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      Rationale and design of the HepZero study: a prospective, multicenter, international, open, randomized, controlled clinical study with parallel groups comparing heparin-free dialysis with heparin-coated dialysis membrane (Evodial) versus standard care: study protocol for a randomized controlled trial

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          Abstract

          Background

          Anticoagulation for chronic dialysis patients with contraindications to heparin administration is challenging. Current guidelines state that in patients with increased bleeding risks, strategies that can induce systemic anticoagulation should be avoided. Heparin-free dialysis using intermittent saline flushes is widely adopted as the method of choice for patients at risk of bleeding, although on-line blood predilution may also be used. A new dialyzer, Evodial (Gambro, Lund, Sweden), is grafted with unfractionated heparin during the manufacturing process and may allow safe and efficient heparin-free hemodialysis sessions. In the present trial, Evodial was compared to standard care with either saline flushes or blood predilution.

          Methods

          The HepZero study is the first international (seven countries), multicenter (10 centers), randomized, controlled, open-label, non-inferiority (and if applicable subsequently, superiority) trial with two parallel groups, comprising 252 end-stage renal disease patients treated by maintenance hemodialysis for at least 3 months and requiring heparin-free dialysis treatments. Patients will be treated during a maximum of three heparin-free dialysis treatments with either saline flushes or blood predilution (control group), or Evodial. The first heparin-free dialysis treatment will be considered successful when there is: no complete occlusion of air traps or dialyzer rendering dialysis impossible; no additional saline flushes to prevent clotting; no change of dialyzer or blood lines because of clotting; and no premature termination (early rinse-back) because of clotting.

          The primary objectives of the study are to determine the effectiveness of the Evodial dialyzer, compared with standard care in terms of successful treatments during the first heparin-free dialysis. If the non-inferiority of Evodial is demonstrated then the superiority of Evodial over standard care will be tested. The HepZero study results may have major clinical implications for patient care.

          Trial registration

          ClinicalTrials.gov NCT01318486

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          Most cited references28

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          Citrate pharmacokinetics and calcium levels during high-flux dialysis with regional citrate anticoagulation

          Background. Regional citrate anticoagulation is a very effective anticoagulation method for haemodialysis. However, it is not widely used, primarily due to the risk of hypocalcaemia. We studied citrate and calcium kinetics to better understand safety aspects of this anticoagulation method. Methods. During 15 haemodialysis treatments with a calcium-free dialysis solution, citrate was infused pre-dialyser and calcium was substituted post-dialyser. Systemic and extracorporeal citrate and calcium concentrations were repeatedly measured to calculate citrate and calcium pharmacokinetics. Results. Removal by dialysis constituted the major elimination pathway of citrate (83 ± 5%). Systemic citrate load and concentrations were low (17 ± 7 mmol/4 h, 0.3 ± 0.15 mmol/l). Combined use of calcium-free dialysate and citrate infusion increased diffusible calcium to 80% of total calcium and induced substantial dialytic loss of calcium (43 ± 4 mmol/4 h). Since calcium was substituted, systemic calcium balances were positive (∼+5 mmol) and concentrations stable. Calcium supplementation correlated with calcium dialytic losses, which in turn were dependent on total calcium and haematocrit. Conclusions. When using calcium-free dialysate during citrate anticoagulation, hypocalcaemia is very likely unless calcium is re-infused, because large amounts of calcium are lost in the dialysate. However, an accumulation of citrate in the patient's systemic circulation is an unlikely cause of hypocalcaemia since most of the citrate is removed by dialysis. Calcium substitution and monitoring are the most important safety measures. We propose a rational approach based on haematocrit and total calcium for the choice of the starting calcium supplementation rate.
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            Heparin-coated polyacrylonitrile membrane versus regional citrate anticoagulation: a prospective randomized study of 2 anticoagulation strategies in patients at risk of bleeding.

            Hemodialysis requires anticoagulation to prevent clotting of the extracorporeal circuit. Systemic anticoagulation with heparin is contraindicated in patients at high risk of bleeding. In these patients, regional citrate anticoagulation (RCA), with either calcium-free (RCA-Ca0) or calcium-containing dialysate (RCA-Ca3.0), and heparin-coated membranes (1.3 m(2); AN69ST; Nephral 300ST, Gambro-Hospal, Meyzieu, France) may represent valid alternatives. To compare the efficacy and safety of these regional anticoagulation modalities, we performed a prospective randomized trial including 33 hemodialysis patients at high risk of bleeding. Regional anticoagulation was achieved by means of either AN69ST (11 patients, 31 sessions), RCA-Ca0 (11 patients, 32 sessions), or RCA-Ca3.0 (11 patients, 30 sessions). Patients assigned to RCA were dialyzed using a polysulfone membrane (1.3 m(2); F60; Fresenius Medical Care, Bad Homburg, Germany). Scheduled dialysis time was 4 hours. At the end of each dialysis session, the dialyzer was inspected for visible signs of thrombus formation and scored semiquantitatively (0, no clotting, to 4, severe clotting). Solute clearances were monitored at the second and fourth treatment hour as a parameter of subclinical clotting of the dialyzer. Clotting phenomena necessitating premature termination of the dialysis session were encountered in 39%, 13%, and 0% using AN69ST, RCA-Ca3.0, and RCA-Ca0, respectively (P < 0.005). All clotting with AN69ST occurred after the second treatment hour. Mean dialyzer clotting scores were 2.7, 1.5, and 1.1, respectively (P < 0.0001). Significantly greater instantaneous urea nitrogen clearances were achieved at 2 hours during RCA compared with AN69ST. Except for clotting phenomena, no adverse events were observed. Citrate provides superior regional anticoagulation compared with AN69ST membranes.
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              Section V. Chronic intermittent haemodialysis and prevention of clotting in the extracorporal system.

              (2001)
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                Author and article information

                Journal
                Trials
                Trials
                Trials
                BioMed Central
                1745-6215
                2013
                1 June 2013
                : 14
                : 163
                Affiliations
                [1 ]INSERM, Centre d’Investigations Cliniques 9501, Institut lorrain du Cœur et des Vaisseaux Louis Mathieu, 4 Rue du Morvan, 54500 Vandoeuvre lès Nancy, France
                [2 ]Université de Lorraine, Lorraine 54500 Vandoeuvre lès Nancy, France
                [3 ]CHU de Nancy, Nancy 54500 Vandoeuvre lès Nancy, France
                [4 ]INSERM U1116, 54500 Vandoeuvre lès Nancy, France
                [5 ]Association Lorraine pour le Traitement de l’Insuffisance Rénale, 54500 Vandoeuvre lès Nancy, France
                [6 ]Centre hospitalier universitaire Dr-Georges-L-Dumont, Moncton NB E1C 2Z3 Canada
                [7 ]Nephrology Department, Dialysis unit, University Hospiital Vall d'Hebron, Paseo Vall d’Hebron 119-129, 08035 Barcelona, Spain
                [8 ]Autonomous University of Barcelona, Barcelona, Spain
                [9 ]Gambro-Hospal, 69881 Meyzieu, France
                [10 ]Service de Néphrologie, Centre Hospitalier Lyon-Sud, 69495 Pierre-Bénite, France
                [11 ]Université Lyon 1, 69100 Villeurbanne, France
                [12 ]Inserm U1060-Institut CarMeN, 8 Avenue Rockefeller, 69373 Lyon, France
                [13 ]Association pour l’Utilisation du Rein artificiel à Lyon (AURAL), 124 Rue Villon, 69008 Lyon, France
                Article
                1745-6215-14-163
                10.1186/1745-6215-14-163
                3681640
                23725299
                d239bfbe-0c41-43bb-a6c7-4ae0c217b6c0
                Copyright ©2013 Rossignol et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 January 2013
                : 1 May 2013
                Categories
                Study Protocol

                Medicine
                hemodialysis,heparin-free,evodial,randomized controlled trial
                Medicine
                hemodialysis, heparin-free, evodial, randomized controlled trial

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