Prospective Randomized Studies and Meta-analyses of Interventional Studies

Results of the DOPPS study, in line with previous clinical reports, have stimulated interest for HDF and triggered four European interventional prospective randomized controlled trials (RCTs) (1).

The first study to be reported was the CONTRAST, the Dutch CONvective TRAnsport Study. In this prospective study, 714 chronic hemodialysis Dutch and Canadian patients were assigned to either start online postdilution hemodiafiltration (HDF) (n=358) or to continue low-flux HD (n=356) (2,3). A median substitution volume of 19.8 L/session was delivered overall.  The primary outcome measure was all-cause mortality, and the main secondary endpoint was a composite of major cardiovascular events. After a mean follow-up of three years, there was no significant difference between treatment groups with regard to all-cause or CV mortality. However, in a post hoc analysis considering convection volume, patients receiving high-volume HDF (>21.95 L/ses) were associated with lower all-cause mortality, a finding that persisted after adjusting for potential confounders and dialysis facility. The strengths of the study are its randomized design and the accuracy of monitoring and data collection. The main limitations of the study are the inclusion of prevalent patients, that 9% of the HDF treatments were delivered as high-flux hemodialysis, and more importantly the lack of compliance to assigned convection volume (6L/hr.; 24L/session) in about two-thirds of HDF-treated patients (4-6).

The second study was the Turkish HDF study (THDF study). The aim of the THDF study was to compare postdilution online HDF and high-flux HD in terms of morbidity and mortality (7). This prospective, randomized, controlled trial enrolled 782 patients undergoing thrice-weekly HD and randomly assigned them in a 1:1 ratio. The mean follow-up period was 22.7 ± 10.9 months. The primary outcome was a composite of death from any cause and nonfatal cardiovascular events. The mean substitution volume delivered in HDF was 17.2 ± 1.3 liters. The primary outcome was not different between groups or with respect to cardiovascular and overall survival. In a post hoc analysis, the subgroup of HDF patients treated with a median substitution volume > 17.4 L/session (equivalent to convection volume of 20.5 L/session) had significantly better cardiovascular and overall survival compared with the high-flux HD group. In adjusted Cox-regression analysis, treatment with high-efficiency HDF was associated with a 46% risk reduction for overall mortality and a 71% risk reduction for cardiovascular mortality compared with high-flux HD. The study had additional limitations that included the fact that enrolled patients were prevalent, relatively young with low comorbid profiles, and particularly well-treated patients (i.e., 90% had blood pressure control without medication and AV fistula).

The third study to be reported was ESHOL (Estudio de Super-vivencia de Hemodiafiltración On-Line). A Spanish multicenter, open-label, randomized controlled trial involving 906 prevalent patients (8). In this study, patients were assigned either to continue high flux HD (n=450) or switch to high-efficiency postdilution online HDF (n=456). The median convection volume achieved was 22.9–23.9 L/session in 90% of HDF patients. The primary outcome was all-cause mortality, and secondary outcomes included cardiovascular mortality, all-cause hospitalization, treatment tolerability, and laboratory data. HDF–treated patients had a 30% lower risk of all-cause mortality, a 33% lower risk of cardiovascular mortality, and a 55% lower risk of infection-related mortality compared to HD. The incidence rates of dialysis sessions complicated by hypotension and of all-cause hospitalization were lower in patients assigned to online HDF.  Results were consistent in distinct subgroups of patients according to age, sex, diabetes mellitus, the Charlson comorbidity index, and vascular access. The strengths of this study include the randomized design, the large sample size, and long follow-up, as well as the achievement of high convection volumes in vast majority of patients. This fact indicates that good clinical practices were performed in all facilities participating in this clinical trial (i.e., staff and care giver training, high blood flow, and relatively long dialysis time). Limitations of the study may include confounding factors such as imbalance in vascular access type, age, history of diabetes, Charlson Comorbidity Index, 6% low-flux treatments, transplantation rate and patient screening on blood flow performances (9,10). However, this was the first prospective, RCT showing that high-efficiency postdilution online HDF reduces all-cause mortality compared with high–flux HD, including in a post hoc re-analysis that included competing risk factors (11).  

The fourth study was the French HDF study (FRENCHIE, French Convective HDF Study In Elderly). In the FRENCHIE study, a prospective, open-label randomized controlled trial, 381 elderly prevalent hemodialysis patients (over age 65) were randomly assigned in a one-to-one ratio to either high-flux HD or online postdilution HDF with 24 months follow-up (12). The median substitution volume achieved was 21 L/session overall for a targeted convection volume of 24 L/session. The primary outcome was intradialytic tolerance (day 30-day 120). The secondary outcome was a composite of all-cause and CV mortality, intermediary outcomes (i.e., biomarkers) and health-related quality of life. During the observational period for intradialytic tolerance, 85% and 84% of patients in high-flux hemodialysis and online hemodiafiltration arms, respectively, experienced at least one adverse event without significant difference between groups. In an exploratory analysis, intradialytic tolerance was also studied, using the sessions as a statistical unit according to treatment actually received. Over a total of 11,981 sessions, 2,935 were complicated by the occurrence of at least one adverse event, with a significantly lower occurrence in online hemodiafiltration with fewer episodes of intradialytic symptomatic hypotension and muscle cramps. In contrast, health-related quality of life, morbidity, and mortality were not different between groups. An improvement in the control of metabolic bone disease biomarkers and β2-microglobulin level, without change in serum albumin concentration, was observed with online hemodiafiltration (12). Although no significant difference in all-cause and cardiovascular mortality was observed between high-flux and HDF patients at 24 months, overall outcomes favored online hemodiafiltration over high-flux hemodialysis in the elderly. Notably, the study was underpowered and mortality in the ESRD population was low. 

In brief, two prospective RCTs (CONTRAST and Turkish HDF studies) failed to show beneficial effects on all-cause or cardiovascular mortality in overall analyses. However, post hoc analyses of both studies showed beneficial effects in patients with high convection volumes (>23 L/session) (3,7). The ESHOL study, which achieved the highest median convection volume, demonstrated a 30% reduction in both all-cause and cardiovascular mortality in patients treated with high-volume HDF (8). The FRENCHIE study, which was performed in elderly patients, showed that HDF patients experienced significantly fewer episodes of symptomatic intradialytic hypotension and muscle cramps, while no differences were seen for health-related quality of life, morbidity, or mortality. Control of metabolic bone disease biomarkers and b2-microglobulin levels were much improved in the HDF group (12). A brief summary of the four RCT studies is presented in the table. 

 

Randomized controlled trial Renal Replacement Modalities Number of
patients		 Study end point Result HDF group Post hoc analysis considering Vcon
CONTRAST study 3 LF-HD ⬌ olHDFpost 714 Primary end point
all-cause mortality		 No significant benefits
on primary end point		 Significant benefits on primary end point when Vcon > 22 L / session
Turkish HDF
Study 7		 HF-HD ⬌ olHDFpost 782 Primary end point
all-cause mortality and nonfatal CV events		 No significant benefits
on primary end point		 Significant benefits on primary end point when Vcon > 20.5 L/session
ESHOL
Study 8		 HF-HD ⬌ olHDFpost 906 Primary end point
all-cause mortality		 30% lower risk of
all-cause mortality		 45% mortality risk reduction when Vcon > 25 L/session
FRENCHIE
Study 12		 HF-HD ⬌ olHDFpost 381 Primary endpoint
intradialytic tolerance
Secondary endpoint mortality		 Less intradialytic hypotension and muscle cramps
No benefits on
secondary end point		 No significant benefits on secondary end point when Vcon ≥20.5 L/session
HF, High-Flux; LF, Low-Flux; HD, hemodialysis; HDF, hemodiafiltration: ol-HDF, online hemodiafiltration; Vcon convection volume, CV cardiovascular
CONTRAST Dutch CONvective TRAnsport Study; THDFS Turkish HDF Study; ESHOL Estudio de Super-vivencia de Hemodiafiltración On-Line;
FRENCHIE French Convective HDF Study In Elderly

 

Historical meta-analyses and/or systematic reviews addressing benefits of HDF compared to standard HD have reported conflicting results (13-15). Unfortunately, some of these meta-analyses aggregated several different convection-based methods under the umbrella of “convective therapies” (i.e., hemofiltration, acetate-free biofiltration, low volume hemo­diafiltration) and failure to account for the effective convection volume achieved presents a major shortcoming in their findings (16,17).

In their meta-analysis, Nistor et al. (14) compared mortality in patients on hemodiafiltration, hemofiltration, and acetate-free biofiltration to hemodialysis. Including low-convection volume treatments, such as offline hemofiltration/hemodiafiltration and acetate-free biofiltration, which can hardly be considered modern convective therapies, as the convection volumes of 10–12 L/session achieved are similar to the amount of internal filtration obtained with high-flux HD and different from high volume HDF (18,19). Another meta-analysis in which convection volume was included identified improved outcomes in patients receiving adequately dosed HDF (20). In conclusion, data suggest that convective dialysis may reduce cardiovascular but not all-cause mortality, and that effects on nonfatal cardiovascular events and hospitalization are inconclusive, considering shortcomings in study methods and reporting (14).

All reported studies (observational and interventional) support the notion that total convection volume delivered, regardless of substitution mode (i.e., post, pre, or mixed), on a regular basis matter. Convective dose represents the driving force for patient outcome improvement in a dose-dependent manner (21,22).

That a positive outcome depends on the convection volume was supported further by the results of analyses of individual-patient data meta-analysis (IPD-MA) from the four European RCTs (23). In aggregate, 2793 patients were included in these analyses. After a median follow-up of 2.5 years, 769 of the 2793 patients had died, with 292 of the deaths being cardiovascular. HDF patients were divided into tertiles based on delivered convection volume and all-cause and cardiovascular mortality compared to that with HD, and hazard ratios were calculated using Cox proportional hazard regression models (23). In the first analysis, a survival benefit of online HDF was found for patients in the highest tertile of convection volume, but results varied depending on how convection volume was standardized to body size (24). All-cause mortality in the tertile receiving the highest convection volumes was reduced when the convection volume was not standardized, or standardized to body surface area or total body water (hazard ratios (95% confidence intervals of 0.66 (0.52 – 0.83), 0.71 (0.57 – 0.90) and 0.71 (0.57 – 0.89), respectively; no reduction was found for standardization to body weight or body mass index. These results were confirmed in a second analysis where online HDF was shown to reduce all-cause mortality by 14% and cardiovascular mortality by 23% compared to HD. There was no evidence for a differential effect in pre-determined subgroups and, again, the largest survival benefit was for patients receiving the highest delivered convection volume (>23 L/1.73 m2 body surface area) (24). In a cause-specific analysis on mortality, it was also shown that HDF had a significant reduction effect on fatal cardiac events, including ischemic heart disease as well as congestion (25). It was then calculated that the patient number needed to treat by HDF in order to prevent one cardiovascular death was 75 per year (25). 

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