~1.81 million chronic kidney disease patients globally were undergoing hemodialysis ( hd ) treatment , with an estimated 90,000 ( 5% ) thereof being treated with hemodiafiltration ( hdf).1 online hdf has been suggested as a possible cost - effective alternative compared to standard hd , mainly due to its superior middle molecule clearance resulting from the combination of diffusion and convection solute removal mechanisms .
several studies suggest that hdf may lead to better clinical results than high - flux hd ( hf - hd).2,3 according to a recent survey , hdf was started to prevent dialysis complications , increase the efficiency of dialysis for uremic accumulates , treat dialysis - related hypotension and dialysis - related amyloidosis , and for intractable pruritus , restless leg syndrome and arthralgia not related to dialysis - related amyloidosis.4 however , to date , randomized studies have not conclusively supported the superiority of hdf regarding clinical outcomes.57 in addition , concerns have been raised about its cost - utility,8 leading investigators to conduct cost analyses to assess the differential expenditures between the two therapies.9 in a recent editorial , vanholder et al concluded that more expensive therapies should be reimbursed only when evidence of their cost - utility , defined as the ratio of treatment cost to treatment outcome , taking into consideration also the quality of life ( qol ) , is sufficiently robust.10 the cost of hdf per se has decreased in recent years due to 1 ) increased market penetration and the subsequent economy of scale in the production of equipment and disposables , 2 ) the pressure on health care costs due to the economic crises prevailing since 2008 , and 3 ) the safety and reliability of online method that have reduced demand for microbiological testing and monitoring.11,12 furthermore , after the publication of the study of canaud et al,2 hdf treatment effectiveness has increasingly been understood to be positively associated with the magnitude of the convection volume used , resulting in trends toward the application of higher hdf convection volumes than were applied in earlier cost analyses . accordingly , there is a need for a new cost - effectiveness evaluation . the aim of this study is to assess the cost - effectiveness of hdf compared to hd by a simulation using existing study data .
these data facilitate an understanding of whether longer survival and better health - related quality of life ( hrqol ) are able to offset the possibly higher costs of hdf , and thus whether it is worth investing in this more innovative therapy .
the analysis comprised a simulation1315 based on results from combined previous observational studies , randomized clinical trials , and a meta - analysis with the following steps : 1 ) estimation of a ) the survival function of hf - hd patients from the membrane permeability outcome study16 dataset and b ) estimation of the survival function of hdf patients using the risk reduction estimates due to the treatment effect from the meta - analysis of mostovaya et al17 ( even though it includes also studies comparing hdf to low - flux hd , it was considered the best proxy with respect to other alternative meta - analyses available in the literature ) ; 2 ) simulation of the survival of the same sample of patients as if allocated to hf - hd or hdf using three - state markov models ; 3 ) application of state - specific hrqol coefficients and differential costs ( materials , testing , and consumption of water ) derived from the literature .
in addition , in a secondary subgroup analysis we considered the eshol5 estimations related to diabetics and nondiabetics .
this was done because among all the studies considered the eshol study provides results related to these particular subgroups of patients .
two mirror - image markov models ( figure 1 ) were developed with the aim to generate a simulation comparing the survival of the same sample of patients treated with hf - hd and hdf .
three possible states were considered : alive and under therapy , dead due to the disease under therapy , and dead for other cause ( ie , considering the overall mortality , based on age- and sex - adjusted life tables ) .
the probabilities defining the transition of patients between each of these states were calculated from the previously estimated hazard functions and were specified over a defined time frame ( cycle ) .
the model was run for a specified number of cycles to see how the hypothetical cohort of patients moved between states .
the length of the cycle was fixed to 1 year and the number of cycles to ten , for a total of 10 years .
accordingly , total dialysis costs can be divided into : 1 ) direct health care costs , such as staff , material , vascular access , routine diagnostics , hospitalization , drugs , and medications ; 2 ) direct nonhealth care costs , such as cost of transport and cost of informal care ; and 3 ) indirect nonhealth care costs , productivity losses due to disability or premature death .
it is reasonable to assume that direct nonhealth care costs and indirect nonhealth care costs are the same for the two therapies , and also that most of the direct health care costs do not vary by treatment . as a consequence ,
the comparison on the incremental costs of hdf with respect to hf - hd focused only on the costs of equipment , disposables , ultrapure water testing , and water consumption.18 in order to obtain more generalizable results , we analyzed two alternative cost settings , involving or not involving the use of ultrapure water .
the first was based on the assumption that , since dialyzers used to perform both hdf and hf - hd are designed to have better solute clearances on a wider range of uremic toxins and higher hydraulic permeability , it is reasonable to argue that the same water and dialysis fluid microbiological purity were necessary for both therapies due to backfiltration phenomena , leading to similar costs of water testing . as a consequence , and because differences in total water consumption are negligible , it was possible to limit the analysis to the costs of disposables ( blood lines , dialyzers ) and equipment only .
in the prospective observational study by oates et al,9 some patients on hf - hd were switched to hdf and others remained on hf - hd .
the additional cost of disposables related to hdf was of  1.32 per session (  207 per annum [ p.a . ] ) in the standard case , that is , with the use of a cuvette for relative blood volume monitoring .
the alternative cost setting was based on the analysis by lebourg et al12 where , in addition to a cost variability due to disposables and monitors , the difference in cost between the two different therapies caused by water analysis and water consumption was considered .
the additional hdf cost per session ranged from a minimum value of 1.29 ( 202 p.a . ) to a maximum value of  4.86 (  730 p.a . ) .
once the relevant costs were determined , the corresponding estimated and discounted costs ( or a differential cost ) taken from the literature were allocated to each state of the model .
contradicting results have been reported on the difference in qol related to hf - hd and hdf .
few studies addressed the qol evaluation , and none provided hrqol coefficients for the specific comparison of hf - hd and hdf , fundamental for the purpose of this analysis .
mazairac et al8 estimated higher scores with euroqol 5d for patients on hdf compared with hd .
this preference - based measure yields a set of weights on which quality - adjusted life years ( qalys ) calculations can be based . in this study
as there are no other data about qol differences between hdf and hf - hd in the literature , these coefficients have been used in our simulation . in particular , the hrqol coefficients linked to age were selected for the model because otherwise a fundamental component of the benefit measurement would have been neglected . as recommended by the economic analysis guidelines,19 an annual discount rate of 3.5% for both costs and benefits was selected , and changes in results as a function of different values of these parameters were considered .
parameter uncertainty was included in the model through a probabilistic sensitivity analysis , taking the intrinsic imprecision of the estimate of the parameters of the survival model into account .
consequently , the quality and quantity of information available can be reflected in the probability distributions assigned to each input parameter in the model.20 several monte carlo simulations were performed , also for patients with different risk profiles by age ( patients aged 40 , 50 , and 60 years ) , sex , and diabetic status.21,22 for the sake of simplicity , the cohort of simulated 50-year - old male patients were selected as the reference population for the analysis . as discussed in the next section , we found similar results in all age subgroups , with identical conclusions in terms of cost - effectiveness ; therefore , we used this cohort to briefly recap the main results of our analysis .
the characteristics of this cohort are coherent with the results from the edta registry reported by van de luijtgaarden et al:23 in the last 20 years indeed the mean age of patients who started with hd treatment was 5560 years , and on average > 60% of patients were male .
output analyses included scatter plots of simulations in the cost - effectiveness plane , the estimation of incremental cost - effectiveness ratios ( icers ) and the computation of cost - effectiveness acceptability curves ( ceacs ) .
the results of the 1,000 monte carlo simulations for the cohort of 50-year - old male patients are shown in the cost - effectiveness scatter plot in figure 2 . from the mean values of all the simulations in this specific cohort of patients ,
the icer was  6,982/qaly . on the basis of these simulations it was possible to derive the probability of cost - effectiveness given different thresholds , as shown in figure 3 .
the ceac corresponding to hdf starts from 0 , meaning that there is no possibility that this alternative therapy is cost - saving
. the threshold must be at least  2,000 per qaly to have a probability of cost - effectiveness > 0 .
the probability of cost - effectiveness increased to 50% with a threshold of  7,000/qaly , to 70% with a threshold of  15,000/qaly and to 81% with the commonly accepted threshold of  40,000/qaly .
the probability of cost - effectiveness always stayed below 84% for a threshold of over  40,000/qaly .
this asymptotic value results from the fact that a fraction of the simulations represent cases where the alternative therapy ( hdf ) causes higher costs and provided fewer benefits .
this means that even with any budget constraint , there is some probability that the alternative therapy is not cost - effective and the traditional one ( hf - hd ) is preferred . the same analyses were carried out for the subgroups of 40- , 50- , and 60-year - old male and female patients ( table 1 ) : hdf appears to be more cost - effective for younger patients .
this message is reinforced in figure 4 , which shows that a given threshold value is associated to a higher probability of hdf being cost - effective for the 40- and 50-year - old patients than for the 60-year - old ones .
moreover , for the 60-year - old groups there is a probability of around 28% for both females and males that hdf is not cost - effective even at extreme values of the threshold . regarding the discount rates for costs and benefits , results were robust even after considering alternative scenarios with lower or higher discount rates .
by applying a 0% or a 5% discount rate for both costs and effects , 50-year - old male patient icer decreased to  6,676/qaly and increased to  6,960/qaly , respectively , confirming the robustness of the estimations .
a further analysis was performed to investigate the importance of the qualitative component of the qalys ( qol ) compared to the quantitative one ( life years ) .
the effect of using overall hrqol coefficients ( rather than the hrqol coefficients linked to patient age ) on the cohort of 50-year - old male patients is shown in figure 5 .
the mean icer increased to  19,423/qaly but , more importantly , almost 37% of the simulations were on the left of the qaly zero value ( less effectiveness , more costs ) and , accordingly , the uncertainty around the decision whether to invest in the new therapy was much higher .
even an infinite value of the threshold would not lead to a probability of cost - effectiveness > 65% ( data not shown ) .
this is caused by the uncertain values of the overall hrqol coefficients , leading to some cases where one period spent under hf - hd is worth even more than the same period under hdf .
this shows that it is crucial to consider the role of qol is in such evaluations .
previously , cost inputs were point estimates , whereas now costs vary over the range assessed by lebourg et al.12 the ceac for the subgroup of 50-year - old male patients shows that 21.5% of the simulations are cost - saving ( figure 6 ) .
the probability of being cost - effective reaches 80% at the commonly accepted threshold of  40,000/qaly , and it increases only by 2.4 percentage points even with a threshold of  70,000/qaly .
, hdf seems a little more expensive : for instance , the icers of the younger patients rise from  5,878/qaly and  5,732/qaly to  7,748/qaly and  7,724/qaly for female and male patients , respectively ( table 2 ) .
this subgroup analysis confirmed the previous results : the icer increases with the age of the cohort .
diabetic patients follow a different survival function and are subject to a different treatment effects of the alternative therapy compared to nondiabetic patients .
nevertheless , the comparison between a cohort of 50-year - old diabetic male patients and a cohort of 50-year - old nondiabetic male patients did not reveal significant differences ( figure 7 ) .
given the commonly accepted threshold of  40,000/qaly , this study demonstrated that , compared to hf - hd , hdf is a cost - effective treatment for patients on dialysis .
this is particularly true for patients < 60 years , irrespective of sex or diabetic status .
either way , the variability in the results due to different characteristics of the patients does not affect the conclusions about the cost - effectiveness of hdf .
these results are quite different from those reported by mazairac et al8 in their cost - utility analysis of hdf versus conventional low - flux hd based on the unadjusted results for convective volume of the convective transport study ( contrast).7 their estimated incremental cost per quality - adjusted life year of hdf compared to low - flux hd was  287,679 and certainly not below  140,000 under the most favorable assumptions ( eg , applying a convection volume > 20.3 l ) .
they argued that the hdf is characterized by higher cost and better health and was not cost - effective given the currently accepted cost - utility thresholds .
however , it has to be mentioned that the same analysis performed on patients treated in montreal ( canada ) according to the same protocol yielded different , positive , results.24 our analysis , on the other hand , reports that hdf is cost - effective with a probability of ~81% .
this conclusion is based on what is considered the commonly accepted threshold for health policy decisions,25 which is ~40,000 ( or 30,000 gbp , or 50,000 usd ) per qaly . even if this threshold is difficult to quantify and
is often based on a rule of thumb , it is commonly applied as an estimate of the forgone health resulting from services displaced to accommodate the additional costs of the new technology . of note
, the magnitude of the difference between the two studies may be related to the different comparison groups , which is low - flux hd in the contrast study and hf - hd in our model .
the icer estimates show a good value for money , but some doubts about the cost - effectiveness of hdf over hf - hd remain due to the residual ~20% probability of costs being higher and/or benefits being lower with hdf .
this line of reasoning is also shared by mcbrien and manns26 in their commentary of the mazairac study , where they argued that hdf is characterized by higher procedural costs and has no proven health benefit .
our study specifies that the survival difference is not the only important factor ( especially considering the lack of agreement on this aspect ) , but that differences in terms of qol are of fundamental importance and must be measured .
this was the rationale for conducting a value - based study incorporating hrqol as a main outcome of hdf versus hf - hd .
convective treatments as hdf indeed reduce intradialytic hypotension ( which affects qol ) , and possibly limit the poor appetite and nutritional state in patients with chronic kidney disease .
however , we believe that more research is warranted to assess the impact of hdf specifically on the nutritional state of end - stage renal disease patients
. therefore , this study recommends prioritizing the research which evaluates the qol related to hdf .
it must be stressed that the purpose itself of an economic decision model is to synthesize all the relevant evidence in order to make a sense of it and inform the decision about the adoption of a new technology in an uncertain context.15 we have indeed identified the relevant studies involving the therapies under assessment , and we have included all the uncertainty in our parameter estimates , without neglecting any relevant information in the literature .
our result is therefore based on published data , but its accuracy is sensitive to some decisions that we were forced to take in the model construction phase .
the first decision was to use survival estimates from the hf - hd arm of the membrane permeability outcome16 randomized clinical trial .
this trial was based on incident patients , whereas other studies on hdf were mainly performed on prevalent european dialysis patients .
additionally , the low crude mortality rate observed in the membrane permeability outcome study may produce results not completely transferrable to ordinary ( nontrial participating ) patients .
indeed , as stressed by palmer et al,20 relative risk reductions applied to low baseline risks produce low absolute reduction in event rates and low gains in health .
it is possible that this low overall mortality rate affected the lack of difference between diabetic and nondiabetic patients .
as previously stressed , one of the main requirements for an economic evaluation is to include all the relevant evidence . with regard to the effectiveness data , this concept does not change , and meta - analysis
is the usual technique employed to synthesize all the available evidence . to date five meta - analyses aggregating the results of the main convective dialysis therapy studies17,2730
have been published . however , a huge heterogeneity of interventions was included in these meta - analyses , and the meta - analysis by mostovaya et al17 was the only one which focused on trials on hdf as convective therapy with appropriate definition of convective volume .
nevertheless , there is still a great variety of patients and treatment modalities characteristics among the studies .
indeed , for instance , both high- and low - flux modalities were included in the comparison . as a consequence ,
a relative risk based on a random effects model has been used , which makes the estimate of the pooled effect more conservative , and takes into account the clinical heterogeneity among the single studies . of note
, this meta - analysis includes also the contrast study , and our cost - effectiveness analysis does include all the relevant randomized clinical trials . on the contrary , for instance
, the economic evaluation by mazairac is based only on the contrast study ; this is a subjective decision , while a complete cost - effectiveness analysis should instead take into consideration all the relevant available evidence , as previously pointed out . with regard to the subanalysis of the diabetic patients , the eshol5 estimates of risk reduction have been used .
as the eshol study provided the most positive results in favor of hdf , concerns about the overestimation of the reduction in mortality could be raised .
nevertheless , the model did not show any difference between the two groups of patients , and this result highlights again that the impact on mortality is less important than the effect on the qol .
the estimations used for this study were mainly derived from a meta - analysis with basically 23 years follow - up time , but a more appropriate time horizon would be the patient s lifetime . this is especially true in the case of treatment of chronic diseases where the initiation of an intervention in middle - aged patients may have cost and effect implications on the rest of their lives.31 an important role of a decision model , therefore , is to bridge the gap between what has been observed in trials and what would be expected to happen over the long - term , forcing one to make assumptions about the long - term effects and consequences of treatment modalities .
additionally , the lack of qol coefficients related to hf - hd forced the use of data from a comparison of hdf with low - flux hd.8
uncertainty around results is high , but this is typical in this kind of analyses : neglecting some available evidence only because of its uncertainty would contrast with the comprehensive nature of an economic model .
this study contributes also to show the scarcity and heterogeneity of data available in the literature that jeopardize the economic evaluation of hdf when compared to hf - hd .
new studies are needed to assess more precisely the differential benefits between the therapies : value - of - information analysis might help to identify more specifically the parameters which would be worth to be further investigated .
a more comprehensive evaluation performed in a randomized clinical trial is required in order to include other relevant cost components ( eg , pharmaceuticals , hospitalizations , prevention of long - term dialysis - related complications , beta-2 microglobulin - amyloidosis , and transplantation access ) in the analysis .
possible savings resulting from a reduction in the cost of ancillary pharmacological therapy and hospitalization have not been considered in the current analysis .
 backgroundclinical studies suggest that hemodiafiltration ( hdf ) may lead to better clinical outcomes than high - flux hemodialysis ( hf - hd ) , but concerns have been raised about the cost - effectiveness of hdf versus hf - hd . 
 aim of this study was to investigate whether clinical benefits , in terms of longer survival and better health - related quality of life , are worth the possibly higher costs of hdf compared to hf-hd.methodsthe analysis comprised a simulation based on the combined results of previous published studies , with the following steps : 1 ) estimation of the survival function of hf - hd patients from a clinical trial and of hdf patients using the risk reduction estimated in a meta - analysis ; 2 ) simulation of the survival of the same sample of patients as if allocated to hf - hd or hdf using three - state markov models ; and 3 ) application of state - specific health - related quality of life coefficients and differential costs derived from the literature . 
 several monte carlo simulations were performed , including simulations for patients with different risk profiles , for example , by age ( patients aged 40 , 50 , and 60 years ) , sex , and diabetic status . 
 scatter plots of simulations in the cost - effectiveness plane were produced , incremental cost - effectiveness ratios were estimated , and cost - effectiveness acceptability curves were computed.resultsan incremental cost - effectiveness ratio of  6,982/quality - adjusted life years ( qaly ) was estimated for the baseline cohort of 50-year - old male patients . given the commonly accepted threshold of  40,000/qaly , hdf is cost - effective . 
 the probabilistic sensitivity analysis showed that hdf is cost - effective with a probability of ~81% at a threshold of  40,000/qaly . 
 it is fundamental to measure the outcome also in terms of quality of life . 
 hdf is more cost - effective for younger patients.conclusionhdf can be considered cost - effective compared to hf - hd . 
Introduction
Methods
Results
Discussion
Conclusion