Severe Heart Failure

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82 Severe Heart Failure

Eduard Shantsila, Benjamin Wrigley, Michael D. Sosin, Gregory Y.H. Lip

Heart failure is a very common condition with high mortality and morbidity rates. Data from the Framingham heart study suggest that at 40 years of age, the lifetime risk for congestive heart failure is 21.0% (95% confidence interval [CI], 18.7%-23.2%) for men and 20.3% (95% CI, 18.2%-22.5%) for women.1 The prevalence of heart failure is between 2% and 3% and reaches 10% and 20% in those older than 70 years.2 In the United States, approximately 5 million patients have heart failure, with over 550,000 new cases diagnosed each year.3 Despite improvements in treatment, the overall prevalence of heart failure is increasing because of the aging of the population and better survival following myocardial infarction (MI).3,4 Total heart failure–related costs were about $28 billion in 2005 and consume approximately 2% of national expenditure on health in Europe.5 Patients with severe heart failure often present in extremis, and their condition may deteriorate rapidly, so a sound knowledge of immediate treatment is vital for critical care and emergency physicians. Such patients often respond rapidly to appropriate treatment, making this a very satisfying condition to treat. However, it is important to note that outlook remains poor despite initial clinical improvement.

In this chapter, we will discuss causes, presentation, investigation, treatment, and prognosis of severe heart failure, including new developments in the investigation and management of this common, serious condition.

image Etiology

Ischemic heart disease is the most common cause of heart failure, commonly related to previous MI. Although epidemiologic surveys such as the Framingham study suggest a high prevalence of hypertension as the “cause” of heart failure, it is likely that associated ischemic heart disease or arrhythmias also contribute. Other studies have demonstrated similar findings (Table-82-1).

TABLE 82-1 Epidemiologic Studies of Etiology of Heart Failure

image

It should be pointed out that epidemiologic studies such as the Framingham study have been almost exclusively carried out in white populations, and etiologic factors may have different relative importance in other ethnic groups. For example, in Afro-Caribbeans, hypertension is the predominant etiologic factor, whereas in Indo-Asians, coronary artery disease and diabetes are common. It is important to note that different causes may coexist in the same patient.

Ischemic Heart Disease

Ischemic heart disease is the most common cause of heart failure in the Western world. Many patients presenting with severe heart failure will give a history of previous MI. However, an episode of severe heart failure may also be the first manifestation of ischemic heart disease, either due to massive MI causing cardiogenic shock6 or as a result of previous silent (or unreported) episodes of ischemia/infarction. It is therefore important to exclude MI in all patients presenting with severe heart failure. Additionally, once the patient is stabilized, adequate secondary preventive strategies are vital to prevent further ischemia or infarction. Some patients with ischemic cardiomyopathy may show evidence of “hibernation” of segments of myocardium,7 and cardiac function in these patients may improve with revascularization (see later discussion).

Hypertensive Heart Disease

Hypertension causes a significant proportion of cases of heart failure. An episode of severe heart failure may be the first presentation of hypertension—such patients have had unrecognized severe hypertension for many years. The onset of heart failure may result in a previously raised blood pressure becoming normal or even low, which can make the diagnosis difficult in a patient with previously undiagnosed hypertension. Electrocardiography and echocardiography may show evidence of left ventricular hypertrophy. Patients with hypertension also commonly have diastolic dysfunction as a cause for heart failure. In this situation, systolic contraction is normal or minimally impaired, but the main abnormality is in diastolic relaxation and ventricular compliance. The incidence of diastolic abnormalities increases with age, and while the mortality rate associated with diastolic heart failure appears to be lower than that of systolic heart failure, it is still significant. To date, the ideal method of defining abnormal diastolic function has not been clearly ascertained.

Dilated Cardiomyopathy

Dilated cardiomyopathy is defined as left ventricular dysfunction of unknown cause. It is therefore a diagnosis of exclusion, and a firm diagnosis of dilated cardiomyopathy can only be made in the presence of a normal coronary angiogram. Intensive investigation of patients with a label of dilated cardiomyopathy may yield a definite cause in at least 50% of cases (Table 82-2). As many as 30% of patients with dilated cardiomyopathy may have a genetic cause of the disease.8

TABLE 82-2 Final Diagnoses in 1230 Patients with Initially Unexplained Cardiomyopathy

Diagnosis Number Percentage
Idiopathic dilated cardiomyopathy 616 50
Myocarditis 111 9
Ischemic heart disease 91 7
Infiltrative cardiomyopathy 59 5
Peripartum cardiomyopathy 51 4
Hypertension 49 4
Human immunodeficiency virus infection 45 4
Connective tissue disease 39 3
Substance abuse 37 3
Familial 25 2
Valvular disease 19 1.5
Doxorubicin therapy 15 1
Endocrine disorder 11 1
Others 62 5.5

Data from Felker GM et al. Underlying causes and long term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077-84.

Dilated cardiomyopathy can manifest at any age, and because heart failure may be perceived as a disease of the elderly, this can often result in misdiagnosis in younger patients.

Valvular Heart Disease

Structural Valve Disease

Valvular heart disease was once a leading cause of heart failure in the Western world. Owing to the rise in ischemic heart disease and the decrease in rheumatic fever, it is now less often the primary cause of an episode of severe heart failure. However, it is important not to discount significant valve disease in patients presenting with severe heart failure and to remember that signs may be difficult to elucidate in the acutely ill patient. Because all patients with severe heart failure should undergo echocardiography soon after admission, most if not all cases of significant valve disease should be detected. As noted earlier, after extensive MI, acute mitral regurgitation can develop, causing sudden-onset severe heart failure days after a patient’s initial presentation with chest pain.

Functional Valve Disease

Patients with heart failure of any cause with dilation of the left ventricle and mitral valve ring can develop functional mitral regurgitation. This further reduces left ventricular performance; in selected patients, mitral valve repair or replacement may be indicated.

Diabetes

In addition to the role of diabetes as a risk factor for the development of ischemic heart disease and resultant heart failure, there is evidence for a distinct diabetic cardiomyopathy.8 Current guidelines recognize diabetes as a risk factor for heart failure.8 Hemoglobin A1c levels have been shown to be an independent progressive risk factor for cardiovascular and total mortality and rehospitalization rate in heart failure patients.9,10 All patients presenting with heart failure should be screened for diabetes, both for this reason and so that appropriate secondary prevention can be instituted.

Other Possible Causes or Exacerbating Factors

Rare causes of heart failure must always be considered, especially in younger patients, and these include amyloidosis and hemochromatosis. Another important cause is human immunodeficiency virus (HIV) infection, and HIV-associated cardiomyopathy has been well described. Given that HIV infection is considered pandemic by the World Health Organization, many more patients may present in this way in the future.

Patients with a long history of stable heart failure may decompensate as the result of a number of different factors. Intercurrent infection is a common cause of decompensation, and prompt recognition and treatment are important. Arrhythmias are also a common cause for decompensation of a previously stable heart failure patient, and a recent meta-analyses of 16 randomized clinical trials (53,969 patients) revealed that the presence of AF is associated with an adverse effect on total mortality, with an odds ratio of 1.40 (95% CI, 1.32-1.48).11 Another common cause of decompensation is anemia, which is often poorly tolerated in patients with heart failure. A meta-analysis of 34 studies comprising 153,180 patients, of whom 37.2% were anemic, showed that adjusted mortality risk of anemia had a hazard ratio of 1.46 (95% CI, 1.26-1.69).12 Poor prognosis associated with presence of atrial fibrillation or anemia was irrespective of left ventricular systolic function, either preserved or impaired.11,12 It is vital to consider and treat such exacerbating conditions where appropriate.

image Presentations of Severe Heart Failure

Severe heart failure can manifest in several ways. The patient may or may not have a previous history of heart failure or precipitating conditions such as angina or hypertension. It is important to note that gradual-onset heart failure can easily be mistaken for asthma, and patients presenting to an emergency department may well have been given a diagnosis of asthma in the weeks or months preceding their admission.

Acute Presentation: Pulmonary Edema

The classic presentation of heart failure is with acute pulmonary edema. Such patients present with extreme shortness of breath, often unable to speak because of their rapid respiratory rate. Symptoms may come on very suddenly. Even patients with ischemic heart failure may not report chest pain, either because the ischemia is silent or because the pain is being masked by the profound shortness of breath. Many patients will be unable to give a history owing to their shortness of breath, and therefore examination findings and basic investigations are vital to make the diagnosis.

General Examination

Examination may often reveal pallor, sweating, and dyspnea. The patient will have a high respiratory rate and increased work of breathing, using accessory muscles of respiration. Peripheral edema is not always present, particularly in patients presenting with a first episode of heart failure. Equally, the jugular venous pulse may not be elevated.

Respiratory Examination

Percussion is unlikely to be of value, owing to difficulty in examining the patient. A pleural effusion large enough to cause such dyspnea as to simulate severe heart failure will usually be obvious on auscultation. Percussion can be performed afterward if needed to confirm such a diagnosis. Patients with heart failure may well have pleural effusions, but they are usually relatively small and unlikely to benefit from drainage. Auscultation usually reveals extensive fine crepitations, usually equal bilaterally and greatest at the lung bases. However, some patients have predominant wheeze due to edema of the bronchial walls, and this may cause diagnostic confusion. In such patients, the preferred option may be to treat both bronchospasm and pulmonary edema. Similarly, in the most severely affected and exhausted patients, the chest may be surprisingly silent because of reduced tidal volumes. A single dose of an intravenous (IV) diuretic agent is unlikely to cause harm to patients with breathlessness of other causes, and in situations of diagnostic difficulty, a rapid response to diuretics may be helpful.

Cardiovascular Examination

Examination of the pulse may reveal atrial fibrillation. Patients in sinus rhythm are usually tachycardic, although patients with a history of ischemic heart disease may well be taking beta-blockers, which mask tachycardia. Heart rate appears to be an independent and powerful factor of prognosis in heart failure. In the BEAUTIFUL study, heart failure patients with heart rates of 70 bpm or greater had 34% higher risk for cardiovascular death and 53% higher risk admission to hospital than those with heart rate blow 70 bpm. The study has shown 8% and 15% increments of cardiovascular death and hospital admission for every increase of 5 bpm.13

The blood pressure is preserved in approximately 80% of patients presenting with decompensated heart failure overall, but a significant number are hypotensive at presentation. This is the single most important factor affecting treatment (see later discussion) and is also likely to be altered by treatment, and so must be measured frequently. Palpation may or may not reveal a displaced apex beat, depending on the length of the history. There may be palpable heaves or thrills, but these are likely to be difficult to appreciate in the acutely breathless patient. Auscultation of the heart sounds may well be difficult. There may be a third or fourth heart sound, or there may be murmurs representing chronic stenotic or regurgitant valves, or an acute mitral valve prolapse or ventricular septal defect following MI. (These latter two conditions can even occur several days after admission in a patient with extensive MI.) It is important to reexamine the patient regularly; once initial treatment has commenced, the patient may become less breathless, and previously inaudible signs may become clear.

Abdominal Examination

Examination of the abdomen can also be difficult in the acutely breathless patient. Where possible, such examination may reveal ascites, edema of the abdominal wall or genitalia, and enlargement of the liver. Pulsation of the liver can indicate tricuspid regurgitation.

Subacute Presentation: Shortness of Breath/Peripheral Edema

Many patients with severe heart failure present less acutely with varying combinations of breathlessness and edema. This is often the case in patients with a previous diagnosis of heart failure and can be precipitated by intercurrent infection or withdrawal of diuretic or other medication (by the patient or a physician). In the early stages, edema may be more prominent unilaterally, and this may result in diagnostic difficulty. Such patients may be referred for exclusion of deep venous thrombosis (and it is important to be aware that the two conditions can coexist). These patients often report gradually increasing breathlessness with symptoms of orthopnea (shortness of breath occurring when lying supine) and paroxysmal nocturnal dyspnea (sudden shortness of breath waking the patient from sleep). Patients may resort to sleeping in a chair, leading to additional gravitational edema. Edema of the bowel can lead to reduced appetite, so called “cardiac cachexia,” and further edema from hypoproteinemia. Peripheral edema is therefore often multifactorial in patients with heart failure. Differential diagnoses of peripheral edema are listed in Table 82-3.

TABLE 82-3 Causes of Peripheral Edema

Heart failure
Hypoproteinemia
Liver cirrhosis
Nephrotic syndrome
Lymphedema
Malnutrition
Gravitational edema

Examination findings are similar to those for the acute presentation, although the patient is not in extremis and is able to speak sufficiently to give a full history. A full examination is possible more often in this situation, including auscultation of the heart sounds and abdominal examination. Peripheral edema may well be extensive, up to the abdominal wall and sacral areas. The jugular venous pulse may be elevated. Patients with extensive peripheral edema but a low jugular venous pulse may have hypoproteinemia rather than heart failure.

Chest Pain

As noted earlier, ischemic heart disease is an extremely common cause of heart failure. Patients presenting with chest pain thought to be ischemic in nature must be examined closely for subtle signs of heart failure. Patients presenting with extensive MI may develop symptoms and signs of heart failure hours or days after admission. This may be precipitated by treatment (such as acute use of beta-blockers or calcium channel blockers) or by a complication of the MI, such as ventricular septal defect or mitral valve prolapse due to chordal rupture.

Collapse/Cardiac Arrest

Patients with severe heart failure of any cause are at high risk for malignant arrhythmias and thromboembolic disease such as pulmonary embolism. It is therefore not unusual for patients with severe heart failure to present with collapse or cardiac arrest. In such patients, the outlook is extremely poor. Even for patients presenting with ventricular tachycardia or ventricular fibrillation who are successfully cardioverted, the chance of surviving to discharge from hospital is low. Such patients can be considered for implantable cardioverter-defibrillators (see later and Chapter 81). Pulmonary embolism and ventricular arrhythmias are covered in Chapters 62 and 79, respectively, so will not be discussed in detail here.

image Investigations

Electrocardiography

All patients presenting with severe heart failure require at least one electrocardiogram (ECG). In cases of diagnostic difficulty, an entirely normal ECG virtually excludes systolic heart failure as the cause of symptoms.14 In heart failure, an ECG is essential to diagnose arrhythmias such as atrial fibrillation, which may complicate management, as well as to look for evidence of myocardial ischemia or infarction and conduction abnormalities such as left bundle branch block or bradycardia due to high-degree atrioventricular block, which may respond to pacing. In patients in whom ischemia is suspected, serial ECGs are recommended, as changes may evolve during the course of the patient’s treatment. Patients with acute severe heart failure should have continuous ECG monitoring during the acute phase, as they are at high risk for malignant ventricular arrhythmias. Patients with biventricular pacemakers (discussed later) in situ may have paced QRS complexes that are narrower than in those with single-chamber right ventricular leads.

Cardiac Enzymes and Other Biomarkers

All patients presenting with severe heart failure, either as a first presentation or an exacerbation, should raise the question of MI. As noted earlier, patients with ischemia often do not report chest pain in the setting of acute heart failure symptoms. Therefore, the use of biomarkers of cardiac muscle necrosis—ideally troponin I or T, assayed at presentation and repeated after 12 hours—is important for most patients presenting with heart failure, in conjunction with ECG findings, as noted earlier.

Chest Radiography

Acutely, the chest radiograph is useful mainly in cases of diagnostic difficulty. In cases in which the diagnosis is reasonably clear from clinical information, treatment should not be delayed while waiting for a radiograph. However, most patients should have a chest radiograph early in the course of the admission.

The chest radiograph may show cardiomegaly, although this is poorly sensitive or specific for a diagnosis of heart failure (NB: portable films using anteroposterior projection may exaggerate the cardiac outline). A globular heart suggests the presence of pericardial fluid, which can be determined definitively by early echocardiography. Signs of pulmonary edema range from mild blunting of the costophrenic angles, perhaps with evidence of fluid in the horizontal fissure of the right lung, to upper lobe blood diversion (due to hypoxic vasoconstriction in the edematous dependent lung and opposite changes in the relatively edema-free upper lobes), to frank pulmonary edema. The chest radiograph may reveal signs of coexistent consolidation requiring antibiotic therapy. Pacemakers are also visible on chest radiographs, and it is important to examine and count the number of pacing leads to establish whether a patient has an implantable cardioverter-defibrillator (ICD) or biventricular pacemaker present. This is particularly important if the patient is unable to give an adequate history because of their acute clinical condition.

Echocardiography

Echocardiography should be carried out early in all cases of suspected heart failure. In recent years, bedside echocardiography devices have been developed that can be useful in the emergency department to assess the left ventricle and valves initially. In all cases, a full echocardiogram should be carried out when the patient is sufficiently stabilized.

Echocardiography is useful both to determine the extent of left ventricular dysfunction and to identify the cause. In cases of ischemic cardiomyopathy, regional wall motion abnormalities are commonly seen (although these can occasionally occur in cases of cardiomyopathy of other causes). Valve disease is readily identified by echocardiography. Echocardiography can be used to calculate the left ventricular ejection fraction, but in experienced hands, a qualitative assessment of left ventricular function can be equally useful. Some patients presenting with severe heart failure have preserved systolic function, and echocardiography can also be used to assess diastolic function. In the patient presenting with shortness of breath, in whom the cause is unclear, echocardiography can readily determine the presence or absence of systolic heart failure. Although a number of diagnostic criteria have been developed for assessment of the diastolic left ventricular function, their reliability in predicting intracardiac filling pressures is not always satisfactory and needs further development.15 A clear distinction can sometimes be made only by measurements of gas exchange or blood oxygen saturation or by invasive hemodynamic measurements during graded levels of exercise following the clinical stabilization.

It is important to emphasize that heart failure is not directly equivalent to the impairment of left ventricular contractility, and there is a poor correlation between parameters of myocardial function and the symptoms. About half of heart failure patients have preserved contractility. However, prognosis for patients presenting with symptomatic heart failure is equally poor for those with normal or decreased ejection fraction.

Brain Natriuretic Peptide

Natriuretic peptides are currently emerging as a novel test in cases of heart failure. The group includes three structurally related peptides, with variable activity at three distinct natriuretic peptide receptor subtypes, of which two are of potential use in patients with heart failure. Atrial natriuretic peptide is released from the atria in response to wall stretch. Brain natriuretic peptide (BNP), so called because it was first identified in brain tissue, is mainly released by the cardiac ventricles in response to wall stretch.16 All the natriuretic peptides are elevated in acute coronary syndromes and MI, owing to release from myocytes. In addition, decompensated heart failure is associated with elevations of natriuretic peptide levels. Many possible applications for assays of these peptides have been proposed, but at present the most widely accepted indications for use of BNP (which appears to have the best sensitivity/specificity of all the natriuretic peptides) are as follows:

1 In the acutely dyspneic patient in whom there is diagnostic difficulty, a high BNP level is very suggestive of underlying cardiac failure.
2 In the dyspneic patient with no clinical signs of heart failure, a normal BNP level has a high negative predictive value—that is, it is useful in excluding heart failure as a cause.

The use of BNP for monitoring progress in heart failure is controversial; some studies have suggested that BNP may be useful to guide treatment. Indeed, many studies have found that BNP levels may have prognostic implications. It is also important to note that BNP levels must be used in conjunction with clinical assessment of the patient, as unexpected values may occur in some patients, such as a high BNP level in a stable patient. Recent findings do not support routine use of the peptides in all dyspneic patients admitted to the emergency department.17 Of particular note is the fact that patients with severe heart failure due to cardiogenic shock may exhibit a paradoxically normal or even low BNP level. It has been suggested that myocytes in such a situation are unable to produce BNP. This theory is supported by studies of serial BNP levels in patients recovering from an episode of cardiogenic shock. An initially low BNP level is followed by a high level as recovery of myocardial function begins, and as recovery continues, the level returns to normal.

However, the measurement of BNP during admission with acute decompensated heart failure may help to assess prognosis and guide therapy following stabilization.18,19 A soluble form of ST2, an interleukin 1 (IL-1) receptor family member, has also been found to be potentially useful for identifying heart failure patients at risk of sudden cardiac death and may provide additional information to BNP.20

Invasive Investigations

Central Venous Catheter

Placement of a central venous catheter may be necessary for certain drugs such as inotropic agents or amiodarone, which cannot be given into a peripheral vein. The central venous pressure measurement may give some idea as to right-sided filling pressure but does not give reliable information about the status of the left ventricle. In situations in which detailed information regarding filling pressures would affect management of a seriously ill patient, the Swan-Ganz catheter should be considered instead.

Swan-Ganz Catheter

Insertion of a pulmonary artery (Swan-Ganz) catheter may provide additional hemodynamic information. The procedure has been associated with increased mortality and therefore should be used only in severely ill patients in whom the results are likely to influence management. It is important to note that echocardiography can provide much of the information obtainable by Swan-Ganz catheterization when adequate images can be obtained.

image Treatment

Acute Treatment

Simple Measures

The patient should be in erect sitting position. High-flow oxygen therapy should be administered to hypoxic patients with pulmonary edema. A single small dose of opiate (such as morphine, 2.5 mg) may alleviate distress and also temporarily reduce cardiac preload; it is also clearly indicated for patients presenting with ischemic chest pain in addition to pulmonary edema.

Urinary catheterization is essential in the severely compromised patient to monitor urine output but may also be therapeutic to reduce the need for exertion, particularly if large doses of diuretics are to be used.

Diuretics

Although not supported by randomized trials, it is clear that IV diuretic therapy can cause rapid relief of pulmonary edema and symptoms of acute decompensated heart failure. Care is needed in patients with compromised renal function or hypotension, as diuretic therapy may exacerbate such problems. It is usual to give an initial bolus IV dose of diuretic, which should be tailored to the patient’s previous use of diuretics. A diuretic-naïve patient will usually respond to a single 50-mg IV dose of furosemide, whereas patients already taking diuretics long term may need much larger doses. Subsequent therapy is often given as further boluses of IV diuretic at intervals, although there is some evidence that a continuous infusion of diuretic may be more efficacious and cause less renal dysfunction.

Some patients with significant fluid overload may require combination diuretic therapy—for example, with the addition of a thiazide diuretic such as metolazone. Metolazone is a weak diuretic when used alone, but increased sodium delivery to, and reabsorption in, the distal renal tubule resulting from the use of a loop diuretic is blocked by metolazone, resulting in a profound diuresis. Care is needed to avoid dehydration and hyponatremia with this strategy. An alternative may be to combine furosemide with an aldosterone blocker in the acute phase.

Thromboprophylaxis

Patients with severe heart failure are often poorly mobile due to breathlessness, peripheral edema, and the presence of monitoring and treatment equipment. They are at high risk for the development of deep venous thrombosis and pulmonary embolism. The MEDENOX (prophylaxis in MEDical patients with ENOXaparin) trial, which included 1102 hospitalized patients, including 376 with NYHA class III/IV heart failure, found that 14.9% of placebo-treated patients suffered venous thromboembolism. Importantly, in the group treated with enoxaparin, only 5.5% suffered venous thromboembolism.21 This trial also included patients with other serious medical illnesses including cancer, so this may be an overestimate of the risk of thromboembolism in heart failure. In cases of moderate to severe heart failure, particularly in hospitalized patients, some of this increased risk may be related to immobility, which is a well-known risk factor for deep venous thrombosis. Indeed, in previous years when bed rest was standard treatment for patients with heart failure, the rate of pulmonary embolism was very high. All patients with severe heart failure who are not anticoagulated and in whom there are no contraindications (such as active bleeding) should receive thromboprophylaxis with unfractionated or low-molecular-weight heparin, with the dose adjusted according to the patient’s body weight.

Vasodilators: Glyceryl Trinitrate/Sodium Nitroprusside

Infusion of glyceryl trinitrate has been a standard part of therapy for pulmonary edema with preserved blood pressure for many years. It is a direct-acting vasodilator that reduces left ventricular preload and afterload by release of the potent vasodilator, nitric oxide. Glyceryl trinitrate has a very short half-life and is given by continuous IV infusion, with dose titrated according to response and the patient’s blood pressure. The most frequent adverse effect is hypotension, which is readily reversible on stopping or reducing the rate of infusion. Glyceryl trinitrate is additionally antianginal and therefore of particular benefit in the patient with ischemic chest pain and pulmonary edema. Patients receiving glyceryl trinitrate rapidly develop tolerance to the drug, which can limit its effectiveness if given for long periods.

Sodium nitroprusside is an alternative vasodilator that is also effective in patients with heart failure and preserved blood pressure. The drug is given by continuous infusion and must be protected from sunlight. However, its use is limited by concerns over the toxic effects of the metabolites of sodium nitroprusside: cyanide and thiocyanide.

Nesiritide

The natriuretic peptides have a variety of beneficial effects on the heart and circulation, causing diuresis, increasing sodium excretion, and reducing pre- and afterload by causing venous and arterial dilatation. They may also reduce left ventricular remodeling and fibrosis. These attributes have recently led to the therapeutic use of natriuretic peptides in heart failure, and short-term studies have shown that nesiritide infusion is at least as efficacious as standard therapy (dobutamine, milrinone, or glyceryl trinitrate) and is associated with reduced diuretic use in patients with acutely decompensated heart failure.22 Nesiritide (recombinant human BNP) has been approved by the U.S. Food and Drug Administration (FDA) for use in patients with acutely decompensated heart failure in whom systolic blood pressure is above 90 mm Hg. It is given by IV bolus (2 µg/kg) followed by continuous infusion (0.01 µg/kg/min) as an alternative to glyceryl trinitrate. Treatment is usually continued for 24 to 48 hours.

Inotropes

Approximately 80% of patients presenting with acute decompensated congestive heart failure have preserved blood pressure and can therefore receive cardiac load–reducing therapy such as glyceryl trinitrate or nesiritide. However, these treatments are contraindicated in hypotensive patients with heart failure. If such patients do not respond to initial diuretic therapy favorably or show evidence of deterioration, inotropic therapy may be considered. Long-term use of inotropic therapy is likely to be harmful in patients with heart failure,23 but potentially appropriate uses of inotropes include use as temporary treatment of diuretic-refractory acute heart failure decompensations or as a bridge to definitive treatment such as revascularization or cardiac transplantation.

Experimental Agents

A number of novel and promising treatments for acute decompensated heart failure are currently under clinical development. Infusion of cinaciguat (BAY 58-2667), the first of a new class of soluble guanylate cyclase activators, has potent preload- and afterload-reducing effects, thereby increasing cardiac output.24 Administration of relaxin, a natural human peptide that affects multiple vascular control pathways, improved symptoms and reduced cardiovascular death or readmission due to heart or renal failure at day 60 compared with placebo (2.6% [95% CI, 0.4-16.8] versus 17.2% [9.6-29.6]; P = 0.053). Both agents were safe and well tolerated, and further clinical development is warranted.25

Intraaortic Balloon Counterpulsation

Intraaortic balloon counterpulsation is an invasive strategy to preserve coronary flow in the presence of very poor cardiac output. A percutaneous approach is used to position a balloon in the descending aorta. The balloon is inflated during diastole, diverting blood into the coronary arteries. This technique may be used to maintain circulation to the heart and brain at the expense of other tissues as a bridge to transplantation or other surgical intervention. Use of intraaortic balloon counterpulsation is associated with a significant adverse event rate—up to 60% in one study of patients with cardiogenic shock.26 There is no definite evidence that use of intraaortic balloon counterpulsation improves the mortality rate among patients in heart failure; however, a comparison of patients from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) study showed a significantly lower rate of mortality in those undergoing intraaortic balloon counterpulsation up to 1 day after admission as compared with all other patients (57% versus 67%).27 It has been recently shown that continuous aortic flow augmentation improved cardiac performance and pulmonary capillary wedge pressure, but not clinical outcomes.28

Assisted Ventilation

Noninvasive Ventilation

Noninvasive ventilation is a form of ventilatory support that does not require paralysis and intubation. Positive pressure is provided via a tight-fitting mask that may lie over the nose only or over the full face. Some patients are unable to tolerate the mask or the sensation of assisted ventilation.

Continuous positive airway pressure (CPAP) has an accepted role in the treatment of sleep apnea syndromes. It is now recognized that sleep apnea is prevalent in patients with heart failure and may play a role in the development and progression of heart failure. In addition, noninvasive ventilation has favorable effects on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Noninvasive ventilation has been used to treat acute heart failure. Several randomized trials have suggested that use of CPAP results in more rapid increase in PaO2, decrease in PCO2, and lower rates of intubation compared with standard treatment.29 Noninvasive ventilation may be considered in patients with rising PCO2 levels despite adequate medical therapy. Its use results in decreased blood pressure, so it may have a deleterious effect in patients who are already hypotensive. To be used successfully, noninvasive ventilation requires careful attention to mask fitting and close patient observation. It should be used only in a high-dependency setting with appropriately trained staff.

Intermittent Positive-Pressure Ventilation

Patients with evidence of exhaustion or worsening arterial blood gases despite adequate treatment may require invasive ventilation. The prognosis of patients with such refractory pulmonary edema is poor, but some patients show dramatic improvement after only a short period of intermittent positive-pressure ventilation. Intermittent positive-pressure ventilation results in decreased venous return due to increased intrathoracic pressure and therefore can have a deleterious effect on blood pressure. Blood pressure must be maintained (with inotropic agents if necessary) before intubation.

Surgery

Valve Replacement

Patients with severe heart failure due to valvular heart disease or functional mitral regurgitation may benefit from valve replacement or repair. Ideally, surgery should be delayed until the patient is stable, but selected patients not improving on initial therapy may benefit from emergency valve replacement, although such patients are inherently at high risk for such major surgery. A multidisciplinary team consisting of cardiologist, cardiovascular surgeon, and intensivist/anesthetist is needed to select suitable patients for intervention. A full discussion of indications for surgery is beyond the scope of this chapter.

Left Ventricular Assist Device

Left ventricular assist devices (LVADs) are surgically implanted devices developed to allow short- or long-term support to the failing left ventricle. Commonly, an inflow cannula receives blood from the left ventricle, which is then pumped out through a cannula in the ascending aorta. Although initially used as a bridge to transplantation, some studies have demonstrated recovery of function, allowing explantation of the device after a period of left ventricular support in certain subgroups of patients together with appropriate pharmacologic therapy.30 LVAD therapy for patients with terminal heart failure but who are not eligible for heart transplantation has been shown in the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial31 to be superior to medical therapy in ameliorating symptoms and to produce a 48% mortality reduction at 2 years’ follow-up. However, the frequency of serious adverse events in the LVAD group was more than twice that in the medical therapy group, mainly due to infection, bleeding, and malfunction of the device. A number of devices are available. Choice depends on availability and local expertise.

New continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices. In one randomized trial,the continuous-flow device improved 2-year survival of patients with severe heart failure by 24% to 58%.32

The main complications of LVADs include thromboembolism, right ventricular failure, and device failure (equivalent to severe aortic regurgitation, as the devices do not have valves). Careful patient selection is necessary to gain most benefit from such devices.

Revascularization

In recent years, the phenomena of “stunned” and “hibernating” myocardium have been recognized and widely investigated. Hibernating myocardium is defined as poorly functioning myocardium caused by reduced perfusion, which may recover function if perfusion is restored. Stunned myocardium results from an episode of ischemia. The segment of myocardium regains normal blood flow after the episode, but recovery of function is delayed (although recovery occurs spontaneously). In patients with chronic ischemic cardiomyopathy, revascularization may therefore result in improvement in left ventricular function. Patients with cardiogenic shock due to acute MI have a very poor prognosis (see later discussion), and in recent years several studies have addressed the possible benefits of acute revascularization in such patients. Retrospective analysis of the patients from the GUSTO-I study with cardiogenic shock (7.2%) showed that revascularization was associated with decreased mortality rate (overall 30-day mortality, 55%; patients undergoing coronary artery bypass grafting, 29%; patients undergoing percutaneous transluminal coronary angioplasty, 22%).33

The treatments were not allocated randomly, however. The two randomized controlled trials of medical therapy versus revascularization (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock [SHOCK]34 and Swiss Multicenter Angioplasty for SHOCK [SMASH]35) had difficulties in recruitment, and both reported no significant difference in early mortality, although the SHOCK trial did show decreased mortality rate at 6 months in the intervention group. It is important to note that results from the SHOCK trial registry, which showed that patients selected to undergo angiography had better outcomes whether or not they went on to be revascularized, suggest that bias may be involved in the results of these studies. Furthermore, adding surgical ventricular reconstruction to coronary revascularization reduced the left ventricular volume, as compared with revascularization alone, but not the rate of death or hospitalization for cardiac causes.36 Current evidence certainly does not support aggressive revascularization of all patients with cardiogenic shock, but revascularization may be appropriate in selected patients.

Stabilization and Chronic Treatment

A full discussion of long-term treatment for patients with heart failure is beyond the scope of this book. However, patients presenting with acute heart failure may need to be established on a variety of medications during their index admission, and so a brief summary of the main drugs used in heart failure treatment maintenance is presented here.

Loop Diuretics

As noted earlier, loop diuretic therapy may provide rapid symptom relief in patients with fluid overload. However, loop diuretics may be associated with a number of adverse effects such as volume depletion, and no mortality benefit has been demonstrated in cases of heart failure. Although some patients with chronic heart failure may be able to have diuretic therapy withdrawn once they are appropriately stabilized, most require at least a small dose of maintenance diuretic, tailored to clinical evidence of fluid overload. Regular weighing is a simple method of monitoring the fluid status of heart failure patients. Care must be taken to monitor renal function in patients on high doses of diuretics. Diuretics may cause hypokalemia, although combining them with angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics such as spironolactone (see later discussion) may reduce this problem.

Angiotensin-Converting Enzyme Inhibitors/Angiotensin II Receptor Blockers

Multiple large randomized trials have shown that ACE inhibitors (e.g., ramipril, perindopril, lisinopril) are of unequivocal benefit in patients with heart failure and asymptomatic left ventricular dysfunction.37 All patients should be started on an ACE inhibitor as soon as possible after a diagnosis of heart failure has been made—this is almost always during the index admission. Most patients will require gradual introduction of the drug, with monitoring of blood pressure and renal function. Effort should be made to achieve the highest tolerated dose of the chosen ACE inhibitor.

Some patients are unable to tolerate ACE inhibitors as a consequence of cough due to elevated levels of bradykinin, which is usually degraded by ACE. An alternative in such patients are angiotensin II receptor blockers, which directly block the angiotensin II receptor and do not cause bradykinin buildup. There is not yet sufficient evidence on angiotensin II receptor blockers to recommend them over ACE inhibitors as first-line therapy in heart failure patients. However, the recent Candesartan in Heart Failure—Assessment of Reduction in Mortality (CHARM) study demonstrated that in patients unable to tolerate ACE inhibitors, the angiotensin II receptor blocker, candesartan, provided similar mortality benefit.38 Another arm of the CHARM study (CHARM-ADDED) showed additional benefit (reduction in the primary endpoint of cardiovascular death or hospital admission for congestive heart failure) when candesartan was added to ACE inhibitors.

Recently the Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan (HEAAL) trial showed that triple increase of losartan dose (150 mg daily compared with traditional 50 mg) is required to achieve maximal reduction of rate of death or admission in patients with heart failure.39

Beta-Blockers

For many years, beta-blockers were thought to be harmful in patients with heart failure because of their negative inotropic effect. More recently, however, several large randomized trials have demonstrated consistent benefit of beta-blockers such as carvedilol,40 bisoprolol,41 and metoprolol.42 Beta-blockers are indicated in patients with stabilized heart failure and are rarely started during the index admission. Their use involves careful dose titration, best supervised in a specialist heart failure clinic. The degree of heart rate reduction is more important than the maximal dose of beta-blocker achieved, and for every heart rate reduction of 5 bpm, there is an 18% reduction in the risk for death (but no significant relationship between all-cause mortality and beta-blocker dosing).39

Aldosterone Inhibitors

The landmark Randomised Aldactone Evaluation Study (RALES) showed that in patients with severe heart failure, spironolactone reduced mortality by 30%.43 More recently, a more selective aldosterone inhibitor, eplerenone, has been developed, which (because of its lack of action at sex hormone and glucocorticoid receptor sites) lacks the unpleasant side effects of spironolactone, such as painful gynecomastia. The recent EPHESUS study, which recruited 6642 post-MI patients with left ventricular ejection fraction less than 40% and clinical heart failure and randomized them to receive eplerenone or placebo (in addition to otherwise optimized medical therapy), demonstrated a 15% reduction in all-cause mortality among the eplerenone group after a mean follow-up period of 16 months.44 It is likely that aldosterone antagonists will be used increasingly in the management of patients with chronic heart failure.

Aldosterone blockers may cause hyperkalemia, particularly in combination with ACE inhibitors; patients on this combination should have regular renal function testing. In the EPHESUS study, the eplerenone added to standard therapy significantly improved outcomes, without an excess risk of hyperkalemia when periodic monitoring of serum potassium was performed.45

Antithrombotic Therapy

Patients with heart failure and atrial fibrillation have clear indications for anticoagulation with adjusted-dose warfarin. There is no clear evidence for the use of antithrombotic therapy in patients with heart failure in sinus rhythm, although such patients fulfill Virchow’s triad (abnormal flow, abnormal vessel wall, abnormal blood constituents) for a prothrombotic state. Recently completed trials also failed to demonstrate benefits of warfarin over antiplatelet agents in heart failure patients.46

Direct thrombin inhibitors (such as dabigatran etexilate) and factor Xa inhibitors (such as rivaroxaban) may become an alternative to warfarin and are currently being investigated for a number of indications. They have advantages over warfarin in that dose adjustment and INR monitoring are not required.

Digoxin

Digoxin therapy in patients with heart failure in sinus rhythm (i.e., for inotropic effect) is common practice in North America but is less frequently used in Europe. Evidence of benefit is somewhat limited. Withdrawal of digoxin from patients with symptomatic heart failure resulted in increased risk of heart failure decompensation.47 The Digitalis Investigation Group (DIG) trial48 demonstrated no difference in survival associated with the use of digoxin. A reduction in the risk of death from progressive heart failure in the DIG trial was balanced by an increase in the risk of sudden cardiac death. Digoxin may therefore be considered as additional therapy for patients on ACE inhibitors and beta-blockers but is not an alternative to these drugs.

Cardiac Resynchronization Therapy

Patients with heart failure may exhibit dyssynchronous contraction of the left ventricle resulting from abnormal electrical conduction pathways. Typically this results in septal contraction occurring some time before contraction of the free wall of the left ventricle. Such dyssynchronous contraction results in significant circulation of blood in the left ventricular cavity, rather than forward flow of blood. The use of biventricular pacing to restore synchronous contraction of the left ventricle (cardiac resynchronization therapy) has increased in popularity in recent years. However, the optimal method for selecting patients for cardiac resynchronization therapy is unclear. Current guidelines use duration of the ECG QRS complex, but recent studies have shown that some patients with narrow QRS complexes or even less advanced heart failure (i.e., with NYHA I-II functional class) may benefit from cardiac resynchronization therapy, and equally, not all patients with wide QRS complexes benefit.49 Echocardiographic evidence of dyssynchronous contraction in combination with the ECG might prove to be a better method of selecting candidates for cardiac resynchronization therapy. More recent findings indicate that the benefit of cardiac resynchronization therapy can be maximized by simultaneous implantation of a defibrillator.50,51

Arrhythmia Therapy

Atrial Fibrillation

Atrial fibrillation can result in significant impairment of left ventricular function due to loss of atrial contraction and abnormal left ventricular filling. Atrial fibrillation in the presence of reduced left ventricular function results in a very high risk of thromboembolic stroke, so all patients with atrial fibrillation and reduced left ventricular function should be anticoagulated in the absence of contraindications. In the presence of poor left ventricular function or dilated left ventricle or left atrium on echocardiography, DC cardioversion is unlikely to cause sustained conversion to sinus rhythm but could be considered in situations in which palpitations due to atrial fibrillations cause significant distress to the patient. Pharmacologic rate control is likely to be more successful. Digoxin is commonly used for this purpose, although in the presence of renal impairment or diuretic-induced hypokalemia, toxicity is common. If tolerated, beta-blockers may achieve rate control, although the need to introduce such drugs gradually makes them less suitable for initial rate control. It may be possible to control the rate initially with careful digoxin therapy, then consider withdrawing digoxin once the patient is established on a sufficiently high dose of beta-blocker. Amiodarone is an alternative antiarrhythmic safe for use in heart failure patients, which can be used to control atrial fibrillation, although side-effects are problematic.

Ventricular Arrhythmias

Patients with heart failure frequently suffer from sudden death. Although it is now recognized that some episodes of sudden death are caused by thrombosis such as pulmonary embolism, it is clear that malignant arrhythmias are a common cause of death in heart failure. Surprisingly, therefore, multiple trials of a variety of antiarrhythmic drugs in patients with heart failure have failed to show a mortality benefit (amiodarone)52 or have even shown a worsening of mortality (e.g., flecainide).53 Routine use of antiarrhythmic drugs in patients with heart failure is therefore not recommended. In contrast, recent studies involving the use of ICD devices in patients with reduced ejection fraction following MI have shown reduced mortality. The recent COMPANION study,54 which compared optimal medical treatment alone to optimal medical treatment plus cardiac resynchronization therapy plus or minus ICD therapy, found that combined cardiac resynchronization therapy/ICD reduced mortality but not hospitalization as compared with cardiac resynchronization therapy alone. At present, routine use of implantable cardioverter defibrillators (which in any case would be prohibitively expensive in most countries) in all heart failure patients cannot be recommended. Current indications for ICD therapy in heart failure are listed in Table 82-4.

TABLE 82-4 Indications for Implantable Cardioverter-Defibrillator Therapy in Patients with Heart Failure

Cardiac arrest due to ventricular fibrillation or ventricular tachycardia
Spontaneous sustained ventricular tachycardia
Syncope of unknown origin with inducible ventricular tachycardia or ventricular fibrillation at electrophysiologic study
Nonsustained ventricular tachycardia with inducible ventricular fibrillation/ventricular tachycardia at electrophysiologic study
Left ventricular ejection fraction < 30% at least 1 month after myocardial infarction or 3 months after coronary artery bypass grafting

Other Therapies

Anemia is common in heart failure and associated with a worse prognosis, but interventions directed at increasing hemoglobin levels (e.g., using erythropoietin) have shown inconsistent results. However a meta-analysis of randomized clinical trials suggests that administration of erythropoiesis-stimulating proteins is associated with a significantly lower risk of heart failure–linked hospitalizations.55 Similar benefits were seen with IV ferric carboxymaltose.56

Although uniform conclusions cannot be drawn at present, statin use in patients with heart failure may be indicated. Some data are suggestive of potential benefits of administration of atorvastatin and possible simvastatin in terms of the prognosis, while rosuvastatin only appears to be of use in patients with heart failure due to ischemic heart disease who have relatively low levels of BNP.57 However, treatment with statins is probably useful in those with hypercholesterolemia.

Of interest, long-acting testosterone administration has been shown to improve exercise capacity, muscle strength, and glucose metabolism in men with moderately severe heart failure, providing the basis for further development in this direction.58

image Further Management: Specialist Heart Failure Clinic

Patients with heart failure are at high risk of further admissions and sudden death. Careful follow-up and adequate secondary prevention using the drugs and devices detailed here is essential to reduce the risk of readmission and other complications of heart failure. Ideally, such patients should be followed in a specialist heart failure clinic, with access to a cardiologist specializing in heart failure, specialist heart failure nursing, and access to investigations such as echocardiography, cardiac catheterization, and BNP. Nurse-led clinics are ideal for dose titration of beta-blockers and ACE inhibitors and also provide opportunities for monitoring of fluid status and symptoms. A recent meta-analysis has shown that remote patient monitoring may facilitate reduction of deaths and hospitalizations.59 This can take place via different methods, including regular structured telephone contact between patients and healthcare providers and electronic transfer of physiologic data using remote-access technology via remote external, wearable, or implantable electronic devices. Intriguingly, patient self-monitoring of atrial pressures with implanted investigational left atrial pressure monitoring, followed by appropriate individualized adjustments of the therapy guided by these pressures, was associated with highly significant improvement of event-free survival over a median follow-up of 25 months (hazard ratio, 0.16 [95% CI, 0.04-0.68], P = 0.012).60

image Prognosis

Heart failure has a poor prognosis—diagnosis of chronic heart failure is associated with a mortality rate worse than that of many cancers.61 As noted earlier, patients with severe heart failure often present in extremis but may respond rapidly to prompt effective management. However, their inpatient course is associated with a high risk of complications such as thromboembolism (particularly in the presence of atrial fibrillation) and sudden death, even in patients who show signs of recovery from their initial event. Close follow-up and secondary preventive measures are essential to improve prognosis in this high-risk group.

image Summary

Severe heart failure is a common disorder, with high rates of mortality and morbidity. Patients often present in extremis, so good knowledge of initial treatment is essential for all physicians and emergency department staff. Patients often respond rapidly to effective initial treatment, making this a satisfying condition to treat. However, patients may also deteriorate rapidly and may require involvement of intensivists, cardiologists, and cardiac surgeons. Once stabilized, there are a number of evidence-based treatments that improve prognosis in these patients. Careful follow-up, ideally in a specialist heart failure clinic, is recommended after discharge.

Key Points

1 Severe heart failure is a common emergency presentation associated with a high rate of mortality and a high rate of morbidity among survivors.
2 Ischemic heart disease is the most common underlying cause in the Western world, although the cause may differ between ethnic groups. Severe heart failure may be the first presentation of ischemic heart disease. Other common causes are hypertensive heart disease and dilated cardiomyopathy.
3 The diagnosis of heart failure is not always straightforward—it may be confused with asthma or chronic airway disease. Classic examination findings of heart failure are not sensitive or specific and require confirmation by the early use of investigations such as echocardiography.
4 Assessment for B-type natriuretic peptide may be a useful method of ruling out heart failure in the acutely breathless patient but is not sufficiently sensitive to diagnose heart failure without additional investigations.
5 Initial therapy for an episode of severe heart failure should involve diuretic therapy, and a single dose of IV morphine can be considered. In patients with preserved systolic blood pressure, an infusion of vasodilator or recombinant BNP (nesiritide) may be considered. In patients with hypotension, inotropic agents can be considered, although studies suggest increased risk of mortality with such agents.
6 Patients who do not show evidence of improvement, or whose condition deteriorates, should be considered for additional support such as intraaortic balloon counterpulsation or assisted ventilation early. Patients with cardiogenic shock due to ischemic heart disease should be considered for revascularization.
7 Once stabilized, patients must be established on appropriate secondary preventive therapy, including angiotensin-converting enzyme inhibitors and beta-blockers. Long-term follow-up is best provided by a specialist heart failure clinic.

Annotated References

ESC Committee for Practice Guidelines (CPG)Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson Pa, et al. 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. Eur Heart J. 2008;29:2388-2442.

The last update of the recommendation of the diagnostics and management of heart failure issued by the European Society of Cardiology.

Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-90.

Current recommendation on the assessment and management of heart failure approved by the American College of Cardiology and the American Heart Association.

Halperin JL, the Executive Steering Committee, SPORTIF III and V Study Investigators. Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V). Am Heart J. 2003;146:431-438.

The ongoing SPORTIF III (open label, 23 countries) and V (double blind, 409 U.S. centers) trials are comparing ximelagatran with adjusted-dose warfarin in patients with atrial fibrillation and at least one other risk factor (including heart failure).

MERIT-HF Investigators. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007.

The benefit of beta-blockers in heart failure was proved in these randomized controlled studies (MERIT-HF, CIBIS-II, and U.S. Carvedilol Heart Failure Study), bringing to an end the idea that beta-blockade could be harmful in patients with heart failure.

Rich MW, Beckham V, Wittenberg C, et al. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med. 1995;333:1190-1195.

This trial demonstrated that a multidisciplinary intervention involving nutritional advice, counseling, patient education, and exercise training could significantly reduce readmission rates and length of hospital stay in elderly patients with heart failure.

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