Heart failure: epidemiology, investigation and management

HEART MUSCLE DISEASE

Heart failure: epidemiology, investigation and management

What’s new? C

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Roy S Gardner Theresa A McDonagh

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Abstract Heart failure (HF) is a clinical syndrome characterized by dyspnoea, fatigue and fluid retention accompanied by objective evidence of cardiac dysfunction. The syndrome affects around 2% of the general population, affecting men more commonly than women (under the age of 80), with incidence and prevalence rising steeply with age. HF causes substantial morbidity and reduced life expectancy, and coronary artery disease accounts for two-thirds of cases in developed countries. Investigation is important to ascertain the diagnosis, identify the aetiology (which might be reversible) and give some indication of prognosis. Currently, more than 40% of people die within 18 months of a new diagnosis of HF. Treatment has been revolutionized by large randomized-controlled clinical trials studying the effects of antagonism of the renineangiotensinealdosterone and sympathetic nervous systems, and, more recently, the effects of device therapy. Cardiac transplantation remains an option for patients who are severely symptomatic (and at high risk) despite optimal medical and appropriate device therapy.

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the diagnosis of heart failure with preserved systolic function is more difficult and often attributed to diastolic dysfunction (although abnormalities of systolic and diastolic function frequently co-exist) e treatment options in this setting are limited.

Epidemiology Prevalence A recent European population-based study has shown the prevalence of HF to be 2e3%, increasing to 7% in the elderly.1 Importantly, around 50% of patients with significant left ventricular systolic dysfunction (ejection fraction [EF] 30%) are asymptomatic. The prevalence of HF with preserved EF is 9.7/1000 (44% of total HF prevalence). The prevalence of chronic HF is projected to increase by 50% in the next 20 years as a result of:  changing demography of the population, i.e. more elderly at risk  improved survival of other cardiovascular diseases, e.g. acute myocardial infarction  improved survival rates for HF itself.

Keywords cardiomyopathy; epidemiology; heart failure; investigation; prognosis; treatment

Introduction Heart failure (HF) is a clinical syndrome characterized by dyspnoea, fatigue and fluid retention accompanied by objective evidence of cardiac dysfunction. It may result from any type of cardiac dysfunction and is most commonly attributable to left ventricular systolic impairment (although it can also occur in the presence of preserved systolic function). Diagnosis is usually relatively easy using a range of non-invasive methods and treatment has been revolutionized over the last two decades. However,

Incidence The US Framingham Heart cohort study reported an annual incidence of HF of 0.2e0.3% in those aged 50e59 years, rising 10-fold in those aged 80e89 (Figure 1).2 UK population data are similar, with an annual incidence of 0.12% in those aged 55e64, rising to 1.2% in those aged over 85 e equivalent to 63 000 new cases of HF each year. Median age at diagnosis is 76 years and incidence higher in men than women at all ages (M:F w 1.8:1).3

Roy S Gardner MBChB MD MRCP is a Consultant Cardiologist at the Scottish Advanced Heart Failure Service, Golden Jubilee National Hospital, Clydebank, UK. Competing interests: none declared.

Aetiology HF is a syndrome, not a diagnosis, and identification of the underlying aetiology is important for a number of reasons (Table 1). First, it might be reversible. Second, it may give some indication of prognosis. Third, familial conditions may have an impact on the lives of offspring, siblings and parents. There is significant geographical variation in the cause of heart failure. In Westernized societies, two-thirds are secondary

Theresa A McDonagh BSc MBChB MD FRCP FESC is a Consultant Cardiologist and Honorary Reader at the Royal Brompton Hospital, London, UK. She is the current chair of the British Society for Heart Failure and a member of the Specialist Advisory Committee in Cardiology, the Heart Failure Network Committee of the Heart Failure Association of the European Society of Cardiology and executive steering committees for several multicentre randomized controlled trials in heart failure across the world. Competing interests: none declared.

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Patients with HF following myocardial infarction or left ventricular systolic dysfunction associated with diabetes mellitus benefit from treatment with eplerenone Statins do not alter clinical outcome in patients with heart failure (HF), even when there is underlying ischaemic heart disease Aquaretics (tolvaptan, a vasopressin V2 receptor antagonist) improve early symptoms of breathlessness, increase weight loss (fluid) and resolve hyponatraemia (where present) in patients hospitalized with HF. However, there is no demonstrable effect on mortality or need for repeat hospital admission The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) demonstrated a lower risk of HF events in patients with mild symptoms who received CRT in addition to an implantable cardioverter defibrillator

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HEART MUSCLE DISEASE

The incidence of heart failure Males

The changing pattern of aetiology of CHF in the Framingham study with time

Females n=31

30

50

n=28

Average annual incident/1,000 people

Average annual incident/1,000 people

35

25

20 n=17 15

n=13 n=9

10 n=5 5 n=1

n=2

n=6

n=3

0 45–54

55–64

65–74

75–84

Males

Females

40 30 20 10

Hypertension

Valvar heart disease

0

Coronary artery disease

–10 –20

Diabetes

–30 –40

85–94 –50

Age (years)

Reproduced from McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart 2000; 83: 596–602, with permission from the BMJ Publishing Group Ltd.

Reproduced from McKee PA et al. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285: 1441–6, with permission from the Massachusetts Medical Society.

Figure 1

Figure 2

to ischaemic heart disease e particularly amongst males and the elderly. Other major contributors include hypertension (particularly in African-Americans) and valve disease, although these are decreasing in importance, due to earlier detection and treatment (Figure 2).

diagnosis (Figure 3).4 In the Framingham study, 5-year mortality of HF was 62% in men and 42% in women.2 HF can be extremely disabling and is often associated with frequent, recurrent hospitalization. Indeed, quality of life is reduced to a greater extent than many other chronic medical disorders, including arthritis and stroke. However, US data suggest that survival is improving, perhaps as a result of increasing use of disease-modifying therapy.5 Despite the powerful evidence base, a recent multicentre European survey reported that one-third of patients with HF are not offered treatment with an ACE inhibitor

Prognosis Prognosis is poor with a particularly high early mortality. It is important to appreciate that population-based studies report significantly lower survival rates than those seen in treatment trials. In the UK, 30% of patients found to have HF are dead at 6 months, and over 40% do not survive 18 months beyond

Mortality after a first diagnosis of heart failure Causes of chronic heart failure

C C C C

C C C C C C C C C

C

Coronary heart disease Hypertension Valve disease Congenital heart disease Infective: for example, viral myocarditis, Chaga’s, HIV, Lyme disease Alcohol Toxins: for example, anthracyclines, abstruzimab Deficiencies: for example, selenium, beri beri, thiamine Haemochromatosis Idiopathic Familial Peripartum Tachycardia induced Infiltrative states: amyloid, sarcoid, endomyocardial fibrosis, hypereosinophilic syndrome High output: for example, A-V fistulae, Paget’s disease

Cumulative survival (%)

C

100

80 70 60 50 40 220

166

152

126

102

74

49

25

11

18

21

24

Number of patients 0

3

6

9

12

15

Months from indentification Reproduced from Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: a population based study. Heart 2000; 83: 505-10, with permission from the BMJ Publishing Group Ltd.

Table 1

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90

Figure 3

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HEART MUSCLE DISEASE

and two-thirds are not offered treatment with a b-blocker. Improved uptake of such therapies should lead to further prognostic benefit.

Flow chart for the diagnosis of heart failure with natriuretic peptides in untreated patients with symptoms suggestive of heart failure

Investigation Investigation is important to ascertain the diagnosis, identify the aetiology (which might be reversible) and give some indication of prognosis. The most commonly undertaken investigations are:  Electrocardiography e an ECG is mandatory and abnormal in >90% of individuals with HF resulting from left ventricular systolic dysfunction. Common abnormalities include: B Rate. Bradycardia (<60/min) is particularly common in patients on b-blockers and requires further investigation and management if associated with second- or thirddegree heart block. Tachycardia (>100/min) may be the cause or a consequence of HF. B Atrial fibrillation. Prevalence ranges from 10e50% in HF e prognostic significance is controversial. B Intraventricular conduction delay. QRS duration >120 ms confers an increased risk of death (particularly left bundle branch block e LBBB) and may help identify patients who benefit from CRT. B Regional versus local changes (i.e. Q waves). Suggest underlying ischaemic heart disease. B Left ventricular hypertrophy (e.g. secondary to hypertension).  Chest radiography is also mandatory. B A normal chest X-ray does not exclude HF. B Cardiomegaly (cardiothoracic ratio >0.50), particularly with evidence of pulmonary congestion, suggests a cardiac abnormality. B May identify other causes of breathlessness.  Blood tests: B Urea and electrolytes. HF is commonly associated with renal impairment and electrolyte disturbance e hyponatraemia indicates adverse prognosis. B FBC. Anaemia is common in HF and associated with adverse prognosis. B Ferritin. Haemochromatosis is an uncommon but reversible cause of HF. B Liver function tests. Abnormal in the presence of hepatic congestion. B Thyroid function tests. Thyrotoxicosis may cause left ventricular systolic dysfunction and hypothyroidism can accelerate coronary artery disease. B Urate. Often elevated in those taking diuretics e hyperuricaemia is associated with adverse prognosis. B B-type natriuretic peptide (BNP) or NT-proBNP. Useful in diagnosis (strong negative predictive value) and determination of prognosis (Figure 4).  Echocardiography is an accessible and non-invasive diagnostic test which can identify (and in some instances quantify) the following aspects of cardiac function: B Left ventricular dimensions and systolic function. Most commonly by subjective visual assessment, wall motion score index, or calculation of EF. B Regional or localized abnormalities. Suggestive of underlying ischaemic heart disease. B Valve function. B Right ventricular function and estimation of pulmonary artery pressure.

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Clinical examination ECG, CXR, Echo

Natriuretic peptides

BNP ‹ 100pg/ml

BNP 100–400pg/ml

BNP › 400pg/ml

NT-proBNP ‹ 400pg/ml

NT-proBNP 400–2000pg/ml

NT-proBNP › 2000pg/ml

CHF unlikely

Uncertain diagnosis

CHF likely

Adapted from ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Dickstein K et al. Euro Heart J 2008; 29: 2388–442, with permission from Oxford University Press.

Figure 4

Presence or absence of a pericardial effusion. Diastolic function.  Cardiac magnetic resonance (CMR). An emerging tool in the investigation of HF, CMR is the most accurate and reproducible method for the measurement of cardiac volumes and left ventricular mass. It helps characterize cardiac tissue and can also identify areas of infarction or infiltration.  Other investigations which may be useful are: B Coronary angiography e coronary artery disease is a potentially reversible cause of cardiac dysfunction. B Cardiopulmonary exercise testing to quantify peak VO2 (a useful prognostic marker). B Nuclear imaging e radionuclide ventriculography provides accurate assessment of left and right ventricular EF. B B

Treatment The medical treatment of HF has been revolutionized by large randomized, controlled clinical trials studying the effects of antagonists of the renineangiotensinealdosterone and sympathetic nervous systems (Figure 5). It is of paramount importance to realize that prevention is better than cure. Efforts should be made to modify known risk factors for ischaemic heart disease and offer prompt and effective treatment of myocardial infarction. Once established, HF is usually associated with poor prognosis and disabling symptoms e therapy is therefore aimed at reducing mortality and improving morbidity.

Disease-modifying therapy ACE inhibitors First-line agents which should be given to all patients with left ventricular systolic dysfunction e whether symptomatic6,7 or not8 e and combined with a diuretic if there is evidence of cardiac decompensation (e.g. peripheral or pulmonary oedema). In clinical trials involving more than 7000 patients ACE inhibitors achieve an average 20e25% relative risk reduction in both morbidity and mortality.

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HEART MUSCLE DISEASE

Treatment of chronic heart failure resulting from left ventricular systolic dysfunction

Steps in the up-titration of ACE inhibitors Drug

Start dose Up-titration (mg) steps (mg)

Target dose Frequency (mg)

Captopril Enalapril Lisinopril Ramipril Trandolapril

6.25 2.5 5 2.5 0.5

50 20 35e40 5 4

Left ventricular systolic dysfunction

Seek reversible cause Evidence of fluid overload

Diuretic and fluid restriction

It is imperative that b-blockers are started only when patients are euvolaemic and then up-titrated slowly e ‘start low, go slow’. Chronic obstructive airways disease without airways reversibility and mildemoderate peripheral vascular disease are NOT contraindications to b-blocker therapy. Drugs with proven efficacy in clinical trials are carvedilol, bisoprolol, metoprolol CR/XL and nebivolol17 (Table 3).

Beta-blocker

NYHA II/III

Angiotensin receptor blocker

NYHA I

Observe and review1

NYHA III/IV

Aldosterone antagonists Spironolactone reduces mortality and morbidity in patients with moderateesevere HF (NYHA classes III & IV) when used in addition to standard therapy (ACE inhibitor and b-blocker).18 More recently, eplerenone has been shown to have similar effects in patients with heart failure, or left ventricular systolic dysfunction and diabetes mellitus, post-myocardial infarction.19 Caution should be exercised with these drugs as they can impair renal function and cause significant hyperkalaemia.

Spironolactone

Improves

Worsens or remains severly symptomatic

Angiotensin II receptor antagonists Angiotensin II receptor antagonists are an effective alternative in truly ACE-intolerant individuals, although ACE inhibitors remain the first-line treatment of choice. In the recent CHARM study however, the addition of candesartan to existing therapy reduced the combined endpoint of cardiovascular death and hospitalization for HF by 15% (largely driven by reduction in hospitalization).20 This trial suggests that there is another therapeutic option in patients who remain symptomatic despite ACE inhibitor and b-blocker therapy, and who are not suitable for an aldosterone antagonist. However, the combination of all four

Consider other options2 1 Review process: symptoms, signs, weight, urea and electrolytes, Can disease-modifying therapy be optimized? Can diuretics be reduced? 2 Consider: increasing diuretic if evidence of cardiac decompensation, digoxin, anticoagulation (particularly for atrial fibrillation or left ventricular thrombus), biventricular pacing (cardiac resynchronization therapy), ventricular assist devices (VAD), cardiac transplantation.

Steps in the up-titration of b-adrenoreceptor antagonists

Figure 5

Unless there is a contraindication, such as significant renal disease, angio-oedema or ACE inhibitor-induced cough, their use is mandatory. Drugs with proven efficacy in clinical trials are captopril, enalapril, ramipril, lisinopril and trandolapril (see Table 2). b-adrenoreceptor antagonists (b-blockers) There is also now unequivocal evidence that the b-blockers, bisoprolol,9 carvedilol10e14 and sustained-release metoprolol,15 provide both a significant mortality and long-term symptomatic benefit in patients with all grades of HF, and in left ventricular systolic dysfunction following myocardial infarction. In the COMET study, carvedilol reduced all-cause mortality by 17% more than metoprolol succinate16 (although it was the alternative long-acting metoprolol tartrate that demonstrated benefit in the MERIT study).15

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8 hourly 12 hourly daily 12 hourly daily

Table 2

ACE inhibitor

NYHA I

12.5e25e50 5e10e20 10e30e30e40 2.5 1e2e4

* #

Drug

Start dose Up-titration steps (mg) (mg)

Target dose Frequency (mg)

Carvedilol Bisoprolol Metoprolol# CR/XL Nebivolol

3.125 1.25 12.5#/25

6.25e12.5e25e50* 25/50* 2.5e5e75e10 10 25e50e100e200 200

12 hourly daily daily

1.25

2.5e5e10

daily

10

Where patient is >85 kg. Preparation not available in the UK.

Table 3

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HEART MUSCLE DISEASE

Heart Failure Outcome Study with Tolvaptan (EVEREST) study.33 Despite a promising improvement in some secondary endpoints (including patient-assessed dyspnoea, body weight and oedema), there were no differences in the primary end points of all-cause mortality and cardiovascular death or hospitalization for HF.

agents is to be discouraged due to lack of supportive evidence and significant risk of renal impairment. Hydralazine and nitrates The combination of hydralazine and nitrates can be considered in patients intolerant to both ACE inhibitors and angiotensin II receptor antagonists,21,22 or as an addition to either of these agents in African-Americans.23

Drugs to avoid It is important, if possible, to avoid drugs that may exacerbate HF, including non-steroidal anti-inflammatory drugs (NSAIDs), ratelimiting calcium antagonists (diltiazem and verapamil), class I antiarrhythmic drugs, corticosteroids and tricyclic antidepressants.

Symptomatic therapy Diuretics Diuretics retain an important place in the management of the symptoms and signs of fluid retention in HF. It should be remembered that they do not confer a mortality benefit and that higher doses are associated with poorer outcome.24,25 Therefore, one should try to use as low a dose as possible in combination with fluid restriction where necessary (see below). A loop diuretic (e.g. furosemide or bumetanide) is usually necessary e once a dose of 80 mg furosemide twice daily (or equivalent) is reached, sequential nephron blockade using a thiazide, or thiazide-like, diuretic (e.g. bendroflumethiazide or metolazone) may relieve fluid retention more effectively than further increases in the dose of loop diuretic. Renal function and potassium levels should be monitored closely.

Non-pharmacological intervention and lifestyle modification Lifestyle modifications, such as cessation of smoking and alcohol consumption (especially if this is thought to be the aetiology34), weight loss (where appropriate) and engagement in aerobic exercise, should be encouraged.35 Immunization against influenza (yearly) and pneumococcus is recommended.36 Fluid intake should be restricted to between 1.5 and 2 l/day and the patient advised of the importance of monitoring fluid balance (e.g. daily weights). Salt-rich foods should be avoided. A

REFERENCES 1 McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 1997; 350: 829e33. 2 Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol 1993; 22: 6Ae13. 3 Cowie MR, Wood DA, Coats A, et al. Incidence and aetiology of heart failure: a population-based study. Eur Heart J 1999; 20: 421e8. 4 Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: a population based study. Heart 2000; 83: 505e10. 5 Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002; 347: 1397e402. 6 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293e302. 7 The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). New Engl J Med 1987; 316: 1429e35. 8 The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. [published erratum appears in N Engl J Med 1992 Dec 10; 327(24): 1768]. N Engl J Med 1992; 327: 685e91. 9 Anonymous. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. [see comments]. Lancet 1999; 353: 9e13. 10 Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651e8. 11 Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349e55. 12 Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. [see comments]. J Am Coll Cardiol 1995; 25: 1225e31. 13 Anonymous. Effects of carvedilol, a vasodilator-beta-blocker, in patients with congestive heart failure due to ischemic heart disease.

Digoxin The role of digoxin is not altogether clear. Current recommendations suggest its use in patients who remain symptomatic despite maximal medical therapy, or to provide rate control in patients with atrial fibrillation. In the large studies with digoxin,26,27 patients with atrial fibrillation were excluded and no mortality benefit was demonstrated. Indeed, post-hoc analyses have suggested higher mortality associated with treatment in some patient groups.28,29 Digoxin is therefore best reserved for patients who remain very symptomatic with a large heart and frequent hospitalization and avoided in those with ventricular arrhythmias. Other pharmacological therapy The merits of warfarin therapy in HF were recently investigated in the WATCH study.30 The primary outcome of time to death, non-fatal myocardial infarction, or non-fatal stroke did not support the superiority of warfarin or clopidogrel over aspirin. However, warfarin was associated with fewer non-fatal strokes than aspirin or clopidogrel and reduced hospitalization for HF. Statin therapy is of unequivocal benefit in the primary and secondary prevention of ischaemic heart disease. However, patients with HF have usually been excluded from statin studies so two large randomized trials were specifically designed to investigate their effects in the HF population. CORONA was a large trial involving over 5000 patients with NYHA IIeIV HF of ischaemic aetiology which demonstrated no significant differences in the primary composite outcome of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke between the patients treated with rosuvastatin or placebo.31 This result was replicated in GISSI-HF, where patients with NYHA class IIeIV HF of any cause or measure of left ventricular EF were randomly assigned to treatment with rosuvastatin or placebo.32 The aquaretic Tolvaptan, a vasopressin V2 receptor antagonist, was compared with placebo in over 4000 patients hospitalized with HF in the Efficacy of Vasopressin Antagonism in

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31 Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007; 357: 2248e61. 32 Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231e9. 33 Konstam MA, Gheorghiade M, Burnett Jr JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007; 297: 1319e31. 34 Guillo P, Mansourati J, Maheu B, et al. Long-term prognosis in patients with alcoholic cardiomyopathy and severe heart failure after total abstinence. Am J Cardiol 1997; 79: 1276e8. 35 Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome. [see comments]. Circulation 1999; 99: 1173e82. 36 Opasich C, Febo O, Riccardi PG, et al. Concomitant factors of decompensation in chronic heart failure. Am J Cardiol 1996; 78: 354e7.

AustraliaeNew Zealand Heart Failure Research Collaborative Group. Circulation 1995; 92: 212e18. Bristow MR, Gilbert EM, Abraham WT, et al. Carvedilol produces doserelated improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996; 94: 2807e16. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERITHF). [see comments]. Lancet 1999; 353: 2001e7. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003; 362: 7e13. Flather MD, Shibata MC, Coats AJS, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005; 26: 215e25. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. [see comments]. N Engl J Med 1999; 341: 709e17. Pitt B, Remme W, Zannad F, et al, for the Eplerenone post-acute myocardial infarction heart failure efficacy and survival study investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med 2003; 348: 1309e21. McMurray Jj V, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362: 767e71. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazineeisosorbide dinitrate in the treatment of patients with chronic congestive heart failure. N Engl J Med 1991; 325: 303e10. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314: 1547e52. Taylor AL. The African American Heart Failure Trial: a clinical trial update. Am J Cardiol 2005; 96(suppl): 44ie8. Neuberg GW, Miller AB, O’Connor CM, et al. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J 2002; 144: 31e8. Batin P, Wickens M, McEntegart D, Fullwood L, Cowley AJ. The importance of abnormalities of liver function tests in predicting mortality in chronic heart failure. Eur Heart J 1995; 16: 1613e8. Anonymous. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group [see comments]. N Engl J Med 1997; 336: 525e33. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study [see comments]. N Engl J Med 1993; 329: 1e7. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002; 347: 1403e11. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289: 871e8. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation 2009; 119: 1616e24.

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FURTHER READING Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur Heart J 2008; 29: 2388e442. Gardner RS, McDonagh TA, Walker NL. Heart failure. Oxford: Oxford University Press, 2007. NICE Guideline. Chronic heart failure. Available from: www.nice.org.uk/. SIGN Guideline 95: Management of chronic heart failure. Available on: www.sign.ac.uk/pdf/sign95.pdf.

Practice points C

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Aetiology of HF should be sought following diagnosis and any reversible cause treated All patients with left ventricular systolic dysfunction should be treated with an ACE inhibitor and (when euvolaemic) a b-blocker (except where absolute contra-indications exist). ‘Start low, go slow’ with b-blockers If hypotension is a problem, it is better to be on small doses of both an ACE inhibitor and a b-blocker than a larger dose of one or the other Avoid the use of four disease-modifying agents (ACE inhibitor, b-blocker, aldosterone antagonist and angiotensin II receptor antagonist). In patients already established on an ACE inhibitor, use either an aldosterone antagonist OR an angiotensin II receptor antagonist Fluid balance is very important e what goes in, must come out! Restrict fluid and salt, and ensure the smallest effective dose of diuretic Encourage patients to take responsibility for their condition e daily weights and lifestyle modification Review patients e they can get better as well as worse. Has the correct aetiology/diagnosis been identified? Is there another explanation for worsening breathlessness? Established patients not taking an ACE inhibitor or b-blocker may not be truly intolerant of these drugs New therapeutic options are available, including CRT, ICDs and left ventricular assist devices. Cardiac transplantation remains an option for those patients who worsen or fail to improve despite maximum disease-modifying therapy

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