Alberto Dominguez-Rodriguez, Julia Gonzalez-Gonzalez, Carima Belleyo-Belkasem and Pedro Abreu-Gonzalez

1Department of Cardiology, Hospital Universitario de Canarias, Tenerife, Spain

2Facultad de Ciencias de la Salud, Universidad Europea de Canarias, La Orotava, Tenerife, Spain

3Departamento de Ciencias Médicas Básicas (Unidad de Fisiología), Universidad de La Laguna, Santa Cruz de Tenerife,Spain

Epidemiology of Heart Failure in Europe

A number of large-scale registries, such as Euro-Heart Failure Survey I and EuroHeart Failure Survey II [1–3] and the European Society of Cardio logy (ESC) Heart Failure Pilot registry [4],have provided some epidemiological evidence on acute heart failure (AHF) in Europe. All patients admitted for AHF are older than 70 years and about half of them are male. Most have a history of heart failure (HF). About 40%–55% have a preserved left ventricular ejection fraction. Concerning cardiovascular comorbid conditions, most AHF patients have a history of arterial hypertension, about half have coronary artery disease, and one third or more have atrial fi brillation. In terms of noncardiovascular comorbidities, about one third of patients admitted for AHF have a history of diabetes mellitus, about one fourth have renal dysfunction and chronic obstructive pulmonary disease, whereas anemia is also present in 15%–30% of patients. According to these registries,in-hospital mortality ranges from 4% to 7%. The median length of hospital stay ranged from 8 to 11 days. Postdischarge mortality up to 3 months was 6.6%. Postdischarge rehospitalization rates are quite high, as about one fourth of patients are readmitted within 3 months (Table 1).

European Society of Cardiology Specialist HF Curriculum

HF is a complex clinical syndrome – it is essentially the end stage of all serious forms of cardiovascular disease. All patients with HF require diagnosis of the underlying cardiac condition(s) driving the HF and comorbidities. Subsequent to this, they need therapy directed at the underlying condition as well as the HF. That therapy is increasingly complex and spans pharmacology, devices, and surgical therapy.It also has to be delivered as part of a multidisciplinary management strategy which bridges primary,secondary, and tertiary care [5]. It is well established that organized care of HF patients, including specialist treatment by cardiologists, improves patient outcomes. In response to this, in the United States HF subspecialty curricula have been developed within cardiology training curricula [6].

Recently, the Heart Failure Association of the ESC has provided a framework which can be used as a blueprint for training across Europe [7]. This program is designed to last 2 years. The first year is devoted to the specialist HF module. The second year allows completion of the optional modules of advanced imaging, device therapy for implanters,cardiac transplantation, and mechanical circulatory support. The second year can also be devoted to continuation of specialist HF training and/or research for those not wishing to continue with the advanced modules [7].

Clinical Classification of Patients with AHF in Europe

These classif i cations, although they characterize important underlying pathophysiological and clinical features with precipitating factors, may not have a direct translation into therapeutic decisions in routine clinical practice. According to the ESC guidelines [8], a patient with AHF may present with one of the following clinical categories:

·Decompensated chronic HF.This occurs when a patient with chronic HF progressively deteriorates and signs and symptoms worsen. Peripheral edema and pulmonary congestion are characteristic of this clinical category. These patients may present with low blood pressure, which is often associated with a reduced left ventricular ejection fraction [9].

·Pulmonary edema. For many physicians, pulmonary edema is the real clinical presentation of AHF. Typically, signs and symptoms develop rapidly, and patients demonstrate severe respiratory distress with tachypnea, orthopnea, and pulmonary congestion [9].

·Hypertensive HF. Hypertensive HF is associated with elevated blood pressure with accompanying dyspnea and signs of pulmonary congestion,often in patients with a relatively preserved left ventricular ejection fraction [9].

·Isolated right ventricular HF. Isolated right ventricular HF is characterized by low output syndrome in the absence of pulmonary congestion, with low left ventricular filling pressures. Importantly, a clear differentiation is needed here between patients with chronic HF who gradually develop signs and symptoms of right ventricular HF (elevated jugular venous pressure, peripheral edema, hepatomegaly, gut congestion), which at some stage dominate the clinical picture, versus patients with new-onset isolated right ventricular HF, often secondary to either acute coronary syndrome or pulmonary embolism; although the former does not fulf i ll the diagnostic criteria – often with some pulmonary congestion and elevated left ventricular filling pressure – many physicians tend to put such patients in this category [9].

·Cardiogenic shock. Cardiogenic shock characterizes severe peripheral hypoperfusion with subsequent end-organ damage. Typically it is associated with low blood pressure (systolic blood pressure less than 90 mmHg) and low urine output (less than 0.5 mL/kg/min) [9].

這會兒孟導心情已經從剛才的大起大落里找回了平衡，再加上到了自己擅長的飯局環(huán)節(jié)，談吐間又變回了在電視臺里叱咤風云的導演。老賈也是做生意全憑一張嘴，牙似弓，舌似箭，吐字如飛，和孟導講在一處，也毫不含糊。反倒是葉總惜字如金，只在一旁牽線搭橋，默默平衡話題的走向。

·Acute coronary syndrome complicated by HF.Between 15% and 20% of patients admitted with acute coronary syndrome have signs and symptoms of HF, and an additional 10% develop HF during hospital stay [10]. The incidence is even higher in reports focusing on patients with AHF,where up to 40% may have acute coronary syndrome as a precipitating factor [11]. Acute coronary syndrome complicated by AHF is now often viewed as a separate clinical entity, characterized by complex structural, hemodynamic, and neurohormonal interactions, the need for urgent referral for coronary intervention, and poor outcome.On the other hand, patients with AHF often demonstrate troponin release (typically of moderate magnitude) [12], which may further complicate the whole diagnostic process [9].

Pharmacological Therapy for AHF:A European Perspective

Often treatment must be administered in parallel with the diagnostic workup. Systolic blood pressure, heart rhythm and rate, saturation of peripheral oxygen with a pulse oximeter, and urine output should be monitored on a regular and frequent basis until the patient’s condition has stabilized. Although not “evidence based” in the same way as treatments for chronic HF, the key drugs are oxygen, diuretics (furosemide, torsemide, hydrochlorothiazide,indapamide, spironolactone, eplerenone, amiloride and triamterene), and vasodilators (nitroglycerine and nitroprusside) [8]. The opiates (morphine), inotropes (dobutamine, recommendation IIaC; levosimendan, recommendation IIbC), and vasopressors(dopamine or norepinephrine, recommendation IIbC) are used more selectively [8].

Pharmacological Therapy for Systolic HF: A European Perspective

The goals of treatment in patients with established HF are to relieve symptoms and signs, prevent hospital admission, and improve survival [9].Three neurohumoral antagonists – an angiotensinconverting enzyme inhibitor (or angiotensin receptor blocker), a beta-blocker, and a mineralocorticoid receptor antagonists – are fundamentally important in modifying the course of systolic HF,and should at least be considered in every patient.They are commonly used in conjunction with a diuretic given to relieve the symptoms and signs of congestion [8].

However, the main novelty of the 2012 ESC guidelines concerning the pharmacological treatment of systolic HF is the introduction of ivabradine and the grade of recommendation of four drug groups: mineralocorticoid receptor antagonists,angiotensin receptor blocker, digoxin and the combination of isosorbide dinitrate and hydralazine [8].

lvabradine

The 2012 guidelines include the indication for ivabradine according to the original design of the ivabradine and outcomes in systolic HF (SHIFT)study [13], recommending its use in patients who, despite optimal treatment and the maximum tolerated dose of beta-blockers, angiotensinconverting enzyme inhibitors, and mineralocorticoid receptor antagonists have a heart rate in sinus rhythm of more than 75 beats per minute [8].

Mineralocorticoid Receptor Antagonists

After the publication of the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS) [14], use of mineralocorticoid receptor antagonists was indicated in patients with symptomatic HF and a left ventricular ejection fraction of 35% or less, displacing use of angiotensin receptor blockers. What the guidelines do not specify is the first-line choice of drug, whether spironolactone and eplerenone, giving the impression that all mineralocorticoid receptor antagonists are equal. Therefore, in Europe the choice of spironolactone or eplerenone will depend on the following:(a) the patient’s clinical prof i le, (b) the safety profile, and (c) cost (higher for eplerenone, although this will change with the imminent introduction of the generic drug) [15].

Angiotensin Receptor Blockers

Several trials have shown that angiotensin receptor blockers have the same benef i cial effect as angiotensin- converting enzyme inhibitors in patients with HF with a reduced left ventricular ejection fraction [8]. Nevertheless, if the benef i cial effect obtained with double blockade of the reninangiotensin-aldosterone system by combination of an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker versus the combination of an angiotensin-converting enzyme inhibitor with a mineralocorticoid receptor antagonist,the benef i ts obtained with this latter combination are more evident and robust [15]. Consequently,the first-choice combination is an angiotensinconverting enzyme inhibitor plus a mineralocorticoid receptor antagonist (versus an angiotensinconverting enzyme inhibitor plus an angiotensin receptor blocker). The guidelines establish a class IA recommendation use of for angiotensin receptor blockers in patients with intolerance to angiotensin-converting enzyme inhibitors or mineralocorticoid receptor antagonists [8].

Digoxin

In patients with symptomatic HF and atrial fibrillation, digoxin may be used to slow a rapid ventricular rate. Moreover, its use may be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with a left ventricular ejection fraction of 45% or less who are unable to tolerate a beta-blocker (ivabradine is an alternative in patients with a heart rate of 70 beats per minute or more). Patients should also receive an angiotensin-converting enzyme inhibitor (or an angiotensin receptor blocker) and a mineralocorticoid receptor antagonist [8].

Combination of lsosorbide Dinitrate and Hydralazine

HF with Preserved Ejection Fraction:A European Perspective

Current ESC guidelines now fully acknowledge HF with preserved ejection fraction as an important HF syndrome, in line with robust evidence that(a) patients with HF with preserved ejection fraction constitute almost half the HF population in epidemiological studies [16], (b) classic hemodynamic changes of HF are present in HF with preserved ejection fraction (elevated left ventricular filling pressures and abnormal vasorelaxation in both the systemic circulation and the pulmonary circulation)[17], and (c) neurohormonal activation characteristic of HF (renin-angiotensin-aldosterone axis, sympathetic nervous system) also occurs in HF with preserved ejection fraction [18].

In general, all proposed diagnostic criteria to date share three features in common: (a) clinical signs or symptoms of HF; (b) evidence of a preserved ejection fraction; and (c) evidence of abnormal left ventricular structure and/or diastolic dysfunction[19]. The E SC consensus provided practical recommendations on the evaluation of diastolic dysfunction by echocardiography (both Doppler based and structural assessments of left ventricular mass and left atrial size), measurement of natriuretic peptide levels, and the presence of atrial fi brillation, in addition to cardiac catheterization [20].

Current international guidelines acknowledge a lack of evidence in the management of HF with preserved ejection fraction. The ESC recommends the use of diuretic agents to relieve breathlessness and edema, an optimal management of hypertension or myocardial ischemia, and to control heart rate since elevated heart rate is usually poorly tolerated in these patients with left ventricular stiffness [8].

lron Deficiency: A New HF Comorbidity in European Guidelines

Iron deficiency is frequent in patients with chronic HF, with a reported prevalence of between 30% and 50%, independent of the presence of anemia [21].Recent studies have suggested that it is an independent predictor of impaired functional capacity in patients with HF and a reduced ejection fraction [22]and its treatment with intravenously administered iron relives symptoms and improves quality of life[23]. Therefore, the ESC guidelines for the diagnosis and treatment of acute and chronic HF from 2012 recommended iron deficiency assessment as with other comorbidities [8].

There is no specific recommendation for iron deficiency management in European guidelines, but available data suggest that absolute iron deficiency(serum ferritin concentration less than 100 μg/L)and functional iron deficiency (serum ferritin concentration 100–299 μg/L and transferrin saturation less than 20%) should be treated in symptomatic patients with HF and a reduced ejection fraction.It has been assessed in randomized clinical trials with intravenously administered iron sucrose in the FERRIC-HF study [24] and with intravenously administered ferric carboxymaltose in the FAIR-HF [25] and CONFIRM-HF [23] studies,with an improvement in peak oxygen consumption adjusted for body weight, New York Heart Association functional class, or 6-min-walk test. Evidence for a clinical benef i t from the use of orally administered iron preparations in HF is limited, but there are ongoing clinical trials, such as IRONOUT study(NCT02188784) [26].

HF and MitraClip: A European Perspective

Currently, the most effective therapies for secondary mitral regurgitation in HF are focused on the underlying left ventricular dysfunction (optimal medical therapy, biventricular pacing, or coronary revascularization) [27]. The role of surgical and transcatheter mitral valve repair or replacement is less established [28].

The interventional treatment of mitral valve regurgitation by the MitraClip (Evalve, Inc., CA,USA) procedure has grown rapidly in Europe [29]since its CE-mark approval in March 2008. The largest published registry is from Germany, with 1064 patients [30]. In contrast to its initial use in pivotal studies in the United States (EVEREST[31] and EVEREST II [32]), the MitraClip has been most commonly used in Europe for secondary mitral regurgitation. Many registries have shown high rates of procedural success with favorable clinical outcomes. In the MitraClip Therapy Economic and Clinical Outcomes Study Europe(ACCESS-EU) registry [33], 567 symptomatic patients with signif i cant mitral regurgitation and high surgical risk were treated with the MitraClip system at 14 European sites, 77% of them with secondary mitral regurgitation. There was a 99.6%procedural success and a signif i cant reduction in mitral regurgitation severity (mitral regurgitation of 2+ or less in 91% of patients) and functional class and improvement in 6-min walk test distance at 1-year follow-up. The European Sentinel Pilot Registry [34] showed data from 628 patients with symptomatic mitral regurgitation and high surgical risk treated with the MitraClip system, 72% of them with secondary mitral regurgitation. It demonstrated reduction in mitral regurgitation severity and relief of clinical symptoms too. The estimated 1-year mortality was 15.3%, which was similar for functional mitral regurgitation and degenerative mitral regurgitation, but the estimated 1-year rate of rehospitalization for HF was higher in the functional mitral regurgitation group.

On the basis of the available evidence, the 2012 European guidelines on the management of valvular heart disease recommended that the percutaneous MitraClip procedure may be considered in symptomatic patients with severe secondary mitral regurgitation despite their receiving optimal medical therapy (including biventricular pacing) who are judged to inoperable or at high surgical risk by a heart team and have a life expectancy greater than 1 year [28].

Mechanical Circulatory Support:A European Perspective

Mechanical circulatory support has emerged as an alternative treatment for patients with end-stage HF. Its use has increased rapidly in the last 15 years as a result of technological advances, growing experience with these devices, the increasing number of patients with end-stage HF, and the limited donor pool [35]. The sixth Interagency Registry for Mechanically Assisted Circulatory Support(INTERMACS) reported nearly 10,000 patients receiving durable mechanical circulatory support in the United States [36].

In Europe, there are regional databases in some European countries (Belgium, Spain, United Kingdom), but there has been an attempt to set up a European registry. The European Registry of Patients with Mechanical Circulatory Support(EUROMACS) was created in 2009 in Germany,with 15 other founding international members[37]. The last report provided data on nearly 1,400 patients receiving durable mechanical circulatory support devices in Europe.

Multicenter studies have demonstrated a continued improvement in outcomes with durable mechanical circulatory support, with an overall 1-year survival rate of approximately 85% [38].The continuous-f l ow durable devices have been the most used mechanical circulatory support devices since 2008. The HeartMate II (Thoratec, Pleasanton, CA, USA) was approved by the Food and Drug Administration as a bridge to transplant therapy in 2008 and for destination therapy in 2010 [36]. On the basis of the available evidence [39], the Heart-Ware II system (HeartWare International, Framingham, MA, USA) received the CE mark for use as mechanical circulatory support in the bridge to transplant therapy in March 2009, and for long-term use in end-stage HF patients at risk of death in May 2012. Currently, the HeartWare II system has been approved by the Food and Drug Administration only as a bridge to transplant therapy. The results from the ENDURANCE study (NCT01166347),which compares outcomes with HeartWare II and HeartMate II as destination therapy, may expand the range of indications for the HeartWare II system in the United States. The postmarket Registry to Evaluate the HeartWare Left Ventricular Assist System (ReVOLVE) study [38], which was performed in seven centers in Europe and two centers in Australia, collected data from 254 patients and confirmed good clinical outcomes from previous clinical trials, with a 1-year success rate of 85%.

Mortality of patients with durable mechanical circulatory support continues to decrease in the United States and in Europe too [40], and current investigations focus on reduction in the incidence of adverse events, as thrombosis, gastrointestinal bleeding,infections, HF/arrhythmia, and readmission [35].The largest studies have been performed in the United States, but interest is growing in Europe about this setting [41]. Fiore et al. [41] published a single-center study which evaluated the potential use of light transmission aggregometry to guide antiplatelet therapy in 24 patients with a left ventricular assist device and reported rates of 12.5% for thromboembolic events and 33% for major bleeding complications. They conclude that this testing needs to be assessed in a larger study.

The interaction between mechanical circulatory support and the native heart has also been examined.Myocardial recovery has been described in selected patients [42]. Yacoub [43] reported the benef i t of addition of pharmacological treatment to use of a left ventricular assist device to increase myocardial recovery. Dandel et al. [44] determined echocardiographic parameters of left ventricular function, size,and geometry during temporary cessation of pump fl ow as predictive measures of myocardial recovery in nonischemic cardiomyopathy and cardiac stability after explantation.

Future discussion will revolve around reevaluation of current indications for implantation and management of durable devices. Current management has been guided by center-specific protocols,and randomized clinical trials are needed to guide patient selection and care [45].

Conclusion and Take-Home Message

HF remains a pertinent problem across Europe. It is responsible for large economic costs, frequent hospitalization, and high levels of mortality. Much epidemiological work has been done across Europe to illustrate prevalence, with the acknowledgement that increasing numbers of elderly patients are likely to cause signif i cant problems over the next few decades. The real challenge facing European health care systems is how to cope with the rise in prevalence and the consequent care at primary,secondary, and tertiary care levels. All of this is becoming even more relevant with the current global economic backdrop and fi nancial limitations.

Acknowledgment

We thank Veronica Dominguez-Gonzalez for technical assistance.

Conflict of lnterest

The authors declare no conf l ict of interest.

Funding

This research received no specif ic grant from any funding agency in the public, commercial, or notfor-profit sectors.

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