Effect of Increased Convective Clearance by On-Line Hemodiafiltration on All Cause Mortality in Chronic Hemodialysis Patients

Cardiovascular Disease Clinical Trial

— CONTRAST  

Official title:

Effect of Increased Convective Clearance by On-line Hemodiafiltration on All Cause and Cardiovascular Mortality in Chronic Hemodialysis Patients: The Dutch Convective Transport Study (CONTRAST)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00205556
• Other study ID #: METC VUmc 03/097
• Secondary ID: ISRCTN38365125CC
• Status: Completed
• Phase: N/A
• First received: September 12, 2005
• Last updated: January 20, 2011
• Start date: June 2004
• Est. completion date: January 2011

Study information

• Verified date: January 2011
• Source: VU University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the effect of low flux hemodialysis with online hemodiafiltration on all cause mortality and a combination of cardiovascular morbidity and mortality in chronic hemodialysis patients.

Description:

Today, an increasing number of patients with chronic renal failure (CRF) is treated with (on-line) hemodiafiltration (HDF). This practice is based on the assumption that the high incidence of cardiovascular (CV) disease, as observed in patients with CRF, is at least partially related to the retention of uremic toxins in the middle and large-middle molecular (MM) range. As HDF lowers these molecules more effectively than HD, it has been suggested that this treatment improves CV outcome, if compared to standard HD.

Thus far, no definite data on the effects of HDF on CV parameters and/or clinical end-points are available. Promising data include a reduction of left ventricular mass index (LVMi) after one year of treatment with acetate free bio-filtration (AFB). Furthermore, relatively high survival rates were reported in a single center non-experimental study on patients who were treated with HDF, if compared to the EDTA registry data on HD-treated patients. Yet, these data are of observational nature, with the possibility of being biased by confounding by indication.

As the accumulation of MMW substances has been implicated in increased oxidative stress and endothelial dysfunction, a reduction of these compounds might improve these derangements. In addition, cardiac dysfunction, atherosclerosis (as measured by left ventricular mass index [LVMi], carotid intima media thickness [CIMT]) and vascular stiffness (as measured by pulse wave velocity [PWV]) might be reduced during HDF, as compared to low-flux HD.

Therefore, we propose a prospective, randomized multicenter trial, comparing (on-line) HDF with HD. After a stabilization period, an expected number of 700 chronic HD patients will be randomized to either HDF or low-flux HD and followed during 1-6 years. Primary end points are all cause mortality and combined CV events and mortality. In addition, LVMi, PWV, CIMT and various parameters of oxidative stress, acute phase reaction (APR) and endothelial function will be assessed and compared between treatment groups.

This study will provide strong evidence on the efficacy of HDF compared to low flux HD on CV morbidity and mortality, which is currently lacking but urgently needed. It is highly likely that the outcome of this study will affect current clinical practice considerably, in the Netherlands as well as internationally. Moreover, the study will point towards the mechanisms underlying the effects of HDF.

The following hypotheses will be tested:

1. All-cause mortality and combined CV morbidity and mortality in patients treated with (on-line) HDF is lower than in patients treated with standard low-flux HD.

2. A reduction in MMW uremic toxins by HDF leads to an improvement of the 'uremic profile' (as measured by AGE-levels, homocysteine levels, oxidative stress, and endothelial dysfunction), if compared to standard low-flux HD.

3. The improvement of the 'uremic profile' in HDF-treated patients results in an improvement of endothelial function with a reduction in the progression of vascular injury (as measured by CIMT and PWV) and a reduction in LVMi, if compared to standard low-flux HD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 715
• Est. completion date: January 2011
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients treated by HD 2 or 3 times a week, for at least 2 months

• Patients able to understand the study procedures

• Patients willing to provide written informed consent

Exclusion Criteria:

• Current age < 18 years

• Treatment by HDF or high flux HD in the preceding 6 months

• Severe incompliance (severe non-adherence to the dialysis procedure and accompanying prescriptions, especially frequency and duration of dialysis treatment and fluid restriction)

• Life expectancy < 3 months due to non renal disease

• Participation in other clinical intervention trials evaluating cardiovascular outcome

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases
• End-stage Renal Disease
• Kidney Failure, Chronic

Intervention

Procedure:
• on-line hemodiafiltration
addition of convective transport to regular dialysis treatment by using on-line hemodiafiltration
• low flux hemodialysis
standard treatment

Locations

Country	Name	City	State
Canada	Dr Georges-L. Dumont Regional Hospital	Moncton	New Brunswick
Canada	Centre Hospitalier de L'Université de Montreal, Hopital Notre Dame	Montreal
Netherlands	Jeroen Bosch Ziekenhuis	's Hertogenbosch
Netherlands	Medisch Centrum Alkmaar	Alkmaar
Netherlands	Academical Medical Center	Amsterdam
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam
Netherlands	Vrije Universiteit Medisch Centrum	Amsterdam
Netherlands	Ziekenhuis Rijnstate	Arnhem
Netherlands	Dialyse Kliniek Noord	Beilen
Netherlands	Haga Ziekenhuis (locatie Leyenburg)	Den Haag
Netherlands	Slingeland Ziekenhuis	Doetinchem
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Catharina Ziekenhuis	Eindhoven
Netherlands	Oosterscheldeziekenhuis	Goes
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	Rijnland Ziekenhuis	Leiderdorp
Netherlands	University Medical Center St Radboud	Nijmegen
Netherlands	Franciscus Ziekenhuis	Roosendaal
Netherlands	Medisch Centrum Rijnmond Zuid - locatie Clara	Rotterdam
Netherlands	Sint Franciscus Gasthuis	Rotterdam
Netherlands	Orbis Medisch en Zorgcentrum	Sittard
Netherlands	Ziekenhuis Zeeuws-Vlaanderen	Terneuzen
Netherlands	St Elisabeth Ziekenhuis	Tilburg
Netherlands	Stichting Dianet	Utrecht
Netherlands	University Medical Center Utrecht	Utrecht
Netherlands	VieCuri Medisch Centrum	Venlo
Netherlands	Isala Klinieken	Zwolle
Norway	Haukeland Universitetssykehus	Bergen

Sponsors (10)

Lead Sponsor	Collaborator
VU University Medical Center	Baxter Healthcare Corporation, Dutch Kidney Foundation, Fresenius Medical Care North America, Gambro Renal Products, Inc., Julius Center for Health Sciences and Primary Care, Utrecht, Maasstad Hospital, Medical Center Alkmaar, Roche Pharma AG, UMC Utrecht

Countries where clinical trial is conducted

Canada,  Netherlands,  Norway, 

References & Publications (15)

den Hoedt CH, Mazairac AH, van den Dorpel MA, Grooteman MP, Blankestijn PJ. Effect of hemodiafiltration on mortality, inflammation and quality of life. Contrib Nephrol. 2011;168:39-52. doi: 10.1159/000321743. Epub 2010 Oct 7. Review. — View Citation

Mazairac AH, de Wit GA, Grooteman MP, Penne EL, van der Weerd NC, van den Dorpel MA, Nubé MJ, Lévesque R, Ter Wee PM, Bots ML, Blankestijn PJ; CONTRAST investigators. A composite score of protein-energy nutritional status predicts mortality in haemodialys — View Citation

Mazairac AH, de Wit GA, Penne EL, van der Weerd NC, de Jong B, Grooteman MP, van den Dorpel MA, Buskens E, Dekker FW, Nubé MJ, Ter Wee PM, Boeschoten EW, Bots ML, Blankestijn PJ; CONTRAST investigators. Changes in quality of life over time--Dutch haemodia — View Citation

Mazairac AH, de Wit GA, Penne EL, van der Weerd NC, Grooteman MP, van den Dorpel MA, Nubé MJ, Buskens E, Lévesque R, Ter Wee PM, Bots ML, Blankestijn PJ; CONTRAST investigators. Protein-energy nutritional status and kidney disease-specific quality of life — View Citation

Penne EL, Blankestijn PJ, Bots ML, van den Dorpel MA, Grooteman MP, Nubé MJ, ter Wee PM. [New study evaluating online haemodiafiltration for the reduction of cardiovascular morbidity and mortality in patients undergoing chronic haemodialysis]. Ned Tijdschr Geneeskd. 2006 Jul 15;150(28):1583-5. Dutch. — View Citation

Penne EL, Blankestijn PJ, Bots ML, van den Dorpel MA, Grooteman MP, Nubé MJ, ter Wee PM; CONTRAST Group. Resolving controversies regarding hemodiafiltration versus hemodialysis: the Dutch Convective Transport Study. Semin Dial. 2005 Jan-Feb;18(1):47-51. Review. — View Citation

Penne EL, Blankestijn PJ, Bots ML, van den Dorpel MA, Grooteman MP, Nubé MJ, van der Tweel I, Ter Wee PM; the CONTRAST study group. Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients - the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125]. Curr Control Trials Cardiovasc Med. 2005 May 20;6(1):8. — View Citation

Penne EL, van Berkel T, van der Weerd NC, Grooteman MP, Blankestijn PJ. Optimizing haemodiafiltration: tools, strategy and remaining questions. Nephrol Dial Transplant. 2009 Dec;24(12):3579-81. doi: 10.1093/ndt/gfp333. Epub 2009 Jul 13. — View Citation

Penne EL, van der Weerd NC, Blankestijn PJ, van den Dorpel MA, Grooteman MP, Nubé MJ, Ter Wee PM, Lévesque R, Bots ML; CONTRAST investigators. Role of residual kidney function and convective volume on change in beta2-microglobulin levels in hemodiafiltrat — View Citation

Penne EL, van der Weerd NC, Bots ML, van den Dorpel MA, Grooteman MP, Lévesque R, Nubé MJ, Ter Wee PM, Blankestijn PJ; CONTRAST investigators. Patient- and treatment-related determinants of convective volume in post-dilution haemodiafiltration in clinical — View Citation

Penne EL, van der Weerd NC, Grooteman MP, Mazairac AH, van den Dorpel MA, Nubé MJ, Bots ML, Lévesque R, ter Wee PM, Blankestijn PJ; CONTRAST investigators. Role of residual renal function in phosphate control and anemia management in chronic hemodialysis — View Citation

Penne EL, van der Weerd NC, van den Dorpel MA, Grooteman MP, Lévesque R, Nubé MJ, Bots ML, Blankestijn PJ, ter Wee PM; CONTRAST Investigators. Short-term effects of online hemodiafiltration on phosphate control: a result from the randomized controlled Con — View Citation

Penne EL, Visser L, van den Dorpel MA, van der Weerd NC, Mazairac AH, van Jaarsveld BC, Koopman MG, Vos P, Feith GW, Kremer Hovinga TK, van Hamersvelt HW, Wauters IM, Bots ML, Nubé MJ, Ter Wee PM, Blankestijn PJ, Grooteman MP. Microbiological quality and quality control of purified water and ultrapure dialysis fluids for online hemodiafiltration in routine clinical practice. Kidney Int. 2009 Sep;76(6):665-72. doi: 10.1038/ki.2009.245. Epub 2009 Jul 15. — View Citation

van der Weerd NC, Penne EL, Grooteman MP. Effect of hemofiltration on mortality: no definite answer yet. Am J Kidney Dis. 2009 Mar;53(3):562-3; author reply 563. doi: 10.1053/j.ajkd.2008.09.029. — View Citation

van der Weerd NC, Penne EL, van den Dorpel MA, Grooteman MP, Nube MJ, Bots ML, ter Wee PM, Blankestijn PJ. Haemodiafiltration: promise for the future? Nephrol Dial Transplant. 2008 Feb;23(2):438-43. Epub 2007 Nov 28. Review. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	all cause mortality		entire follow up (until dead or end of study, 1-7 years)
Secondary	fatal and non-fatal cardiovascular events		entire follow up (until death or end of study, 1-7 years)
Secondary	Left ventricular mass index (LVMi), carotid IMT (intima media thickness), aortic pulse wave velocity (PWV)		first 3 years
Secondary	laboratory markers of endothelial dysfunction, micro-inflammation, oxidative stress		first three years of follow up
Secondary	lipid profiles, uremic toxins		first three years
Secondary	quality of life		entire follow up (until death or end of study, 1-7 years)
Secondary	nutritional state		entire follow up (until death or end of study 1-7 years)
Secondary	anemia management	hemoglobin levels, erythropoietin use / resistance iron saturation / ferritin levels, prescription of iron medication	first 12 months of follow up
Secondary	cost utility analysis		entire follow up (until death or end of study, 1-7 years)
Secondary	hospital admissions	hospitalization days hospital admission for infections hospital admission for any cause	entire follow up (until death or end of study, 1-7 years)
Secondary	blood pressure and antihypertensive medication		entire follow up (until death or end of study, 1-7 years)
Secondary	residual kidney function		entire follow up (until death or end of study, 1-7 years)
Secondary	mineral bone disease	laboratory parameters of mineral bone disease and medication (phosphate binders, vitamin D (or analogues), cinacalet)	entire follow up (until death or end of study, 1-7 years)
Secondary	parameters of treatment / treatment delivery	dialysis efficiency (Kt/V urea); bloodflow, dialysate flow, ultrafiltration volume, (HDF:) convection volume	entire follow up (until death or end of study, 1-7 years)