Results of the HepZero study comparing heparin-grafted membrane and standard care show that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis Gambro-Hospal, Meyzieu, FranceHeparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standardof-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standardof-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.

Appropriate anticoagulation for hemodialysis (HD) requires a subtle balance between under-and over-heparinization to prevent extracorporeal circuit (ECC) clotting and bleeding, respectively. We discuss five key issues relating to anticoagulation therapy for chronic HD in adults following a review of relevant literature published since 2002: (i) options for standardization of anticoagulation in HD settings. The major nephrology societies have issued low evidence level recommendations on this subject. Interventional studies have generally investigated novel lowmolecular weight heparins and provided data on safety of dosing regimens that cannot readily be extrapolated to clinical practice; (ii) identification of clinical and biological parameters to aid individualization of anticoagulation treatment. We find that use of clinical and biological monitoring of anticoagulation during HD sessions is currently not clearly defined in routine clinical practice; (iii) role of ECC elements (dialysis membrane and blood lines), dialysis modalities, and blood flow in clotting development; (iv) options to reduce or suppress systemic heparinization during HD sessions. Alternative strategies have been investigated, especially when the routine mode of anticoagulation was not suitable in patients at high risk of bleeding or was contraindicated; (v) optimization of anticoagulation therapy for the individual patient. We conclude by proposing a standardized approach to deliver anticoagulation treatment for HD based on an individualized prescription prepared according to the patient's profile and needs.Maintaining full patency in the extracorporeal circuit (ECC) during hemodialysis (HD) sessions is a prerequisite for optimal HD quality (1-4). A complex disturbance of the coagulation system is commonly encountered in patients at the terminal stage of chronic kidney disease (CKD), leading to considerable morbidity and mortality (5). Although HD reduces the bleeding risk by the removal of uremic toxins, interaction between blood and artificial surfaces contributes to activate coagulation pathways. This nonphysiological environment leads to clotting on these foreign surfaces which reduces HD efficiency, shortens circuit lifetime, and increases patient blood loss, nursing workload, disposable consumption, and thus the cost of treatment (3,4).Appropriate anticoagulation requires a subtle balance between under-and over-heparinization to prevent ECC clotting and bleeding, respectively. HD patients are prone to prolonged bleeding episodes from dialysis fistula, as well as gastrointestinal and intracranial hemorrhage (5). Conversely, they may develop a prothrombotic status or comorbid conditions requiring oral anticoagulants or antiplatelet agents (1,5). Of interest, the dialysis population represents the only group of patients to receive heparin three times per week, with a potential longterm cumulative effect associated with an increased risk of osteoporosis, aldosterone suppression and hyperkalemia, and a deterioration of lipid profile...

This prospective, multicenter, proof-of-concept study aimed to evaluate the possibility to reduce the ordinary heparin dose and the systemic anti-Xa activity during hemodialysis (HD) sessions using a new heparin-grafted HD membrane. In 45 stable HD patients, the use of a heparin-grafted membrane with the ordinary heparin dose was followed by a stepwise weekly reduction of dose. Reduction was stopped when early signs of clotting (venous pressure, quality of rinse-back) occurred during two out of three weekly HD sessions. Heparin dose was decreased for 67% of patients resulting in the lowering of these patients' anti-Xa activity by 50%. Dose reductions were achieved with both types of heparin (low-molecular-weight heparin: 64 ± 14 to 35 ± 12 IU/kg, P < 0.0001; unfractionated heparin: 82 ± 18 to 46 ± 13 IU/kg, P < 0.0001) resulting in a decrease of anti-Xa activity at dialysis session end (low-molecular-weight heparin: 0.51 ± 0.25 to 0.25 ± 0.11 IU/mL, P < 0.0001; unfractionated heparin: 0.28 ± 0.23 to 0.13 ± 0.07 IU/mL, P < 0.0001). Failure to further decrease heparin dose was related to signs of clotting in blood lines (57% of sessions), in dialyzer (9%), or both (34%). Significant reduction of heparin dose and anti-Xa activity at the end of HD sessions was possible in stable HD patients using heparin-grafted membrane. HD patients who require low anti-Xa activity at the end of HD sessions might benefit from a heparin-grafted membrane to reduce bleeding risk and other heparin adverse events.

BackgroundAnticoagulation 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.MethodsThe 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 registrationClinicalTrials.gov NCT01318486

Introduction and Aims: The Frequent Hemodialysis Network Nocturnal trial randomized 87 subjects to 6 times per week home nocturnal hemodialysis (FNHD) or to 3 times per week hemodialysis (3HD) for 1 year. Subjects were subsequently free to modify their treatment schedule. We describe effects of randomized treatment assignment on mortality over a median follow-up of 3.7 years. Methods: We obtained dates of death and kidney transplantation through July 2011 using linkage to USRDS and queries of study centers. We used log-rank tests and Cox regression to relate mortality to the initial randomization assignment. Results: For randomized subjects (FNHD vs. 3HD), 62% vs. 0%, 51% vs. 27%, and 52% vs. 33% received frequent long hemodialysis (≥27 hours of dialysis over ≥4.5 treatments per week) during the trial, the first year after the trial, and subsequently. There were 14 deaths in the FNHD arm and 5 deaths in the 3HD arm overall; during the first year after the trial there were 9 deaths in the FNHD arm and 1 death in the 3HD arm. The overall mortality hazard ratio for randomization to FNHD vs. 3HD was 3.88, (95% CI: 1.27 to 11.79), p = 0.01. The 19 deaths in the two treatment groups included 9 deaths related to cardiac causes, 2 to infection, and 1 to the dialysis procedure itself (unrecognized central venous catheter disconnection at night in a subject randomized to FNHD). Three deaths, all in the conventional group, were due to cancer. The finding of higher mortality for patients randomized to FNHD compared to 3HD was observed consistently for all-cause mortality over the entire follow-up (14 vs. 5 deaths), all-cause mortality censoring transplants (14 deaths vs. 4 deaths), cardiac or infectious deaths (9 vs. 2 deaths), and deaths of all causes excluding cancer (14 vs. 2 deaths).Pre-specified subgroups were tested for interaction with mortality, including age, sex, race, Canadian vs. U.S. center, experienced vs. inexperienced center, ESRD vintage, or baseline left ventricular mass; none approached statistical significance. The trend toward higher mortality in the FNHD group was particularly marked among patients with ≤ 500 ml/day of urine volume at baseline. Vascular access events did not appear to predict mortality: in the FNHD group, 12 post-trial deaths in 43 subjects were evenly distributed among those with and those without vascular access events during the randomized trial phase.The results of as-treated analyses relating mortality to a patient's exposure to frequent long hemodialysis (≥27 hours/week and ≥4.5 treatments/week) over the previous 12 months was 3.06 (95% CI 1.11 to 8.43, p = 0.03) and over the previous 6 months was 1.12 (95% CI: 0.44 to 3.22, p = 0.74). The attenuation of the as-treated hazard ratio reflected the reclassification of 3 deaths from the frequent long category using the 12 month running average to the non-frequent long category using the six month moving average. Conclusions: Our observation of higher mortality among subjects randomized to FNHD compared to 3HD raises concerns regard...

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