Successes and failures of current treatment of heart failure

Abstract

New treatments for heart failure used to be licensed for use because they were shown to improve resting haemodynamics acutely. During the 1980s, the goldstandard shifted from haemodynamics to exercise capacity because this was believed to be an objective measure of patients' symptoms.1Narang R Swedberg K Cleland JGF What is the ideal study design for evaluation of treatment for heart failure?.in: Insights from trials assessing the effects of ACE inhibitors on exercise capacity. Eur Heart J. 17. 1996: 120-134Google Scholar Later, it became apparent that exercise capacity was a poor surrogate for symptoms and that improvement in symptoms could be observed in response to treatment even when exercise capacity was unchanged. Guidelines, developed by the European Society of Cardiology's Working Group on Heart Failure, have helped to clarify standards by which to judge the efficacy of treatments, new and old.2Remme WJ Cleland JGF et al.European Society of Cardiology: guidelines for the management of heart failure.Eur Heart J. 1997; 18: 736-753Crossref PubMed Scopus (404) Google Scholar, 3Cleland JGF Erdmann E Ferrari R et al.Guidelines for the diagnosis of heart failure.Eur Heart J. 1995; 16: 741-751PubMed Google Scholar Treatments must achieve one or more of the goals, preferably without the risk of significant adverse events (panel). The goals encompass both prevention of the development of heart failure and treatment once heart failure is present.PanelGoals of management of chronic heart failure •To improve or maintain quality of life by: Improvement of symptoms or prevention of them worsening Avoidance of side-effects/adverse events from treatment Decrease of the occurrence of major morbid events•To delay death •To improve or maintain quality of life by: Improvement of symptoms or prevention of them worsening Avoidance of side-effects/adverse events from treatment Decrease of the occurrence of major morbid events•To delay death Despite the success of several treatments in clinical trials there is little evidence that the prognosis of heart failure in the community has improved.4Ho KKL Anderson KM Kannel WB Grossman W Levy D Survival after the onset of congestive heart failure in the Framingham heart study subjects.Circulation. 1993; 88: 107-115Crossref PubMed Scopus (1595) Google Scholar, 5Cowie MR Suresh V Wood DA et al.Prognosis of heart failure—a population based study of the outcome in incident cases.JACC. 1998; 31 (abstr): 218ASummary Full Text PDF Google Scholar This finding may reflect the failure of doctors to implement effective therapy, the methodology for selecting patients for clinical trials, or the effects of studying populations at different points in the natural history of their disease. Among patients with severe heart failure the outlook is grave, and treatment is of limited efficacy, and yet it is these patients who are most likely to be referred to hospital and treated. Patients with mild heart failure, in whom the long-term effects of treatment may be more effective, are less likely to be treated aggressively. Despite improved treatment, age-adjusted hospital admissions for heart failure continue to rise by about 10% per annum, particularly in patients older than 65 years.6Brown A Cleland JGF Influence of pattern of concomitant disease on patterns of hospitalisation in patients with heart failure discharged from Scottish hospitals in 1995.Eur Heart J. 1998; 19: 1063-1069Crossref PubMed Scopus (129) Google Scholar, 7Reitsma JB Mosterd A De Craen AJM et al.Increase in hospital admission rates for heart failure in the Netherlands, 1980–1993.Heart. 1996; 76: 388-392Crossref PubMed Scopus (117) Google Scholar, 8Krumholz HM Parent EM Tu N et al.Readmission after hospitalization for congestive heart failure among medicare beneficiaries.Arch Intern Med. 1997; 157: 99-104Crossref PubMed Google Scholar, 9Croft JB Giles WH Pollard RA Casper ML Anda RF Livengood JR National trends in the initial hospitalisation for heart failure.J Am Geriatrics Society. 1997; 45: 270-275PubMed Google Scholar Current treatments have failed to control this rise and an effective management strategy to contain the problem has not been identified. Heart failure accounts for about 2% of hospital admissions (medical and surgical) and 5% of medical admissions.6Brown A Cleland JGF Influence of pattern of concomitant disease on patterns of hospitalisation in patients with heart failure discharged from Scottish hospitals in 1995.Eur Heart J. 1998; 19: 1063-1069Crossref PubMed Scopus (129) Google Scholar Hospital stay is frequently lengthened and often recurrent.6Brown A Cleland JGF Influence of pattern of concomitant disease on patterns of hospitalisation in patients with heart failure discharged from Scottish hospitals in 1995.Eur Heart J. 1998; 19: 1063-1069Crossref PubMed Scopus (129) Google Scholar, 10McMurray JM McDonagh T Morrison CE Dargie HJ Trends in hospitalisation for heart failure in Scotland 1980–1990.Eur Heart J. 1993; 14: 1158-1162Crossref PubMed Scopus (309) Google Scholar Hospital admissions for cardiovascular reasons, such as angina, myocardial infarction, arrhythmia, and stroke account for a large proportion of admissions and more than 50% of admissions are caused or complicated by noncardiovascular diseases, such as pulmonary disease, diabetes, and renal failure.6Brown A Cleland JGF Influence of pattern of concomitant disease on patterns of hospitalisation in patients with heart failure discharged from Scottish hospitals in 1995.Eur Heart J. 1998; 19: 1063-1069Crossref PubMed Scopus (129) Google Scholar Heart failure is a truly general medical problem requiring a multidisciplinary approach for its optimum management. The cost of managing heart failure is high, especially when the cost of managing concomitant disorders is taken into account. Across Europe the reported cost of managing heart failure is about £5–30 million per million adult population,11Cleland JGF Health economic and quality of life issues in heart failure.Eur Heart J. 1998; (in press)Google Scholar the upper limit of this estimate being similar to the estimated cost in the USA (table 1). Reanalysis suggests that the UK costs may now be double those reported previously by McMurray and colleagues due, in part, to the increasing rate of hospital admissions.11Cleland JGF Health economic and quality of life issues in heart failure.Eur Heart J. 1998; (in press)Google ScholarTable 1Cost of heart failure11Cleland JGF Health economic and quality of life issues in heart failure.Eur Heart J. 1998; (in press)Google ScholarCountryYearCost (million UK£)Cost/million adults (age >25 years, million UK£)USA19895400£32France19901200£33UK1991600£15Netherlands1988153£15 Open table in a new tab Effective treatment rarely decreases costs because the costs of greater longevity more than balance-any, due to reduced rates of hospital admission. However, the cost per life-year gained or per quality-adjusted life-year for angiotensin-converting-enzyme (ACE) inhibitors and β-blockers in heart failure is slight compared with most other accepted procedures.11Cleland JGF Health economic and quality of life issues in heart failure.Eur Heart J. 1998; (in press)Google Scholar Unless an accurate diagnosis has been made it is impossible to be sure that the appropriate treatment has been applied. This has led to the concept of the rules of halves for heart failure, although the term halves should not be taken too literally (figure 1).12Cleland JGF Screening for left ventricular dyfunction and heart failure: should it be done and if so how?.Dis Management Health Outcomes. 1997; 1: 169-184Crossref Scopus (28) Google Scholar Among patients currently receiving treatment for heart failure, up to half may have no evidence of cardiac dysfunction. Of those patients who do have cardiac dysfunction, half or less have left-ventricular systolic dysfunction and of those with left-ventricular systolic dysfunction less than half are receiving appropriate therapy. A simpler rule of half exists for patients with major left-ventricular systolic dysfunction, which states that half or more will have no symptoms (figure 2).12Cleland JGF Screening for left ventricular dyfunction and heart failure: should it be done and if so how?.Dis Management Health Outcomes. 1997; 1: 169-184Crossref Scopus (28) Google Scholar, 13McDonagh TA Morrison CE Lawrence A et al.Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population.Lancet. 1997; 350: 829-833Summary Full Text Full Text PDF PubMed Scopus (555) Google Scholar These conceptual rules require further testing, particularly the evidence that diastolic heart failure is common. Many non-cardiac disorders may mimic the features of heart failure. Patients with respiratory disease, joint disease, varicose veins, or obesity may have symptoms that could be mistaken for those of diastolic heart failure.Figure 2Rule of halves: left ventricular systolic dysfunctionView Large Image Figure ViewerDownload Hi-res image Download (PPT) Despite evidence that ACE inhibitors are effective, many patients with heart failure who fulfil the criteria of the clinical trials do not receive this treatment, and when they do, it is usually given in inadequate doses. Intuitively, there is a strong link between adequate diagnosis and adequate therapy and there is evidence to support this. Patients who are looked after by cardiologists are more likely to be appropriately investigated, are more likely to receive an ACE inhibitor, and are more likely to receive them in effective doses.14Clark A Coats AJS Severity of heart failure and dosages of angiotensin converting enzyme inhibitors.BMJ. 1996; 310: 973-974Crossref Scopus (32) Google Scholar, 15Mair FS Crowley TS Bundred PE Prevalence, aetiology and mangement of heart failure in general practice.Br J Gen Pract. 1996; 46: 77-79PubMed Google Scholar, 16Philbin EF Andreou C Rocco TA Lynch LH Baker SL Patterns of angiotensin-converting enzyme inhibitor use in congestive heart failure in two community hospitals.Am J Cardiol. 1996; 77: 832-838Summary Full Text PDF PubMed Scopus (134) Google Scholar There seems to be a link between echocardiography and the likelihood of receiving an ACE inhibitor.17Hillis GS Al-Mohammad A Wood M Jennings KP Changing patterns of investigation and treatment of cardiac failure in hospital.Heart. 1996; 76: 427-429Crossref PubMed Scopus (33) Google Scholar When echocardiography is not readily available, not only is the uptake of ACE inhibitors low but many patients without systolic dysfunction may be treated inappropriately. Much advice has been offered about the importance of education of patients, the needs for dietary salt restriction, for cholesterol reduction,18Kjekshus J Pedersen TR Olsson AG Faegeman O Pyorala K The effects of simvastatin on the incidence of heart failure in patients with coronary disease.J Cardiac Failure. 1997; 3: 249-254Summary Full Text PDF PubMed Scopus (338) Google Scholar for more rest or more exercise19European Heart Failure Training GroupExperience from controlled trials of physical training in chronic heart failure: protocol and patient factors in effectiveness in the improvement of exercise tolerance.Eur Heart J. 1998; 19: 466-475Crossref PubMed Scopus (223) Google Scholar or for vaccination in patients with established heart failure.2Remme WJ Cleland JGF et al.European Society of Cardiology: guidelines for the management of heart failure.Eur Heart J. 1997; 18: 736-753Crossref PubMed Scopus (404) Google Scholar Such recommendations are founded mainly on opinion or on the extrapolation of data far beyond its clinical context. Putting some of the above opinions into practice could do as much harm as good. The mean age of patients in the community with heart failure is 74 years.20Parameshwar J Shackell MM Richardson A Poole Wilson PA Sutton GC Prevalence of heart failure in three general practices in north west London.Br J Gen Pract. 1992; 42: 287-289PubMed Google Scholar The growing proportion of the population aged over 70 years in industrialised countries is a major factor driving the increase in the number of patients with heart failure. The mean age of patients in clinical trials, with few exeptions,21Pitt B Segal R Martinez FA et al.on behalf of the ELITE study groupRandomised trial of losartan versus captopril in patients over 65 with heart failure.in: Evaluation of losartan in the elderly study, ELITE. Lancet. 349. 1997: 747-752Google Scholar, 22Swedberg K for the CONSENSUS trial study groupEffects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).Lancet. 1997; 349: 747-752Summary Full Text Full Text PDF PubMed Scopus (1656) Google Scholar, 23The NETWORK Investigators: clinical outcome with enalapril in symptomatic chronic heart failure: a dose comparison.Eur Heart J. 1998; 19: 481-489Crossref PubMed Scopus (194) Google Scholar is closer to 60 years. Older patients have more concomitant disease, which may complicate treatment or render it ineffective.6Brown A Cleland JGF Influence of pattern of concomitant disease on patterns of hospitalisation in patients with heart failure discharged from Scottish hospitals in 1995.Eur Heart J. 1998; 19: 1063-1069Crossref PubMed Scopus (129) Google Scholar, 24Cleland JGF ACE inhibitors for the prevention and treatment of heart failure: why are they "under used"?.J Hum Hypertens. 1995; 9: 435-442PubMed Google Scholar It is dangerous to assume that treatments that have been shown to be effective in younger patients also work in older patients. On the other hand, older patients with heart failure have greater morbidity and poorer prognosis and may benefit more from treatment in absolute terms than younger patients. Older patients are also more likely to have evidence of heart failure but have well preserved systolic function,25Vasan RS Benjamin EJ Levy D Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective.J Am Coll Cardiol. 1995; 26: 1565-1574Summary Full Text PDF PubMed Scopus (674) Google Scholar This may be due to the difficulties of assessing breathlessness in older people, leading to an overdiagnosis of heart failure, or due to more diastolic dysfunction reflecting a greater contribution of hypertension to the occurrence of heart failure. Alternatively, older patients with strikingly impaired systolic function may have an extremely poor prognosis and may therefore be under-represented in crosssectional studies. No adequate clinical trials have been reported among patients with evidence of heart failure in the absence of major left-ventricular systolic dysfunction. More evidence of the effectiveness of treatment in older patients with heart failure, including those patients without major ventricular dysfunction, is urgently required. A large trial of this type with the ACE inhibitor perindopril is underway. A synopsis of the effects of treatments in large clinical trials is shown in Table 2, Table 3, Table 4, Table 5. The relative and absolute effects of treatment are shown and the duration of study required to show such effects. Outcome is also expressed as the number needed to treat to prevent one patient being admitted to hospital or one death over a given treatment period.Table 2Efficacy of digoxin and non-ACE vasodilators in long-term studies of heart failureStudyComparisons versus placeboPlacebo mortalityFollow-up (months)Relative and absolute decreases (95% CI) in mortalityNumber needed to treat to prevent one eventAdmission to hospitalAdmission for heart failureDeathThe DIG study42The Digitalis Investigation Group: the effect of digoxin on mortality and morbidity in patients with heart failure.N Engl J Med. 1997; 336: 525-533Crossref PubMed Scopus (2678) Google ScholarDigoxin (mean dose) 0·25 mg one a day vs placebo35·1%37No effect7 at 3 years6 at 3 yearsNo effectPRAISE86Packer M O'Connor CM Ghali JK et al.for the PRAISE Study GroupEffect of amlodipine on morbidity and mortality in severe chronic heart failure.N Engl J Med. 1996; 335: 1107-1114Crossref PubMed Scopus (1064) Google ScholarAmlodipine 10 mg/day vs placebo33·0%13·8R:16 (−2 to 31) A:5·0Excess of events23 over 1 year (12 to ∞)V-HeFT-I52Cohn J Archibald DG Ziesche S et al.Effect of vasodilator therapy on mortality in chronic congestive heart failure.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2059) Google ScholarHydralazine 300 mg and nitrate 160 mg vs placebo53·6%27·6R:7 A: 3·9No effectNo effect20 over 3 years (CI includes ∞)V-HeFT-IHydralazine 300 mg and nitrate 160 mg vs placebo46·9% censored at 3 years36R: 36 (11–54) A: 10·7No effectNo effect9 over 3 years (6–30)CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality where given. Open table in a new tab Table 3Long-term studies of ACE inhibitors in chronic left-ventricular dysfunction or heart failureStudyComparisonsControl mortalityFollow-up (months)Relative and absolute decreases (95% CI) in mortalityNumber needed to treat to prevent one event over 3 years (unless stated otherwise)Admission to hospitalAdmission for heart failureDeathSOLVD-prevention47Yusuf S Nicklas JM Timmis G et al.Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.N Engl J Med. 1992; 327: 685-691Crossref PubMed Scopus (3504) Google ScholarEnalapril 10 mg twice a day vs placebo15·8%37·4R: 8 (−8 to 21) A: 1·01115104 (40 to ∞)SOLVD-treatment49Yusuf S Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med. 1991; 325: 293-302Crossref PubMed Scopus (6672) Google ScholarEnalapril 10 mg twice a day vs placebo39·7%41·4R: 16 (5 to 26) A: 4·53526 (16 to 82)CONSENSUSEnalapril 20 mg twice a day vs placebo52% at 1 year12R:31(CI NR) A: 16Increase in hospital days due to improved survival6 over 1 year (CI NR)Dose-ranging studiesATLAS overallLisinopril 32·5 to 35 mg/day vs lisinopril 2·5 to 5·0 mg/day44·9%46R: 8 (−3 to 18) A: 2·4CO527 (12 to ∞)ATLAS NYHA IILisinopril 32·5 to 3·5 mg/day vs lisinopril 2·5 to 5·0 mg/day42·0%46R: 23 (5 to 43) A: 7·6%310 (5 to ∞)Versus another agentV-HeFT-II52Cohn J Archibald DG Ziesche S et al.Effect of vasodilator therapy on mortality in chronic congestive heart failure.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2059) Google ScholarEnalapril 10 mg twice a day vs hydralazine 300 mg/day and nitrate 160 mg/day38·2% oil nitrate30R: 14% (includes O) A: 5·4%No differenceNo difference15 (in favour of enalapril, CI includes ∞)ELITE21Pitt B Segal R Martinez FA et al.on behalf of the ELITE study groupRandomised trial of losartan versus captopril in patients over 65 with heart failure.in: Evaluation of losartan in the elderly study, ELITE. Lancet. 349. 1997: 747-752Google ScholarCaptopril 50 mg three times a day vs Iosartan 50 mg once a day8·7% on captopril12R: 46 (5 to 69) A: 3·913 for 1 year (in favour of Iosartan)No effect26 over 1 year (14 to 45)CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality where given. Open table in a new tab Table 4Long-term studies of the efficacy of ACE inhibitors in post-infarction heart failureStudyComparisonsPlacebo mortalityFollow-up (months)Relative and absolute decreases (95% CI) in mortalityNumber needed to treat to prevent one event over 3 years (unless stated otherwise)Admission to hospitalAdmission for heart failureDeathSAVE48Pfeffer MA Braunwald E Moye LA et al.Effect of captopril on mortality and morbidity in patients with left ventricular dusfunction after myocardial infarction—results of the survival and ventricular enlargement trial.N Engl J Med. 1992; 327: 669-677Crossref PubMed Scopus (5461) Google ScholarCaptopril 50 mg three times a day vs placebo24·6%42R: 19 (3 to 32) A: 4·1NR5142 (26 to 291)AIRE50Ball SG Hall AS Mackintosh AF et al.Effect of ramipril and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.Lancet. 1993; 342: 821-828PubMed Google ScholarRamipril 5 mg twice a day vs placebo22·6·0%15R: 27 (11 to 40) A: 5·761611 (7 to 27)TRACD51Kober L Torp Pedersen C Carlsen JE et al.A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.N Engl J Med. 1995; 333: 1670-1676Crossref PubMed Scopus (1637) Google ScholarTrandolaparil 4 mg/day vs placebo42·3%27R: 22 (9 to 33) A: 7·6NR1914 (9 to 34)CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality where given. Open table in a new tab Table 5Long-term studies of (-blockers in chronic heart failureStudyComparisonsPlacebo mortalityFollow-up (months)Relative and absolute decreases (95% CI) in mortalityNumber needed to treat to prevent one event over 1 yearAdmission to hospitalAdmission for heart failureDeathUS carvedilol76Packer M Bristow MR Cohn JN et al.for the US carvedilol study groupThe effect of carvedilol on morbidity and mortality in patients with chronic heart failure.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (4193) Google ScholarCarvediilol 25 to 50 mg twice a day vs placebo7·8%6·5R: 65 (39 to 80) A: 4·671612 (7 to 29)CIBIS-I81Lechat P Jaillon P Fontaine ML et al.A randomized trial of beta-blockade in heart failure: The Cardiac Insufficiency Bisoprolol Study (CIBIS).Circulation. 1994; 90: 1765-1773Crossref PubMed Scopus (1079) Google ScholarBisoprolol 10 mg once a day vs placebo20·90%23R: 20 (−15 to 44) 4·371345 (20 to ∞)MDC75Waagstein F Bristow MR Swedberg K et al.Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy.Lancet. 1993; 342: 1441-1446Summary PubMed Scopus (1190) Google ScholarMetoprolol 50 mg three times a day vs placebo10·1%18No effect on mortalityNRAbout 9No effectANZ carvedilol77Doughty RN Rodgers A Sharpe N MacMahon S Effects of beta-blocker therapy on mortality in patients with heart failure—systematic overview of randomised controlled trials.Eur Heart J. 1997; 18: 560-565Crossref PubMed Scopus (233) Google ScholarCarvedilol 25 to 50 mg twice a day vs placebo12·6%19R: 24 (-36 to 58) A: 2·9202335 (15 to ∞)CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality wheregiven. Open table in a new tab CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality where given. CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality where given. CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality where given. CIs for numbers needed to treat have been calculated by proportions from the reported relative decrease in mortality wheregiven. Diuretics remain the most popular choice of treatment for heart failure in many countries. Diuretics are undoubtedly successful at relieving breathlessness and oedema when overt fluid overload is present. Some placebo-controlled studies have shown that diuretics effectively relieve symptoms.26Sherman LG Chang Seng Liang Baumgardner S et al.Piretanide, a potent diuretic with potassium-sparing properties, for the treatment of congestive heart failure: an epidemiologic perspective.J Am Coll Cardiol. 1995; 26: 1565-1574Summary Full Text PDF PubMed Scopus (774) Google Scholar, 27Patterson JH Adams Jr, KF Applefeld MM Corder CN Masse BR Oral torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte excretion.Pharmacotherapy. 1994; 14: 514-521PubMed Google Scholar, 28Cleland JGF Cowburn PJ McMurray JJV Cleland JGF Heart failure: a systematic guide to clinical practice. Science Press, London1997Google Scholar Studies have also shown a high incidence of recurrent symptoms when diuretics have been withdrawn 29Walma EP Hoes AW Van Dooren C Prins A Van der Does E Withdrawal of long term diuretic medication in elderly patients: a double blind randomisation trial.BMJ. 1997; 315: 464-468Crossref PubMed Scopus (93) Google Scholar, 30Andrews R Charlesworth A Evans A Cowley AJ A double-blind, cross-over comparison of the effects of a loop diuretic and a dopamine receptor agonist as first line therapy in patients with mild congestive heart failure.Eur Heart J. 1997; 18: 852-857Crossref PubMed Scopus (16) Google Scholar or substituted with an ACE inhibitor31Grinstead WC Francis MJ Marks GF Tawa CB Zoghbi WA Young JB Discontinuation of chronic diuretic therapy in stable congestive heart failure secondary to coronary artery disease or to idiopathic diated cardiomyopathy.Am J Cardiol. 1994; 73: 881-886Summary Full Text PDF PubMed Scopus (81) Google Scholar, 32Richardson A Scriven AJ Poole Wilson PA et al.Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure.Lancet. 1987; 2: 709-711Summary PubMed Scopus (30) Google Scholar, 33Magnani B Magelli C Captopril in mild heart feature: preliminary observations of a long-term, double-blind, placebo-controlled multicentre trial.Postgrad Med J. 1986; 62: 153-158PubMed Google Scholar among patients with moderately severe heart failure. Diuretics also seem to be as effective as adding an ACE inhibitor in improving exertional dyspnoea, even when fluid overload is not immediately obvious.28Cleland JGF Cowburn PJ McMurray JJV Cleland JGF Heart failure: a systematic guide to clinical practice. Science Press, London1997Google Scholar, 34Lewis SJ Roberts CJC Double-blind comparison of high-dose bumetanide and half-dose bumetanide together with captopril in heart failure.Curr Ther Res Clin Exp. 1991; 50: 3-13Google Scholar, 35Cowley AJ Stainer K Wynne RD et al.Symptomatic assessment of patinets with heart failure: double-blind comparison of increasing doses of diuretics and captopril in moderate heart failure.Lancet. 1986; ii: 770-772Summary Scopus (62) Google Scholar However, in mild heart failure, diuretics may be withdrawn for extended periods without recurrence of symptoms, and substitution of diuretic therapy with an ACE inhibitor may be appropriate in such patients, providing they have never experienced an episode of pulmonary oedema.32Richardson A Scriven AJ Poole Wilson PA et al.Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure.Lancet. 1987; 2: 709-711Summary PubMed Scopus (30) Google Scholar, 33Magnani B Magelli C Captopril in mild heart feature: preliminary observations of a long-term, double-blind, placebo-controlled multicentre trial.Postgrad Med J. 1986; 62: 153-158PubMed Google Scholar, 36Remme WJ Bodin F Benazepril heart failure study groupIs monotherapy with ACE inhibition preferable to diuretics in mild heart failure?.in: A comparison of benazepril and hydrochlorothiazide. J Am Coll Cardiol. 27. 1996: 228aGoogle Scholar Much more research is needed to find out the optimum way to use loop-diuretics; for instance, whether it is better to give them daily or only intermittently according to weight gain. New loop-diuretics with high and consistent bioavailability may be more effective in decreasing episodic decompensation37Murray MD Adams LD Forthofer MM et al.Decreased hospitalisation for CHF by using a completely and predictably absorbed loop diuretic.J Am Coll Cardiol. 1998; 31 (abstr): 465CGoogle Scholar and, although appreciably more expensive, may prove cost effective in the long run by reducing recurrent hospital admissions. The development of newer classes of agents with diuretic potential, such as the neutral endopeptidase inhibitors38Good JM Peters M Wilkins M Jackson N Oakley CM Cleland JGF Renal response to candoxatrilat in patients with heart failure.J Am Coll Cardiol. 1995; 25: 1273-1281Summary Full Text PDF PubMed Scopus (45) Google Scholar and arginine vasopressin antagonists,39Abraham WT Oren RM Crisman TS et al.Effects of an oral, nonpeptide, selective V2 receptor vasopressin antagonist in patients with chronic heart failure.J Am Coll Cardiol. 1997; 29 (abstr): 169ASummary Full Text PDF Google Scholar are stimulating renewed research in diuretic agents. Placebo-controlled withdrawal studies40Uretsky BF Young JB Shahidi E Yellen LG Harrison MC Jolly K on behalf of the PROVED investigator groupRandomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial.J Am Coll Cardiol. 1993; 22: 955-962Summary Full Text PDF PubMed Scopus (512) Google Scholar, 41Packer M Gheorghiade M Young JB et al.Withdrawal of dixogin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors.N Engl J Med. 1993; 329: 1-7Crossref PubMed Scopus (670) Google Scholar that used large doses of digoxin in relatively young patients have shown that digoxin withdrawal leads to worsening of symptoms. The effect seems to be greatest among patients with dilated cardiomyopathy. The DIG trial (table 2)42The Digitalis Investigation Group: the effect of digoxin on mortality and morbidity in patients with heart failure.N Engl J Med. 1997; 336: 525-533Crossref PubMed Scopus (2678) Google Scholar showed that digoxin was safe in standard doses. St