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JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure

2021; Elsevier BV; Volume: 27; Issue: 12 Linguagem: Inglês

10.1016/j.cardfail.2021.04.023

1532-8414

Hiroyuki Tsutsui, Tomomi Ide, Hiroshi Ito, Yasuki Kihara, Koichiro Kinugawa, Shintaro Kinugawa, Miyuki Makaya, Toyoaki Murohara, Koichi Node, Yoshihiko Saito, Yasushi Sakata, Wataru Shimizu, Kazuhiro Yamamoto, Yoshiyuki Bando, Yu‐ki Iwasaki, Yoshiharu Kinugasa, Isamu Mizote, Hitoshi Nakagawa, Shogo Oishi, Akiko Okada, Atsushi Tanaka, Takashi Akasaka, Minoru Ōno, Takeshi Kimura, Shun Kohsaka, Masami Kosuge, Shin‐ichi Momomura,

Cardiomyopathy and Myosin Studies

Joint Working Groups: The Japanese Circulation Society; the Japanese Heart Failure Society; the Japanese Association for Thoracic Surgery; the Japanese Society of Hypertension; Japanese Society of Echocardiography; the Japanese Society for Cardiovascular Surgery; Japanese College of Cardiology; the Japanese Association of Cardiac Rehabilitation; the Japan Society of Ultrasonics in Medicine; the Japan Diabetes Society; Japanese Heart Rhythm Society; “the Study Group on Idiopathic Cardiomyopathy” supported by the Health and Labor Sciences Research Grant on Intractable Diseases; and “the Study Group on the Multi-center Observational Study of Dilated- phase Hypertrophic Cardiomyopathy”, supported by the “Practical Research Project for Rare/intractable Diseases by the Japan Agency for Medical Research and Development. In March 2018, the JCS/Japanese Heart Failure Society jointly published the 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure. In this revised edition, a research group comprised of members recommended by 11 academic societies, including the JCS, Japanese Heart Failure Society, Japanese Association for Thoracic Surgery, Japanese Society of Hypertension, Japanese Society of Echocardiography, Japanese Society for Cardiovascular Surgery, Japanese College of Cardiology, Japanese Association of Cardiac Rehabilitation, Japan Society of Ultrasonics in Medicine, Japan Diabetes Society, and Japanese Heart Rhythm Society, was organized. In addition, 2 study groups participated in this revision, the “Survey and research on idiopathic myopathy” of the Research Program on Rare and Intractable Diseases, Ministry of Health, Labour and Welfare, and “A Multicenter Registered Observational Study on the Dilated Phase of Hypertrophic Cardiomyopathy” of the Japan Agency for Medical Research and Development Practical Research Project for Rare/Intractable Diseases. Taking the latest guidelines of Western countries into considerations, we published the revised edition as the guidelines presenting standard treatment of acute and chronic heart failure by incorporating evidence and actual clinical experience in Japan. The major change in this revised edition is the integration of the previous heart failure treatment guidelines, which were separated into acute heart failure and chronic heart failure. This change was based on the recognition that separate treatment guidelines into acute and chronic sections is not realistic because many patients with acute heart failure are acute exacerbation of chronic heart failure and the seamless management from the acute to chronic phase is necessary. The main points of the 2017 revised edition are as follows:1)The definition of heart failure was clarified and a definition easy to understand for the general public was newly described.2)Heart failure, stage with progression of the risk, and treatment target were newly described.3)Heart failure was classified based on the left ventricular ejection fraction (LVEF).4)The heart failure diagnosis algorithm was newly presented.5)Management concerning prevention of heart failure was newly added.6)The heart failure treatment algorithm was newly presented.7)The descriptions of the clinical state and treatment of comorbidities were expanded.8)The flow chart of acute heart failure treatment based on the time course and clinical state was newly presented.9)The treatment algorithm of severe heart failure with a ventricular assist device (VAD) was newly presented.10)The description of palliative care was expanded. After the publication of the revised edition, therapeutic drugs described in “Future Treatment” were approved and important evidence for pharmacologic therapy and nonpharmacologic therapy has been reported. These changes are related directly to routine clinical practice for heart failure and the contents were important and should be reflected in the guidelines. Therefore, it was decided to publish the JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure without waiting for the next revision. The main revised points included in this Focused Update are as follows:1.General Principles: Proposal of a new LVEF-based classification and changes in the definition about heart failure with mid-range EF (HFmrEF) and heart failure with recovered EF (HFrecEF) (2017 edition, Chapter II; Focused Update, Chapter 1). Based on the importance of time-dependent changes in LVEF, new classification of heart failure as HFrecEF, heart failure with worsened EF (HFworEF), and heart failure with unchanged EF (HFuncEF) was presented.2.Basic Principles for the Treatment of Heart Failure: Updated treatment algorithms for heart failure (2017 edition, Chapter V; Focused Update, Chapter 2). Newer drugs including If channel blocker or HCN channel blocker, ivabradine, angiotensin receptor neprilysin inhibitor (ARNI), sacubitril and valsartan, and sodium glucose cotransporter 2 (SGLT2) inhibitor were included in the revised treatment algorithms.3.Pharmacologic Therapy: Updated descriptions regarding If channel blockers (HCN channel blocker), ARNI, and SGLT2 inhibitors based on new clinical trials performed also in Japan such as J-SHIFT study and PARALLEL-HF study (2017 edition, Chapter VI; Focused Update, Chapter 3). Updated descriptions regarding vericiguat based on VICTORIA and omecamtiv mecarbil based on GALACTIC-HF.4.Nonpharmacologic Therapy: Updated statements based on the transcatheter aortic valve implantation (TAVI) low-risk study, PARTER 3 study, and EVOLUT study and percutaneous mitral valve repair system and presentation of new tables (2017 edition, Chapter VII; Focused Update, Chapter 4).5.Comorbidity: Atrial fibrillation. Updated statements based on the CASTLE-AF study and CABANA study (2017 edition, Chapter IX; Focused Update, Chapter 5).6.Comorbidity: Diabetes mellitus. Updated statements based on the DAPA-HF, EMPEROR-Reduced, and SOLOIST-WHF study and recent trials (2017 edition, Chapter IX; Focused Update, Chapter 5).7.Surgical treatment. Updated statements regarding mechanical circulatory support including Impella (2017 edition, Chapter XI; Focused Update, Chapter 6).8.Disease Management: Addition of statements about certified heart failure educator newly established as a measure to develop human resources in “The Five-Year Plan for Overcoming Stroke and Cardiovascular Disease” formulated by the JCS and Japan Stroke Society in December 2016 (2017 edition, Chapter XII; Focused Update, Chapter 7).9.Palliative Care: Updated statements regarding palliative care treatment (2017 edition, Chapter XIII; Focused Update, Chapter 8).10.Future treatment. Updated descriptions about WAON therapy (2017 edition, Chapter XIV; Focused Update, Chapter 9) Based on the results of clinical trials of pharmacologic and nonpharmacologic therapies for heart failure have been published in Japan and other countries in 2018 and, thereafter, focused major revisions were made to a part of the recommendation levels and contents of statements based on such accumulated new evidence in this update. In addition, regarding the recommendation class, class III was classified into cases without efficacy or usefulness (no benefit) and those with harm based on the clinical usefulness (Table 1). Level of Evidence (Table 2), the Medical Information Network Distribution Service (MINDS) Grades of Recommendation and MINDS Levels of Evidence were described together in this edition (Tables 3 and 4). The classification of recommendations and levels of evidence are described similarly to our previous heart failure guidelines using a style similar to those used in the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines and the European Society of Cardiology (ESC) guidelines (Tables 1 and 2). In Japan, guidelines for cardiovascular diseases have extensively used a common style that is highly consistent with Western guidelines. In contrast, the Japan Council for Quality Health Care uses a different style in its MINDS to show grades of recommendations and levels of evidence as described in the “Minds Handbook for Clinical Practice Guideline Development 2007” (Tables 3 and 4).1MINDS Guideline CenterJapan Council for Quality Health Care. MINDS handbook for clinical practice guideline development 2007.Igaku-Shoin. 2007; : 15-16Google Scholar Accordingly, the present document shows classification of recommendations and level of evidence in the tables including both styles; class of recommendation, level of evidence, grade of recommendation (MINDS), and level of evidence (MINDS). The grade of recommendation is determined based on a comprehensive assessment of the level and quantity of evidence, variation of conclusion, size of effectiveness, applicability to the clinical setting, and evidence on harms and costs.Table 1Classes of RecommendationClassRecommendationIThere is evidence and/or general agreement that a given procedure or treatment is effective and/or useful.IIaThere is a high probability of efficacy/usefulness based on evidence and opinion.IIbEffectiveness/usefulness is not well-established based on evidence and opinion.III (No benefit)There is evidence or general agreement that the procedure or treatment is not effective and/or useful.III (Harm)There is evidence and/or general agreement that the procedure or treatment is harmful. Open table in a new tab Table 2Level of EvidenceADemonstrated by multiple randomized clinical trials or meta-analysis.BDemonstrated by a single randomized clinical trial or large nonrandomized studies.CConsensus from expert opinion and/or small clinical trials (including retrospective studies and case series). Open table in a new tab Table 3Medical Information Network Distribution Service Grades of RecommendationsGrade AStrongly recommended and supported by strong evidenceGrade BRecommended with moderately strong supporting evidenceGrade C1Recommended despite no strong supporting evidenceGrade C2Not recommended because of the absence of strong supporting evidenceGrade DNot recommended as evidence indicates that the treatment is ineffective or even harmful(Adapted from MINDS Treatment Guidelines Selection Committee. Tsuguya Fukui et al., IGAKU-SHOIN Ltd. p. 16. 2007.1MINDS Guideline CenterJapan Council for Quality Health Care. MINDS handbook for clinical practice guideline development 2007.Igaku-Shoin. 2007; : 15-16Google Scholar) Open table in a new tab Table 4Medical Information Network Distribution Service Levels of Evidence (Levels of Evidence in the Literature on Treatment)ISystematic review/meta-analysis of randomized controlled trialsIIOne or more randomized controlled trialsIIINonrandomized controlled trialsIVaAnalytical epidemiologic studies (cohort studies)IVbAnalytical epidemiologic studies (case-control studies and cross-sectional studies)VDescriptive studies (case reports and case series)VINot based on patient data, or based on opinions from a specialist committee or individual specialists(Adapted from MINDS Treatment Guidelines Selection Committee. Tsuguya Fukui et al., IGAKU-SHOIN Ltd. p. 16. 2007.1MINDS Guideline CenterJapan Council for Quality Health Care. MINDS handbook for clinical practice guideline development 2007.Igaku-Shoin. 2007; : 15-16Google Scholar) Open table in a new tab (Adapted from MINDS Treatment Guidelines Selection Committee. Tsuguya Fukui et al., IGAKU-SHOIN Ltd. p. 16. 2007.1MINDS Guideline CenterJapan Council for Quality Health Care. MINDS handbook for clinical practice guideline development 2007.Igaku-Shoin. 2007; : 15-16Google Scholar) (Adapted from MINDS Treatment Guidelines Selection Committee. Tsuguya Fukui et al., IGAKU-SHOIN Ltd. p. 16. 2007.1MINDS Guideline CenterJapan Council for Quality Health Care. MINDS handbook for clinical practice guideline development 2007.Igaku-Shoin. 2007; : 15-16Google Scholar) Important contents of the 2017 revised edition of the guidelines were partially overlapped in this focused update; however, overlapping was avoided as much as possible. To make the sections revised from the 2017 revised edition easy to understand, the chapter numbers in the 2017 revised edition were described together. Heart failure is defined as a clinical syndrome consisting of dyspnea, malaise, swelling, and/or decreased exercise capacity owing to the loss of compensation for cardiac pumping function owing to structural and/or functional abnormalities of the heart (Table 5).Table 5Definition of Heart FailureDefinition of heart failure in the present guidelinesClinical syndrome consisting of dyspnea, fatigue, edema and/or decreased exercise capacity owing to the loss of compensation for cardiac pumping function caused by structural and/or functional abnormalities of the heartDefinition of heart failure for the public (patient-friendly version)Heart failure is a heart disease that causes shortness of breath and swelling, gets worse with time, and shortens life expectancy. Open table in a new tab Previously, acute heart failure was defined as a “clinical state in which the compensation mechanism of heart pump function rapidly collapses and induces ventricular end-diastolic pressure elevation and failure of perfusion to the main organs, resulting in acute appearance or aggravation of symptoms and signs.” In contrast, chronic heart failure was distinguished by being defined as “the clinical state in which congestion of the pulmonary and/or systemic venous system and tissue hypoperfusion continue due to chronic heart pump ataxia and interfere with daily life.” The distinction between acute and chronic heart failure relates to the efficacy of pharmacotherapies. However, this classification of acute and chronic heart failure became less important as the usefulness of early therapeutic intervention before the appearance of obvious symptoms and signs has been confirmed. In the diagnosis of heart failure, patients should be examined first for symptoms, medical history, their family history, physical findings, electrocardiogram, and chest radiographic findings. Next, the concentration of brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) in the blood should be determined. Heart failure is a disease condition where the heart is unable to fill with and eject enough blood for various reasons, such as epicardial, myocardial, or endocardial lesions; valvular disease; coronary arterial disease; aortic disease; arrhythmias; and endocrine disorders. However, left ventricular dysfunction is present in many cases with heart failure, and is the most important factor in determining monitoring and treatment strategies. Heart failure should thus be defined and classified according to left ventricular function. In this edition, the JCS partially revised the left ventricular dysfunction-based heart failure classification table referring to the 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure (2017 revised edition).2The Japanese Circulation Society, Japanese Heart Failure Society. JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure. Available at: https://www.j-circ.or.jp/cms/wp-content/uploads/2017/06/JCS2017_tsutsui_h.pdf Accessed February 18, 2021.Google Scholar The previously used classification based on LVEF evaluated at the time of examination (Table 6) is essential for making decision on treatment strategy, so that this feature was not changed. However, we often encounter improvement and aggravation of LVEF with treatment and time course in patients with heart failure, that is, transition of the phenotype from that judged based on LVEF at the onset occurs with the course. Multiple clinical studies have demonstrated that changes in LVEF were related to the outcome. Because evaluation of the clinical state including the course may be also necessary from this viewpoint, it was decided to separately present classification based on time-course changes in LVEF (Table 7). There is no clear rule on the interval to investigate changes in LVEF, but many study reports were based on LVEF evaluated at an interval of more than 1 month or 6 months to a few years on average.3Tsuji 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.Eur J Heart Fail. 2017; 19: 1258-1269Google Scholar,4Savarese G Vedin O D'Amario D Uijl A Dahlström U Rosano G et al.Prevalence and prognostic implications of longitudinal ejection fraction change in heart failure.JACC Heart Fail. 2019; 7: 306-317Google Scholar Nonetheless for the purposes of the present document, LVEF at the time of clinical evaluation was used to determine the classification and treatment of heart failure.Table 6Classification of Heart Failure by LVEF on ExaminationPhenotypeLVEFDefinitionHeart failure with reduced ejection fraction: HFrEF<40%Left ventricular systolic dysfunction.In many clinical studies, patients with a low LVEF despite standard medical treatment for heart failure are enrolled as patients with HFrEF.Heart failure with preserved ejection fraction: HFpEF≥50%Left ventricular diastolic dysfunction.Other diseases that may cause similar symptoms should be ruled out. No effective treatments have been established.Heart failure with midrange ejection fraction: HFmrEF40%–<50%Borderline heart failure.Clinical features and prognosis have not yet been fully characterized. Treatment should be selected on an individual basis.LVEF, left ventricular ejection fraction. Open table in a new tab Table 7Classification of Heart Failure Based on Time-Dependent Changes in LVEFChanges in phenotypeDefinitionHeart failure with recovered EF: HFrecEFLVEF improved during the treatment course and the condition transitioned from HFrEF to HFmrEF or HFpEF, or from HFmrEF to HFpEF. The outcome is relatively favorable.Heart failure with worsened EF: HFworEFLVEF decreased with the treatment course and the condition transitioned from HFpEF to HFmrEF or HFrEF, or from HFmrEF to HFrEF. The outcome is poor.Heart failure with unchanged EF: HFuncEFNo major change is observed in LVEF throughout the courseHFmrEF, heart failure with midrange ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction. Open table in a new tab LVEF, left ventricular ejection fraction. HFmrEF, heart failure with midrange ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction. In many large-scale clinical studies in heart failure, heart failure with reduced EF (HFrEF) was defined as heart failure with a LVEF of 35% or less or less than 40% (Table 6). In the guidelines in Japan and Western countries, 40% or less or less than 40% LVEF is adopted as a criterion of HFrEF.2The Japanese Circulation Society, Japanese Heart Failure Society. JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure. Available at: https://www.j-circ.or.jp/cms/wp-content/uploads/2017/06/JCS2017_tsutsui_h.pdf Accessed February 18, 2021.Google Scholar,5Yancy CW Jessup M Bozkurt B Butler J Casey Jr, DE Drazner MH et al.2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2013; 62: e147-e239Google Scholar,6Ponikowski P Voors AA Anker SD Bueno H Cleland JG Coats AJ 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.Eur J Heart Fail. 2016; 18: 891-975Google Scholar In HFrEF, left ventricular dilatation is frequently observed and it is accompanied by not only left ventricular systolic dysfunction represented by reduced LVEF but also diastolic dysfunction. In Japan, previously, nonischemic etiology, such as dilated cardiomyopathy, accounted for a high percentage of the main causes of HFrEF, but the proportion of coronary artery disease has been gradually increasing.7Ushigome R Sakata Y Nochioka K Miyata S Miura M Tadaki S et al.Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure in Japan – report from the CHART Studies.Circ J. 2015; 79: 2396-2407Google Scholar The standard concept of diagnosing heart failure with preserved EF (HFpEF) is consideration based on the following 3 points: (1) manifestation of clinical symptoms of heart failure, (2) normal or retention of LVEF, (3) the presence of left ventricular diastolic dysfunction.8Vasan RS Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria.Circulation. 2000; 101: 2118-2121Google Scholar In the guidelines in Japan and Western countries, a 50% or higher LVEF is adopted as a standard value, and based on the results of previous epidemiologic surveys, HFpEF accounts for about one-half of patients with heart failure.9Yaku H Ozasa N Morimoto T Inuzuka Y Tamaki Y Yamamoto E et al.KCHF study investigators. Demographics, management, and in-hospital outcome of hospitalized acute heart failure syndrome patients in contemporary real clinical practice in Japan - observations from the prospective, multicenter Kyoto Congestive Heart Failure (KCHF) registry.Circ J. 2018; 82: 2811-2819Google Scholar Because it is not easy to diagnose diastolic dysfunction in routine practice and there is no established diagnostic criterion for HFpEF, a comprehensive diagnostic method using multiple indices assessed on echocardiography has been proposed.10Nagueh SF Smiseth OA Appleton CP Byrd 3rd, BF Dokainish H Edvardsen T et al.Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.J Am Soc Echocardiogr. 2016; 29: 277-314Google Scholar,11Pieske B Tschöpe C de Boer RA Fraser AG Anker SD Donal E et al.How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).Eur Heart J. 2019; 40: 3297-3317Google Scholar Background factors strongly associated with HFpEF include advanced age, hypertension, atrial fibrillation, coronary artery disease, diabetes, and obesity.12Ho JE Lyass A Lee DS Vasan RS Kannel WB Larson MG et al.Predictors of new-onset heart failure: differences in preserved versus reduced ejection fraction.Circ Heart Fail. 2013; 6: 279-286Google Scholar A simple screening tool, the H2FPEF score, scoring obesity, hypertension requiring polypharmacy, atrial fibrillation, pulmonary hypertension, advanced age, and left atrial pressure elevation as variables has been proposed.13Reddy YNV Carter RE Obokata M Redfield MM Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction.Circulation. 2018; 138: 861-870Google Scholar The challenges of defining heart failure based on LVEF was verified by an epidemiologic survey performed in Japan.14Tsuchihashi-Makaya M Hamaguchi S Kinugawa S Yokota T Goto D Yokoshiki H et al.Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).Circ J. 2009; 73: 1893-1900Google Scholar This intermediate range between HFpEF and HFrEF has both similarities and differences with each of these clinical entities. There are data positioned at intermediate between HFrEF and HFpEF in the age, sex ratio, and atrial fibrillation complication rate in patients belonging to the heart failure with mid-range EF (HFmrEF) category,3Tsuji 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.Eur J Heart Fail. 2017; 19: 1258-1269Google Scholar,15Steinberg BA Zhao X Heidenreich PA Peterson ED Bhatt DL Cannon CP et al.Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.Circulation. 2012; 126: 65-75Google Scholar,16Takei M Kohsaka S Shiraishi Y Goda A Nagatomo Y Mizuno A et al.Heart failure with midrange ejection fraction in patients admitted for acute decompensation: a report from the Japanese multicenter registry.J Card Fail. 2019; 25: 666-673Google Scholar but it has been reported that the distribution of underlying heart diseases is similar to that of HFrEF and ischemic heart disease accounts for a high rate.17Nauta JF Hummel YM van Melle JP van der Meer P Lam CSP Ponikowski P et al.What have we learned about heart failure with mid-range ejection fraction one year after its introduction?.Eur J Heart Fail. 2017; 19: 1569-1573Google Scholar,18Lam CSP Gamble GD Ling LH Sim D Leong KTG Yeo PSD et al.Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.Eur Heart J. 2018; 39: 1770-1780Google Scholar The survival rate of patients with HFmrEF has not been correlated with LVEF in some studies,14Tsuchihashi-Makaya M Hamaguchi S Kinugawa S Yokota T Goto D Yokoshiki H et al.Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).Circ J. 2009; 73: 1893-1900Google Scholar,19Bhatia RS Tu JV Lee DS Austin PC Fang J Haouzi A et al.Outcome of heart failure with preserved ejection fraction in a population-based study.N Engl J Med. 2006; 355: 260-269Google Scholar,20van Veldhuisen DJ Linssen GC Jaarsma T van Gilst WH Hoes AW Tijssen JG et al.B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.J Am Coll Cardiol. 2013; 61: 1498-1506Google Scholar whereas it was similar to that of patients with HFpEF and higher than that of patients with HFrEF in other studies,3Tsuji 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.Eur J Heart Fail. 2017; 19: 1258-1269Google Scholar,18Lam CSP Gamble GD Ling LH Sim D Leong KTG Yeo PSD et al.Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.Eur Heart J. 2018; 39: 1770-1780Google Scholar but it has been reported as a consistent result that the relationship between BNP/NT-proBNP and outcome is not affected by the LVEF.3Tsuji 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.Eur J Heart Fail. 2017; 19: 1258-1269Google Scholar,18Lam CSP Gamble GD Ling LH Sim D Leong KTG Yeo PSD et al.Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.Eur Heart J. 2018; 39: 1770-1780Google Scholar,20van Veldhuisen DJ Linssen GC Jaarsma T van Gilst WH Hoes AW Tijssen JG et al.B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.J Am Coll Cardiol. 2013; 61: 1498-1506Google Scholar Regarding HFmrEF, an investigation of whether there is a population with a characteristic condition different from those of HFrEF and HFpEF or whether patients to be included in HFpEF and those to be included in HFrEF were mixed in the population without a unique characteristic of HFmrEF is awaited. Further studies are required to better understand and define HFmrEF. In tachycardia-induced cardiomyopathy caused by tachycardiac atrial fibrillation, ischemic heart disease, and dilated cardiomyopathy, improvement of LVEF compared with that at onset of heart failure may be noted during the course owing to the effects of treatment (Table 7, Figure 1). According to previous clinical studies, approximately 20%–40% of HFrEF cases transitioned to HFmrEF or HFpEF and about 20%–40% of HFmrEF cases transitioned to HFpEF.3Tsuji 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.Eur J Heart Fail. 2017; 19: 1258-1269Google Scholar,4Savarese G Vedin O D'Amario D Uijl A Dahlström U Rosano G et al.Prevalence and prognostic implications of longitudinal ejection fraction change in heart failure.JACC Heart Fail. 2019; 7: 306-317Google Scholar,21Punnoose LR Givertz MM Lewis EF Pratibhu P Stevenson LW Desai AS. Heart failure with recovered ejection fraction: a distinct clinical entity.J Card Fail. 2011; 17: 527-532Google Scholar,22Clarke CL Grunwald GK Allen LA Barón AE Peterson PN Brand DW et al.Natural history of left ventricular ejection fraction in patients with heart failure.Circ Cardiovasc Qual Outcomes. 2013; 6: 680-686Google Scholar In the results of multiple studies, female, young age, and nonischemic heart dise