Resumo

Arq Bras Cardiol

abc

Arquivos Brasileiros de Cardiologia

Arq. Bras. Cardiol.

0066-782X 1678-4170

Sociedade Brasileira de Cardiologia - SBC

gDwZDxDQRczTBSpZCQWDqNM

S0066-782X2022000300646

abc.20201257

10.36660/abc.20201257

Artigo de Revisão

Deficiência de Ferro na Insuficiência Cardíaca com Fração de Ejeção Reduzida: Fisiopatologia, Diagnóstico e Tratamento

0000-0001-7833-2994

Pereira

Guilherme Augusto Reissig

¹ ²

0000-0002-5702-210X

Beck-da-Silva

Luís

² ³

1 Hospital São Lucas Pontifícia Universidade Católica do Rio Grande do Sul

Porto Alegre

Brasil Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS – Brasil 2 Programa de Pós-Graduação em Cardiologia Universidade Federal do Rio Grande do Sul

Porto Alegre

Brasil Programa de Pós-Graduação em Cardiologia – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS – Brasil 3 Hospital de Clínicas de Porto Alegre

Porto Alegre

Brasil Hospital de Clínicas de Porto Alegre, Porto Alegre, RS – Brasil

Correspondência: Luis Beck-da-Silva • Hospital de Clínicas de Porto Alegre – Serviço de Cardiologia - Ramiro Barcelos, 2350, 2º andar. CEP 90440-050, Porto Alegre, RS – Brasil E-mail: lbneto@hcpa.edu.br , luisbeckdasilva@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa, Obtenção de dados, Análise e interpretação dos dados, Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Pereira GAR, Beck-da-Silva L.

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18 03 2022

03 2022

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Resumo

A deficiência de ferro (DF) ou ferropenia é uma importante comorbidade na insuficiência cardíaca com fração de ejeção reduzida (ICFER) estável, e muito prevalente tanto nos anêmicos como não anêmicos. A ferropenia na ICFER deve ser pesquisada por meio da coleta de saturação de transferrina e ferritina. Há dois tipos de ferropenia na IC: absoluta, em que as reservas de ferro estão depletadas; e funcional, onde o suprimento de ferro é inadequado apesar das reservas normais. A ferropenia está associada com pior classe funcional e maior risco de morte em pacientes com ICFER, e evidências científicas apontam melhora de sintomas e de qualidade de vida desses pacientes com tratamento com ferro parenteral na forma de carboximaltose férrica. O ferro exerce funções imprescindíveis como o transporte (hemoglobina) e armazenamento (mioglobina) de oxigênio, além de ser fundamental para o funcionamento das mitocôndrias, constituídas de proteínas à base de ferro, e local de geração de energia na cadeia respiratória pelo metabolismo oxidativo. A geração insuficiente e utilização anormal de ferro nas células musculares esquelética e cardíaca contribuem para a fisiopatologia da IC. A presente revisão tem o objetivo de aprofundar o conhecimento a respeito da fisiopatologia da ferropenia na ICFER, abordar as ferramentas disponíveis para o diagnóstico e discutir sobre a evidência científica existente de reposição de ferro.

Ferro Deficiência de Ferro Insuficiência Cardíaca Sistólica

O Problema Clínico

A insuficiência cardíaca (IC) tem sido considerada um problema de saúde pública global que afeta 26 milhões de pacientes no mundo todo.¹ O número de pacientes com IC em 2015 no Brasil foi de aproximadamente 2.846.000, correspondendo à 2% da população adulta, sendo que ocorre aumento da prevalência com o avançar da idade.²

Em registro brasileiro de pacientes internados por IC de diferentes regiões do Brasil, a mortalidade intra-hospitalar encontrada foi de 12,6%.³ Além da alta mortalidade intra-hospitalar, estima-se que 50% dos pacientes diagnosticados com IC estarão mortos dentro de um período de 5 anos.^{4 , 5} Outro ponto que merece destaque é o impacto financeiro da doença. Em 2015 a IC gerou no Brasil um custo substancial de R$ 22,1 bilhões de reais.²

A anemia é uma doença comum na insuficiência cardíaca com fração de ejeção reduzida (ICFER).⁶ Define-se como a concentração de hemoglobina < 13,0 g/dl em homens e < 12,0 g/dl em mulheres.⁷ As causas mais comuns de anemia nos pacientes com IC são deficiência de ferro (DF), anemia da doença crônica, dilucional e secundária à insuficiência renal.⁸ A DF ou ferropenia é uma importante comorbidade na IC, estando presente em metade dos pacientes^{9 , 10} não estando restrita apenas aos anêmicos, visto que ocorre em 46% dos pacientes não anêmicos com IC estáveis.¹¹

A ferropenia na IC é mais encontrada em pacientes com doença avançada (pior classe funcional e maior valor de peptídeo natriurético cerebral) e em mulheres.^{11 , 12} A presença de ferropenia influencia o prognóstico. Em estudo observacional com 546 pacientes com ICFER, a ferropenia foi apontada como um forte preditor independente de morte ou necessidade de transplante cardíaco, aumentando o risco desses desfechos em aproximadamente 60%.¹² Em outra coorte constituída de 1506 pacientes europeus com IC crônica, a ferropenia (sem presença de anemia) também foi considerada um preditor de morte.¹¹ A alta prevalência e poder prognóstico da ferropenia na IC são justificativas para maior compreensão de sua fisiopatologia, diagnóstico e tratamento.

Fisiopatologia Ferro – Absorção, distribuição e funções no organismo

O ferro é um micronutriente metabolicamente ativo com características bioquímicas únicas. Encontra-se em dois estados oxidativos: ferroso (Fe2+), encontrado no meio intracelular; e férrico (Fe3+), encontrado no meio extracelular.¹³

O consumo médio diário de ferro é de 10–20 mg/dia, mas apenas 10–20% do ferro da dieta é normalmente absorvido utilizando sistemas de transporte específicos, principalmente através dos enterócitos duodenais. O ferro pode ser eliminado por descamação de células mucosas intestinais, menstruação ou outras perdas sanguíneas, porém o corpo não tem um mecanismo fisiologicamente regulado de excreção do ferro, logo a regulação da absorção através do duodeno tem um papel fundamental na homeostase do ferro no organismo.¹⁴ A maior parte do ferro necessário para eritropoiese (20-25mg) é derivado da reciclagem dos eritrócitos senescentes através da fagocitose dos macrófagos do sistema reticuloendotelial.^{13 , 15}

O ferro é distribuído principalmente na hemoglobina das hemácias (65%). Aproximadamente 10% é encontrado em fibras musculares (na mioglobina). O restante é armazenado no fígado, macrófagos do sistema reticuloendotelial e medula óssea.¹⁶

O ferro tem um papel fundamental no transporte de oxigênio por meio da hemoglobina e armazenamento de oxigênio por parte da mioglobina (células musculares esquelética e cardíaca). Age como componente das enzimas envolvidas na oxidação (fosforilação oxidativa e geração de energia) e das proteínas ferro enxofre (Fe-S) e Heme da cadeia respiratória das mitocôndrias. Também atua na síntese e degradação de proteínas, lipídeos e ácidos ribonucleicos.^{13 , 17}

O ferro é potencialmente tóxico porque causa a redução de moléculas de oxigênio dentro da célula, levando à formação de espécies reativas de oxigênio. Logo, o ferro necessita de um neutralizante intracelular na forma de ferritina e intravascular pela ligação à transferrina.⁹

A transferrina age como um reservatório de ferro solúvel. Trata-se de uma glicoproteína transportadora de ferro para células alvo como células eritróides, imunológicas, musculares e hepatócitos. O ferro ligado à transferrina penetra nas células utilizando o receptor de transferrina tipo 1 (TfR1) via endocitose.¹⁶

O ferro encontra-se armazenado no fígado, medula óssea e baço na forma de ferritina, considerada a principal proteína de reserva do ferro. Em situações de sobrecarga de ferro ou inflamação, ocorre aumento da ferritina tecidual.¹³

A hepcidina é um peptídeo hormonal produzido principalmente pelos hepatócitos, sendo considerada a principal reguladora do metabolismo do ferro.¹⁵ Sua síntese é regulada pelas mudanças de demanda de ferro no organismo; tem ação direta sobre a ferroportina, um canal transmembrana de ferro. A ferroportina localiza-se na superfície de enterócitos duodenais, responsáveis pela absorção de ferro, assim como nos hepatócitos e macrófagos, responsáveis pelo armazenamento de ferro. Quando ocorre a ligação da hepcidina com a ferroportina, essa é destruída dentro do lisossomo, causando menor liberação de ferro.^{13 , 15 , 18}

Em estudo com ratos submetidos à dieta deficiente em ferro durante 12 semanas, comparados aos controles, os animais deficientes em ferro apresentaram coração de peso e tamanho maiores. O exame por microscopia revelou desorganização estrutural dos sarcômeros e mitocôndrias aberrantes no tecido miocárdico.¹⁹

A ferropenia no organismo pode causar efeitos deletérios desde em estruturas mais básicas, como mitocôndrias e células, até níveis mais complexos ( Figura 1 ).^{13 , 20}

Figura 1 – <italic>Efeitos prejudiciais da deficiência de ferro em diferentes níveis de complexidade do organismo (adaptado de Jankowska et al.13 e Stugiewicz et al.20). Fe-S: ferro-enxofre; O2: oxigênio.</italic>

Estudo com portadores de IC avançada submetidos a transplante cardíaco mostrou depleção de ferro intramiocárdico nesses pacientes em comparação a corações (saudáveis) selecionados para o transplante, sugerindo que a ferropenia intramiocárdica pode ter um papel na patogênese e progressão da IC.²¹

Não apenas a DF causa a IC, como também a IC parece ser capaz de induzir DF, logo a teoria de um ciclo vicioso pode ser formulada.¹⁰ O surgimento da ferropenia pode ser resultante da baixa captação de ferro devido à desnutrição e sobrecarga de volume; sangramentos associados com uso de antiplaquetários e anticoagulantes, e desordem na utilização e armazenamento do ferro devido ao estado inflamatório da IC.^{22 , 23}

Pacientes com estados inflamatórios crônicos como IC, doença renal crônica, câncer e doença inflamatória intestinal apresentam maior risco de desenvolver ferropenia.⁹ Pacientes com IC apresentam aumento na produção de hepcidina no fígado, como já visto, que compromete a absorção de ferro do trato gastrintestinal e a mobilização de ferro proveniente dos estoques de ferro incluindo o sistema reticuloendotelial.^{13 , 23 , 24}

Diagnóstico

A distinção da anemia com ferropenia de anemia da doença crônica é notoriamente difícil. Na ausência de inflamação, níveis séricos de ferritina < 30ng/mL indicam ferropenia.²⁵ Em trabalho com pacientes com IC avançada e anemia, foi medido o conteúdo de ferro na biópsia de medula óssea; 73% tinham reservas de ferro reduzidas, sendo que a média de ferritina foi 75 ng/mL nos pacientes com DF e 211 ng/mL nos pacientes sem deficiência. Na IC a ferritina pode estar aumentada ou com nível normal devido ser uma proteína de fase aguda, mesmo em situações como a ferropenia. Logo, o uso de marcadores bioquímicos e pontos de corte convencionais derivados de coortes não-inflamatórias para identificar ferropenia na IC é questionável.²⁶

Há dois tipos de ferropenia: absoluta, a qual reflete as reservas de ferro depletadas, com homeostase do ferro e eritropoiese preservadas; e funcional, onde o suprimento de ferro está inadequado para atender a demanda apesar das reservas de ferro normais ou abundantes, devido o ferro estar preso dentro das células do sistema reticuloendotelial e estar indisponível para o metabolismo celular.¹³

Em pacientes com ICFER, convencionou-se ferropenia absoluta como ferritina < 100mg/L, e ferropenia funcional como ferritina 100-299 mg/L e saturação de transferrina (TSAT) <20%.^{27 - 29}

Ferropenia - Um alvo terapêutico

Foram realizados vários ensaios clínicos randomizados (ECRs) para tratamento da DF na ICFER estável ou crônica ( Tabela 1 ). O IRON-HF³⁰ foi o primeiro ECR a comparar uso de ferro oral, endovenoso e placebo. Não houve diferença estatística da variação do VO2 de pico entre os grupos. O ensaio foi finalizado antes do previsto devido recrutamento prolongado e problemas de financiamento. Em outro estudo, o IRONOUT-HF, o uso de ferro oral foi comparado com placebo e, novamente, não houve diferença na variação do VO2 de pico.³¹ Esses estudos corroboram o fato de que o ferro por via oral não traz benefício clínico em pacientes com ICFER e DF.

Tabela 1 – Ensaios clínicos randomizados com tratamento de deficiência de ferro em pacientes com insuficiência cardíaca

Toblli et al.³³ FERRIC-HF³² FAIR-HF³⁴ IRON-HF³⁰ CONFIRM-HF³⁵ EFFECT-HF⁵⁸ IRONOUT-HF³¹

n SHF: 20 Placebo: 20 SHF: 24 Placebo: 11 CF: 304 Placebo: 155 SHF: 10 SF: 7; Placebo: 6 CF: 150 Placebo: 151 CF: 86 Terapia padrão: 86 PF: 111 Placebo: 114

Cegamento Duplo-cego Aberto Duplo-cego Duplo-cego Duplo-cego Aberto Duplo-cego

Centro(s) Multicêntrico Unicêntrico Multicêntrico Multicêntrico Multicêntrico Multicêntrico Multicêntrico

Sintomas (CF da NYHA) II-IV II-III II-III II-IV II-III II-III II-IV

FEVE ≤35% ≤45% ≤40% ou ≤45% <40% ≤45% ≤45% ≤40%

Definição de DF Ferritina<100ng/mL e/ou TSAT<20% Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20% Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20% Ferritina < 500 μg/L e TSAT<20% Ferritina<100ng/ml ou ferritina 100-299ng/ml + TSAT<20% Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20% Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20%

Hb <12,5 g/dL <12,5 g/dL (anêmicos), 12,5-14,5 g/dL (não-anemicos) 9-13,5 g/dL 9-12 g/dL <15 g/dL <15 g/dL 9-13,5 g/dL

Via do Ferro Injetável Injetável Injetável Injetável e Oral Injetável Injetável Oral

Tipo de Ferro SHF SHF CF SHF e SF CF CF PF

Fase de correção (dosagem) 200mg/sem 5 sem 200mg/sem 4 sem 200mg/sem* SHF 200mg/sem SF 200mg 3xd 500-2000mg semanas 0 e 6 500-2000mg semanas 0 e 6 150mg 2xd 16sem

Fase de manutenção (dosagem) - 200mg/mês 200mg/mês - 500mg a cada 12 sem^† 500mg a cada 12 sem^† -

Duração tratamento 5 sem 16 sem 24 sem 5 sem (SHF) 8 sem (SF) 36 sem 12 sem 16 sem

Seguimento 24 sem 18 sem 24 sem 12 sem 52 sem 24 sem 16 sem

Desfecho primário de interesse Mudança no NT-proBNP e PCR Mudança no pVO2 Mudança na classe funcional NYHA e no PGA Mudança no pVo2 Mudança no teste da caminhada de 6 minutos Mudança no pVo2 Mudança no pVo2

Diferença no desfecho primário Sim Não Sim Não Sim Sim Não

	Toblli et al.³³	FERRIC-HF³²	FAIR-HF³⁴	IRON-HF³⁰	CONFIRM-HF³⁵	EFFECT-HF⁵⁸	IRONOUT-HF³¹
n	SHF: 20 Placebo: 20	SHF: 24 Placebo: 11	CF: 304 Placebo: 155	SHF: 10 SF: 7; Placebo: 6	CF: 150 Placebo: 151	CF: 86 Terapia padrão: 86	PF: 111 Placebo: 114
Cegamento	Duplo-cego	Aberto	Duplo-cego	Duplo-cego	Duplo-cego	Aberto	Duplo-cego
Centro(s)	Multicêntrico	Unicêntrico	Multicêntrico	Multicêntrico	Multicêntrico	Multicêntrico	Multicêntrico
Sintomas (CF da NYHA)	II-IV	II-III	II-III	II-IV	II-III	II-III	II-IV
FEVE	≤35%	≤45%	≤40% ou ≤45%	<40%	≤45%	≤45%	≤40%
Definição de DF	Ferritina<100ng/mL e/ou TSAT<20%	Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20%	Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20%	Ferritina < 500 μg/L e TSAT<20%	Ferritina<100ng/ml ou ferritina 100-299ng/ml + TSAT<20%	Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20%	Ferritina<100ng/mL ou ferritina 100-299ng/mL + TSAT<20%
Hb	<12,5 g/dL	<12,5 g/dL (anêmicos), 12,5-14,5 g/dL (não-anemicos)	9-13,5 g/dL	9-12 g/dL	<15 g/dL	<15 g/dL	9-13,5 g/dL
Via do Ferro	Injetável	Injetável	Injetável	Injetável e Oral	Injetável	Injetável	Oral
Tipo de Ferro	SHF	SHF	CF	SHF e SF	CF	CF	PF
Fase de correção (dosagem)	200mg/sem 5 sem	200mg/sem 4 sem	200mg/sem*	SHF 200mg/sem SF 200mg 3xd	500-2000mg semanas 0 e 6	500-2000mg semanas 0 e 6	150mg 2xd 16sem
Fase de manutenção (dosagem)	-	200mg/mês	200mg/mês	-	500mg a cada 12 sem^†	500mg a cada 12 sem^†	-
Duração tratamento	5 sem	16 sem	24 sem	5 sem (SHF) 8 sem (SF)	36 sem	12 sem	16 sem
Seguimento	24 sem	18 sem	24 sem	12 sem	52 sem	24 sem	16 sem
Desfecho primário de interesse	Mudança no NT-proBNP e PCR	Mudança no pVO2	Mudança na classe funcional NYHA e no PGA	Mudança no pVo2	Mudança no teste da caminhada de 6 minutos	Mudança no pVo2	Mudança no pVo2
Diferença no desfecho primário	Sim	Não	Sim	Não	Sim	Sim	Não

* Dose calculada de acordo com fórmula de Ganzoni. ^† se deficiência de ferro persistir. CF: carboximaltose férrica; DF: deficiência de ferro; FEVE: fração de ejeção do ventrículo esquerdo; Hb: hemoglobina; CF da NYHA: classe funcional da New York Heart Association; PCR: proteína C reativa; PF: polissacarídeo de ferro; PGA: Patient Global Assessment; pVO2: pico do consumo máximo de oxigênio; sem: semana(s); SF: sulfato ferroso; SHF: sacarato de hidróxido férrico; TSAT: saturação de transferrina; NT-proBNP: fragmento N-terminal do peptídeo natriurético tipo B.

Enquanto os primeiros estudos de intervenção com ferro endovenoso utilizaram o sacarato de hidróxido férrico,^{32 , 33} os estudos mais recentes utilizaram a carboximaltose férrica, outra forma de ferro parenteral. Em 2009, foi publicado o FAIR-HF, considerado o maior ECR (n=459) comparando reposição de carboximaltose férrica endovenosa com placebo. Os desfechos primários de interesse foram a classificação funcional da New York Heart Association (NYHA) para IC e o Patient Global Assessment (PGA) com 24 semanas. O PGA é uma ferramenta onde o paciente dá notas sobre gravidade e evolução da sua doença. No braço carboximaltose férrica, 47% apresentavam classe funcional NYHA I ou II após 24 semanas, comparado com 30% dos que receberam placebo (OR para melhora=2,40; IC95%, 1,55-3,71; p<0,001). O PGA na semana 24 foi melhor no grupo intervenção, 50% relataram estar moderadamente ou muito melhor, comparado com 28% no grupo placebo (OR para melhora=2,51; IC95%, 1,75-3,61; p<0,001). Resultados foram semelhantes em pacientes com anemia e sem anemia.³⁴

O estudo CONFIRM-HF foi realizado em nove países da Europa com 301 pacientes, com seguimento mais longo (52 semanas) que o FAIR-HF. De forma semelhante, comparou-se a carboximaltose férrica EV com placebo. O desfecho primário foi a mudança do teste de caminhada de 6 minutos da semana 24 em relação ao basal. Observou-se um aumento de 33 ± 11 metros em favor do grupo que recebeu a carboximaltose, o qual foi mantido até o final do seguimento de 52 semanas. O efeito foi observado tanto nos anêmicos como não-anêmicos, reforçando a ideia de que a ferropenia é um alvo terapêutico independente válido.³⁵ Essa diferença excedendo 30 metros nos últimos seis meses do estudo foi robusta e clinicamente significativa, visto que em estudos de intervenção prévios, benefícios de tal magnitude foram apenas vistos com ressincronização cardíaca, relatados em revisão sistemática.³⁶ Também foi encontrado menor risco de hospitalização por IC descompensada (HR 0,39; IC95%, 0,19–0,82; p=0,009). Não houve diferença no desfecho de morte cardiovascular (HR 0,96; IC95%, 0,42-2,16; p=0,91).

Em metanálise com cinco ECRs, e total de 851 pacientes, comparando o uso de ferro EV com placebo, não houve diferença na mortalidade cardiovascular (OR 0,80; IC95%, 0,39-1,63; p=0,54) e mortalidade por todas as causas (OR 0,83; IC95% 0,43-1,59; p=0,57). A hospitalização por IC, esta foi menos frequente nos pacientes tratados com ferro endovenoso (OR 0,28; IC95% 0,16-0,50; p<0,0001). Importante ressaltar que 89% dos pacientes incluídos na metanálise receberam ferro parenteral na forma de carboximaltose férrica.³⁷

Em outra metanálise³⁸ com quatro ECRs e 839 pacientes, comparou-se carboximaltose endovenosa exclusivamente com placebo. Houve redução no desfecho primário de hospitalização de causa cardiovascular e mortalidade cardiovascular (RR 0,59; IC95%, 0,40–0,88; p=0,009) no grupo intervenção. Quando analisada a mortalidade cardiovascular como desfecho isolado, não houve diferença entre os grupos (RR 0,84; IC95%, 0,43-1,66; p=0,620).³⁸ A partir dos resultados do CONFIRM-HF e das metanálises, a carboximaltose férrica passou a ser considerada capaz de reduzir as hospitalizações por IC ou causa cardiovascular nos pacientes com fração de ejeção do ventrículo esquerdo (FEVE) reduzida, estáveis e sintomáticos.

A ferropenia passou a ser considerada um alvo terapêutico na ICFER estável, independente da presença de anemia. A diretriz europeia²⁷ de IC passou a considerar recomendação IIa a reposição com carboximaltose férrica endovenosa em pacientes NYHA II-III para melhora de sintomas, capacidade de exercício físico e qualidade de vida.²⁷ No ano seguinte, a diretriz americana ( American College of Cardiology /AHA) de IC utilizou recomendação IIb para o uso de ferro endovenoso na ICFER.²⁹ Em 2018 foi publicada a diretriz brasileira de IC, sendo abordada a DF na ICFER, independente da presença de anemia. Foi definida como uma recomendação IIa a administração de ferro endovenoso com intuito de aumento da capacidade de exercício, melhora na qualidade de vida e diminuição de hospitalizações.⁸

Assim, a identificação dos candidatos à reposição de ferro ( Figura 2 ) é importante e, para isso, é necessário o rastreio de todos os pacientes com IC estáveis e fração de ejeção ≤45%, por meio da medida de ferritina e TSAT.^{10 , 27} A segurança do uso de ferro parenteral é desconhecida em pacientes com IC e hemoglobina >15 g/dL.

Figura 2 – <italic>Algoritmo diagnóstico e terapêutico de pacientes com insuficiência cardíaca e deficiência de ferro (adaptado de Rocha et al.)10. DF: deficiência de ferro; EV: endovenoso; FE: fração de ejeção; Hb: hemoglobina; IC: insuficiência cardíaca; NYHA: New York Heart Association; TSAT: saturação de transferrina; DF: deficiência de ferro; EV: endovenosa; HB: hemoglobina; FE: fração de ejeção.</italic>

O diagnóstico de DF na IC aguda ainda é um desafio. Em estudo observacional com 47 pacientes com IC aguda, o perfil laboratorial do ferro foi obtido no dia da admissão hospitalar e 30º dia. A prevalência de DF foi 83% na admissão, sendo que em 30 dias houve uma queda para 68%. A mediana da ferritina e TSAT foi 93µg/L (IQR: 76–107 μg/L) e 13% (IQR: 6–20%) respectivamente no dia da admissão; com aumento para 159 µg/L (IQR: 134–190 μg/L; p <0,0001) e 17% (IQR: 12–23%; p =0,0176) respectivamente no dia 30, sem qualquer terapia com ferro. Esse estudo demonstra que os marcadores sanguíneos do metabolismo do ferro não são estacionários na IC aguda, mesmo em curto período de observação, tornando questionável o diagnóstico de ferropenia no cenário de descompensação aguda.³⁹

Existem outros exames laboratoriais a serem usados na investigação de DF, como o receptor solúvel de transferrina (sTfR) e a hepcidina. No cenário de IC aguda especialmente, o sTfR com valor ≥ 1,59 ng/mL e a hepcidina <14,5 ng/mL parecem ser mais adequados para revelar a DF.⁴⁰ Além disso, foi encontrado que o sTfR tem valor prognóstico na IC, pois seu nível aumentado esteve associado com pior classe funcional de NYHA (p <0,05).⁴¹

Ferro no miocárdico

O diagnóstico de DF na IC é relativamente simples de realizar, pois depende apenas de exames laboratoriais (ferritina e TSAT). Em estudo pré-transplante de pacientes com IC avançada, realizaram-se biópsias de miocárdio dos ventrículos para mensurar o ferro miocárdico, investigar sua correlação com marcadores sanguíneos, e compará-los a de doadores (coração saudável). Não foi encontrada correlação entre o ferro intramiocárdico e TSAT, ferritina, ou ferro sérico.⁴² Isso reforça que o metabolismo sistêmico do ferro e do ferro miocárdico são em parte independentes.⁴³

Ressonância Magnética Cardíaca

A Ressonância Magnética Cardíaca (RMC) é uma ferramenta útil para avaliação de pacientes com IC, fornecendo informações a respeito da etiologia e prognóstico.⁴⁴ Anderson et al.⁴⁵ desenvolveram a técnica da sequência T2* (T2-estrela) dentro da RMC, e demonstraram que valores de T2* < 20 ms estão associados à sobrecarga de ferro miocárdico e disfunção ventricular.⁴⁵

Pelo fato da sequência T2* ter sua utilidade estabelecida na sobrecarga de ferro miocárdico, passou-se a questionar se seria capaz de detectar a ferropenia no miocárdio. Em estudo caso-controle de pacientes portadores de IC submetidos à RMC, foi sugerido que um valor de T2* maior estaria relacionado com menor conteúdo de ferro intramiocárdico.⁴⁶ Em um ECR duplo-cego com pacientes portadores de IC sintomáticos (NYHA II e III), fração de ejeção < 50% e ferropenia, os pacientes receberam carboximaltose férrica ou placebo. O desfecho primário foi mudança das sequências T2* e T1 na RMC com sete dias e 30 dias após tratamento. O T2*(ms) foi menor no grupo que recebeu carboximaltose férrica com sete dias [36,6 (34,6–38,7) versus 40 (38–42,1); p=0,025] e 30 dias [36,3 (34,1–38,5) versus 41,1 (38,9–43,4), p=0,003]. Essas mudanças no T2* foram sugestivas de repleção miocárdica após a terapia com carboximaltose.⁴⁷

Até o momento não está estabelecido um ponto de corte de T2* para definição de ferropenia miocárdica, logo a utilidade dessa ferramenta não invasiva na avaliação de pacientes com ferropenia ainda merece mais investigação.

Tratamento

Na Tabela 2 , encontram-se recomendações de dose da carboximaltose férrica. Depois da correção da ferropenia, considera-se reavaliar os marcadores do ferro (ferritina e TSAT) 1-2x ao ano.²³

Tabela 2 – Dose de carboximaltose férrica endovenosa em pacientes com insuficiência cardíaca e deficiência de ferro10

Peso e Hb Fase de correção Fase de manutenção

Sem 0 Sem 6 Sem 12 Sem 24 Sem 36 Sem >36

35-70 Kg e Hb <10g/dL 1000 mg 500 mg 500mg se DF persiste 500mg se DF persiste 500mg se DF persiste Sem evidência

35-70 Kg e Hb ≥10g/dL 1000 mg 0 mg

> 70 Kg e Hb <10g/dL 1000 mg 1000 mg

> 70 Kg e Hb ≥10g/dL 1000 mg 500 mg

Peso e Hb	Fase de correção	Fase de manutenção
35-70 Kg e Hb <10g/dL	1000 mg	500 mg	500mg se DF persiste	500mg se DF persiste	500mg se DF persiste	Sem evidência
35-70 Kg e Hb ≥10g/dL	1000 mg	0 mg
> 70 Kg e Hb <10g/dL	1000 mg	1000 mg
> 70 Kg e Hb ≥10g/dL	1000 mg	500 mg

Tabela adaptada de Rocha et al.10 DF: deficiência de ferro; Hb: hemoglobina; IC: insuficiência cardíaca; Sem: semana(s).

A carboximaltose férrica demonstrou ser custo-efetiva a partir de mudança de classe funcional dos pacientes e redução na taxa de hospitalização.⁴⁸ Comparativamente a outras formulações EV, a carboximaltose férrica é infundida menos vezes, logo o custo total do tratamento pode ser menor,⁴⁹ além de um bom perfil de segurança. Os efeitos indesejáveis dificilmente levam à suspensão da droga. Os efeitos adversos mais comuns (1-10% dos casos) são flushing, tontura, hipertensão arterial, cefaleia, hipofosfatemia e reações locais no sítio de infusão (dor, e descoloração ou irritação da pele).⁵⁰ Pacientes devem ser observados por pelo menos 30 minutos depois da injeção endovenosa para avaliar a ocorrência de efeitos adversos. As contraindicações para o uso da carboximaltose férrica são: hipersensibilidade à carboximaltose ou seus excipientes; hipersensibilidade séria a outro produto parenteral contendo ferro; anemia não atribuída à ferropenia e evidência de sobrecarga de ferro ou distúrbios na utilização do ferro.²³

Tratamento da ferropenia na IC aguda

Diferentemente dos outros ensaios já citados em que os participantes eram pacientes estáveis (ambulatoriais), o ECR multicêntrico AFFIRM-AHF, recentemente publicado, incluiu pacientes com FEVE < 50% e DF hospitalizados por IC aguda. Após estabilizados e antes da alta hospitalar os participantes receberam carboximaltose férrica ou placebo por 24 semanas. O desfecho primário foi um composto de hospitalizações totais por IC e morte cardiovascular com 52 semanas, o qual não houve diferença entre os grupos (RR 0,79; IC95%, 0,62-1,01; p=0,059). O desfecho isolado de morte cardiovascular não foi diferente (HR 0,96; IC95% 0,70-1,32; p=0,81), enquanto hospitalizações totais por IC foi menor no braço carboximaltose (RR 0,74; IC95% 0,58-0,94; p=0,013).^{51 , 52} Esta é uma evidência científica atual e relevante, visto que corrobora a indicação de reposição com carboximaltose férrica para pacientes hospitalizados com ICFER e DF com objetivo de diminuir o risco de nova hospitalização por IC.

Áreas de incerteza

Os critérios para ferropenia utilizados em vários ECRs foram arbitrariamente definidos, sem serem sido validados com a dosagem de ferro no aspirado de medula óssea, considerado o método padrão ouro. Em trabalho⁵³ realizado com portadores de IC com FEVE ≤ 45% submetidos à cirurgia de revascularização miocárdica (n=42), foi realizada a dosagem dos marcadores do ferro (ferro sérico, ferritina e TSAT) e aspirado de medula óssea do esterno. A DF foi confirmada na medula óssea em 40% dos pacientes. A partir do diagnóstico de ferropenia da medula óssea, a TSAT ≤ 19,8% apresentou sensibilidade de 94,1% e especificidade de 84% para diagnóstico de ferropenia, enquanto ferro sérico ≤ 13 μmol/L teve sensibilidade 94% e especificidade de 88%. Em contrapartida, a ferritina com valor ≤ 145 ng/mL teve sensibilidade 70,6% e especificidade 60%.⁵³ Trata-se de um estudo pequeno, mas levanta a questão se a TSAT e o ferro sérico teriam maior valor para o diagnóstico de ferropenia em vez da ferritina.

A maioria dos pacientes incluídos em ECRs (FAIR, CONFIRM e EFFECT) apresentavam DF absoluta (80-90%), enquanto a DF funcional foi pouco representada.¹⁰ Em estudo transversal realizado com pacientes com ICFER, os pacientes foram classificados dentro de categorias: transporte de ferro reduzido (TSAT < 20%); DF absoluta (ferritina < 100 μg/L); e status do ferro normal. Os pacientes com transporte de ferro reduzido isoladamente apresentaram níveis maiores de fragmento N-terminal do peptídeo natriurético tipo B (NT-proBNP) e pior qualidade de vida [OR 1,7 (1,2–2,5); p=0,005] quando comparados àqueles com status de ferro normal [OR 2,1 (1,5–2,9) p<0,001], e não houve diferença do NT-proBNP e qualidade de vida quando comparados os grupos com DF absoluta e status do ferro normal.⁵⁴ Os achados desse estudo tornam relevante a discussão sobre a importância dos pacientes com TSAT <20% ou DF funcional terem maior representatividade nos ECRs.

Até a presente data, os ECRs já realizados não foram desenhados com poder suficiente para avaliar o benefício do ferro endovenoso em reduzir mortalidade em pacientes com ICFER estáveis. Está em andamento o ECR duplo-cego placebo controlado, FAIR-HF 2,⁵⁵ o qual pretende recrutar pacientes com ICFER e ferropenia de modo a avaliar se a carboximaltose férrica é capaz de reduzir o desfecho primário combinado de hospitalização por IC e morte cardiovascular.

A maior parte da evidência científica de ferropenia e IC origina-se de estudos de pacientes com fração de ejeção reduzida. Existe uma lacuna de conhecimento a respeito de estudos de intervenção na ferropenia e IC com fração de ejeção preservada (ICFEP). Em revisão sistemática e metanálise com 1877 pacientes com ICFEP, a prevalência de ferropenia foi de 59%. Os portadores de ferropenia apresentaram pior classe funcional, capacidade de exercício e qualidade de vida quando comparados aos sem ferropenia. Não houve diferença quanto ao risco de morte ou de hospitalização.⁵⁶ Outro ECR, o FAIR-HFpEF,⁵⁷ está sendo conduzido para avaliar a eficácia e a segurança da reposição de carboximaltose férrica nos pacientes com ICFEP e ferropenia.

Conclusões

A ferropenia é uma comorbidade muito comum nos portadores de ICFER e passou a ser considerada um alvo terapêutico. A carboximaltose férrica endovenosa melhora os sintomas, capacidade de exercício físico e qualidade de vida nos pacientes com ICFER estáveis, sintomáticos e com FEVE ≤45%, tanto nos anêmicos como não anêmicos. Também há evidência de redução do risco de hospitalização por IC. Em contrapartida, a formulação de ferro oral não traz benefício clínico em pacientes com ICFER e DF. Até o momento não há evidência científica que sustente a indicação de carboximaltose férrica nos pacientes com ICFEP.

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Vinculação acadêmica

Este artigo é parte de dissertação de mestrado de Guilherme Augusto Reissig Pereira pelo Programa de Pós-Graduação em Cardiologia – Universidade Federal do Rio Grande do Sul.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

Fontes de financiamento: O presente estudo não teve fontes de financiamento externas.

Review Article

Iron Deficiency in Heart Failure with Reduced Ejection Fraction: Pathophysiology, Diagnosis and Treatment

0000-0001-7833-2994

Pereira

Guilherme Augusto Reissig

¹ ²

0000-0002-5702-210X

Beck-da-Silva

Luís

² ³

1 Brasil Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS – Brasil 2 Brasil Programa de Pós-Graduação em Cardiologia – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS – Brasil 3 Brasil Hospital de Clínicas de Porto Alegre, Porto Alegre, RS – Brasil

Mailing Address: Luis Beck-da-Silva • Hospital de Clínicas de Porto Alegre – Serviço de Cardiologia - Ramiro Barcelos, 2350, 2º andar. Postal Code 90440-050, Porto Alegre, RS – Brazil E-mail: lbneto@hcpa.edu.br, luisbeckdasilva@gmail.com

Author Contributions

Conception and design of the research, Acquisition of data, Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Pereira GAR, Beck-da-Silva L.

Potential Conflict of Interest

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

Abstract

Iron deficiency (ID) is an important comorbidity in heart failure with reduced ejection (HFrEF) and is highly prevalent in both anemic and non-anemic patients. In HFrEF, iron deficiency should be investigated by measurements of transferrin saturation and ferritin. There are two types of ID: absolute deficiency, with depletion of iron stores; and functional ID, where iron supply is not sufficient despite normal stores. ID is associated with worse functional class and higher risk of death in patients with HFrEF, and scientific evidence has indicated improvement of symptoms and quality of life of these patients with treatment with parenteral iron in the form of ferric carboxymaltose. Iron plays vital roles such as oxygen transportation (hemoglobin) and storage (myoblogin), and is crucial for adequate functioning of mitochondria, which are composed of iron-based proteins and the place of energy generation by oxidative metabolism at the electron transport chain. An insufficient generation and abnormal uptake of iron by skeletal and cardiac muscle cells contribute to the pathophysiology of HF. The present review aims to increase the knowledge of the pathophysiology of ID in HFrEF, and to address available tools for its diagnosis and current scientific evidence on iron replacement therapy.

Iron Iron Deficiency Heart Failure, Systolic

Clinical issue

Heart failure (HF) is a global health problem that affects 26 million people in the world.¹ In Brazil, the number of patients with HF was approximately 2,846,000 in 2015, with increasing prevalence with age.²

In a Brazilian registry of patients hospitalized for HF in different parts of the country, in-hospital mortality was 12.6%.³ In addition to the high in-hospital mortality, it is estimated that nearly 50% of patients diagnosed with HF will die within five years.^{4 , 5} Also, HF has a strong economic impact, leading to a cost of 22.1 billion Brazilian reals in 2015.²

Anemia is a common problem in HF with reduced ejection fraction (HFrEF).⁶ It is defined as hemoglobin (Hb) levels <13.0 g/dL in men and <12.0 g/dL in women.⁷ The most common causes of anemia are iron deficiency (ID), chronic diseases, dilutional anemia and renal failure.⁸ ID is a common comorbidity in HF, affecting nearly half of HF patients;^{9 , 10} it is not restricted to anemic patients, since 46% of patients without anemia with stable HF has ID.¹¹

ID in HF is more commonly seen in patients with more advanced disease (worse functional class and higher brain natriuretic peptide levels) and in female patients.^{11 , 12} The presence of ID affects the prognosis. In an observational study with 546 patients with HFrEF, ID was a strong independent predictor of death or need for heart transplantation, increasing the risk for these outcomes by nearly 60%.¹² In another cohort composed of 1,506 European patients with chronic HF, ID (without anemia) was also considered a predictor of death.¹¹ The high prevalence and the strong prognostic power of ID in HF warrant a better understanding of its pathophysiology, diagnosis and treatment.

Pathophysiology Iron – Absorption, distribution and functions in the body

Iron is a metabolically active micronutrient with unique biochemical features. It has two oxidation states – ferrous (+2) and ferric (+3), found inside and outside cells, respectively.¹³

Mean daily intake of iron is 10-20mg/day, although only 10-20% of dietary iron is actually absorbed through specific transportation systems, especially duodenal enterocytes. Iron can be eliminated from the body by desquamation of intestinal mucosal cells, menstruation, or other blood losses. However, because of the lack of a physiologically regulated excretion system for iron in the body, the regulation of its absorption through the duodenum plays a crucial role in iron homeostasis in the body.¹⁴ Most iron required for erythropoiesis (20-25 mg) is derived from recycling of senescent erythrocytes from macrophage phagocytosis in the reticuloendothelial system.^{13 , 15}

Regarding iron distribution in human body, approximately 65% of the mineral is found in hemoglobin of erythrocytes, and nearly 10% is found in myoglobin of muscle fibers. The remaining is stored in the liver, macrophages of the reticuloendothelial system, and bone marrow.¹⁶

Iron plays a fundamental role in oxygen transport by hemoglobin and in oxygen storage in the myoglobin of skeletal and cardiac muscle cells. Iron acts as a component of enzymes involved in oxidation (oxidative phosphorylation) and of iron-sulfur and heme proteins in the respiratory chain of mitochondria. Iron participates in the synthesis and degradation of proteins, lipids and ribonucleic acids.^{13 , 17}

Iron is a potentially toxic metal as it causes the reduction of oxygen molecules in the cells, resulting in the formation of oxygen reactive species. Thus, iron requires an intracellular and an extracellular neutralizer, in the form of ferritin and transferrin, respectively.⁹

Transferrin is a glycoprotein that acts as a storage depot and mediates the transport of soluble iron. Transferrin receptor 1 (TfR1) mediates the uptake of transferrin-bound iron by receptor-mediated endocytosis.¹⁶

Iron is stored in the liver, bone marrow and spleen in the form of ferritin, which is the main storage protein of iron. Concentrations of tissue ferritin increase in situations of iron overload or inflammation.¹³

Hepcidin is a hormone peptide produced mainly by hepatocytes and is considered the main regulator of iron metabolism.¹⁵ Its synthesis is regulated by changes in iron requirements in the body. Hepcidin directly acts on ferroportin, a transmembrane protein that transports iron. Ferroportin is located on the surface of duodenal enterocytes, responsible for iron absorption, and on hepatocytes and macrophages, responsible for iron storage. When hepcidin binds ferroportin, the transporter is degraded in lysosomes, resulting in reduced iron release.^{13 , 15 , 18}

In an experimental study, rats receiving a diet deficient in iron for 12 weeks exhibited increased heart weight and size compared with the control group. Analysis by microscopy revealed abnormal sarcomere structure and mitochondrial ultrastructural aberrations in myocardial tissue.¹⁹

Iron depletion may have deleterious effects in the body, involving since basic structures, such as mitochondria and cells, until more complex ones ( Figure 1 ).^{13 , 20}

Figure 1 – <italic>Harmful effects of iron deficiency at different levels of organism complexity (adapted from Jankowska et al.13and Stugiewicz et al.20). Fe-S: iron-sulfur; O2: oxygen.</italic>

A study on patients with advanced HF undergoing heart transplantation demonstrated depletion of myocardial iron in these patients as compared with healthy controls, suggesting that myocardial iron depletion may play a role in the pathogenesis and progression of HF.²¹ ID causes HF, and HF itself seems to induce ID, suggesting the theory of a vicious cycle.¹⁰ The development of ID may be resultant of reduced iron uptake due to malnutrition and volume overload, hemorrhage associated with antiplatelet and anticoagulants, and disturbances in iron utilization and storage caused by inflammation in HF.^{22 , 23}

Patients with chronic inflammatory conditions such as HF, chronic renal disease, cancer, and inflammatory bowel disease are at higher risk of developing ID.⁹ in HF patients, hepcidin production in the liver is increased, affecting iron absorption in the gastrointestinal tract and iron mobilization from iron stores, including the reticuloendothelial system.^{13 , 23 , 24}

Diagnosis

The distinction between ID anemia and anemia of chronic disease is difficult. In the absence of inflammation, serum levels of ferritin < 30 ng/mL are indicative of ID.²⁵ In a study on patients with advanced anemia, bone marrow aspiration was performed, and ID was confirmed in 73% of patients. Mean ferritin was 75 ng/mL in iron deficient patients, and 211 ng/mL in non-iron deficient patients. As ferritin is an acute-phase protein, their levels may be either normal of increased in HF, even in situations of ID. Thus, the use of conventional biomarkers and conventional cut-off points obtained from patients with non-inflammatory conditions to identify ID in HF is questionable.²⁶

There are two types of ID: absolute deficiency, which reflects depletion of iron stores, with preserved iron homeostasis and erythropoiesis; and functional ID, where iron supply is not sufficient to meet the requirements despite normal or even excess reserve, because iron is trapped inside cells of the reticuloendothelial system and is not available for cellular metabolism.¹³

In patients with HFrEF, absolute ID was defined as ferritin < 100mg/L, and functional ID as ferritin of 100-299 mg/L and transferrin saturation (TSAT) < 20%.^{27 - 29}

Iron deficiency – a therapeutic target

Several randomized clinical trials (RCTs) of treatment of ID in stable and chronic HFrEF have been performed ( Table 1 ). The IRON-HF³⁰ was the first RCT to compare the use of oral iron, intravenous iron and placebo. No statistically significant difference was found in changes of peak VO2 between the groups. Due to prolonged recruitment and financing issues, the trial was stopped before planned. In another study, the IRONOUT-HF, therapy with oral iron was compared with placebo and, again, no difference in peak VO2 was observed between the groups.³¹ These studies corroborate the fact that oral iron supplementation has no clinical benefit in patients with HFrEF and ID.

Table 1 – Randomized clinical trials on treatment of iron deficiency in patients with heart failure

Toblli et al.³³ FERRIC-HF³² FAIR-HF³⁴ IRON-HF³⁰ CONFIRM-HF³⁵ EFFECT-HF⁵⁸ IRONOUT-HF³¹

n FHS: 20 Placebo: 20 FHS: 24 Placebo: 11 FC: 304 Placebo: 155 FHS: 10 SF: 7; Placebo: 6 FC: 150 Placebo: 151 FC: 86 Standard therapy: 86 FP: 111 Placebo: 114

Bliding Double-blind Open Double-blind Double-blind Double-blind Open Double-blind

Center (s) Multicentric Single-center Multicentric Multicentric Multicentric Multicentric Multicentric

Symptoms (NYHA functional class) II-IV II-III II-III II-IV II-III II-III II-IV

LVEF ≤35% ≤45% ≤40% or ≤45% <40% ≤45% ≤45% ≤40%

ID definition Ferritin<100ng/mL and/or TSAT<20% Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20% Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20% Ferritin < 500 μg/L and TSAT<20% Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20% Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20% Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20%

Hb <12.5 g/dL <12.5 g/dL (anemic), 12.5-14.5 g/dL(non-anemic) 9-13.5 g/dL 9-12 g/dL <15 g/dL <15 g/dL 9-13.5 g/dl

Iron pathway Injectable Injectable Injectable Injectable and oral Injectable Injectable Oral

Type of iron FHS FHS FC FHS and FS FC FC PF

Correction phase (dosage) 200mg/week 5 weeks 200mg/week 4 weeks 200mg/week* SHF 200mg/week SF 200mg 3xd 500-2000mg week 0 and 6 500-2000mg week 0 and 6 150mg 2xd 16sem

Maintenance phase (dosage) - 200mg/month 200mg/month - 500mg every 12 weeks^† 500mg every 12 weeks^† -

Treatment duration 5 weeks 16 weeks 24 weeks 5 weeks (SHF) 8 weeks (FS) 36 weeks 12 weeks 16 weeks

Follow-up 24 weeks 18 weeks 24 weeks 12 weeks 52 weeks 24 weeks 16 weeks

Primary outcome of interest Change in NT-proBNP and CRP Change in pVO2 Change in NYHA FC and PGA Change in pVO2 Change in the six-minute walk test distance Change in pVO2 Change in pVO2

Difference in primary outcome Yes No Yes No Yes Yes N

	Toblli et al.³³	FERRIC-HF³²	FAIR-HF³⁴	IRON-HF³⁰	CONFIRM-HF³⁵	EFFECT-HF⁵⁸	IRONOUT-HF³¹
n	FHS: 20 Placebo: 20	FHS: 24 Placebo: 11	FC: 304 Placebo: 155	FHS: 10 SF: 7; Placebo: 6	FC: 150 Placebo: 151	FC: 86 Standard therapy: 86	FP: 111 Placebo: 114
Bliding	Double-blind	Open	Double-blind	Double-blind	Double-blind	Open	Double-blind
Center (s)	Multicentric	Single-center	Multicentric	Multicentric	Multicentric	Multicentric	Multicentric
Symptoms (NYHA functional class)	II-IV	II-III	II-III	II-IV	II-III	II-III	II-IV
LVEF	≤35%	≤45%	≤40% or ≤45%	<40%	≤45%	≤45%	≤40%
ID definition	Ferritin<100ng/mL and/or TSAT<20%	Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20%	Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20%	Ferritin < 500 μg/L and TSAT<20%	Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20%	Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20%	Ferritin<100ng/mL or ferritin 100-299ng/mL + TSAT<20%
Hb	<12.5 g/dL	<12.5 g/dL (anemic), 12.5-14.5 g/dL(non-anemic)	9-13.5 g/dL	9-12 g/dL	<15 g/dL	<15 g/dL	9-13.5 g/dl
Iron pathway	Injectable	Injectable	Injectable	Injectable and oral	Injectable	Injectable	Oral
Type of iron	FHS	FHS	FC	FHS and FS	FC	FC	PF
Correction phase (dosage)	200mg/week 5 weeks	200mg/week 4 weeks	200mg/week*	SHF 200mg/week SF 200mg 3xd	500-2000mg week 0 and 6	500-2000mg week 0 and 6	150mg 2xd 16sem
Maintenance phase (dosage)	-	200mg/month	200mg/month	-	500mg every 12 weeks^†	500mg every 12 weeks^†	-
Treatment duration	5 weeks	16 weeks	24 weeks	5 weeks (SHF) 8 weeks (FS)	36 weeks	12 weeks	16 weeks
Follow-up	24 weeks	18 weeks	24 weeks	12 weeks	52 weeks	24 weeks	16 weeks
Primary outcome of interest	Change in NT-proBNP and CRP	Change in pVO2	Change in NYHA FC and PGA	Change in pVO2	Change in the six-minute walk test distance	Change in pVO2	Change in pVO2
Difference in primary outcome	Yes	No	Yes	No	Yes	Yes	N

* Calculated using the Ganzoni equation.^†if iron deficiency persists. FC: ferric carboxymaltose; ID: iron deficiency; LVEF: left ventricular ejection fraction; Hb: hemoglobin; CRP: C-reactive protein; IP: iron polysaccharide; PGA: Patient Global Assessment; pVO2: peak oxygen consumption; FS: ferrous sulfate; FHS: ferric hydroxide saccharate; TSAT: transferrin saturation; NT-proBNP: N-terminal B-type natriuretic peptide fragment; NYHA: New York Heart Association.

While the first interventional studies with intravenous iron used ferric hydroxide saccharate complex,^{32 , 33} more recent trials used ferric carboxymaltose, another form of parenteral iron. In 2009, the FAIR-HF, considered the largest RCT comparing intravenous administration of ferric carboxymaltose with placebo. Primary outcomes of interest were New York Heart Association (NYHA) functional class and Patient Global Assessment (PGA) at 24 weeks. PGA is a rating scale on which patients rate disease severity and progression. In the ferric carboxymaltose arm, 47% showed improvement in NYHA functional class (to I or II) at 24 weeks, compared with 30% of those who received placebo (OR =2.40; 95%CI 1.55-3.71; p<0.001). PGA at week 24 was better in the interventional group, where 50% of patients reported a moderate or marked improvement, compared with 28% in the placebo group (OR for improvement 2.51; 95% CI 1.75-3.61; p<0.001). Results were similar in patients with and without anemia.³⁴

The CONFIRM-HF study was performed in nine countries in Europe, including 301 patients, with a longer follow-up period (52 weeks) compared with the FAIR-HF. Both studies compared the use of intravenous ferric carboxymaltose with placebo. Primary outcome was improvement in six-minute walk test at 24 weeks compared with baseline. There was an increase in distance walked by 33 ± 11 meters in the group who received carboxymaltose, until the end of the follow-up period at 52 weeks. The effect was observed in both anemic and non-anemic patients, reinforcing the idea that ID is a valid independent therapeutic target.³⁵ This difference of more than 30 meters in the last six months of study was robust and clinically significant, especially considered that in previous interventional studies, benefits of this magnitude have been reported with cardiac resynchronization by a systematic review.³⁶ Lower risk of hospitalization was also found in decompensated HF (HR 0.39; 95%CI 0.19–0.82; p=0.009). No difference was found in cardiovascular mortality outcome (HR 0.96; 95%CI, 0.42-2.16; p=0.91).

In a meta-analysis with five RCTs and 851 patients comparing intravenous iron with placebo, no difference found in cardiovascular mortality (OR 0.80; 95%CI 039-1.63; p=0.54) or all-cause mortality (OR 0.83; 95%CI 0.43-1.59; p=0.57). Hospitalization for HF was less frequent in patients treated with intravenous iron (OR 0.28; 95%CI 0.16-0.50; p<0.0001). It is worth pointing out that 89% of patients included in this meta-analysis received parenteral iron in the form of ferric carboxymaltose.³⁷

Another meta-analysis with four RCTs and 839 patients compared administration of intravenous carboxymaltose with placebo; there was a reduction in cardiovascular hospitalizations and cardiovascular mortality (RR 0.59; 95%CI 0.40–0.88; p=0.009) in the intervention group. When cardiovascular mortality was analyzed alone, no difference was found between the groups (RR 0.84; 95%CI, 0.43-1.66; p=0.620).³⁸ Based on the results of the CONFIRM-HF study and other meta-analyses, ferric carboxymaltose has been considered effective in reducing HF or cardiovascular hospitalizations in stable, symptomatic, patients with reduced left ventricular ejection fraction (LVEF).

Then, ID has become a therapeutic target in stable HFrEF, independent of the presence of anemia. The European guidelines on HF²⁷ have considered intravenous administration of ferric carboxymaltose a IIa recommendation for improvement of symptoms, exercise capacity, and quality of life in NYHA class II/III patients.²⁷ In the next year, the American (American College of Cardiology/AHA) guidelines on HF gave a class II b recommendation for intravenous iron in HFrEF.²⁹ In 2018, the Brazilian guidelines on HF were published, which addressed ID in HFrEF, independent of the presence of anemia. Intravenous administration of iron was given a IIa recommendation to improve exercise capacity and quality of life and reduce hospitalizations.⁸

Therefore, it is important to identify candidates for iron replacement therapy ( Figure 2 ), by screening of all patients with stable HF and ejection fraction ≤45% by measurement of serum ferritin and TSAT.^{10 , 27} The safety of parenteral iron is still unknown in HF patients with hemoglobin > 15g/dL.

Figure 2 – <italic>Diagnostic and therapeutic algorithm for patients with heart failure and iron deficiency (adapted from Rocha et al.)10. ID: iron deficiency; NYHA: New York Heart Association; EF: ejection fraction: Hb: hemoblogin; B12: vitamina B12; IV: intravenous; TSAT: transferrin saturation.</italic>

The diagnosis of ID in acute HF is still a challenge. In an observational study with 47 patients with acute HF, iron profile was measured at admission and on day 30. The prevalence of ID was 83% at admission, with a decrease to 68% on day 30. Median ferritin and TSAT were 93µg/L (IQR: 76–107 μg/L) and 13% (IQR: 6–20%), respectively, on admission, and 159 µg/L (IQR: 134–190 μg/L; p <0.0001 compared with admission) and 17% (IQR: 12–23%; p =0.0176) respectively on the 30th day, without iron replacement therapy. This study demonstrates that biomarkers of iron metabolism are not steady in acute HF, even in a short period of observation, making the diagnosis of ID in acutely decompensated HF questionable.³⁹

Other laboratory tests may be used in the investigation of ID, such as soluble transferrin receptor (sTfR) and hepcidin. In the scenario of acute IC, a sTfR ≥1.59ng/mL and a hepcidin < 14.5ng/mL seem adequate to detect ID.⁴⁰ In addition, sTfR was found to have a prognostic value in HF, as increased sTfR levels were associated with worse NYHA functional class (p<0.05).⁴¹

Myocardial iron

The diagnosis of ID in HF is relatively easy to be made, as it depends on laboratory tests (ferritin and TSAT) only. In a study with pretransplant patients with advanced HF, ventricular myocardial biopsies were performed to measure myocardial iron in the explanted failing hearts, compared to non-failing hearts, and to assess the correlation of myocardial iron with serum markers. No correlation was found of myocardial iron with TSAT, ferritin, or serum iron,⁴² reinforcing that the metabolism of systemic iron and myocardial iron are partly independent.⁴³

Cardiac magnetic resonance

Cardiac magnetic resonance (CMR) is a useful tool in the assessment of patients with HF, that provides information regarding its etiology and prognosis.⁴⁴ Anderson et al.⁴⁵ developed the cardiovascular T2-star (T2*) magnetic resonance technique, and demonstrated that a myocardial T2* of <20 ms was associated with myocardial iron overload and ventricular dysfunction.⁴⁵

As myocardial T2* was shown to be useful in the evaluation of myocardial iron overload, studies have been made to test its utility in detecting myocardial ID also. In a case-control study with HF patients undergoing CMR, a higher T2* seemed to be related with lower myocardial iron content.⁴⁶ In a double-blind RCT with symptomatic HF patients (NYHA II and III), ejection fraction < 50% and ID, patients received either ferric carboxymaltose or placebo. Primary outcome was changes in magnetic resonance T2* and T1 at seven and 30 days of treatment. T2* (ms) was significantly lower in the ferric carboxymaltose arm on day seven (36.6 [34.6–38.7] versus 40 [38–42.1], p=0.025) and day 30 (36.3 [34.1–38.5] versus 41.1 [38.9–43.4], p=0.003). These changes in T2* were suggestive of myocardial iron repletion with ferric carboxymaltose administration.⁴⁷

So far, the cut-off point of T2* for detecting myocardial ID has not been established, and hence the usefulness of this non-invasive tool in the assessment of patients with ID still requires further investigation.

Treatment

Recommended therapeutic dosages of ferric carboxymaltose are described in Table 2 . After correction of ID, reevaluation of serum iron markers (ferritin and TSAT) once-twice a year.²³

Table 2 – Dose of intravenous ferric carboxymaltose in patients with heart failure and iron deficiency10

Weight and Hb Correction phase Maintenance phase

Week 0 Week 6 Week 12 Week 24 Week 36 Week >36

35-70 Kg and Hb <10g/dL 1000 mg 500 mg 500mg if ID persists 500mg if ID persists 500mg if ID persists No evidence

35-70 Kg and Hb ≥10g/dL 1000 mg 0 mg

> 70 Kg and Hb <10g/dL 1000 mg 1000 mg

> 70 Kg and Hb ≥10g/dL 1000 mg 500 mg

Weight and Hb	Correction phase	Maintenance phase
35-70 Kg and Hb <10g/dL	1000 mg	500 mg	500mg if ID persists	500mg if ID persists	500mg if ID persists	No evidence
35-70 Kg and Hb ≥10g/dL	1000 mg	0 mg
> 70 Kg and Hb <10g/dL	1000 mg	1000 mg
> 70 Kg and Hb ≥10g/dL	1000 mg	500 mg

Table adapted from Rocha et al.¹⁰ID: iron deficiency; Hb: hemoglobin; HF: heart failure.

Ferric carboxymaltose has been shown to be cost effective by changes in functional class and reduction in hospitalization rates.⁴⁸ Since the number of infusions of ferric carboxymaltose is relatively lower, as compared with other intravenous formulations, the total cost of treatment may be lower,⁴⁹ in addition to a good safety profile. The therapy is rarely discontinued due to undesirable effects. The most common adverse effects (1-10% of the cases) are flushing, seizure, arterial hypertension, headache, hypophosphatemia, and local reaction on the site of infusion (skin discoloration, pain, irritation).⁵⁰ Patients should be monitored for at least 30 minutes after intravenous injection for the occurrence of adverse effects. Contraindications to the use of ferric carboxymaltose are: hypersensitivity to carboxymaltose and its excipients; severe hypersensitivity to other parenteral formulations containing iron; non-iron-deficiency anemia; and evidence of iron overload or disturbances in iron utilization.²³

Treatment of ID in acute HF

Unlike other trials above mentioned, that included stable outpatients, the recently published multicentric RCT AFFIRM-AHF included patients with LVEF < 50% and ID hospitalized for acute HF. After stabilization and before hospital discharge, participants received ferric carboxymaltose or placebo for 24 weeks. The primary composite outcome was total admissions for HF and cardiovascular death within 52 weeks, which was not different between the groups (RR 0.79; 95%CI, 0.62-1.01; p=0.059). The outcome of cardiovascular death alone was not different (HR 0.96; 95%CI, 0.70-1.32; p=0.81), whereas total admissions for HF was lower in the carboxymaltose (RR 0.74; 95%CI, 0.58-0.94; p=0.013).^{51 , 52} This is a relevant, up-to-date scientific evidence, as it corroborates the indication of ferric carboxymaltose supplementation for patients hospitalized for HFrEF and ID, aiming at reducing the risk for readmissions for HF.

Areas of uncertainty

The criteria to define ID adopted in several RCTs have been arbitrarily established, without validation with iron staining on bone marrow aspirate smears, which is considered the gold-standard method. Grote Beverborg et al.⁵³ conducted a study with HF patients with LVEF ≤ 45% undergoing myocardial revascularization surgery (n=42) and performed measurements of iron-related markers (serum iron, ferritin, TSAT) and bone marrow aspiration with iron staining. Bone marrow ID was found in 40% of the HF patients. Based on the diagnosis of ID confirmed by bone marrow aspiration, TSAT ≤ 19,8% had a sensitivity of 94.1% and a specificity of 84%, and serum iron ≤13 µmol/L had a sensitivity of 94% and specificity of 88%. On the other hand, ferritin ≤145 ng/mL had a sensitivity of 70.6% and specificity of 60%.⁵³ Although this was a small study, it raised the question on whether TSAT and serum iron would be more important for the diagnosis of ID than ferritin.

Most patients included in RCTs (FAIR, CONFIRM and EFFECT) had absolute ID (80=90%), whereas functional ID was poorly represented.¹⁰ In a cross-sectional study, patients with HFrEF were categorized into the following: impaired iron transport (TSAT < 20%); absolute ID (ferritin < 100 μg/L); and normal iron status. Patients with isolated impaired iron transport had higher N-terminal pro b-type natriuretic peptide (NT-proBNP) levels (OR 2.1 [1.5–2.9] p<0.001) and worse quality of life (OR 1.7 [1.2–2.5]; p=0,005) as compared with patients with normal iron status, and no difference in NT-proBNP levels compared with patients with absolute ID and normal iron status.⁵⁴ These findings highlight the importance of including patients with TSAT<20% or functional ID in RCTs.

The currently available RCTs do not have enough power to evaluate the benefit of intravenous iron in reducing mortality in patients with stable HFrEF. The ongoing double-blind, placebo-controlled study FAIR-HF 2,⁵⁵ aims to evaluate whether ferric carboxymaltose can reduce the primary composite endpoint of hospitalization for HF and cardiovascular death in patients with HFrEF and ID.

Most of the evidence available to date is based on studies with patients with reduced ejection fraction. There is a gap in knowledge for patients with HF and preserved ejection fraction (HFpEF). In a systematic review and meta-analysis of 1,877 with HFpEF, the prevalence of ID was 59%. Patients with ID had worse functional class, exercise capacity and quality of life compared with those without ID. No difference was found regarding risk of death or hospitalization.⁵⁶ Another RCT, the FAIR-HFpEF,⁵⁷ currently in progress, aims to evaluate the efficacy and safety of ferric carboxymaltose administration in patients with HFpEF and ID.

Conclusions

ID is a very common comorbidity in patients with HFpEF that has become a therapeutic target. Intravenous ferric carboxymaltose improves symptoms, exercise capacity and quality of life in symptomatic patients with stable HFrEF and LVEF ≤45%, in both anemic and non-anemic patients. There is also evidence of a reduction in the risk of HF. On the other hand, oral iron formulations have no clinical benefits in patients with HFrEF and ID. So far, there is no clinical evidence supporting ferric carboxymaltose administration in patients with HFrEF.

Study Association

This article is part of the thesis of master submitted by Guilherme Augusto Reissig Pereira, from Programa de Pós-Graduação em Cardiologia – Universidade Federal do Rio Grande do Sul.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Sources of Funding: There were no external funding sources for this study.

Peso e Hb	Fase de correção		Fase de manutenção

	Sem 0	Sem 6	Sem 12	Sem 24	Sem 36	Sem >36
35-70 Kg e Hb <10g/dL	1000 mg	500 mg	500mg se DF persiste	500mg se DF persiste	500mg se DF persiste	Sem evidência
35-70 Kg e Hb ≥10g/dL	1000 mg	0 mg
> 70 Kg e Hb <10g/dL	1000 mg	1000 mg
> 70 Kg e Hb ≥10g/dL	1000 mg	500 mg

Weight and Hb	Correction phase		Maintenance phase

	Week 0	Week 6	Week 12	Week 24	Week 36	Week >36
35-70 Kg and Hb <10g/dL	1000 mg	500 mg	500mg if ID persists	500mg if ID persists	500mg if ID persists	No evidence
35-70 Kg and Hb ≥10g/dL	1000 mg	0 mg
> 70 Kg and Hb <10g/dL	1000 mg	1000 mg
> 70 Kg and Hb ≥10g/dL	1000 mg	500 mg