1.

3 Heart failure

Section 1.3 Heart failure

Learning outcomes
On completion of this section, you will be able to: Explain the aetiology of heart failure and the risk factors associated with heart failure Describe and explain the signs and symptoms of heart failure Understand the various classifications of heart failure Describe the tests commonly used in diagnosing heart failure Explain the mechanisms of action of drugs that are used to manage heart failure Describe the roles of the various drug classes that are used in managing heart failure

Topics
Risk factors for heart failure Characteristics of heart failure Signs and symptoms of heart failure Diagnosis of heart failure Management of heart failure Multidisciplinary approaches to chronic heart failure management Heart transplantation

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Introduction
Heart failure is one of the major consequences of coronary heart disease. It is estimated that the incidence of heart failure is about one new case per 1000 population per year and is rising at about 10% per year. This increase can be partly explained by better management of acute heart conditions and an increasing elderly population. Between 0.5% and 2% of the general European population are affected by heart failure. In the UK, approximately 1.5 million people are estimated to have heart failure. Prognosis is uniformly poor if the underlying problem cannot be rectified. Between 10% and 50% of people are not expected to survive 12 months post diagnosis. Approximately 50% of all deaths from heart failure are sudden, frequently but not always, of an arrhythmic origin. Acute heart failure accounts for a total of 1 million inpatient bed days (2% of all NHS inpatient bed days) and 5% of emergency admissions.

What is heart failure?

Heart failure is normally described as a complex clinical syndrome arising from the inability of the heart to pump blood at a sufficient rate to meet the current metabolic demand. This can be caused by any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. The cardiac manifestations of heart failure are dyspnoea and fatigue, which may limit exercise tolerance, and fluid retention, which may lead to pulmonary congestion and peripheral oedema. Since not all patients have volume overload at the time of initial or subsequent evaluation, the term heart failure is preferred over the older term congestive heart failure. Approximately two thirds of patients with heart failure have underlying coronary artery disease, which may limit exercise tolerance by causing angina, or may lead to further myocardial injury by causing a myocardial infarction. Therefore, doctors should manage both the symptomatic and prognostic consequences of the patients underlying coronary artery disease in accordance with contemporary guidelines. A simple objective definition of chronic heart failure is not possible as there is no cut-off value of cardiac or ventricular dysfunction or change in flow, pressure, dimension, or volume that can be used reliably to identify patients with heart failure. The diagnosis of heart failure relies on clinical judgement, based on history, physical examination, and appropriate investigations.

Major risk factors

Next to ischemic heart disease, the two most easily identified risk factors are hypertension (both systolic and diastolic) and diabetes. In the Framingham Heart study, hypertension accounted for 39% of heart failure cases in men and 59% in women. In addition, the benefits of treating hypertension in patients who have had a prior MI are even more dramatic, with an 81% reduction in the incidence of heart failure.

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Hypertension exerts a deleterious effect on ventricular function by causing both structural and functional changes in the heart. Doctors should make every effort to control both systolic and diastolic blood pressure. Other contributory factors include age, sex (male), smoking, alcohol abuse, hypercholesterolaemia and rheumatic heart disease. Such factors can lead to reduced cardiac muscle mass, cardiac muscle damage or mechanical problems resulting in chronic heart failure. Pre-existing failure may be made worse by circumstances that place increased demands on the heart and circulation, e.g. fever, anaemia, a hot environment, hyperthyroidism, salt and water retention, and pregnancy. Patients with diabetes are not only at higher risk of developing heart failure but also tend to be more symptomatic for a given degree of systolic dysfunction and have a higher mortality than non-diabetic individuals. The early recognition and treatment of risk factors may delay or prevent the development of heart failure. In populations with a high cardiovascular risk, statins or antiplatelet therapy with clopidogrel have shown a reduction in the development of heart failure. Women with heart failure may have differences in the response to drug therapy. Several studies have shown that women may not show survival benefits with ACEIs. Women may also have a different safety profile to men, as evidenced by their higher risk of ACEI-induced cough. Heart failure is also more common in Afro-Caribbean populations, affecting approximately 3% of all Afro-Caribbean adults. They develop symptoms of heart failure at an earlier average age, possibly due to their increased risk for hypertension and diabetes, and they more frequently exhibit sodium retention, ventricular hypertrophy, and vascular injury. In addition, heart failure progresses more rapidly after diagnosis. There is no data to suggest that Afro-Caribbean and other ethnic minorities with heart failure should be treated differently. Afro-Caribbean patients may experience less efficacy from the use of ACEIs and Asian patients have a higher than average risk of ACEI-induced cough.

Characteristics of heart failure

Left ventricular dysfunction begins with some injury to, or stress on, the myocardium and is generally a progressive process, even in the absence of a new identifiable insult to the heart. The left ventricle (LV) changes in geometry and size, a process referred to as cardiac remodelling. The change not only increases haemodynamic stress on the walls of the failing heart, reducing performance, but also increases regurgitant flow through the mitral valve. These effects serve to sustain and exacerbate the remodelling process. The clinical symptoms of cardiac remodelling can be felt by the patient within months or years after the precipitating event, in the form of heart failure. Often the left ventricle fails before the right, causing pulmonary congestion. Fluid leaks from capillaries and accumulates in the walls of the alveoli of the
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lungs. Gaseous diffusion becomes less efficient since diffusion distance is increased. Fluid escaping from the capillaries can enter the alveoli, and foaming may occur as it mixes with the inspired air. As the situation deteriorates, red blood cells often escape from the capillaries into the lungs. When left-sided failure becomes acute, the right ventricle will be overloaded, causing it to fail. The right ventricle will also be overloaded in cases of COPD when pulmonary vascular resistance is increased. In either case, symptoms associated with right-sided failure include increased venous congestion and pulmonary oedema.

Signs and symptoms of heart failure

Signs and symptoms of heart failure are listed in table 4. Table 4: Signs and symptoms of heart failure (CREST guidelines, 2005) Symptoms Shortness of breath on exertion Shortness of breath on lying flat Wake up short of breath Fatigue Weight loss (muscle loss) Weight gain (oedema) Poor appetite Irregular heart beat Wheezy chest Irritating cough Dyspnoea This is the sensation of shortness of breath and suffocation and is a prominent symptom on exertion. In heart failure, the fluid accumulation in the lungs makes the tissue less elastic with less capacity to distend at each breath. Oedema This refers to accumulation of fluid in the tissues due to failure of the right and left ventricles, which become unable to pump out all the blood returned to them. This results in congestion in the liver, which swells (hepatomegaly), in the viscera and in the lower limbs and ankles due to the effects of gravity. Congestion in the lungs leads to pulmonary oedema. Orthopnoea In advanced stages, dyspnoea is precipitated by lying flat as the normal pooling of blood in the lungs, which occurs when lying flat, is added to the already congested pulmonary vascular system, leading to pulmonary oedema. Signs Tachycardia Tachypnoea Raised Jugular Venous pressure (JVP) Gallop rhythm (3rd or 4th heart sound) Fine end-inspiratory crepitations Rhonchi Dependent oedema Cachexia

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Paroxysmal nocturnal dyspnoea This causes the patient to waken during the night and results from redistribution of oedema fluid from the lower limbs to the lungs. Cough Associated with fluid in the lungs, and when the situation is very severe the sputum becomes frothy and may be blood stained. Weakness Origins of weakness and fatigue are complex, including low cardiac output, peripheral hypoperfusion, as well as skeletal muscle deconditioning. Cachexia This is a frequent complication in advanced heart failure and involves loss of muscle mass (including cardiac muscle) as well as adipose tissue. Aim to increase non-oedematous body mass with small frequent meals to lessen nausea and bloating. Tachycardia The heart rate increases, in response to sympathetic stimulation, in an attempt to preserve cardiac out-put. This may not be present in some patients, particularly in the presence of a beta-blocker. Cardiac enlargement Known as cardiomegaly, this reflects the stretching of the chambers of the heart due to increased venous return. Best seen on chest x-ray or echocardiogram. Extra heart sounds A third heart sound is usually considered to be present in patients with severe heart failure and left ventricular systolic dysfunction, however, it is not specific to heart failure. The presence of extra heart sounds may indicate a valvular cause to the heart failure. Peripheral oedema, raised venous pressure, and hepatomegaly are the characteristic signs of congestion of systemic veins. The presence of a raised jugular venous pressure (JVP) is a reliable sign of volume overload. Clinical signs of hypoperfusion include a narrow pulse pressure (see hypertension section for definition), cool extremities, altered mentation, Cheyne-Stokes respiration, resting tachycardia, and a disproportional elevation of blood urea nitrogen relative to serum creatinine. There is a poor relationship between symptoms experienced by the patient and the severity of cardiac dysfunction. However, the degree of symptoms and their response to therapy provides a basis of prognosis.
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Students should be familiar with the various descriptive terms used in heart failure: Left-sided vs. right-sided heart failure Most commonly heart failure is left-sided and systolic, i.e. associated with reduced left ventricular filling and contraction. Right-sided failure is characterised by hepatomegaly, dependent pitting oedema and, less commonly, ascites. It is most commonly secondary to leftsided heart failure. The terms do not necessarily indicate which ventricle is most severely damaged. Acute vs. chronic heart failure Acute heart failure describes a new onset acute, or decompensation of chronic, heart failure and is characterised by signs of pulmonary and/or peripheral congestion. Chronic heart failure is the most common form of heart failure. Patients may be adequately managed, therefore experiencing very little limitations, or have ongoing difficulty (see NYHA classification). The New York Heart Association (NYHA) functional classification is based on the symptoms of heart failure and their effect on the patients activity (Table 5). The severity of symptoms characteristically fluctuates, even in the absence of changes in medication. This classification system is subject to considerable inter-observer variability and is insensitive to important changes in exercise capacity. Symptom severity does not always reflect the underlying severity of the heart problem. Table 5: NYHA classification NYHA class Class I Severity of symptoms No restriction of activity at all asymptomatic left ventricular function is included in this category. Slight limitation by symptoms comfortable at rest, however, ordinary activity results in breathlessness, fatigue, palpitations, or angina. Marked limitation by symptoms comfortable at rest, however, less than ordinary activity will produce symptoms. Unable to undertake any activity without symptoms symptoms at rest that increase with any activity.

Class II

Class III

Class IV

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Systolic vs. diastolic heart failure Systolic heart failure (enlarged heart and reduced ejection fraction) Systolic heart failure is usually caused by damage to the contractile nature of the heart muscle through myocardial infarctions, ischaemic heart disease or left ventricular hypertrophy. Patients have a reduced left ventricular ejection fraction (LVEF), typically <50%. Diastolic heart failure (near normal size heart and ejection fraction) Diastole is when the myocardium returns to an unstressed length and force. Diastolic dysfunction occurs when these events are prolonged, slowed, or are incomplete. Diastolic heart failure is often diagnosed when symptoms of heart failure occur in the presence of a normal /preserved LVEF (LVEF >50%). The left ventricle has impaired relaxation and decreased diastolic compliance. As most patients have evidence of both systolic and diastolic heart failure, they should not be considered as separate pathophysiological entities. Drug treatment is similar because of the presence of co-morbid conditions (atrial fibrillation, hypertension, diabetes mellitus and coronary artery disease). Clinical characteristics alone cannot distinguish reliably between systolic and diastolic heart failure. High output vs. low output heart failure High output failure results from problems in other body systems which, in time, increase demands on the heart. Examples include anaemia, hyperthyroidism and fluid overload. In these cases, there is excessive cardiac drive which ultimately cannot be maintained. Low output failure is much more common and is generally caused by a defect of the myocardium that prevents the heart from meeting increased, or even normal, demands. Some of the main causes are listed below: Cause Coronary heart disease Effect Loss of functional muscle. This is one of the most common causes of heart failure, resulting in poor supply of oxygen and nutrients to the myocardium. If more than 40% of functional ventricular muscle is lost due to myocardial infarction, there is a high risk that patients may develop irreversible heart failure. Loss of contractility may be due to biochemical changes, e.g. breakdown of conversion of chemical to mechanical energy due to electrolyte or metabolic disorders, e.g. diabetes mellitus. Heart failure is caused by long-lasting overload of the heart muscle working against a raised resistance to outflow.

Disease of the myocardium (cardiomyopathy) Hypertension, valvular disease, aortic stenosis, obstructive lung diseases

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Responses to reduced cardiac output

When contractility is compromised, the cardiac output (CO) must be maintained in other ways. Since less blood is being pumped out of the heart, the preload will increase due to inability to deal with the venous return. The increased left ventricular end-diastolic pressure (LVEDP) or volume will result in stretching of the myocardial fibres during diastole and, up to a point, the force of contraction will be greater (Frank-Starling mechanism). Once the LVEDP increases beyond approximately 22mmHg, congestion will occur, with movement of fluid into the extracellular space, resulting in a fall in CO. The lowering of CO brings about stimulation of the sympathetic nervous system with arterial vasoconstriction resulting from alpha-adrenoceptor stimulation, and increased heart rate and contractility due to betaadrenoceptor stimulation. This will help to redistribute blood from skeletal muscle, the splanchnic bed and the skin to vital organs such as the heart, brain and lungs. Venous tone will be increased and the overall capacity of the venous bed will fall. Eventually, such high levels of sympathetic activity will predispose to ventricular arrhythmias. In severe congestive heart failure (CHF), poor kidney perfusion will lead to renin secretion and activation of RAAS, causing production of angiotensin II, a very potent vasoconstrictor. Angiotensin II stimulates release of aldosterone and the production of arginine vasopressin, another potent vasoconstrictor. The vasoconstriction reduces renal blood flow and glomerular filtration, causing salt and water retention. The overall result is an increase in blood volume, increased stiffness of the vascular wall due to accumulation of water and salt and capillary compression due to a rise in interstitial fluid. The blood flow and oxygen supply to skeletal muscle will be reduced and will severely limit exercise capacity. Increased heart rate will reduce diastolic filling time and, as this is the period during which blood flow to the heart muscle itself normally occurs, the reduced blood flow and ischemia may contribute to the reduced contractile force. Myocardial hypertrophy will occur in response to chronic increases in pressure and volume. The increase in mass of contractile tissue will reduce oxygen supply to the enlarged muscle cells since capillary diffusion distances will be increased in the thickened myocardial walls. Also, the larger the heart, the greater the stress in its walls and the greater the oxygen consumption (Laplace relationship). Chronic myocardial hypertrophy is thought to be associated with accelerated myocardial cell death. Eventually, the effect of the inappropriate compensatory adjustments will be an increase in afterload and in preload and therefore a further reduction in cardiac output. It is known that aldosterone has a part to play in producing vascular damage leading to coronary artery disease and left ventricular dysfunction and
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fibrosis. Another vascular event of aldosterone is that it appears to be able to feedback to the rest of the renin-angiotensin system and amplify the production of angiotensin II from angiotensin I. Therefore, in theory, aldosterone antagonists should also possess some ACE inhibiting properties.

Diagnosis of heart failure

The signs and symptoms of heart failure are often difficult to identify as they are frequently confused with other disorders, or are attributed to aging, obesity, or lack of conditioning. Limitations of exercise tolerance can occur so gradually that patients may adapt their lifestyles (consciously or unconsciously) to minimize symptoms, and thus fail to report them to their general practitioner. The aetiology of heart failure and the presence of exacerbating factors, or other diseases that may have an important influence on management, should be carefully considered in all cases. In Europe, reduced myocardial function secondary to a myocardial infarction is the most common cause of heart failure over the age of 75 years. Systolic hypertension (see earlier section) and cardiac hypertrophy, as well as cell loss and fibrosis may be more important causes of heart failure in the elderly and may be more likely to manifest as diastolic dysfunction. Table 6 summarises the main differences between heart failure in the middle and elderly age groups. Table 6: Factors distinguishing heart failure in the elderly from heart failure at middle age Middle age Prevalence Sex Aetiology Clinical features LVEF Co-morbidities Physician Randomised controlled trials Therapy <1% Men>women Coronary artery disease Typical Reduced Few Cardiologist Many Evidenced-based 10% Women>men Hypertension Atypical Normal Multiple Primary care Few Empiric Elderly

(From Rich MW. Am J Med 2005;118:342)

Patient history
A detailed patient history is important in the attempt to identify the cause(s) of heart failure and should include the following:

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Comments Hypertension Myocardial infarction (MI) One of the major causes of heart failure Enquire regarding past MI(s). Possible that this admission for heart failure may have been triggered by an MI. Both NIDDM and IDDM are risk factors, especially if poorly controlled. In men, DM only modestly increases the risk of heart failure. However, it increases the relative risk of heart failure more than 3 fold among women. Major risk factor Patients who have had rheumatic fever in the past may have a valvular cause to heart failure,

Diabetes

Dyslipidaemia Rheumatic fever

Known congenital heart / valve defects Coronary or peripheral vascular disease Mediastinal irradiation Exposure to cardiotoxic agents

Alcohol, smoking and illicit drug use

Patients with known atherosclerotic disease are likely to develop heart failure., Usually for treatment of cancer. Heart failure can occur years later, Heart failure can occur years after exposure to drugs. Anthracyclines (doxorubicin, daunorubicin, idarubicin), immunotherapy (trastuzumab (Herceptin)), high dose cyclophosphamide. Patients who receive trastuzumab in combination with anthracyclines are at particular risk of heart failure. Dexrazoxane may confer some cardiotoxic protection against anthracycline-based chemotherapy. Chronic alcohol consumption can be cardiotoxic and patients with alcoholinduced heart failure should abstain from alcohol. Alcohol may have other detrimental effects on the heart by precipitating arrhythmias.

Exposure to sexually transmitted diseases Thyroid disorder

Hyperthyroidism and hypothyroidism can be a primary or contributing cause of heart failure.

Phaeochromocytoma Obesity Family history of heart disease

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Precipitating Factors
In mild cases of heart failure with minimal reduction in contractility, the heart can meet the circulatory demands at rest (compensated failure). However, anything that increases cardiac work requirements may precipitate signs and symptoms of failure. Non-cardiac and cardiac precipitating factors in heart failure include: Obesity Infection Anaemia Hypertension Thyrotoxicosis Reduction or discontinuation of medication Increased physical and mental stress Excessive salt intake Cardiac arrhythmias Myocardial infarction Pulmonary embolism Alcohol abuse Drug induced thiazolidinediones have been associated with increased peripheral oedema which could precipitate and worsen heart failure in patients with underlying risk factors. Minoxidil should be avoided due to its sodium-retaining effects. Bradycardia

Essential tests
All patients at first presentation of heart failure should undergo tests to ascertain the potential cause of the heart failure and the presence of any interventions that may alleviate symptoms. Electrocardiogram (ECG) ECG changes in patients with heart failure are frequent, therefore all patients should have a 12-lead ECG at presentation. A normal ECG suggests that the diagnosis of heart failure should be reviewed. The most common treatable atrial arrhythmia is atrial fibrillation, which affects 10% to 30% of patients with chronic heart failure and is associated with a reduction in the exercise capacity and a worse long term prognosis. Chest x-ray (CXR) All patients should receive a chest x-ray. This is useful in detecting the presence of pulmonary congestion, pleural effusions and cardiomegaly. Haematology and biochemistry All patients should receive a comprehensive blood profile which should include the following tests:

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Complete blood count Anaemia may exacerbate pre-existing heart failure A raised white cell count suggests an infective cause to an exacerbation of heart failure

Serum electrolytes Hyponatraemia imparts a worse prognosis Potassium levels may be deranged due to aggressive drug therapy (hypokalaemia with diuretics; hyperkalaemia with ACEIs, ARBs, aldosterone antagonists). Even modest decreases in potassium can increase the risks of using digoxin and antiarrhythmic drugs, and even modest increases in serum potassium may prevent the utilization of treatments known to prolong life. Hence, many experts believe that serum potassium concentrations should be targeted in the 4.0 to 5.0 mmol/L range. Magnesium levels are frequently deranged in line with potassium.

Serum creatinine Renal dysfunction has emerged as one of the most potent risk markers in heart failure

Liver function tests Liver enzymes may be deranged due to poor hepatic perfusion, especially in the setting of peripheral oedema. This is usually transient as long as the congestion is treated.

Serum glucose Diabetes is a risk factor for cardiac heart disease.

Optional tests include: Urinalysis C-reactive protein and ESR B-type natriuretic peptide (BNP) - plasma concentrations of natriuretic peptides are elevated in heart failure, left ventricular hypertrophy, valvular heart disease, acute or chronic ischaemia, hypertension, pulmonary embolism, atrial fibrillation, renal insufficiency, advancing age and sleep apnoea. Thyroid function tests - heart failure due to thyrotoxicosis is frequently associated with atrial fibrillation, which may be the presenting feature of thyrotoxicosis in the elderly. Hypothyroidism may also present as heart failure. Patients on amiodarone who present with new AF or ventricular arrhythmias should always be investigated for thyroid status.

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Transthoracic echocardiogram (TTE) The single most useful diagnostic test in the evaluation of patients with heart failure is a transthoracic echocardiogram. Coupled with Doppler flow, this can determine whether abnormalities of the myocardium, heart valves, or pericardium are present and which chambers are involved. In most centres there is a long wait for an echocardiogram, therefore their use is rationalised. The most important measurement of ventricular function for distinguishing patients with cardiac systolic dysfunction from patients with preserved systolic function is the LVEF. Reproducibility of LVEF among different observers is poor, even when the same techniques are used. A low LVEF is an important prognostic marker for the development of worsening heart failure and death. Pulmonary function tests Measurements of pulmonary function are of little value in diagnosing heart failure, but they are useful in excluding respiratory causes of breathlessness. Peak expiratory flow rate (PEFR) and forced expiratory volume in 1 second (FEV1) are reduced in heart failure, but not to the same extent as obstructive airway disease. May be useful at identifying pulmonary toxicity induced by amiodarone. Cardiac catheterization Coronary angiography should be considered in patients with acute or acutely decompensated heart failure who are not responding to initial treatment. Patients with a history of ischaemic heart disease may benefit from an angiogram if not responding to anti-ischaemic treatment. Revascularisation of hibernating or ischaemic myocardium may improve heart failure, however, this has not been shown to improve outcome in controlled trials.

Management of heart failure

Although heart failure is a chronic syndrome, it does not evolve gradually. Periods of relative cardiac stability alternate with acute destabilisations. Current treatment not only concerns symptomatic improvement, but also increasingly focuses on preventing the transition of asymptomatic cardiac dysfunction to symptomatic heart failure, preventing worsening of symptoms/functional limitations of heart failure and reducing mortality. Therefore, short and long term objectives with individual therapies should be identified. In acute heart failure, the goal is to stabilise the patient with the use of medications (diuretics), some of which have not been shown to improve mortality in chronic heart failure. In chronic heart failure, the goal of therapy is to use agents which have been shown to improve mortality, reduce disease progression and minimise acute episodes leading to hospitalizations.

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Identification of the precipitating factor is important in the planned method of management. Treatment options may involve pharmacological therapy, invasive procedures, mechanical devices, surgical interventions and nonpharmacological strategies. Management plan Confirm the diagnosis of heart failure Assess the severity of the presenting symptoms and grade using the NYHA classification Determine the aetiology of heart failure and any other concomitant disease states Identify precipitating and exacerbating factors and assess how to manage these Estimate the prognosis Counsel patient and relatives Choose appropriate management (drug and non-drug therapy) Monitor progress and manage accordingly

Non-pharmacological management Patients and families require education in relation to: Daily weight monitoring A sudden unexpected weight gain or weight loss of >2kg in 3 days would need management of diuretic therapy (dose increase or dose decrease respectively) Diet The wasting of total body fat and lean body mass that accompanies weight loss is called cardiac cachexia. This is present in 50% of patients with severe heart failure. This is an important predictor of reduced survival. Patients should maintain adequate food intake. Sodium intake Reduction in dietary salt is more relevant in advanced heart failure. Patients must be warned against salt substitutes which contain potassium. Fluid intake Fluid restriction to 1.5L to 2L per day is advised in advanced heart failure. This will depend on the clinical status of the patient Obesity Smoking Alcohol intake Moderate intake is permitted. Patients with alcohol induced cardiomyopathy must not drink alcohol Compliance Early recognition of symptoms of deterioration Immunisations Should be offered an annual vaccination against influenza and vaccination for pneumococcal infection (only required once). Drugs to avoid, e.g. NSAIDs, Coxibs, corticosteroids (unless necessary)

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Exercise reduction in exercise can lead to cardiac and skeletal muscle deconditioning. It is recommended that patients should maintain exercise training within their own limitations. Sexual activity Travel High altitudes and very hot or humid places should be discouraged. Diuretic use may need to be reduced in hot / humid places. Heart failure advice line (if available) Community heart failure nurse follow-up Palliation in primary / secondary care (as appropriate)

Drug treatment
Learning activity Download the CREST Guidelines on the management of chronic heart failure in Northern Ireland from www.crestni.org.uk and familiarise yourself with the left ventricular systolic dysfunction treatment algorithm in appendix 2. (Link available on module web page)

The aim of drug treatment for heart failure is to interrupt the hearts deleterious compensatory mechanisms, that in the short term prove beneficial, but ultimately lead to a reduction in cardiac output and symptoms of heart failure. Combination therapy is nearly always necessary.

Diuretics
Diuretics remain an essential part of treatment and should be considered for all patients with signs of sodium and water retention. They act by increasing renal excretion of sodium and water, thereby reducing plasma volume, which, in turn, reduces venous return and preload. Hence, lung and heart congestion are relieved and peripheral oedema is decreased. Movement of oedema fluid can be conveniently monitored in terms of weight loss, which should be no more than 1kg per day. If this is exceeded, the circulatory volume will drop; this may lead to hypotension since removal of oedema fluid depends on the rate at which it can be transferred from tissues to the circulation. Diuretics produce symptomatic benefits more rapidly than any other drug in heart failure. They can relieve pulmonary and peripheral oedema within hours and days, whereas the clinical signs of digoxin, ACEIs and beta-blockers may take weeks and months to become apparent. In intermediate-term studies, diuretics have been shown to improve cardiac function, symptoms, and exercise tolerance in patients with heart failure. There have been no long-term studies in patients with heart failure, therefore their effects on morbidity and mortality are unknown, Loop diuretics, thiazides and metalozone are used at various stages of heart failure. In mild heart failure, a thiazide diuretic may control symptoms,
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however, as heart failure worsens, a loop diuretic is usually necessary. At equivalent doses, all loop diuretics (furosemide, bumetanide, torasamide) produce a comparable increase in urine. In the IV form, they are the mainstay of emergency treatment for acute left-sided failure, either as single doses or as a continuous infusion. Furosemide is particularly useful in acute pulmonary oedema due to its rapid vasodilator action. Loop diuretics are active within one hour of oral administration and the diuresis will be complete within 6 hours. They maintain their effectiveness until the GFR falls below 5ml/min, whereas, the thiazide diuretics lose their effectiveness in patients with impairment of renal function. If the loop diuretics prove ineffective, then metolazone can be added. This acts on the distal tubule and therefore has a synergistic action when used with loop diuretics, but may cause profound diuresis and electrolyte imbalance, and should be used with care. As diuretics stimulate the RAAS, addition of an ACEI will reduce the rise in angiotensin II, therefore enhancing the effectiveness of diuretic therapy. Side effects include: Hyponatraemia Hypokalaemia / hypomagnesaemia - chronic heart failure is associated with reduced total body potassium. Elderly patients are particularly susceptible since they have a reduced dietary intake, decreased body stores and less effective renal conservation of potassium Hypotension Nausea, GI upset Tinnitus

The response to a diuretic is dependent on the concentration of the drug and the time course of its entry into the kidney. Patients with mild heart failure respond favourably to low doses of diuretics because they absorb diuretics rapidly from the bowel and deliver these rapidly to the renal tubules. As heart failure advances, the absorption of the drug may be incomplete and delayed by bowel oedema and intestinal hypoperfusion, and the delivery of the drug and response to a given intratubular concentration may be impaired by a decline in renal perfusion and function. Therefore, patients with worsening heart failure often require increasing doses of loop diuretics. Furosemide bioavailability is greatly influenced by gastrointestinal oedema. In such cases, replacement of furosemide with torasemide may improve matters because the bioavilability of the latter is not reduced in patients with heart failure. Due to the better absorption of torasemide, a more stable diuretic treatment may be achieved with a reduction of readmissions for heart failure. Further increases in the dose of loop diuretics may require twice daily dosing due to their short half-lives. In a motivated patient, the dose of diuretic can be self-managed within individualised limits based on changes in symptoms and fluid balance. This form of practice should be encouraged. Optimal use of diuretics is the cornerstone of any successful approach to the treatment of heart failure.
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Potassium sparing diuretics (with the exception of spironolactone) should only be used if hypokalaemia persists despite an ACEI or ARB.

Agents that inhibit the Renin-Angiotensin-Aldosterone-System (RAAS)

Inhibition of the RAAS can take place at several levels (figure 15): 1. At the conversion of angiotensin I to angiotensin II (ACEI). 2. At the angiotensin II receptor (ARBs). 3. At the receptor for aldosterone (aldosterone antagonists)

Vasocontriction Cell growth Na /H O retention Sympathetic system

+ 2

Angiotensinogen
Renin Blocker

ARB

renin Angiotensin I
ACEI

AT1

Angiotensin II ACE Aldosterone AT2

Inactive Fragments
Aldosterone Antagonists

Vasodilation Endothelial protection Slow contraction Antiplatelet aggregation

Bradykinin

Cough Angioedema

Fluid retention

Vasodilation Antiproliferation
(kinins)

Figure 15: Renin-Angiotensin Aldosterone System (RAAS)

Angiotensin converting enzyme inhibitors (ACEIs)

ACEIs improve symptoms, reduce event rates and reduce mortality in chronic heart failure. The benefits seem to be more marked with more severe left ventricular systolic dysfunction, although there is benefit for all NYHA classes. High doses of ACEI do not necessarily improve symptoms or prolong life more than low doses, but do appear to be more effective in reducing the risk of hospitalizations. ACEIs should be used in all patients with a recent or remote history of MI, regardless of EF or presence of heart failure, and should be used in patients with a reduced LVEF and no symptoms of heart failure, even if they have not experienced an MI.
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Learning activity Familiarise yourself with the algorithm for the use of ACEI in chronic heart failure in the CREST Guidelines on the management of chronic heart failure in Northern Ireland.

ACEIs act on both the venous and arterial sides of the heart by means of their inhibitory effect on the RAAS, reducing preload and afterload. Although their action on the RAAS is important, in the long-term their beneficial effect continues regardless of plasma renin levels. They may also reduce ventricular dilatation, and therefore prevent and reduce the hypertrophy (ventricular remodelling) which may ultimately result in failure, and they have the potential to decrease ventricular arrhythmias, possibly resulting from reduced sympathetic tone and increased production of prostacyclins. Several randomised trials indicate that early intervention with ACEIs or ARBs significantly reduces the occurrence of heart failure in high cardiovascular risk populations, such as patients with previous cardiovascular disease, diabetes and hypertension. ACEIs should be initiated at low doses and titrated upwards to the doses shown to be effective in trials. They should not be titrated based on symptomatic improvement. Although symptoms may improve in some patients within the first 48hours of therapy, the clinical responses to these drugs are generally delayed and may require several weeks, months, or more to become apparent. Abrupt withdrawal of treatment with an ACEI can lead to clinical deterioration and should be avoided unless needed for life-threatening complications (i.e. angioedema). Side-effects of ACEIs include: Hypotension especially in patients heavily pre-treated with diuretics reduced by stopping the diuretic for 2-3 days before starting the ACEI. Patients with a systolic BP <100mmHg should have an ACEI started under specialist medical care. ACEIs to be used with caution if systolic <80mmHg. Cough on average 10% of European patients will experience a cough with an ACEI, this rises to 50% in Chinese patients. Only troublesome cough should be an indication for switching to an ARB. A cough may often be due to heart failure or concomitant diseases (e.g. respiratory disease or pulmonary fibrosis induced by amiodarone) Worsening renal function Moderate renal insufficiency is not a contraindication. A rise in serum creatinine of 10-15% is expected with ACEI. Creatinine levels either will remain stable or decrease to pre-treatment levels on continuous therapy. A temporary reduction in the dose of diuretic can improve matters. Use with caution with serum creatinine >200 mol/L.
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Hyperkalaemia Use with caution if potassium levels of >5.0 mmol/L. ACEIs should be avoided if levels >5.5 mmol/L - this may necessitate discontinuation of the ACEI. Risk is highest in patients with impaired renal function, taking other drugs known to conserve potassium and diabetes Angioedema occurs in <1% patients. More frequent in AfroCaribbean population.

If an ACEI has been initiated or up-titrated whilst in hospital, the patients general practitioner must be informed that regular monitoring of renal function is recommended at 1-2 weeks post discharge, then at regular 3-6 month intervals, depending on patients renal function.

Angiotensin II receptor blockers (ARBs)

There is some evidence that ARBs have a similar benefit in heart failure to ACEIs, therefore, an ARB can be used as an alternative in ACEI intolerance. A number of studies have reported on the effectiveness of ARBs in heart failure. The Candesartan in Heart Failure Assessment of Reduction in Morbidity and mortality (CHARM) study showed that candesartan reduced cardiovascular death and hospitalizations better than placebo. The ELITE II study showed that losartan was not as effective as captopril and the LIFE study showed that treating patients with losartan, who were hypertensive, reduced the incidence of left ventricular hypertrophy, which subsequently reduced the risk of atrial fibrillation developing. ACEI plus an ARB In the Valsartan heart failure trial (Val-Heft), the addition of valsartan to background therapy, including ACEI, reduced significantly heart failure hospitalizations and improved signs/symptoms of heart failure and quality of life. In CHARM, candesartan in addition to an ACEI significantly reduced the primary outcome of cardiovascular death or hospital admission for heart failure by 15%. These results suggest the beneficial role of dual inhibition of the renin angiotensin system. The higher risk of hypotension/ dizziness, hyperkalaemia and renal impairment indicate need for careful monitoring. In post-myocardial infarction with left ventricular dysfunction or heart failure, the valsartan in acute myocardial infarction trial (VALIANT) showed the combination of an ARB and an ACEI had similar efficacy compared to treatment with either agent alone, but was associated with a higher incidence of side-effects. Similar to other treatments for heart failure, doses of an ARB should be aimed at those found to be effective in trials.

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Aldosterone receptor antagonists

Learning activity Familiarise yourself with the algorithm for the use of spironolactone in heart failure in the CREST Guidelines on the management of chronic heart failure in Northern Ireland

Spironolactone is a direct aldosterone antagonist and, whilst aldosterone is indirectly suppressed by ACEI, this is transient and incomplete. In low doses, spironolactone is not considered as a potassium sparing diuretic, and produces very little diuresis. The lack of long-term aldosterone suppression by both ACEIs and ARBs is important, because experimental data suggests that aldosterone exerts adverse effects on the structure and function of the heart, independently of, and in addition to, the deleterious effects produced by angiotensin II. Aldosterone antagonists are recommended in addition to ACEIs, betablockers and diuretics in advanced heart failure (NYHA III-IV) to improve survival and morbidity. The RALES mortality trial showed that spironolactone 12.5mg-50mg once daily on top of an ACEI, a loop diuretic and digoxin markedly and progressively improved the survival of patients with advanced heart failure, irrespective of aetiology. The risk of death was reduced from 46% to 35% (30% relative risk reduction) over 2 years, with a 35% reduction in heart failure hospitalisations and an improvement in functional class. Eplerenone, a more selective aldosterone antagonist, was shown to reduce mortality by 15%, as well as the number of patient admissions with acute heart failure. Eplerenone is currently considered as second line to spironolactone intolerance. It has a much lower incidence of gynaecomastia due to more selective binding to the mineralocorticoid receptor rather than the androgen receptor. Side-effects of aldosterone receptor antagonists include: Painful gynaecomastia - developed in 10% of patients in the RALES trial with spironolactone due to the drugs affinity for androgen receptors. Hyperkalaemia due to inhibition of potassium excretion both eplerenone and spironolactone. If potassium >6.0 mmol/L or creatinine >350 mol/L, stop spironolactone. Risk is increased in renal dysfunction.

The potential benefits of decreased death and hospitalizations for heart failure must be balanced against the risk of life-threatening hyperkalaemia when selecting patients for treatment with aldosterone antagonists. They should be avoided if serum creatinine clearance <30ml/min. Under circumstances where monitoring for hyperkalaemia or renal dysfunction is not feasible, the risks may outweigh the benefits of aldosterone antagonists.
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Although aldosterone antagonists usually have relatively weak diuretic effect, some patients may experience marked potentiation of other diuretic therapy. Fluid depletion can occur, which further increases the risk of renal dysfunction and hyperkalaemia. Care is required in prescribing spironolactone to heart failure patients with diabetes in whom hyporeninaemic hypoaldosteronism is common and diligent monitoring of serum potassium concentration is required. All patients should be counselled to avoid high potassium-containing foods.

Beta-adrenoceptor antagonists

Learning activity Familiarise yourself with the algorithm for the use of beta-blockers in chronic heart failure in the CREST Guidelines on the management of chronic heart failure in Northern Ireland

Beta blockers principally inhibit the adverse effects of the sympathetic nervous system in patients with heart failure, and these effects far outweigh their well known negative inotropic effects. Whereas cardiac adrenergic drive initially supports the performance of the failing heart, long term activation of the sympathetic nervous system exerts deleterious effects that can be antagonised by the use of beta-blockers. Deleterious effects of the sympathetic nervous system in heart failure include: Increased ventricular volumes and pressure due to peripheral vasoconstriction Impairment of sodium excretion by the kidneys Induce cardiac hypertrophy but restrict the ability of coronary arteries to supply blood to the thickened ventricular wall, leading to myocardial ischaemia Provoke arrhythmias Increase heart rate and oxidative stress Trigger programmed cell death or apoptosis

Due to the nature of their action in decreasing the contractility of the heart (negatively inotropic), beta-blockers given acutely in conventional doses can greatly exacerbate heart failure. However, started in stable patients with low doses and titrated slowly up to the doses recommended in trials (start low, go slow approach) they can improve the condition. In several large randomised placebo-controlled trials, carvedilol (US carvedilol heart failure study group, 1996), bisoprolol (CIBIS-II, 1999) and metoprolol succinate (MERIT-HF, 1999, RESOLVD, 2000) have been associated with long-term reduction in total mortality, cardiovascular mortality, sudden death and death that is caused by progression of heart

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failure. Beta-blockers also reduce hospitalisations, improve the functional class and lead to less worsening of heart failure. Beta-blockers have an additive effect to ACEIs and the combination should be recommended, as documented in both the SOLVD and SAVE trials. Beta-blockers are recommended for patients with stable disease (NYHA class II-IV), although, since there may be differences in out-come among the group, only those that have been studied in heart failure should be recommended (bisoprolol, carvedilol, nebivolol and metoprolol succinate). The 1-selectivity of both metoprolol and bisoprolol is lost at the higher doses used in heart failure, therefore, caution is required in patients with unstable reversible airway disease. During the initiation of a beta blocker the heart rate may be excessively reduced leading to fluid retention and precipitating heart failure. Those patients with fluid retention before initiation are at higher risk. Patients can detect this by an increase in body weight. Therefore, doctors must ensure that patients are not fluid overloaded before starting beta-blockers. To compensate for this initial effect, the dose of diuretics may need to be temporarily increased. Patients must be counselled on temporary symptomatic deterioration (estimated 20-30% of cases) during the initiation / up-titration phase. The CREST guidance advises, if there is increasing congestion on initiation or up-titration of a beta-blocker, then double the dose of diuretic and/or halve the dose of beta-blocker (if increasing diuretic does not work). If there is marked fatigue (and/or bradycardia), halve the dose of the beta blocker. If serious deterioration occurs, halve the dose of beta-blocker or stop this treatment (rarely necessary) and seek specialist advice. Clinical response can be delayed and may require 2 to 3 months to become apparent. The order of drug therapy in patients with heart failure has been in debate for some time. Most recommendations are to initiate with an ACEI. The study, CIBIS III, hinted that in patients with NYHA class II or III heart failure over the age of 65 years, initiating therapy with a beta-blocker followed by an ACE, rather than the reverse, reduced overall mortality. The main benefit was a significant reduction in the risk of sudden cardiac death, but a slight increased worsening of heart failure.

Cardiac glycosides
Digoxin exerts its effects in heart failure due to its ability to inhibit the sodiumpotassium ATPase (Na/K-ATPase) pump. In cardiac tissue this leads to a transient increase in intracellular sodium, which in turn promotes an influx of calcium, increasing the contractile state of the heart and a theoretical risk of increased arrhythmias. For decades the effects of digoxin in heart failure were assumed to be due to this positive inotropic effect. However, it is now believed that the benefits of digoxin in heart failure are due to effects on the Na/K-ATPase pump in non-cardiac tissue. Inhibition of the Na/K-ATPase
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pump in the vagal afferent fibres acts to sensitize cardiac baroreceptors, which in turn reduce the sympathetic outflow from the central nervous system. Inhibition of the Na/K-ATPase pump in the kidneys reduces the renal tubular reabsorption of sodium. The resulting increase in the delivery of sodium to the distal tubules leads to the suppression of renin secretion from the kidneys. Sinus slowing and atrioventricular (AV) nodal inhibition results from parasympathetic activation. The extent of the inhibitory effect on the AV node depends partly on the degree of vagal tone, which varies from person to person. Although digoxin is only a weak positive inotrope, it does have a unique profile of properties. It slows down the ventricular rate, especially in atrial fibrillation, which allows better ventricular filling. It also decreases the sympathetic drive generated by the failing circulation, which provides the rationale for its use in heart failure in sinus rhythm. The combined inotropicbradycardic action of digoxin is unique when compared to many sympathomimetic inotropes that all tend to cause tachycardia. Digoxin is the glycoside used most frequently in Europe. In the DIG trial, in 6800 patients with an ischaemic or non-ischaemic cardiomyopathy and mild to moderate heart failure, long-term digoxin did not improve survival. A small decrease in death from heart failure was offset by an increase in the risk of death from other causes. A significant reduction was observed for hospitalisations for heart failure and all-cause hospitalisations. The benefit of digoxin in heart failure is the reduction of symptoms and improvement in clinical status, and thereby to decrease the risk of hospitalisation for heart failure without an impact on survival. Digoxin is also indicated in atrial fibrillation (AF) with any degree of heart failure. Digoxin slows the ventricular response to AF and improves ventricular function and symptoms. Digoxin slows the atrio-ventricular conduction more effectively at rest than during exercise. Hence, digoxin does not block the excessive exercise-induced tachycardia that may limit the functional capacity of patients with heart failure. Beta-blockers are more effective than digoxin during exercise and are preferred due to their favourable effects in heart failure. The combination of digoxin and a beta-blocker in the treatment of AF is superior to either agent used alone. Digoxin should not be used in patients with bradycardia, second or third degree AV block, sick sinus syndrome, carotid sinus syndrome, WolfParkinson-White syndrome, hypertrophic obstructive cardiomyopathy (since the inotropic effect can worsen the obstruction), hyperkalaemia / hypokalaemia. There is no reason to use loading doses of digoxin to initiate therapy in patients with heart failure, unless treating patients with AF. There is currently debate as to the optimal digoxin blood levels for heart failure. Currently 1- 2ng/ml is the level aimed for. Levels as low as <0.5ng/ml may be beneficial. 0.5 to 1.0ng/ml is recommended in the United States. In the DIG trial, risk-adjusted mortality increased as the plasma concentration
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exceeded 1.0ng/ml. This trial recommended a concentration range of 0.5 to 0.8ng/ml. Digoxin is renally excreted. In mild renal failure, the daily dose should be reduced accordingly. Side-effects of digoxin include: Cardiac arrhythmias (ectopic and re-entry cardiac rhythms and heart block) Gastrointestinal (anorexia, nausea, vomiting) Neurological (visual disturbances, disorientation, confusion)

Usually, digoxin toxicity occurs with levels >2ng/ml. However, in the presence of hypokalaemia and hypomagnesaemia, it can occur at much lower plasma levels. Digoxin should not be used in patients with a low ejection fraction, sinus rhythm, and no history of heart failure symptoms, since, in this population, the risk of harm is not balanced by any known benefit. The National Institute for Health and Clinical Excellence NICE) advocate a progressively more specialist approach to the treatment of heart failure as new drugs are added to the treatment regimen (figure 16).

Generalist
New diagnosis

Add Diuretic Diuretic therapy is Likely to be required to control Congestive symptoms And fluid retention

Start ACE Inhibitor and Titrate upwards

Or if ACEI not tolerated consider Angiotensin-II Receptor antagonist

Specialist input

Add Digoxin If a patient in sinus Rhythm remains symptomatic despite therapy with diuretic, ACEI (or Angiotensin-II receptor antagonist) and a beta blocker. Or if a patient is in atrial fibrillation then use as first line therapy

Add beta-blocker and Titrate upwards

Add Spironolactone If patient remains moderately to severely Symptomatic despite optimal drug therapy listed above

Specialist

Seek specialist advice For further options

Figure 16: NICE Guidance on treating symptomatic Heart Failure

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Vasodilator agents
Table 7 lists the actions of vasodilator drugs used in heart failure. Table 7: Vasodilator drugs used in heart failure Drug ACEI Calcium channel blockers Glyceryl trinitrate Hydralazine Isosorbide di/mono nitrates Nitroprusside Prazosin Reduction in preload (venodilator) ++ + +++ 0 +++ + + Reduction in afterload (arterial vasodilator) ++ ++ + +++ + +++ ++

Hydralazine and isosorbide dinitrate combination In patients who cannot tolerate an ACEI or ARB or where they are contraindicated, the combination of high dose hydralazine (up to 300mg) and isosorbide dinitrate (up to 160mg) is an alternative. The hydralazine is an arterial vasodilator with relatively little effect on venous tone, whereas nitrates are predominantly venodilators. The rationale for combined use is to achieve both venous and arterial vasodilation. In a trial comparing the combination with enalapril, the combination increased exercise performance more than enalapril. A 2004 trial in Afro-Caribbean patients with heart failure showed the combination to reduce mortality and morbidity and improve quality of life. The combination is less effective than an ACEI in the treatment of heart failure and is less well tolerated. Nitrates Nitrates (glyceryl trinitrate, isosorbide mononitrate) are used as adjunctive therapy for angina and relief of dyspnoea. If heart failure is complicated by severe aortic stenosis, the use of nitrates should be reconsidered. Nitrate therapy may decrease symptoms of dyspnoea at night and during exercise and may improve exercise tolerance in patients who have persistent limitations despite optimization of therapy. Recent evidence suggests that nitrates can inhibit abnormal myocardial and vascular growth and may thereby attenuate the process of ventricular remodelling and improve symptoms. Calcium channel blockers (CCBs) In heart failure caused by systolic dysfunction (EF <40%), CCBs are not recommended, particularly the non-dihydropyridine CCBs (diltiazem,
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verapamil) as they are negatively inotropic. Newer long acting dihydropyridine CCBs (felodipine, amlodipine) do not improve or worsen heart failure. They should be considered only to treat concomitant angina or hypertension.

Inotropic agents
Table 8 lists the actions of inotropic drugs used in heart failure. Table 8: Inotropes used in heart failure Dobutamine Receptors Inotropic effect Arteriolar vasodilation Vasoconstriction Chronotropic effect Blood pressure effect Diuretic effect (direct) Arrhythmia potential 1>2> High dose 0 Dopamine Dopaminergic >; high dose High dose 0, High dose High dose Norepinephrine 1>>2 0 Epinephrine 1=2> High dose 0, 0 Isoprenaline 1>2 0 0 Milrinone PDE inhibitor 0 0 0

= increase; 0 = no change; = decrease (Adapted from: Drugs for the Heart, 6th edition. Lionel H Opie, Bernard J Gersh) Sympathomimetic agents could benefit the acutely failing heart: 1-stimulation has an inotropic effect, 2-stimulation produces afterload reduction (peripheral arterial vasodilation), and alpha-stimulation restores pressure in hypotensive states. Intravenous inotropic support is used to correct haemodynamic disturbances during acute decompensated heart failure. Prolonged inotropic therapy increases mortality. Dobutamine is most often used. However, tachyphylaxis, tachycardia, induction of malignant tachyarrhythmias, and/or myocardial ischaemia hinder its use. Rapid weaning from this agent can cause deterioration in some patients for whom a slower wean can be successful. Long term inotropic therapy is used in palliation for patients with end-stage disease who cannot be stabilized with standard medical treatment.

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Anti-thrombotic / anticoagulant therapy

Patients with heart failure have a higher risk of thromboembolic events due to: 1. Low cardiac output with relative stasis of blood in dilated cardiac chambers 2. Poor myocardial contractility (low ejection fraction) 3. Regional wall motion abnormalities and concomitant atrial fibrillation. Ischaemic heart disease is the most common cause of heart failure and antiplatelet therapy has been used effectively to reduce the risk of myocardial infarction and death in ischaemic heart disease. Left ventricular thrombi are detected in patients with heart failure ranging from <3% to 40% depending on which study is examined. It remains uncertain whether ventricular thrombi detected by echocardiography increase the risk of embolisation, as most thrombi remain stable and do not embolise. Embolic events are probably related to thrombi that are not visualized. Aspirin should be avoided in patients with recurrent admissions with heart failure, as aspirin may theoretically reduce the effectiveness of ACEIs. Clopidogrel should be used as an alternative in those patients. The prophylactic use of aspirin in patients with heart failure but without known ischemic heart disease may well be inappropriate. Oral anticoagulation with warfarin is used in patients with concomitant atrial fibrillation and patients with severe myocardial wall motion abnormalities because of the increased incidence of clot formation in these disorders.

Antiarrhythmics
Antiarrhythmic drugs should be avoided if possible in patients with heart failure due to their negative inotropic effects and their proarrhythmic effects. Class 1 agents (quinidine, procainamide, flecainide) may provoke fatal ventricular arrhythmias, have an adverse haemodynamic effect and reduce survival. Only beta-blockers and amiodarone are recommended in heart failure; beta-blockers as they reduce sudden death in heart failure, although, due to its extensive toxicity, amiodarone should not be considered as part of the routine treatment of patients with heart failure.

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Summary of drug treatments

Table 9 summarises recommendations taken from the European Society of Cardiology on treating patients with left ventricular dysfunction. Table 9: Treatment of left ventricular dysfunction (European Society of Cardiology) Stage of heart failure Asymptomatic LV dysfunction Symptomatic HF (NYHA II) Worsening HF (NYHA III-IV) End-stage HF (NYHA IV) ACEI Indicated ARB ACEI intolerance With or without an ACEI With or without an ACEI With or without an ACEI Diuretic Not indicated Indicated Betablocker Post-MI Aldosterone antagonist Recent MI Digoxin In AF

Indicated

Indicated

Recent MI

Indicated

Indicated combination of diuretics Indicated combination of diuretics

Indicated

Indicated under specialist care Indicated under specialist care

Indicated

(a) In AF (b)Symptom control Indicated

Indicated

Indicated

Multidisciplinary approaches to chronic heart failure management

Since heart failure generally involves both hospital and community-based health services, incorporating many healthcare professionals, it is important that there is good communication. To improve the service to heart failure patients, many health authorities have introduced heart failure teams. Heart failure teams include lead physicians, specialist nurses and, in some cases, a pharmacist. Heart failure nurses working within both hospital and community have been shown to improve patient outcomes. Specialist nurse-led heart failure clinics have been shown to improve both survival and self-care behaviour in patients with chronic heart failure. The combination of a pharmacist and a clinical nurse specialist working in a heart failure team has been proven to reduce the number of admissions and readmissions for heart failure. (Lock J. The benefit of adding a pharmacist to the heart failure team. Hospital Pharmacist Feb 2004;10:81-83).

Heart transplantation
Patients with severe heart failure with no alternative form of treatment should be considered eligible for heart transplantation. Although no studies have been conducted, it is considered to significantly increase survival, exercise capacity and quality of life. Besides the problem with lack of donor hearts, patients have to face the risk of tissue rejection and a high mortality rate within the first year. Long-term effects are related to the immunosuppressant

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medication that is needed to prevent rejection (myocardial infarction; hypertension; renal disease; malignancy). Contraindications for cardiac transplantation include: Age >60 years (some variations between centres) Alcohol/drug abuse Uncontrolled psychiatric illness Uncontrolled infection Severe renal/liver failure High pulmonary vascular resistance Systemic disease with multi-organ involvement Treated cancer in remission but with <5 years follow-up Recent thromboembolism Other disease with a poor prognosis

New drug management

Investigational drug therapies currently undergoing phase III evaluation for the treatment of heart failure include: Vasopressin receptor antagonists Intermittent nesiritide infusions Levosimendan

Vasopressin Receptor antagonists The primary function of vasopressin (also known as arginine vasopressin (AVP) and antidiuretic hormone) is to regulate the bodys water content and blood pressure by influencing the rate of water excretion by the kidney. Vasopressin is increased in patients with CHF. Two agents, conivaptan and tolvaptan are antagonists at various vasopressin receptors and have been tested in patients with heart failure, although trials so far have been disappointing. The ACTIV CHF trial investigated tolvaptan in 319 patients with a LVEF <40%. There was an improvement in natraemia and diuresis, however, at the end of the trial, the degree of CHF worsening was the same as placebo. Side effects were dry mouth and thirst, and the dropout rate was relatively high at 33%. Further studies are underway to fully examine this class of dugs in the management of heart failure. Nesiritide B-type natriuretic peptides (BNP) are released as an adaptive response to pressure and volume overload in the cardiovascular system. The action of BNP is: Vasodilation Diuresis Natriuresis Neurohormonal inhibition
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Coronary vasodilation

They therefore act to relieve dyspnoea and oedema. Nesiritide,is a new class of vasodilator, developed for the treatment of acute heart failure. It is a recombinant human brain natriuretic peptide identical to the endogenous peptide produced in the ventricles. It has venous, arterial, and coronary vasodilatory properties that reduce preload and afterload, and increases cardiac output without a direct inotropic effect. Recent studies have shown it to improve subjective dyspnoea score as well as inducing significant vasodilation when given intravenously to patients with acute heart failure. However, the effect on morbidity and mortality has not been clear from trials. Levosimendan Current inotropes have failed in improving medium term outcome, mainly due to increased myocardial exhaustion and ventricular arrhythmias. Levosimendan is a calcium sensitizer. It increases contractility without increasing intracellular calcium ions. This has the benefit of not increasing the incidence of ventricular arrhythmias that occur due to an increase of intracellular calcium. In addition, levosimendan is a potassium channel agonist, leading to vasodilation. The LIDO study was set up to compare a 24 hour infusion of levosimedan with dobutamine in patients with severe low output failure. Even though the results were in favour of levosimendan, the study had drawbacks in its design. The haemodynamic effects of levosimendan, unlike those of dobutamine, are not attenuated by the concurrent use of beta-blockers. There is a theoretical additive effect by combining levosimendan with dobutamine as they act on different receptors.

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