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• Left ventricular (systolic) function is impaired, with poor output leading to increased left atrial and pulmonary venous pressures with pulmonary congestion and oedema.
Right-sided failure
• Right-sided failure is often due to chronic lung disease (cor pulmonale).
• Right ventricular output falls, leading to increased venous pressure, with peripheral oedema.
Biventricular failure
• Both main chambers are affected because left and right ventricular failure often coincide.
Diseases such as IHD may have affected both ventricles.
• Often, left ventricular failure leads to pul-monary congestion, which in turn impairs right ventricular function, causing failure on the right side as well.
Clinical features
As one might predict from a failure of the heart to meet circulatory needs, cardiovascular-related features are:
• reduced ejection fraction (<45%), as identified on an echocardiogram; this leads to impaired exercise tolerance
• hypotension, leading to tiredness and possibly dizziness
• reduced urine flow
• cold peripheries Lungs:
oedema−
dyspnoea left−sidedin failure
Preload
Aldosterone Angiotensin II
ACE Renin
Kidney Afterload
Sympathetic nervous system
Risk of atrial fibrillation and thromboembolism
Na+ + water retention +
+ +
+ +
+ +
+
Figure 15.1 Schematic diagram of the principal pathophysiological changes and interactions in chronic heart failure.
Activation of the renin–angiotensin systems leads to increased levels of angiotensin II (via angiotensin-converting enzyme [ACE]) which activates the release of aldosterone, promotes sodium retention, and causes arterial and venous vasocon-striction, and cardiac remodelling. The sympathetic nervous system also stimulates renin release and causes both arterial and venous vasoconstriction. Aldosterone promotes sodium retention and is associated with cardiac fibrosis. Sodium and water retention increase the circulating volume, with increases in preload and afterload.
• breathlessness
• oedema.
With associated, non-specific symptoms:
• fatigue, listlessness
• poor exercise tolerance (determines grade)
• weight loss or even gain due to oedema.
Left ventricular failure
The key feature is pulmonary oedema, which leads to dyspnoea with a sensation of drowning.
There is often marked orthopnoea, because lying down leads to further venous congestion, which is relieved on sitting up or standing. This is par-ticularly pronounced in bed and patients often describe having to go to the window ‘to get air’.
Using pillows to prop the patient up may relieve orthopnoea in bed and the number of pillows used may be a guide to the severity of this symptom. The pulmonary congestion may also lead to a cough, with sputum, which may or may not be frothy and contain blood.
Right ventricular failure
The leading feature of right ventricular failure is raised venous pressure, which leads to peripheral oedema (typically in the ankles on standing, and which may shift to the sacral regions while lying down). The raised venous pressure will also manifest as raised jugular venous pressure (JVP, which is raised if >4 cm from the clavicular line).
The increased venous pressure may also lead to hepatomegaly (enlarged liver), with abdominal discomfort.
Although a diagnosis may be made on clinical features, it should be established by an echo-cardiogram. Heart failure may also be suggested by increased plasma levels of B-type natriuretic peptide (BNP), and this is being introduced as a screening test to aid diagnosis.
Atrial fibrillation
A major and common consequence of cardiac failure is a build-up of back-pressure in the heart, as there is impaired ejection. This often leads to dilatation of the left atrium and the physical distension of the muscle causes disturbances
in atrial electrical activity, resulting in atrial fibrillation. This does not greatly impair cardiac function; however, the consequent stasis of blood in the left atria increases the likelihood of thrombi forming. These may dislodge and travel to the cerebral circulation, giving rise to thromboembolic occlusion, resulting in transient ischaemic attacks or stroke.
The key feature of a patient with atrial fibril-lation is an irregularly irregular pulse. Atrial fibrillation is readily identified on an electro-cardiogram (ECG) as the absence of P waves and irregular QRS complexes.
Goals of treatment
The main goal of treatment is to improve the quality of life by relieving symptoms and, if possible, to reverse or modify the disease pro-cesses.
The simplest approach is to treat any under-lying causes, such as valvular disease, IHD or atrial fibrillation. In these cases this may involve cardiac surgery.
The principles of medical management using drugs are to:
• decrease cardiac work, which may be achieved by using diuretics or vasodilators
• increase cardiac output, which may be achieved by using positive inotropic agents
• counteract maladaptation: the key goal, which involves blocking and reversing the neurohormonal adaptation; if this is achieved then the outcome should be improved.
If atrial fibrillation is present, additional aims are to control ventricular rate and prevent thrombus formation, reducing the likelihood of a transient ischaemic attack.
Pharmacological basis of management (Table 15.1)
ACE inhibitors, e.g. captopril, enalapril, lisinopril, perindopril, ramipril
Angiotensin-converting enzyme (ACE) inhibitors are now recognized as first-line therapy in CHF
and may be given to asymptomatic patients.
They have been proved to both reduce symptoms and improve prognosis (Cooperative North Scan-dinavian Enalapril Survival Study [CONSENSUS]
trial: Swedeberg, 1987). By inhibiting ACE, they lead to reductions in the neurohormonal adap-tation due to angiotensin II and aldosterone, with the following consequences:
• reduction in arterial and venous vasoconstric-tion (reduced after- and preload)
• reduction in salt and water retention, hence reduced circulating volume
• indirect positive inotropic effect
• prevention and reversal of cardiac remodel-ling due to RAAS.
Ta b l e 1 5 . 1 Summary of principal effects of drugs used in heart failure
Inhibition of ACE • Decreased arterial and venous vasoconstriction
• Decreased blood volume
• Decreased compensatory effects of RAS
Loop diuretics Kidney: loop of Henle Inhibition of Na+/K+/2Cl⫺ transporter in loop of Henle
• Na+excretion
• Decreased blood volume
• Decreased plasma K+
Thiazide diuretics Kidney: distal convoluted tubule
Inhibition of Na+/Cl⫺ reabsorption
• Na+excretion
• Decreased blood volume
• Decreased plasma K+ Potassium-sparing blockade of Na+ channels
• Weak diuretic effect (increased Na+excretion) with decreased K+ excretion
Potassium-sparing diuretics (spironolactone)
Kidney: as above Aldosterone receptor antagonist
• Weak diuretic effect (increased Na+ excretion) with decreased K+ excretion
• Reverses adverse effects of aldosterone on the heart
Beta-blockers Myocardium Antagonism of cardiac
β-adrenoceptors
• Reduce sympathetic drive to the heart
• Oppose neurohormonal adaptation
• Antiarrhythmic actions Digoxin Myocardium, AV node Inhibition of Na+pump • Positive inotropic effects
• Induces a degree of AV block
Nitrates Vascular smooth
muscle
Increased cGMP production
• Vasodilatation
aBlockers (prazosin or mixed a/b blocker
ACE, angiotensin-converting enzyme; AV, atrioventricular; cGMP, guanosine cyclic 3쎿:5쎿-monophosphate.
Clinical use
By nature of their action, ACE inhibitors may cause severe hypotension (in about 2% of patients) and are best given initially on retiring at night. A low starting dose should be used and titrated up to the maximum tolerated dose. In certain patients at high risk, including those with a systolic blood pressure <90 mmHg, treatment should be initiated in hospital under supervision.
There should be close monitoring of creatinine, urea and electrolyte levels before and after each dosage change.
The renin–angiotensin system is activated in renovascular disease in order to maintain renal perfusion and filtration. Hence ACE inhibitors may cause deterioration of renal function in pre-existing renal disease, and these patients should be identified by measurement of plasma creati-nine and monitoring of renal function through-out treatment.
Angiotensin II receptor antagonists, e.g. candesartan, irbesartan, losartan, valsartan
This newer class of drugs blocks the action of angiotensin II at the angiotensin AT1-receptor, which will also reduce the stimulation of aldos-terone release. Hence AT1-receptor antagonists act in a similar manner to ACE inhibitors but do not give rise to a cough. The ELITE II trial (Pitt et al 2000) reported that losartan was equally effective at reducing mortality in elderly patients with heart failure to captopril, but it was also better tolerated. Similarly results (Val-HeFt: Cohn and Tognoni 2001) have indicated that valsartan improves the quality of life in patients with heart failure. AT1-receptor antagonists may also be used together with ACE inhibitors.
Diuretics: thiazides and related agents (e.g. bendroflumethiazide, indapamide, metolazone)and loop diuretics
(e.g. furosemide)
Diuretics are the mainstay of drug treatment in heart failure and provide rapid symptomatic relief. Diuretics reduce circulating volume, thus
decreasing pre- and afterload, and hence cardiac work. In addition, they may have direct vascular effects leading to venodilatation, which further reduces preload. Diuretics provide relief for the symptoms of congestion but do not affect the progression of the disease.
Thiazides act in the distal convoluted tubule to inhibit Na+/Cl⫺reabsorption. Loop diuretics inhibit the Na+/K+/2Cl⫺ co-transporter in the thick ascending limb of the loop of Henle, inhibiting the establishment of a hyperosmotic interstitium and so reducing the ability of the kidneys to produce concentrated urine, leading to profuse diuresis.
Clinical use
The rational use of diuretics includes situations where there is oedema (peripheral or pul-monary). Thiazides induce modest diuresis and are used in mild failure or in elderly people. Loop diuretics, which are more extensively used, cause very pronounced diuresis and are especially useful in causing rapid relief of pulmonary oedema. Indeed, intravenous furosemide rapidly reduces the dyspnoea associated with pulmonary oedema in acute left ventricular failure. This effect precedes the diuresis and is thought to be due to venodilatation reducing preload on the heart.
Why do thiazides and loop diuretics cause hypokalaemia?
Hypokalaemia is a major side effect of these diuretic agents. By acting on the kidney, largely before the distal tubule, these agents increase the sodium content in the tubular fluid. Under the control of aldosterone, the distal tubule attempts to reabsorb sodium (via amiloride-sensitive sodium channels) but at the cost of excreting potassium. In addition, these agents will also provoke the release of renin and the activation of RAAS, which will further promote the excretion of potassium. By contrast, ACE inhibitors will oppose the aldosterone-sensitive potassium loss and there is a risk of significant hyperkalaemia if the ACE inhibitor is given in addition to potas-sium supplements or potaspotas-sium-sparing diuretics (e.g. amiloride, spironolactone).
Spironolactone
This is an aldosterone receptor antagonist, which acts as a weak potassium-sparing diuretic. It is now used at a low dose (25 mg), which does not have pronounced haemodynamic effects but reverses the aldosterone-mediated neurohor-monal changes. Even after ACE inhibition, aldosterone levels may still be appreciable, so spironolactone is able to exert substantial ben-eficial effects. It is thought that spironolactone inhibits aldosterone-induced fibrosis, which otherwise stiffens the heart and is associated with arrhythmias. It may also inhibit the adverse effects of aldosterone on autonomic and baro-receptor function. The RALES trial (Pitt et al 1999), in which low-dose spironolactone was added to conventional therapies, indicated that this treatment reduced mortality by 30%.
Digoxin
Digoxin used to be the mainstay of therapy and has been in and out of fashion over many years.
Its principal action is as a positive inotrope by inhibiting Na+/K+ATPase (which causes a rise in intracellular sodium, promoting calcium entry, and leading to increased force of contraction).
However, digoxin also directly and indirectly (via central vagal activation) impairs atrioventricular conduction. This induction of heart block and bradycardia is beneficial in heart failure with atrial fibrillation because it controls ventricular rate. Indeed, it is now widely believed that digoxin should be reserved for heart failure with atrial fibrillation, or when treatment with an ACE inhibitor and a diuretic is inadequate for patients in sinus rhythm.
Clinical usage
Digoxin improves the patient’s symptoms, reduces hospitalization but does not affect all-cause mortality (DIG trial: Digitalis Investigation Group 1997). Digoxin has a very narrow thera-peutic window and is largely renally excreted, which means that renal function should be taken into account, with dose reductions to prevent increased plasma concentrations and toxicity.
Digoxin is associated with a range of significant side effects which include:
• anorexia
• nausea
• gastrointestinal disturbances
• visual disturbances
• arrhythmias.
β Blockers: bisoprolol, carvedilol and metoprolol
β-Adrenoceptor antagonists have traditionally been contraindicated in heart failure, because they reduce sympathetic drive to a failing heart or may precipitate failure in compensated failure.
However, there is now evidence that they reduce disease progression, symptoms and mortality (CIBIS-II Investigators and Committee 1999;
MERIT-HF Study Group 1999). Principally, β blockers:
• reduce sympathetic stimulation, heart rate and oxygen consumption
• reduce sudden death by their antiarrhythmic properties
• oppose the neurohormonal activation which leads to myocyte dysfunction.
In addition, carvedilol causes vasodilatation as it is also an ␣ blocker, and its antioxidant prop-erties may be beneficial.
Clinical usage
Metoprolol, bisoprolol and carvedilol are now being increasingly used in patients with stable, moderate heart failure, and are especially useful in patients with cardiac ischaemia. However, they should be used with caution in patients with chronic obstructive pulmonary disease (COPD), which is relatively common in the patient population with the highest incidence of heart failure. Their use would also be contraindi-cated in hypotension and marked bradycardia.
β Blockers should be initiated starting with a low dose under the supervision of a cardiologist or general practitioner (GP) experienced in their usage. The β blocker may initially cause a wors-ening of symptoms but benefit may become apparent after several weeks.
Vasodilators
Nitrates in particular may have a role in CHF because they will cause venodilatation, leading to a reduction in preload. Many patients will also have IHD and so nitrates will be of benefit in these patients. Nitrates may be suitable for people in whom ACE inhibitors are not tolerated but are contraindicated in hypotension and marked anaemia.
Other vasodilators that may be added on to therapy are ␣ blockers such as prazosin, which will reduce peripheral resistance by opposing sympathetic activity. They are of no proven benefit. The arterial vasorelaxant hydralazine is also used as an add-on drug or for those intoler-ant of ACE inhibitors.
Other positive inotropes
In addition to digoxin, phosphodiesterase inhibitors (PDEIs) such as milrinone have a limited role. These drugs act to potentiate adeno-sine cyclic 3쎿:5쎿-monophosphate (cAMP) in myocytes and so have positive inotropic effects;
they are used in end-stage failure on a short-term basis in hospital. It should be noted that their long-term use is associated with increased mor-tality.
Amines such as dobutamine, which acts as a β agonist, similarly may have a role in the man-agement of acute failure and end-stage failure in the context of specialist hospital care.
Choice of drugs
This is largely stage (New York Heart Association or NYHA) dependent:
• stage I (asymptomatic)
• stage II (slight limitations through breathless-ness/fatigue on normal exertion)
• stage III (marked limitations through breath-lessness/fatigue on normal exertion)
• stage IV (breathless at rest).
The guidance of the National Institute for Health and Clinical Excellence (NICE 2003) suggests that ACE inhibitors have a central role
and should be used in all cases of left ventricular systolic dysfunction. If patients are intolerant of ACE inhibitors due to the associated cough then AT1-receptor antagonists may be used instead.
Diuretics are used for symptomatic relief where there is oedema. Although β blockers are now recognized as having an important role, they should be added cautiously to therapy in patients with moderate but stable heart failure. Despite these recommendations it appears that in practice the use of β blockers is less common than would be expected. Digoxin is recommended for refractory disease or in patients with concurrent atrial fibrillation, and spironolactone is also used in cases of CHF that do not respond to optimal therapy (Figure 15.2).
Concurrent disease
Additional considerations when prescribing in CHF:
• Renal impairment may preclude the use of ACE inhibitors and thiazides and lead to a dose reduction with digoxin. In moderate failure higher doses of loop diuretics are required and in anuria their use would be pre-cluded.
• Liver function: close monitoring with ACE inhibitors is important in liver disease.
Warfarin and carvedilol should be avoided and a reduced dose of metoprolol may be required. The use of potassium-sparing diuret-ics may be necessary. This is due to the risk of precipitating coma if hypokalaemia develops during treatment with loop and thiazide diuretics. There is also an increased risk of hypomagnesaemia in alcoholic cirrhosis.
Thiazides should be avoided in severe liver disease.
• Atrial fibrillation would be a compelling reason to use digoxin and an indication for an anticoagulant (see Chapter 16). Amiodarone may also be required.
• Asthma would preclude the use of a β blocker because of the risk of bronchospasm. This is less clear cut in the case of COPD, where the beneficial effects of β blockers in heart failure are significant. The current view is that in
patients with concurrent COPD the cautious use of cardioselective β blockers is acceptable.
• Diabetes mellitus may be a reason not to use a thiazide (due to risk of hyperglycaemia) but may be a compelling reason to use an ACE inhibitor (see Chapter 35). Blood pressure and plasma glucose concentration should be monitored regularly.
• History of stroke would be an indication for perindopril alone or in combination with indapamide. The PROGRESS Collaborative Group (2001) trial has indicated that perindo-pril alone or in combination with indapamide reduces the incidence of stroke (both haemor-rhagic and thromboembolic) in patients who have previously suffered any type of stroke. It remains to be determined if this is specific to perindopril and indapamide or whether it applies to any ACE inhibitor plus a thiazide.
Cerebral haemorrhage would be a contraindi-cation for the use of nitrates.
• Ischaemic heart disease would be a reason to add a β blocker and nitrates. Attention should also be paid to primary or secondary
prevention with antiplatelet agents and correction of hyperlipidaemia (see Chapter 12).
• Risk of infection from influenza and pneumo-nia would be a reason to consider immuniza-tion with influenza and pneumococcal polysaccharide vaccines, respectively.
Additional considerations are: Wolff–Parkin-son–White syndrome (contraindication for digoxin); closed-angle glaucoma (contraindica-tion for nitrates); Addison’s disease (contraindi-cation for thiazides); and gout (contraindi(contraindi-cation for thiazides).
CHF may itself influence drug choice in un-related conditions: important examples are summarized in Table 15.2.
Drug interactions
In the context of drug choice, the interactions between drugs used in CHF should be considered (Table 15.3).
Evidence of LV dysfunction?
Yes
Yes
Cough
AT1-Receptor antagonist
Oedema?
+ ACEI
+ Diuretic
+ β Blocker + Spironolactone + Digoxin
+ Warfarin/
Aspirin
Atrial fibrillation?
Additions/Refractory?
Figure 15.2 A summary of current approaches to the management of chronic heart failure incorporating National Institute for Health and Clinical Excellence (NICE 2003) guidance. Approaches to managing atrial fibrillation in chronic heart failure are also indicated. ACEI, angiotensin-converting enzyme inhibitor; AT, angiotensin; LV, left ventricular.
General counselling
One approach to explaining CHF to a patient is that the heart is simply not able to pump the blood as well as it used to, making exercise more difficult. Patients may notice that they have become increasingly breathless and their ankles swell. In some cases it may be appropriate to
One approach to explaining CHF to a patient is that the heart is simply not able to pump the blood as well as it used to, making exercise more difficult. Patients may notice that they have become increasingly breathless and their ankles swell. In some cases it may be appropriate to