From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, Calif (Drs Jamali, Tang, and Fowler), and the Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio (Dr Khot). Dr Fowler has received grant and research support from SmithKline Beecham Pharmaceuticals, Merck & Co, Inc, and Novartis; has acted as a consultant to SmithKline Beecham Pharmaceuticals, Merck & Co, Inc, and Bristol Myers; and has participated in the speakers bureaus of Astra Zeneca, Roche, SmithKline Beecham, and Merck & Co, Inc.
Clinical and basic science research has repeatedly confirmed the importance of the renin-angiotensin-aldosterone system in the pathophysiology of chronic heart failure. Accordingly, blockade of this system by angiotensin-converting enzyme (ACE) inhibitors has assumed a central role in the treatment of heart failure. Recently, angiotensin II receptor blockers (ARBs) have gained prominence as a possible substitute for ACE inhibitors in therapy for heart failure. However, clinical data compiled on this use of ARBs have shown them to be useful only as alternative therapy in ACE inhibitor–intolerant patients. Continuing large-scale clinical investigations may lead to an expansion of their role in therapy for various cardiovascular diseases.
Angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease morbidity and mortality in virtually all types of heart failure.1- 8 The ability of ACE inhibitors to suppress neurohormonal activation in the renin-angiotensin-aldosterone (RAA) system has been presumed to be the principal mechanism for their therapeutic activity.9 A combination of actions that function to improve hemodynamic variables as well as to regulate the unfavorable trophic actions of angiotensin II (A-II) are considered to encompass much of their benefit.10
Concern that ACE inhibitors produce inadequate long-term suppression of the RAA system has become an important issue.11,12 Intolerance of ACE inhibitors by as much as 10% of patients with heart failure has also hindered their routine use, despite evident indications.13,14 Such limitations have prompted an interest in the search for better therapeutic strategies to counteract the adverse effects of RAA system activation in heart failure.
Recent studies on a new generation of drugs that directly block the actions of A-II have sparked much excitement in heart failure research.13 These A-II receptor blockers (ARBs) specifically block the A-II type 1 (AT1) receptor,15 which is responsible for many of the deleterious effects of A-II (Figure 1).10,16 Since the discovery of losartan potassium in 1992, the Food and Drug Administration has approved 6 new ARBs for the treatment of essential hypertension. Their potential role in patients with heart failure is an area of active investigation.
The renin-angiotensin-aldosterone system. ACE indicates angiotensin-converting enzyme; tPA, tissue plasminogen activator; ARB, angiotensin II receptor blocker; AT1, angiotensin II type 1; AT2, angiotensin II type 2; PAI, plasminogen activator inhibitor; up arrows, increased level or activity; and down arrows, decreased level or activity.
Angiotensin-converting enzyme inhibitors also inhibit the enzyme kininase II, which is responsible for the degradation of bradykinin.17 Recent studies have emphasized the possible role of elevated bradykinin levels in the benefits of ACE inhibitor therapy for heart failure. Beneficial hemodynamic effects mediated by bradykinin may include venodilation,18 vasodilation (coronary and systemic),19 and improved left ventricular relaxation and contractile function.20 Other potential benefits of bradykinin include a reduction in ventricular dilatation and cardiac hypertrophy, an increase in levels of endogenous tissue plasminogen activator, and an improvement in abnormal endothelial function.21- 23 Such effects may be especially important in the 60% of patients with heart failure who have an ischemic cause of their heart failure.14
Additional evidence of the importance of the bradykinin system in ACE inhibition comes from a study by Guazzi et al.24 Their group showed that although losartan and enalapril maleate had similar hemodynamic and clinical effects, the action of enalapril was antagonized by aspirin, whereas that of losartan was not.24 This may be related to the role of the bradykinin in mediating prostaglandin release (Figure 1). This has potentially profound implications for most cardiac patients who are concurrently receiving daily aspirin therapy. Although still preliminary, these results underscore the importance of understanding the differences between these classes of drugs.25
The ACE inhibitor–mediated increase in bradykinin levels is believed to be responsible for the associated cough, which may occur in up to 10% of the population,26,27 as well as angioedema, a potentially lethal complication.28- 30 By directly blocking AT1, ARBs can inhibit the action of A-II while having little or no bearing on the bradykinin system.31 Thus, the incidence of angioedema associated with ARB use is limited to case reports.32 Improvement in tolerability using ARBs can be seen in the Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) Registry, where patients with heart failure intolerant of ACE inhibitors were randomized to candesartan vs placebo. Tolerability of candesartan was comparable to that of placebo at 3 months (83% vs 87%, respectively).14
There is growing evidence that ACE inhibitors provide incomplete long-term suppression of A-II and aldosterone.11,12,33 This is likely due to inadequate suppression of ACE in target tissues, as well as alternative (non-ACE) pathways of A-II production.34 Direct blockade of the action of A-II by ARBs may attenuate this "escape" phenomenon by circumventing problems related to non-ACE production of A-II. This issue has raised concerns about the completeness of the benefit obtained with ACE inhibitor monotherapy, and has prompted investigations into various combination therapies.
Sympathetic nervous system hyperactivity is a short-term compensatory mechanism for cardiac dysfunction, but its prolonged activation may lead to worsening of heart failure.35 Angiotensin-converting enzyme inhibitors have been demonstrated to reduce overall sympathetic tone in heart failure36 and enhance baroreflex control,37- 39 but they can increase plasma norepinephrine levels through the bradykinin cascade.40- 42
Similarly, ARBs attenuate sympathetic tone and increase baroreflex control.37,43 However, their selective blockade of AT1 increases A-II levels and allows for greater occupancy at the A-II type 2 (AT2) receptor. This can increase adrenal catecholamine release,44,45 counteracting other more beneficial effects (Figure 1). The clinical implication of these concepts remains to be elucidated.
The early studies on the use of ARBs in heart failure focused on surrogate outcomes such as hemodynamic effects and neurohormonal activation. Few looked at clinical outcomes such as exercise tolerance, and none were powered to study mortality differences.46- 59
Consistent hemodynamic improvement was observed when ARBs were compared with placebo.46- 50 Reductions in blood pressure and pulmonary capillary wedge pressure were sustained after up to 12 weeks of therapy.47,49 Increased exercise capacity was also demonstrated in short-term studies.46,51
When ARBs were compared with ACE inhibitors in relatively small-scale clinical trials, however, the results consistently yielded no significant differences between ARBs and ACE inhibitors. At the end of follow-ups as long as 12 weeks, patients treated with losartan fared no better on results of objective exercise testing or quality-of-life indexes than those treated with enalapril.52- 54
Several trials evaluated the result of combining ACE inhibition with ARBs (Table 1). This combination theoretically provides the most complete and sustained blockade of the angiotensin system, while still affecting the bradykinin system favorably. In small-scale studies, combination therapy consistently showed superior results to ACE inhibitor monotherapy with regard to exercise tolerance,55- 57 hemodynamic effects,58 and neurohormonal activation.55,58,59 In the study by Hamroff et al,56 more than half of the patients receiving combination therapy (9/16) had an improvement of at least 1 New York Heart Association (NYHA) class, compared with only 1 of 17 patients receiving ACE inhibitors alone.
The recently published Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study by McKelvie et al55 is an ambitious attempt to study increasing levels of neurohormonal blockade. Although much of the data were not statistically significant, combination therapy was superior to monotherapy in lowering blood pressure and in preventing left ventricular dilatation in the long term. In addition, the benefit in ejection fraction achieved with combination therapy was significantly greater than that achieved with either therapy alone. However, the combination therapy cohort was the only one to have a decreased exercise tolerance at 18 and 43 weeks.
The original Evaluation of Losartan in the Elderly (ELITE) study13 was a double-blind, randomized, captopril-controlled trial initially designed to compare the tolerability of losartan potassium (titrated to 50 mg once daily) with that of captopril (titrated to 150 mg/d) in 722 elderly patients with heart failure. The primary end point, a persistent increase in serum creatinine level, was not significantly different between groups (10.5%; P = .63). More patients receiving captopril discontinued therapy because of adverse effects (20.8% vs 12.2%; P = .002). The most intriguing results came in analysis of the secondary end points. Death or hospitalization for heart failure occurred in 49 of 370 patients receiving captopril and 33 of 352 patients receiving losartan (P = .08). Although this particular result was not statistically significant, the difference in all-cause mortality (not a prespecified end point) was statistically significant and showed a reduction in absolute risk of 3.9%, which translated into a relative risk reduction of 44% (P = .04). Most of this difference was due to the rate of sudden death (3.8% in the captopril vs 1.4% in the losartan groups). There was no significant difference in deaths due to progressive heart failure, myocardial infarction, or other vascular causes.
Unfortunately, the ELITE trial did not have the statistical power to determine mortality differences, as only a very small number of events (49 total deaths in the study population) occurred during a relatively short 48-week follow-up. The study supported the theoretical notion that selective blockade of A-II action would be better tolerated than ACE inhibition and certainly implied that it may be more effective.
The follow-up to the ELITE trial, ELITE II, was a direct comparison of losartan vs captopril in a trial designed and powered to detect mortality differences from the outset.60 The ELITE II trial was a randomized, double-blind, multicenter trial with 3152 patients followed up for 2 years. Inclusion criteria included patients who were older than 60 years, with NYHA classes II to IV heart failure and ejection fractions of less than 0.40. One thousand five hundred seventy-four patients were randomized to receive captopril, whereas 1578 were randomized to receive losartan, all in a manner similar to that of the ELITE trial. Both arms were similar in all measured characteristics.
Of the 530 deaths during the 2-year follow-up, 250 occurred in the captopril arm, whereas 280 occurred in the losartan arm (P = .16). In addition, sudden cardiac death occurred more frequently in the losartan arm (9.0% vs 7.3%), although this result was not statistically significant (P = .08). This is particularly interesting because it was in sudden cardiac death that losartan achieved most of the mortality benefit noted in the original ELITE trial. The combination end point of mortality and hospitalization showed no significant difference between losartan and captopril, although it also favored the captopril arm (47.7% vs 44.9%; P = .21).
The single result that showed concordance with the original ELITE trial was the issue of tolerability. Both trials showed losartan to be significantly better tolerated than captopril. In ELITE II, 14.5% of the patients receiving captopril had to discontinue the drug because of adverse effects, whereas only 9.0% of those receiving losartan had to discontinue treatment (P = .001).
The ELITE II study showed that ARBs appear to be equally as effective as ACE inhibitors in heart failure therapy. Before this result, the only clinical trial support for alternatives to ACE inhibitors had been for hydralazine hydrochloride and isosorbide dinitrate, although this combination was shown to be less effective than ACE inhibitors.6
Most of the data available show a benefit to ARB use compared with placebo in patients with left-ventricular systolic dysfunction. However, at present, the ELITE II trial remains the only large-scale trial to assess mortality differences between ARBs and ACE inhibitors in these patients. Because of considerable variation in pharmacodynamics and sympathetic modulation between ARBs,61 it is unclear whether results from particular studies can be generalized to a class effect. In contrast, a large and growing body of clinical trial experience supports the use of ACE inhibitors in heart failure. Thus, further studies are necessary to define accurately the role ARBs should play in therapy for heart failure.
A regimen that includes ACE inhibitors and ARBs would be expected to provide potent, sustained suppression of the RAA system while still providing the benefits of increased activity of bradykinin. Preliminary data on such combination therapy are promising,55 and a number of studies now under way should further define the role of combination therapy (Table 2).62 Indeed, combination therapy could theoretically be augmented further by the addition of aldosterone antagonists, such as spironolactone. However, such triple therapy remains untested in clinical trials.
Another area in which the use of ARBs may have specific benefit is in the setting of ischemic heart disease. Angiotensin-converting enzyme inhibitors have a proven mortality benefit in coronary artery disease, before and after myocardial infarction.7,8,63 It is unclear what effect ARBs will have in these settings, especially as they presumably lack bradykinin-mediated increases in endogenous thrombolysis and vascular reactivity.21 Trials currently under way should clarify this topic and may help us understand the role ARBs can play in patients with a spectrum of cardiovascular diseases.64,65
In conclusion, the use of ACE inhibitors remains the standard of care in patients with heart failure. In patients intolerant of an ACE inhibitor, ARBs can provide a safe and efficacious alternative therapy. At present, the most promising area in which ARBs may assume a role as first-line therapy is as part of a combination with ACE inhibitors. Such a combination has many theoretical advantages, and preliminary results are very promising.
Accepted for publication September 21, 2001.
Corresponding author: Michael B. Fowler, MB, FRCP, Falk-CVRC 295, Stanford University Medical Center, Stanford, CA 94305 (e-mail: email@example.com).
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