The role of losartan in the management of patients with heart failure

CLINICAL THERAPEUTICS®/VOL. 23, NO. 9, 2001

The Role of Losartan in the Management of Patients with Heart Failure Kenneth Dickstein, MD, PhD University of Bergen, Central Hospital in Rogaland, Stavanger, Norway

ABSTRACT

Background: Heart failure places a burden on patients and health care systems worldwide. Although the advent of angiotensin-converting enzyme (ACE) inhibitors markedly improved management of this chronic disorder, treatment is still not optimal, and morbidity and mortality remain high. Objective: This review summarizes existing data on losartan, an angiotensin II (All)receptor antagonist, and compares its potential role with that of ACE inhibitors in the management of patients with heart failure. Methods: Relevant primary studies and review articles were identified through a MEDLINE search of the English-language literature for the past 5 years and through examination of the reference lists of the articles so identified. Search terms included, but were not limited to, angiotensin-converting enzyme inhibitors, angiotensin II-receptor antagonists, and losartan. Results: Preclinical and clinical studies of losartan have demonstrated consistent hemodynamic effects (via selective antagonism of the All type 1 receptor) and a safety profile similar to that of placebo (presumably a reflection of the selective approach to AII blockade). In addition, large-scale end-point studies have shown losartan to have comparable efficacy to ACE inhibitors on a number of morbidity and mortality measures. Conclusions: There is strong evidence for the broad applicability of AII-antagonists in heart failure and for the use of All-antagonists in the treatment of a broader population of patients with heart failure, not only those who are unable to tolerate treatment with ACE inhibitors. Key words: losartan, angiotensin II-antagonists, ACE inhibitors, heart failure. (Clin Ther. 2001;23:1456-1477) Accepted for publication July 19, 2001. Printed in the USA. Reproduction in whole or part is not permitted.

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INTRODUCTION Heart failure is a progressive disorder characterized by frequent hospitalizations and high mortality. It places a burden on patients and health care systems worldwide. Despite significant progress in the prevention and treatment of cardiovascular disease over recent years, the incidence and prevalence of heart failure are increasing. In the United States alone, an estimated 4 to 5 million people suffer from chronic heart failure, with 400,000 new cases each year.l-3 The elderly are particularly at risk. The majority of new cases of heart failure are in patients aged >70 years, who constitute an increasing proportion of the population. 4 In the United States, heart failure is the leading cause of hospitalization among people aged >65 years. 5 In 1997, there were almost 1 million hospital discharges with a primary diagnosis of heart failure, with associated costs of more than $20 billion, of which ~70% were related to hospitalization. 6'7 The prognosis of heart failure is poor. In symptomatic patients, meta-analysis has shown that 1year survival is -65%, whereas the 5-year mortality rate approaches 50%. 4,7 Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces both the morbidity and mortality of chronic heart failure, 8 and ACE inhibitors can be considered the agents of choice for the treatment of this condition. Use of ACE inhibitors by prescribing physicians, however, has not been optimal. A recent study of primary care management of heart failure in Europe 9 found that although most physicians (47%-62%) reported prescribing ACE inhibitors, they did so in a small majority of patients (55%) and at doses lower than recommended by current guidelines. 10.11Their treatment decisions appeared to be driven

more by perceived risks than by potential benefits. Among physicians surveyed, 62% thought there were substantial side effects associated with the use of ACE inhibitors in heart failure. 9 Recently, angiotensin II (AII)-receptor antagonists have been shown to have effects on the morbidity and mortality of congestive heart failure that are comparable to those of ACE inhibitors, with an improved safety profile, and the supporting evidence is growing. 12-15This review summarizes existing data on the use of losartan in the management of patients with heart failure, comparing ACE inhibition and antagonism of the AII type 1 (AT 0 receptor as modes of inhibiting the reninangiotensin-aldosterone (RAA) system. Relevant primary studies and review articles were identified through a MEDLINE search of the English-language literature for the past 5 years and through examination of the reference lists of the articles so identified. Search terms included, but were not limited to, angiotensin-converting en-

zyme inhibitors, angiotensin ll-receptor antagonists, and losartan. HEART FAILURE AND ACTIVATION OF T H E RAA SYSTEM The RAA system plays a central role in the pathophysiology of heart failure. The hemodynamic profile of a patient with heart failure is characterized by elevated filling pressure, reduced cardiac output, and increased peripheral vascular resistance. These characteristics are secondary to neurohumoral stimulation, with increased production of renin causing conversion of circulating angiotensinogen to angiotensin I (AI), which is then rapidly converted to AII via ACE. In turn, AIl causes vasoconstriction and retention ot 1457

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salt and water. These effects, together with elevated levels of noradrenaline, aldosterone, and arginine vasopressin, have a negative effect on myocardial function and elevate systemic vascular resistance, serving to increase cardiac work and exacerbate the existing heart failure. Although diuretic therapy can prevent volume overload in heart failure and is an essential component of overall treatment, it can also augment the already increased renin production in these patients. As such, inhibition of the RAA system is necessary at an early stage to decrease peripheral vascular resistance, prevent vasoconstriction, and delay further progression of heart failure. Inhibition of All production via ACE inhibition has become standard therapy for this purpose. 3'10'11 The beneficial effects of ACE inhibition are well documented. For example, ACE inhibitors have been shown to improve hemodynamics, 16 favorably modify the neuroendocrine profile, 17 alter symptomatic status, 18 and increase exercise capacity in patients with heart failure. 19 Beneficial effects of ACE inhibition have also been seen in patients after myocardial infarction (MI), improving survival in those with left ventricular dysfunction. 2°-22 ACEinhibitor treatment has also been shown to decrease morbidity and mortality resulting from chronic heart failure. 8,23-25 The evidence for the role of the RAA system in heart failure is overwhelming, and the benefits of pharmacologic intervention are clear. The question is not why but how to target the RAA system in the treatment of heart failure. All-RECEPTOR BLOCKADE AII-antagonists directly block the effects of AII at the receptor level. The concept 1458

of AII-receptor blockade in heart failure is pharmacologically attractive for a number of reasons. First, inhibition of AII production is incomplete after ACE-inhibitor treatment, and there is considerable "escape" of free, circulating All, particularly with low-dose therapy. 26 In addition, All can be produced by non-ACE-dependent pathways (eg, via chymase or cathepsin G), particularly in the failing myocardium.27 Thus, even when ACE inhibitors are used, occupation and stimulation of AII receptors can still occur. Second, the actions of ACE are not specific to AI. ACE also cleaves such other peptides as bradykinin, enkephalin, and substance P, and so removes these vasoactive substances from the circulation. Inhibition of ACE allows these peptides to accumulate and can lead to some of the clinically troublesome side effects of ACE inhibitors, such as cough. 2s A third reason for the appeal of AIIreceptor blockade relates to the receptor itself. At least 2 types of AII receptor exist, the 2 subtypes eliciting quite different effects (Table I). The AT l receptors are those that on stimulation, produce the well-known effects of AII (eg, vasoconstriction, aldosterone release, cardiovascular hypertrophy29). The AII type 2 (AT2) receptors, in contrast, appear to mediate antipressor effects, 3° may antagonize the vasoconstrictor actions of AII through the release of nitric oxide, 31 and possess antitrophic rather than trophic properties. 32 All-antagonists such as losartan elevate circulating All levels as a result of inhibition of negative feedback at the AT I receptor. The resulting elevation in circulating All stimulates unblocked ATe receptors. ACE inhibitors, on the other hand, lower circulating All levels and so reduce stimulation of the AT2 receptor.

K. DICKSTEIN

Table I. Possible differential effects mediated by angiotensin II receptor types 1 (AT 1) and 2 (AT2). ATl Receptors Vasoconstriction Growth stimulation Antiapoptotic Profibrotic Prothrombotic Pro-oxidant

AT2 Receptors Vasodilatation Growth inhibition Proapoptotic Antifibrotic Antithrombotic Antioxidant

THE P R E C L I N I C A L P R O F I L E OF LOSARTAN Losartan is an orally active nonpeptide AIIantagonist that specifically blocks the AT~ receptor.33 35 It was the first All-antagonist (others include candesartan, eprosartan, irbesartan, telmisartan, and valsartan). All All-antagonists are selective for the AT l receptor, and all appear to exhibit pharmacologic class effects. There are differences, however, in their pharmacokinetic profiles (eg, metabolism, half-life, affinity for the AT 1 receptor). Although the clinical significance of these differences is not yet clear, the relevant distinguishing characteristics are assumed to be those relating to potency and duration of effect. In humans, losartan is rapidly converted by hepatic oxidation to a potent, longacting metabolite (E3174). This metabolite, which is largely responsible for the drug's clinical activity, displays pharmacologic characteristics similar to those of losartan. It has 10 to 40 times greater affinity than losartan for the AT l receptor and displays noncompetitive rather than competitive antagonism, with slow dissociation from the AT 1 receptor (elimination halflife, - 6 - 7 hours). 36-38

The high affinity and selectivity ot losartan for the AT l receptor (50% inhibitory concentration, 5-30 nmol/L) was first demonstrated in vitro in competitive binding assays and studies in isolated vascular tissue. Losartan was able to antagonize the vascular responses to AII without affecting responses to other vasoactive agents (eg, noradrenaline, acetylcholine, bradykinin). 29,36These findings were confirmed in studies across a range of species and animal models, in which losartan inhibited virtually all known effects of AII, including inhibition of the release of aldosterone, vasopressin, and noradrenaline. 39-41 However, the principal evidence for losartan-induced inhibition of endogenously released AII came from studies in AII (renin)-dependent hypertensive rats. 42 In these rats, losartan produced a dosedependent reduction in blood pressure after both acute and chronic dosing. Tissue-protective effects beyond those explained by blood pressure reduction have been seen with losartan treatment in a number of experimental models of cardiovascular disease, including left ventricutar hypertrophy, heart failure, renal failure, and stroke. 43 In models of heart failure, 44 treatment with losartan improved hemodynamics, decreased fluid retention, and reversed cardiac hypertrophy. Survival benefits after MI were also observed in animal models. 45 CLINICAL EXPERIENCE It is estimated that >10 million patients have been treated with losartan for hypertension and heart failure since the drug was approved for the indication of hypertension in 1994. The clinical experience with losartan in heart failure is growing and, as of 2000, included an estimated 1459

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300,000 patients worldwide (data on file, Merck & Co, Inc).

Early Hemodynamic Studies The initial clinical experience with losartan in heart failure consisted of 2 invasive, placebo-controlled, dose-finding hemodynamic studies in patients with mild to moderate heart failure (New York Heart Association [NYHA] functional class II-IV, left ventricular ejection fraction <40%). 46,47 In the first of these studies, 46 60 patients were randomized to receive a single dose of double-blind losartan 5 to 150 mg or placebo, and hemodynamic and neurohumoral variables were measured over the subsequent 24 hours. Treatment with losartan produced dose-dependent vasodilatation. Mean arterial pressure and systemic vascular resistance decreased significantly compared with placebo (P < 0.05). The cardiac index increased and filling pressure and right atrial pressure decreased in patients treated with losartan, although the differences were not statistically significant; there was no marked change in heart rate. As expected, there were compensatory increases in plasma AII and renin activity and a reduction in aldosterone levels with losartan compared with placebo (all comparisons, P < 0.05). The second study 47 investigated both the acute and chronic hemodynamic effects of losartan. One hundred fifty-four patients were randomized to receive losartan 2.5, 10, 25, or 50 mg OD or placebo for 12 weeks, and hemodynamic assessments were carried out acutely after drug administration and 12 weeks later. During shortterm treatment with losartan, systemic vascular resistance and blood pressure were markedly decreased. There was no evi1460

dence of attenuation of the effect of losartan after 12 weeks; in fact the hemodynamic profile was improved. Systemic vascular resistance and blood pressure were still decreased, filling pressure and heart rate were reduced, and the cardiac index was increased (Figure 1). The greatest hemodynamic efficacy was seen with losartan 50 mg/d, many of the hemodynamic changes (systemic vascular resistance, pulmonary capillary wedge pressure, cardiac index, mean arterial pressure, and heart rate) achieving statistical significance compared with placebo (all, P < 0.05). Two subsequent pilot exercise studies compared the effects of losartan and enalapril over 8 to 12 weeks in patients with moderate (NYHA II-III) or more severe (NYHA III-IV) heart failure. 48,49 In both studies, patients whose condition was already stabilized with ACE-inhibitor therapy were randomly assigned to either losartan 25 or 50 mg/d or enalapril 20 mg/d. Results were consistent across the 2 studies, demonstrating that exercise capacity (6-minute walk test or treadmill exercise time) and clinical status (dyspneafatigue index) were not significantly altered after ACE-inhibitor therapy was replaced with losartan. Larger studies further evaluated the hemodynamic efficacy of losartan in heart failure and investigated its potential impact on morbidity and mortality. In 2 multicenter, double-blind, placebo-controlled exercise studies, 5° 736 patients with heart failure (NYHA class II-IV, left ventricular ejection fraction <40%) were randomized to receive losartan or placebo in a 2:1 ratio. Although changes in exercise performance did not differ between losartan and placebo after 12 weeks of treatment, significant improvements in hospitalization and survival rates were seen with

K. DICKSTEIN

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losartan (P < 0.05). Overall, 6.9% of placebo recipients were admitted to the hospital for heart failure, compared with 3.1% of losartan recipients. Similarly, 5.3% of placebo recipients died during the study, compared with 1.4% of losartan recipients (Figure 2). In a meta-analysis of mortality data from 6 of the early double-blind, multipledose studies of losartan in heart failure (total, 1894 patients), 14 losartan had an observed effect on survival relative to placebo or active treatment (Figure 3). The odds of death in the losartan groups were approximately half those in the control groups (odds ratio, 0.51; P = 0.004). The total number of deaths was, however, small (36 losartan, 47 control), and the follow-up period short (mean, 25.4 weeks), underlining the need for large comparative studies with ACE inhibitors. The E L I T E Trial

Over the past decade, large-scale investigations in patients with heart failure and systolic left ventricular dysfunction have been dominated by studies of ACE inhibitors, starting with the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)fl 3 The abundance of clinical data demonstrating the efficacy of ACE inhibitors in heart failure has precluded placebo-controlled studies of such therapeutic alternatives as AII-antagonists. Comparisons with ACE inhibitors are, however, clinically justified. The Evaluation of Losartan in the Elderly (ELITE) 12 trial was the first longterm study (as determined by MEDLINE search) to compare an ACE inhibitor with an All-antagonist in patients with heart failure due to systolic left ventricular dysfunction. It compared the effects of 1462

losartan and captopril in 722 ACEinhibitor-naive elderly patients (age, >65 years) with symptomatic heart failure (NYHA class II-IV, left ventricular ejection fraction <40%). Patients were randomized to receive losartan titrated to 50 mg OD or captopril titrated to 50 mg TID and were followed for 48 weeks. The primary end point was a safety measure of renal dysfunction (persistent increase in serum creatinine >0.3 mg/dL). Secondary end points were death and/or hospital admission for heart failure, total mortality, hospital admission for heart failure, worsening of heart failure, hospital admission for MI or unstable angina, withdrawal from the study due to drug intolerance, and changes in neurohumoral profile. Although there was no difference between treatments in the incidence of the primary end point (10.5% increase in serum creatinine levels with both losartan and captopril), an unexpected reduction in overall mortality was observed in favor of losartan (4.8% losartan vs 8.7% captopril; risk reduction = 46%; P = 0.035). The cumulative Kaplan-Meier survival curves separated early and remained separate throughout the 48 weeks of treatment. Analysis of causes of death suggested that the lower total mortality in the losartan group was primarily the result of a reduction in sudden cardiac death. The rate of hospital admissions due to heart failure was the same for losartan and captopril (5.7%), and the improvement in NYHA functional class from baseline was similar in both groups (80% of losartan-treated patients and 81% of captopril-treated patients were NYHA class I or II at study completion). Overall, hospital admission rates were significantly lower with losartan (22.2%) than captopril (29.7%; P = 0.014). Losartan

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was also better tolerated than captopril, with fewer losartan patients discontinuing treatment due to adverse events (12.2% losartan vs 20.8% captopril; P = 0.002). Despite these findings, the superiority of losartan to captopril was based on a small number of events that were not the primary end point in a study that was neither designed nor powered to evaluate mortality. The authors concluded that further evaluation of the effects of losartan and captopril on mortality and morbidity in a larger number of patients was warranted. 1464

The Losartan Heart Failure Survival Study The Losartan Heart Failure Survival Study (ELITE II) 13 compared the effects on mortality of losartan and captopril in 3152 patients from 46 countries. Entry criteria were similar to those of the ELITE study, 12 in that patients were aged >60 years and had NYHA class II-IV heart failure and a left ventricular ejection fraction <40%. The primary end point was all-cause mortality, and the secondary end

K. DICKSTEIN

point was the composite of sudden cardiac death and resuscitated arrest. The results demonstrated no statistical difference between losartan and captopril in terms of all-cause mortality (17.7% deaths losartan vs 15.9% deaths captopill) (Figure 4A), sudden death or resuscitated arrest (9.0% vs 7.3%), or combined total mortality/hospitalization for any reason (47.7% vs 44.9%) (Figure 4B). Mortality did not differ significantly between predefined subgroups (eg, age <70 or >70 years, male or female sex, N Y H A class I l l - I V vs class II) at baseline or by concomitant medication at randomization. In both the losartan and captopril groups, patients taking beta-blockers had a more beneficial outcome than patients not taking beta-blockers, which was consistent with data from other studies supporting the use of beta-blockers in this patient population.51 As in the ELITE trial] 2 losartan was better tolerated than captopril. There were fewer withdrawals from treatment due to adverse events in the losartan group (9.7%) compared with the captopril group (14.7%; P < 0.001). The authors concluded that although losartan was not superior to captopill in terms of improved survival in elderly patients with heart failure, it was better tolerated. A subsequent analysis of data from ELITE II compared the effect of losartan and captopril on health care resource use. 52,53 All randomized patients were included in the analysis and were followed for a median of 1.5 years. The results demonstrated no significant differences between treatment groups on any end point: time to first all-cause emergency department visit or hospitalization (95% CI of the hazard ratio, 0.94-1.15); annual rate of all-cause hospitalization; annual rate of all-

cause emergency department visits; annual rate of outpatient visits; and total number of hospital days per patient over the follow-up period (Figure 5). The findings were consistent with a 48-week analysis ot health care resource use in the ELITE study. 54 In both analyses, losartan was considered to be as effective as an ACE inhibitor in reducing health care resource use in older patients with heart failure. Given the results of ELITE II and the data from previous placebo-controlled trials showing a significant benefit of ACEinhibitor treatment on morbidity and mortality, ACE inhibitors should still be considered the initial treatment of choice for patients with heart failure and left systolic dysfunction. Treatment guidelines describe losartan as a useful alternative in patients who are unable to tolerate ACE inhibitors.55 TOLERABILITY CONCERNS As in the treatment of any chronic disorder, tolerability is an important consideration in treating heart failure. If a therapy is to be effective and the potential benefits on morbidity and mortality are to be realized, long-term maintenance therapy is necessary. Clinical observation suggests that patients are more likely to continue a therapy when they tolerate it well. Clinical studies of losartan have shown that it is well tolerated, with a side-effect profile similar to that of placebo. In a pooled analysis involving 2900 hypertensive patients in double-blind trials, 56 drugrelated adverse events were reported by 13.5% of losartan patients, compared with 15.5% of those receiving placebo. Discontinuation rates due to adverse events were 2.3% and 3.7% for losartan and placebo, respectively. 1465

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Figure 4. Effects of losartan (n = 1578) and captopril (n = 1574) in the ELITE II study. (A) All-cause mortality: 280 (17.7%) deaths in the losartan group and 250 (15.9%) deaths in the captopril group (hazard ratio = 1.13, 95% CI = 0.95-1.35). (B) All-cause mortality or hospital admission: 752 (47.7%) patients in the losartan group and 707 (44.9%) patients in the captopril group (hazard ratio = 1.07, 95% CI = 0.97-1.19). Reproduced with permission from Pitt B, PooleWilson PA, Segal R, 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;355:1582-1587. © by The Lancet Ltd, 2000. 1466

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Many of the side effects associated with ACE-inhibitor treatment relate not to inhibition of All production per se but to the potentiation of other vasoactive peptides. The occurrence of cough and its relationship to kinin accumulation are well documented. 28,57 The incidence of ACE inhibitor-associated cough reported in the literature varies57-59; clinically, the incidence is generally thought to be between 6% and 14%. 6o Because All-antagonists block AII at the receptor site, adverse events of the sort associated with ACE inhibition would not be expected. This hypothesis was tested in a study that compared the incidence of cough with losartan, iisinopril, and hydrochlorothiazide (HCTZ) in patients who had previously reported cough

when taking ACE inhibitors. 6° HCTZ was included as a comparator because its diuretic action stimulates the RAA system, yet it is not commonly associated with cough as an adverse experience. One hundred thirty-five patients were randomized to receive losartan 50 mg/d, lisinopril 20 mg/d, or HCTZ 25 mg/d for 8 weeks. A significantly higher proportion of patients exhibited dry cough in the lisinopril group compared with the losartan and HCTZ groups (71.17%, 29.2%, and 34.1%, respectively; P < 0.001). Overall, there were more drug-related adverse experiences in patients treated with lisinopril (45.7%) than with losartan (22.9%; P < 0.05) or HCTZ (17.1%; P < 0.01). The cough experienced by patients taking ACE inhibitors is generally described 1467

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as "dry," "tickly," and "bothersome" Although not overtly serious, cough is often the reason patients discontinue ACE-inhibitor treatment. In both ELITE 12 and ELITE II, 13 for example, cough was one of the most common causes of study withdrawal in the captopril group (3.8% of captopril patients in ELITE withdrew due to cough and 2.7% did so in ELITE II). Significantly more captopril patients than losartan patients withdrew due to cough (P < 0.002 ELITE, P < 0.001 ELITE II) (Figure 6). EFFICACY VERSUS T O L E R A B I L I T Y Routine use of ACE inhibitors is generally accepted in the heterogeneous group of patients with heart failure; the documentation is impressive and the treatment

guidelines unanimous. 3,14-16 Nonetheless, nearly 30% of the target population remains untreated. 61 All-antagonists have not demonstrated superior efficacy to ACE inhibitors; however, the data are consistent with their comparability across measures of morbidity and mortality. Furthermore, treatment efficacy in heart failure cannot be considered in isolation; tolerability is an important and oftenunderestimated part of the equation. The use of All-antagonists has potential tolerability benefits. Evidence suggests that these agents are better tolerated than ACE inhibitors, as, for example, in the comparison of losartan and captopril in ELITE 12 and ELITE II. 13 Because of this superior tolerability, practitioners often find AII-antagonists easier to use than

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K. DICKSTEIN

ACE inhibitors. This would suggest that more patients might be treated and continue therapy with All-antagonists, for potentially greater long-term gains. In the worst-case scenario, All-antagonists might have 25% less benefit on mortality than ACE inhibitors--as can be extrapolated from the 95% CI data (0.75-1.05) from ELITE II13--and yet be 50% better tolerated (14.5% of captopril patients in ELITE II discontinued treatment due to adverse events vs 9.4% of losartan patients). If 40% of a group of 10,000 patients were treated with an ACE inhibitor and there was a reduction in the annual mortality rate from 15% to 12%, 1380 patients would die. If use of an All-antagonist allowed treatment of 60% of patients in the same population (50% better tolerability) and resulted in a reduction in the annual mortality rate to 12.75% (25% lower effectiveness), 1365 patients would die. Fifteen additional lives would be saved. In the best-case scenario, Allantagonists would be 5% more efficacious than ACE inhibitors, which would translate into a saving of 69 lives. 62 O N G O I N G STUDIES OF LOSARTAN A N D O T H E R AII-ANTAGONISTS A number of large-scale clinical trials are currently in progress that should help clarify the relative roles of ACE inhibitors and AII-antagonists in the management of heart failure (Table II). These studies are investigating the efficacy and tolerability of ACE inhibitors and All-antagonists alone and in combination, the hypothesis being that additional benefit may be gained from coadministration of agents that inhibit the RAA system by different and possibly complementary mechanisms.

Studies in Heart Failure The Valsartan Heart Failure Trial (ValHEFT) 63 is the first large-scale, randomized, multinational study (as determined by MEDLINE search) to assess the efficacy and safety of the addition of valsartan to conventional therapy (including ACE inhibitors) in patients with heart failure. The primary hypothesis is that addition of valsartan to an ACE inhibitor may improve mortality compared with placebo (ie, that the combination will be better than an ACE inhibitor alone). A total of 5009 patients with NYHA class I I - I V heart failure and a left ventricular ejection fraction _<40% have been randomized to receive either valsartan 160 mg/d or placebo. Preliminary data suggest that the addition of valsartan to usual therapy does not affect all-cause mortality but does produce a significant reduction in the combined end point of all-cause mortality and morbidity (-13.3%; P = 0.009 vs placebo). Hospitalization due to heart failure has also been significantly reduced with valsartan (-27.5%; P < 0.001 vs placebo). 15 Although the data are preliminary, they suggest that valsartan has an additional clinical benefit on morbidity when added to existing standard therapy. The benefits of valsartan on all-cause mortality and morbidity were particularly apparent in patients who were not taking a beta-blocker and in patients not taking an ACE inhibitor (44.5% reduction in morbidity with valsartan; P < 0.001) (Figure 7). Although a small increase in allcause mortality risk was seen in the group receiving valsartan plus an ACE inhibitor plus a beta-blocker compared with placebo, this interaction was not confirmed by the combined end point ot all-cause mortality/all-cause hospitaliza1469

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Figure 7. Combined all-cause mortality and morbidity in 366 patients in the Valsartan Heart Failure Trial 15,63 who were not taking a concomitant angiotensin-converting enzyme inhibitor. Risk reduction, 44.5%; P < 0.001 valsartan versus placebo. tion. A negative interaction between Allantagonist, ACE inhibitor, and betablocker would seem biologically unlikely, and this possibility should be viewed with some skepticism. This concern should be adequately addressed in the ongoing Valsartan in Acute Myocardial Infarction Trial (VALIANT),64 which is discussed later. The Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) 65 study has been designed to assess the clinical usefulness of candesartan across a broad spectrum of patients with heart failure. It is similar to the Val-HeFT study 63 in adding an Allantagonist to existing ACE-inhibitor therapy but consists of 3 independent, concurrent, placebo-controlled studies: CHARM I, including 2300 patients with left ventricular ejection fraction _<40% who are also taking an ACE inhibitor; CHARM II, including 1700 patients with left ventricular ejection fraction <40% who are unable to tolerate an ACE inhibitor; and CHARM III, including 2500 patients with heart failure but preserved systolic func-

tion who are not taking an ACE inhibitor. The primary objective of each study is to evaluate the effects of candesartan on the combined end point of cardiovascular mortality and hospitalization due to heart failure. Each of the 3 studies is powered separately, but data from all 3 can be combined to evaluate the effects of candesartan on all-cause mortality across a broad population of patients with heart failure. Secondary end points include effects on MI (eg, number of events, number of hospitalizations), all-cause hospitalization, and resource use. Recruitment was completed in January 2001; the follow-up period will be a minimum of 2 years.

Treatment

of MyocardialInfarction

The underlying mechanisms of heart failure have been well documented in recent years, and the association of heart failure with coronary artery disease and subsequent MI now seems clear. Gheorghiade and Bonow, 66 in their review of 13 multicenter trials in the treatment of heart 1471

CLINICAL THERAPEUTICS ®

failure involving over 20,000 patients, found coronary artery disease to be the cause of heart failure in almost 70% of patients. Survivors of acute MI complicated by heart failure and/or resulting left ventricular dysfunction are at risk for death and major nonfatal cardiovascular events. Although ACE inhibitors have consistently demonstrated mortality and morbidity benefits in these patients, 2°-22 All-antagonists may offer a pharmacologically more specific approach. It can be postulated, for example, that selective ATl-receptor antagonism (which prevents cardiac remodeling) coupled with compensatory AT 2receptor agonism (which attenuates the pathologic trophic response) could provide more benefit to the failing myocardium than do ACE inhibitors, which do not completely block the production of All in the myocardium and are essentially devoid of AT2-agonistic properties. Importantly, >90% of the All found in the myocardium is produced locally via nonACE-dependent pathways. 67 The Optimal Therapy in Myocardial Infarction with the All Antagonist Losartan (OPTIMAAL) 68 study has been designed to compare the effects of losartan and captopril in post-MI patients with left ventricular dysfunction. Clinically stable patients aged >50 years with acute MI have been randomized to either losartan titrated to 50 mg/d or captopril titrated to 50 mg TID and will continue to receive other standard therapies throughout the trial (eg, beta-blockers, nitrates). The primary hypothesis is that losartan will decrease the primary end point of all-cause mortality risk by 20% compared with captopril. The trial, which has randomized 5477 patients from 327 centers in 7 countries, is expected to be completed in early 2002. 69 1472

The VALIANT64 trial is a double-blind, parallel-group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in a planned 14,500 patients with MI associated with heart failure and/or left ventricular dysfunction. The primary end point is all-cause mortality; secondary end points include cardiovascular death, acute coronary syndromes, cardiovascular morbidity, revascularization procedures, cardiovascular procedures, and all-cause mortality or hospitalization. The study is designed with sufficient statistical power to detect even a small additional clinical benefit from combining an ACE inhibitor and an AII-antagonist. This is important in this high-risk population, in which even small clinical improvements can translate into substantial societal benefits. Although different in design, both OPTIMAAL 6s and VALIANT 64 will use prospective, noninferiority hypotheses in the interpretation of data. This means that the studies will have sufficient statistical power to detect whether the efficacies of losartan and valsartan are comparable to, if not different from, that of captopril. In terms of the implications for clinical practice, if losartan and/or valsartan are shown to be noninferior to captopril, prescribing physicians can initiate therapy with an AII-antagonist or switch therapy from an ACE inhibitor to an AII-antagonist knowing that morbidity and mortality benefits will not be lost. CONCLUSIONS Despite the clear rationale for inhibition of the RAA system in patients with heart failure and the strong evidence of efficacy from large cardiovascular end-point trials, ACE inhibitors are still underused in this

K. DICKSTEIN

patient population. Treatment is not optimal in a large segment of this considerable population, and morbidity and mortality remain high. In many cases, A C E inhibitors are underused because of a perception that they are poorly tolerated and therefore difficult to use in clinical practice. To some extent, this perception is true: ACE inhibitors are associated with a relatively high incidence of cough, renal dysfunction, and hypotension, and such responses can lead to withdrawal from treatment in many cases. All-antagonists, by c o m p a r i s o n , have an excellent sideeffect profile, and their use is now accepted in patients who are unable to tolerate ACE inhibitors. In addition to the role of All-antagonists in patients with heart failure who are unable to tolerate A C E inhibitors, evidence for their broader use in heart failure is accumulating. Symptomatic improvement with losartan has been comparable to that seen with ACE inhibitors. Continued research on both basic science and clinical end points will help establish the relative roles of ACE inhibitors and A l l antagonists in the m a n a g e m e n t o f heart failure and shape the future treatment of this complex disorder.

ACKNOWLEDGMENT The author wishes to acknowledge Helen Whalley, PhD, for her expert assistance in manuscript preparation.

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A d d r e s s c o r r e s p o n d e n c e to: Kenneth Dickstein, MD, PhD, University of Bergen, Central Hospital in Rogaland, Stavanger, 4011, Norway. E-mail: [email protected]

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