ACE inhibitors and ARBs in chronic heart failure: the established, the expected, and the pragmatic

Med Clin N Am 87 (2003) 373–389

ACE inhibitors and ARBs in chronic heart failure: the established, the expected, and the pragmatic Philip A. Poole-Wilson National Heart and Lung Institute, London, United Kingdom

Arguably, the most important advances in the treatment of heart failure (HF) in the last half-century were the introduction of powerful diuretics [1] and the availability of orally active angiotensin-converting enzyme (ACE) inhibitors [2]. The combination of these two classes of drugs is now the bedrock of current treatment (Table 1). More recently, b-blockers have come to be used in addition to treatment with an ACE inhibitor and a diuretic [3–5]. Whether a b-blocker alone would confer similar benefit as the combination of an ACE inhibitor and a b-blocker remains unknown. The angiotensin receptor blockers (ARBs) were conceived as an alternative to ACE inhibitors with the possible advantage of having fewer side-effects and some biologic advantages. Several trials have reported recently, and more are due, on the use of an ARB either in addition to an ACE inhibitor or as an alternative. There remain a surprising number of unresolved questions with regard to the use of ACE inhibitors and ARBs. These issues should not be allowed to confuse the general advice that the majority of patients with HF, fluid retention caused by an abnormality of the heart, or a large heart (systolic HF) with exercise limitation should be treated, whenever possible, with a diuretic and an ACE inhibitor. A major problem in the delivery of care to those with HF is the apparent reluctance of physicians to prescribe treatments shown to be effective in large trials and meta-analyses.

* Division of Cardiac Medicine, Imperial College Faculty of Medicine, The National Heart and Lung Institute, London SW3 6LY, United Kingdom. E-mail address: [email protected] 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0025-7125(02)00174-8

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Table 1 Hierarchy of end points in clinical trials Mortality Mortality, hospitalization Mortality, hospitalization, events and symptoms eg, MI, stroke Peripheral vascular disease Need for a specified therapy Freedom from a stated list of unwanted outcomes Event-free survival Cause specific mortality eg, sudden death, arrhythmic death MI Progression of HF Quality of life Abbreviations: HF, heart failure; MI, myocardial infarction.

Objectives when treating HF The mantra of this age is evidenced-based medicine. That is a glib phrase, used to convey the idea that treatment should be based on the results of large trials, meta-analyses of trials, structured reviews, and, to a lesser extent, on clinical experience; so it should. The concept is beloved of those who manage or control health delivery because the mantra implies that specific protocols be followed and that defined treatments be given to categorized patients. By contrast, a doctor is usually more concerned as to whether a drug will benefit an individual patient with observed or identified characteristics. The patient may have a different perception and is concerned only with the unattainable knowledge of whether a particular drug will benefit an individual person (themselves) rather than the impact on the many other persons who may have been in clinical trials. There is a conflict between the good intentions of health administrators and the wishes of the individual patient; the doctor is the pig in the middle proffering advice to the individual. Many trials of pharmaceutical agents have used surrogate markers as end points rather than clinical outcomes. A particular outcome is often determined by a trial Steering Committee or by industrial sponsors with the purpose of maximizing the possibility of obtaining a positive result from the trial. A positive trial is to the advantage of both those running the trial and of the industry. Doctors and patients are more concerned with modifying the end points of disease. With regard to HF, the desired end points of treatment are, as for most diseases in medicine, mortality and symptoms. The objective in HF is to maximize the period when symptoms do not limit life style (compression of morbidity) and to prolong life (Fig. 1). The desirable hierarchy of end points begins with mortality and then moves on to other measures relating to symptoms under the broad heading of morbidity (Table 2). A popular end point in recent heart failure trials has been

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Fig. 1. Healthy life versus longevity (symptomatic progression over time). The right-hand curve is the most desirable.

hospitalization used as a measure of morbidity. Caution is needed in interpreting hospitalization in that way because hospitalization for heart failure varies greatly between countries and the indications for hospitalization may be determined by the culture, structure, and social provisions of the health service delivery system in a country. The presentation of results to patients can be extremely confusing. The long-term outcome data (Fig. 2) from the CONSENSUS trial [2,6] is now known. Patients had severe heart failure on admission to the trial, and almost all the patients who entered into the trial are dead. The overall lifetime advantage can be calculated, and not just the advantage over a short period of years in which, say, up to 25% of the patients in a study die. The total patient years of survival increased by about 50% with enalapril, but nevertheless the overall outcome was gloomy with 90% of patients being dead at 4 years. What is also evident is that risk reduction varies with time. The use of this term at arbitrary times (usually the duration of the study) is a misleading way of presenting information to patients. Perhaps a more useful figure is the fall of absolute mortality [3–5,7–15] over a period of 1 year (Fig. 3). Similar information may become available in the future over Table 2 Putative mechanisms of action of ACE inhibitors in heart failure Vasodilation/hemodynamics Renal interaction with diuretics Remodelling of ventricle Reduced ischemic episodes Other biochemical mechanisms

Unknown mechanism unrelated to ACE inhibition

Reduction of myocardial stress Increased net loss of sodium Shape, hypertrophy, fibrosis Smooth muscle proliferation Structure of atheromatous plaques Thrombogenic/fibrinolytic effect Increased bradykinin Interaction with b-receptors

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Fig. 2. Long-term outcome of treatment with ACE inhibitors in the CONSENSUS trial. (Adapted from Swedberg K, Kjekshus J, Snapinn S. Long-term survival in severe heart failure in patients treated with enalapril. Ten-year follow-up of CONSENSUS I. Eur Heart J 1999;20: 136–9; with permission).

longer periods of time. What is apparent is that the reduction of absolute mortality after 1 year of treatment for heart failure is appreciable (up to 7.4% on a background of a placebo mortality of 9%–22%), whereas for trials aimed at the prevention of heart disease the absolute reduction in 1 year is small (0.4%–0.6%) on a background of a low placebo mortality of 2.1%–2.7%. Mechanisms A major theoretical difficulty with regard to the use of ACE inhibitors in heart failure is the continuing debate over the possible mechanism by which this class of drug might bring about benefit in heart failure (Fig. 4) (Table 3). Initially, ACE inhibitors were thought to give an advantage to patients

Fig. 3. Annual mortality in trials of drugs in heart failure.

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Fig. 4. The renin-angiotensin system.

because they were vasodilators, and as a consequence of lowering blood pressure. Many other drugs that are more specific vasodilators and that lower blood pressure have been shown not to be of benefit in heart failure (eg, prazosin and moxonidine) [14]. ACE inhibitors are known to have advantageous effects on the kidney, and to increase bradykinin, limit the effects of catecholamines, and modify the hypertrophic and apoptopic effects of angiotensin II within the heart muscle itself. The neutral results of the recent ELITE II [10] trial emphasize the need for humility among cardiologists in predicting clinical benefit from a drug on the basis of a known biologic property of the drug. There were many reasons why ARBs, which would block the effect of angiotensin II without having any impact on bradykinin or other peptide pathways, were expected to have a benefit in comparison with ACE inhibitors (Table 4). The trials so far have shown otherwise. As a consequence, the hypotheses put forward are also likely to be invalid. Moving from biologic concepts to clinical predictions can be a journey from misdirected hope to expensive error. Table 3 Losartan Heart Failure Survival Study—ELITE II: putative theories to reconsider knowing outcome of the trial Non-ACE–dependent angiotensin II formation not important No advantage of unopposed stimulation of AT2 receptors having blocked AT1 receptors Bradykinin-induced norepinephrine release not harmful Bradykinin-induced remodelling not advantageous Escape from inhibition of renin-angiotensin system not critical No advantage from any differential effect on electrolytes No specific effect of AT1 receptor blockade on arrhythmias Differential effects on thrombotic pathways

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Table 4 Issues concerning ACE inhibitors for heart failure Dose Interaction between aspirin and ACE inhibitors d Efficacy if EF near normal; benefit if ventricle large not on diuretic d Efficacy in women and elderly d Use to delay onset of heart failure d Not effective as sole treatment if fluid retention has been present d Population to be treated after acute MI d Possible reduction of coronary events d Possible different mechanisms for effect on symptoms and mortality d Reduction of mortality small compared to total mortality d d

Abbreviation: EF, ejection fraction.

ACE inhibitors for the prevention of heart failure ACE inhibitors have been shown to be beneficial in hypertension in that the surrogate end point of blood pressure is reduced. Increasing evidence suggests that mortality and morbidity including coronary events and stroke are also diminished; several large trials are not yet completed. The treatment of hypertension is known to reduce the onset of heart failure [16], largely because high blood pressure is a risk factor for atherosclerosis and coronary heart disease which in turn is the major cause of heart failure. A further mechanism is that a reduction of blood pressure will lessen the stress on the left ventricle and thereby diminish the progression of myocardial damage and heart failure in a ventricle already damaged by myocardial ischemia. The evidence that ACE inhibitors are advantageous when prescribed alone in patients with a large heart but without symptoms is scanty. The prevention trial of SOLVD [17] did not show a reduction in mortality but did show a reduction in the combined end point of mortality and hospitalization. There are three possible interpretations of this data. The first is that the use of the ACE inhibitor did genuinely inhibit the progression of heart failure, possibly by a beneficial effect on the preservation of myocardium. The second is that, because ACE inhibitors do have a mild diuretic effect [18], the advantage was merely the result of the patient being on treatment at a time when fluid retention would have been manifest as a consequence of worsening heart failure. The third interpretation is that an equivalent benefit could have been gained by the use of a low dose of a diuretic or within a different health delivery system. For example, if patients were seen frequently by doctors and the drugs used at the earliest onset of symptoms for heart failure, then hospitalization might have been avoided. The data does not yet provide unequivocal support for the notion that ACE inhibitors should always be used on a prophylactic basis in asymptomatic patients with large hearts, although many physicians and scientists believe and wish that idea to be correct. The recent HOPE study [8] showed a reduction in the occurrence of heart failure in a population at high

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risk of ischemic events. That does indicate a role in prevention, though the mechanism still remains unclear and could be simply the effect on blood pressure or a reduction of coronary events [19]. Several studies have been undertaken on the use of ACE inhibitors alone in heart failure [18,20]. These studies show clearly that ACE inhibitors cannot replace diuretics when heart failure is accompanied by fluid retention, and when ACE inhibitors have only a small diuretic action if given alone. In mild heart failure, the renin angiotensin system is not strongly activated until patients are treated with diuretics [21–24]. There is, therefore, a strong logical case for introducing an ACE inhibitor whenever a diuretic is being used in heart failure. ACE inhibitors in established heart failure The evidence from clinical trials overwhelmingly demonstrates that ACE inhibitors are an appropriate treatment in patients with a large heart (and, inevitably, a low ejection fraction) and fluid-retaining heart failure treated with diuretics [25,26]. These trials have demonstrated a reduction in mortality, an improvement in exercise ability, a reduction in hospitalization, and an improvement in symptoms. Trials have reported rather conflicting outcomes with regard to the mode of death [25,27]. That is almost certainly because of the impossibility of distinguishing between sudden death and death from worsening heart failure [25,27]. The apparently contradictory findings probably reflect more the difficulties of classification rather than any real property of the drugs themselves. Uncertainties with ACE inhibitors A surprising number of issues with regard to ACE inhibitors remain unresolved (Table 5). These are the reasons why the number of patients found to be prescribed ACE inhibitors is less than might be expected from an application of the evidence (Tables 6 and 7) [28]. Physicians tend to be cautious and, in general, choose to treat those patients where the benefit is Table 5 Use of ACE inhibitors in Europe for treatment of heart failure

Great Britain Netherlands France Germany Italy Spain

% patients reported to be on ACE inhibitor

% patients actually on ACE inhibitor

54 52 61 62 62 47

43 — 38 41 26 25

From Hobbs FD. Primary care physicians: champions of or an impediment to optimal care of the patient with heart failure. Eur J Heart Failure 1999;1:11–5; with permission.

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Table 6 Perceived reasons for low use of ACE inhibitors in heart failure as determined by market research Concern over side-effects Lack of awareness HF underdiagnosed Conservatism HF inappropriately managed GP lack of confidence HF undertreated

61% 36% 19% 16% 9% 9% 7%

definitely established, particularly if a treatment is associated with sideeffects or perceived risk. The trials of ACE inhibitors [2–4,10–12,14,15, 17,29–34] have been undertaken in a young population often as much as 15 years less than the mean age of persons with heart failure in the community, namely 75 years (Table 8). Only a small proportion of women have been studied. Heart failure in the presence of a normal-size heart or only marginally enlarged heart (commonly called diastolic heart failure) is common in the elderly and has not been studied extensively in terms of the response to standard treatments for heart failure. For these reasons, the evidence base for treating patients with heart failure with an ACE inhibitor is (contrary to popular opinion) greatly limited; it is in the young patient with heart failure and a large heart (systolic heart failure) where the evidence is very strong. A further issue is the identification of those patients who, having sustained a myocardial infarct, will benefit from an ACE inhibitor [35–37]. The trial evidence would seem to point to those with anterior infarcts, large hearts, or any evidence of heart failure. The HOPE trial [8] is the only study to suggest long-term benefit from ACE inhibitors in essentially asympTable 7 Heart failure trials: age and gender n

Age

% women

CONSENSUS VHeFT I VHeFT II SOLVD Rx SOLVD Pr PRAISE US Carvedilol CIBIS II MERIT DIG RALES ATLAS ELITE II

253 642 804 2569 4228 1153 1094 2647 3991 6800 1663 3192 3152

70 58 61 61 59 65 58 61 — 64 65 64 72

29 0 0 20 11 24 23 20 22 22 27 21 31

Population

6478

75

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Table 8 ACE inhibitors in heart failure side-effects causing problems as determined by market research Cough Renal impairment Hypotension Rash

58% 43% 40% 7%

tomatic patients who are at risk of developing heart failure. Further information is needed on this particular issue from that study. Two large trials of ACE inhibitors in chronic angina (EUROPA and PEACE) are currently coming to an end and will provide further important information. The major known side-effects of ACE inhibitors are alleged in market research to cause problems in a high proportion of patients (Table 9). This data is rather different from that obtained from the clinical trials. That may be because different patient groups are being studied; different clinical criteria are applied; patient management is different; or knowing a symptom such as cough can occur encouraged the detection of the symptom. Initially, it is also true that ACE inhibitors were prescribed in too high a dose and the dose was not titrated upward. Indeed, the optimal dose of an ACE inhibitor remains largely unknown [38]. Many small trials have tried to show a dose-response effect but always with surrogate end points [39–42]. Several small studies have shown a benefit from low doses of ACE inhibitors [43–48]. The NETWORK trial [49] in 1533 patients did not show a dose response for enalapril over a 6-month period using a combined end point. The larger ATLAS trial with3164 patients [50] failed to show a difference in Table 9 Actions of angiotensin II Organ

Cellular effect

Consequence

Arteriolar smooth muscle oocytes, fibroblasts Terminal neurone Glomeruli

Vasoconstriction expression of proto-oncogene Vasoconstriction Promotes microglobulinu

Xtaglomerular apparatus

Increase IP3, Ca2þþ Stimulate PKC cell growth Release of noradrenaline Constricts efferent arterioles Enlarges glomerular pores Inhibits renin release

Adrenal cortex

Synthesis of aldosterone

Fibrinolysis

Increase of PAI-1

Lowering of raised glomerular pressure Sodium retention Potassium loss Impaired fibrinolysis

From Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin-II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 1993;87:1969–73; and Timmermans P, Wong PC, Chiu AT. Angiotensin-II receptors and angiotensin-II receptor antagonists. Pharmacological Reviews 1993;45:205–51; with permission. Abbreviation: PKC, protein kinase C.

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the primary end point of death comparing 2.5/5.0 mg with 32.5/35 mg of lisinopril. The ATLAS trial did show a difference in almost every other endpoint such as all-cause death and hospitalization, and death or hospitalization for heart failure. This trial is a good example of a trial regarded as not being positive but which would have been if one of the currently favored (and flawed) end points for heart failure trials had been adopted. Most physicians and guidelines currently recommend that the dose of an ACE inhibitor is not left as the initial low starting dose but is titrated up toward the doses used as the targets in the clinical trials. That does not mean that every patient must have the dose pushed to the highest possible dose, but, equally, patients should not be left on the lowest initial dose. Angiotensin receptor blockers (ARB) in the treatment of heart failure In view of the success of the use of ACE inhibitors and the known unwanted effects, alternative drugs, impacting on the renin-angiotensin pathway, have been developed. Although ACE inhibitors appear to have long-term benefit (at least over 5 years from trial evidence) and the plasma levels of plasma ACE activity remain low, the plasma angiotensin II concentrations increase (Figs. 5 and 6) [51,52]. These observations indicate escape from inhibition of the system by ACE inhibitors. Several mechanisms have been proposed, including the existence of alternative pathways for the conversions of angiotensin I to angiotensin II (Fig. 4). There are several other arguments that support the contention that selective inhibition of the angiotensin II receptor would have advantages over the less selective inhibition of the conversion of angiotensin I to angiotensin II (Fig. 7). The

Fig. 5. Plasma ACE and angiotensin II with time while on treatment with an ACE inhibitor. (Adapted from Biollaz J, Brunner HR, Gavras I, Waeber B, Gavras H. Antihypertensive therapy with MK 421: angiotensin II–renin relationships to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol 1982;4:966–72; with permission).

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Fig. 6. Angiotensin II in patients after long-term treatment with an ACE inhibitor. (From Rousseau MF, Konstam MA, Benedict CR, Donckier J, Galanti L, Melin J, et al. Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensinconverting enzyme inhibitor. Am J Cardiol 1994;73:488–93; with permission).

beneficial outcome in the RALES trial [15] in terms of both mortality and morbidity suggested that inhibition of the pathway at a point closer to the generation of aldosterone had additional advantages to inhibition of the conversion of angiotensin alone. The interpretation of the RALES study remains contentious. Many physicians, and certainly those who ran the trial, believe that much of the effect of spironolactone was not simply attributable to the presence of an additional diuretic that could have acted synergistically with other diuretics. That hypothesis could have been tested by including a third arm to the trial in which a diuretic such as a thiazide was added to standard therapy. Rather, it is argued that the effects of aldosterone such as the promotion of fibrosis in the myocardium were inhibited [53], and that the progression of damage to the left ventricular myocardium was delayed. If that idea were correct, then it is logical to expect an ARB to confer similar benefits.

Fig. 7. The effects of aldosterone.

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The ARBs have been prescribed extensively in the treatment of hypertension. Much is known about the doses required to lower blood pressure. Experience in hypertensive patients has indicated, furthermore, that this class of drug has remarkably few side-effects. Early studies showed that ARBs, such as losartan, had hemodynamic effects in heart failure that would be expected to be advantageous [54,55]. Hemodynamic changes in heart failure are not a good surrogate of benefit in terms of outcome measures but do at least indicate a dose that has an observable effect and gives confidence in terms of safety in using a new drug in heart failure. There have been four key studies reported with ARBs. The first was the ELITE study [56] which sought to show whether there were disadvantageous effects on plasma potassium and renal function in 722 elderly and ACE-naı¨ ve patients with heart failure randomized to captopril or losartan. No differences in effects on the primary end points were observed. An unexpected finding was a statistically significant difference in mortality from 32 (8.7%) with captopril to 17 (4.8%) with losartan over a period of 48 weeks. Another early pilot study was RESOLVD [57]. This was a complex study (768 heart failure patients, ejection fraction 27%) with many subgroups comparing candesartan (4–16 mg once daily, or od), enalapril 20 mg od and the combination. Patients were cross-randomized with metoprolol, and the primary end point was not entirely clear. Exercise capacity, New York Heart Association class, and quality of life measures were unchanged. Left ventricular (LV) end-diastolic volume was lower, and ejection fraction higher, with the combination of enalapril and candesartan, but there was no difference between the individual drugs. Death and hospitalization was greater with the combination compared with enalapril alone (P < 0.037). The conclusion was perhaps surprising: ‘‘Candesartan alone was effective, safe and tolerable as enalapril.’’ As a consequence of the results of ELITE [56], a second study was undertaken. In ELITE II [10], 3152 patients aged 71 years with a mean ejection fraction of 31% were followed for a mean duration of 1.5 years. The trial compared captopril with losartan. Deaths (the primary end points) were 280/1578 (17.7%) on losartan and 250/1574 (15.9%) on captopril (RR ¼ 1.13, 95% CI 0.95–1.13, P ¼ 0.16). Withdrawals were less on losartan (153) than on captopril (231) (P < 0.002). The interpretation of the findings in this study has been widely debated. A beneficial effect on the primary end point was not shown. But some have argued that if side-effects and withdrawals were less and outcomes no different, then losartan would be the drug to choose. The issue rests on complex statistical and clinical debate as to what constitutes equivalence or no difference in a clinical trial. Formally, the study was not an equivalence study and did not have the power to establish equivalence. From the clinical standpoint, it is tempting and, to some, irresistible to argue that if, in a study of 3152 patients, no difference can be demonstrated; then, any real difference is likely to be small and possibly irrelevant to clinical decision-making. The trial brings into

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sharp contrast the consequences of applying rigid statistical concepts and the basis of medical decision-making. Many guidelines recommend that if, for one reason or another, an ACE inhibitor cannot be used in the treatment of heart failure, then an ARB is a reasonable alternative. That position has not been agreed to by several of the world’s major drug agencies. It is rare, and a matter causing considerable public disquiet, when statisticians, drug agencies, and medical opinion are in clear disagreement. The view of the Steering Committee of ELITE II was that an ACE inhibitor should remain the first drug to be prescribed because of the greater body of evidence supporting the efficacy of ACE inhibitors in heart failure. A difficulty with that position is that a minor and easily elicited symptom such as cough can be used as a reason for changing to an ARB. The situation has not been simplified by the Val HeFT study [58]. This study included 5010 patients aged 63 years with an ejection fraction of 27%, followed for a mean of 1.9 years and comparing valsartan with placebo against a background of conventional treatment including an ACE inhibitor. There were two primary end points. The first, mortality, was unaffected (495/2511 (19.7%) versus 484/2499 (19.4%) RR 1.02, 95% CI 0.90–1.15, P ¼ 0.8). The second endpoint was mortality and morbidity and was in favor of valsartan (P < 0.009). Seemingly, this trial has a positive result. The word ‘‘morbidity’’ in this study was actually hospitalzation for heart failure. It is difficult to obtain the result for total death and total hospitalization, but this would appear to be no different between the two groups (3106 on placebo and 2856 on valsartan, P ¼ 0.14). Thus, if hospitalization for heart failure was decreased, then there is a possibility that hospitalization for other causes has increased. The point is critical because, if total hospitalization is not reduced, then it is unlikely that the treatment is cost-effective, because hospitalization is the main driver of costs in care of the patient with heart failure. A further difficulty is that in those patients who were not on background therapy with an ACE inhibitor valsartan had a substantial benefit which accounted for much of the overall benefit. The results were further complicated by the observation that those patients on triple therapy (ACE inhibitor, ARB, and a b-blocker) did worse than any other group, and, indeed, there appeared to be harm in terms of mortality. Val HeFT has not answered the key clinical issue as to whether patients with heart failure are equally well served by initial treatment with a diuretic, and either an ACE inhibitor or an ARB; the interaction with a b-blocker adds to confusion. One further piece of evidence will emerge shortly. The CHARM study [59] includes a total of 6500 patients divided into three groups, each randomized to placebo or candesartan, those with an ejection fraction above 40%, those unable for any reason to be placed on an ACE inhibitor, and a group where all patients are on an ACE inhibitor (so-called add-on therapy). This study is the only one to have a large group of patients not on an ACE inhibitor who are randomizaed to an ARB or placebo; most

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physicians would anticipate that this arm of the study will have a positive result. If the arm of the study using candesartan as add-on therapy was positive, then that would be in contrast with the results of Val HeFT and ELITE II; such a result would complicate understanding of the role of the rennin-angiotensin system in heart failure. Summary ACE inhibitors have been shown to reduce mortality, reduce hospitalization, reduce symptoms, and increase exercise capacity in patients with heart failure and a large heart (low ejection fraction). The evidence is overwhelming. There are some subgroups of patients, such as the very elderly and those with a normal ejection fraction, where uncertainty still exists. The combination of a diuretic and an ACE inhibitor is currently the proper treatment of congestive heart failure; a b-blocker should be added in selected patients. The evidence for the efficacy of ARB is less persuasive and, for the present, this class of drug should be prescribed only when an ACE inhibitor cannot be tolerated. The results of the trials emphasize an emerging problem in medicine, namely how to evaluate a new treatment that may be as efficacious as current therapy but with fewer side-effects. Proving equivalence in efficacy will be difficult, requiring large studies comparing new drugs with the best current treatment. The most common etiology of heart failure is coronary heart disease. If further studies provide more support for the idea that ACE inhibitors prevent ischemic episodes and delay the onset of heart failure, then a new indication for ACE inhibitors will be the prevention of heart failure. References [1] Slater JDH, Nabarro JDN. Clinical experience with chlorothiazide. Lancet 1958;1:124–6. [2] 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). The CONSENSUS Trial Study Group. N Engl J Med 1987;316: 1429–35. [3] CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. [4] MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7. [5] Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–8. [6] Swedberg K, Kjekshus J, Snapinn S. Long-term survival in severe heart failure in patients treated with enalapril. Ten year follow-up of CONSENSUS I. Eur Heart J 1999;20:136–9. [7] The Scandinavian Simvastatin Survial Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9.

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[8] Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: 145–53. [9] Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747–52. [10] Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial–the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355: 1582–7. [11] Cohn JN, Johnson G, Ziesche S, Cobb F, Francis GS, Tristani F, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:302–10. [12] 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;325:293–302. [13] The b-Blocker Evaluation of Survival Trial Investigators. A trial of the b-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344: 1659–67. [14] Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, 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;314:1547–52. [15] Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17. [16] Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA 1997;277:739–45. [17] The SOLVD investigators. 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;327:685–91. [18] Anand IS, Kalra GS, Ferrari R, Wahi PL, Harris PC, Poole-Wilson PA. Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention. Int J Cardiol 1990;28:341–6. [19] Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992;340:1173–8. [20] Richardson A, Bayliss J, Scriven AJ, Parameshwar J, Poole-Wilson PA, Sutton GC. Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. Lancet 1987;2:709–11. [21] Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-Wilson P. Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J 1987;57:17–22. [22] Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med 1985;103:1–6. [23] Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang C, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. Circulation 1990;82:1724–9. [24] Remes J, Tikkanen I, Fyhrquist F, Pyorala K. Neuroendocrine activity in untreated heart failure. Br Heart J 1991;65:249–55. [25] Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450–6.

388

P.A. Poole-Wilson / Med Clin N Am 87 (2003) 373–389

[26] Townend JN, Littler WA. Angiotensin converting enzyme inhibitors in heart failure: how good are they? Br Heart J 1993;69:373–5. [27] Narang R, Cleland JGF, Erhardt L, Ball SG, Coats AJS, Cowley AJ, et al. Mode of death in chronic heart failure. A request and proposition for more accurate classification. Eur Heart J 1996;17:1390–403. [28] Hobbs FD. Primary care physicians: champions of or an impediment to optimal care of the patient with heart failure? Eur J Heart Fail 1999;1:11–5. [29] Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107–14. [30] Clark AL, Skypala I, Coats AJS. Ventilatory efficiency is unchanged after physical training in healthy persons despite an increase in exercise tolerance. Journal of Cardiovas. Risk 1994;1:347–51. [31] The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–33. [32] Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100: 2312–18. [33] Cowie MR, Wood DA, Coats AJS, Thompson SG, Poole-Wilson PA, Suresh V, et al. Incidence and aetiology of heart failure. A population-based study. Eur Heart J 1999;20:421–8. [34] Cowie MR, Mosterd A, Wood DA, Deckers JW, Poole-Wilson PA, Sutton GC, et al. The epidemiology of heart failure. Eur Heart J 1997;18:208–25. [35] ISIS-4. (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet 1995;345:669–85. [36] Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, et al. Long-term ACEinhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000;355:1575–81. [37] Latini R, Tognoni G, Maggioni AP, Baigent C, Braunwald E, Chen ZM, et al. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group. J Am Coll Cardiol 2000;35:1801–7. [38] Cleland JGF, Poole-Wilson PA. ACE inhibitors for heart failure: a question of dose. Br Heart J 1994;72:S106–10. [39] Riegger GAJ. Effects of quinapril on exercise tolerance in patients with mild to mederate heart failure. Eur Heart J 1991;12:705–11. [40] Vagelos R, Nejedly M, Willson K, Yee G, Fowler M. Comparison of low versus high dose of enalapril therapy for patients with severe congestive heart failure (CHF). J Am Coll Cardiol 1991;17:275A. [41] Pacher R, Globits S, Bergler-Klein J, Teufelsbauer H, Wutte M, Baumgartner W, et al. Clinical and neurohumoral response of patients with severe congestive heart failure treated with two different captopril dosages. Eur Heart J 1993;14:273–8. [42] Pacher R, Stanek B, Globits S, Berger R, Hulsmann M, Wutte M, et al. Effects of two different enalapril dosages on clinical, haemodynamic and neurohumoral response of patients with severe congestive heart failure. Eur Heart J 1996;17:1223–32. [43] Brilla CG, Kramer B, Hoffmeister HM, Muller-Schauenburg W, Risler T, Seipel L. Lowdose enalapril in severe chronic heart failure. Cardiovasc Drugs Ther 1989;3:211–8. [44] Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study. Circulation 1984;70:271–8.

P.A. Poole-Wilson / Med Clin N Am 87 (2003) 373–389

389

[45] Franciosa JA, Wilen MM, Jordan RA. Effects of enalapril, anew angiotensin converting enzyme inhibitor, in a controlled trial in heart failure. J Am Coll Cardiol 1985;5:101–7. [46] Kleber FX, Niemoller L, Doering W. Impact of converting enzyme inhibition on progression of chronic heart failure: results of the Munich Mild Heart Failure Trial. Br Heart J 1992;67:289–96. [47] Ray SG, Pye M, Oldroyd KG, Christie J, Connelly DT, Northridge DV, et al. Early treatment with captopril after acute myocardial infarction. Br Heart J 1993;69:215–22. [48] Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G. Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition. Lancet 1991;337:872–6. [49] The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. Eur Heart J 1998;19:481–9. [50] Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study. ELITE). Lancet 1997;349:747–52. [51] Biollaz J, Brunner HR, Gavras I, Waeber B, Gavras H. Antihypertensive therapy with MK 421: angiotensin II-renin relationships to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol 1982;4:966–72. [52] Rousseau MF, Konstam MA, Benedict CR, Donckier J, Galanti L, Melin J, et al. Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitor. Am J Cardiol 1994;73:488–93. [53] Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2002;345:1689–97. [54] Gottlieb SS, Dickstein K, Fleck E, Kostis J, Levine TB, LeJemtel T, et al. Haemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation 1993;88:1602–9. [55] Crozier I, Ikram H, Awan N, Cleland J, Stephen N, Dickstein K, et al. Losartan in heart failure. Hemodynamic effects and tolerability. Losartan Hemodynamic Study Group. Circulation 1995;91:691–7. [56] Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisonpril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312–8. [57] McKelvie RS, Yusuf SPD, Avezum A, Burns RJ, Probstfield J, et al and The RESOLVD Pilot Study Investigators. Comparison of candesartan, enalapril, and their combination in congestive heart failure. Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. Circulation 1999;100:1056–64. [58] Cohn JN, Tognoni G, for The Valsartan Heart Failure Trial Investigators. A randomised trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2002;345:1667–75. [59] Swedberg K, Pfeffer M, Granger C, Held P, McMurray J, Ohlin G, et al. Candesartan in heart failure–assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Program Investigators. J Card Fail 1999;5:276–82.