Epidemiology, pathophysiology, diagnosis and management of chronic right-sided heart failure and tricuspid regurgitation. A clinical consensus statement of the Heart Failure Association (HFA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

Right-sided heart failure and tricuspid regurgitation are common and strongly associated with poor quality of life and an increased risk of heart failure hospitalizations and death. While medical therapy for right-sided heart failure is limited, treatment options for tricuspid regurgitation include surgery and, based on recent developments, several transcatheter interventions. However, the patients who might benefit from tricuspid valve interventions are yet unknown, as is the ideal time for these treatments given the paucity of clinical evidence. In this context, it is crucial to elucidate aetiology and pathophysiological mechanisms leading to right-sided heart failure and tricuspid regurgitation in order to recognize when tricuspid regurgitation is a mere bystander and when it can cause or contribute to heart failure progression. Notably, early identification of right heart failure and tricuspid regurgitation may be crucial and optimal management requires knowledge about the different mechanisms and causes, clinical course and presentation, as well as possible treatment options. The aim of this clinical consensus statement is to summarize current knowledge about epidemiology, pathophysiology and treatment of tricuspid regurgitation in right-sided heart failure providing practical suggestions for patient identification and management.

Incidence, risk assessment and prevention of sudden cardiac death in cardiomyopathies.

Cardiomyopathies are a significant contributor to cardiovascular morbidity and mortality, mainly due to the development of heart failure and increased risk of sudden cardiac death (SCD). Despite improvement in survival with contemporary treatment, SCD remains an important cause of mortality in cardiomyopathies. It occurs at a rate ranging between 0.15% and 0.7% per year (depending on the cardiomyopathy), which significantly surpasses SCD incidence in the age- and sex-matched general population. The risk of SCD is affected by multiple factors including the aetiology, genetic basis, age, sex, physical exertion, the extent of myocardial disease severity, conduction system abnormalities, and electrical instability, as measured by various metrics. Over the past decades, the knowledge on the mechanisms and risk factors for SCD has substantially improved, allowing for a better-informed risk stratification. However, unresolved issues still challenge the guidance of SCD prevention in patients with cardiomyopathies. In this review, we aim to provide an in-depth discussion of the contemporary concepts pertinent to understanding the burden, risk assessment and prevention of SCD in cardiomyopathies (dilated, non-dilated left ventricular, hypertrophic, arrhythmogenic right ventricular, and restrictive). The review first focuses on SCD incidence in cardiomyopathies and then summarizes established and emerging risk factors for life-threatening arrhythmias/SCD. Finally, it discusses validated approaches to the risk assessment and evidence-based measures for SCD prevention in cardiomyopathies, pointing to the gaps in evidence and areas of uncertainties that merit future clarification.

Multinational cost-effectiveness analysis of empagliflozin for heart failure patients with ejection fraction >40.

AIMS: Heart failure is a chronic progressive condition, with considerable burden on patients' quality of life and economic burden for the healthcare systems. Before the approval of empagliflozin, there were no proven effective treatments for patients with heart failure with left ventricular ejection fraction (HF LVEF) > 40%. The aim of this study was to evaluate the cost-effectiveness of empagliflozin + standard of care (SoC) compared with SoC alone for patients with HF LVEF > 40%, from the perspective of the healthcare systems of the United Kingdom (UK), Spain, and France, and to quantify the healthcare costs for these patients. METHODS AND RESULTS: A lifetime Markov cohort state-transition model was developed based on discrete health states defined by Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score quartiles to track disease severity. Model inputs relied primarily on the EMPEROR-Preserved trial data or obtained from published literature or country-specific databases, as well as local guidelines for the requirements for the conduct of the economic evaluation of healthcare technologies. The total lifetime cost of receiving SoC per patient was £10 092, €15 765, and €14 958 in the UK, Spain, and France, respectively, which increased by £1407, €1148, and €1485, respectively, with the addition of empagliflozin to the SoC. Empagliflozin + SoC was associated with significantly reduced number of hospitalization for HF or cardiovascular death compared with SoC alone, which was a key driver offsetting its drug acquisition costs. The incremental cost-effectiveness ratio per quality-adjusted life year (QALY) gained was consistently favourable at £14 851, €11 706, and €15 447 in the UK, Spain, and France, respectively. Scenario analysis using the New York Heart Association functional class showed similar results. Probabilistic sensitivity analyses showed more than 50% probability for cost-effectiveness for a willingness-to-pay (WTP) threshold of £/€20 000/QALY for the three countries. CONCLUSIONS: Empagliflozin was found to be the first targeted treatment option that is clinically effective and cost-effective for patients with HF LVEF > 40%. Prescribing empagliflozin with SoC to patients with HF LVEF > 40% is expected to improve clinical outcomes and patients' quality of life and substantially below accepted WTP threshold for the healthcare systems in the UK, Spain, and France.

Cost-effectiveness of empagliflozin in heart failure patients irrespective of ejection fraction in England.

AIMS: Heart failure (HF) is a complex syndrome commonly categorized into two main phenotypes [left ventricular ejection fraction (LVEF) below or above 40%], and although empagliflozin is the first approved medication with proven clinical effectiveness for both phenotypes, its cost-effectiveness of treating the entire HF population remains unknown. METHODS: The analysis was performed utilizing two preexisting, LVEF phenotype-specific cost-effectiveness models to estimate the cost-effectiveness of empagliflozin in adults for the treatment of symptomatic chronic HF, irrespective of ejection fraction (EF). The results of the phenotype-specific models were combined using a population-weighted approach to estimate the deterministic and probabilistic incremental cost-effectiveness ratios (ICERs). RESULTS: Based on combined results, empagliflozin + standard of care (SoC) is associated with 6.13 life-years (LYs) and 3.92 quality-adjusted life-years (QALYs) compared with 5.98 LYs and 3.76 QALYs for SoC alone over a lifetime, resulting in an incremental difference of 0.15 LYs and 0.16 QALYs, respectively. Total lifetime healthcare costs per patient are £15 246 for empagliflozin + SoC and £13 982 for SoC giving an incremental difference of £1264. The ICER is £7757/QALY, which is substantially lower than the willingness-to-pay (WTP) of £30 000 per QALY used by NICE. The results of the probabilistic sensitivity analyses are in line with the deterministic results. CONCLUSION: Empagliflozin is the first efficacious, approved, and cost-effective treatment option for all HF patients, irrespective of EF. The combined ICER was consistently below the WTP threshold. Therefore, empagliflozin offers value for money for the treatment of the full HF population in England.

Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the Heart Failure Association of the European Society of Cardiology.

Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline-recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice.

Clinical and economic impact of ferric carboxymaltose treatment for iron deficiency in patients stabilized following acute heart failure: a multinational study.

OBJECTIVE: To estimate clinical events and evaluate the financial implications of introducing ferric carboxymaltose (FCM) to treat iron deficiency (ID) at discharge in patients hospitalized for acute heart failure (AHF) with left ventricular ejection fraction (LVEF) <50% in the UK, Switzerland and Italy. METHODS: A decision analytic cost-offset model was developed to evaluate the costs associated with introducing FCM for all eligible patients in three countries compared to a world without FCM, over a five-year time horizon. Data from AFFIRM-AHF clinical trial were used to model clinical outcomes, using an established cohort state-transition Markov model. Country-specific prevalence estimates were derived using data from real-world studies to extrapolate number of events and consequent cost totals to the population at risk on a national scale. RESULTS: The cost-offset modeling demonstrated that FCM is projected to be a cost-saving intervention in all three country settings over a five-year time horizon. Savings were driven primarily by reduced hospitalizations and avoided cardiovascular deaths, with net cost savings of -£14,008,238, -CHF25,456,455 and -€105,295,146 incurred to the UK, Switzerland and Italy, respectively. LIMITATIONS: Although AFFIRM-AHF was a multinational trial, efficacy data per country was not sufficiently large to enable country-specific analysis, therefore overall clinical parameters have been assumed to apply to all countries. CONCLUSIONS: This study provides further evidence of the potential cost savings achievable by treating ID with FCM at discharge in patients hospitalized for AHF with LVEF <50%. The value of FCM treatment within the healthcare systems of the UK, Switzerland and Italy was demonstrated even within a limited time frame of one year, with consistent cost savings indicated over a longer term.

Impact analysis of heart failure across European countries: an ESC-HFA position paper.

Heart failure (HF) is a long-term clinical syndrome, with increasing prevalence and considerable healthcare costs that are further expected to increase dramatically. Despite significant advances in therapy and prevention, mortality and morbidity remain high and quality of life poor. Epidemiological data, that is, prevalence, incidence, mortality, and morbidity, show geographical variations across the European countries, depending on differences in aetiology, clinical characteristics, and treatment. However, data on the prevalence of the disease are scarce, as are those on quality of life. For these reasons, the ESC-HFA has developed a position paper to comprehensively assess our understanding of the burden of HF in Europe, in order to guide future policies for this syndrome. This manuscript will discuss the available epidemiological data on HF prevalence, outcomes, and human costs-in terms of quality of life-in European countries.

Ferric carboxymaltose for the treatment of iron deficiency in heart failure: a multinational cost-effectiveness analysis utilising AFFIRM-AHF.

AIMS: Iron deficiency is common in patients with heart failure (HF). In AFFIRM-AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron-deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost-effectiveness of FCM compared with placebo in iron-deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM-AHF trial from Italian, UK, US and Swiss payer perspectives. METHODS AND RESULTS: A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM-AHF trial. Health states were defined using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all-cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM-AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost-effective in Italy [incremental cost-effectiveness ratio (ICER) EUR 1269 per quality-adjusted life-year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43-0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost-effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology. CONCLUSION: Ferric carboxymaltose is estimated to be a highly cost-effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems.

Interdisciplinary assessment and diagnostic algorithm: The role of the cardiologist.

Patients with diabetes have an increased risk of developing heart failure and those with heart failure are at higher risk of developing diabetes. In patients with diabetes antidiabetic medications and the metabolic alterations of diabetes increase the risk of developing heart failure. In diabetic patients with heart failure and in those with an increased likelihood of developing the disease a stepwise approach based on the use of natriuretic peptides and echocardiography to rule out the presence of heart failure should be used. Once the diagnosis of heart failure is established it will be important to define the phenotype according to the left ventricular function and, where appropriate, use additional tests to identify possible additional underlying causes of heart failure like coronary artery disease. A multidisciplinary heart failure management programs is recommended in all patients with diabetes mellitus and heart failure to enable appropriate investigations, accurate diagnosis, and appropriate agreed evidence-based therapy and care plan. The implementation of a multidisciplinary heart failure management program requires a multidisciplinary team that will have to follow the patients throughout the whole heart failure trajectory and that should consider a holistic approach to the diabetic patient with heart failure rather than focussing merely on either heart failure or diabetes.

Epidemiology, pathophysiology and contemporary management of cardiogenic shock - a position statement from the Heart Failure Association of the European Society of Cardiology.

Cardiogenic shock (CS) is a complex multifactorial clinical syndrome with extremely high mortality, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large spectrum of CS presentations resulting from the interaction between an acute cardiac insult and a patient's underlying cardiac and overall medical condition. Phenotyping patients with CS may have clinical impact on management because classification would support initiation of appropriate therapies. CS management should consider appropriate organization of the health care services, and therapies must be given to the appropriately selected patients, in a timely manner, whilst avoiding iatrogenic harm. Although several consensus-driven algorithms have been proposed, CS management remains challenging and substantial investments in research and development have not yielded proof of efficacy and safety for most of the therapies tested, and outcome in this condition remains poor. Future studies should consider the identification of the new pathophysiological targets, and high-quality translational research should facilitate incorporation of more targeted interventions in clinical research protocols, aimed to improve individual patient outcomes. Designing outcome clinical trials in CS remains particularly challenging in this critical and very costly scenario in cardiology, but information from these trials is imperiously needed to better inform the guidelines and clinical practice. The goal of this review is to summarize the current knowledge concerning the definition, epidemiology, underlying causes, pathophysiology and management of CS based on important lessons from clinical trials and registries, with a focus on improving in-hospital management.

Living with stable angina: patients' pathway and needs in angina.

AIMS: There is evidence that stable angina patients may suffer from emotional disorders that further impair their quality of life. However, the emotional experience of living with stable angina from the patient's perspective still has to be explored. Thus, the main aim of this study was to explore patients' emotional experience of having stable angina and their reported needs during the pathway from the first symptoms, through the process of diagnosis, to management and related lifestyle changes. METHODS: A survey was conducted in 75 chronic ischemic heart disease patients with angina (Brazil, China, Romania, Russia, and Turkey) using a 75-min, face-to-face in-depth interview. RESULTS AND CONCLUSION: Patients' responses highlighted the need to increase individuals' awareness on the first signs and symptoms of the disease. The survey also showed that chronic stable angina patients need constant emotional support to overcome stress, anxiety, and depression. Finally, this study suggests the need to offer greater space for dialogue with healthcare professionals to get more comprehensive and 'patient-friendly' information.

Low quality of some generic cardiovascular medicinal products represents a matter for growing concern.

AIMS: Generic medicinal products (GMPs) are low-priced copies of off-patent medicines that reduce healthcare costs and broaden access to healthcare. Thus, healthcare authorities, professionals, and providers recommend their use. In recent years, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved hundreds of GMPs based on specific bioequivalent trials. The question is whether the brand name drugs and GMPs or the different GMPs similar in purity, efficacy, and safety. METHODS AND RESULTS: We have reviewed the progressive increasing recalls and warning letters of cardiovascular GMPs issued recently by the FDA/EMA. Both Agencies found numerous irregularities in the purity, safety, effectiveness, and current good manufacturing practices in some GMPs widely used in cardiovascular therapy. This evidence and the recent identification of nitrosamine impurities classified as probable human carcinogens in several angiotensin receptor blockers confirm that the presence of low-quality/substandard GMPs represents a serious public health problem with significant impact on national clinical and economic burden. CONCLUSION: A global strategy that unifies the efforts of all the stakeholders, including drug manufacturers, healthcare providers, governments, health professionals, patients, and judicial systems are needed to protect the drug chain supply and ensure that only high-quality GMPs are available for use.

Cost-effectiveness of direct acting oral anticoagulants in the prevention of thromboembolic complications: limits and concerns of economic evaluations.

: Economic evaluations have a widespread application in many areas of clinical research and play a key role in the clinical decision-making process. However, economic analyses have been sometimes used to produce new 'evidence' that is not adequately tested in the target population. This is the case of data arising from a systematic review of clinical trials evaluating the use of direct acting oral anticoagulants for the prevention of stroke in patients with atrial fibrillation. Taking into account this example, here we discuss the concerns raised by the improper interpretation of the results. Our conclusions are three-fold. Data from economic analyses should not be shifted to a clinical recommendation. Simulation models should not be used to generate new 'evidence' that is not supported by experimental data and is misleading. Clinical judgment is therefore pivotal to interpret results emerging from economic analyses.

Innovative imaging methods in heart failure: a shifting paradigm in cardiac assessment. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology.

Myriad advances in all fields of cardiac imaging have stimulated and reflected new understanding of cardiac performance, myocardial damage and the mechanisms of heart failure. In this paper, the Heart Failure Association assesses the potential usefulness of innovative imaging modalities in enabling more precise diagnostic and prognostic evaluation, as well as in guiding treatment strategies. Many new methods have gradually penetrated clinical practice and are on their way to becoming a part of routine evaluation. This paper focuses on myocardial deformation and three-dimensional ultrasound imaging; stress tests for the evaluation of contractile and filling function; the progress of magnetic resonance techniques; molecular imaging and other sound innovations. The Heart Failure Association aims to highlight the ways in which paradigms have shifted in several areas of cardiac assessment. These include reassessing of the simplified concept of ejection fraction and implementation of the new parameters of cardiac performance applicable to all heart failure phenotypes; switching from two-dimensional to more accurate and reproducible three-dimensional ultrasound volumetric evaluation; greater tissue characterization via recently developed magnetic resonance modalities; moving from assessing cardiac function and congestion at rest to assessing it during stress; from invasive to novel non-invasive hybrid techniques depicting coronary anatomy and myocardial perfusion; as well as from morphometry to the imaging of pathophysiologic processes such as inflammation and apoptosis. This position paper examines the specific benefits of imaging innovations for practitioners dealing with heart failure aetiology, risk stratification and monitoring, and, in addition, for scientists involved in the development of future research.

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.

Are elderly and women under-represented in cardiovascular clinical trials? Implication for treatment.

Elderly and women have been often under-represented in randomised clinical trials testing the effect of treatments on cardiovascular diseases even though these diseases highly affect both of them.Compared to their younger counterparts elderly have a higher incidence of disease-related morbidities, take more medicines and account for more adverse drug-related events. Similarly women present several differences in pathophysiology, clinical manifestations and outcomes in comparison to their male counterparts. For these reasons the results of randomised clinical trials obtained in younger men cannot be simply translated in elderly and women and the conduction of research and clinical trials in these patient populations is a key aspect to acquire evidence-based knowledge in the understanding and management of their conditions and treatment.Although the under-representation of elderly and women has been discussed for several years and several international guidelines or recommendation have been published to suggest how to improve the recruitment of these two populations, their recruitment is still insufficient. In particular, frail elderly and those with co-morbidities are not included questioning the external validity and the safety of most treatments.Aim of this review is to critically analyse how current recommendations for treatments of cardiovascular disease are not adequately devised for elderly and women.

Need for streamlined use of DPP-4 inhibitors in the treatment of type 2 diabetes.

Regulatory agencies request an assessment of cardiovascular safety for all "new" oral anti-diabetic drugs in order to avoid possible negative effects on cardiovascular events. Dipeptidyl peptidase 4 inhibitors have emerged as a new therapeutic alternative for the treatment of type 2 diabetes mellitus, but the several large post-marketing clinical trials have shown only a modest effect in glycaemic control and, more importantly, a neutral effect on total and cardiovascular events. Conversely a recent trial with empagliflozin, a sodium-glucose co-transporter 2 inhibitor, has shown significant effect on overall and cardiovascular mortality. Although glycaemic control is an important aspect of diabetes management, the results of the EMPA-REG outcome trial suggest that it is possible to develop anti-diabetic drugs that may exert an overall beneficial effect beyond the mere improvement of glycaemic control. While the regulatory hurdles should not be increased, there is the need for evaluation of the net clinical impact and cost effectiveness of all anti-diabetic agents. Therefore, a better collaboration among all stakeholders is needed in order to develop studies with endpoints that will be both clinically meaningful including appropriate follow-up, and economically relevant in patients with type 2 diabetes mellitus.

Steps forward in regulatory pathways for acute and chronic heart failure.

A workshop was organized by the Agenzia Italiana del Farmaco (AIFA) to discuss unmet needs and ways forward in the development of medicines in heart failure, their rationale, and cost-effective use. An integrated, multidisciplinary approach, including patients' needs and perspectives, was advocated by all the participants as the way to the most effective treatment regimens. More work is needed for reaching consensus on clinical and functional endpoints, for validating patient reported outcomes and measurements of well-being. Similarly, the integration into the clinical programmes of the health technology assessment/payers perspective, in particular, the evaluation of 'real-life' treatment effectiveness and of health as a value, would help in shifting the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole health care regimen. Through this kind of workshop, AIFA is trying to build a template for meetings devoted to debate unmet needs with all stakeholders towards tentative road maps for the future.