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Arquivos Brasileiros de Cardiologia

Arq. Bras. Cardiol.

0066-782X 1678-4170

Sociedade Brasileira de Cardiologia - SBC

São Paulo, SP, Brazil

L6Kn7PDgd4dxJdPBYGCvz3Q

00016

S0066-782X2010000300016

S0066-782X(10)09400316

10.1590/S0066-782X2010000300016

Artigos Originais

Disfunção renal e anemia em pacientes com insuficiência cardíaca com fração de ejeção reduzida versus normal

Villacorta

Humberto

Saenz-Tello

Bolivar F.

Santos

Eduarda Barcellos dos

Steffen

Ricardo

Wiefels

Christiane

Lima

Luiz Costa

Sales

Ana Luíza F.

Soares

Pedro

Mesquita

Evandro Tinoco

Niterói

Rio de Janeiro

Universidade Federal Fluminense Hospital Universitário Antônio Pedro Brazil

03 2010

94 3 378 384 26 02 2008 04 11 2008 14 05 2009

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

FUNDAMENTO: A presença de anemia e de disfunção renal confere mau prognóstico em pacientes com insuficiência cardíaca (IC) e fração de ejeção reduzida (ICFER). O impacto em pacientes com IC e fração de ejeção normal (ICFEN) é pouco estudado. OBJETIVOS: Estudar a prevalência e o prognóstico da anemia e da disfunção renal (DR) em pacientes com IC de acordo com o tipo de disfunção ventricular. MÉTODOS: Foram estudados prospectivamente 209 pacientes com IC crônica estável. Pacientes com fração de ejeção <50 % foram considerados como tendo ICFER. Anemia foi definida pelos critérios da OMS como hemoglobina <13 g/dl em homens e <12 g/dl em mulheres. A função renal foi calculada pela fórmula sMDRD (Simplified Modified Diet Renal Disease). Hospitalizações, visitas a emergências e óbitos por causas cardíacas foram considerados como eventos cardíacos. RESULTADOS: Noventa pacientes tinham ICFER e 119, ICFEN. A taxa de filtração glomerular (TFG) foi menor no grupo com ICFER (57,6 ± 66,2 versus 94,8 ± 36,6 ml/min/1,73m²; p=0,01). Não houve diferença na prevalência da anemia nos dois grupos (23,3% versus 18,5%; p=0,34). A prevalência da DR moderada a grave foi maior no grupo com ICFER (32,2% versus 16,8% p=0,01). A DR foi o único fator associado à anemia e associou-se independentemente com eventos cardíacos (HR 2,52; IC 95% = 1,27 - 5,2; p=0,01). CONCLUSÃO: DR foi menos prevalente na ICFEN, enquanto a prevalência de anemia não diferiu entre os dois grupos. A DR foi preditora de eventos cardíacos, independentemente da fração de ejeção.

Insuficiência cardíaca anemia insuficiência renal

28 04 2010

ARTIGO ORIGINAL

INSUFICIÊNCIA CARDÍACA

Disfunção renal e anemia em pacientes com insuficiência cardíaca com fração de ejeção reduzida versus normal

Humberto Villacorta; Bolivar F. Saenz-Tello; Eduarda Barcellos dos Santos; Ricardo Steffen; Christiane Wiefels; Luiz Costa Lima; Ana Luíza F. Sales; Pedro Soares; Evandro Tinoco Mesquita

Universidade Federal Fluminense - Hospital Universitário Antônio Pedro, Niterói, RJ, Brasil

Correspondência

RESUMO

OBJETIVOS: Estudar a prevalência e o prognóstico da anemia e da disfunção renal (DR) em pacientes com IC de acordo com o tipo de disfunção ventricular.

MÉTODOS: Foram estudados prospectivamente 209 pacientes com IC crônica estável. Pacientes com fração de ejeção <50 % foram considerados como tendo ICFER. Anemia foi definida pelos critérios da OMS como hemoglobina <13 g/dl em homens e <12 g/dl em mulheres. A função renal foi calculada pela fórmula sMDRD (Simplified Modified Diet Renal Disease). Hospitalizações, visitas a emergências e óbitos por causas cardíacas foram considerados como eventos cardíacos.

RESULTADOS: Noventa pacientes tinham ICFER e 119, ICFEN. A taxa de filtração glomerular (TFG) foi menor no grupo com ICFER (57,6 ± 66,2 versus 94,8 ± 36,6 ml/min/1,73m²; p=0,01). Não houve diferença na prevalência da anemia nos dois grupos (23,3% versus 18,5%; p=0,34). A prevalência da DR moderada a grave foi maior no grupo com ICFER (32,2% versus 16,8% p=0,01). A DR foi o único fator associado à anemia e associou-se independentemente com eventos cardíacos (HR 2,52; IC 95% = 1,27 - 5,2; p=0,01).

CONCLUSÃO: DR foi menos prevalente na ICFEN, enquanto a prevalência de anemia não diferiu entre os dois grupos. A DR foi preditora de eventos cardíacos, independentemente da fração de ejeção.

Palavras chave: Insuficiência cardíaca, anemia, insuficiência renal.

Introdução

Anemia e disfunção renal (DR) são duas comorbidades prevalentes e que alteram para pior o curso da insuficiência cardíaca (IC)^1-4. Vários mecanismos fisiopatológicos foram propostos para explicar a presença de anemia em pacientes com IC, entre eles anemia de doenças crônicas⁵, disfunção renal, hemodiluição⁶, menor produção de eritropoetina pelo uso dos inibidores da enzima conversora de angiotensina (IECA) e bloqueadores dos receptores de angiotensina (BRA)^7,8. Independentemente do mecanismo presente, a presença de anemia confere mau prognóstico⁶.

A DR está presente em cerca de 30% dos pacientes com IC e também é considerada um importante fator prognóstico^9-11. Ela leva à produção de fatores inflamatórios, sobrecarga hidrossalina e alterações do metabolismo do cálcio e fósforo, que podem levar ao agravamento da IC¹². A própria disfunção renal promove anemia, levando a um círculo vicioso denominado por alguns autores como síndrome anemia cardiorrenal, a qual tem sido relacionada a aumento da mortalidade^13-16. Vários estudos avaliaram a influência da anemia e da disfunção renal em pacientes com IC e fração de ejeção reduzida (ICFER). No entanto, a inter-relação dessas duas variáveis foi pouco estudada em pacientes com IC e fração de ejeção normal (ICFEN).

O objetivo deste estudo foi avaliar a prevalência e o impacto prognóstico da anemia e da DR em pacientes portadores de IC crônica ambulatorial, de acordo com o tipo de disfunção cardíaca.

Métodos

Entre os meses de dezembro de 2005 até fevereiro de 2007, foram triados 230 pacientes com diagnóstico de IC crônica, sendo 114 de um programa de atenção comunitária (médico de família) e 116 pacientes provenientes de um ambulatório especializado em IC, em um hospital universitário. Os critérios de inclusão foram escore de Boston acima de 8 pontos e idade acima de 18 anos. Dos 230 pacientes, foram excluídos 21 por não atingirem o valor dos critérios de Boston acima citados, restando 209 pacientes que foram incluídos neste estudo.

Na primeira entrevista, todos os participantes foram submetidos a anamnese completa, exame físico, hemograma completo, bioquímica, raios X de tórax, eletrocardiograma e ecocardiograma, determinando-se a fração de ejeção do ventrículo esquerdo (FEVE) pelo método de Simpson. Pacientes que apresentaram FEVE<50% foram classificados como tendo ICFER, e pacientes com FEVE>50%, na presença de qualquer grau de disfunção diastólica determinada pela ecocardiografia, classificados como sendo portadores de ICFEN. Os estágios de disfunção diastólica foram avaliados de acordo com o padrão de fluxo mitral avaliado pelo Doppler convencional e classificados como estágio I (normal), II (déficit de relaxamento), III (padrão pseudonormal) e IV (padrão restritivo).

Definição de disfunção renal e de anemia

O cálculo da função renal foi feito por meio da fórmula da taxa de filtração glomerular (TFG) Simplified Modified Diet Renal Disease (sMDRD). Para o sexo masculino, utilizou-se a fórmula 186 x creatinina sérica^-1,154 x idade ^-0,203; homens negros: sMDRD x 1,212. Para o sexo feminino, utilizou-se a fórmula sMDRD x 0,742; mulher negra: sMDRD x 0,742 x 1,212). Posteriormente, todos foram classificados de acordo com sua função renal em: normal (TFG>90 ml/min/1,73m²), disfunção renal leve (TFG<90 e >60 ml/min/1,73m²), disfunção renal moderada (TFG<60 e >30 ml/min/1,73m²), e disfunção renal grave (TFG<30 ml/min/1,73m²). Anemia foi diagnosticada pelos critérios da OMS como taxas de hemoglobina <13g/dl em homens e <12 g/dl em mulheres.

Definição dos eventos cardiovasculares

A inclusão de pacientes encerrou-se no final do mês de fevereiro do ano 2007. Foi determinado um seguimento mínimo de 60 dias para os últimos participantes incluídos no estudo. Todos foram reavaliados no mês de abril do ano 2007, independentemente da sua data de inclusão, para determinação dos desfechos clínicos nos dois grupos. O seguimento médio foi de 12,4 ± 8 meses. Foram considerados desfechos hospitalizações não programadas, visitas à sala de emergência ou morte de origem cardíaca.

Análise estatística

As variáveis contínuas foram expressas como médias e seus respectivos desvios padrões e comparadas pelo teste t de Student ou ANOVA. As variáveis categóricas se expressaram sob forma de valores absolutos e percentagem e foram comparadas utilizando-se o teste de Chi-quadrado ou teste exato de Fischer para as amostras com valores esperados menores que cinco. As variáveis que foram estatisticamente significativas na análise univariada foram incluídas na análise multivariada (regressão logística) comparando-se os pacientes com e sem anemia. Foram realizadas análises multivariadas para estabelecer o valor independente das variáveis com os desfechos no seguimento, utilizando-se a análise do modelo de riscos proporcionais de Cox. As variáveis anemia e DR foram incluídas nos modelos multivariados como variáveis categóricas. Considerou-se como DR moderada ou grave presente, TFG<60 ml/min/1,73m². A análise foi realizada pelos programas estatísticos EPIINFO 3.4 e SPSS, versão 11.0. Valores de p<0,05 foram considerados estatisticamente significativos.

Bioética

Este estudo foi aprovado pelo Comitê de Ética em Pesquisa do nosso hospital, em consoante à declaração de Helsinki, sob o número 17906. Todos os participantes foram informados dos riscos, benefícios do estudo e assinaram termo de consentimento esclarecido.

Resultados

Características basais

De um total de 209 pacientes com diagnóstico clínico de IC, 90 pacientes (43,1%) eram portadores de ICFER e 119 pacientes (56,9%) de ICFEN. A tabela 1 mostra as características basais dos pacientes. Conforme observado, os portadores de ICFER apresentavam maior prevalência de infarto do miocárdio prévio, menores valores de pressão arterial e pior função renal. Os portadores de ICFEN eram em sua maioria mulheres, com maiores níveis de colesterol total e com maior prevalência de obesidade e hipertensão arterial. Não se observaram diferenças significativas quanto a idade nem quanto a níveis de hemoglobina nos dois grupos. A maioria dos pacientes estava em classe funcional I ou II (73%).

Os medicamentos utilizados no momento da inclusão no estudo encontram-se na tabela 2. A maioria das medicações usadas no tratamento da IC foi prescrita mais frequentemente para pacientes com ICFER. Pacientes com ICFEN utilizaram mais diuréticos tiazídicos. Não houve diferença significativa na taxa de prescrição de ácido acetilsalicílico (AAS).

Prevalência de disfunção renal

Qualquer DR (TFG<90 ml/min/1,73m²) estava presente em 121 (57,9%), enquanto DR moderada ou grave estava presente em 23,3% da população como um todo. A classificação dos pacientes nos dois grupos de acordo com a TFG encontra-se na tabela 3. A prevalência de DR moderada ou grave foi duas vezes maior nos pacientes com ICFER quando comparada aos portadores de ICFEN (32,2% versus 16,8%; p=0,01), conforme mostrado na figura 1. No grupo com ICFER, apenas 29 (32,2%) pacientes apresentaram função renal normal contra 59 (49,6%) no grupo com ICFEN (p=0,01). No grupo ICFEN, a distribuição dos valores de creatinina nos estágios II a IV de disfunção diastólica, respectivamente, foi 0,98 ± 0,26, 1,08 ± 0,3 e 1,26 ± 0,32 (p=0,02).

Prevalência de anemia

A prevalência de anemia na população como um todo foi de 20,6%. Não houve diferença significativa na prevalência de anemia nos pacientes com ICFER comparados aos com ICFEN (23,3% versus 18,5%; p=0,34). No grupo ICFEN, a distribuição dos valores de hemoglobina nos estágios II a IV de disfunção diastólica foi 13,8 ± 1,03, 11,7 ± 1,12 e 10,9 ± 1,32 (p=0,04).

Fatores associados à anemia

A tabela 4 compara as características dos pacientes portadores e não portadores de anemia. Os pacientes anêmicos eram predominantemente do sexo masculino, apresentavam pior função renal e utilizavam mais frequentemente diuréticos de alça quando comparados a não anêmicos. Por meio de análise multivariada, a única variável associada de modo independente à anemia foi a presença de disfunção renal, com razão de chances de 3,89 (intervalo de confiança de 95% = 1,74 a 7,37; p=0,001). A fração de ejeção não se associou à anemia.

Valor prognóstico da DR e da anemia

Sete pacientes (3,7%) morreram por IC descompensada, sendo todos do grupo de ICFER (7,7% versus 0%; p=0,004). A presença de desfechos combinados foi maior no grupo ICFER (34 [36,6%] versus 28 [24,3%]; p=0,037). Em análise univariada, os principais fatores relacionadas aos eventos cardiovasculares foram disfunção renal moderada ou grave, diabete melito, infarto do miocárdio prévio, sexo masculino e a presença de fração de ejeção reduzida. Ao realizar-se a análise de regressão multivariada pelo modelo de riscos proporcionais de Cox (tabela. 5), observamos que a DR correlacionou-se independentemente com os eventos cardiovasculares (hazard ratio) 2,52 [IC 95% = 1,27 a 5,2]; p=0,01), assim como fração de ejeção reduzida (HR=1,6 [IC 95%=1,05 a 2,04], p=0,03). Anemia não foi preditora de eventos, observando-se presença de desfechos em anêmicos versus não anêmicos de 15 (34,8%) versus 47 (28,3%) pacientes, p=0,38. A taxa de eventos de acordo com a presença de DR e anemia é mostrada na figura 2.

Discussão

A relação entre anemia e função renal em pacientes com IC tem sido motivo de várias investigações. Neste estudo, demonstramos que pacientes com ICFER apresentam mais frequentemente disfunção renal que pacientes com ICFEN, embora a prevalência de anemia tenha sido semelhante nas duas populações. Além disso, demonstramos que a DR foi a única variável associada à anemia e foi preditora independente de eventos, a despeito da fração de ejeção. Interessantemente, nos pacientes com ICFEN, observou-se pior função renal e menores níveis de hemoglobina nos estágios mais avançados de disfunção diastólica.

Prevalência da disfunção renal

DR é frequente em pacientes com IC e está associada a pior prognóstico, tanto em pacientes ambulatoriais, quanto em pacientes hospitalizados^1,16-23. Graus mais avançados de disfunção são particularmente frequentes em pacientes descompensados. No registro ADHERE²³, em que pacientes hospitalizados por IC descompensada (com FEVE reduzida ou preservada) foram incluídos, 63,3% dos pacientes apresentavam TFG<60 ml/min/1,73m². Em pacientes ambulatoriais, uma meta-análise mostrou prevalência de qualquer disfunção renal em 51% dos casos e de disfunção moderada ou grave em 10%¹. A prevalência de DR e seus níveis de gravidade em nosso estudo foram próximos aos encontrados nessa meta-análise.

Quando comparamos pacientes com ICFER versus ICFEN, encontramos maior prevalência de DR no primeiro grupo. Após estratificação dos pacientes em diferentes estágios de acordo com a TFG, evidenciamos que apenas um terço dos pacientes com ICFER apresentaram função renal normal e 32% apresentaram disfunção renal moderada ou grave, contra 16,8% no grupo ICFEN. Esse fato está de acordo com o observado por outros autores^9,10,19.

Vale salientar que apesar de mais prevalente na ICFER, quase 20% dos pacientes com ICFEN apresentaram comprometimento moderado ou grave da função renal, sugerindo que o comprometimento renal na IC envolve mecanismos outros que baixo débito cardíaco e má perfusão renal, típicos de pacientes com ICFER. De fato, sabe-se hoje que o aumento da pressão venosa central, levando a aumento da pressão em veias renais, é um dos mecanismos envolvidos na síndrome cardiorrenal e poderia explicar sua gênese em pacientes com ICFEN^12,24.

Prevalência da anemia

No presente estudo observamos que 20% dos pacientes apresentaram anemia. A prevalência da anemia na IC tem variado de estudo para estudo. Isso pode ser explicado pelos diferentes critérios diagnósticos e por diferentes contextos clínicos. Em um estudo retrospectivo, em população hospitalar, feito no Brasil, encontrou-se que 45% dos pacientes com IC apresentavam anemia, utilizando-se um corte de 12 g/dl, independentemente do sexo²⁰. Já em outro estudo brasileiro, utilizando-se corte de hemoglobina <13 g/dl para mulheres e <12 g/dl para homens, a prevalência de anemia subiu para 62,6%²⁵.

Quando comparamos as prevalências da anemia na ICFER e na ICFEN, não observamos diferença significativa. Outros autores encontraram achados semelhantes. No estudo CHARM²⁶, a prevalência de anemia em pacientes com ICFER e ICFEN, respectivamente, foi de 25% e 27%. Em um estudo brasileiro, em pacientes com IC descompensada, a prevalência da anemia foi até significativamente maior no grupo com ICFEN²⁷. Nossos achados, portanto, confirmam que a incidência de anemia em pacientes com ICFEN é tão freqüente quanto em pacientes com ICFER.

Em análise multivariada, o único fator associado de modo independente à anemia foi a DR. Embora não tenha sido o objetivo deste estudo estabelecer os mecanismos envolvidos na gênese da anemia, esse dado sugere que a DR tem papel importante como causa da anemia em pacientes com IC. No entanto, como a prevalência de DR foi menor em pacientes com ICFEN, outros mecanismos além da função renal, podem estar envolvidos nesse grupo.

Disfunção renal e anemia como fatores prognósticos

DR em nosso trabalho foi associada independentemente com os eventos cardiovasculares, fato esse bem estabelecido na literatura¹. O impacto prognóstico da DR de acordo com o tipo de disfunção ventricular, no entanto, não está bem estabelecido. Apesar de os pacientes portadores de ICFER serem considerados mais graves, alguns estudos mostram que a DR tem impacto prognóstico também em pacientes com ICFEN. De fato, é descrito que função renal reduzida pode piorar a função diastólica²⁸. No estudo DIG, encontrou-se maior mortalidade relacionada à DR em pacientes com ICFEN quando comparados aos com ICFER¹⁹. Grigorian e cols.¹⁰, entretanto, observaram que o prognóstico da IC foi pior em pacientes com disfunção renal independentemente da fração de ejeção¹⁰. Já Silva e cols.²⁰, em um estudo feito no Brasil, determinaram que a fração de ejeção de VE reduzida e níveis elevados de creatinina estiveram relacionados à maior mortalidade²⁰. Em nosso trabalho, encontramos achados semelhantes, mostrando que DR e fração de ejeção reduzida foram preditores independentes de eventos. Analisando todos esses estudos, concluímos que a função renal têm impacto na evolução da IC, independentemente da FEVE.

Anemia em nosso estudo não foi preditora de eventos, ao contrário do demonstrado por outros autores. No estudo CHARM²⁶, anemia foi preditora de eventos tanto em pacientes com ICFER quanto com ICFEN. Uma explicação para nosso achado pode ter sido a casuística relativamente pequena. De fato, houve maior número de eventos nos pacientes anêmicos (34,8% versus 28,3%), não atingindo, no entanto, significância estatística. Baseado nos dados prognóstico mostrados na literatura, tornou-se atraente a hipótese de tratar a anemia em pacientes com IC. É descrito que sua correção em pacientes renais crônicos retarda a piora da função renal²⁹. Em pacientes com IC, dados iniciais foram animadores, mostrando que a correção da anemia melhorou sintomas e capacidade funcional^20,30. Um estudo recente, no entanto, não mostrou benefícios no aumento da tolerância ao exercício, embora tenha havido tendência à redução de mortalidade e hospitalizações por IC³¹.

O presente trabalho sugere que a função renal tem papel mais importante que a anemia na evolução de pacientes com IC crônica estáveis. Estratégias para preservar função renal são necessárias e têm sido pesquisadas na literatura, tanto em pacientes ambulatoriais quanto hospitalizados^32-35, não havendo, no entanto, um consenso sobre o benefício dessas novas drogas ou procedimentos na função renal.

Limitações

Não estudamos outros mecanismos de anemia além da disfunção renal, não sendo possível estabelecer relação causal nem temporal entre anemia e DR. A casuística relativamente pequena pode ter contribuído para erro do tipo II, especialmente no que diz respeito ao valor prognóstico da anemia. A maior proporção de pacientes com ICFEN em relação aos com ICFER no presente estudo não pode ser extrapolada para a população geral com IC, pois deve-se provavelmente a viés de seleção, em razão do maior número de pacientes com ICFEN encaminhados do programa de atenção primária para esse projeto.

Conclusões

A prevalência da disfunção renal foi mais elevada na ICFER quando comparada à ICFEN. Não houve diferença na prevalência de anemia nos dois grupos. A DR foi o único fator associado à anemia nos dois grupos, embora não se possa estabelecer relação de causalidade. A DR e baixa fração de ejeção do VE correlacionaram-se independentemente com os eventos cardiovasculares, independentemente da presença de anemia.

Potencial Conflito de Interesses

Declaro não haver conflito de interesses pertinentes.

Fontes de Financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação Acadêmica

Este artigo é parte de dissertação de Mestrado de Bolivar F. Saenz-Tello pela Universidade Federal Fluminense.

Correspondência:

Humberto Villacorta Junior

Rua Visconde de Silva, 154/402 - Humaitá

22271-090 - Rio de Janeiro, RJ, Brasil

E-mail:

hvillacorta@cardiol.br

Artigo recebido em 04/11/08; revisado recebido em 26/02/08; aceito em 14/05/09.

1. Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, Di Capua P, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006; 47: 1987-96.

Renal impairment and outcomes in heart failure: systematic review and meta-analysis

J Am Coll Cardiol 2006 1987 96 47

Smith

Lichtman

Bracken

Shlipak

Phillips

Di Capua

2. de Silva R, Nikitin PN, Witte KKA, Rigby AS, Goode K, Bhamari S, et al. Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to ventricular systolic dysfunction: contributing factors and relationship to prognostic. Eur Heart J. 2006; 27: 569-81.

Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to ventricular systolic dysfunction: contributing factors and relationship to prognostic

Eur Heart J 2006 569 81 27

de Silva

Nikitin

Witte

KKA

Rigby

Goode

Bhamari

3. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002; 39: 1780-6.

Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure

J Am Coll Cardiol 2002 1780 6 39

Horwich

Fonarow

Hamilton

MacLellan

Borenstein

4. Anand IS, McMurray JJ, Whitmore J, Warren M, Pham A, McCamish MA, et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004; 110: 149-54.

Anemia and its relationship to clinical outcome in heart failure

Circulation 2004 149 54 110

Anand

McMurray

Whitmore

Warren

Pham

McCamish

5. Berry C, Norrie J, Hogg K, Brett M, Stevenson K, McMurray JJ. The prevalence, nature and importance of hematologic abnormalities in heart failure. Am Heart J. 2006; 151: 1313-21.

The prevalence, nature and importance of hematologic abnormalities in heart failure

Am Heart J 2006 1313 21 151

Berry

Norrie

Hogg

Brett

Stevenson

McMurray

6. Androne AS, Kats SD, Lund L, Swedberg K, McMurray JJ, Yusuf S, et al. Hemodilution is common in patients with advanced heart failure. Circulation. 2003; 107: 226-9.

Hemodilution is common in patients with advanced heart failure

Circulation 2003 226 9 107

Androne

Kats

Lund

Swedberg

McMurray

Yusuf

7. Yildiz A, Cine N, Akkaya V, Sahin S, Ismailoglu V, Turk S, et al. Comparison of the effects of enalapril and losartan on post-transplantation erythrocytosis in renal transplant recipients: prospective randomized study. Transplantation. 2001; 72: 542-4.

Comparison of the effects of enalapril and losartan on post-transplantation erythrocytosis in renal transplant recipients: prospective randomized study

Transplantation 2001 542 4 72

Yildiz

Cine

Akkaya

Sahin

Ismailoglu

Turk

8. Plata R, Cornejo A, Arratia C, Anabaya A, Perna A, Dimitrov BD, et al. Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial. Lancet. 2002; 359: 663-6.

Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial

Lancet 2002 663 6 359

Plata

Cornejo

Arratia

Anabaya

Perna

Dimitrov

9. Hillege HL, Nitsh D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, et al. Renal function as a predictor of outcome in broad spectrum of patients in heart failure. Circulation. 2006; 113: 671-8.

Renal function as a predictor of outcome in broad spectrum of patients in heart failure

Circulation 2006 671 8 113

Hillege

Nitsh

Pfeffer

Swedberg

McMurray

Yusuf

10. Grigorian L, Varela A, Román A, Pedreira Perez M, Otero IG, Lamela AV, et al. La insuficiencia renal es um factor de riesgo independiente de la mortalidad em pacientes hospitalizados por insuficiencia cardíaca y se asocia com um peor perfil de riesgo cardiovascular. Rev Esp Cardiol. 2006; 2: 99-108.

La insuficiencia renal es um factor de riesgo independiente de la mortalidad em pacientes hospitalizados por insuficiencia cardíaca y se asocia com um peor perfil de riesgo cardiovascular

Rev Esp Cardiol 2006 99 108 2

Grigorian

Varela

Román

Pedreira Perez

Otero

Lamela

11. Chae C, Albert C, Robert C. Mild renal insufficiency and risk of congestive heart failure in men and women over 70 years of age. Am J Cardiol. 2003; 92: 682-6.

Mild renal insufficiency and risk of congestive heart failure in men and women over 70 years of age

Am J Cardiol 2003 682 6 92

Chae

Albert

Robert

12. Ronco C, Haapio M, House AA, Anavecar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008; 52: 1527-39.

Cardiorenal syndrome

J Am Coll Cardiol 2008 1527 39 52

Ronco

Haapio

House

Anavecar

Bellomo

13. Silverberg DS, Wexler D, Blum M, Keren G, Sheps D, Leibovitch E, et al. The use of subcutaneous erythropoietin and intravenous iron for anemia in severe, resistant, congestive heart failure improves cardiac and renal function and functional cardiac class and markedly reduces hospitalizations. J Am Coll Cardiol. 2000; 35: 1737-44.

The use of subcutaneous erythropoietin and intravenous iron for anemia in severe, resistant, congestive heart failure improves cardiac and renal function and functional cardiac class and markedly reduces hospitalizations

J Am Coll Cardiol 2000 1737 44 35

Silverberg

Wexler

Blum

Keren

Sheps

Leibovitch

14. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DN, Levey AS, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001; 38: 955-62.

Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction

J Am Coll Cardiol 2001 955 62 38

Al-Ahmad

Rand

Manjunath

Konstam

Salem

Levey

15. Abramsom J, Jurkovitz C, Vaccarino V, Weintraub W, McClellan. Chronic kidney disease, anemia and incident stroke in a middle-age, community-based population: the ARIC study. Kidney Int. 2003; 64: 610-5.

Chronic kidney disease, anemia and incident stroke in a middle-age, community-based population: the ARIC study

Kidney Int 2003 610 5 64

Abramsom

Jurkovitz

Vaccarino

Weintraub W

McClellan

16. Celik T, Iyisoy A, Kursaklioglu H, Grungor M, Yuksel UC. Anemia and cardiorenal syndrome: a deadly association? Int J Cardiol. 2008; 128: 255-6.

Anemia and cardiorenal syndrome: a deadly association?

Int J Cardiol 2008 255 6 128

Celik

Iyisoy

Kursaklioglu

Grungor

Yuksel

17. Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Grady D, Shlipak MG. Renal insufficiency as an independent predictor of mortality among women with heart failure. J Am Coll Cardiol. 2004; 44 (8): 1593-600.

Renal insufficiency as an independent predictor of mortality among women with heart failure

J Am Coll Cardiol 2004 1593 600 8 44

Bibbins-Domingo

Lin

Vittinghoff

Barrett-Connor

Grady

Shlipak

18. Damman K, Navis G, Voors A, Asselbergs FW, Smilde TD, Cleland JG, et al. Worsening renal function and prognosis in heart failure: a systematic review and meta-analysis. J Card Fail. 2007; 13: 599-608.

Worsening renal function and prognosis in heart failure: a systematic review and meta-analysis

J Card Fail 2007 599 608 13

Damman

Navis

Voors

Asselbergs

Smilde

Cleland

19. Ahmed A, Rich MW, Sanders PW, Perry GJ, Bakris GL, Zile MR, et al. Chronic kidney disease associated mortality in diastolic versus systolic heart failure: a propensity matched study. Am J Cardiol. 2007; 99: 393-8.

Chronic kidney disease associated mortality in diastolic versus systolic heart failure: a propensity matched study

Am J Cardiol 2007 393 8 99

Ahmed

Rich

Sanders

Perry

Bakris

Zile

20. Silva RP, Barbosa PH, Kimura OS, Sobrinho CR, Souza Neto JD, Silva FA, et al. Prevalence of anemia and its association with cardiorenal syndrome. Int J Cardiol. 2007; 120: 232-6.

Prevalence of anemia and its association with cardiorenal syndrome

Int J Cardiol 2007 232 6 120

Silva

Barbosa

Kimura

Sobrinho

Souza Neto

Silva

21. Macclellan W, Flanders D, Langston R, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol. 2002; 13: 1928-36.

Anemia and renal insufficiency are independent risk factors among patients with congestive heart failure admitted to community hospitals: a population-based study

J Am Soc Nephrol 2002 1928 36 13

Macclellan

Flanders

Langston

Jurkovitz

Presley

22. Luthi J, Flanders W, Burnier M, Burnand B, McClellan W. Anemia and chronic kidney disease are associated with poor outcomes in heart failure patients. BMC Nephrol. 2006; 6: 2-28.

Anemia and chronic kidney disease are associated with poor outcomes in heart failure patients

BMC Nephrol 2006 2 28 6

Luthi

Flanders

Burnier

Burnand

McClellan

23. Heywood JT, Fonarow GC, Constanzo MR, Mathur VS, Wigneswaran JR, Wynne J, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail. 2007; 13: 422-30.

High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database

J Card Fail 2007 422 30 13

Heywood

Fonarow

Constanzo

Mathur

Wigneswaran

Wynne

24. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, et al. Cardiorenal interactions: insights from the ESCAPE Trial. J Am Coll Cardiol. 2008; 51: 1268-74.

Cardiorenal interactions: insights from the ESCAPE Trial

J Am Coll Cardiol 2008 1268 74 51

Nohria

Hasselblad

Stebbins

Pauly

Fonarow

Shah

25. Sales ALF, Villacorta H, Reis L, Mesquita ET. Anemia as a prognostic factor in a population hospitalized due to decompensated heart failure. Arq Bras Cardiol. 2004; 84: 237-40.

Anemia as a prognostic factor in a population hospitalized due to decompensated heart failure

Arq Bras Cardiol 2004 237 40 84

Sales

ALF

Villacorta

Reis

Mesquita

26. O'Meara E, Clayton T, McEntegart MB, Mc Murray JJ, Lang CC, Roger SD, et al. Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure. Results of the Candesartan in Heart Failure: Assesment of Reduction in Mortality and Morbidity (CHARM) Program. Circulation. 2006; 113 (7): 986-94.

Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: Results of the Candesartan in Heart Failure: Assesment of Reduction in Mortality and Morbidity (CHARM) Program

Circulation 2006 986 94 7 113

O'Meara

Clayton

McEntegart

Mc Murray

Lang

Roger

27. Latado AL, Passos LCS, Darzé ES, Lopes AA. Comparison of the effects of anemia on in-hospital mortality in patients with versus without preserved left ventricular ejection fraction. Am J Cardiol. 2006; 98: 1631-4.

Comparison of the effects of anemia on in-hospital mortality in patients with versus without preserved left ventricular ejection fraction

Am J Cardiol 2006 1631 4 98

Latado

Passos

LCS

Darzé

Lopes

28. Bruch C, Rothenburguer M, Gotzmann M, Wichter T, Scheld HH, Breithardt G, et al. Chronic kidney disease in patients with chronic heart failure: impact on intracardiac conduction, diastolic function and prognosis. Int J Cardiol. 2007; 178: 375-80.

Chronic kidney disease in patients with chronic heart failure: impact on intracardiac conduction, diastolic function and prognosis

Int J Cardiol 2007 375 80 178

Bruch

Rothenburguer

Gotzmann

Wichter

Scheld

Breithardt

29. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int. 2004; 66 (2): 753-60.

Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial

Kidney Int 2004 753 60 2 66

Gouva

Nikolopoulos

Ioannidis

Siamopoulos

30. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003; 107: 294-9.

Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure

Circulation 2003 294 9 107

Mancini

Katz

Lang

LaManca

Hudaihed

Androne

31. Ghali JK, Anand IS, Abraham WT, Fonarow GC, Greenberg B, Krum H, et al. on behalf of the Study of Anemia on Heart Failure Trial (STAMINA-HeFT) Group. Randomized double blind trial of darbopoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008; 117: 526-35.

on behalf of the Study of Anemia on Heart Failure Trial (STAMINA-HeFT) Group: Randomized double blind trial of darbopoetin alfa in patients with symptomatic heart failure and anemia

Circulation 2008 526 35 117

Ghali

Anand

Abraham

Fonarow

Greenberg

Krum

32. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002; 287: 1531-40.

Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial

JAMA 2002 1531 40 287

33. Ghiorghiade M, Konstan MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007; 297: 1332-43.

Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials

JAMA 2007 1332 43 297

Ghiorghiade

Konstan

Burnett JC

Grinfeld

Maggioni

Swedberg

34. Konstan MA, Ghiorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007; 297: 1319-31.

Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial

JAMA 2007 1319 31 297

Konstan

Ghiorghiade

Burnett JC

Grinfeld

Maggioni

Swedberg

35. Constanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerling JR, et al. for the UNLOAD Trial Investigators. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007; 49: 675-83.

for the UNLOAD Trial Investigators: Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure

J Am Coll Cardiol 2007 675 83 49

Constanzo

Guglin

Saltzberg

Jessup

Bart

Teerling

Original Articles

Renal dysfunction and anemia in patients with heart failure with reduced versus normal ejection fraction

BACKGROUND: The presence of anemia and renal dysfunction grants a bad prognosis for patients with heart failure and reduced ejection fraction (HFREF). The impact on patients with heart failure and normal ejection fraction (HFNEF) is not widely studied. OBJECTIVES: To study the prevalence and the prognosis of anemia and renal dysfunction (RD) in patients with heart failure according to the type of ventricular dysfunction. METHODS: A total of 209 patients with chronic and stable heart failure were prospectively studied. Individuals with ejection fraction <50% were considered as HFREF patients. Anemia was defined, based on WHO criteria, as hemoglobin <13 g/dl for men and <12 g/dl for women. Renal function was calculated by means of the Simplified Modified Diet Renal Disease (sMDRD) formula. Hospitalizations, emergency admittances and obit by cardiac causes were considered as cardiac events. RESULTS: Ninety patients had HFREF and 119 had HFNEF. The glomerular filtration rate (GFR) was smaller in HFREF group (57.6 ± 66.2 versus 94.8 ± 36.6 ml/min/1.73m²; p=0.01). There was no difference in the prevalence of anemia between groups (23.3% versus 18.5%; p=0.34). Moderate to severe RD prevalence was higher in HFREF group (32.2% versus 16.8%; p=0.01). RD was the only factor associated with anemia that was independently associated with cardiac events (HR 2.52; 95%CI=1.27-5.2; p=0.01). CONCLUSION: RD was less prevalent in HFNEF, while the prevalence of anemia did not differ between groups. RD was predictor of cardiac events independently on ejection fraction.

Heart failure anemia renal insufficiency

ORIGINAL ARTICLE

Renal dysfunction and anemia in patients with heart failure with reduced versus normal ejection fraction

Humberto Villacorta; Bolivar F. Saenz-Tello; Eduarda Barcellos dos Santos; Ricardo Steffen; Christiane Wiefels; Luiz Costa Lima; Ana Luíza F. Sales; Pedro Soares; Evandro Tinoco Mesquita

Universidade Federal Fluminense - Hospital Universitário Antônio Pedro, Niterói, RJ - Brazil

Mailing address

ABSTRACT

OBJECTIVES: To study the prevalence and the prognosis of anemia and renal dysfunction (RD) in patients with heart failure according to the type of ventricular dysfunction.

METHODS: A total of 209 patients with chronic and stable heart failure were prospectively studied. Individuals with ejection fraction <50% were considered as HFREF patients. Anemia was defined, based on WHO criteria, as hemoglobin <13 g/dL for men and <12 g/dL for women. Renal function was calculated by means of the Simplified Modified Diet Renal Disease (sMDRD) formula. Hospitalizations, emergency admittances and obit by cardiac causes were considered as cardiac events.

RESULTS: Ninety patients had HFREF and 119 had HFNEF. The glomerular filtration rate (GFR) was smaller in HFREF group (57.6 ± 66.2 versus 94.8 ± 36.6 mL/min/1.73m²; p=0.01). There was no difference in the prevalence of anemia between groups (23.3% versus 18.5%; p=0.34). Moderate to severe RD prevalence was higher in HFREF group (32.2% versus 16.8%; p=0.01). RD was the only factor associated with anemia that was independently associated with cardiac events (HR 2.52; 95%CI=1.27-5.2; p=0.01).

CONCLUSION: RD was less prevalent in HFNEF, while the prevalence of anemia did not differ between groups. RD was predictor of cardiac events independently on ejection fraction.

Key words: Heart failure; anemia; renal insufficiency.

Introduction

Anemia and renal dysfunction (RD) are two prevalent comorbidities that worsen the development of heart failure¹^-4. Many physiopathological mechanisms have been proposed to explain the presence of anemia in patients with heart failure, like chronic diseases anemia⁵, renal dysfunction, hemodilution⁶, reduced production of eritropoetine by angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB)^7,8. Independently on the mechanism, the presence of anemia grants bad prognosis⁶.

RD is present in approximately 30% of patients with heart failure, and is also considered an important prognostic factor^9-11. It unleashes inflammatory factors, hydrosalin overload and alterations on the metabolism of calcium and phosphorus, which may worsen the cardiac insufficiancy¹². The renal dysfunction itself raises anemia, initiating a vicious circle called cardio-renal anemia syndrome by some authors, which has been associated with an increase in mortality rates^13-16. Several studies assessed the influence of anemia and renal dysfunction in patients with heart failure and reduced ejection fraction (HFREF). However, these two variables interrelation has not been much studied in patients with heart failure and normal ejection fraction (HFNEF).

The objective of this study was to assess the prevalence and the prognostic impact of anemia and RD in patients with ambulatory chronic heart failure, according to the type of cardiac dysfunction.

Methods

Between December 2005 and February 2007, 230 patients with chronic heart failure were selected, as 114 were from a community attention program (family doctor) and 116 were from an ambulatory specialized in heart failure of a University Hospital. Inclusion criteria were Boston score higher than 8 points and patients older than 18 years old. Amongst the 230 patients, 21 were excluded because they did not fulfill the abovementioned Boston criteria, remaining 209 patients that were included in the study.

At the first interview, all patients were submitted to complete anamnesis, physical exam, complete hemogram, biochemistry, thoracic X-ray, electrocardiogram and echocardiogram, as to determine the left ventricle ejection fraction (LVEF) by Simpson method. The participants who presented LVEF<50% were characterized as HFREF patients, and those with LVEF>50% in the presence of any diastolic dysfunction degree determined by echocardiography were characterized as HFNEF patients. The stages of diastolic dysfunction were assessed according to the mitral flow pattern evaluated by conventional Doppler exam and characterized as stage I (normal), II (relaxing debt), III (pseudonormal) and IV (restrictive pattern).

Renal dysfunction and anemia definitions

The measurement of renal function was carried out by means of glomerular filtration rate (GFR) Simplified Modified Diet Renal Disease (sMDRD). For males, the formula 186 x serum creatinine^-1,154 x age^-0,203 was used; for black men: sMDRD x 1.212. For females, the formula sMDRD x 0.742 was used; for black women: sMDRD x 0.742 x 1.212). Later on, all patients were characterized according to their renal function: normal (GFR>90 mL/min/1.73m²), light renal dysfunction (GFR<90 and >60 mL/min/1.73m²), moderate renal dysfunction (GFR<60 and >30 mL/min/1.73m²), and severe renal dysfunction (GFR<30 mL/min/1.73m²). Anemia was diagnosed based on WHO criteria, like hemoglobin rates <13g/dL for men and <12g/dL for women.

Cardiovascular events definition

Patients' inclusion was finished at the end of February 2007. A minimum 60-day follow-up was determined for the participants that were last included in this study. All patients were reassessed in April 2007, independently on their inclusion date, as to determine clinical outcomes in both groups. Mean follow-up was 12.4 ± 8 months. Non-planned hospitalizations, visits to the emergency room or obit due to cardiac events were considered to be outcomes.

Statistical analysis

The continuum variables were expressed as mean values and respective standard deviations and compared through Student's t-test or ANOVA. Categorical variables were expressed in absolute values and percentage, being compared by means of chi-square or Fisher's exact tests for samples with expected values inferior to 5. The variables that were statistically significant at univariate analysis were included in the multivariate analysis (logistic regression), as patients with and without anemia were compared. Multivariate analyses were carried out as to establish the independent value of variables with follow-up outcomes, by means of the analysis of Cox proportional hazards model. Anemia and RD were included in the multivariate models as categorical variables. GFR<6 mL/min/1.73m² was considered as presence of severe or moderate RD. The analysis was performed with the software Epi-Info 3.4 and SPSS version 11.0. Values of p<0.05 were considered statistically significant.

Bioethics

The present study was approved by the Ethics Committee of the hospital, in compliance with Helsinki declaration, under number 17906. All participants were informed about risks and benefits of the study and signed the informed consent.

Results

Basal characteristics

From 209 patients clinically diagnosed with heart failure, 90 (43.1%) had HFREF and 119 (56.9%) had HFNEF. Table 1 shows the patients' basal characteristics. As observed, HFREF patients presented higher prevalence of previous myocardium infarction, lower values of blood pressure and worse renal function. HFNEF patients were mainly women with higher levels of total cholesterol and higher prevalence of obesity and arterial hypertension. No significant differences were observed with regard to age or hemoglobin levels in both groups. The majority of patients were in functional class I or II (73%).

The medicines administered at the moment of inclusion in the study are presented in Table 2. Most of medicines used in heart failure treatment were more frequently prescribed for HFREF patients. HFNEF patients used more tiazidic diuretics. There was no significant difference in acetylsalicylic acid (ASA) prescription rate.

Renal dysfunction prevalence

Any RD (GFR<90 mL/min/1.73m²) was present in 121 patients (57.9%), while moderate or severe RD were present in 23.3% of the whole sample. The classification of both groups' patients according to GFR is shown in Table 3. The prevalence of moderate or severe RD was twice higher among HFREF patients in comparison to HFNEF patients (32.2% versus 16.8%; p=0.01), as presented in Figure 1. In HFREF group, only 29 patients (32.2%) presented normal renal function versus 59 (49.6%) in HFNEF group (p=0.01). In HFNEF group, the distribution of creatinine values in stages II to IV of diastolic dysfunction, respectively, was 0.98 ± 0.26; 1.08 ± 0.3 and 1.26 ± 0.32 (p=0.02).

Anemia prevalence

The prevalence of anemia in the general studied population was 20.6%. There was no significant difference in the prevalence of anemia among HFREF patients in comparison to HFNEF patients (23.3% versus 18.5%; p=0.34). In HFNEF group, the distribution of hemoglobin in stages II to IV of diastolic dysfunction was 13.8 ± 1.03; 11.7 ± 1.12 and 10.9 ± 1.32 (p=0.04).

Factors associated with anemia

Table 4 shows a comparison between patients with and without anemia. Anemic patients were predominantly males, presented worse renal function and used diuretics more frequently in comparison to non-anemic patients. Through multivariate analysis, the only variable that was independently associated with anemia was presence of renal dysfunction, with Odds Ratio of 3.89 (95% confidence interval = 1.74 to 7.37; p=0.001). Ejection fraction was not associated with anemia.

Prognostic value of RD and anemia

Seven patients (3.7%) died because of decompensate heart failure, and all of them were part of HFREF group (7.7% versus 0%; p=0.004). The presence of combinative outcomes was higher in HFREF group (34 [36.6%] versus 28 [24.3%]; p=0.037). In the univariate analysis, the main factor related to cardiovascular events were moderate or severe renal dysfunction, diabetes mellitus, previous myocardium infarction, being male and the presence of reduced ejection fraction. At the multivariate regression analysis by Cox proportional hazards model (Table 5), we observed that RD was independently correlated to cardiovascular events (hazard ratio)2.52 [95%CI = 1.27 to 5.2]; p=0.01), as well as reduced ejection fraction (HR=1.6 [95%CI=1.05 to 2.04], p=0.03). Anemia was not an event predictor, as we observed that the presence of outcomes in anemic versus non-anemic patients of 15 (34.8%) versus 47 (28.3%) patients, p=0.38. The events rate according to the presence of RD and anemia are shown in Figure 2.

Discussion

The relation between anemia and renal function in patients with heart failure has been reason for investigations. In the present study, we demonstrated that HFREF patients presented renal dysfunction more frequently than HFNEF patients, though the prevalence of anemia have been similar in both populations. Moreover, we demonstrated that RD was the only variable associated with anemia and that was an independent events predictor despite ejection fraction. Interestingly, HFNEF patients presented worse renal function and lower levels of hemoglobin in the most advanced stages of diastolic dysfunction.

Renal dysfunction prevalence

RD is frequent in patients with heart failure and is associated with worse prognosis in both ambulatory and hospital patients^1,16-23. Advanced degrees of dysfunction are particularly frequent in decompensate patients. In ADHERE register²³, in which patients hospitalized due to decompensate heart failure (with reduced or preserved LVEF) were included, 63.3% of patients presented GFR<60 mL/min/1.73m². In ambulatory patients, meta-analysis showed prevalence of any renal dysfunction in 51% of cases, and of severe or moderate dysfunction in 10%¹. The prevalence of RD and its severity levels in the present study was similar to that found in the abovementioned meta-analysis.

When HFREF and HFNEF patients were compared, a higher prevalence for RD was found in the first group. After the stratification of patients in different stages according to GFR, we found that only the third part of HFREF patients presented normal renal function, as 32% presented moderate or severe renal dysfunction, against 16.8% in HFNEF group. This fact is consistent with what was observed by other authors^9,10,19.

It is important to emphasize that though it is more prevalent in HFREF patients, almost 20% of HFNEF patients presented moderate or severe endangering of renal function, which suggests that renal endangering in heart failure comprises other mechanisms besides low cardiac debt and bad renal perfusion typical of HFREF patients. Actually, it is known that the increase in central venous pressure, which leads to an increase in renal veins pressure, is one of the mechanisms involved in cardiac-renal syndrome and could explain its genesis in HFNEF patients^12,24.

Anemia prevalence

In the present study, we observed that 20% of patients presented anemia. Anemia prevalence in heart failure varies from study to study. It may be explained by the different diagnosis criteria and different clinical contexts. In a retrospective study with a hospital population, carried out in Brazil, it was found that 45% of the patients with heart failure presented anemia, as a cut of 12 g/dL was used independently on the sex²⁰. In other Brazilian study, in which the cut was hemoglobin <13 g/dL for women and <12 g/dL for men, the prevalence of anemia reached 62.6%²⁵.

When the prevalence of anemia in HFREF and HFNEF was compared, there was no significant difference. Other authors have found similar results. In CHARM study²⁶, the prevalence of anemia in HFREF and HFNEF patients was 25% and 27%, respectively. In a Brazilian study carried out with patients with decompensate heart failure, the prevalence of anemia was significantly higher among HFNEF patients²⁷. Our findings, however, confirm that the incidence of anemia in HFNEF patients is as frequent as in HFREF patients.

In a multivariate analysis, RD was the only factor that was independently associated with anemia. Though the objective of this study was not to establish the mechanisms involved in anemia genesis, these data suggest that RD plays an important role as anemia cause in patients with heart failure. Notwithstanding, as RD prevalence was lower in HFNEF patients, other mechanisms besides renal function may be implicated in this group.

Renal dysfunction and anemia as prognostic factors

In the current study, RD was independently associated with cardiovascular events, a fact that is well established in literature¹. The prognostic impact of RD according to the type of ventricle dysfunction, however, is not yet well known. Although HFREF patients are considered to be more severe, some studies show that RD also has prognostic impact in HFNEF patients. Actually, it is described that reduced renal function may worsen the diastolic function²⁸. In DIG study, there was a higher mortality rate related to RD among HFNEF patients in comparison to HFREF patients¹⁹. Grigorian et al¹⁰, however, observed that heart failure prognostic was worse among patients with renal dysfunction independently on ejection fraction¹⁰. Silva et al²⁰, in a study carried out in Brazil, determined that the reduced ejection fraction of left ventricle and high levels of creatinine were associated with a higher mortality rate²⁰. In our study, we found similar results, which shows that RD and reduced ejection fraction were independent event predictors. After analyzing all these studies, we concluded that renal function brings impact in heart failure development independently on LVEF.

Anemia was not an event predictor in our sample, a result that is contrasting to those found by other authors. In CHARM study²⁶, anemia was predictor of events in both HFREF and HFNEF patients. Our relatively small sample may be an explanation for such findings. In fact, there were a larger number of events among anemic patients (34.8% versus 28.3%), but no statistical significance was reached. Based on prognostic data found in literature, the hypothesis of treating anemia in patients with heart failure became attractive. It is described that its correction in chronic renal patients delays and worsens renal function²⁹. In patients with heart failure, the initial data were encouraging, showing that anemia correction ameliorated symptoms and functional capacity^20,30. A recent study, however, did not show benefits in the increase of exercises tolerance, despite the tendency to mortality and heart failure hospitalizations reduction³¹.

The present paper suggests that the renal function plays a much important role than anemia in the development of patients with stable chronic heart failure. Strategies on preservation of renal function are necessary and have been studied in literature in ambulatory and hospitalized patients^32-35, but there is no consensus on the benefits brought by these new drugs or procedures to renal function.

Limitations

No other mechanisms of anemia besides renal dysfunction were herein studied, so it is not possible to establish a cause or time relation between anemia and RD. Our relatively small sample may have contributed with type II error, mainly with regard to the prognostic value of anemia. The bigger proportion of HFNEF patients in relation to HFREF cannot be spread to general population with heart failure, for it is probably due to selection sloping, considering the greater number of HFNEF patients referred from the primary attention program to this project.

Conclusions

The prevalence of renal dysfunction was higher among HFREF than in HFNEF patients. There was no difference in anemia prevalence in both groups. RD was the only factor associated with anemia in both groups, though it is not possible to establish a cause relation. RD and reduced ejection fraction of left ventricle were independently correlated to cardiovascular events in the presence or absence of anemia.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of master submitted by Bolivar F. Saenz-Tello, from Universidade Federal Fluminense.

References