
  • Roskilde, Denmark, 4000
    • Recruiting
    • Medicinsk afdeling, SUH Roskilde
    • Contact: Rikke Borg, phd; Email: rbor@regionsjaelland.dk
    • Contact: Mette Koefoed; Email: mkof@regionsjaelland.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Chronic hemodialysis, peritoneal dialysis or CKD 5 treated conservatively
• aged 18-85
• indication for treatment with Erythropoiesis-stimulating agents (ESA)

Exclusion Criteria:

1. Known allergy to ASA
2. Known contraindication to ASA, e.g. recent bleeding episode.
3. Known indication for ASA. If the patient is being treated with ASA, and the physician does not find any indication for this treatment, this can be stopped, and the patient included after 4 weeks.
4. Raised reticulocyte count
5. Current anticoagulant therapy, e.g. warfarin, ADP receptor inhibitor (excepting short-term anticoagulant therapy in connection with dialysis)
6. Short expected length of life
7. Inability to give informed consent
8. Expected non-compliance
9. Active cancer - except for non-melanoma skin-cancer
10. Iron deficiency (defined as a reticulocyte Hgb <1,8 fmol. Patients can be included when their iron deficiency has been cured. .
11. Change in ESA dosis >33,3% within previous 2 month
12. Fertile women. Pregnancy is excessively rare in dialysis patients. Women who are <50 years, or who are still menstruating will be excluded from the study.
13. Stable Aranesp ® dose <20 µg/week.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dialysis patients; Patients will tablet acetylsalicylic acid 75mg x 1 for 4 weeks.	Drug: Acetylsalicylic acid; Se arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thrombocytaggregometry	Multiplate induced with arachidonic acid, ADP (adenosine diphosphate) and TRAP (Thrombin receptor-activating peptid)	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
D-dimer	D-dimer, (FEU mg/L)	16 weeks
MPV	Mean platelet volume, (fL=femtoliters)	16 weeks
Total platelet count	Total platelet count (units per milliliters)	16 weeks
PDW	platelet distribution width (fL = femtoliters)	16 weeks
IPC	immature platelet count (platelets/microliter)	16 weeks
IPF	Immature platelet fraction (%)	16 weeks
H-IPF	Highly immature platelet fraction (%)	16 weeks
ROTEM	Thromboelastometry	16 weeks
TGF-beta	Transforming growth factor beta	16 weeks
sP-selectin	Soluble platelet selectin	16 weeks
Thrombomodulin	Thrombomodulin	16 weeks

Collaborators and Investigators

• Sponsor: Zealand University Hospital
• Investigators: Study Director: James G Heaf, Department of medicine, Zealand University Hospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2020
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 20, 2020
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (Actual): April 1, 2020

Study Record Updates

• Last Update Posted (Actual): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: platelet function; erythropoietin; hemodialysis; anaemia; thrombosis
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: REG-018-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No