2019/2020
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
Eva Isabel Silva Fernandes
Heart failure with mid-range ejection fraction: 3
years after its creation, what do we know?
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: up201402866@med.up.pt
Phone: 910 653 382
Abstract word count: 223
Contagem de palavras do resumo: 26
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?
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.
1
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.
2
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.
3
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
4 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, high left ventricular mass, or a high E/ e’ ratio.
5 Patient with suspected HF
Clinical history taking +
Physical Examination +
ECG
No symptoms or signs of HF. ECG without alterations.
HF improbable
Symptoms or signs of HF. Abnormalities in the ECG
Natriuretic Peptides available: BNP ≥ 35 pg/mL NT-proBNP ≥ 125 pg/mL Natriuretic Peptides unavailable: Echocardiography
Figure 1. Heart failure diagnosis algorithm
BNP - B-type natriuretic peptide; HF – Heart Failure; NT-proBNP - N-terminal pro b-type natriuretic peptide.
6
Characterization of the HFmrEF population
HFrEF and HFpEF have traditionally been associated with systolic and diastolic myocardial dysfunction, respectively, however researchers nowadays are increasingly aware that both display some grade of both types of myocardial dysfunction.6 Furthermore, left ventricular hypertrophy is also present in all three HF groups, however it is due to concentric remodelling in HFpEF and also in HFmrEF, though in a smaller extent, and due to eccentric remodelling in HFrEF patients.6 (Table 1)
Tsuji et al.7 stated that HFmrEF represented a transitional state between HFpEF and HFrEF. After a follow-up of 3 years, 45% of HFmrEF patient had transitioned into the preserved EF group, and 21% into the reduced EF group, this group displayed significantly worse outcomes. Ischemic heart disease was significantly related to lower LVEF in all groups.7
There are still gaps when it comes to understanding epidemiology, aetiology, prognosis and treatment of HFmrEF. The mid-range group remains a grey area between the other two groups when it comes to most pathophysiology (Table 1), characteristics (Table 2) and outcomes (Table 3). Nevertheless, these new findings show us the important role of ischemic disease in HFmrEF patients. (Table 2) With an aging population and a better management of coronary disease we may witness an increase in the prevalence of HFmrEF patients in the overall universe of HF. 8
7
HFrEF HFmrEF HFpEF
LV filling pressure + + +
LV hypertrophy ++ + +
LV remodelling Eccentric Concentric
(less expressive) Concentric
Diastolic dysfunction + + + Laboratory markers NT‐proBNP ↑ ↑ Serum creatinine Troponin T Cystatin C ↑ ↑ tP1NP Prealbumin ↓ ↓ SGPT Haemoglobin
Table 1. Echocardiographic measures and laboratory markers in HF.
HFmrEF – Heart failure with mildly reduced ejection fraction; HFpEF – Heart failure with preserved ejection fraction; HFrEF – Heart failure with reduced ejection fraction; LV – Left ventricle; NT-proBNP - N‐terminal pro‐B‐type natriuretic peptide; SGPT - serum glutamate pyruvate transaminase; tP1NP - total procollagen type 1 amino‐terminal propeptide.
8
GWTG-HF 9 CHARM Program 10 PINNACLE registry 11
HFrEF HFmrEF HFpEF HFrEF HFmrEF HFpEF HFrEF HFmrEF HFpEF n = 18,398 n = 3285 n = 18,299 n = 4323 n = 1322 n = 1953 n = 316,628 n = 56,527 n = 324,387 Prevalence 46.0% 8.2% 45.8% 57% 17% 26% 36.1% 7.5% 56.5% % female 40.99% 51.51% 67.58% 25.8% 29.9% 45.5% 33.1% 33.1% 51.5% Age (years) 79 (73–85) 81 (74–86) 82 (75–87) 65 ± 11 65 ± 11 67 ± 11 67.8 ± 13.5 70.1 ± 12.8 69.7 ± 13.6 DM 38.31% 41.57% 38.83% 28.6% 28.6% 28.1% 25.9% 30.0% 25.7% Hypertension 69.86% 75.29% 77.88% 48.6% 56.2% 68.7% 69.3% 79.1% 79.1% MI 22.29% 17.51% 11.11% 58.3% 57.6% 37.0% 22.2% 25.2% 14.5% AF/ FA 34.52% 37.43% 38.92% 26.2% 25.6% 31.3% 33.0% 40.3% 34.4%
AF/ FA- Atrial flutter/ fibrillation; CHARM - Candesartan in HF - Assessment of Reduction in Mortality and Morbidity; DM – Diabetes mellitus; GWTG-HF - Get with The Guidelines - Heart Failure; GWTG-HFmrEF – Heart failure with mid-range ejection fraction; GWTG-HFpEF – Heart failure with preserved ejection fraction; HFrEF – Heart failure with reduced ejection fraction; MI – myocardial infarction; PINNACLE - Practice Innovation and Clinical Excellence.
9 Source AC mortality CV mortality
AC hospitalization HF hospitalization (Lauritsen et al., 2018)12 HFmrEF < HFrEF < HFpEF HFmrEF = HFpEF < HFrEF - HFpEF < HFmrEF < HFrEF (Lund et al., 2018)10 HFmrEF = HFpEF < HFrEF HFmrEF = HFpEF < HFrEF HFmrEF < HFpEF = HFrEF HFmrEF = HFpEF < HFrEF (Altaie et al., 2018)13 HFmrEF = HFpEF < HFrEF HFmrEF = HFrEF < HFpEF HFmrEF = HFpEF = HFrEF HFmrEF = HFpEF = HFrEF (Shah et al., 2017)9 HFmrEF = HFpEF = HFrEF - HFrEF < HFpEF < HFmrEF HFpEF < HFmrEF = HFrEF (Lyu et al., 2019)14 HFmrEF = HFpEF < HFrEF HFmrEF = HFpEF < HFrEF HFmrEF = HFpEF = HFrEF -
Regarding prognosis, the above cited studies seem to agree that cardiovascular and all-cause mortality rates are lower in HFmrEF patients. 9, 10, 12-14 (Table 3) Nevertheless, the follow up time was not uniform between protocols, therefore further studies with large cohorts and longer follow up time are needed to draw reasonable conclusions about this topic.
Table 3. Outcomes of HF patients across LVEF spectrum
AC – All cause; CV – Cardiovascular; HF – Heart Failure; HFmrEF – Heart failure with mildly reduced ejection fraction; HFpEF – Heart failure with preserved ejection fraction; HFrEF – Heart failure with reduced ejection fraction.
10
Treatment of HFmrEF
Drugs with proven benefits on morbimortality in HFrEF:
ACE inhibitors/ ARB First-line treatment in patients with reduced EF.
ARNI
ARNIs can replace ACEIs in HFrEF patients whose symptomatology remains despite optimal therapy with an ACEI,
BB and MRA.
MRA
Spironolactone or eplerenone are recommended in all patients with HFrEF who remain symptomatic despite being treated with
an ACEI and a beta-blocker.
Beta-blockers
First-line treatment in patients with reduced EF. There is some evidence that nebivolol could help reduce hospitalization rates in
HFpEF patients.
Ivabradine
Ivabradine significantly reduces the composite outcome of mortality/ hospitalization in HFrEF patients in sinus rhythm
whose HR ≥ 70 bpm.
Drugs with uncertain/ unproved benefits
Digitalis
Digoxin could be an option in HFrEF patients in sinus rhythm who remain symptomatic despite optimal therapy.
Statins
If a patient is already being treated with a statin due to another underlying disease this therapy should be carried-on. Table 4. Classes of drugs indicated in heart failure treatment.2
11 Renin inhibitors
Renin inhibitors are not recommended as a viable alternative to being treated with an ACEI or ARB.
CCB
Non-dihydropyridine CCBs are not preconized to treat HFrEF patients. Its role in HFpEF/ HFmrEF AF patients is unknown at
the moment.
Reviewed studies
Observational studies:
Savarese et al.15 conducted an observational study based on the Swedish HF registry database. The team investigated the connection between B-type natriuretic peptide levels and cardiovascular events.15 This study included 15 849 patients, which 21% had a mid-range EF. Patients who were treated with an ACEI/ ARB had lower cardiovascular (CV) event rates (Hazard Ratio (HR) 0.78 95%Confidence Interval (CI) 0.67-0.92) and similar positive results when it came to non CV events (HR 0.80 95%CI 0.67-0.95). Analogous conclusions were drawn about beta blockers effect in CV (HR 0.78 95%CI 0.66-0.92) and non CV (HR 0.82 95%CI 0.69-0.97) event rates in this population.15 This was an observational retrospective study and, therefore, no randomization was conducted, resulting in a high probability of existence of confounding factors.
ACE - Angiotensin-converting-enzyme; AF – atrial fibrillation; ARB - Angiotensin II receptor blockers; ARNI - Angiotensin Receptor-Neprilysin Inhibitors; BB – Beta Blocker; CCB – Calcium Channel blockers; EF – Ejection Fraction; ESC – European Society of Cardiology; HF – Heart Failure; HFpEF – Heart failure with preserved ejection fraction; HFrEF – Heart failure with reduced ejection fraction; MRA - Mineralocorticoid receptor antagonist.
12 Tsuji et al.7 conducted an observational study based on the Japanese population. This cohort encompassed 10 219 patients aged ≥ 20 years who suffered from either coronary disease, structural heart disease, or had an history of symptomatic HF. For this analysis patients whose LVEF measurements were available were included, resulting in a sample of 3 480 HF patients, 17.1% with a mid-range EF.7 In this study beta blockers showed a statistically significant positive effect (HR 0.57 95%CI 0.37–0.87) and diuretics a statistically significant negative effect (HR 2.01 95%CI 1.24–3.28) on mortality rates. No effects were linked to the use of ACEI/ ARBs, statins or calcium channel blockers. 7
Gwag et al.16 conducted a retrospective analysis based on the data from the Korean Acute Heart Failure cohort. 3 085 patients were included in this analysis, excluding all patients whose HF aetiology was considered reversible and those who had no LVEF registry. 454 of those patients were labelled as HFmrEF patients, but only 276 were subjected to follow-up LVEF measurements. 16 During the follow up ACEI/ ARBs (HR 0.309 95%CI 0.162–0.588) and MRA (HR 0.240 95%CI 0.085–0.673) treatment was linked to a significant lower all-cause mortality in HFmrEF patients. Beta blocker therapy was linked to an improved LVEF at follow-up, nevertheless we cannot state that this leads to an increased survival. 16
Sá et al.17 carried out a retrospective observational study based on the Portuguese Registry of Acute Coronary Syndrome. The authors excluded patients with a previous diagnose of HF or no echocardiographic evaluation, culminating in a population of 9429 patients of which 20.4% were patients with mid-range EF. 17 The hospital use of beta blockers was identified as an in-hospital mortality reducing factor in mid-range EF patients (odds ratio (OR) 0.3 95%CI 0.1– 0.6).17 However this data only applies to post acute coronary syndrome patients.
Lee et al.18 performed a retrospective cohort study using data from the Kaiser Permanente Southern California healthcare system. The final cohort included 13 440 patients, and 11.8% of those were labelled as HFmrEF. 18 The team goal was to enlighten the link between statins use and morbimortality across the EF spectrum. The authors concluded that despite improving
13 survival and lowering hospitalization rates in the HFpEF group, statins encompassed no effect in the two other clusters.18 However, the information about statin use was inferred from dispensing data, and this cohort was based on a population with no access to health insurance, which can mean there were some not accounted socioeconomical factors.
Randomized Controlled Trials
Abdul-Rahim et al.19 conducted a retrospective analysis based on the Digitalis Investigation Group randomized controlled trial (RCT) data. 19 This RCT was based on two branches: the reduced ejection fraction branch, and a supplementary branch of patients with preserved/ mid-range EF, both branches were assigned to receive either digoxin or placebo. This team reorganized patients creating three branches (reduced, mid-range and preserved EF) and analysed their outcomes, concluding that digoxin only benefited patients with EF lower than 35%, displaying no significant impact on HF hospitalization rate nor in cardiovascular mortality in patients with mid-range EF. 19
Tumasyan et al.20 presented a poster at the 2019 ESC congress that compared the results of treatment with ramipril + spironolactone and valsartan + spironolactone versus sacubitril/valsartan and spironolactone + sacubitril/valsartan on HF patients’ prognosis and functional parameters. The authors revealed that sacubitril/ valsartan alone or in combination with spironolactone was associated with better prognosis in HFmrEF patients (24.7% and 21.6% relative risk reduction in mortality, and 27.3% and 24.3% relative risk reduction in hospitalizations in HFmrEF patients treated with sacubitril/valsartan and sacubitril/ valsartan + spironolactone respectively).20 However only the abstract of this study was available.
Xin et al.21 conducted and RCT comparing the effects of a high and a low dosage of spironolactone with a placebo group in HFmrEF patients. 279 patients diagnosed with HFmrEF in a Chinese university hospital were included in this study. 21 The combined outcome of death and HF rehospitalization was significantly lower in those being treated with spironolactone (21.3%) when compared with the untreated group (34.5%). This article found no difference
14 between the two spironolactone dosages. 21 Although these results look promising, this was a small sample of Chinese patients, and maybe cannot be applied to western patients.
Solomon et al.22 employed data from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial which assigned either spironolactone or a placebo to 3 445 patients whose EF was equal or greater than 45%. 23 This team evaluated the link between spironolactone and the patients’ EF, concluding that patients in the lowest spectrum of the sample (EF < 50%) were the ones that benefited from being treated with spironolactone. 22 However, this analysis did not include all the mid-range EF spectrum.
Lund et al.10 conducted a retrospective analysis of the 7599 patients included in the Candesartan in HF - Assessment of Reduction in Mortality and Morbidity programme. These patients were divided into three groups according to their ejection fraction (preserved, reduced and mid-range) and randomly assigned candesartan or placebo treatment.10 Candesartan displayed a positive effect regarding the primary outcome (cardiovascular death/ HF hospitalization) (HR 0.76, 95% CI 0.61–0.96); HF hospitalization (HR 0.48 95% CI 0.33–0.70) and recurrent HF hospitalization rates (HR 0.72 95% CI 0.55–0.95). The authors linked candesartan to a similar benefit in HFrEF and HFmrEF patients.10
Meta-analysis
Xiang et al.24 meta-analysis included eleven RCTs, resulting in a universe of 4 539 patients contemplating both preserved and mid-range EF patients. 24 The team found no significant differences in mortality between spironolactone and controls (risk reduction 0.72; 95% CI 0.31–1.69), however patients treated with spironolactone had fewer admissions (OR 0.84; 95%CI 0.73–0.95). Some included studies uncovered that spironolactone improved patients’ functional classification. 24 However this study did not differentiate between the two EF groups.
Cleland et al.25 produced a meta-analysis about the effects of beta-blockers according to patients’ LVEF. The final cohort comprised 14 262 patients in sinus rhythm and 3050 patients in
15 atrial fibrillation/ flutter, of those 4.2% were HFmrEF patients.25 Beta blocker treatment significantly reduced cardiovascular mortality in HFmrEF patients presenting with sinus rhythm (HR 0.48, 95% CI 0.24–0.97), however it bared no effect on patients presenting with atrial fibrillation. 25
Drug Class Study Design
Participants (% mrEF) Conclusions ACEi/ ARB (Gwag et al. 2018)16 Cohort (retrospective analysis) n = 3 085 (14.7%)
RASBs were associated with increased survival rate in acute
HFmrEF patients. (Lund et al. 2018)10 RCT (Retrospective analysis) n = 7 598 (17%)
Candesartan reduced the CV death + HF hospitalization rate. (Savarese et al. 2018)15 Retrospective Cohort n = 15 849 (21%)
RASB therapy significantly reduced the risk of CV and
non-CV events. (Tsuji et al. 2017)7 Prospective Cohort n = 3 480
(17.1%) RASB bared no significant impact.
ARNI (Tumasyan et
al. 2019) 20 RCT
n = 334 (32.3%)
Sacubitril/ valsartan significantly reduced morbimortality. MRA (Gwag et al. 2018)16 Cohort (retrospective analysis) n = 3 085 (14.7%)
MRAs were associated with increased survival rate in acute
HFmrEF patients. (Solomon et al. 2015)22 RCT (Retrospective analysis) n = 3 444 (15.1%)
Spironolactone was associated with lower HF hospitalization rates in patients whose EF < 50%.
(Xin, Chen et
al. 2019)21 RCT
n = 279 (100%)
Spironolactone significantly reduced the composite outcome of Table 5. Studies reporting therapeutic interventions in HFmrEF
16 all-cause mortality + HF hospitalization. (Xiang et al. 2019)24 Meta-analysis n = 4539 (unknown)
Spironolactone reduced the admission rates of preserved and
mid-range EF patients Beta-blockers (Cleland et al. 2018) 25 Meta-analysis n = 17 312 (4.2%) BB significantly reduced CV death. (Sá et al. 2019)17 Retrospective Cohort n = 9 429 (20%)
BB treatment was a predictor of lower in hospital mortality in post
ACS HFmrEF patients.
(Tsuji et al. 2017)7 Prospective Cohort n = 3 480 (17.1%)
BB therapy was associated with reduced mortality. (Savarese et al. 2018)15 Retrospective Cohort n = 15 849 (21%)
BB therapy significantly reduced the risk of CV and non-CV events.
Digitalis (Abdul-Rahim et al. 2018)19 RCT (Retrospective analysis) n = 7 788 (15%)
Digoxin showed no significant benefit in HFmrEF patients.
Statins
(Lee et al. 2018)18
Retrospective
Cohort
Statins displayed no significant benefit in HFmrEF patients. (Tsuji et al. 2017)7 Prospective Cohort n = 3 480 (17.1%)
Diuretics (Tsuji et al.
2017)7
Prospective Cohort
n = 3 480 (17.1%)
Diuretics were associated with worse prognosis.
ACEi - Angiotensin-converting-enzyme inhibitors; AF – Atrial Fibrillation; ARB - Angiotensin II receptor blockers; BB – Beta-blocker; CV – Cardiovascular; HF – Heart Failure; HFmrEF – Heart failure with mid-range ejection fraction; LVEF – Left ventricular ejection fraction; MRA - Mineralocorticoid receptor antagonist; RASB - Renin–angiotensin– aldosterone system blockers; RCT - Randomized controlled trial.
17 In this descriptive review, beta blockers and MRAs were, undoubtedly, the two classes of drugs most frequently contemplated, followed by ACEIs and ARBs, which have also been investigated by several studies. According to the aforementioned results, beta blockers are the pharmacological class that seems to present more encouraging results in the outcomes of patients with mid-range EF, followed by spironolactone, which, however, presents some contradictory conclusions between studies. (Table 5) These conclusions are in line with previous similar studies.26
ACEi ARB MRA ARNI BB
HFrEF ✓ ✓ ✓ ✓ ✓
HFmrEF ? ? ✓ ✓ ✓
HFpEF X ? ? X ?
Table 6. Drug effects according to ejection fraction groups.
X – evidence does not support its use; ? – evidence does not agree on its effects; ✓ - evidence supports its use
ACEi - Angiotensin-converting-enzyme inhibitors; ARB - Angiotensin II receptor blockers; ARNI - Angiotensin Receptor-Neprilysin Inhibitors; BB – Beta-blocker; HFmrEF – Heart failure with mid-range ejection fraction; HFpEF – Heart failure with preserved ejection fraction; HFpEF – Heart failure with mid-range ejection fraction; MRA - Mineralocorticoid receptor antagonist;
18
Discussion
The results obtained by the aforementioned studies reflect how recent the concept of mid-range EF is. The vast majority of the included papers were post-hoc analyses and, therefore, are associated with a serious risk of confounding factors. In addition, most of the cited studies cited have a relatively small sample of patients in the mid-range group with a relatively short follow-up time and, therefore, may not reflect the global universe of existing patients.
Last, but not least, there is great intra and inter-observer variability in the measurement of ejection fraction even with the use of increasingly automated methods, with clinicians themselves having a natural tendency to "round" the values of EF obtained or to report an assessment that allows patients to be included in the research being conducted.
This review is just a brief reflection on heart failure with mid-range EF and does not necessarily reflect all the existing evidence about this group of patients, as the methodology used was not systematic and the choice of articles cited only mirrors the interpretations of a single reviewer. This work is not intended to be an exhaustive review but rather to serve as a brief introduction to this group of patients who must now be flagged and treated accordingly in clinical practice.
Despite all the limitations cited here, there are indeed ongoing promising results. Within the above-mentioned pharmacological classes, beta-blockers and mineralocorticoid receptor antagonists stand out as being the most associated with significant beneficial results in HFmrEF patients. Why these drugs present positive effects in HFmrEF patients but not in the HFpEF ones is still debatable, but we contemplate that this effect could be at least partially explained by the different aetiologies of HF in these two groups. However, further research in undoubtably needed.
19
Conclusion
HF with mid-range EF continues to be the youngest, and sometimes unaccepted, branch of heart failure. However, one must remember that HFmrEF patients constitute an average of 13 to 24% of the HF population, making it not rare to encounter one of these patients in the clinical setting. 27
The above cited studies don’t carry enough statistical power to be used as therapeutic guidelines, but they could, and should, be used as a basis to design new randomized controlled trials. The response of HF patients to treatment should be the subject of further investigations, not only on the group of patients with mid-range EF, but on all HF patients and taking into account the variation in their ejection fraction over time, as this variation demonstrates a profound connection with the outcome of these patients. 28
The creation of this “artificial” category should, more than demarcate the differences between each group, highlight the similarities between populations, thus showing that EF is a continuous variable in which exact and mathematical cut off points are not absolute and unquestionable truths. Medicine remains an art and highly depends on clinical judgment and critical thinking for its exercise. The population of patients with HF cannot be defined by a singular assessment over time, but must be framed within their comorbidities, the aetiology of their pump failure and, above all, their life expectancy and the limitations that HF brings to their daily life.
20 References
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2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal. 2016;37(27):2129-200. doi: 10.1093/eurheartj/ehw128.
3. Lam CS, Solomon SD. The middle child in heart failure: heart failure with mid-range ejection fraction (40-50%). Eur J Heart Fail. 2014;16(10):1049-55. Epub 2014/09/12. doi: 10.1002/ejhf.159. PubMed PMID: 25210008.
4. Savarese G, Vedin O, D'Amario D, Uijl A, Dahlstrom U, Rosano G, et al. Prevalence and Prognostic Implications of Longitudinal Ejection Fraction Change in Heart Failure. JACC Heart Fail. 2019;7(4):306-17. Epub 2019/03/11. doi: 10.1016/j.jchf.2018.11.019. PubMed PMID: 30852236.
5. Triposkiadis F, Butler J, Abboud FM, Armstrong PW, Adamopoulos S, Atherton JJ, et al. The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J. 2019;40(26):2155-63. Epub 2019/04/09. doi: 10.1093/eurheartj/ehz158. PubMed PMID: 30957868.
6. Rickenbacher P, Kaufmann BA, Maeder MT, Bernheim A, Goetschalckx K, Pfister O, et al. Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure
21 (TIME-CHF). Eur J Heart Fail. 2017;19(12):1586-96. Epub 2017/03/16. doi: 10.1002/ejhf.798. PubMed PMID: 28295985.
7. Tsuji K, Sakata Y, Nochioka K, Miura M, Yamauchi T, Onose T, et al. Characterization of heart failure patients with mid-range left ventricular ejection fraction—a report from the CHART-2 Study. European Journal of Heart Failure. 2017;19(10):1258-69. doi: 10.1002/ejhf.807.
8. Koh AS, Tay WT, Teng THK, Vedin O, Benson L, Dahlstrom U, et al. A comprehensive population-based characterization of heart failure with mid-range ejection fraction. Eur J Heart Fail. 2017;19(12):1624-34. Epub 2017/09/28. doi: 10.1002/ejhf.945. PubMed PMID: 28948683.
9. Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, et al. Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes. J Am Coll Cardiol. 2017;70(20):2476-86. Epub 2017/11/17. doi: 10.1016/j.jacc.2017.08.074. PubMed PMID: 29141781.
10. Lund LH, Claggett B, Liu J, Lam CS, Jhund PS, Rosano GM, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail. 2018;20(8):1230-9. Epub 2018/02/13. doi: 10.1002/ejhf.1149. PubMed PMID: 29431256.
11. Ibrahim NE, Song Y, Cannon CP, Doros G, Russo P, Ponirakis A, et al. Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry(R). ESC Heart Fail. 2019;6(4):784-92. Epub 2019/07/04. doi: 10.1002/ehf2.12455. PubMed PMID: 31268631; PubMed Central PMCID: PMCPMC6676450.
12. Lauritsen J, Gustafsson F, Abdulla J. Characteristics and long-term prognosis of patients with heart failure and mid-range ejection fraction compared with reduced and preserved ejection fraction: a systematic review and meta-analysis. ESC heart failure. 2018;5(4):685-94. Epub 2018/04/16. doi: 10.1002/ehf2.12283. PubMed PMID: 29660263.
22 13. Altaie S, Khalife W. The prognosis of mid-range ejection fraction heart failure: a systematic review and meta-analysis. ESC Heart Failure. 2018;5(6):1008-16. doi: 10.1002/ehf2.12353.
14. Lyu S, Yu L, Tan H, Liu S, Liu X, Guo X, et al. Clinical characteristics and prognosis of heart failure with mid-range ejection fraction: insights from a multi-centre registry study in China. BMC Cardiovasc Disord. 2019;19(1):209-. doi: 10.1186/s12872-019-1177-1. PubMed PMID: 31477021.
15. Savarese G, Orsini N, Hage C, Vedin O, Cosentino F, Rosano GMC, et al. Utilizing NT-proBNP for Eligibility and Enrichment in Trials in HFpEF, HFmrEF, and HFrEF. Jacc-Heart Failure. 2018;6(3):246-56. doi: 10.1016/j.jchf.2017.12.014. PubMed PMID: WOS:000426507700011.
16. Gwag HB, Lee GY, Choi JO, Lee HY, Kim JJ, Hwang KK, et al. Fate of Acute Heart Failure Patients With Mid-Range Ejection Fraction. Circ J. 2018;82(8):2071-8. Epub 2018/04/24. doi: 10.1253/circj.CJ-17-1389. PubMed PMID: 29681584.
17. Sá FM, Carvalho R, Ruivo C, Santos LG, Antunes A, Soares F, et al. Beta-blockers for post-acute coronary syndrome mid-range ejection fraction: a nationwide retrospective study. European Heart Journal-Acute Cardiovascular Care. 2019;8(7):599-605. doi: 10.1177/2048872619827476. PubMed PMID: WOS:000489065200003.
18. Lee MS, Duan L, Clare R, Hekimian A, Spencer H, Chen W. Comparison of Effects of Statin Use on Mortality in Patients With Heart Failure and Preserved Versus Reduced Left Ventricular Ejection Fraction. Am J Cardiol. 2018;122(3):405-12. Epub 2018/09/12. doi: 10.1016/j.amjcard.2018.04.027. PubMed PMID: 30201108.
19. Abdul-Rahim AH, Shen L, Rush CJ, Jhund PS, Lees KR, McMurray JJV. Effect of digoxin in patients with heart failure and mid-range (borderline) left ventricular ejection fraction.
23 Eur J Heart Fail. 2018;20(7):1139-45. Epub 2018/03/02. doi: 10.1002/ejhf.1160. PubMed PMID: 29493058.
20. Tumasyan L, Adamyan KG, Chilingaryan AL, Tunyan LG, Mkrtchyan VA, Budagyan LG. Comparative efficacy of renin-angiotensin aldosteron system modulators and angiotensin receptor neprilyzin inhibitor in chronic heart failure with reduced, mid-ranged and preserved ejection fraction. European Heart Journal. 2019;40(Supplement_1). doi: 10.1093/eurheartj/ehz745.0402.
21. Xin YG, Chen X, Zhao YN, Hu J, Sun Y, Hu WY. Outcomes of spironolactone treatment in patients in Northeast China suffering from heart failure with mid-range ejection fraction. Curr Med Res Opin. 2019;35(4):561-8. Epub 2018/09/06. doi: 10.1080/03007995.2018.1520695. PubMed PMID: 30183419.
22. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. European Heart Journal. 2015;37(5):455-62. doi: 10.1093/eurheartj/ehv464.
23. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine. 2014;370(15):1383-92. doi: 10.1056/NEJMoa1313731. PubMed PMID: 24716680.
24. Xiang Y, Shi W, Li Z, Yang Y, Wang SY, Xiang R, et al. Efficacy and safety of spironolactone in the heart failure with mid-range ejection fraction and heart failure with preserved ejection fraction: A meta-analysis of randomized clinical trials. Medicine (Baltimore). 2019;98(13):e14967. Epub 2019/03/29. doi: 10.1097/md.0000000000014967. PubMed PMID: 30921200; PubMed Central PMCID: PMCPMC6456096.
25. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual
24 patient-level analysis of double-blind randomized trials. Eur Heart J. 2018;39(1):26-35. Epub 2017/10/19. doi: 10.1093/eurheartj/ehx564. PubMed PMID: 29040525; PubMed Central PMCID: PMCPMC5837435.
26. Srivastava PK, Hsu JJ, Ziaeian B, Fonarow GC. Heart Failure With Mid-range Ejection Fraction. Curr Heart Fail Rep. 2020;17(1):1-8. Epub 2020/01/12. doi: 10.1007/s11897-019-00451-0. PubMed PMID: 31925667.
27. Mesquita ET, Barbetta LMDS, Correia ETdO. Heart Failure with Mid-Range Ejection Fraction - State of the Art. Arq Bras Cardiol. 2019;112(6):784-90. doi: 10.5935/abc.20190079. PubMed PMID: 31314831.
28. Farré N, Lupon J, Roig E, Gonzalez-Costello J, Vila J, Perez S, et al. Clinical characteristics, one-year change in ejection fraction and long-term outcomes in patients with heart failure with mid-range ejection fraction: a multicentre prospective observational study in Catalonia (Spain). BMJ Open. 2017;7(12):e018719-e. doi: 10.1136/bmjopen-2017-018719. PubMed PMID: 29273666.
Agradecimentos
Este trabalho representa o culminar de um período de aprendizagem de seis anos, que em muito me enriqueceu científica e pessoalmente. Como tal, não poderia de deixar aqui o meu mais profundo agradecimento a todos os que me acompanharam nesta caminhada.
Antes de mais, agradeço ao meu orientador Doutor Vaz da Silva, e à minha coorientadora, Doutora Elisabete Martins, dois profissionais excecionais e incansáveis, que me apoiaram, aconselharam e ouviram em todo este percurso e sem os quais nada disto seria possível. Obrigada pelo espírito científico e de interajuda, e pelo incrível exemplo de um médico e de um ser humano que representam para mim.
Em segundo, gostaria de agradecer à minha família, aqueles que são o meu porto seguro e que sempre estiveram lá para me ouvir e apoiar nos momentos mais duros. Obrigada por nunca me deixarem cair.
Por último, agradeço aos meus amigos que foram a minha segunda casa nesta jornada. Obrigada por me fazerem rir, por compreenderem o que apenas um estudante de medicina pode compreender, e por fazerem este caminho comigo. Tem sido um orgulho fazer parte do vosso trajeto e crescer convosco.
A todos aqueles que, profissional ou pessoalmente, me marcaram nos últimos seis anos, deixo aqui o meu agradecimento. Obrigada por me mostrarem o lado humano da ciência, por me ensinarem que a medicina é uma arte, e por me mostrarem que a vida é uma aprendizagem contínua. Irei carregar comigo todos estes ensinamentos, regressarei com carinho a estas memórias e sei que encontrarei para sempre na Faculdade de Medicina da Universidade do Porto um segundo lar.
AUTHOR INFORMATION PACK 30 Mar 2020 www.elsevier.com/locate/repce 1
REVISTA PORTUGUESA DE CARDIOLOGIA
(ENGLISH EDITION)
AUTHOR INFORMATION PACK
TABLE OF CONTENTS
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• Description
• Abstracting and Indexing
• Editorial Board
• Guide for Authors
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ISSN: 2174-2049DESCRIPTION
.The Portuguese Journal of Cardiology, the official journal of the Portuguese Society of Cardiology, was founded in 1982 with the aim of keeping Portuguese cardiologists informed through the publication of scientific articles on areas such as arrhythmology and electrophysiology, cardiovascular surgery, intensive care, coronary artery disease, cardiovascular imaging, hypertension, heart failure and cardiovascular prevention. The Journal is a monthly publication with high standards of quality in terms of scientific content and production. Since 1999 it has been published in English as well as Portuguese, which has widened its readership abroad. It is distributed to all members of the Portuguese Societies of Cardiology, Internal Medicine, Pneumology and Cardiothoracic Surgery, as well as to leading non-Portuguese cardiologists and to virtually all cardiology societies worldwide. It has been referred in Medline since 1987.
ABSTRACTING AND INDEXING
.Hinari
EDITORIAL BOARD
.Editor-in-Chief
Nuno Cardim, Hospital da Luz, Lisboa, Portugal Deputy Editor
Manuel J. Antunes, Universidade de Coimbra, Coimbra, Portugal Associate Editors
Carlos Aguiar, Hospital de Santa Cruz, Carnaxide, Portugal Ana G. Almeida, Hospital de Santa Maria, Lisboa, Portugal Manuel Almeida, Hospital de Santa Cruz, Carnaxide, Portugal Dulce Brito, Hospital de Santa Maria, Lisboa, Portugal
J. Silva Cardoso, Hospital de São João, Porto, Portugal Jorge Ferreira, Hospital de Santa Cruz, Carnaxide, Portugal Henrique Girão, Universidade de Coimbra, Coimbra, Portugal Mário Oliveira, Hospital de Santa Marta, Lisboa, Portugal Fátima Pinto, Hospital de Santa Marta, Lisboa, Portugal
AUTHOR INFORMATION PACK 30 Mar 2020 www.elsevier.com/locate/repce 2
GUIDE FOR AUTHORS
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INTRODUCTION
The Portuguese Journal of Cardiology, the official journal of the Portuguese Society of Cardiology, was founded in 1982 with the aim of keeping Portuguese cardiologists informed through the publication of scientific articles on areas such as arrhythmology and electrophysiology, cardiovascular surgery, intensive care, coronary artery disease, cardiovascular imaging, hypertension, heart failure and cardiovascular prevention.The Journal is a monthly publication with high standards of quality in terms of scientific content and production. Since 1999 it has been published in English as well as Portuguese, which has widened its readership abroad.
The Journal accepts the following categories of articles:
Research (Original Investigation and Meta-Analysis), Review and Education (Narrative Reviews,
Systematic Reviews -without meta-analysis, Guidelines, Case Reports, Images in Cardiology and Snapshots), Opinion (Current Perspective), Correspondence (Editorial Comment, Letters to the Editor, Research Letter and Observation)
Types of article
Manuscripts submitted for publication should be prepared in accordance with the "Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals" of the International Committee of Medical Journal Editors (ICMJE). This document is available at http:// www.icmje.org/recommendations/.
Summary table of Revista Portuguesa de Cardiologiatypes of articles characteristics.
Original Investigation
Original Investigation articles cover areas of clinical or basic research: Clinical trial, Meta-analysis, Intervention study, Cohort study, Case-control study, Epidemiologic assessment, Survey with high response rate, Cost-effectiveness analysis, Decision analysis, Study of screening and diagnostic tests, Other observational studies) . They should have a maximum of 5000 words, with a total of up to 15 tables and/or figures, and should be structured as follows: Abstract (maximum 250 words; divided into Introduction and Objectives, Methods, Results and Conclusion(s)); 3-10 keywords; Introduction; Objectives; Methods; Results; Discussion; Conclusion(s); Acknowledgements, if any; References (up to 75); and figure legends, if any. Follow EQUATOR Reporting Guidelines.
Review Articles and Systematic Reviews
Review Articles should have a maximum of 5000 words, with a total of up to 15 tables and/or figures, and should be structured as follows: Abstract (maximum 250 words; unstructured); 3-10 keywords; Introduction; thematic sections at the discretion of the authors; Conclusion(s); Acknowledgements, if any; References (up to 100); and figure legends, if any. Systematic Reviews should be structured as Introduction, Methods, Results, Discussion and Conclusion(s). The subject should be clearly defined. The objective of a systematic review should be to produce an evidence-based conclusion. The Methods should give a clear indication of the literature search strategy, data extraction, grading of evidence and analysis. Systematic Reviews should not normally exceed 4000 words, with a total of up to 6 tables and/or figures and up to 100 references.
Authors are strongly recommended to consult the PRISMA statement (http://www.prisma-statement.org/), which is intended to help improve the reporting of systematic reviews and meta-analyses. We encourage authors to develop a systematic review protocol (e.g. following PRISMA-P) and register with PROSPERO.
Guidelines
It is recommended to consult the AGREE II instrument for which items should be reported that highlighted particular quality aspects of guideline development. In general, published statements intended to guide clinical care (e.g., guidelines, practice parameters, recommendations, consensus statements and position papers) should describe the clinical problem to be addressed, the mechanism by which the statement was generated, a review of the evidence for the statement (if available), and the statement on practice itself. To minimize confusion and to enhance transparency, such statements should begin with the following questions, followed by brief comments addressing each question:
AUTHOR INFORMATION PACK 30 Mar 2020 www.elsevier.com/locate/repce 3 What other guideline statements are available on this topic?
Why was this guideline developed?
How does this statement differ from existing guidelines? Why does this statement differ from existing guidelines?
The statement should have an unstructured abstract of up to 350 words, 3 to 10 keywords and can include up to 4000 words, a total of up to 6 tables and/or figures and up to 100 references.
Case Reports
Authors should use the CARE guidelines as a guiding framework. Case reports should not exceed 1500 words of body text, with up to 15 references and four tables or figures. They must include an abstract (unstructured, maximum 250 words) and bulleted statements (maximum 70 words) in answer to the following questions: What's already known about this topic? and What does this study add?
Images in Cardiology
Images in Cardiology should have a maximum of 250 words, without Abstract, keywords, tables, or division into sections and up to 5 references may be included.
Snapshots
This section is intended for the publication of rare or educational cases or novel techniques in cardiology. The text should not exceed 500 words and up to 3 figures with brief captions and up to 5 references may be included. Snapshots must have no more than 3 authors.
Current Perspective
This type of manuscript is submitted upon invitation by the Editorial Board. It may cover a broad diversity of themes focusing on cardiology and healthcare: current or emerging problems, management and health policies, history of medicine, society issues and epidemiology, among others. An author who wishes to propose a manuscript in this section is requested to send an abstract to the Editor-in-Chief including the title and Author list for evaluation. The text should not exceed 1200 words, and up to 10 references, two tables or two figures are allowed. An abstract is not required.
Editorial Comment
Editorials are submitted at the invitation of the Editor. They should not exceed 1500 words and can contain up to 20 references and 1 table and 1 figure. They do not have an Abstract or keywords.
Letters to the Editor
Letters to the Editor on articles previously published in the Journal will be considered up to 8 weeks after the publication of the article in question. They should not exceed 800 words and can contain up to 2 figures but without Abstract, keywords or tables. They should have no more than 3 authors.
Research Letter
Research Letters are concise, focused reports of original research. These should not exceed 600 words of text and 6 references and may include up to 2 tables or figures. Online supplementary material is not allowed. Research Letters may have no more than 7 authors.
Observation
Observations consisting of short reports of 1 or 2 complicated, unique cases should not exceed 600 words of text (not including acknowledgment, tables, figures, acknowledgments, and references) and 6 references and may include up to 2 tables or figures. Online supplementary material is not allowed. Observations may have no more than 7 authors. If the patient(s) described in these manuscripts is identifiable, a Patient Permission form must be completed and signed by the patient(s) and submitted with the manuscript. Omitting data or making data less specific to deidentify patients is acceptable but changing any such data is not acceptable.
Contact details for submission
You can send your manuscript at https://www.editorialmanager.com/repc Language
This journal is published in Portuguese and in English language.
AUTHOR INFORMATION PACK 30 Mar 2020 www.elsevier.com/locate/repce 4 Articles submitted to the Journal should be clearly written in Portuguese (from Portugal) and/or English of a good standard. Text may be edited to maintain linguistic quality and to conform with standard American English.
Submission checklist
You can use this list to carry out a final check of your submission before you send it to the journal for review. Please check the relevant section in this Guide for Authors for more details.
Ensure that the following items are present:
One author has been designated as the corresponding author with contact details: • E-mail address
• Full postal address
All necessary files have been uploaded: Manuscript:
• Include keywords
• All figures (include relevant captions)
• All tables (including titles, description, footnotes)
• Ensure all figure and table citations in the text match the files provided • Indicate clearly if color should be used for any figures in print
Graphical Abstracts / Highlights files (where applicable) Supplemental files (where applicable)
Further considerations
• Manuscript has been 'spell checked' and 'grammar checked'
• All references mentioned in the Reference List are cited in the text, and vice versa
• Permission has been obtained for use of copyrighted material from other sources (including the Internet)
• A competing interests statement is provided, even if the authors have no competing interests to declare
• Journal policies detailed in this guide have been reviewed
• Referee suggestions and contact details provided, based on journal requirements For further information, visit our Support Center.
BEFORE YOU BEGIN
Ethics in publishing
Please see our information pages on Ethics in publishing and Ethical guidelines for journal publication. Studies in humans and animals
If the work involves the use of human subjects, the author should ensure that the work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. The manuscript should be in line with the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals and aim for the inclusion of representative human populations (sex, age and ethnicity) as per those recommendations. The terms sex and gender should be used correctly.
The privacy rights of human subjects must always be observed. A statement must be included to the effect that the study was conducted in accordance with the amended Declaration of Helsinki, that the local institutional review board or independent ethics committee approved the protocol, and that written informed consent was obtained from all patients. The name of the committee, the name of the chairperson of the committee (or the person who approved the protocol), the date of approval and the approval number should follow this statement in the Methods section. For multicenter studies, a list of the relevant approvals may be provided in a separate document to be published as supplementary material.
All animal experiments should comply with the ARRIVE guidelines and should be carried out in accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU for animal experiments, or the National Institutes of Health guide for the care
AUTHOR INFORMATION PACK 30 Mar 2020 www.elsevier.com/locate/repce 5 and use of Laboratory animals (NIH Publications No. 8023, revised 1978) and the authors should clearly indicate in the manuscript that such guidelines have been followed. The sex of animals must be indicated, and where appropriate, the influence (or association) of sex on the results of the study. Informed consent and patient details
Studies on patients or volunteers require ethics committee approval and informed consent, which should be documented in the paper. Appropriate consents, permissions and releases must be obtained where an author wishes to include patient descriptions, photographs, video, and pedigrees of patients and any other individuals (parents or legal guardians for minors) who can be identified (including by the patients themselves) in such patient descriptions, photographs, video, and pedigrees. Written consents must be retained by the author but copies should not be provided to the journal. Only if specifically requested by the journal in exceptional circumstances (for example if a legal issue arises) the author must provide copies of the consents or evidence that such consents have been obtained. For more information, please review the Elsevier Policy on the Use of Images or Personal Information of Patients or other Individuals. Unless you have written permission from the patient (or, where applicable, the next of kin), the personal details of any patient included in any part of the article and in any supplementary materials (including all illustrations and videos) must be removed before submission.
Patient Identification
Omitting data or making data less specific to deidentify patients is acceptable, but changing any such data is not acceptable. Only those details essential for understanding and interpreting a specific case report or case series should be provided. Although the degree of specificity needed will depend on the context of what is being reported, specific ages, race/ethnicity, and other sociodemographic details should be presented only if clinically or scientifically relevant and important. Cropping of photographs to remove identifiable personal features that are not essential to the clinical message may be permitted as long as the photographs are not otherwise altered. Please do not submit masked photographs of patients. Patients' initials or other personal identifiers must not appear in an image. Conflicts of Interest and Financial Disclosures
All authors must disclose any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. Examples of potential competing interests include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. A conflict of interest may exist when an author (or the author's institution or employer) has financial or personal relationships or affiliations that could influence (or bias) the author's decisions, work, or manuscript. All authors are required to report potential conflicts of interest including specific financial interests relevant to the subject of their manuscript.
Authors must disclose any interests in two places:
1. A summary declaration of interest statement in the title page file (if double-blind) or the manuscript file (if single-blind). If there are no interests to declare then please state this: 'Declarations of interest: none'. This summary statement will be ultimately published if the article is accepted.
2. Detailed disclosures as part of a separate Declaration of Interest form, which forms part of the journal's official records. It is important for potential interests to be declared in both places and that the information matches. More information.
Submission declaration and verification
Submission of an article implies that the work described has not been published previously (except in the form of an abstract, a published lecture or academic thesis, see 'Multiple, redundant or concurrent publication' for more information), that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder. To verify originality, your article may be checked by the originality detection service Crossref Similarity Check.
AUTHOR INFORMATION PACK 30 Mar 2020 www.elsevier.com/locate/repce 6 Authorship
Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content. One or more authors should take responsibility for the integrity of the work as a whole, from inception to published article. According to the guidelines of the International Committee of Medical Journal Editors (ICMJE), authorship credit should be based on the following 4 criteria:
1. substantial contributions to conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; and
2. drafting of the work or revising it critically for important intellectual content; and 3. final approval of the version to be published; and
4. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Changes to authorship. Role of the corresponding author
A single corresponding author (or coauthor designee in the event that the corresponding author is unavailable) will serve on behalf of all coauthors as the primary correspondent with the editorial office during the submission and review process. If the manuscript is accepted, the corresponding author will review an edited manuscript and proof, make decisions regarding release of information in the manuscript to the news media or federal agencies, handle all postpublication communications and inquiries, and will be identified as the corresponding author in the published article. The corresponding author also is responsible for ensuring that the Acknowledgment section of the manuscript is complete and that the conflict of interest disclosures reported of the manuscript are accurate, up-to-date, and consistent with the information provided in each author's potential conflicts of interest section in the Authorship Form.
Authors are expected to consider carefully the list and order of authors before submitting their manuscript and provide the definitive list of authors at the time of the original submission. Any addition, deletion or rearrangement of author names in the authorship list should be made only
before the manuscript has been accepted and only if approved by the journal Editor. To request
such a change, the Editor must receive the following from the corresponding author:(a) the reason for the change in author list and (b) written confirmation (e-mail, letter) from all authors that they agree with the addition, removal or rearrangement. In the case of addition or removal of authors, this includes confirmation from the author being added or removed.
Only in exceptional circumstances will the Editor consider the addition, deletion or rearrangement of authors after the manuscript has been accepted. While the Editor considers the request, publication of the manuscript will be suspended. If the manuscript has already been published in an online issue, any requests approved by the Editor will result in a corrigendum.
Clinical trial results
In line with the position of the International Committee of Medical Journal Editors, the journal will not consider results posted in the same clinical trials registry in which primary registration resides to be prior publication if the results posted are presented in the form of a brief structured (less than 500 words) abstract or table. However, divulging results in other circumstances (e.g., investors' meetings) is discouraged and may jeopardise consideration of the manuscript. Authors should fully disclose all posting in registries of results of the same or closely related work.
Reporting clinical trials
The ICMJE defines a clinical trial as any research project that prospectively assigns human participants to intervention or comparison groups to study the cause-and-effect relationship between an intervention and a health outcome. Interventions include but are not limited to drugs, surgical procedures, devices, behavioral treatments, educational programs, dietary interventions, quality improvement interventions, process-of-care changes, and the like.
All manuscripts reporting clinical trials, including those limited to secondary exploratory or post hoc analysis of trial outcomes, must include the following: CONSORT flow diagram
Completed trial checklist
Registry at an appropriate online public clinical trial registry
A Data Sharing Statement to indicate if data will be shared or not. Specific questions regarding the sharing of data are included in the manuscript submission system.
AUTHOR INFORMATION PACK 30 Mar 2020 www.elsevier.com/locate/repce 7 Trial Registration
In concert with the ICMJE, our journal requires, as a condition of consideration for publication, registration of all trials in a public trials registry that is acceptable to the ICMJE (ie, the registry must be owned by a not-for-profit entity, be publicly accessible, and require the minimum registration data set as described by ICMJE).
Acceptable trial registries include the following and others listed at http://www.icmje.org: anzctr.org.au clinicaltrials.gov isrctn.org trialregister.nl umin.ac.jp/ctr Copyright
Upon acceptance of an article, authors will be asked to complete a 'Journal Publishing Agreement' (see more information on this). An e-mail will be sent to the corresponding author confirming receipt of the manuscript together with a 'Journal Publishing Agreement' form or a link to the online version of this agreement.
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Open access
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Researcher Academy is a free e-learning platform designed to support early and mid-career researchers throughout their research journey. The "Learn" environment at Researcher Academy offers several interactive modules, webinars, downloadable guides and resources to guide you through the process of writing for research and going through peer review. Feel free to use these free resources to improve your submission and navigate the publication process with ease.
Language (usage and editing services)
Please write your text in good English (American or British usage is accepted, but not a mixture of these). Authors who feel their English language manuscript may require editing to eliminate possible grammatical or spelling errors and to conform to correct scientific English may wish to use the English Language Editing service available from Elsevier's Author Services.
Submission
Our online submission system guides you stepwise through the process of entering your article details and uploading your files. The system converts your article files to a single PDF file used in the peer-review process. Editable files (e.g., Word, LaTeX) are required to typeset your article for final publication. All correspondence, including notification of the Editor's decision and requests for revision, is sent by e-mail.
Submit your article
Please submit your article via https://www.editorialmanager.com/repc Referees
Please submit the names and institutional e-mail addresses of several potential referees. For more details, visit our Support site. Note that the editor retains the sole right to decide whether or not the suggested reviewers are used.
