European Journal of Heart Failure Supplements

European Journal of Heart Failure SupplementsVolume 11, Issue S1 p. S11-S12 Sunday 20 May 2012, 16:30–18:00, Room: PirotFree Access Judges Choice: Basic Science First published: 17 May 2012 https://doi.org/10.1093/eurjhf/hss004AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume11, IssueS1May 2012Pages S11-S12 RelatedInformation

European Journal of Heart Failure SupplementsVolume 11, Issue S1 p. S121-S125 Monday 21 May 2012, 11:00–12:30, Room: PirotFree Access Rapid Fire Session 2 First published: 17 May 2012 https://doi.org/10.1093/eurjhf/hss010AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume11, IssueS1May 2012Pages S121-S125 RelatedInformation

Purpose: Heart failure is a major cause of mortality and morbidity, while anemia is a frequent comorbidity in chronic heart failure with significant impact on the long-term outcome. Our aim was to assess the prognostic value of anemia on short-term outcome in acute worsening of advanced, but prior stable chronic heart failure. Methods: We performed retrospective study of 263 consecutive patients hospitalised for acute exacerbation of decompensated chronic heart failure, New York Heart Association functional class 3 and 4, whose ejection fraction measured by echocardiography was ≤ 40%. All of these patients were stable more than 30 days prior to hospitalisation. Among these patients 138 (73 female) had anemia and 125 were without anemia (64 female). Anemia was defined by WHO criteria, as hemoglobin at admission <120 g/l for women and <130 g/l for men. Statistical analysis included comparison of demographic, clinical, laboratory and therapeutic data between these two groups, with an emphasis on 30-days mortality rate. All patients had optimal therapy in accordance with the actual ESC guidelines and anemia was treated if indicated. Results: Patients in both groups were similar age (77, 5 ±8 vs. 75±9, 8 years, p=0, 067) and had average length of hospital stay around 8 days (8 [95% C.I. 89-93]vs.8 [95% C.I. 90-94], P=0.817). Although 30-days mortality rate was higher in anemic patients, that difference was not statistically significant (11.4% vs. 9.5%, P=0.764). Hemoglobin concentration at admission is not in corelation with 30-days mortality in male (P=0.472) neither female (P=0.767) patients. The group of anemic patients had significantly wider QRS complex (118ms [95% C.I. 96-124] vs. 92ms [95% C.I. 84-109], P=0.013), higher concentration of urea (11.8 mmol/l [95% C.I. 10.2-13.5] vs. 9.2 mmol/l [95% C.I. 8.6], P=0.015) and creatinine (139μmol/l [95% C.I. 128-155] vs. 111 μmol/l [95% C.I. 107-125], P<0.001) than nonanemic patients. Oxygen saturation slightly differed between the groups (88, 67% vs. 88, 48% P=0.817). Conclusion: In according to our results anemia does not affect the short-term outcome in patients hospitalised for acute worsening of advanced chronic heart failure.

Purpose: We performed a study to evaluate the accuracy of admission UA serum level as a predictor of major adverse cardiac events (MACE) in the context of acute myocardial infarction (AMI). Methods: We evaluated results of cohort of 210 patients hospitalized in our center from January till December 2010 for ischemic chest discomfort within first 12 hours from the onset of symptoms and diagnosed with either non-ST segment elevation MI or ST segment elevation MI. None of the patients has been previously diagnosed with CAD. Exclusion criteria included previously documented elevated UA levels, chronic kidney disease, malignancy and chronic alcoholism. Follow up was achieved by means of standard hospital database and chart reviews and telephone calls at 30th day post admission. Measured MACE conditions were acute heart failure, new symptoms of CAD that required treatment, and cardiac death. The ROC curve analyses was used in order to determine optimal UA gender specific cut-off values for prediction of MACE during 30 days of follow-up. Cox proportional hazards regression model was employed to calculated the risk of adverse outcomes with elevated UA after adjusting for sex, age, body mass index, hypertension, diabetes, hyperlipidaemia, smoking, diuretics, angiotensin converting enzyme inhibitors and statins. Results: The mean age was 63 years with 20% of patient at least 75 years old. Women accounted for 26.4% of the study population. The index diagnosis was STEMI in 80.5% and NSTEMI in 19.5%. Most patients underwent PCI (75%) during the index hospitalization (mean days in hospital 7.2). The mean left ventricular EF was 45.6%, Killip class II-IV in 19.0% patients, eGFR median value was 87.4 ml/min/1.73 m2 with 9.5% lower than 60 ml/mi/1.73 m2. Patients were classified into two subgroups, having serum UA level under or above the gender specific ROC determined cut off value (360 μmol/l for men and 309 μmol/l for women). The incidence of total MACE was 35.2% with significant differences between two groups 23% vs. 49% p < 0.001 (acute cardiac failure 14% vs. 31%, p = 0.004, new symptoms of CAD 6% vs. 9%, p=0.298 and cardiac death 4% vs. 9%, p = 0.149). The instantaneus relative risk of MACE during the 30-day period with respect to the UA level measured at admittance to the hospital is 2.52 with 95% CI 1.57- 4.06. Conclusion: Our results suggest that the patient having serum UA at admittance above the gender specified value is more likely to develop AMI related complications in 30-days period therefore elevated serum uric acid level can be considered a reliable marker for predicting adverse events in AMI.

Introduction: Sustained hypertension (HT) leads to left ventricular hypertrophy (LVH) and left ventricular dilatation, processes associated with loss of cardiac myocytes through apoptosis. Nevertheless, the relationship of apoptosis, myocardial fibrosis and diastolic function remains unknown. Therefore, the aims of the present study were to analyze the relationship between aminoterminal propeptide levels of type III procollagen (PIIINP), sFas, soluble TNF receptor 1 (sTNF-R1) and diastolic function in essential HT. Hypothesis: We assessed the hypothesis that increased cardiac collagen turnover would be associated with LVH, diastolic dysfunction and apoptosis even in asymptomatic HT. Methods: The asymptomatic hypertensive group consisted of 253 Caucasian patients (mean age 60±13 years, 139 males) from 11 hospitals. A routine physical examination, laboratory analyses, and echo-Doppler study were performed. Results: Serum concentrations of PIIINP were higher in hypertensive patients compared to control group [4.18 (3.55 – 5.04 μ g/L) vs. 3.54 (2.98 – 4.54 μ g/L), p=0.006] and also plasma levels of sFas and sTNF-R1 [1.40 (1.13 – 1.69 ng/mL) vs. 1.00 (0.84 – 1.27 ng/mL), p<0.0001; 385 (291 – 545 pg/mL) vs. 236 (194 – 302 pg/mL), p<0.0001]. Log-transformed concentrations of anti-apoptotic cytokines were correlated between them (r=0.404, p<0.0001). Moreover, serum PIIINP concentrations were associated with log-transformed sFas (r=0.386, p<0.0001) and sTNF-R1 (r=0.298, p<0.001). Then, multivariate analyses included sFas (p<0.0001) and sTNF-R1 (p<0.0001) as independent factors of serum procollagen levels. Finally, marker concentrations were significantly correlated with diastolic parameters. Conclusions: This study showed increased circulating levels of PIIINP, sFas and sTNF-R1 in our group of asymptomatic hypertensive patients. Furthermore, sFas and sTNF-R1 are independent factors of serum type III procollagen, and diastolic parameters showed a highly significant relationship with myocardial fibrosis and anti-apoptotic cytokines.

Cardiac hypertrophy is an adaptive response to pressure or volume overload, in order to preserve cardiac function.A sustained hypertrophic response can lead to heart failure.Several proteins have been shown to be involved in hypertrophic signalling pathways such as Ras, and calcium-sensitive proteins including calcineurin and CaMKII.Calcineurin is a well known activator of the nuclear factor of activated T cells (NFAT) transcription factor.Recently, a protein named carabin has been discovered in immune cells as a calcineurin and Ras inhibitor (Pan et al., Nature 445: 433, 2007).Carabin contains a putative Ras GTPase activating (GAP) domain and a Cterminal domain that can interact with the phosphatase calcineurin.In this study, we examined whether carabin could inhibit prohypertrophic signalling in neonatal rat cardiac myocytes.We found by western blot that carabin was upregulated in response to hypertrophic stimuli such as 1 mM isoproterenol (Iso, b-adrenergic receptor agonist) or 10 mM phenylephrine (PE, a-adrenergic receptor agonist).Interestingly, transfection of carabin inhibited NFAT and myocyte enhancer factor 2 (MEF2) transcriptional activity induced by Iso or PE (Luciferase assay experiments).In addition, a carabin mutant, inactive in its Ras-GAP domain, failed to inhibit NFAT and MEF2 transcriptional activity.Consistent with its inhibitory effect on NFAT activation, carabin overexpression significantly blocked calcineurin activity.Finally, we showed that carabin blocked a downstream effector of the small G protein Ras since it prevented the phosphorylation of the MAP Kinase ERK in cells treated with 10 mM PE.The inhibition of ERK phosphorylation was not observed in the presence of a carabin mutant in the RasGAP domain.In conclusion, our data identified carabin as a potential therapeutic target for the treatment of cardiac hypertrophy leading to heart failure.

European Journal of Heart Failure SupplementsVolume 9, Issue S1 p. S4-S5 Sunday 30 May 2010Free Access Nursing Investigator Award First published: 27 May 2010 https://doi.org/10.1093/eurjhf/hsq007AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume9, IssueS1May 2010Pages S4-S5 RelatedInformation

European Journal of Heart Failure SupplementsVolume 8, Issue p. i5-i10 ArticleFree Access Comorbidities in heart failure: a key issue C.E. Angermann, C.E. AngermannSearch for more papers by this author C.E. Angermann, C.E. AngermannSearch for more papers by this author First published: 07 April 2009 https://doi.org/10.1093/eurjhf/hfp009AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Introduction Despite improvements in pharmacotherapy, morbidity and mortality rates in community-based populations with chronic heart failure (CHF) have remained high,18 exceeding by far those reported for placebo groups in pharmacological trials, on which treatment guidelines for CHF are built. This divergence between clinical study participants and the 'real world' CHF population is largely explained by restrictive study enrolment criteria, and only a minority of individuals in the community, who usually are elderly, fit the profile of typical clinical trial populations. The most important differences are that these patients often have preserved left ventricular systolic function and almost invariably suffer from multiple comorbidities.16 The chronic heart failure syndrome – a systemic disorder Figure 1 depicts the pathophysiological cascade of the CHF syndrome. Various conditions predispose to its development. The occurrence of CHF transforms the clinical manifestations and the prognosis of the underlying diseases profoundly. For example, in patients after a myocardial infarction, mortality rates increase by a factor of four with the onset of CHF.7 Irrespective of the primary clinical picture, CHF is fairly uniformly characterized by a specific set of symptoms in the medical history (dyspnea, fatigue, and cerebral dysfunction) and physical signs (edema, rales, and muscle wasting) in the physical examination.28 Although CHF symptoms tend to progress, their severity may fluctuate. With appropriate medication and lifestyle modifications, some patients may experience remarkable clinical recovery, which may also be associated with improvements in cardiac structural and functional abnormalities. Figure 1. The chronic heart failure syndrome – a systemic disorder.Open in figure viewerPowerPoint Although the CHF syndrome has traditionally been looked upon as a hemodynamic disorder, the correlation between measures of cardiac performance and CHF symptoms may be poor in the individual patient. The mechanisms responsible for the exercise intolerance of patients with CHF have not been clearly defined. Thus, severely impaired left ventricular pump function is sometimes present in clinically asymptomatic patients, whereas individuals with preserved systolic function may experience severely disabling CHF symptoms. This apparent discordance between left ventricular ejection fraction and the degree of individual functional impairment is not well understood and may only partially be explained by factors such as cardiac rhythm, left ventricular asynchrony, secondary valvular incompetence, or the degree of right ventricular impairment. Instead, there is growing evidence that various disease conditions affecting other organs than the heart are pathophysiologically closely interrelated with the occurrence of CHF, and impact on both disease progression and the prognosis of the patient, rendering it a complex systemic syndrome. Notwithstanding the likely possibility of pre-existing organ damage (e.g. renal impairment in patients with hypertension), most comorbidities and functional abnormalities are diagnosed at the time of the first clinical manifestation of CHF. These conditions comprise renal dysfunction with abnormal sodium handling, anemia, and hemodilution; respiratory disorders including sleep-disordered breathing; depression and cognitive dysfunction; changes in peripheral muscular and vascular function; wasting and cachexia; neurohormonal and reflex autonomic activation; and coagulation abnormalities increasing the risk of thromboembolism and stroke. Although for the most part considered complications following the presence of CHF, most of these disorders appear to be interrelated with the CHF syndrome by adversely influencing cardiac remodeling, maintaining and enhancing disease progression, aggravating symptoms, and worsening prognosis. This may explain why hemodynamic improvement, e.g. as a result of resynchronization therapy and/or pharmacological treatment, will not necessarily translate into immediate clinical improvement and in some cases altogether fail to ameliorate the patient's condition. Risk factors, risk modifiers, and 'reverse epidemiology' The increasing incidence and consistently high morbidity and mortality rates in CHF suggest that risk factors and risk modifiers of pathogenetic relevance have – by and large – remained unaltered by the presently available CHF treatment options. Immune activation and systemic inflammation, which frequently have been associated with adverse outcomes in the past, may represent such unmodified mechanisms. However, considering that studies which investigated the effects of anticytokine therapy on outcome in CHF showed no or even adverse effects, it appears that the role of inflammation in CHF is probably more complex and may also involve adaptive and even cardioprotective effects.29 More recently, hyperuricemia has been highlighted as a feature of metabolic imbalance and was identified as an independent marker of adverse prognosis in CHF patients.2 Hyperglycemia and insulin resistance in diabetic patients can induce myocardial contractile systolic and diastolic abnormalities at the cellular level. Although multiple mechanisms are responsible for the development of CHF in diabetes, atherosclerosis leading to ischemic heart disease probably plays the most important role.11 Further, mortality rates are again significantly higher for patients with CHF and concomitant diabetes mellitus than for non-diabetics. Left ventricular hypertrophy is a potent, independent predictor of cardiac events, which besides increasing the risk of CHF also augments the risk of coronary and cerebrovascular diseases; moreover, it may contribute directly to CHF development and progression through pathological changes in cardiac structure.28 The term 'reverse epidemiology' refers to paradoxical and counterintuitive epidemiological associations between classical cardiovascular risk factors such as obesity, high blood pressure, and hypercholesterinemia and prognosis.8 In distinct populations suffering from chronic progressive diseases such as CHF, advanced renal failure, or chronic obstructive lung disease (COPD), these risk factors were repeatedly shown to correlate with better survival. As a common characteristic, these diseases share a progressive catabolic state associated with anorexia, decreasing muscle and fat mass leading to weight loss, and abnormalities of hepatic, glucose, and lipid metabolism. In this context, 'wasting' may be described as the end stage of an inappropriate interplay between multiple cytokines, neuropeptides, stress hormones, and intermediate substrate metabolism.10 The survival paradox observed in such populations may be related to multiple factors such as better hemodynamic stability in hypertension and obesity, protective adipokine profiles, endotoxin–lipoprotein interaction, toxin sequestration of fat, and antioxidation of muscle. It becomes clear from these considerations that risk factors and comorbid conditions acting as risk mediators in cardiovascular disorders apparently change their role as the disease progresses. It is presently unclear at which stage of the disease continuum the risks associated with the chronic progressive 'wasting' process supersede those originally mediated by the classical risk factors. 'Cross talk' between the heart and other organs Data from the Scottish morbidity records obtained in more than 25 000 patients with CHF as the primary diagnosis indicate that a large proportion of deaths and hospital discharges for CHF are associated with conditions other than CHF, which may precipitate, contribute to, or complicate admission.4 In patients suffering from several illnesses concurrently, unrelated disorders may be undertreated if one problem consumes all the attention of the attending physician.19 A recent cross-sectional study in 122 630 CHF patients aged ≥65 years, representing a 5% random sample of all U.S. Medicare beneficiaries, assessed the relationship of the 20 most common non-cardiac comorbidities to one-year potentially preventable hospitalizations and total mortality. The results indicated that non-cardiac comorbidities are highly prevalent in older patients with CHF and are strongly related to adverse clinical outcomes and increased hospitalization rates.3 Observations from our prospective cohort study 'Interdisciplinary Network for Heart Failure' (INH-Registry)26 showed a significant association between the number of comorbidities and risk factors and the all-cause mortality risk (Figure 2). Figure 2. Mortality from all causes according to the number of risk factors, risk mediators, or comorbidities. Data from the prospective cohort study of the Interdisciplinary Network for Heart Failure, Würzburg (INH Registry, n = 1054).26Open in figure viewerPowerPoint Amongst the broad variety of diseases which are typically associated with the CHF syndrome, chronic renal dysfunction, anemia, COPD, and depression have more recently attracted particular attention. All of them have been recognized as conditions that interact with CHF in a complex fashion and are of crucial importance for disease progression and outcome. The cardio-renal syndrome The term 'cardio-renal syndrome' refers to the complex interrelation between heart and kidneys, and denotes the decline of renal function in the setting of CHF. It originates from the observation that even minor alterations in renal function, as evidenced by reduced glomerular filtration rate and microalbuminuria, represent potent cardiovascular risk factors. The excess cardiovascular risk related to renal damage is partly related to a higher prevalence of traditional atherosclerotic risk factors, but also to specific features of chronic kidney disease itself. Renal damage promotes hypertension and dyslipidemia, which in turn enhance the progression of chronic renal dysfunction, and – at the same time – are associated with increased sympathetic nervous system activity, systemic inflammation, and activation of the renin-angiotensin system. In industrialized countries, diabetic nephropathy is the leading cause of renal damage. Thus the triad of hypertension, dyslipidemia, and diabetes represents an important part of the overall cardiovascular risk burden, which appears to be related to enhanced production of reactive oxygen species, endothelial dysfunction, and subsequent atherosclerosis, leading to a higher incidence of coronary and peripheral arterial disease, as well as CHF.23 Specific risk factors related to kidney disease include hyperphosphoremia and elevated calcium–phosphorous product, predisposing to the formation of cardiovascular calcifications. Further, renal disease is a major contributing factor to anemia in CHF, which among other negative effects enhances left ventricular hypertrophy.17,27 Figure 3 shows a simplified representation of this complex vicious circle which inevitably promotes progression of all three conditions – renal dysfunction, anemia, and CHF – and is therefore sometimes also termed the 'cardio-renal anemia syndrome'. Figure 3. Simplified schematic diagram of the pathophysiological interrelations between chronic kidney disease (CKD), congestive heart failure (CHF), and anemia. P: phosphorus; Ca: calcium; LVH: left ventricular hypertrophy; MA: microalbuminuria; PTH: parathyroid hormone. Modified from Obialo (2007).Open in figure viewerPowerPoint Therapeutic strategies in the cardio-renal syndrome need to aim at both cardiovascular and renal protection. Adequate blood pressure control is mandatory in order to slow down worsening of renal damage and to prevent cardiovascular events. Better outcomes of renal function but also improved morbidity and mortality rates from CHF are achieved by inhibition of the renin-angiotensin system in both diabetic and non-diabetic patients. Thus, angiotensin converting enzyme (ACE) inhibitors and/or angiotensin 2 type 1 receptor blockers (ARBs) are considered an integral part of current antihypertensive organ-protective pharmacotherapy. The anemia of chronic heart failure Anemia is also common in CHF, with prevalence rates between 20% and 50%. The incidence increases with New York Heart Association (NYHA) functional class. Anemia has consistently emerged as a strong independent predictor of impaired survival and is associated with increased morbidity and hospitalization rates.24,27 Bone marrow depression, reduced intestinal iron uptake, sodium and water retention, hemodilution, and systemic inflammation leading to erythropoietin resistance have been recognized as important mediators, and the use of ACE inhibitors and ARBs may additionally inhibit the bone marrow response to erythropoietin. Old age, female sex, renal insufficiency, decreased body mass index, peripheral edema, neurohormonal activation, and plasma levels of pro-inflammatory cytokines and other markers of inflammation such as C-reactive protein were found to be inversely related to hemoglobin levels.27 In this context, we must be aware, however, that hemodilution caused by CHF may also mimic anemia. Compared with non-anemic patients, the presence of anemia is associated with clinically worse cardiac status, left ventricular hypertrophy, more severe systolic and diastolic dysfunction, higher plasma levels of natriuretic peptides, increased extracellular and plasma volume, a more rapid deterioration of renal function, a lower quality of life, and increased health care expenditure.24 The only way to determine whether anemia is merely an indicator of more severe CHF or actually contributes to CHF progression is to investigate if the treatment of anemia favorably influences CHF. In several reports of both controlled and uncontrolled studies, correction of anemia with various erythropoiesis-stimulating agents in conjunction with oral and intravenous iron has been associated with an improvement in clinical status, decreased hospitalizations, improved cardiac and renal function, and improved quality of life.24 Larger, randomized, double-blind, controlled studies are required, however, to verify these initial observations. Prior to transferral of this treatment option into routine clinical practice, we need to better understand the therapeutic effects potentially related to non-hematologic functions of erythropoiesis-stimulating agents such as neovascularization, prevention of apoptosis of endothelial, myocardial, cerebral, and renal cells, the increase in endothelial progenitor cells, as well as anti-inflammatory and antioxidant effects. Until this information is accumulated and the positive effects of erythropoiesis-stimulating agents are reliably ascertained, administration should not be recommended outside clinical trials. Chronic obstructive pulmonary disease and chronic heart failure COPD is frequent in patients with CHF, with a prevalence ranging from 20% to 30%. Since the coexistence of both conditions has important therapeutic implications, early recognition is critical. However, COPD may be missed in patients with CHF, because dyspnea is erroneously attributed to CHF, and vice versa. Measurement of plasma natriuretic peptide levels may be useful to uncover unsuspected CHF in COPD patients. Non-invasive cardiac imaging, preferably using echocardiography, is superior to biomarkers for the detection of left ventricular functional abnormalities in patients with stable COPD.13 Tobacco constitutes a well-known risk factor for both COPD and cardiovascular disease. Cigarette smoke causes inflammation in the airways, leading to airway obstruction, and in the lung tissues, leading to emphysema. Further, it induces systemic inflammation, vasomotor and endothelial dysfunction, and augmented serum concentrations of pro-coagulant and inflammatory factors. Although the interrelations are incompletely understood, this may help to explain the dramatic increase in cardiovascular risk in patients with COPD. Having symptoms of chronic bronchitis alone increases the risk of a cardiovascular death by 50%.25 CHF and COPD share adverse health effects including weight loss, nutritional abnormalities, skeletal muscle dysfunction, and low grade inflammation, the latter being present even in non-smokers with COPD. As outlined above, COPD is also associated with 'reverse epidemiology' regarding traditional cardiovascular risk factors [19]. Correspondingly, improvement of pulmonary or cardiac function cannot be expected to translate into improved functional state in patients with COPD or CHF unless the systemic alterations regress concomitantly. The presence of COPD may impact on the treatment of CHF, as COPD is still often viewed as a contraindication to beta-blockade. However, a large body of data indicates that patients with COPD tolerate well selective beta-blockade, which should not be withheld from CHF patients with concomitant COPD.13 Treatment of CHF according to guidelines may have additional beneficial effects, as ACE inhibitors and ARBs may reduce pulmonary obstruction by decreasing angiotensin II levels, decrease pulmonary inflammation and pulmonary vascular constriction, and ameliorate alveolar–membrane gas exchange.22 Statins may, due to their anti-inflammatory potential and possibly other pleiotropic effects, also be beneficial.13 Aldosterone antagonists may have positive effects on gas diffusion, as aldosterone harms the alveolar–capillary membrane.22 Depression in chronic heart failure Compared with the general population, depression is four to five times more common in CHF. In a recent meta-analysis, the overall prevalence of clinically significant (major) depression was reported to be 21.5% in patients with CHF.21 We and others have demonstrated significantly higher short- and long-term morbidity and mortality risks in patients with CHF suffering from major (but not minor) depression as a comorbidity.9,6 Worse outcome in terms of health-related quality of life and higher medical costs has also been reported. Possible mechanisms mediating these effects include biological, behavioral, genetic, and psychosocial factors. Figure 4 depicts hypotheses regarding the interrelationship between CHF and depression. Besides the possibility of independent coincidence, shared pathogenetic pathways have been postulated. On the one hand, there is evidence to suggest that CHF causes and aggravates depression; it has been hypothesized that elevated plasma levels of pro-inflammatory cytokines, as frequently observed in CHF, may induce cytokine production in the brain, which then activates the hypothalamus-pituitary-adrenal axis, elicits a stress response, and inhibits serotonin activity, thus inducing the increased prevalence of depressive symptoms in CHF.15 On the other hand, depression has been shown to increase the risk for cardiac events even among initially healthy individuals. Based on meta-analysis, people with clinically significant depression have, compared with the general population, a more than 2.5-fold elevated risk of myocardial infarction or cardiac death.20 Dysregulation of autonomic nervous control represents one plausible mediator of the adverse effects of depression in CHF. Reduced parasympathetic and increased sympathetic tone lowers the threshold for myocardial ischemia and cardiac events. High levels of circulating catecholamines may contribute to recurrent endothelial injury. Most studies investigating the role of the sympathetic nervous system in depression found a higher resting heart rate, decreased heart rate variability, and increased norepinephrine excretion – all serious risk factors, even in the general population. Last but not least, depression may also adversely impact on behavioral factors such as smoking, diet, physical activity, and compliance with treatment recommendations. Figure 4. Hypotheses regarding the interrelationship between chronic heart failure and depression.Open in figure viewerPowerPoint Although several previous outcome trials in depressed patients with cardiovascular disease proved the safety and antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs; reviewed in),1 there is no evidence that these strategies impact favorably on morbidity and mortality. So far, no large randomized trials have been published evaluating antidepressants in CHF patients for their effects on hard somatic endpoints. The MOOD-HF study will be the first to generate long-term data on the safety and antidepressant efficacy of an SSRI (escitalopram), in terms of mortality, morbidity, severity of depression, and surrogates presumed to possess clinical and/or prognostic relevance in NYHA functional class II-IV CHF.1 Beyond the desirable goal of improvement of depression and quality of life in individual patients, there are presently no evidence-based treatment recommendations for depressed subjects with cardiovascular diseases in general and CHF in particular. If physicians wish to prescribe an antidepressant, SSRIs are a reasonable option in view of their lack of significant cardiovascular side effects and relative lack of toxicity at overdose. The low potential for drug–drug interactions is also attractive in CHF patients, who usually suffer from numerous other comorbidities and take a variety of concomitant medications. Other antidepressant drugs, in particular tricyclic antidepressants, should not be used in CHF because of their recognized cardiovascular side effects. Economy and management of heart failure – an issue of comorbidities In a recent study addressing health care expenditures of patients with various chronic conditions, multiple comorbidities emerged as the most important determinant of health care costs.5 Another problem related to multiple comorbidities is polypharmacy, as the risk of drug–drug interactions rises exponentially in users of more than five different drugs.12 Conversely, the presence of several concurrent diseases may also lead to underutilization of evidence-based CHF pharmacotherapy because of safety concerns (e.g. diminished utilization of aldosterone antagonists in patients with renal dysfunction or of beta-blockers in patients with asthma). If discharge management is inadequate, patients may, in addition, be unable or lack insight into the necessity to comply with complex treatment regimens frequently introduced during hospitalization. Thus, comorbidities appear as a critical, yet frequently neglected determinant of both clinical management requirements and outcome of CHF patients, as well as costs. More recently, clinical decision rules such as the Seattle Heart Failure Model14 have been designed that permit estimation of the projected benefit of adding medications or devices to an individual patient's therapeutic regimen. These tools may provide a rational basis to develop individualized strategies for the comprehensive management of the elderly CHF patient with multiple comorbid conditions. Conclusions Comorbidities, risk factors, and risk modifiers are highly prevalent in CHF and are associated with adverse outcomes. There is growing evidence that many conditions affecting other organs than the heart are pathophysiologically closely linked with the occurrence of CHF, and impact on both disease progression and the prognosis of the patient, rendering CHF a complex systemic disease. Physicians in charge of these patients need to consider all facets of the CHF syndrome and tailor management strategies to individual patients. Despite the proven efficacy of pharmacotherapy, there is still room for drug development targeting the systemic consequences of this grave condition. 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The impact of comorbidityJ Gen Intern Med2007 22 464 469 6FallerHStörkSSchowalterMDepression and survival in chronic heart failure: does gender play a role?Eur J Heart Fail2007 9 1018 1023 7HasdaiDTopolEJKilaruRFrequency, patient characteristics, and outcomes of mild-to-moderate heart failure complicating ST-segment elevation acute myocardial infarction: lessons from 4 international fibrinolytic therapy trialsAm Heart J2003 145 73 79 8HorwichTBFonarowGCReverse epidemiology beyond dialysis patients: chronic heart failure, geriatrics, rheumatoid arthritis, COPD, and AIDSSemin Dial2007 20 549 553 9JiangWKuchibhatlaMClaryGLRelationship between depressive symptoms and long-term mortality in patients with heart failureAm Heart J2007 154 102 108 10Kalantar-ZadehKHorwichTBOreopoulosARisk factor paradox in wasting diseasesCurr Opin Clin Nutr Metab Care2007 10 433 442 11KamaleshMHeart failure in diabetes and related conditionsJ Card Fail2007 13 861 873 12KöhlerGIBode-BögerSMBusseRHoopmannMWelteTBögerRHDrug-drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug useInt J Clin Pharmacol Ther2000 38 504 513 13Le JemtelTHPadelettiMJelicSDiagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failureJ Am Coll Cardiol2007 49 171 180 14LevyWCMozaffarianDLinkerDTThe Seattle Heart Failure Model: prediction of survival in heart failureCirculation2006 113 1424 1433 15MaierSFBi-directional immune-brain communication: Implications for understanding stress, pain, and cognitionBrain Behav Immun2003 17 69 85 16MasoudiFAHavranekEPWolfePMost hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failureAm Heart J2003 146 250 257 17ObialoCICardiorenal consideration as a risk factor for heart failureAm J Cardiol2007 996B 21D 24D 18RathoreSSMasoudiFAWangYSocioeconomic status, treatment, and outcomes among elderly patients hospitalized with heart failure: findings from the National Heart Failure ProjectAm Heart J2006 152 371 378 19RedelmeierDATanSHBoothGLThe treatment of unrelated disorders in patients with chronic medical diseasesN Engl J Med1998 19 1516 1520 20RuguliesRDepression as a predictor for coronary heart disease. a review and meta-analysisAm J Prev Med2002 23 51 61 21RutledgeTReisVALinkeSEGreenbergBHMillsPJDepression in heart failure. A meta-analytic review of prevalence, intervention effects, and associations with clinical outcomesJ Am Coll Cardiol2006 48 1527 1537 22RuttenFHCramerMJLammersJWGrobbeeDEHoesAWHeart failure and chronic obstructive pulmonary disease: An ignored combination?Eur J Heart Fail2006 8 706 711 23SchiffrinELLipmanMLMannJFChronic kidney disease: effects on the cardiovascular systemCirculation2007 116 85 97 24SilverbergDSWexlerDIainaASchwartzDThe interaction between heart failure and other heart diseases, renal failure, and anemiaSemin Nephrol2006 26 296 306 25SinDDManSFChronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortalityProc Am Thorac Soc2005 2 8 11 26StörkSHenseWZehntgrafCPharmacotherapy according to treatment guidelines is associated with lower mortality in a community-based sample of patients with chronic heart failure. A prospective cohort studyEur J Heart Fail2008 10 1236 1245 27TangYDKatzSDAnemia in chronic heart failure: prevalence, etiology, clinical correlates, and treatment optionsCirculation2006 113 2454 2461 28VerdecchiaPAngeliFAchilliPEchocardiographic left ventricular hypertrophy in hypertension: marker for future events or mediator of events?Curr Opin Cardiol2007 22 329 334 29YndestadADamåsJKØieEUelandTGullestadLAukrustPRole of inflammation in the progression of heart failureCurr Cardiol Rep2007 9 236 241 Volume8IssueSpecial Issue: Managing Heart Failure: A Vision for the FutureApril 2009Pages i5-i10 FiguresReferencesRelatedInformation

The management of chronic heart failure is a complex process that can involve a large number of pharmacological and non-pharmacological approaches to management (Figure 1). Guidance on drug use is provided by guidelines at the international level (such as those from the European Society of Cardiology and the joint American Heart Association/American College of Cardiology initiative) and the national level (for example, the National Institute of Clinical Excellence, the Scottish Intercollegiate Guidelines Network,16 and the Scottish Intercollegiate Group), with directions on implementation at the local or hospital level (such as regional planning groups and hospital drug formularies). This review will focus on three controversial aspects of the management of chronic heart failure: diagnosis, dose and sequence, and polypharmacy. In the patient with a potential diagnosis of heart failure, it is important first to confirm that heart failure is present and secondly to identify the underlying cause. The European Society of Cardiology (ESC) provides clear guidelines on the approach to diagnosing chronic heart failure (Figure 2). For identifying the underlying cause, many diseases may potentially lead to heart failure, including chronic heart disease, hypertension, valvular disease, and cardiomyopathy, and these can be present in combination. These diseases may affect the heart by causing scarring, fibrosis, and arrhythmia; and again, these effects may be present in combination. The choice of drug therapy must reflect whichever pharmacological effects - whether vasodilating, chronotropic, inotropic, and anti- or pro-arrhythmic - are beneficial (or harmful) in this context. There are also multiple comorbidities that may complicate treatment in the heart failure patient, such as the presence of hypertension, angina, diabetes, renal impairment, dementia, arthritis, gastrointestinal disease, anaemia, and cachexia. The need for polypharmacy and the potential for drug interactions is a further complication in the approach to treatment. It is noteworthy that patients with comorbidities are usually excluded from controlled trials and treatment in these patients may not, therefore, be supported by trial evidence. Left ventricular systolic dysfunction (LVSD) is characterized by a dilated and poorly contracting heart at echocardiography. This is the type of heart failure for which the greatest amount of evidence exists. Optimal management for the patient with LVSD includes a combination of diuretic, ACE inhibitor, and beta-blocker. The benefit of adding further antagonists of the renin-angiotensin system, such as an angiotensin receptor blocker or spironolactone, is an area of controversy, as too is the role of digoxin in LVSD. There is little debate that ACE inhibitors are effective agents in heart failure. There is similarly little debate that angiotensin receptor blockers are an effective alternative to ACE inhibitors when ACE inhibitors cannot be tolerated, as shown for candesartan in CHARM-Alternative8 (Figure 3). Based on these data, candesartan is the only angiotensin receptor blocker licensed for this indication in Europe. The addition of candesartan to the combination of ACE inhibitor, beta-blocker, and diuretic is a further potential step. In CHARM-Added, the addition of candesartan to these medications reduced the rate of cardiovascular death or hospital readmission for chronic heart failure11. In CHARM-Added, however, these benefits of candesartan were accompanied by increased rates of creatinine and potassium elevation. Based on this evidence, the Scottish Intercollegiate Group (SIGN) has recommended that candesartan may be added to an ACE inhibitor and beta-blocker in patients with NYHA II/III, but only with specialist supervision. An older antagonist of the renin-angiotensin system is spironolactone, which is a non-selective aldosterone receptor antagonist. RALES demonstrated that spironolactone had a pronounced effect on all-cause mortality when added to an ACE inhibitor, diuretic, and (in the minority of patients) beta-blocker (14) (Figure 4). Spironolactone showed few complications in RALES, including little effect on serum creatinine. It is, however, important to remember that baseline creatinine levels were low in patients in RALES and the situation in routine clinical practice may differ. SIGN recommends that spironolactone may be added to an ACE inhibitor and beta-blocker in patients with NYHA III/IV, but only with specialist supervision. Combining an ACE inhibitor, angiotensin receptor blocker, and spironolactone in routine care is not recommended by SIGN. Another area of controversy is the management of patients who remain symptomatic when other agents are added or who do not tolerate the addition of antagonists of the renin-angiotensin system. The A-HeFT study of African-Americans showed that addition of isosorbide dinitrate (ISDN; 20 mg tds) and hydralazine (37.5 mg tds) to standard medications caused a marked reduction in all-cause mortality (6.2%, vs 10.2% with placebo; P = 0.02)18. Whether ISDN and hydralazine may offer benefits in patients from different ethnic groups cannot be answered without further trials. However, if a patient is resistant to other treatments or does not tolerate them, this approach may be attempted under close supervision. Another consideration in the treatment cascade is digoxin. In my practice, digoxin is reserved for more severe patients who remain symptomatic after all other treatments are attempted. The DIG study showed that there was no benefit on mortality from digoxin therapy6. It should, however, be remembered that many patients who are candidates for digoxin therapy are elderly. In these patients, an improved quality of life through symptom control, rather than prolongation of survival, may be the primary management consideration. The management of heart failure after acute myocardial infarction (AMI) is another controversial area. In this setting, AMI leads to left ventricular dysfunction and heart failure in the presence of numerous other potential events including re-infarction, arrhythmia, and angina. Cardiac changes post-MI can include stunning, hibernation, and remodeling. Only one trial – CAPRICORN – has assessed the effects of beta-blockers in post-MI patients with significant left ventricular dysfunction or heart failure5. CAPRICORN showed that the addition of carvedilol to ACE inhibitor and thrombolysis reduced the all-cause mortality (Figure 5). The addition of an aldosterone antagonist, eplerenone, was also shown to reduce all-cause mortality in the EPHESUS trial14 (Figure 6). Whether any other beta-blocker would be as effective as carvedilol and whether spironolactone would be as efficacious as eplerenone in post-MI patients remains unknown. However, from my perspective, these controlled trials at least provide a template for treatment. Typically, in the presence of preserved systolic function, the ventricle is hypertrophied and moves stiffly during filling, but the ejection fraction remains normal. An MRI scan may show the reason for the stiffness to be fibrosis of the majority of muscle. Preserved systolic function is relatively common in patients admitted with heart failure. The European Heart Failure Survey identified a range of ejection fractions in admitted patients, with approximately 50% having preserved systolic function2. The survey also found that the prevalence of preserved systolic function in heart failure patients increased with patient age (Figure 7). Whether there are effective treatments for “preserved systolic function heart failure” is uncertain. CHARM-Preserved found that candesartan had little effect compared to placebo on the rate of cardiovascular death or readmission for heart failure20. The PEP-CHF study suggested that perindopril had an early beneficial effect on the composite endpoint of total mortality and hospitalization compared to placebo, but that subsequently the endpoint rates for perindopril and placebo approximated each other4 (Figure 8). As most patients in PEP-CHF received an ACE inhibitor as the study progressed, it is difficult to draw firm conclusions on management from this trial. One interesting observation from the PEP-CHF study, however, was that patients in the highest quartile for brain natriuretic peptide (BNP) had a higher mortality than other groups (Figure 9), suggesting that BNP levels might, in future, be utilized to identify patients who will benefit from ACE inhibitor and angiotensin receptor blocker therapy. The SENIORS trial of beta-blocker therapy in patients aged 70 years or more included a proportion of patients with preserved systolic function7. In this group, nebivolol had a beneficial effect on event-free survival (Figure 10). Nebivolol has properties in addition to beta-blockade, however, and whether other beta-blockers would be as effective in this setting is unclear. It is important to remember that guidelines offer guidance and not instructions or rules. In routine clinical practice, patients frequently fall outside the categories described in guidelines. The COMET trial, at the time it was published, purported to show that carvedilol was more effective than metoprolol based on a mortality reduction over 5 years (16) (Figure 11). This conclusion surprised many observers, as metoprolol has a long and successful history in heart failure. However, a comparison of the effects of different metoprolol preparations on heart rate indicates that a much larger dose of metoprolol is required for the preparation used in COMET compared to the preparation that was used in MERIT-HF10. From this insight, the COMET trial may not have demonstrated that carvedilol is superior to metoprolol, but rather have confirmed the importance of an adequate dose. Which drug should be introduced first, an ACE inhibitor or a beta-blocker? This question has been addressed in a number of trials, including CIBIS III and CARMEN. CIBIS III indicated that the outcome was similar regardless of whether bisoprolol or enalapril was initiated first19 (Figure 12). This finding suggests that a beta-blocker may be introduced first in patients whose characteristics are similar to those in CIBIS III, when an ACE inhibitor may not be wished to be prescribed first. Numerous trials, such as RALES, COPERNICUS, and CARE-HF, have shown the benefits of polypharmacy to reduce mortality in heart failure3,12,13 (Figure 13). There are problems associated with polypharmacy, however, including reduced rates of adherence. Patients in real life are not followed as closely as those in clinical trials and may not take their medications as carefully. Medication non-compliance is possibly the most important cause of decompensation in patients with heart failure, and is associated particularly with a complex drug regimen. It is not always possible for patients with severe heart failure to receive all the drugs that were planned for. It may, for example, be necessary to withdraw a beta-blocker to allow a diuretic to be effective. In other circumstances, it may be necessary to revise the dose of an existing medication to permit the introduction of another. The concurrent use of statins is a potential complication in heart failure treatment. This situation is common, as many patients with chronic heart failure have ischaemic heart disease and are likely to be receiving a statin. Meta-analyses and observational data suggested that statins are beneficial in this setting1 (Figure 14), but this was not confirmed in a randomized controlled trial in more than 5000 patients with heart failure and coronary artery disease9. GISSI-Heart Failure will provide further data on the merits of statins in heart failure and is due to report in the near future: this trial includes patients with ischaemic and non-ischaemic cardiomyopathy17. Even with guidance from guidelines, the treatment of heart failure is complex and calls for close integration of heart failure services. Patients who do not respond as predicted to initial therapy and who may benefit from more advanced treatments should be offered a rapid pathway to specialist assessment and management. Patients with heart failure, unfortunately, remain poorly catered for in current health systems.

There is a pressure on healthcare budgets, which means we cannot do everything that we would like to do within the healthcare system. Pressures on budgets derive from the growing size of the elderly population accompanied by relatively reduced numbers of tax payers, rising expectations among the public such as for local access to specialist facilities, and rising costs of care based on the availability of new treatments and staff salaries. On what basis should care be prioritized in the face of limited resources and rising expectations? One approach is to prioritize care toward the biggest burden to society, based on the cause of most deaths or the biggest cost to the health service. By this criterion, there is a clear-cut argument for the use of resources in cardiology when compared to, for example, dermatology. Even though the burden may be large, a second factor in prioritization is whether there is an impact on outcome from spending these resources. Cardiovascular medicine demonstrates a clear impact on mortality, and trials have more recently begun to focus on the improvements in quality of life. A final issue is to reflect the opinion of the public on the prioritization of resources. Opinions from the public typically reflect the stratum that is asked and may not always be well informed. Politicians also exert a powerful role in prioritization, although they may tend to simplify issues by focusing on single targets such as reduced waiting times for tests or referrals. Quick and cheap but not reliable Quick and reliable but not cheap Cheap and reliable but not quick Free and comprehensive, but it may not be high quality Comprehensive and high quality, but it may not be free Free and high quality, but it may not be comprehensive The dilemma in achieving prioritization is that cost must be one of the factors, but not the dominant factor. As healthcare professionals, how do we include cost without losing the focus on making patients better? We need to find a way to pull costs and effectiveness together into the same framework. Economics, I firmly believe, can assist us in the decision-making process. Evidence-based medicine is based not just on clinical effectiveness but also on cost-effectiveness. As healthcare professionals, it is our responsibility to become involved in, and to inform, that process. However, it is important to remember that economic evaluation aids decision-making, but it cannot replace ethical considerations in individual patients, where expensive resources may be utilized at times for potentially small gains, e.g. patient admitted to intensive care. There is general agreement that the most cost-effective therapy should be applied first, and that further therapies are added to the extent that they produce additional incremental benefit. The least cost-effective therapies are introduced only after cheaper alternatives have been attempted, and if society can afford them. This process is a part of society's choices and reflects the resources that the society has access to. Economics is not the answer on its own. To quote an economist: “Economics does not prescribe how to settle conflicts over resource utilization but may provide a framework for conceptualizing the problems of resource utilization and a set of tools to use in setting priorities”.1 Therefore, the key question that economics should help us to answer is: “Does a therapy improve ‘outcome’ sufficiently to justify the additional cost”? There are very few innovations that do not add to the cost of therapy. When any new intervention is considered, it may be asked where it falls on the curve of additional yield in terms of health outcome versus additional cost (Figure 1). At the low point in the curve there is little expenditure for a large additional health benefit – one example is provision of fresh water. Most interventions are in the middle part of the curve. But some very “high-tech” interventions are at the high point where a large amount of money is spent for relatively little benefit overall. A tool that economists use to quantify health gain is the quality-adjusted life-year (QALY), which is a simple concept to capture changes in quality of life as well as length of life (QOL). An example of how a QALY quantifies health gain is shown in the following example. A patient survives for an additional 3 years following treatment with an existing medicine. The patient's QOL during this period is not perfect, with a score ranging from 0.8 in year 1, to 0.7 in year 2, and to 0.3 in year 3 (where a QOL score of 1 is perfect and 0 is death). The QALY with existing treatment is therefore 0.8 + 0.7 + 0.3 = 1.8. With a new medicine, the patient lives for 5 years instead of 3 years and the QOL is 0.9 in each year. The QALY for the new medicine is therefore 0.9 × 5 = 4.5, representing a gain of 2.7 compared to the existing medicine. The new medicine costs €30 000 compared to €3000 for the old medicine, representing an additional €27 000. Therefore, €27 000 is paid for 2.7 more QALYs, so the added cost per QALY gained is €10 000. This calculation is also called the incremental cost-effectiveness ratio (ICER), and represents an index of value for money that permits comparisons across different diseases and different healthcare systems. How do we interpret the index and what is good value? The UK National Institute for Clinical Excellence (NICE) suggests that it has no threshold of acceptability for ICER, but its decisions over the last few years indicate a cut point at ∼£20 000 per QALY as acceptable. Above this, a medication must be very convincing in terms of clinical effectiveness, such as life-saving. An ICER above £30 000 very rarely receives a NICE recommendation for approval. Where do these cut points come from? The figures are a compromise between the public's desire to have new medicines but a reluctance to pay for them in higher taxes. Some commentators believe that these values are too high for the NHS, although other countries such as the USA, with greater wealth, may be able to afford them. Some examples can be taken from coronary heart disease, starting with the QALY gain of statins in secondary prevention. Figure 2 (left) shows that the QALY gain from statins varies in different age groups and across genders. Are statins cost-effective? Statins prolong life, but the total cost remains high, despite unit costs reducing as statins come ‘off’ patent. NICE appraisal indicated that for secondary prevention, for example after myocardial infarction, statins are quite cost-effective, at £10 000 to £17 000 per QALY. In primary prevention, the cost-effectiveness is quite different, ranging from £20 000 to £57 000 according to age and sex. The higher values - in elderly men or women - are reaching a level where most healthcare providers would not choose to fund statins. A key issue to remember is that in heart failure we have some of the most cost-effective therapies known. Analyses suggest that, in many cases, ACE inhibitors, beta-blockers, and angiotensin receptor blockers are actually cost-saving through prolonging life, improving QOL, and reducing healthcare utilization costs in terms of hospitalization. A proviso with these analyses, however, is that they are based on trials, which tend to be short, use appropriate doses, and include younger patients. No economist in the EU would argue that we should not be using ACE inhibitors, beta-blockers, or angiotensin receptor blockers in heart failure. Use of devices is a more complicated issue and the outcomes of analyses for these therapies are quite different. For devices, as for surgery, much of the cost is borne up front – for the device itself, its implantation, and any early complications. This contrasts with drug therapy, which has similar costs through the duration of treatment. The benefit of device therapy takes some time to become clear and continues for the life of the patient. This is the reason why lifetime economic analyses are required to understand the costs of devices. SCD-HeFT may be taken as an example. SCD-HeFT investigated the prevention of sudden cardiac death in a range of patients with NYHA Class II or III chronic heart failure and an ejection fraction ≤35%, using a median follow-up of 45.5 months. The economics methodology was based on lifetime cost-effectiveness analysis, projecting lifetime costs and life expectancy beyond the duration of the study. Extrapolated data for life expectancy, measured as area under the curve, was 8.41 years for placebo and 10.87 years for ICD. Based on generally accepted assumptions for benefits and costs, analysis indicated a cost of approximately $40 000 per QALY gained (Figure 3).2 This represents a relatively expensive use of resources. Confidence intervals were quite wide and indicated that, in approximately 80% of occasions that these analyses are run, the outcome would fall below a notional cost-effectiveness threshold of $50 000 per LY, and thus be considered good value for money. Therefore, whether ICDs are a good use of money in the healthcare system is a complicated issue. Their cost-effectiveness is similar to that of other interventions, but is orders of magnitude greater than for drug therapy for heart failure. Returning to the earlier recommendation that the least expensive therapy should be used first, drug therapy should therefore be attempted before device technologies are considered. Budgets will be under growing pressure and we have to make tough choices if we want to defend free, high-quality care. Economics offers a way to do this by providing analyses that incorporate cost and patient health. It is imperative that economists and clinicians speak with each other in this process.

As an electrophysiologist, I am referred large numbers of patients with, or at risk of, arrhythmias as part of the heart failure complex. In this review I will concentrate on the role of pacemakers and defibrillators in heart failure, because these are my areas of greatest experience. Left ventricular assist devices and implantable hemodynamic monitors will not be reviewed. The first controversy for discussion is how to assess patients for suitability to receive these devices. Patients with heart failure are frequently fitted into a New York Heart Association (NYHA) class. The NYHA class is, however, a blunt instrument for decision-making that is based on a physician's or nurse's impression of how patients express their symptoms. Two patients with similar levels of symptomatology but with different responses to their symptoms may therefore receive different NYHA classifications and be candidates for different management approaches. Guidelines such as those from the European Society of Cardiology (ESC) offer valuable guidance on the use of cardiac resynchronization therapy (CRT).12 There are, however, issues in the use of CRT which the guidelines do not consider. Controversies that relate particularly to CRT include the identification of which patients benefit most from this technique and the characterization of its role in atrial fibrillation, in patients with bradycardia, and in non-responders. CRT has been available for approximately 10 years. An early meta-analysis of randomized controlled trials of CRT, including CONTAK-CD, InSync ICD, MIRACLE, and MUSTIC, showed that CRT reduced death from progressive heart failure by 51%, reduced heart failure hospitalization by 29%, and showed a trend to reduced all-cause mortality2 (Figures 12–3). Some of these trials included a defibrillator component, which made characterization of the effects of CRT alone problematic. Subsequent to these trials, the CARE-HF study was performed. CARE-HF observed that CRT produced a 37% reduction in all-cause mortality or unplanned hospitalization compared to medical therapy over 4 years (P < 0.0001)5 (Figure 4). All-cause mortality alone was reduced 36% by CRT when compared to optimal medical therapy (P = 0.0019). CARE-HT was the first major trial to demonstrate a definite improvement in all-cause mortality from CRT pacing. The COMPANION study included patients at higher risk than those in CARE-HF and investigated three treatment limbs – optimal pharmacological therapy, biventricular pacing, and biventricular defibrillation.3 COMPANION was not powered to detect a difference in outcome between the two types of biventricular device, but did appear to show that biventricular defibrillation was superior to medical therapy based on the secondary endpoint of all-cause mortality at 12 months (Figure 5). On the basis of these trials, the ESC guidelines recommend that “CRT using biventricular pacemakers can be considered [my italics] in patients with reduced ejection fraction and ventricular asynchrony (QRS width ≥120 ms) who remain symptomatic despite optimal medical therapy (NYHA III/IV) to improve symptoms, hospitalizations, and mortality”.12 From my viewpoint, this statement may require to be updated in the revised ESC guidelines and CRT should be performed much more commonly than presently. National guidelines from the Scottish Intercollegiate Guidelines Network (SIGN), which have been more produced recently (2007) than those from the ESC (2005), make a similar statement – namely, that CRT “should be considered” in patients with characteristics similar to those described in the ESC guidelines. The English National Institute for Clinical Excellence (NICE) Health Technology Appraisal of the place of CRT in heart failure (2007) states that: “CRT with a pacing device (CRT-P) is recommended as a treatment option for patients with heart failure who fulfill the following criteria. They are currently experiencing or have recently experienced NYHA class III-IV symptoms. They are in sinus rhythm either with a QRS duration 150 ms or longer … or with a QRS duration of 120–149 ms and mechanical dyssynchrony. They have a LVEF of 35% or less. They are receiving optimal pharmacological therapy.” The NICE guidelines therefore strongly recommend CRT for a precisely defined group of patients. The NICE guidelines also offer guidance on the use of CRT with a defibrillator (CRT-D). “CRT-D may be considered for people who fulfill the criteria for implantation of a CRT-P device and who separately fulfill the criteria for use of an ICD as recommended in NICE Technology Appraisal Guidance 95.” The latter criteria include wide QRS and poor LV function post-myocardial infarction. There is controversy over whether mechanical dyssynchrony is also required for the selection of patients for CRT. Considerable heterogeneity exists in the echocardiographic criteria adopted to define dyssynchrony, but a few small observational studies suggest that echocardiographic measurement of mechanical dyssynchrony may best identify patients who are likely to benefit from CRT.7 Further work is required in this area. What are the cost implications of using CRT-P and CRT-D? Based on data from the CARE-group using data from COMPANION, the incremental cost-effectiveness of CRT-P versus medical therapy was €7538 per quality-adjusted life-year (QALY), and the incremental cost-effectiveness of CRT-D versus CRT-P was €47 909.13 CRT-P was concluded to be relatively inexpensive, while CRT-D was of borderline cost-effectiveness. The patient's age comes into consideration in deciding who, among eligible patients, should receive CRT-D. In younger patients, CRT-D may be considered affordable in order to keep patients alive for as long as possible. In patients aged above 70 years, by contrast, other factors are more likely to cause death and the cost of CRT-D compared to CRT-P becomes prohibitive. The use of CRT in patients with atrial fibrillation (AF) is a contentious issue. The ESC guidelines do not specify a rhythm, but most other guidelines do specify the presence of sinus rhythm (SR) in their recommendations. Most trials have included only patients in SR, although the MUSTIC study included approximately equal numbers of patients in SR and AF. In MUSTIC, patients in SR improved significantly, whereas those in AF did not.4,8 For patients in SR, activation of the pacemaker was associated with an improvement in 6-min walking distance, which worsened when the device was inactivated. However, it is notable that only 37 of 64 patients in AF completed both limbs of the study. A long-term follow-up of patients in MUSTIC at 9 and 12 months found that all SR patients and 88% of AF patients were programmed to biventricular pacing.9 The two groups experienced similar magnitudes of improvement in walking distance, peak VO2, quality of life, NYHA class, and ejection fraction (Figure 6). Therefore, for every factor measured, AF patients appeared to do as well as SR patients in the long term. MUSTIC and some smaller studies represent the only trial evidence on which to base treatment in patients with AF. This raises the question of whether the potential benefits of CRT should be denied to AF patients in the absence of large-scale randomized studies. Opinions obtained from members of the Heart Rhythm UK suggest that most large centers are implanting CRT devices in a proportion of AF patients. There are two schools of thought on the type of AF patient who may benefit from CRT. In one school, CRT should be offered to the relatively small numbers of patients in whom rigorous rate control can be achieved by medical therapy and, if necessary, ablation of atrioventricular conduction to ensure biventricular pacing all of the time. According to the results of MUSTIC, this group may improve. This is called the “rate control” group. In the second school of thought, patients should be selected in whom stringent efforts will be made to restore and maintain SR. CRT may help by increasing the ejection fraction, lowering mitral regurgitation, and lowering left ventricular pressure. Cardioversion will be easier, and amiodarone and atrial catheter ablation may be added. This is called the “rhythm control” group. It is clear that the rate control group and the rhythm control groups encompass almost all patients with AF who fit CRT criteria. In other words, there is little agreement on which patients not to implant. Another controversial area is that, in every trial, there are patients classified as “non-responders”, who represent approximately 40% of the study population. In a proportion of these cases, however, the CRT device is stabilizing the patient who would otherwise deteriorate. Although the patient may complain of not feeling better, the device may actually be preventing deterioration or death. This situation illustrates the difficulty in measuring response. Other indices may need to be assessed, such brain natriuretic peptide levels, echocardiography/magnetic resonance imaging, and evidence of dyssynchrony, in order to identify patients who will benefit from CRT. CRT-D is an option in younger patients, especially those considered for future transplantation, while CRT-P may be provided in older patients to improve symptoms and reduce hospitalization. CRT-D may be considered in the presence of risk factors for sudden death, such as non-sustained ventricular tachycardia (VT) or T-wave alternans. The role of CRT-D in Class IV heart failure and AF requires clarification. Controversies that relate particularly to the use of implantable cardioverters-defibrillators (ICDs) include the identification of which patients will benefit from an ICD or from a CRT plus an ICD, whether the trial evidence for coronary artery disease can be extrapolated to dilated cardiomyopathy (DCM), and issues of deactivation at end of life. The ESC guidelines state that: “Implantation of an ICD in combination with biventricular pacing can be considered (my italics) in patients who remain symptomatic with severe heart failure (NYHA class III/IV) with LVEF [left ventricular ejection fraction] ≤35% and QRS duration >120 ms to improve morbidity or mortality”. “ICD therapy is recommended (my italics) to improve survival in patients who have survived cardiac arrest or who have sustained VT, which is either poorly tolerated or associated with reduced systolic LV function.” “ICD implantation is reasonable (my italics) in selected symptomatic patients with LVEF <30–35%, not within 40 days of a myocardial infarction, on optimal background therapy … to reduce sudden death.” The largest trial that has provided evidence to substantiate these statements is SCD-HeFT.1 SCD-HeFT randomized 2500 patients with symptomatic heart failure (NYHA II/III) and LVEF <35% to no antiarrhythmic therapy, amiodarone, or ICD with a 5-year follow-up. One half of the patients had an ischaemic etiology and one half had idiopathic DCM. Patients were relatively young (mean 60 years) and a proportion were overweight (mean 85 kg). Background medication use with an ACE inhibitor or angiotensin receptor blocker and beta-blocker was good, with rates approaching 90% and 80%, respectively, and use of spironolactone (31% at last follow-up) was reasonable. Loop diuretics were prescribed in the majority. Annual mortality over 5 years was 7.2% in the placebo group. Amiodarone had no influence on morality (hazard ratio [HR] 1.06. P = 0.529 vs placebo), but ICD significantly reduced the mortality rate (HR 0.77, P = 0.007 vs placebo) (Figure 7). Analysis of subgroups showed that the HR of mortality for ICD versus placebo was 0.54 in patients with NYHA II and 1.16 in those with NYHA class III, indicating that patients with Class II heart failure benefited while those with Class III tended to fare worse. Patients with an ischaemic or non-ischaemic etiology had HRs of 0.79 and 0.73, respectively, suggesting equal benefit from ICD. Further subgroup analyses indicated that patients with a low EF (≤30%) had the most to gain (HR 0.73, vs 1.08 for those with an EF >30%), as did those on beta-blocker therapy (HR 0.68, vs 0.92 for those not on beta-blocker therapy), which emphasizes that ICD therapy is not a substitute for good medical therapy. There have been problems in interpreting the outcomes of studies such as SCD-HeFT and MADIT-II.10 The reliance on subgroup analyses in these trials has reduced the power of these studies. Inaccuracies in measurement utilizing LVEF cutoff values and NYHA class has further hampered interpretation, and the relationship between the severity of the condition and the magnitude of improvement requires clarification. No “evidence base” exists on which to guide practice at end of life. Discussing these issues with the patient and relatives is difficult, but needs to be done openly and with sensitivity if any crisis or deterioration develops. Booklets and websites are a valuable source of information that patients can choose to look at, and base decisions on, at their own pace. In the UK, information for patients on websites is available from the British Heart Foundation (www.bhf.org) and the Arrhythmia Alliance (www.arrhythmiaalliance.org.uk). Primary prevention ICDs may be considered in stable heart failure patients who are already receiving optimal medical therapy. ICD should not be considered as a substitute for medical therapy. Ischaemic and non-ischaemic patients benefit equally from ICD, and the worse the LV function, the greater is the benefit. ICD may be considered as a bridge to transplant or, alternatively, as a means to keep the patient away from transplant.

The syndrome of chronic heart failure consists of two main components – cardiac dysfunction and its related symptoms. In every patient, the severity of the syndrome reflects the course of these two components. Establish that the patient has heart failure Identify presenting symptom(s) Assess the severity of limitation Determine the etiology Exclude or confirm concomitant disease Predict the prognosis Choose the therapy Monitor progress Choosing and tailoring therapy for the individual patient is based primarily on changes in symptoms. A number of factors may influence symptom response and these form the focus for this review: adherence, comorbidities, and renal function. Key issues in the appropriate tailoring of therapy are also discussed. Adherence to treatment is an important issue in cardiology, and particularly in heart failure, where patients are likely to require a combination of treatments. The importance of adherence to treatment was demonstrated in CHARM, the largest randomized trial of heart failure to be performed to date5. In the placebo arm of CHARM (n = 3774), patients who adhered to therapy at a rate ≤80% were at significantly increased risk of death (P < 0.001) (Figure 1). The explanation of these findings is that patients who adhered poorly to placebo (and, probably to their other, life-saving medications) were at increased risk of death. Comorbidities may have a substantial impact on the prognosis of heart failure. The following discussion focuses on three significant comorbidities: diabetes, depression, and anemia. An analysis of the impact of comorbidities in CHARM identified diabetes as a strong, independent prognostic risk factor for all-cause mortality, which ranked second in impact only to age, and above myocardial systolic function (Figure 2)11. Diabetes clearly requires to be managed carefully following its diagnosis in patients with heart failure. Depression is increasingly recognized as an important comorbidity in heart failure that impacts on prognosis independently of other factors such as the patient's age and the severity or etiology of heart failure. A meta-analysis of seven studies that investigated the impact of depressive symptoms on mortality in heart failure identified a twofold elevated risk of short- to medium-term mortality for patients who had depressive symptoms (odds ratio 2.24; range 1.39–3.60)2. Why depression should increase the risk of mortality in heart failure remains to be elucidated. There may be a number of mechanisms. Depression may, for instance, decrease adherence to changes in lifestyle, increase the number of risk factors for heart failure, increase the risk of arrhythmias/sudden cardiac death, alter inflammatory markers, increase platelet aggregation, and increase coronary blood flow through increased stress4. Depression is a common finding in patients with chronic heart failure, at a frequency of 13.9% for major depressive episodes and 21% for mild or subclinical depression1. Screening for depression is straightforward and can be performed based on two simple questions: “Have you lost interest in pleasurable activities” and “Are you feeling blue or down”? A positive answer to these questions will identify patients in need of further investigation. The impact of depression on heart failure will likely be investigated widely in the next few years. These investigations may extend to include the impact of interventions for depression, for which there is little evidence currently. Anaemia is an independent predictor of increased mortality in chronic heart failure, as shown recently in a meta-analysis of seven studies13. By this analysis, the risk of death increased as the haemoglobin concentration decreased. 13 also observed that an elevated risk of anemia in patients with chronic heart failure is associated with a number of clinical characteristics. These characteristics include advanced age, female gender, chronic renal disease, heart failure severity, acute (as compared to chronic) settings, other comorbidities, decreased body mass index, and the use of ACE inhibitor therapy. The appropriate management of anaemia in chronic heart failure remains unclear. Experience of anaemia in chronic renal disease suggests that to elevate haemoglobin levels too greatly increases the risk of mortality. An ongoing trial – RED-HF – is investigating the management of anemia in chronic heart failure and, it is hoped, will offer guidance on therapy. Renal function and cardiac function are interrelated via the cardiorenal axis, and dysfunction in one system may lead to deterioration in the other. The influence of renal dysfunction on heart function is exemplified by data from CONSENSUS, which was the first trial to show that ACE inhibitors improve survival in heart failure3. An analysis of the effects of enalapril on mortality in CONSENSUS showed that benefits of treatment were predominantly in patients with a baseline creatinine level above 120 µmol/l, i.e. those patients at greatest risk of developing renal dysfunction (Figure 3). The impact of renal dysfunction was also investigated in CHARM, a study in which a large proportion of patients had a baseline glomerular filtration rate (GFR) <60 ml/min/1.73 m2,6. Patient outcome, measured in terms of cardiovascular death or rehospitalization due to heart failure, was significantly related to the degree of baseline renal dysfunction (Figure 4). The influence on outcome of a GFR at 35 ml/min/1.73 m2 was similar in magnitude to that of a left ventricular ejection fraction of 20%. GFR and New York Heart Association (NYHA) class act together to increase risk of mortality, so that patients with a high NYHA class and a low GFR require strenuous efforts to improve their prognosis7. Therapy may need to be adjusted if there is deterioration in cardiac function or in symptoms. Options to adjust therapy to successfully reverse the patient's deterioration include changing the agent administered, amending the dose of the agent given, and introducing a combination of agents. As the ESC guidelines point out, choosing an appropriate combination of agents is the key to successful therapy for many patients. It is recommended that almost all patients, regardless of their NYHA class, should receive a combination of an ACE inhibitor and a beta-blocker. Patients may additionally, according to their individual clinical circumstances, receive an angiotensin receptor blocker or an aldosterone antagonist (Figure 5). Complementing these approaches for improved survival, the components of diuretic therapy may be modified to improve symptom control. The beta-blockers were, until relatively recently, contraindicated for the treatment of chronic heart failure because of their potential for adverse affects. These deleterious effects included hypotension, hypoperfusion, increased fluid retention, atrioventricular block, and (in the longer term) increased symptoms of heart failure. Now it is well established that beta-blockers are among the most effective agents available for the treatment of chronic heart failure9. Beta-blockers, together with ACE inhibitors, are indicated in the first-line treatment of potentially all patients with stable mild or moderate heart failure. Providing appropriate cautions are taken or specialist advice is sought, the use of beta-blockers may be attempted in all patients, with the sole exception of those with bronchial asthma. The beta-blockers recommended in the ESC guidelines are limited to those agents for which well-documented evidence is available, and the guidelines include specifications on the target dose (Figure 6). Clinical trials suggest that the target dose for a beta-blocker may be achieved in as many as two thirds of patients. It is likely that the target dose is reached in a lower proportion of patients in routine care because dose escalation is halted early. Although this is less than optimal, it is better to administer some beta-blocker therapy than none at all. Monitoring during beta-blocker dose escalation must include the patent's heart rate, blood pressure, and clinical status (in particular, for signs of congestion and change in body weight). A specialist heart failure nurse in a nurse-led outpatient clinic can offer valuable assistance in a number of roles including patient education, follow-up, and dose titration. A continued deterioration in the patient's symptoms may require adjustment to therapy. For instance, if congestion is increasing, the diuretic dose may be doubled and, if that measure alone is not successful, the beta-blocker dose may be halved. In a patient with marked fatigue and / or bradycardia, the beta-blocker dose may be halved, followed by review at 1–2 weeks; specialist advice should then be sought, if required. A serious deterioration in symptoms may similarly indicate a halving in the beta-blocker dose and the need for specialist advice. No change in beta-blocker therapy is usually required for patients with asymptomatic low blood pressure. For patients with symptomatic hypotension in the presence of dizziness, light-headedness, and / or confusion, supplemental therapy with nitrates, calcium channel blockers, or other vasodilators may be considered. In the absence of signs or symptoms of congestion, the diuretic dose may also be reduced. Specialist advice is recommended if these measures do not resolve the symptoms. A frequently asked question is how should beta-blockers be combined with ACE inhibitors in patients with low blood pressure, which is a particular problem in advanced heart failure. For these patients, the ACE inhibitor should usually be initiated and optimally titrated before the beta-blocker is added. An earlier initiation of beta-blocker therapy may be considered for some patients, however, including those who remain tachycardic. Patients with dilated cardiomyopathy, in particular, may show a dramatic response to beta-blocker therapy in these circumstances. Beta-blockers should never be stopped suddenly, unless absolutely necessary, because of the risk of a rebound in myocardial ischaemia/infarction and arrhythmias. Ideally, specialist advice should be sought before beta-blocker therapy is discontinued. ACE inhibitors have a well-known mechanism of action (Figure 7) and well-established efficacy in heart failure, and these agents will not be considered in detail here. Despite the benefits of ACE inhibitor therapy in terms of short-term mortality, there remains an enormous unmet need. This is exemplified in the CONSENSUS trial, which found that, by 5 years, almost all the patients in the trial had died12. A practical approach to meeting the unmet needs of a patient who is receiving combined ACE inhibitor and beta-blocker therapy is to consider which additional agent to add. The options include a therapy that targets the ATII receptor or one that targets other effects of angiotensin II, such as production of aldosterone. The effects of adding an angiotensin receptor blocker were investigated in CHARM. In this placebo-controlled trial, candesartan added to beta-blocker therapy (with background ACE inhibitor therapy in 60% of patients) reduced the one-year mortality by 33% (P < 0.001) compared to placebo added to background therapy14. Candesartan additionally reduced morbidity, measured as rehospitalization for worsening heart failure (hazard ratio 0.80, P < 0.001). The second option, of adding an aldosterone antagonist, was investigated in RALES10. This trial demonstrated that spironolactone improved survival over 3 years compared to placebo in symptomatic patients with systolic dysfunction. Of note, only 10% of patients in RALES were receiving background beta-blocker therapy. There are no trials that directly compare the benefits of an angiotensin receptor blocker and an aldosterone antagonist when added to existing therapy. However, analyses of the effects of candesartan and spironolactone in NYHA III/IV patients in CHARM and RALES indicate that these two therapies offer similar benefits on mortality, with hazard ratios of 0.70 and 0.79, respectively, compared to placebo (Figure 8). To summarize this section, patients who remain symptomatic during treatment with an ACE inhibitor and a beta-blocker should additionally receive either an angiotensin receptor blocker or an aldosterone antagonist, followed by close monitoring of the response. A practical approach to combination therapy with these agents, based on the trial evidence available, is provided in Figure 98. Comorbidities have a substantial impact on the prognosis of patients with chronic heart failure and assessments should include indications for diabetes, depression, and anemia. Renal dysfunction is additionally important because of its potential to interact with heart disease. In patients who deteriorate during therapy, a structured approach to optimizing therapy is recommended. This typically comprises tailoring patients' therapy with a combination of additional agents.

The aim of this review is to discuss the delivery of heart failure care and how to join up the sectors of care through which the heart failure patient passes. I will start with an illustration of how heart failure care is delivered in the UK. Here, there are many approaches, ranging from virtually no organized care through to very intensive care. In terms of diagnosis, there are a number of models. General practitioners (GPs) can refer a patient with suspected heart failure to a cardiologist, an internal medicine specialist, or a geriatrician. Alternatively, if the GP is a specialist in cardiovascular medicine, he or she may make the diagnosis. GPs can use open-access echocardiography services, when patients bring a report back to the GP to interpret, and approximately 20–30% of GPs also have access to B-type natriuretic peptide (BNP) assessment. Some GP practices additionally employ heart failure specialist nurses. There is similar diversity elsewhere in Europe. The follow-up of patients is also very variable. Sometimes all follow-up is in primary care or all in secondary care. If the latter, the number of species of doctors involved can include heart failure specialists, cardiologists, internal medicine specialists, and geriatricians, with or without nurses. The time is now right to consider how heart failure care is delivered and how this may be improved. These considerations come far down the line in the evolution of heart failure care. It is 20 years since the publication of the CONSENSUS study on enalapril, while the first heart failure guidelines were published in 1995.1 Despite these guidelines, registry data show that the uptake of recommended medications in the community remains low, and morbidity and mortality remain high. As described elsewhere in this supplement, the management of heart failure is becoming increasingly complex. Heart failure is difficult to diagnose, etiologies are diverse, comorbidities are frequent, and the list of drugs and devices continues to grow. In this midst of this complexity is the typical heart failure patient, described as the “poly-patient”. This is not the patient included in clinical trials. The typical patient has a mean age of 76 years, with “poly-comorbidities” (such as COPD and worsening renal function), polypharmacy, and “poly-side effects”. The patient sees poly-doctors at poly-clinics with poly-blood tests. Not surprisingly, this has led to a very confused patient. A paradigm shift has occurred in the management of heart failure toward multiprofessional or multidisciplinary care. A single piece of evidence can be selected to show the benefits of this approach. An early study by Rich et al in 1995 randomized elderly patients (>70 years) with at least 4 admissions in the past year to a nurse-directed multidisciplinary service that included education, dietary advice, inhospital cardiologist review, home visits, and telephone contact. Compared to control care, this multidisciplinary approach reduced all-cause hospitalization and heart failure admissions (Figure 1). A number of similar studies have been performed since that by Rich et al, including many in Europe. An analysis of 29 randomized controlled trials of managed care in heart failure shows a consistent message of reduced mortality and heart failure hospitalizations2 (Figure 2). The guidelines have incorporated this evidence and most recommend structured multidisciplinary heart failure care as a Class 1A recommendation. Availability of specially trained heart failure nurses Education of patients on heart failure, including precipitating factors, dietary advice, and the need for compliance. Access to clinicians trained in heart failure, mainly cardiologists but also internal medicine specialists and geriatricians with a special interest Key personnel Agreed local guidelines Key diagnostic services Robust follow-up arrangements For specialist heart failure nurses, the suggested minimum number is one per 100 000 population. Nurses can function in a number of ways and their optimal role is when based in the acute setting, with access to a cardiologist. There, they function in and between primary and secondary care, with a principal focus on patient education and optimization of medication. The BSH does not suggest that new guidelines should be developed, but recommends that existing guidelines, such as produced by the European Society of Cardiology, are adapted to the local health care situation. Another key component to put in place is the heart failure clinic. Patients admitted to hospital frequently receive a rapid and accurate diagnosis, but subsequently experience delays with outpatient referrals. A heart failure clinic that is established with the appropriate professionals and tests in place allows patients to move through the process more seamlessly. The heart failure clinic has the additional benefit of providing a supporting role for the professionals who operate within it, including their supervision and training, while it facilitates better management of nurse time by encouraging patient attendance in place of home visits. When setting up a heart failure service, guidelines should include the elements that are needed for an outpatient diagnosis of heart failure. The BSH has suggested that for optimal diagnosis, in addition to routine haematology, biochemistry, and ECG services, BNP testing should be available to all GPs. Good links with an echocardiography service are also required to ensure that high-quality and appropriate cardiac dysfunction tests are available to patients on the same day. Future needs may include the provision of access to cardiac magnetic resonance imaging. In terms of therapeutic services, the guidelines should describe which drugs and devices to give. If devices cannot be delivered on site, referral pathways and strategies should be put in place so that patients can be sent to the appropriate center. The same applies to rarer therapies such as transplantation. Importantly, good links must also be developed with palliative care and similarly with good cardiac rehabilitation. The prototype heart failure program described for the UK is aspirational. Approximately 20–30% of the UK is now covered by heart failure management programs and it is hoped that these will be rolled out further. These programs are a good way forward to ensure that patients receive the medications and devices that represent the optimal therapy.