Heart Failure with Mid-Range Ejection Fraction: 3 Years After Its Creation, What Do We Know?
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2019/2020 Eva Isabel Silva Fernandes Heart failure with mid-range ejection fraction: 3 years after its creation, what do we know? MARÇO, 2020 Eva Isabel Silva Fernandes Heart failure with mid-range ejection fraction: 3 years after its creation, what do we know? Mestrado Integrado em Medicina Área: Medicina Clínica Tipologia: Monografia Trabalho efetuado sob a Orientação de: Doutor Manuel Joaquim Lopes Vaz da Silva E sob a Coorientação de: Dra. Elisabete Lousada Martins Oliveira Bernardes Trabalho organizado de acordo com as normas da revista: Revista Portuguesa de Cardiologia MARÇO, 2020 Title: Heart failure with mid-range ejection fraction: 3 years after its creation, what do we know? Título: Insuficiência cardíaca com fração de ejeção “intermédia”: 3 anos após a sua criação, o que sabemos nós? Authors: Eva Fernandes1, Elisabete Martins1,2, Manuel Vaz da Silva1,2 1Faculty of Medicine of the University of Porto 2Department of Cardiology, São João Hospital, Porto, Portugal Corresponding author information: Eva Isabel Silva Fernandes Rua de Macedinho, 13, 5360-202 Trindade, Vila Flor E-mail: [email protected] Phone: 910 653 382 Abstract word count: 223 Contagem de palavras do resumo: 26 Manuscript word count: 4079 Abstract Who are the patients with mid-range ejection fraction? Why did the European Society of Cardiology create this category? Does this new group have differences in its epidemiology and in its response to pharmacological therapy? In this descriptive review we seek to characterize heart failure patients with mid-range ejection fraction, their comorbidities and the way they respond to pharmacological treatment. Although these patients show an intermediate phenotype in terms of sex and age, confirming their status as the "middle brother" between the two classic ejection fraction groups, this class also shows some unique features, such as its particularly high incidence of ischemic coronary disease. While their prognosis brings them closer to patients with preserved ejection fraction, their response to pharmacological therapy appears to be vastly superior to the preserved ejection fraction one. Mid- range ejection fraction patients seem to display significant better outcomes when treated with beta blockers and mineralocorticoid receptor antagonists, however only small and mostly retrospective analysis are available at the moment. Will the next guidelines change the therapeutic approach to this new branch of heart failure? Bigger and better research needs to be conducted and, above all, the medical community needs more time to understand patients with mid-range ejection fraction and heart failure in general. At the end of this review, a question remains: are we labelling our patients the right way? Keywords: heart failure, mid-range ejection fraction, drug therapy. Resumo Quem são os pacientes com fração de ejeção intermédia? Porque criou a Sociedade Europeia de Cardiologia esta categoria? Terá este grupo diferenças na sua epidemiologia e na sua resposta à terapia farmacológica? Nesta revisão narrativa, procuramos caracterizar os pacientes com insuficiência cardíaca com fração de ejeção intermédia, as suas comorbilidades e a maneira como respondem ao tratamento farmacológico. Embora estes pacientes apresentem um fenótipo intermédio em termos de sexo e idade, confirmando o seu estatuto de "irmão do meio" entre as duas categorias clássicas de fração de ejeção, esta classe mostra também algumas características únicas, como a sua incidência particularmente alta de doença arterial isquémica. Embora o seu prognóstico os aproxime dos pacientes com fração de ejeção preservada, a sua resposta à terapia farmacológica parece ser muito superior à destes. Os pacientes com fração de ejeção intermédia parecem apresentar resultados significativamente melhores quando tratados com betabloqueadores e antagonistas dos recetores dos mineralocorticóides, no entanto, a maior parte dos estudos disponíveis no momento recorrem a populações relativamente pequenas e a análises de teor retrospetivo. Irão as próximas diretrizes mudar a abordagem terapêutica desse novo ramo da insuficiência cardíaca? Maiores e melhores pesquisas precisam ser conduzidas e, acima de tudo, a comunidade médica precisa de mais tempo para entender os pacientes com fração de ejeção intermédia e com insuficiência cardíaca em geral. No final desta revisão, permanece uma pergunta: estaremos a categorizar os nossos pacientes da forma certa? Palavras chave: insuficiência cardíaca, fração de ejeção intermédia, terapêutica farmacológica. Introduction According to the American Heart Association (AHA), heart failure (HF) is predicted to affect 2.97% of the worldwide population in 2030.1 In addition to the quality of life that patients lose, there is also an economic impact since this pathology encompasses large expenses for health care systems and workers loose workdays. Despite all the negative impact that this syndrome has on the lives of patients and their families, the last few years have been poor in terms of developments in the treatment of HF, particularly for patients who suffer from HF with preserved ejection fraction (HFpEF). In 2016, the European Society of Cardiology (ESC) introduced the concept of heart failure with mid-range ejection fraction (HFmrEF), a group that encompasses those whose left ventricular ejection fraction (LVEF) is estimated to stand between 40 and 49%. This was created to fill the void generated by two other classic ejection fraction groups in heart failure, preserved and reduced ejection fraction.2 The introduction of this concept, more than creating a new HF class, was intended to draw attention from researchers to HF and its therapy. Due to these facts, we developed a review summarizing the epidemiological characteristics of HFmrEF patients, and its response to pharmacological treatment. We hope to understand if the ESC initiative to boost research can be considered successful and anticipate if this group should really be treated in a differentiated way. 1 Methods To elucidate various drug classes effect in individuals with mid-range ejection fraction (EF), we conducted an online search using the following databases: Cochrane Library, MEDLINE, and Web of Science Core Collection databases. The research was conducted using the following MeSH terms: "Heart Failure" and "Drug Therapy", combined with the term "mid- range" that has not been coded so far. From this research, and after eliminating duplicate results, we ended with 48 articles whose abstracts were analysed and selected. This selection resulted in a universe of 17 articles whose whole content was read. 10 papers addressing the effects of various classes of drugs in the outcomes of HFmrEF patients were included in the review presented here. Furthermore, two additional studies about pharmacological treatment and multiple studies about HFmrEF population’s characteristics and outcomes were included. 2 What is heart failure? Heart failure is currently defined as a clinical syndrome comprising of a specific set of signs and symptoms due to cardiac structural or functional anomalies, such as dyspnea, legs oedema, low exercise tolerance or the presence of the third heart sound. However, we are increasingly aware that before displaying symptoms patients can already suffer from cardiac disfunction and recognizing early signs plays a crucial part in the patients’ outcome. 2 The diagnosis of HF requires a carefully collected clinical history before prescribing supplementary exams. After collecting the patient’s medical history, physical examination should be performed with a particular focus in cardiac and pulmonary auscultation. 2 The first exam performed should be the ECG since it has a very high sensitivity for the diagnosis of HF (98%), it is non-invasive and is available in most medical offices. 2 If any ECG irregularities are present, an evaluation of natriuretic peptides (NP) levels must be performed, if available. The gold-standard for cardiac abnormalities diagnosis is echocardiography, being the most informative exam, non-invasive, and providing evidence about chamber volumes, ventricular function, myocardial wall thickness, and filling pressure.2 (Figure 1) The historically most accepted way to classify HF is through the LVEF, usually obtained by transthoracic echocardiography. The categorization of patients based on EF is meaningful because past and current studies show us significant differences in these populations' characteristics regarding age, sex, comorbidities, and their outcomes to treatment with the same drugs.3 However, LVEF displays many variations through time, changing patients’ classification and recommended therapies. Previous studies have shown that patients whose LVEF improved exhibited significantly better prognosis than patients whose LVEF stayed the same.4 Some authors even argue that stratifying patients solely based on their LVEF is a too narrow approach, claiming 3 that patients should be stratified based on their HF etiology, or using artificial intelligence to examine data about patients’ outcomes and detect common characteristics between them.5 Despite these facts, according to ESC guidelines, most clinical trials nowadays divide patients into preserved (≥50%), reduced (<40%) and mid-range EF (40 to 49%). The diagnosis of HFmrEF requires the following criteria: 2 1. Symptoms and/ or signs of HF; 2. Mid-range LVEF (40 - 49% EF); 3. High levels of natriuretic peptides; 4. Key structural/ functional alterations of the heart such as high left atrial volume,