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Clinical trials in ahf


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Clinical trials in ahf

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Clinical trials in ahf

  1. 1. POSITION STATEMENT Clinical trials in acute heart failure: simpler solutions to complex problems. Consensus document arising from a European Society of Cardiology cardiovascular round-table think tank on acute heart failure, 12 May 2009† Theresa A. McDonagh1*, Michel Komajda2, Aldo P. Maggioni3, Faiez Zannad4, Mihai Gheorghiade5, Marco Metra6, and Henry J. Dargie7 1 Cardiology Department, King’s College Hospital, Denmark Hill, London SE5 9RS, UK; 2 CHU Pitie´-Salpeˆtrie`re, Institut de Cardiologie, Paris, France; 3 ANMCO Research Center, Florence, Italy; 4 Department of Cardiology, Nancy University, Nancy, France; 5 Center for Cardiovascular Innovation, Northwestern University Chicago, IL, USA; 6 Section of Cardiovascular Diseases, University of Brescia, Italy; and 7 Western Infirmary, Glasgow, UK Received 30 January 2011; revised 30 June 2011; accepted 8 July 2011; online publish-ahead-of-print 29 September 2011 This European consensus document aims to identify the main reasons for the apparent lack of progress in the introduction of new medicines for acute heart failure. Relevant issues include not only the heterogeneity of the patient group but also the pharmacology of the medicines themselves and the design of the trials. Above all, this document attempts to provide some pragmatic solutions to this complex syndrome to simplify the execution of meaningful therapeutic endeavours in this area of undoubted unmet clinical need in the future. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Acute heart failure † Clinical trials Introduction Acute heart failure (AHF), often defined as the rapid onset of symptoms and/or signs of heart failure, occurring for the first time (de novo) or recurring in a patient with known heart failure (acute decompensated chronic heart failure) continues to be a serious public health problem in both Europe and the USA.1,2 Within the European Union during 2010, there were 15 million patients with heart failure, we can expect there to be 3.6 million emergency admissions to hospital for AHF of which the substantial majority will be for worsening symptoms of chronic heart failure (CHF).2 The in-hospital mortality rate in Europe, according to the EuroHeart Failure Study, is 8.1% for de novo heart failure, 9.1% for those presenting with pulmonary oedema, and 40% for cardiogenic shock3 (Figure 1). A more recent pilot study showed some improvements, quoting a 5.6% mortality rate for pulmonary oedema and 22% for cardiogenic shock.4 However, the combined event rate for death or rehospitalization after an admission with AHF at about 50% at 6 months.5 –8 It has become fashionable when reviewing the treatment of AHF, to lament the disappointing lack of progress compared with CHF. In clinical trials, the annualized mortality in patients with CHF has fallen remarkably from 50% in the placebo arm of CONSENSUS to 10% in the treatment arm of CARE-HF follow- ing the sequential addition to baseline diuretics, of angiotensin- converting enzyme inhibitors (ACEI), beta-blockers, aldosterone and angiotensin receptor blockers, and cardiac resynchronization therapy.9– 11 In clinical trials of AHF, however, there has been no such cause for celebration. Indeed, there is yet to be published a single trial in which unequivocal benefit can be reasonably claimed for any of the several putative candidate therapies which have been proposed for its treatment. Similarly, our therapeutic armamentarium for AHF has not progressed in this time, consisting of diuretics, vasodilators, and inotropes. Underpinning the impression of lack of progress is a large number of ‘failed clinical trials’ of new drugs which have resulted in a sense of futility in the scientific community for advancing new developments in this area12 –18 (Table 1). † Other members of the think tank are listed in the Appendix. * Corresponding author. Tel: +44 203 299 4257, Fax: +44 207 351 8634, Email: Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: European Journal of Heart Failure (2011) 13, 1253–1260 doi:10.1093/eurjhf/hfr126 atEuropeanSocietyofCardiologyonNovember6,2013,2013,2013,2013,2013,2013,2013,2013
  2. 2. This document aims to identify the main reasons for the appar- ent lack of progress in the introduction of new medicines for AHF. Relevant issues include not only the heterogeneity of the patient group but also the pharmacology of the medicines themselves and the design of the trials. Above all, this paper attempts to provide some pragmatic solutions to this complex syndrome to simplify the execution of meaningful therapeutic endeavours in this area of undoubted unmet clinical need in the future. ‘Seeing the trees from the wood’ Patient selection A fundamental problem in performing AHF trials is the hetero- geneous nature of the patients presenting with AHF. The latest European Society of Cardiology (ESC) Guidelines categorize AHF into six different clinical presentations, which also have con- siderable overlap2 (Figure 2). Clearly, AHF is not a distinct diagnosis but rather a collection of syndromes with different causes and varying clinical features which fall under the heart failure umbrella and require urgent medical intervention. Treating these AHF syn- dromes as a single entity and attempting to evaluate the benefits of a single new agent would appear to be futile. Moreover, patients with certain clinical presentations, especially those with ‘de novo’ heart failure, are more difficult to study in clinical trials. First, a diag- nosis of the underlying cause of the clinical presentation is required. Second, due to the potential instability of the underlying disease processes involved such as acute valve malfunction or acute myocardial diseases such as myocarditis, baseline stability of clinical, or haemodynamic status cannot be assumed or even expected. For these reasons clinical trials in AHF have been confined mainly to patients with acutely decompensated CHF. However, even within this group there is a large amount of hetero- geneity within the trials, even when they have tested similar groups of AHF drugs. (Table 1) The one important exception to this are the heart failure trials in acute myocardial infarction (AMI), in ................................................................................ Table 1 Drug failures in acute heart failure Trial name Drug tested Patients enrolled VMAC Nesiritide Decompensated CHF Excluded SBP , 90 mmHg Mean SBP . 124 mmHg No LVEF cut point OPTIME Milrinone Decompensated systolic heart failure, not requiring inotropes Excluded SBP , 80 mmHg Mean SBP ¼ 120 mmHg Mean LVEF ¼ 23% VERITAS Tezosentan Acute heart failure Two out of four- BNP, pulmonary oedema, CXR congestion, LVEF , 40% Mean LVEF ¼ 20% in VERITAS I and 28% in VERITAS II Mean SBP ¼ 131 in VERITAS I and 132 in VERITAS II SURVIVE Levosimendan Acute decompensated HF requiring inotropes LVEF , 30% Mean LVEF ¼ 24$ Mean SBP-116 mmHg REVIVE -2 Levosimendan Acute decompensated HF Symptomatic despite i.v. diuretic LVEF , 35% Excluded SBP , 90 mmHg EVEREST Tolvaptan Hospitalized for decompensated CHF LVEF ≤ 40% Excluded SBP , 120 mmHg Mean LVEF ¼ 27.5% Mean SBP ¼ 120 mmHg PROTECT I and II Rolofylline Acute heart failure Impaired renal function BNP ASCEND-HF Nesiritide Acute decompensated heart failure Recent drug trials in acute heart failure showing the heterogeneity of patients recruited. LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; BNP, B-type natriuretic peptide; CXR, chest X-ray; CHF, chronic heart failure. Figure 2 The heterogeneity of acute heart failure syndromes according to the recent European Society of Cardiology Guidelines. Figure 1 Mortality of acute heart failure syndromes. In-hospital mortality in EuroHeart Failure Survey II by history of heart failure and clinical class. EHFS II, EuroHeart Failure Survey II. T.A. McDonagh et al.1254
  3. 3. which ACEI and beta-blockers have been successfully evaluated with positive results.19,20 What can we learn from the success stories in cardiovascular therapeutics in the two major disease areas where there has been spectacular success, CHF and AMI? The advances in myocar- dial infarction (MI) care have been achieved by studying distinct clinical presentations of the pathology, ST Segment Elevation MI (STEMI) and Non-ST Elevation MI (NSTEMI). Similarly, the achievements in CHF therapeutics have stemmed from investigation of a specific subgroup of patients, i.e. those with left ventricular systolic dysfunction (LVSD). The differences are, however, fairly major since AMI has a precise mechanistic cause which is plaque rupture leading to occlu- sive or non-occlusive thrombus formation and the typical clinical and electrocardiographic signs of STEMI or NSTEMI. The treat- ment for STEMI is to reperfuse the artery either by the use of lysis or more recently by percutaneous coronary intervention. For NSTEMI the aim is to prevent total or subtotal occlusion by using anti-thrombotic therapy. No such simple approach works for AHF as the causes are more diverse and, in some cases, not specifically cardiac since they include lack of adherence to proven21 heart failure medicines and lifestyle advice together with intercurrent chest or other infec- tions or anaemia, and other precipitating factors.3,6 They also include situations not remediable by conventional medical treat- ments, such as acute mechanical problems including valve incom- petence, cardiac tamponade, or even ruptured papillary muscles. As in CHF, most AHF trials have been performed in patients with LVSD. Thus, a potential problem may be that many patients in AHF trials are already on standard therapy for LVSD and, as with CHF trials, we are therefore treating an already-well-treated group of patients whose baseline medications have been shown to markedly reduce symptoms and improve outcomes.13 It is possible to simplify this crucial step of more accurate patient characterization. There are three main areas to be considered namely the clinical presentation, the underlying cardiac phenotype, and finally the underlying aetiology of the AHF episode. Ideally, these three areas should be clearly defined before randomization to a new therapy. An obvious example is the patient presenting with pulmonary oedema associated with LVSD due to ischaemic heart disease who might benefit from a very different type of medi- cine than one presenting with pulmonary oedema associated with preserved systolic function and left ventricular (LV) hypertrophy due to hypertension. For the two main types of presentation, breathlessness and oedema, simple diuretic therapy, especially when given intrave- nously (i.v.), is very effective in relieving symptoms rapidly. However, we do not know what impact this has on short-, medium- or long-term outcome. Clinical presentation Acute heart failure occurs most frequently as an acute decompen- sation of CHF, while in about one-third of patients it presents ‘de novo’. Both of these may present as one of the recognized ‘AHF syndromes’ which include pulmonary oedema, cardiogenic shock, and severe peripheral oedema.22 This characterization of the mode of presentation is important as it links the pathophysiology to the pharmacology of potential new therapeutic agents.23 It is also crucial to categorize patients according to some simple clinical biometrics because clinicians in the AHF setting must initiate treatment as quickly as possible while identifying suitability for entry into a clinical trial. The most important variables are heart rate, systolic blood pressure (which can be low, normal, or high), and the presence or absence of renal impairment.24,25 The latter has become simpler due to the adoption of the National Kidney Foundation Classification, where simple clinical formulae such as the modification of diet in renal disease (MDRD, which has been validated in heart failure) can be used to calculate the estimated glomerular filtration rate (eGFR).26 For the future we will undoubtedly need to consider biomarkers to classify the AHF population further. Many new candidates will emerge but at the present time we should have a measure of B-type natriuretic peptide, a raised plasma concentration of which confirms that the patients are very likely to have cardiac dysfunction underlying their symptoms while excluding those with normal levels who are extremely unlikely to have heart failure.27,28 Similarly, the measurement of troponin at baseline will also be useful, not only to help define those presenting with overt myocardial ischaemia and heart failure but as a baseline for future monitoring of myocardial injury.29 – 31 Cardiac phenotype It is of paramount importance to classify AHF patients according to the type of cardiac dysfunction underlying the presentation. At present, patients should be divided into those predominantly with LVSD and those whose heart failure occurs in the presence of preserved left ventricular ejection fraction. Of note, for the latter group of patients there must be some evidence of cardiac dysfunction before the heart failure diagnosis can be made, the most useful indicators being the presence of a large left atrial size/volume or the presence of LV hypertrophy32 as well as trans- mitral Doppler flow indices suggestive of increased pulmonary pressure. Cardiac pathology Finally, it is mandatory to match the patient subgroups according to the underlying cardiac pathology which has caused the cardiac dysfunction. Of particular relevance is ischaemic heart disease, by far the most common cause of heart failure.33 Thus, patients should be categorized at presentation into those with heart failure due to ischaemic heart disease stratified as acute MI or chronic coronary artery disease (CAD); and those whose heart failure is non-ischaemic the most common causes being hyperten- sion, arrhythmias, and dilated cardiomyopathy. Using this simple classification it is easier to envisage a clinical trial population at which a specific drug can be targeted, e.g. patients in known CHF presenting with pulmonary oedema, with a low blood pressure, evidence of renal impairment, systolic dysfunction, and known ischaemic heart disease represent a very different group to those presenting de novo, in cardiogenic shock with systolic dysfunction and acute MI or those with flash pulmon- ary oedema in the context of uncontrolled hypertension. Clinical trials in AHF 1255
  4. 4. ‘Horses for courses’ Matching drugs to subpopulations After patients have been appropriately characterized, specific novel therapies can be usefully targeted. Of the novel therapies currently being studied or those in the pipeline, we can divide the drugs broadly into five groups which have obvious clinical targets (Table 2). These are: vasodilator agents (for use in those with normal or high systolic blood pressure), inotropes (for those in cardiogenic shock or pulmonary oedema/fluid retention, and low blood pressure), renal preser- vation agents (for those with worsening renal function), diuretics (for patients with fluid overload), and myocardial protection agents (for those with CAD or ongoing ischaemia). Novel vasodilator drugs currently being studied include cinaciguat and relaxin.34,35 However, some new drugs have more than one mode of action, for example, chimeric natriuretic peptides such as CD-NP have both venodilatory and natriuretic effects.36,37 Similarly, some novel inotropes also have other properties. Istaroxime is a Na-K/ATPase inhibitor which increases SERCA 2a activity and is both inotropic and lusitropic38 and the cardiac myosin activators, while being thought of as inotropes actually prolong stroke volume by an improved energy efficiency of the contractile apparatus rather than increasing dP/dt and increasing myocardial oxygen demand like conventional inotropes.17 Urocortins also exhibit powerful inotropic and lusitropic effects.39 Novel myocardial pro- tection agents include adenosine regulators such as acadesine, which has anti-ischaemic effects and ameliorates glucose uptake and free fatty acid oxidation hence increasing ATP synthesis.40 Novel classes of drugs which are in the advanced stages of development in CHF may also have a role in AHF, e.g. direct renin inhibitors,41 macronutrients such as omega-3 fatty acids,42 and micronutrients such as thiamine, amino acids, L-carnitine, and coenzymeQ10.43 It is also important to consider device therapies here. In particu- lar, ultrafiltration devices for those with fluid overload and renal impairment, mechanical assist devices for cardiogenic shock and conventional heart failure devices, cardiac resynchronization therapy, and defibrillators, the latter of which are as yet untested in the acute setting.44 –46 Careful matching of drugs and devices is needed not just with regard to the subgroup being studied but also bearing in mind the mechanism of action of the drug. Specific mechanistic targets should be addressed in defined patient subgroups. For this area to be addressed more satisfactorily we need to know much more about the underlying pathophysiology of AHF syndromes. It is insufficient just to know that the condition has high short-term mortality—it is much more important to know when and how people are dying with AHF to meaningfully target new drug/device therapies. Future studies should also focus on aspects of care which may be unrelated to specific agents being given in AHF studies, e.g. the attention to detail in pre-discharge care such as electrolyte balance, optimization of CHF treatment, and stability prior to discharge, which can also impact on short- and long-term outcomes. ‘Turning tribulations into trials’ Clinical trials in acute heart failure After careful consideration of the patient subgroups and the drug mechanisms, we need to give some attention to the design of AHF trials themselves. Timing of interventions is also important, as an intervention given very early in the presentation may have a very different effect to the same intervention given later—an obvious lesson from AMI reperfusion studies.47,48 We have to consider three important areas namely, design, size, and endpoints. Trial design This will depend greatly on the stage of investigation of the agent in question which is conventionally divided into three phases. In Phases 1 and 2 the new agent is being characterized in terms of its pharmacodynamic and pharmacokinetic characteristics while in Phase 3, the definitive trials of efficacy and safety, are often much larger. Of late, these trials have become very large, expens- ive, and time consuming leading to delays in reaching patient care and with a high price of the new drugs for the health systems of even economically well-developed countries to sustain. A detailed account of clinical trial design is beyond the scope of this paper but general principles can be summarized. The first consideration in conducting AHF trials is whether to use a placebo or an active control. This is a key issue as many trials to date have been conducted using a comparator of ‘standard usual care’ which has been ill-defined, is often non-evidence based, and is therefore subject to extreme variation especially in large multicentre and multinational trials.49 (1) We recommend an active comparator if the new medicinal product belongs to an existing therapeutic class, for example: (a) New vasodilator: nitroglycerine. (b) New diuretic: furosemide/other ‘loop’ diuretic. (c) New inotrope: dobutamine. (2) For new classes of drugs (e.g. congestion management, vaso- pressin inhibitors, relaxin, etc.), the study treatment should be tested against placebo as add-on to the existing therapies ................................................................................ Table 2 Some new therapeutic agents for acute heart failure and their potential targets Agent For patients with these clinical features Diuretics, vasopressin antagonists, adenosine antagonists Patients with signs of fluid overload, high BNP Vasodilators Normal to high SBP, high BNP Inotropes Low SBP, signs of hypoperfusion Renal preservation agents Renal dysfunction Myocardial protection agents CAD, or ongoing ischaemia BNP, B-type natriuretic peptide; SBP, systolic blood pressure; CAD, coronary artery disease. T.A. McDonagh et al.1256
  5. 5. as there are no reliable comparators. It is extremely important here to define standard existing practice and background medical therapy in trials of decompensated CHF.50 (3) If the purpose of the trial is an improvement in outcome, then there are no reliable comparators (no evidence-based treat- ments have been shown to improve patient outcomes in AHF), a placebo group should be used as the comparator. Size matters (1) For superiority trials with morbidity and mortality endpoints, the usual methods for calculating sample size should be followed. (2) For defining the absence of a detrimental effect in trials with signs and/or symptoms as the primary endpoint, a non- inferiority approach vs. placebo (e.g. EVEREST) should be used; the boundary margins should be fixed depending on the type of drug and the patient profile.49 In such cases, the effect on symptoms and signs should be clearly demonstrable especially for regulatory purposes. Endpoints Selection of endpoints in AHF trials is challenging. No single endpoint can be uniformly applied to trials across such a hetero- geneous syndrome. Mortality trials have been the benchmark in CHF; however, there is underlying doubt as to whether applying this approach in AHF trials is appropriate. The fundamental question is whether it is possible to improve post-discharge long-term mor- tality or indeed morbidity with a drug that is given i.v. for only a few hours or days in hospital? Because of this unanswered concern, it is not current thinking that a trial in AHF can be conducted with mortality as the sole primary endpoint, because unlike in AMI, in AHF we have no specific pathophysiological target. Theoretically, this could be poss- ible in the future if a specific pathophysiological target could be identified. Current thinking in the testing of AHF drugs is that they should improve symptoms without increasing mortality.49 Against this background, composite mortality/morbidity end- points have to be employed based on combinations of mortality and readmission to hospital for heart failure or days alive and out of hospital with heart failure. Composite endpoints including morbidity and mortality These are necessary where the mechanism of action of the drug may have an impact on future mortality or morbidity. Consider- ation should be given to the following components of the compo- site endpoint: (1) Mortality should be all cause and not just cardiovascular. (2) The timing should be 30–60 days, as measurement of the end- point should occur shortly after symptom onset. Kaplan– Meier curves show that the timing of events in AHF is similar to that for ACS, i.e. they occur early: there is an impressive slope over the first 30–40 days (Figure 3), after which events mirror those in CHF. Therefore, we should fix the timing to that at which most events occur. (3) Readmissions should be included in the endpoint in some way, as they are relevant both clinically and in terms of cost. Stricter definitions of readmission (e.g. within 24 h, necessitating i.v. treatment for heart failure, etc.) are needed to minimize issues of heterogeneity in medical care between centres, countries, and geographical areas. There is also a need for Figure 3 Kaplan–Meier curves for survival from acute heart failure, acute coronary syndromes, and chronic heart failure. AHF, acute heart failure; ACS, acute coronary syndromes; CHF, chronic heart failure. Reproduced with permission from AP Maggioni. Clinical trials in AHF 1257
  6. 6. clinical trial protocols to try to standardize in-hospital care and to minimize differences in length of stay which can affect read- mission times and rates. (4) The composite end point should vary according to the mechanism of action of the drug, e.g. the endpoint could be a composite of all-cause death or readmission for heart failure (and may include other cause specific admissions depending on the potential side effect profile of the drug under study, e.g. seizures for adenosine antagonists). (5) Post-marketing surveys are desirable (but not necessary) to confirm the drug approval. Primary endpoints based on symptoms and/or signs These can be consideredfor short-term interventions. This is an area where a lot of controversy has arisen in previous AHF trials. First, standard therapy in many clinical trials, is very good atrelieving symp- toms such as dyspnoea—it is therefore difficult to prove that a new drug is superior in that regard.51 Second, methods of quantifying symptoms in clinical trials have been poorly validated. In future trials, validated scales such as Likert or Visual Analogue Scales should be employed and the timing of their measurement carefully considered.52 It is now agreed that haemodynamic endpoints are not appropriate in Phase III randomized controlled trials. Some general points about the inclusion of symptoms in end- points are: (1) We do not recommend the inclusion of an endpoint based on signs/symptoms in a composite endpoint that also includes a clinical event. (a) How and when signs/symptoms should be evaluated depends largely on the patients’ clinical profile. (b) To push the bar to a higher level: we need to demonstrate evidence of superiority in terms of signs and symptom relief with a new drug but without evidence of deterio- ration in renal function or of cardiac damage. This is where newer surrogate endpoints should be considered, e.g. troponin rise or measures of renal impairment such as eGFR, cystatin C,53 or neutrophil gelatinase-associated lipocalin.54 (c) For interventions which improve symptoms there must be evidence of absence of a detrimental effect in terms of 6– 12 month mortality. (d) For drugs aimed at improving symptoms, a post-marketing survey is necessary to confirm the drug approval. It may be useful to consider the domains proposed by the Federal Drug Administration (FDA) Study Group as a general guide for choosing the components of the endpoints to be included when testing different types of drugs in different patient subgroups, although not all of them would be necessary in a single trial (45). These domains are: (1) Symptom relief. (2) Measures of congestion relief (i.e. improvement in clinical signs). (3) Index hospitalization data (e.g. length of stay). (4) Prevention of end-organ damage (heart and kidney). (5) Post-discharge: death and rehospitalization data. Information about all of the domains studied could then be pre- sented in the ‘package’ of documentation submitted to the regulat- ory authorities for drug approval, but still using as the primary endpoint morbidity/mortality (if possible) or improvement of symptoms. The other domains tested should offer supportive data. Regulatory harmonization The different approaches used by the two main regulatory auth- orities, the FDA and European Medicines Authority, have led to differences in the licensing of drugs for AHF between the USA and Europe (for example, nesiritide is available in the USA and levosimendan in parts of Europe). The adoption of a more unified strategy, as proposed above, for patient selection, targeting of drugs to patient subgroups according to the mechanism and careful choice of appropriate endpoints should lead to a more rational presentation of data to the regulatory authorities. This should result in more consistent decisions between the different authorities. Conclusions Acute heart failure remains an area of great unmet clinical need. It is possible to do meaningful clinical trials in AHF if we adopt a more coherent strategy of tighter patient selection for more tar- geted drug therapy within appropriate and well thought out clinical trial designs. The European approach outlined above is very much in line with current US thinking on AHF trials. This more harmo- nized approach will hopefully deliver better outcomes for patients with AHF in the future. Conflict of interest: none declared. Appendix Other contributors to the Think Tank Gerasimos Filippatos, University of Athens, Athens, Greece. Alexandre Mebazaa, Department of Anesthesiology and Intensive Care, Lariboisie`re University Hospital, Paris, France. Piotr Ponikowski, Wroclaw Military Hospital, Wroclaw, Poland. Neville C Jackson, Pfizer, New London, CT, USA. Krishna Prasad, The MHRA, 1 Nine Elms Lane, London. References 1. Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, Massie BM, Roland E, Targum S, Collins SP, Filippatos G, Tavazzi L. Acute heart failure syn- dromes: current state and framework for future research. Circulation 2005;112: 3958–3968. 2. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, Vahanian A, Camm J, De Caterina R, Dean V, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Auricchio A, Bax J, Bohm M, Corra U, della Bella P, Elliott PM, Follath F, Gheorghiade M, Hasin Y, Hernborg A, Jaarsma T, Komajda M, Kornowski R, Piepoli M, Prendergast B, Tavazzi L, Vachiery JL, Verheugt FW, Zannad F. Esc guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the task force for the diagnosis and treatment of acute and chronic heart failure 2008 of the european society of cardiology. Developed in collaboration with the heart failure association of the esc (hfa) and endorsed by the european society of intensive care medicine (esicm). Eur J Heart Fail 2008;10:933–989. T.A. McDonagh et al.1258
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