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NDT Advance Access originally published online on February 1, 2007
Nephrology Dialysis Transplantation 2007 22(5):1377-1382; doi:10.1093/ndt/gfl813
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prognostic value of the New York Heart Association classification in end-stage renal disease

Maurizio Postorino, Carmen Marino, Giovanni Tripepi, Carmine Zoccali on behalf of the Calabrian Registry of Dialysis and Transplantation*

CNR-IBIM, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy

Correspondence and offprint requests to: Prof. Carmine Zoccali, CNR-IBIM Istituto di Biomedicina - Consiglio Nazionale delle Ricerche c/o Divisione di Nefrologia e Dialisi Ospedali Riuniti - 89100 Reggio Calabria, Italy. Email: carmine.zoccali{at}tin.it



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. The New York Heart Association (NYHA) classification is a strong predictor of mortality and an established instrument for risk stratification in patients with heart disease but data on the validity of this classification in end-stage renal disease (ESRD) are sparse.

Methods. In this study, we tested the predictive value of the NYHA in patients with ESRD and compared it with that of two established indexes of disease severity, i.e. the Khan index and the renal disease severity score (RDSS). The study cohort was composed of 1322 incident patients in a dialysis registry (772 male and 550 female, age 61 ± 16 years).

Results. During the follow-up period (41 ± 27 months) 551 patients died. A multivariate COX model including the NYHA classification explained 39% of the variation in mortality, a figure almost identical to that of a model based on the RDSS (37%) and superior (P < 0.001) to that provided by the Khan index-based model (32%). The area under the receiver operating characteristic curve of NYHA classification, as related to all-cause mortality, was 0.74 (95% CI: 0.71–0.77, P < 0.001). Again, RDSS had a predictive value for mortality (0.74, 95% CI: 0.72–0.77) identical to that of NYHA and higher than that of the Khan index (0.70, 95% CI: 0.67–0.72).

Conclusion. The NYHA is a powerful predictor of mortality in ESRD and provides prognostic information equal or superior to that given by other established indexes of disease severity. Given the pervasive nature of cardiovascular disease in ESRD, this classification may be recommended for risk stratification in this population.

Keywords: dialysis; heart failure; Khan index; NYHA classification; renal disease severity score



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Cardiovascular complications represent the main factor limiting long-term survival and rehabilitation in the dialysis population [1,2]. Among these complications, heart failure (HF) contributes substantially to adverse outcomes in this population [3]. Clinically defined HF [4] is remarkably similar across studies in end-stage renal disease (ESRD) patients. Indeed, it was 31% in the dialysis cohort studied by Foley and Parfrey [5] in Newfoundland and 36% in the Wave 2 study of the US Renal Data System Dialysis Morbidity and Mortality Study by Stack [6]. The New York Heart Association (NYHA) classification is the most used instrument to grade the severity of HF in the general population and it represents an accepted standard worldwide [7,8]. Notwithstanding the popularity of this instrument in cardiology, NYHA has rarely been used to grade the severity of HF in dialysis patients and to our knowledge there is no prospective study testing the predictive value of this instrument in ESRD. The issue is of relevance because the frequency of HF in ESRD is about one order of magnitude higher than in the general population. In 2002, in an exploratory analysis based on a prevalent cohort of dialysis patients, we demonstrated that a slightly modified NYHA classification is an independent predictor of death [9]. We have therefore set out a study based on a large incident cohort in a regional dialysis registry to analyse the prognostic value of this modified classification and to compare it with that of other established risk scores extensively applied in ESRD, namely the Khan index [10] and the renal disease severity score (RDSS) [11].



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
The protocol of the study was in conformity with the Declaration of Helsinki and informed consent was obtained from each participant.

This study was based on the calabrian registry of uraemia, dialysis and transplantation (C.RE.DI.T). Calabria is a southern Italian region with a resident population of 2.1 million and with a prevalence of ESRD of about 655 patients per million inhabitants. The database of Calabrian Registry collects demographic and clinical data of all patients with ESRD treated in this region from 1994 onwards (http://www.cfc.cs.cnr.it/registro/Home.htm). Patients were included into this registry according to the Guidelines of the Italian Registry of Dialysis and Transplantation, i.e. to be included they had to be considered by renal physicians responsible for their care as patients with irreversible ESRD. This registry comprises the standard data collected by the ERA-EDTA registry as well as detailed information about comorbidities. The study cohort was formed by 1322 incident patients starting regular dialysis treatment between 1994 and 2001 (82% of them started a haemodialysis (HD) programme and 18% a peritoneal dialysis (PD) programme). The demographic and clinical data of these patients are shown in Table 1. All patients were followed-up until death or censoring (study end or renal transplantation) until December 2002 (mean follow up 41 ± 27 months). One-hundred and forty patients were transplanted and 34 patients were lost to follow up.


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  		Table 1. Correlates of NYHA classification

 
The adapted NYHA, inter-observer agreement
The adapted NYHA has been included in the registry since 1994. In this adaptation, patients with no functional limitations were classified as class 0 patients, while those with occasional effort dyspnoea were classified as class I patients. The adapted and the original classification were otherwise identical. To assess the reproducibility of NYHA, blindly and in a context representative of clinical practice, we tested the inter-observer agreement between independent assessors of the adapted classification in a series of 30 dialysis patients that were revaluated during the same calendar year by a second renal physician (unaware of the scoring of the previous assessor) after transfer to another dialysis centre in the same region. Kappa statistics [12] were used for testing whether agreement exceeded chance levels for NYHA ratings and the resulting weighted kappa was 0.51 (P < 0.001). Like the NYHA, the RDSS has been systematically collected by the registry since 1994 [13] and the Khan index was computed from comorbidity data available in the registry.

Statistic
Data are reported as mean ± SD, median and interquartile range or as percent frequency, as appropriate and comparisons among groups were made by P for trend. The association between variables was tested by Pearson correlation coefficient and by Spearman rank (rs) correlation, as appropriate.

The prognostic value for death by the NYHA and by the other two multifactorial risk scores (Khan index and RDSS) was analysed by using Kaplan–Meyer method and by univariate and multivariate Cox regression analysis. In multivariate Cox models of multifactorial risk scores, (NYHA, RDSS and Khan index) we adjusted for age, sex, treatment modality HD and PD as well as for haematocrit, diabetes, peripheral vascular and coronary artery disease, cerebrovascular disease, HF and bronchopulmonary disease when these covariates were not specific components of the corresponding multifactorial risk score. Furthermore, to control for centre effect, we stratified the Cox analysis by dialysis centre. To compare different models, we used the –2 log likelihood (–2 Log L) statistics. This procedure compares different models fitted to the same set of survival data and the smaller the –2 Log L value, the better the agreement between the model and the observed data [14]. The difference between the –2 Log L of the models which are being compared gives a statistical estimate as to which of them provides a better fit to the data. A 3.841 difference in –2 Log L coincides with a significance level of 0.05 in a chi-square distribution with 1 degree of freedom and indicates a better prediction of risk estimate provided by the method leading to the lowest –2 Log L value. The explained variation in mortality attributable to the NYHA and to the other multifactorial scores was calculated by the method proposed by Hosmer and Lemeshow [15]. The predictive value for all cause mortality of NYHA classification, RDSS and Khan index was further analysed by using the receiver operating characteristic (ROC) curve method [16]. We calculated the age-adjusted probability of death associated to RDSS and NYHA score by logistic regression analysis and then tested the adjusted probabilities by ROC curve analysis. Hazard ratios (HR) and their 95% CI were calculated with the use of the estimated regression coefficients and their standard errors in the Cox regression analysis. All calculations were done using a standard statistical package (SPSS for Windows Version 9.0.1, 11 Mar-1999, Chicago, Illinois, USA).



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
In the whole study population, 489 patients out of 1322 (i.e. 37%) displayed symptoms of HF while the remaining 833 patients (i.e. 63%) were asymptomatic. As shown in Table 1, patients with more severe HF were older, with a higher proportion of females, diabetics and of patients with cardiac ischaemia, cerebro-vascular disease and peripheral vascular disease. Likewise, concomitant bronco-pulmonary disease rose in parallel with the severity of HF. Both, the RDSS and the Khan index results were progressively higher at increasing levels of HF severity (Table 1). Accordingly, NYHA classes, RDSS and Khan index were strongly interrelated (NYHA–RDSS, rs = 0.67, P < 0.001; NYHA–Khan index, rs = 0.72, P < 0.001; RDSS–Khan index, rs = 0.74, P < 0.001).

Kaplan–Meier analysis
Five hundred and fifty-one patients died during the follow-up. The median survival of patients with HF (i.e. NYHA class I–IV) was 36 months (95% CI: 29–41 months) which was substantially shorter than that of patients without symptoms of cardiac failure [85 months (95% CI: 72–96 months)]. In a Kaplan–Meier survival analysis the risk of all-cause mortality increased in parallel with NYHA class (Figure 1) so that patients with a NYHA class 3–4 were those at highest risk of death (Log Rank Test: 165, P < 0.001) and survival in this class was 14%. Similarly, the RDSS (Log Rank Test: 112, P < 0.001) and the Khan index (Log Rank Test: 215, P < 0.001) were strongly associated to incident mortality (Figure 1) in a dose-response fashion.


Figure 1
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  		Fig. 1. Kaplan–Meier survival analysis for all cause mortality of Khan index, RDSS and NYHA classification.

 
Mortality, NYHA classification and other risk scores
In an unadjusted Cox regression analysis, the Khan index explained 28% of the variation in mortality of the dialysis population, a figure higher than that of NYHA (22%) and of the RDSS (21%). The (unadjusted) relative risk associated to the highest category (vs the lowest category) of each index was 5.00 for the Khan index (95% CI: 3.96–6.31), 5.17 for NYHA (95% CI: 3.89–6.88) and 4.67 for the RDSS (95% CI: 3.40–6.42).

Cox regression: multivariate analysis
The independent prognostic value of each index for all-cause death was tested in a multivariate Cox analysis always stratifying for dialysis centre. By this analysis, the explained variation in all-cause death of the model including the NYHA score was 39%, i.e. almost identical to that of the model including RDSS (37%), and superior (P < 0.001) to that of the model including the Khan index (32%) (Table 2).


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  		Table 2. Multiple Cox regression analysis

 
ROC curve analysis
The prognostic value for mortality of three (crude) indexes was also tested by ROC analysis. In this analysis the area under the curves of the three indexes was significantly (P < 0.001) higher than the area of diagnostic indifference (Khan index: 0.70, 95% CI: 0.67–0.72; age-adjusted RDSS: 0.74, 95% CI: 0.72–0.77; age-adjusted NYHA score: 0.74, 95% CI: 0.71–0.77, all P < 0.001) (Figure 2). Furthermore, this analysis revealed that the age-adjusted RDSS and NYHA score had a comparable predictive value and these indexes were again superior to the Khan Index (P < 0.01) for the prediction of death.


Figure 2
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  		Fig. 2. ROC curve analysis of Khan index and age-adjusted RDSS and NYHA score for all-cause mortality. Data are also reported in the results section.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
This study shows that, independently of other risk factors, the NYHA score predicts death in the dialysis population. Furthermore, this indicator appears to be a prognostic factor at least as strong as established disease-severity scores currently used for risk stratification in the dialysis population.

HF in western countries is a major public health problem. Analysis of historical trends at the community level shows that the incidence of this disease continues to rise as the population ages [17]. Cardiac insufficiency is a multifactorial problem [8] and the vast majority of cases are attributable to classical risk factors like diabetes, hypertension, hypercholesterolaemia and smoking, i.e. the same factors which are also responsible for chronic kidney disease in the general population [18,19]. This large overlapping of risk factors for heart and renal disease likely explains why about one-third of patients starting regular dialysis are affected by HF. HF in dialysis patients entails a gloomy prognosis because the expected survival in patients who start dialysis with signs of advanced HF is <6 months [20]. The expert panel of the American Kidney Foundation identified prevention of cardio-myopathy and HF as a primary goal for improving survival in ESRD [3]. The diagnosis of HF is made on clinical grounds [8], and the American College of Cardiology [7] and the European Society of Cardiology [8] require echocardiographic studies of heart anatomy and function as an objective basis for the diagnosis of heart disease and the use of NYHA to grade the severity of this disease is formally recommended in clinical guidelines emanated by the same societies [7,8]. Alterations in left ventricular mass and performance are almost universal in the dialysis population. Indeed, cardiac ischaemia apart, about three-fourths of dialysis patients display left ventricular hypertrophy (LVH) [21] and over 90% have either systolic or diastolic ventricular dysfunction or both alterations. Thus virtually all dialysis patients are at risk for heart failure. The NHYA classification identifies dyspnoea as a basic symptom for grading the severity of heart failure. Therefore this classification may be in part confounded by volume overload or by concomitant pulmonary disease. Extra-cellular volume expansion is an important risk factor for eccentric LVH and may trigger or aggravate dyspnoea in patients with underlying heart disease. Because the relative rarity of severe respiratory insufficiency, this factor virtually did not modify the hazard rate associated with NYHA classification. In the present study, we found that mild to severe HF is an exceedingly frequent comorbidity in patients with ESRD. About one-third of patients in the New Foundland cohort [4] and in the wave 2 USRDS study [6] presented signs of HF at the start of long-term dialysis. In our cohort, 36% of patients had at least occasional effort dyspnoea when enrolled into the registry. The NYHA is perhaps one of the most used scoring systems for risk stratification of patients with heart disease. Indeed, this score predicts death and cardiovascular complications in a variety of settings including community-based studies and studies in patients with coronary heart disease or heart failure. The good inter-observer agreement of the NYHA is an advantage of this scoring system which is often used to calibrate other scoring systems [22]. To our knowledge the prognostic value of the NYHA has never been tested in ESRD patients. This is important because the prognostic performance of risk factors and disease-severity indicators should be tested in the specific populations where they are planned to be applied in clinical practice. Such a consideration appears particularly relevant in ESRD, a population with a cardiovascular burden of unique severity and characterized by a combination of risk factors which does not coincide with that commonly observed in the general population [2]. ‘We found the NYHA score not only was a strong predictor of death but also that there was a graded relationship between NYHA class and the outcome, a phenomenon indicating that NYHA classes truly capture an increasing risk for death. Furthermore, this indicator was a prognostic marker as strong as the RDSS and stronger than a well-established scoring system in the dialysis population like the Khan index. Like the NYHA score, the Khan index is very easy to compute because it is based just on three variables, i.e. age class, diabetes and past cardiovascular events. The NYHA needs very simple information which is almost always obtained by doctors during medical encounters.

The RDSS is a multidimensional comorbidity score invented by Craven et al. [11], which proved to be fairly reproducible [13] and associated with survival [23] in our dialysis population. However this indicator is based on 11 scales and requires about 10–15 min to compute being, thus, less apt at being applied in clinical practice than the Khan index [10] or the NYHA. Likewise, the Charlson comorbidity index, another well-validated risk score [24], is based on 16 variables and, outside electronic database management systems, its application may be less immediate than the Khan index or the NHYA.

The NYHA classification is a powerful predictor of mortality in ESRD and provides prognostic information equal or superior to that given by other established indexes of disease severity. This classification may be recommended as a simple and useful adjunct in the risk stratification of the dialysis population.



   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
Renal Physicians involved in the C.RE.DI.T.:

L. Lombardi, G. Merando (Catanzaro); V. Martire-R. Bonofiglio (Cosenza); G. Cuzzocrea, O. Santoro (Crotone); M. Postorino, C. Marino (Reggio Calabria) G. Ascoli (Vibo Valentia); R. Musacchio, A.Minisci (Acri); T. Urso, R.Senatore (Cariati); A. Foscaldi (Castrovillari); F. Grandinetti (Catanzaro Lido); G. Mazza, A. Caglioti (Catanzaro Policlinico); V. Rocchetti, G. Amendola (Cetraro); P. Procopio, A. Mellace (Chiaravalle); R. Roberti (Cosenza ASL 4); F. D’Agostino, E. Falvo (Lamezia); C.Franco (Locri); I. Maimone, A. Confessore (Lungro); A. Sellaro (Mesoraca); C.Vardè, C.Fornaciari (Nicotera); D. Plutino, V. Rondanini (Palmi); M-Rovito, R. Pititto (Paola); F. Fabiamo, M.Pizzini (Praia a Mare) T. Cicchetti, N. Luca’ (Rossano), A. Nicoletti, G.Rizzuto (San Giovanni in Fiore); C. Sapio (S. Marco Argentano); O. Marzolla (Melito PS); D. Galati, R. Regio (Serra San Bruno); A. Pugliese (Soriano); F. Grandinetti (Soverato); M. Gullo, A. Guido (Soveria Mannelli); V. Bruzzese, F.Candito (Taurianova); M. Milei, M.DeGaudio (Trebisacce); G. Alati, C. Pugliese, F. Gioffre’ (Tropea).

Conflict of interest statement. None declared.



   Notes
 
* The full list of investigators involved in the Calabrian Registry is given in the Acknowledgements Back



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 7.11.06
Accepted in revised form: 12.12.06


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