Clinical trials update from the European Society of Cardiology–Heart Failure meeting 2015: AUGMENT‐HF,TITRATION, STOP‐HF,HARMONIZE, LION HEART,MOOD‐HF,and renin–angiotensin inhibitors in patients with heart and renal failure

This article provides an overview on the key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) annual meeting held in Seville, Spain in May 2015. Trials reported include AUGMENT‐AF (myocardial injections of calcium‐alginate hydrogel), a propensity score‐matched study of renin–angiotensin system antagonists in patients with HF and severe renal dysfunction, HARMONIZE (sodium zirconium cyclosilicate used to bind potassium), TITRATION, comparing two regimes for introducing LCZ696, STOP‐HF, a trial of intramyocardial stromal cell‐derived factor‐1, MOOD‐HF (escitalopram for patients with heart failure and depression), and LION HEART, a trial of intermittent levosimendan therapy. Unpublished reports should be considered as preliminary, since analyses may change in the final publication.     

ACC/AHA Versus ESC Guidelines on Heart Failure: JACC Guideline Comparison

The 2013 (with updates in 2016 and 2017) American College of Cardiology/American Heart Association and 2016 European Society of Cardiology guidelines provide practical evidence-based clinical guidelines for the diagnosis and treatment of both acute and chronic heart failure (HF). Both guidelines address noninvasive and invasive testing to establish the diagnosis of HF with reduced ejection fraction and HF with preserved ejection fraction. Extensive trial evidence supports the use of guideline-directed medical therapy and device-based therapies for the optimal management of patients with HF with reduced ejection fraction. Specific recommendations are also provided for HF with preserved ejection fraction although the evidence is substantially weaker. Management of medical comorbidities is now addressed in both guidelines. Acute HF and end-stage disease requiring advanced therapies are also discussed. This review compares specific recommendations across the spectrum of HF phenotypes and disease severity, highlights areas where differences exist, and lists consequential studies published since the latest guidelines.     

The Heart Failure Association Atlas: rationale,objectives, and methods

Heart failure (HF) constitutes the growing cardiovascular burden and the major public health issue, but comprehensive statistics on HF epidemiology and related management in Europe are missing. The Heart Failure Association (HFA) Atlas has been initiated in 2016 in order to close this gap, representing the continuity directly rooted in the European Society of Cardiology (ESC) Atlas of Cardiology. The major aim of the HFA Atlas is to establish a contemporary dataset on HF epidemiology, resources and reimbursement policies for HF management, organization of the National Heart Failure Societies (NHFS) and their major activities, including education and HF awareness. These data are gathered in collaboration with the network of NHFS of the ESC member and ESC affiliated countries. The dataset will be continuously improved and advanced based on the experience and enhanced understanding of data collection in the forthcoming years. This will enable revealing trends, disparities and gaps in knowledge on epidemiology and management of HF. Such data are highly needed by the clinicians of different specialties (aside from cardiologists and cardiac surgeons), researchers, healthcare policy makers, as well as HF patients and their caregivers. It will also allow to map the snapshot of realities in HF care, as well as to provide insights for evidence‐based health care policy in contemporary management of HF. Such data will support the ESC/HFA efforts to improve HF management ant outcomes through stronger recommendations and calls for action. This will likely influence the allocation of funds for the prevention, treatment, education and research in HF.     

Kommentar zu den ESC-Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008

The European Society of Cardiology (ESC) has published updated guidelines for the diagnosis and treatment of heart failure. The new guidelines include all new studies on the therapy of heart failure that have been published since the last version in 2005. Moreover, the ESC has combined the guidelines for the treatment of acute and chronic heart failure. Relevant changes in this updated version compared to the previous ESC guidelines and the guidelines issued by the German Society of Cardiology (DGK) are summarized. Independent updated DGK guidelines will be published as an executive summary only (pocket guideline).     

Palliative care in heart failure guidelines: A comparison of the 2021 ESC and the 2022 AHA/ACC/HFSA guidelines on heart failure

The role of palliative care for patients with heart failure (HF) is discussed in both most recent HF guidelines, the 2021 ESC guideline and the 2022 AHA/ACC/HFSA guideline. This review compares the definitions, concepts and specific recommendations regarding palliative care for patients with HF in these two guidelines. Both HF guidelines define palliative care as a multidisciplinary approach aimed at alleviating physical, psychological and spiritual distress of patients and caregivers. Both agree emphatically on the importance of palliative care across all stages of HF with integration early in the illness trajectory. Also, the guidelines concur that palliative care should include symptom management, communication about prognosis and life-sustaining therapies, as well as advance care planning. Despite this consensus, only the AHA/ACC/HFSA guideline gives official recommendations on the provision of palliative care. Moreover, the AHA/ACC/HFSA guideline advocates for a needs-based approach to palliative care allocation while the ESC guideline ties palliative care closely to advanced HF and end-of-life care. The ESC guideline highlights the need for regular symptom assessment and provides detailed guidance on symptom management. The AHA/ACC/HFSA guideline elaborates further on shared decision-making, caregiver and bereavement support, as well as hospice care, and distinguishes between primary palliative care (provided by all clinicians) and secondary (specialty-level) palliative care. Although there is strong agreement on the importance and components of palliative care for patients with HF, there are nuanced differences between the two HF guidelines. Most notably, only the AHA/ACC/HFSA guideline issues recommendations for the provision of palliative care.     

Should MRAs be at the front row in heart failure? A plea for the early use of mineralocorticoid receptor antagonists in medical therapy for heart failure based on clinical experience

The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in “third place,” i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper.     

The role of angiotensin receptor–neprilysin inhibitors in cardiovascular disease—existing evidence,knowledge gaps,and future directions

Although traditional renin–angiotensin system antagonists including angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers have revolutionized the treatment of cardiovascular disease (CVD), the pivotal PARADIGM‐HF trial demonstrated that sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), was superior to an angiotensin‐converting enzyme inhibitor in reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction. However, despite international regulatory approval and strong recommendations in the guidelines, uptake of sacubitril/valsartan has been disappointing. Sacubitril/valsartan is now the focus of a large programme of clinical trials testing the hypothesis that ARNIs may supplant conventional renin–angiotensin system inhibitors across the spectrum of CVD, including hypertension, secondary prevention after myocardial infarction, and heart failure with preserved ejection fraction. This review summarizes the existing evidence, knowledge gaps, and future directions of ARNIs in CVD based on discussions between clinical trialists, industry representatives, and regulatory authorities at the 2016 Global CardioVascular Clinical Trialists Forum in Washington, D.C.     

Adaptation of 2016 European Society of Cardiology/European Atherosclerosis Society guideline for lipid management to Indian patients – A consensus document

In the year 2016, European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines provided recommendations on dyslipidemia management. The recommendation from these guidelines are restricted to European subcontinent. To adapt the updated recommendations for Indian subset of dyslipidemia, a panel of experts in management of dyslipidemia provided their expert opinions. This document provides expert consensus on adapting 2016 ESC dyslipidemia guidelines recommendations in Indian setting. The document also discussed India-specific relevant literature to support the consensus opinions provided in management of dyslipidemia.     

Inconsistencies in the development of the ESC Clinical Practice Guidelines for Heart Failure

The publication of the European Society of Cardiology (ESC) guidelines for the management of heart failure, in 2012 represented the latest and arguably the most comprehensive document to date summarising recommended treatment and diagnostic options for the care of heart failure patients. The impact of clinical practice guidelines is now so great that it is important to review the processes that underlie guideline development. The ESC guideline process is compared and contrasted to those of other guideline bodies. The ESC uses its own internal experts inclined to review source clinical trial data rather than published or commissioned meta-analyses and systematic reviews. Uncertainties exist in several areas, such as how are the scope of potential treatments to be reviewed chosen, if there is no call for proposals or external consultation?, Two illustrative discrepancies are highlighted i) the non-surgical MitraClip device for reducing mitral regurgitation is given the verbal equivalent of a Class IIb recommendation on the basis of 107 patients in an uncontrolled registry, whereas no drug is reviewed based on such data, and another device, the subject of 3 prospective randomised controlled trials, was not reviewed at all and ii) for Ivabradine the whole trial population was included in the recommendation, despite a subgroup not benefitting, whereas for CRT the sub-group not thought to benefit was excluded from the recommendation. We propose that more interaction is needed between ESC and stakeholders so each can better understand the processes for producing guidelines to improve some of these aspects.     

Inclusion of Performance Parameters and Patient Context in the Clinical Practice Guidelines for Heart Failure

BackgroundTo facilitate evidence-based medicine (EBM) on an individual level, it may be important for clinical practice guidelines (CPGs) to incorporate the performance parameters of diagnostic studies and therapeutic interventions (such as likelihood ratio and absolute benefit or harm), and to incorporate relevant patient contexts that may influence decision-making. We sought to determine the extent to which heart failure CPGs currently incorporate this information.MethodsWe reviewed the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 Heart Failure CPG, the 2017 ACCF/AHA/HFSA update, and European Society of Cardiology (ESC) 2016 Heart Failure CPG. We abstracted variables for each CPG recommendation from the following domains: quality of evidence, strength of recommendation, diagnostic and therapeutic performance parameters, and patient context.ResultsWe examined 169 recommendations from the ACCF/AHA 2013 CPGs and 2017 update and 187 recommendations from the 2016 ESC CPGs. Performance parameters for diagnostic studies (2013 ACCF/AHA: 13%; 2017 ACCF/AHA/HFSA update: 0%; 2016 ESC: 0%) and therapeutic interventions (2013 ACCF/AHA: 65%; 2017 ACCF/AHA/HFSA update: 64%; 2016 ESC: 16%) were not commonly included in CPGs. Patient context was included in about half of ACCF/AHA recommendations and a quarter of ESC recommendations.ConclusionsThe majority of recommendations from heart failure CPGs lack information on diagnostic and therapeutic performance parameters and patient context. Given the importance of these components to effectively implement EBM, particularly for a heterogeneous heart failure population, innovative strategies are needed to optimize CPGs so they provide comprehensive yet succinct recommendations that can improve population-level outcomes and ensure optimal patient-centered care.     

慢性心力衰竭诊断和治疗2012:现状和进步

自2010年以来慢性心力衰竭的现代诊断和治疗理念已经建立。具体体现在我国和欧美国家先后颁布了慢性心力衰竭的诊治指南。这些指南均充分依据了过去20年进行的数十项慢性心力衰竭大型临床试验提供的证据。但仍有许多疑问和尚不确定的问题。现根据新的研究证据和临床经验,回答了这些问题并阐述了作者自已的观点和意见。     

2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure

AimThe “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure” replaces the “2013 ACCF/AHA Guideline for the Management of Heart Failure” and the “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.” The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.MethodsA comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.StructureHeart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.     

2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure: Executive Summary

BackgroundThe 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America (AHA/ACC/HFSA) Guideline for the Management of Heart Failure replaces the 2013 ACCF/AHA Guideline for the Management of Heart Failure and the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose and manage patients with heart failure.MethodsA comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews and other evidence conducted in human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies published through September 2021 were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.Results and ConclusionsHeart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments that have high-quality published economic analyses.     

Heart Failure Association of the European Society of Cardiology Quality of Care Centres Programme: design and accreditation document

Heart failure (HF) is the major contributor to cardiovascular morbidity and mortality. Given its rising prevalence, the costs of HF care can be expected to increase. Multidisciplinary management of HF can improve quality of care and survival. However, specialized HF programmes are not widely available in most European countries. These circumstances underlie the suggestion of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) for the development of quality of care centres (QCCs). These are defined as health care institutions that provide multidisciplinary HF management at all levels of care (primary, secondary and tertiary), are accredited by the HFA/ESC and are implemented into existing health care systems. Their major goals are to unify and improve the quality of HF care, and to promote collaboration in education and research activities. Three types of QCC are suggested: community QCCs (primary care facilities able to provide non‐invasive assessment and optimal therapy); specialized QCCs (district hospitals with intensive care units, able to provide cardiac catheterization and device implantation services), and advanced QCCs (national reference centres able to deliver advanced and innovative HF care and research). QCC accreditation will require compliance with general and specific HFA/ESC accreditation standards. General requirements include confirmation of the centre's existence, commitment to QCC implementation, and collaboration with other QCCs. Specific requirements include validation of the centre's level of care, service portfolio, facilities and equipment, management, human resources, process measures, quality indicators and outcome measures. Audit and recertification at 4–6‐year intervals are also required. The implementation of QCCs will evolve gradually, following a pilot phase in selected countries. The present document summarizes the definition, major goals, development, classification and crucial aspects of the accreditation process of the HFA/ESC QCC Programme.     

Clinical trials update from the Heart Failure Society of America Meeting 2009: FAST,IMPROVE‐HF,COACH galectin‐3 substudy,HF‐ACTION nuclear substudy,DAD‐HF,and MARVEL‐1

This article presents findings and a commentary on late‐breaking trials presented during the meeting of the Heart Failure Society of America in September 2009. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. The FAST trial showed somewhat better performance of intrathoracic impedance for prediction of deterioration in patients with heart failure (HF) when compared with daily weighing. The IMPROVE‐HF study reported the benefits of education on the management of patients with systolic HF. Galectin‐3 appeared a useful method for improving risk stratification of patients with chronic HF in a substudy of the COACH trial. A nuclear substudy of the HF‐ACTION trial failed to demonstrate that resting myocardial perfusion imaging, a measure of myocardial scar and viability, was clinically useful. A small randomized controlled trial (DAD‐HF) suggested that the use of low‐dose dopamine in patients with acutely decompensated HF was associated with less deterioration in renal function and less hypokalaemia. The MARVEL‐1 trial raises further concerns about the safety of myoblast transplantation in ischaemic HF.     

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.     

Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis

Chronic heart failure (HF) with either reduced or preserved ejection fraction is common and remains an extremely serious disorder with a high mortality and morbidity. Many complications related to HF can be related to thrombosis. Epidemiological and pathophysiological data also link HF to an increased risk of thrombosis, leading to the clinical consequences of sudden death, stroke, systemic thrombo-embolism, and/or venous thrombo-embolism. This consensus document of the Heart Failure Association (EHFA) of the European Society of Cardiology (ESC) and the ESC Working Group on Thrombosis reviews the published evidence and summarizes 'best practice', and puts forward consensus statements that may help to define evidence gaps and assist management decisions in everyday clinical practice. In HF patients with atrial fibrillation, oral anticoagulation is recommended, and the CHA(2)DS(2)-VASc and HAS-BLED scores should be used to determine the likely risk-benefit ratio (thrombo-embolism prevention vs. risk of bleeding) of oral anticoagulation. In HF patients with reduced left ventricular ejection fraction who are in sinus rhythm there is no evidence of an overall benefit of vitamin K antagonists (e.g. warfarin) on mortality, with risk of major bleeding. Despite the potential for a reduction in ischaemic stroke, there is currently no compelling reason to use warfarin routinely for these patients. Risk factors associated with increased risk of thrombo-embolic events should be identified and decisions regarding use of anticoagulation individualized. Patient values and preferences are important determinants when balancing the risk of thrombo-embolism against bleeding risk. New oral anticoagulants that offer a different risk-benefit profile compared with warfarin may appear as an attractive therapeutic option, but this would need to be confirmed in clinical trials.     

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health‐related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two‐day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run‐in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.     

Clinical trials update from the American College of Cardiology 2009: ADMIRE‐HF,PRIMA, STICH,REVERSE, IRIS,partial ventricular support,FIX‐HF‐5, vagal stimulation,REVIVAL‐3, pre‐RELAX‐AHF,ACTIVE‐A,HF‐ACTION,JUPITER, AURORA,and OMEGA

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the American College of Cardiology meeting in 2009. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. ¹²³I‐mIBG myocardial scintigraphy was a good predictor of mortality in patients with heart failure in ADMIRE‐HF. In PRIMA, use of individualized target NT‐proBNP levels failed to improve outcomes compared with usual care in patients hospitalized with symptomatic heart failure. In the STICH trial, additional ventricular reconstruction surgery failed to improve outcomes in patients with ischaemic heart failure undergoing CABG. Cardiac resynchronization therapy may modify disease progression in patients with mild heart failure, according to data from REVERSE. Implantation of a defibrillator early after MI in high‐risk patients in the IRIS study failed to improve outcomes compared with usual care. Cardiac contractility modulation showed some beneficial effects on symptoms and exercise capacity in the unblinded FIX‐HF‐5 study. Data from pre‐RELAX‐AHF show that relaxin may have potential as a treatment for acute heart failure. HF‐ACTION showed that patients who complied with an exercise training regime achieved a better outcome, although this may be confounded by the ability of patients with a good prognosis to exercise for longer.     

Recommendations for the management of patients after heart valve surgery.

Approximately 50,000 valve replacement operations take place in Europe annually and almost as many valve repair procedures. Previous European guidelines on management of patients after valve surgery were last published in 1995 and were limited to recommendations about antithrombotic prophylaxis. American guidelines covering the broader topic of the investigation and treatment of patients with valve disease were published in 1998 but devoted relatively little space to post-surgical management. This document represents the consensus view of a committee drawn from three European Society of Cardiology (ESC) Working Groups (WG): the WG on Valvular Heart Disease, the WG on Thrombosis, and the WG on Rehabilitation and Exercise Physiology. In almost all areas of patient management after valve surgery, randomized trials and meta-analyses do not exist. Such randomized trials as do exist are very few in number, are narrowly focused with small numbers, have limited general applicability, and do not lend themselves to meta-analysis because of widely divergent methodologies and different patient characteristics. Recommendations are therefore almost entirely based on non-randomized studies and relevant basic science.