Day-to-day management of patients with heart failure

Cristiana VITALE, MD, PhD
Department of Medical Sciences, IRCCS San Raffaele
Pisana, Rome, ITALY
Center for Clinical Research
San Raffaele Sulmona
Sulmona, ITALY

Day-to-day management of
patients with heart failure

by I . Spoletini , C. Vitale,
and M. Volterrani ,

Heart failure (HF) is a major challenge for health care systems. In acute HF, themain aimof clinicalmanagement is to stabilize the clinical condition, clarify the etiology and precipitating factors, and provide quick symptom relief. In both acute and chronic HF, it is advisable to use a multimarker approach, factoring in several diagnostic and therapeutic pathways simultaneously. The pharmacological approach recommended by current guidelines is a step-by-step procedure. Angiotensin-converting enzyme inhibitors and diuretics are the mainstay of therapy. The next step is β-blockers, which should be uptitrated to the maximum dosage possible. This therapeutic strategy is supported by several large-scale trials, which have shown a significant improvement in survival. Most patients, however, cannot tolerate maximum β-blockade and for these, ivabradine is a life-saving therapeutic option, to be used either in combination with β-blockers or alone in patients with comorbidities. Once these therapies have been implemented, aldosterone antagonists, angiotensin II receptor blockers,metabolic therapy, and iron therapy can all be considered. Furthermore, resynchronization therapy and cardioverter defibrillators should be implanted in all eligible patients. In spite of these clear guidelines, most patients with HF continue to receive suboptimal care, and most of them remain moderately or severely symptomatic. Multidisciplinary management programs have been developed to promote further improvement and implementation of appropriate HF management. Close monitoring of patients during the entire course of the disease encourages self-care management and, consequently, adherence to medication and diet, ensures better symptom recognition, and thus has a considerable impact on symptoms, well-being, and prognosis.

Medicographia. 2011;33:401-408 (see French abstract on page 408)

Heart failure (HF) is a common disease that is increasingly recognized as a major health burden, with a dramatic impact in terms of consumption of human and economic resources, and is one of the major challenges for health care systems throughout the world.1,2 The worldwide prevalence of HF is 2% to 2.5%; it affects close to 6 million people in the US and 14 million people in Europe. HF is the first cause of morbidity and mortality due to cardiovascular disease and results in more hospitalizations than all forms of cancer combined.3 HF remains disabling even after discharge from the hospital, as it considerably impairs quality of life and constitutes a risk factor for stroke, renal failure, and early readmission.4

HF prevalence increases with age, from 1% to 2% in individuals aged 45 to 54 years to >10% in those aged ≥75 years.5 Approximately 80% of patients hospitalized due to HF are older than 65 years. With a population that continues to age and (paradoxically) with the continuing improvement in the treatment of hypertension and myocardial infarction, HF is the fastest-growing clinical cardiac disease entity in all countries3 and its management is therefore assuming pivotal importance.

HF is often caused by ischemic cardiomyopathy, but may also occur in the presence of normal or nearly normal cardiac function. Its clinical presenting signs include shortness of breath and fatigue (left ventricular failure) or physical signs of fluid retention (right ventricular failure).6

Management of heart failure

The current guidelines of the European Society of Cardiology for the diagnosis and treatment of HF call for a quick and efficient approach.6 This is especially true for acute HF, in the context of urgent, unplanned hospitalization. In this case, HF management begins in the Emergency Department, continues during hospitalization, and extends after discharge.7 In the Emergency Department, the management of acute HF aims to stabilize the patient’s clinical condition, clarify the etiology and the precipitating factors, and initiate treatment to provide quick symptom relief. Respiratory support with use of oxygen if necessary, and noninvasive positive pressure ventilation should be provided, in order to avoid intubation.7 Admissions for worsening HF represent a significant health care burden and lead to significant impairment of patient quality of life; they are associated with increased short-term and long-term mortality. This is why special emphasis should be laid on ensuring the best possible management of chronic HF, in order to reduce the need for (re)hospitalization and improve prognosis.

According to current guidelines, the first step in HF management is taking a comprehensive history and carrying out a thorough physical examination in search of causal factors such as the presence of prior or current evidence of myocardial infarction, valvular disease, or congenital heart disease.6,8,9 In addition to history and physical examination, imaging techniques such as chest x-ray and echocardiography of the cardiac chambers or great vessels are used to identify causal structural abnormalities.9 Transesophageal echocardiography, stress echocardiography (exercise or dobutamine echocardiography), cardiac magnetic resonance imaging, cardiac computed tomography, or radionuclide imaging should be used only if the nature of HF is unclear.6 Coronary arteriography should be performed in HF patients with angina or significant ischemia unless the patient is not eligible for revascularization.9 Pulmonary function tests may be useful in assessing potential respiratory causes of dyspnea.

Evaluation of dyspnea and fatigue, as well as exercise capacity and exertional symptoms relies on exercise testing (determination of mixed venous oxygen saturation [MVO2] or 6-minute walk test [6MWT]).6,10 Physical training improves symptoms and quality of life in patients with chronic HF and is associated with positive effects on morbidity and mortality.11 Therefore, assessment of exercise performance should always be performed in patients with chronic HF in order to monitor the effectiveness of medical and rehabilitative therapies. Exercise training is a core component of HF management, as it induces positive changes in vessel structure, attenuates left ventricular dilation, regresses cellular hypertrophy, and slows the progression of coronary artery disease.12 Thus, physical activity appears to have “pleiotropic” actions on the cardiovascular system.11

To conclude, HF risk stratification requires a multimarker approach based on making an adequate selection of biomarkers known to be individually associated with HF, taking into account several biochemical pathways simultaneously. This allows better prediction of the incidence of HF and of the response to treatment.13

Pharmacological treatment

In spite of the variety of pathophysiological causes, HF is consistently characterized by the presence of neurohumoral activation, metabolic disorders such as testosterone deficiency and insulin resistance, and a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function.14 Consequently, therapeutic strategies targeted to these pathophysiological processes have been developed over the last decades, which have resulted in a substantial improvement in survival rate of patients with HF.1

Current guidelines recommend pharmacological treatment based on a stepped-care approach. The first step involves angiotensin-converting enzyme inhibitors (ACE inhibitors) and diuretics. The second step calls for the introduction of β-blockers. The third step consists in uptitrating β-blocker therapy to reach the maximum dosage possible.

Figure 1
Figure 1. The beneficial effect of -blockers is proportionally related to resting heart
rate reduction.

A statistically significant relationship was found between heart rate reduction and cardiac death (P<0.001). Each 10 bpm reduction in the heart rate (HR) was estimated to reduce the odds ratio of cardiac death by about 30%. After reference 17: Cucherat. Eur Heart J. 2007;28:3012-3019. European Society of Cardiology © 2007,
The Author.

_ ACE-inhibitors and diuretics
ACE inhibitors are the cornerstone of treatment of patients with HF and are recommended as first-line therapy in all patients with current or prior symptoms of HF and reduced left ventricular ejection fraction (LVEF), unless contraindicated.9 They exert beneficial effects on cardiac and systemic hemodynamics the neuroendocrine system, and vascular function, leading to reduction in blood pressure, preload, and afterload. ACE inhibitors also have structural effects on the myocardium, resulting in regression of left ventricular hypertrophy, reduction in interstitial collagen deposition and fibrosis, and prevention of cardiac remodeling.15

In patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention, diuretics and salt restriction are indicated, concurrently with ACE inhibitors.9 In patients with congestive HF, diuretics are of pivotal importance in the presence of symptoms and signs of volume overload.16 Diuretics are often the mainstay of the treatment of the elderly and patients with diastolic dysfunction, as they allow to generate low-normal to normal cardiac output in these patients who are extremely sensitive to changes in volume and preload.

_ &beta-Blockers
As step-two therapy, β-blockers are recommended in all stable patients with current or prior symptoms of HF and reduced left ventricular EF, unless contraindicated.9 CIBIS III (Cardiac Insufficiency BIsoprolol Study–III) clearly showed that β-blocker therapy should be implemented only after adequate diuretic and ACE-inhibitor therapy has been instituted.17 The study failed to show noninferiority of implementation of β-blocker
first versus ACE-inhibitor–first strategy, but showed that initiation of β-blockers before optimization of ACE inhibition was associated with increased risk of hospitalization for HF. The beneficial effects of β-blockers in patients with HF involve a number of mechanisms: (i) they slow the heart rate (increasing left ventricular filling time and reducing myocardial oxygen consumption); (ii) they modify the hemodynamic response to exercise; (iii) they lower the blood pressure. These effects combine to regress left ventricular hypertrophy and reverse ventricular remodeling. In patients with HF adequately treated with ACE inhibitors, the favorable effects of β-blockers are mediated by the heart rate–lowering effect,18 as shown by a meta-analysis of 17 randomized, placebo-controlled trials of long-term treatment with β-blockers or calcium channel blockers in patients surviving myocardial infarction (Figure 1).

The randomized controlled trials (RCTs) on β-blockers in HF have been exhaustively reviewed.6,9 One of the three β-blockers that have been proven to reduce mortality (viz, bisoprolol, carvedilol, and sustained release metoprolol succinate) should be administered whenever possible.19-22 However, although β-blockers represent the mainstay of treatment of patients with HF, these drugs are most often undertitrated for various reasons, despite the lack of real contraindications.4 Our group has recently reported that, among patients with coronary artery disease, 43% of those with HF were not on β-blocker therapy (Figure 2, page 404).23

Similarly, ACE inhibitors are often prescribed at lower dosages than those known to be clinically effective.3 Thus, β-blockers and, to a lesser extent, ACE inhibitors are often not adequately prescribed in patients with HF, most of whom remain moderately or severely symptomatic, because treatment is suboptimal.24 The major problem in implementing the therapeutic dosages of these drugs is hypotension due to the concomitant effect of drugs with hemodynamic action.

Figure 2
Figure 2. Heart rate by β-blocker use in heart failure and coronary
artery disease patients.

Among patients with heart failure (HF), only 56.6% were on β-blocker therapy.
Heart rate was significantly lower in those receiving a β-blocker. No significant
differences were found between New York Heart Association (NYHA) classes
III-IV compared with those in classes I-II.
Based on data from reference 23.

_ Ivabradine
In these patients, ivabradine plays a central role. This specific and selective If inhibitor has been found to improve ischemiarelated end points, either alone or in association with β-blockers. SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) has shown a significant reduction in mortality and hospitalization for HF with ivabradine.25 The prognosticbenefit is related to the magnitude of heart rate reduction and, indeed, patients achieving an heart rate <60 beats/minute are those with the greater survival benefit. Our group has recently consistently shown that in patients receiving inadequate ACE-inhibitor dosages and in those naive to β-blockers, ivabradine alone or in combination with carvedilol was superior to carvedilol alone in improving exercise capacity and quality of life (Figure 3).21 As aforementioned, patients with HF who are candidates for ivabradine are those without atrial fibrillation and not on β-blockers (or receiving inadequate dosagesof β-blockers) because of hypotension and other side effects. In these patients, ivabradine improves symptoms, quality of life, and prognosis. Given the fact that β-blockers are so often not used at adequate dosage, their combination with ivabradine may represent an effective alternative strategy for reducing heart rate in patients with HF.25,26

Once these therapies have been implemented, angiotensin II receptor blockers (ARBs), aldosterone antagonists, metabolic therapy, and iron therapy can be considered.

Figure 3
Figure 3. Changes in heart rate, systolic blood pressure, and diastolic
blood pressure at rest at 4-week follow-up in the bisoprolol
and carvedilol groups.

Study comparing the effectiveness of carvedilol versus bisoprolol for prevention
of postdischarge atrial fibrillation after coronary artery bypass grafting in patients
with heart failure. The bisoprolol group is represented in red bars, the carvedilol
group in blue bars.
Abbreviations: DBP, diastolic blood pressure; HR, heart rate; SBP, systolic
blood pressure.
After reference 21: Marazzi. Am J Cardiol. 2011;107:215-219. © 2011, Elsevier Inc.

Additional pharmacological therapies

_ Angiotensin receptor blockers
ARBs may have a small additional protective effect in patients with HF who are intolerant to ACE inhibitors and/or in those who remain symptomatic despite maximally uptitrated therapy with ACE inhibitors and β-blockers. Use of ARBs should be limited to these patients only, since it is preferable to achieve maximal uptitration of effective therapies such as ACE inhibitors and β-blockers in patients with HF.

ARBs are also recommended in patients with current or prior symptoms of HF and reduced LVEF who are intolerant to ACE inhibitors.9 Addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF already being treated with maximally uptitrated conventional therapy.27 OPTIMAAL (OPtimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan) failed to show noninferiority of losartan to captopril in patients with HF and acute myocardial infarction, but found that fewer patients discontinued the study medication when allocated to losartan (Figure 4).28 Thus, although ACE inhibitors should remain the first-choice treatment in HF patients, losartan can be considered in those who are intolerant to ACE inhibitors.

_ Hydralazine–isosorbide dinitrate combination
Combination treatment with hydralazine and isosorbide dinitrate is an alternative in patients intolerant to both ACE inhibitors and ARBs. This combination should be considered in all patients with HF and persistent symptoms despite maximal treatment. It is effective in reducing the risk of death, and this is particularly true in black patients, known to have reduced sensitivity to ACE inhibitors.9 It is also useful in patients with current or prior symptoms of HF and reduced LVEF in whom ACE inhibitors and ARBs are contraindicated because of drug intolerance, hypotension, or renal insufficiency.29

_ Aldosterone receptor blockers
Aldosterone receptor blockers may be considered in selected patients with moderately severe to severe HF and reduced LVEF who can be carefully monitored for renal function and potassium concentration. Aldosterone receptor blockers are potentially able to improve cardiac function by blocking the effects of aldosterone and thus interfering with collagen deposition and cardiac fibrosis.30

Figure 4
Figure 4. OPTIMAAL trial.

During a mean follow-up of 2.7 years, there were 499 (18%) deaths in the
losartan group and 447 (16%) in the captopril group, with no significant difference
between groups. Losartan was significantly better tolerated than captopril,
with fewer patients discontinuing study medication.
After reference 28: Dickstein. Lancet. 2002;360:752-760. © Elsevier Ltd.

_ Digoxin
Digoxin is effective in controlling ventricular rate, especially when combined with calcium channel blockers or β-blockers, in patients with current or prior symptoms of HF, reduced LVEF, and atrial fibrillation,31 which is a frequent occurrence in older patients.32-34

_ Trimetazidine
Trimetazidine (TMZ) is an effective strategy for treating HF by improving myocardial substrate use through inhibition of oxidative phosphorylation and by shifting energy production from free fatty acids to glucose oxidation.35 A recent meta-analysis of RCTs in HF has confirmed that TMZ improves cardiac function in ischemic and nonischemic HF and reduces mortality, cardiovascular events, and hospitalization.36

_ RLY5016
Hyperkalemia, anemia, hyponatremia, and reduced renal function are common in patients treated with diuretics and ACEinhibitor/ ARB/aldosterone antagonist therapy.6 Hyperkalemia, in particular, may result in discontinuation of a renin-angiotensin- aldosterone system inhibitor/blocker and/or β-blocker or chronic kidney disease. The PEARL-HF study (Evaluation of RLY5016 in Heart Failure Patients) study has recently shown that a nonabsorbed, orally administered, potassium [K+]-binding polymer (RLY5016) may be useful for both prevention and treatment of hyperkalemia in HF patients with or without concomitant chronic kidney disease.37

_ Treatment of iron deficiency
Treatment of anemia has not been established so far as routine therapy in HF.6 However, there is growing evidence that iron deficiency is a valid independent therapeutic target in HF. It is now recognized that iron deficiency in HF patients with or without anemia attenuates aerobic performance and is accompanied by fatigue and exercise intolerance. The FERRICHF trial (Ferric Iron Sucrose in Heart Failure) has shown that intravenous iron sucrose therapy was associated with better exercise capacity and symptom status, especially in anemic HF patients.38 The FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) trial has consistently found that treatment with intravenous iron (ferric carboxymaltose) improved symptoms, functional capacity, and quality of life in chronic HF patients, whether with anemia or without.39 Further studies are needed to unravel the reasons why correction of iron deficiency results in symptomatic improvement even in the absence of a change in hemoglobin.

_ Miscellaneous
Finally, use of analgesics and benzodiazepines is advisable to relieve anxiety, distress, dyspnea, and arrhythmia.<40 Conversely, several drugs should be avoided or withdrawn whenever possible. Nonsteroidal anti-inflammatory drugs, most antiarrhythmic drugs, and most calcium channel blokcers are known to adversely affect the clinical status of patients with current or prior symptoms of HF and reduced LVEF.9 Also, the combined use of an ACE inhibitor, an ARB, and an aldosterone receptor blocker is not recommended in patients with current or prior symptoms of HF and reduced LVEF. Infusion of a positive inotropic drug may be harmful in the long-term and is not recommended, except as a palliative treatment for patients with end-stage disease who cannot be stabilized on standard medical treatment.9

Device therapy: cardiac resynchronization and implantable cardioverter-defibrillators

As an adjunct to optimal medical therapy, cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillators (ICD) should be used in all eligible patients. As recommended by the recent European guidelines on device therapy in HF,41 CRT and ICD should be used in patients with severe HF (New York Heart Association [NYHA] class III-IV) who remain symptomatic and with QRS prolongation despite optimal medical therapy. As summarized in a recent review,42 clinical trials have shown that HF patients implanted with a device had a remarkably low mortality rate. CRT and ICD have also been found to reduce morbidity and mortality in patients with mildly symptomatic HF (NYHA class I-II).41

CRT has resulted in substantial improvement in symptoms and a large reduction in mortality by reducing both sudden death and death due to HF.42 In HF patients, dyssynchronous contraction can be addressed by electrically activating the right and left ventricles in a synchronized manner with a biventricular pacemaker device.9 CRT improves left ventricular geometry, papillary muscle dyssynchrony, and mitral regurgitation.6 Short-term use of CRT has been associated with improvement in cardiac function and hemodynamics, significant improvement in quality of life, functional class, exercise capacity, and LVEF, as well as with reduction in hospitalizations and all-cause mortality.43,44

ICD implantation is indicated in HF patients with a history of previous cardiac arrest or documented sustained ventricular arrhythmia, to reduce the risk of recurrent events.9 In particular, it is indicated for the secondary prevention of death from ventricular tachyarrhythmia in patients with otherwise good clinical function and prognosis, or in those with chronic HF and low LVEF presenting with syncope of unclear origin.

In conclusion, CRT, or a combination of CRT and ICD, is recommended in most HF patients.

How can management of heart failure patients be improved?

The past decades have seen major advances in the management of patients with HF thanks to an extensive body of evidence from RCTs, meta-analyses, and large observational studies, and the resulting revision of the guidelines. This has changed the natural course of this clinical syndrome and improved patient outcomes. However, implementation of optimal HF management is still limited in routine daily practice, and many patients remain symptomatic, with an adverse impact on quality of life,45 and frequently receive substandard care.46 Different reasons may explain this phenomenon.

First, patient characteristics in clinical practice may differ substantially from those in clinical trials. There appears to be a selection bias in RCTs, which results in underrepresentation of the elderly, women, minorities, patients with concomitant comorbidities, such as renal insufficiency, chronic lung disease, obesity, depression, and neurocognitive disorders, and, generally speaking, of patients in less good health. Conversely, patients who are more likely to adhere to the prescribed treatment and follow-up are overrepresented in RCTs.47

Second, as aforementioned, β-blockers are underused, especially in outpatients with HF, as opposed to hospitalized patients. The EuroHeart Failure II survey showed that β-blockers were underprescribed in elderly patients in comparison with younger patients, though there is a substantial increase in the rate of prescription of recommended medications at discharge when compared with the first European Survey.48

In addition, discharge planning and follow-up after hospitalization are frequently insufficient, leading to poor self-care behavior, inadequate support for the patients, and suboptimal treatment. Notably, poor compliance is a main factor of poor prognosis.49 Nonadherence to medication, diet, or symptom recognition is common and may be responsible for over one third of hospital readmissions.6 In contrast, good adherence has been shown to decrease morbidity and mortality and improve well-being.49

There is thus room for further improvement and implementation of appropriate HF management. Current European guidelines recommend management programs to improve outcomes based on a multidisciplinary care approach that follows the HF patient along the course of the disease and calls on various services within the health care system.6

Such multidisciplinary management care ensures structured follow-up to enhance patient education, optimization of medical treatment, psychosocial support, and access to care. Self-care management strategies are now recognized as an integral part of successful HF treatment,50 and promise to exert a significant impact on the symptoms, functional capacity, well-being, morbidity, and prognosis of heart failure patients.51 _

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Keywords: angiotensin-converting enzyme inhibitor; β-blocker; cardioverter-defibrillator; compliance; diuretic; heart failure; ivabradine; management; resynchronization therapy; self-care