Strategies for Asymmetrical Triacetate Dialyzer Heparin-Free Effective Hemodialysis (SAFE)

Strategies for Asymmetrical Triacetate Dialyzer

Not all dialysis patients tolerate heparin anticoagulation. Heparin should be avoided in patients at high risk of bleeding. Strategies include saline infusion, citrate-containing dialysate, regional citrate anticoagulation and heparin-coated membranes. We recently studied the combination of a heparin-coated membrane and citrate-containing dialysate, with a success rate of 94% . Although this combination resulted in low rates of clotting, heparin-coated membranes are not ubiquitously available. The quest for easy to perform, safe and affordable heparin-free dialysis is on. Asymmetric cellulose triacetate (ATA) dialyzers have a low degree of platelet contact activation and might be an alternative to heparin-coated dialyzers.

This is a phase II pilot study in maintenance dialysis patients. Study design is a two-arm open-label cross-over study. In Arm 1, patients were dialyzed using a 1.9 m2 ATA membrane (Solacea™-19H, Nipro Corp., Japan) in combination with citrate (1 mM) containing dialysate. In Arm 2, patients were dialyzed with the same 1.9 m2 ATA membrane, in combination with high volume predilution hemodiafiltration. The primary endpoint was the success rate to complete 4 hours of hemodialysis without preterm clotting.

Study Overview

• Status: Completed
• Conditions: Hemodialysis Complication
• Intervention / Treatment: Device: dialyzer; Combination product: hemodialysis with citrate-containing dialysate; Other: predilution hemodiafiltration

Detailed Description

Anticoagulation is one of the supporting pillars of chronic hemodialysis (HD). The optimal anticoagulant regimen provides full anticoagulation of the extracorporeal circuit with minimal systemic effects and comes at an affordable cost. Unfractionated heparin (UFH) has been the standard of care for many years. In several countries, UFH has gradually been replaced by low molecular weight heparins (LMWH). LMWH are easy to use as they can be administered as a bolus injection and reduce membrane fibrin and platelet deposition. Both UFH and LMWH provide adequate anticoagulation of the extracorporeal circuit, at the price of systemic anticoagulation. Apart from bleeding, the administration of unfractionated heparins has also been associated with dyslipidemia, hypoaldosteronism and hyperkalemia, thrombopenia, osteoporosis, pruritus, and hypersensitivity reactions.

Several alternative anticoagulation regimens have been proposed including saline infusion, heparin coating of the dialyzer membrane as well as regional citrate anticoagulation. Regional citrate anticoagulation is performed by infusing citrate into the arterial line of the dialysis tubing to reduce ionized calcium concentrations in order to minimize propagation of the coagulation cascade. Ionized calcium concentrations are restored by calcium supplementation prior to reinfusion of the blood into the patient. The HepZero study suggested that regional citrate anticoagulation is superior to heparin-coated polyacrylonitrile dialyzers (AN69ST; Nephral 300ST, Gambro) and resulted in in significantly greater instantaneous urea nitrogen clearance. While generally safe and adequate, regional citrate anticoagulation requires additional actions during preparatory phase (preparation of citrate and calcium infusion pumps) as well as during the treatment (measurement of ionized calcium).

Recently, acetate-free citrate-containing dialysate concentrates were introduced into clinical practice. Besides the advantages of acetate-free dialysate, this provides a modest local anticoagulant effect inside the dialyzer. Citrate-containing dialysate allowed to reduce heparin dose while maintaining extracorporeal circuit patency and dialyzer clearance. Recently, citrate-containing dialysate and a heparin-coated dialyzer were combined. In one study, non-inferiority to regional citrate anticoagulation was demonstrated

The abovementioned studies demonstrate that hemodialysis without systemic heparinization is feasible. However, such procedures are more cumbersome, require more manpower, additional biochemical testing and/ or more expensive consumables. The aim of the current study is to test two different strategies for systemic heparin-free dialysis with an asymmetrical tri-acetate hemodialyzer.

Trial objectives To evaluate the feasability, safety and adequacy of systemic heparin-free dialysis using an asymmetrical tri-acetate dialyzer membrane, with or without the combination with citrate containing dialysate.

The main objective of the study is to test efficacy of the two study interventions to perform standard duration (i.e. 4 hours) hemodialysis without interruption due to clotting phenomena and without the use of heparin or low molecular weight heparins.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • University Hospitals Leuven

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients age 18 years, or over. No maximum age is defined.
• Providing signed and dated informed consent (ICF)
• Maintenance dialysis (> 3 months of hemodialysis)
• 'Standard' dialysis regimen (three dialysis sessions / week, dialysis duration 4 hours)
• Hemodynamic stability during 4 weeks preceding study period. Hemodynamic instability is defined as any episode of low blood pressure (asymptomatic or symptomatic requiring intervention (bolus fluid infusion, temporarily withholding or reducing ultrafiltration, preterm termination of dialysis session, resuscitation)
• Hemoglobin 9 - 12 g/dl.

Exclusion Criteria:

• Any known medical disorder favoring either bleeding or clotting (e.g. atypical hemolytic uremic syndrome (aHUS), antiphospholipid syndrome, idiopathic thrombocytopenic purpura (ITP), paroxysmal nocturnal hemoglobinuria (PNH))
• Treatment with a vitamin K antagonist
• Treatment with any one of the NOACs (apixaban, rivaroxaban, edoxaban, dabigatran)
• High risk of bleeding according to the criteria of Swartz (12).
• Patients with a known allergic reaction to asymmetric triacetate
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ATA plus citrate; 1.9 m2 ATA membrane (Solacea™-19H, Nipro Corp., Japan) in combination with citrate (1 mM) containing dialysate	Device: dialyzer; Asymmetric triacetate dialyzer; Other Names: Solacea™-19H (Nipro Corp., Japan); Combination product: hemodialysis with citrate-containing dialysate; acetate-free dialysate; Other Names: Selectbag citrate (1mM citrate, Baxter)
Active Comparator: ATA plus predilution hemodiafiltration; 1.9 m2 ATA membrane (Solacea™-19H, Nipro Corp., Japan), in combination with high volume predilution hemodiafiltration	Device: dialyzer; Asymmetric triacetate dialyzer; Other Names: Solacea™-19H (Nipro Corp., Japan); Other: predilution hemodiafiltration; predilution hemodiafiltration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical patency of the hemodialysis extracorporeal circuit	clotting of the extracorporeal circuit	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clotting of dialyser	Semi-quantitative clotting score	4 hours
dialysis adequacy	single pool Kt/V	4hours
Reduction ratio uremic retention solutes	ratio describing the change in serum concentration over the concentration at the beginning of the dialysis session	4 hours

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: NIPRO
• Investigators: Principal Investigator: bjorn D Meijers, MD, PhD, UZ Leuven

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2018
• Primary Completion (Actual): March 10, 2019
• Study Completion (Actual): May 5, 2020

Study Registration Dates

• First Submitted: May 5, 2020
• First Submitted That Met QC Criteria: May 5, 2020
• First Posted (Actual): May 8, 2020

Study Record Updates

• Last Update Posted (Actual): May 21, 2020
• Last Update Submitted That Met QC Criteria: May 19, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: hemodialysis; anticoagulation; citrate; hemodiafiltration; clotting
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anticoagulants; Pharmaceutical Solutions; Chelating Agents; Sequestering Agents; Calcium Chelating Agents; Dialysis Solutions; Citric Acid; Sodium Citrate
• Other Study ID Numbers: S61285

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