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.

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.

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.

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.

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.

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.

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.

Recognizing hospitalized heart failure as an entity and developing new therapies to improve outcomes: academics', clinicians', industry's, regulators', and payers' perspectives.

Hospitalized heart failure (HHF) is associated with unacceptably high postdischarge mortality and rehospitalization rates. This heterogeneous group of patients, however, is still treated with standard, homogenous therapies that are not preventing their rapid deterioration. The costs associated with HHF have added demands from society, government, and payers to improve outcomes. With coordinated and committed efforts in the development of new therapies, improvements may be seen in outcomes for patients with HHF. This article summarizes concepts in developing therapies for HHF discussed during a multidisciplinary panel at the Heart Failure Society of America's Annual Scientific Meeting, September 2012.

Gender determinants of cardiovascular risk factors and diseases.

This article addresses the various aspects concerning gender dissimilarities in the cardiovascular system. It examines sex differences in the genetic susceptibility to cardiovascular disease (CVD) development or outcome: with the presence of either XX or XY chromosomes, every cell is sexually differentiated and there exist postpuberal differences between male and female cardiovascular systems. The main action mechanisms of sex steroid hormones are discussed, mainly as to testosterone (Te) in men and 17beta-estradiol (E2) and progesterone (Pro) in women. In women, susceptibility to CVD is known to increase in the postmenopausal period, when the ovarian hormone function expires. Some concepts of the sex-based differences in anatomy and physiology are also explained. Although they have the same structural elements, women and men use them in a different way to guarantee cardiovascular system homeostasis. Some examples of differences between men and women in pathological cardiovascular function are given. A further important issue regards the prevalence and role of cardiovascular risk factors in the two genders. Compared to boys of the same age, adolescent girls and premenopausal women have a more favorable risk profile: lower blood pressure (BP), less atherogenic lipid profile, and lower prevalence of cardiovascular risk factors. Women develop CVD later than men and diabetic women have a considerably higher mortality rate compared to men of the same age. Finally, there exist several clinically significant differences between men and women as to prevalence, presentation, management and outcome of CVD. Clinical peculiarities related to gender in presentation of some CVDs, such as coronary heart disease (CHD), stroke and heart failure, are described. We are absolutely convinced that only an accurate knowledge of the sex-specific pathophysiology may allow determination of the appropriate diagnostic instruments and to implement tailored treatments of CVD in men and women.