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

Abstract

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

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

“…Two types of methods were evaluated in parallel: the study group comprised NH-HD treatment with HGM, and the control group comprised NH-HD treatment according to the standard of care defined by the usual procedure in place at each study site (i.e., saline flushes or predilution). The full study protocol was published recently, 17 the methods are detailed in the corresponding section, and extended methods are provided in a Supplementary Appendix online.…”

“…The full study protocol was published recently, 17 and extended methods are provided in a Supplementary Appendix online. Briefly, this clinical study was a prospective, multicenter (ten centers), international (seven countries), open-label, controlled, randomized, clinical study.…”

“…Precalculation according to previously reported data on heparin-free dialysis showed that a sample size of 126 patients per arm (252 for the entire sample) will provide the trial with 80% power to first conclude to noninferiority and then to superiority, with a one-tailed 5% error rate. 17 Indeed, the power of the study to demonstrate superiority with the observed þ 7.9% difference between success rates in the control and HGM groups was about 35%.…”

“…Because that value was greater than the prespecified -15% noninferiority threshold, the noninferiority hypothesis was demonstrated at the 5% error level. Because that value was lower than the prespecified þ 15% superiority threshold, the prespecified criteria for superiority were not reached ( Figure 2 17.1% and a lower bound of the 90% CI of 6.4%; P ¼ 0.012). The events that led to the recording of a primary outcome are described in Table 3.…”

Heparin‐free renal replacement therapy for chronic hemodialyzed patients at high risk for bleeding: a comparison of on‐line predilution hemodiafiltration with conventional hemodialysis

“…Heparin‐free hemodialysis (HD) is a safe and efficient strategy that was used for more than 25 years in patients with high bleeding risk . Several dialysis procedures have been evaluated but they are non‐standardized and none of them have shown full efficacy in controlled studies . As a consequence, a coated‐heparin membrane has been developed but showed equivocal results .…”