The Role of Angiotensin Receptor Blockers in Heart Failure

ARBS IN HF CHF MARCH/APRIL 2000 103 The Role of Angiotensin Receptor Blockers in Heart Failure The effectiveness of ACE inhibitors in reducing morbidity and mortality in patients with heart failure is largely attributable to their suppression of angiotensin II production. Despite chronic therapy with ACE inhibitors, angiotensin II levels may be incompletely suppressed and contribute to the high mortality of patients with heart failure. Recently, angiotensin receptor blockers, which block the effects rather than the production of angiotensin II, have become available. Angiotensin receptor blockers have been evaluated as both monotherapy and in combination with ACE inhibitors. In short term studies, angiotensin receptor blocker monotherapy appears to share many of the hemodynamic and clinical features of ACE inhibitors. In a long term study, Losartan Heart Failure Survival Study, angiotensin receptor blockers failed to demonstrate any beneficial effect over that seen with ACE inhibitors. The addition of an angiotensin receptor blocker to an ACE inhibitor appears to exert favorable short term hemodynamic, clinical, and neurohormonal effects. Four ongoing trials, Valsartan Heart Failure Trial, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity, Optimal Therapy in Myocardial Infarction with Angiotensin II Antagonist Losartan study, and Valsartan In Acute Myocardial Infarction study, are evaluating the role of angiotensin receptor blockers either alone or in combination with ACE inhibitors in the management of left ventricular dysfunction. (CHF. 2000;6:103 109) 2000 by CHF, Inc. Lawrence Baruch, MD; Tariq Jamil, MD From the Bronx Veterans Affairs Medical Center, Mount Sinai School of Medicine, Bronx, NY Address for correspondence/reprint requests: Lawrence Baruch, MD, Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Road, Suite E, Cardiology, Bronx, NY 10468 Manuscript received November 17, 1999; accepted January 24, 2000 ACE inhibitors reduce morbidity and mortality in patients with congestive heart failure and are recommended therapy for all patients with left ventricular systolic dysfunction. 1 3 The effectiveness of ACE inhibitors is largely attributable to their effect on the renin angiotensin system and suppression of angiotensin II production. 4 ACE inhibitors exert other neurohormonal effects as they potentially increase levels of bradykinin. Bradykinin may increase levels of nitrous oxide and improve endothelial function. However, the ability of bradykinin to stimulate nitrous oxide production may be impaired by the endothelial dysfunction commonly present in patients with left ventricular dysfunction. 5 Alternatively, bradykinin may be deleterious in patients with heart failure as it promotes the release of norepinephrine and malignant ventricular arrhythmias. 6 The relative contribution of each of these neurohormonal effects to the reduction in morbidity and mortality demonstrated with ACE inhibitors in heart failure is unknown. Despite chronic therapy with ACE inhibitors, mortality remains high in patients with heart failure. 7 Angiotensin II levels may be incompletely suppressed in patients receiving ACE inhibitors chronically, as non ACE dependent pathways, including chymase, may contribute to the continued production of angiotensin II. 8 13 These pathways, along with the potential for escape from angiotensin I as the level of the ACE inhibitor decreases towards the end of the dosing interval, may contribute to a rise in angiotensin II levels during chronic ACE inhibitor that is associated with a poor prognosis. 12,13 In addition to its direct effects, angiotensin II is also a major regulator of aldosterone synthesis. This incomplete blockade of angiotensin II production may partly explain the 35% reduction in mortality and hospitalization demonstrated when the aldosterone antagonist, spironolactone, was added to ACE inhibitors in the recently completed Randomized Aldactone Evaluation Study (RALES). 14 Recently, angiotensin receptor blockers (ARBs) have become available for use in the treatment of hypertension (Table I). Available ARBs have vary-

104 ARBS IN HF CHF MARCH/APRIL 2000 ing affinities for the angiotensin receptor and may exhibit competitive or noncompetitive binding kinetics. Direct inhibition of the angiotensin receptor is a way of modulating the renin angiotensin system by blocking the actions of angiotensin II as opposed to its production, as occurs with ACE inhibition. This review will focus on our current knowledge of ARBs in the treatment of heart failure with respect to their effects on hemodynamic parameters, symptomatology, exercise duration, and clinical events. Physiology of the Angiotensin II Receptor Family To fully understand the potential of ARBs in heart failure, an overview of angiotensin receptor physiology is helpful. As many as four angiotensin receptors have been identified (AT 1 4 ). 15 Currently available ARBs inhibit the AT 1 receptor only, which is responsible for the deleterious vasoconstrictive, dipsogenic, and steroidogenic effects of angiotensin II, including aldosterone and endothelin production (Fig. 1). 15 The AT 1 receptor is also responsible for the negative feedback on renin production induced by angiotensin II. 16 In contrast to the AT 1 receptor, the AT 2 receptor may promote a number of potentially beneficial effects, including inhibition of cellular proliferation and regulation of cell differentiation, and apoptosis. The effects of the other angiotensin receptors, AT 3 and AT 4, are less well characterized. 17 The use of ARB agents has several consequences beyond direct antagonism of the AT 1 receptor. These effects include unopposed stimulation of the AT 2 receptor with its possibly beneficial effects and increased angiotensin II levels secondary to a rise Figure 1. Conventional view of the renin angiotensin system. TABLE I. CURRENTLY AVAILABLE ARBS WITH THEIR DOSAGES FOR TREATMENT OF HYPERTENSION AND THEIR MECHANISM OF BLOCKADE OF THE AT 1 RECEPTOR AGENT INHIBITION DOSE (MG) Losartan competitive 25 100 Valsartan noncompetitive 80 320 Ibesartan noncompetitive 75 300 Candesartan noncompetitive 4 32 Eprosartan competitive 200 400 Telmisartan noncompetitive 20 80 in plasma renin resulting from the loss of feedback inhibition mediated by the AT 1 receptor. Lastly, ARBs have little or no effect on bradykinin (thus do not produce the cough seen in approximately 10% of ACE inhibitor treated patients), whose significance in heart failure is controversial. It is readily apparent that real pharmacological differences exist between ACE inhibitors and ARBs with respect to bradykinin production, AT 1 antagonism, AT 2 agonism, and angiotensin II production. AT 1 receptor blockade may have the triple benefit of AT 1 receptor antagonism, AT 2 receptor agonism, and bradykinin antagonism (Table II). Whether these pharmacologic differences translate into clinical improvements has been investigated. Clinical Trials ARBs have been evaluated clinically as both monotherapy and as combination therapy together with ACE inhibitors. ARB monotherapy avoids the side effects and potential adverse events secondary to bradykinin, while offering the potential for more complete inhibition of the AT 1 receptor and stimulation of the AT 2 receptor. Combination therapy offers the potential for more complete suppression of the AT 1 receptor, a reduction in angiotensin II levels, and the potential benefits of an increase in bradykinin levels. Monotherapy The hemodynamic effects of monotherapy with an ARB have been evaluated. Gottlieb et al 18 evaluated the acute hemodynamic effects of losartan in 66 patients with NYHA Class II IV heart failure and severe left ventricular dysfunction. Patients were given losartan in dosages of 5, 10, 25, 75, or 150 mg or placebo. Hemodynamic changes progressively increased up to a dosage of 25 mg; higher doses produced no

ARBS IN HF CHF MARCH/APRIL 2000 105 TABLE II. PHARMACOLOGIC DIFFERENCES BETWEEN ACE INHIBITORS AND ARBS ACE INHIBITORS ARBS Bradykinin Angiotensin II AT 1 agonism AT 2 agonism added hemodynamic benefit. Neurohormonal changes seen in response to losartan included compensatory increases in both angiotensin II and renin as well as reductions in aldosterone; no consistent dose dependent effect could be demonstrated above the 25 mg dose. Crozier et al 19 evaluated the acute and chronic hemodynamic effects of losartan in 134 patients with Class II IV heart failure and a mean ejection fraction (EF) of 24%. Patients were given losartan in dosages of 2.5, 10, 25, or 50 mg or placebo. The initial administration of losartan resulted in a maximal change in pulmonary capillary wedge pressure (PCWP) of approximately 5 mm Hg in the group treated with losartan 50 mg at the six hour timepoint. After 12 weeks of therapy, hemodynamic changes and symptomatic improvement were noted in both the 25 and 50 mg cohorts; the 50 mg dosage produced more consistent and greater hemodynamic benefit, achieving a maximal PCWP reduction of 6.3 mm Hg six hours after the dose. In response to the higher doses of losartan, there were significant and acute increases in both angiotensin II and renin, which did not persist during chronic administration. Havranek et al 20 performed a 12 week, dose ranging study to assess the hemodynamic effects of irbesartan in dosages of 12.5, 25, 37.5, 75, and 150 mg in 218 patients with NYHA Class II IV heart failure with a mean EF of 25%. After 12 weeks of therapy, the 37.5, 75, and 150 mg dosages appeared to produce greater reductions in PCWP (4.8 5.9 mm Hg) than the 12.5 mg group (2.3 mm Hg); these reductions were consistently greater than those seen during acute administration. Although the 75 and 150 mg dosages of irbesartan failed to demonstrate any added hemodynamic benefit as compared to the 37.5 mg dosage, the higher dosages did influence other end points including death, hospitalization for worsening heart failure, or discontinuation of study medication for worsening heart failure, which occurred in 13.9% of patients receiving 12.5 or 37.5 mg of irbesartan vs. 5.5% of patients receiving 75 or 150 mg of irbesartan (p=0.04). Mazayev et al 21 compared the hemodynamic effects of valsartan, placebo, and lisinopril in a four week study. One hundred sixteen patients with NYHA Class II IV heart failure (no ACE for a minimum of six months) and a minimum PCWP of 15 mm Hg were randomized to placebo, lisinopril 5 mg uptitrated after one week to 10 mg daily, or valsartan 40, 80, or 160 mg twice daily. After four weeks of therapy, significant reductions in PCWP compared to baseline were seen in the valsartan 40 mg and 160 mg groups. These effects were most dramatic from 4 8 hours after dosing (-6 mm Hg and -6.9 mm Hg, respectively). The lack of a significant response to lisinopril may have been due to the low dosages employed in the study. The effects of ARB monotherapy on exercise capacity, EF, and symptoms have been compared to both placebo and an ACE inhibitor. The effects of losartan as compared to placebo on treadmill exercise time were assessed in two studies comprising a total of 716 patients. 22 Patients with NYHA Class II IV and left ventricular dysfunction (mean left ventricular EF of 24%) were randomized to losartan 25 or 50 mg daily, or placebo for 12 weeks. No significant differences between the three groups were demonstrated with respect to change in exercise duration. A prospectively planned metaanalysis combining the two studies did show a significant reduction (p<0.05) in both mortality (74%) and hospitalization for heart failure (56%) in the losartan treated patients. The effects of losartan as compared to enalapril on treadmill exercise time, EF, six minute walk, and symptoms were assessed in two studies comprising a total of 282 patients. 23,24 Patients with NYHA Class II (19%), III (71%), and IV (10%) heart failure and left ventricular dysfunction (mean EF of 24%), previously treated with an ACE inhibitor, were randomized to losartan 25 or 50 mg daily, or enalapril 10 mg twice daily for 8 (n=166) or 12 weeks (n=116). No significant differences between groups were demonstrated with respect to any parameters. Losartan was well tolerated and comparable to enalapril. These studies suggest that the peak effective dosages of the three ARBs used, irbesartan, losartan, and valsartan, produce similar acute and chronic hemodynamic changes, with a maximal change in PCWP of 5 6 mm Hg occurring approximately six hours after dosing. ARB monotherapy has a tendency toward increased hemodynamic benefit with long term therapy, similar to ACE inhibitors, and in clear distinc-

106 ARBS IN HF CHF MARCH/APRIL 2000 tion to the tachyphylaxis seen with vasodilators. 25 No significant differences in functional class, exercise duration, or symptoms were demonstrated when an ARB was compared to either an ACE inhibitor or placebo in these trials. However, with respect to clinical outcomes, when compared either to placebo or lower dosages of an ARB, it appears that even 2 3 months of moderate dose ARB monotherapy may reduce clinical events. From these short term studies, ARBs when used as monotherapy appear to share many of the hemodynamic and clinical features of ACE inhibitors. Combination Therapy. The potential synergistic effect between ARBs and ACE inhibitors on hemodynamic and clinical parameters has been investigated. Baruch et al 26 compared the hemodynamic effects of adding valsartan 80 or 160 mg twice daily or placebo to background ACE inhibitor therapy in 83 patients with Class II or III heart failure. Of the participants, 75% were receiving a dosage of ACE inhibitors recommended by established heart failure guidelines. Acute administration resulted in a statistically significant reduction in mean PCWP of 2.4 mm Hg (p=0.02) compared to placebo in patients receiving the higher valsartan dose. After four weeks of therapy, the 160 mg dosage produced significant reductions in diastolic pulmonary artery pressure when compared to placebo, achieving a peak reduction of 5.25 mm Hg (p=0.002). Diastolic pulmonary artery pressure also tended to be reduced in patients receiving valsartan 80 mg bid but failed to reach statistical significance. A statistically nonsignificant mean reduction in PCWP of 1.78 mm Hg was noted in the high dose valsartan group. After four weeks of therapy, prior to the administration of ACE inhibitors and valsartan-placebo, at the trough level of ACE inhibitor, diastolic and systolic blood pressure, right atrial pressure, and norepinephrine achieved their maximal reduction when compared to baseline in the group treated with valsartan 160 mg bid. This may have resulted from the increased level of angiotensin I, coupled with escape from ACE inhibition at the end of each dosing period, leading to significant accumulation of angiotensin II. Increases in serum potassium, blood urea nitrogen (BUN), and creatinine accompanied the hemodynamic and neurohormonal changes noted during valsartan therapy and were independent of the background dose of ACE inhibitor, supporting the concept that angiotensin II and one of its end products, aldosterone, are incompletely suppressed despite chronic ACE inhibitor therapy. 27 Hamroff et al 28 examined the tolerability of losartan 50 mg daily when added to background ACE inhibitor therapy in 43 patients with NYHA Class III IV congestive heart failure. Patients were titrated to a maximally recommended or tolerated dose of ACE inhibitor (captopril 50 mg tid or 40 mg daily of the longer acting ACE inhibitors). Losartan was well tolerated in all patients and on average lowered systolic blood pressure by 15 mm Hg (p<0.0001). Interestingly, even the nine patients who developed symptomatic hypotension during ACE inhibitor uptitration tolerated losartan. The authors hypothesized that the acute vasodilatation induced by bradykinin may limit titration of ACE inhibitors in contrast to the initiation and titration of ARBs. These investigators also demonstrated significant improvement in functional class (p<0.01) and exercise capacity (p<0.02) in 33 patients with Class III IV who were randomized to a six month treatment with losartan 50 mg daily as adjunctive therapy to the maximally recommended or tolerated dose of ACE inhibitor. 29 Functional class improved by one class in 9 of 16 patients receiving losartan and in only one of 17 patients receiving placebo. These changes appeared to increase over time. Tonkon et al 30 evaluated the safety and effects of adding irbesartan 150 mg daily to background ACE inhibitor therapy on exercise duration and EF in 109 patients with NYHA Class II (79%) or III heart failure. Exercise time increased by 64 seconds in the irbesartan group and 41 seconds in the placebo group. EF improved from 28.8% to 33.2% in the irbesartan group and from 27.6% to 30.2% in the placebo group. Of the placebo treated patients, 21% experienced worsening heart failure as defined by discontinuation from the study for worsening heart failure, hospitalization, emergency room visit, or a need for supplemental diuretics, as opposed to 12% in the irbesartan treated patients. Thus, in these small studies ARBs appear to act in a consistent manner, exerting favorable hemodynamic, clinical, and neurohormonal effects in patients receiving background ACE inhibitor therapy for congestive heart failure. Long Term Studies Three trials, Evaluation of Losartan In The Elderly (ELITE), Losartan Heart Failure Survival Study (ELITE II), and Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD),

ARBS IN HF CHF MARCH/APRIL 2000 107 Figure 2. Results of ELITE II, mortality and sudden cardiac death, which had been significantly reduced by losartan in ELITE. have evaluated the long term effects of ARBs in heart failure. The ELITE study compared the safety and efficacy of captopril 50 mg tid and losartan 50 mg qd in 722 patients 65 years of age and older with NYHA Class II IV heart failure who had never received an ACE inhibitor. 31 Mortality was reduced by 46% (p=0.035) in the patients receiving losartan and sudden death was reduced by 64%. The study was not designed to assess mortality, but to assess changes in renal function, which did not differ between the two groups. Losartan did not affect the incidence of hospitalization for heart failure or reduce symptomatology. The small number of deaths in the study (n=49) and the short duration of follow up (48 weeks) limited the applicability of the results in clinical practice and was the stimulus for ELITE II. ELITE II compared the effects of captopril 50 mg tid and losartan 50 mg qd on mortality in 3152 patients with NYHA Class II IV heart failure. 32 All patients were 60 years of age and older (86% >65 years) with a left ventricular EF of 40%. Patients could not have received an ACE inhibitor or angiotensin II receptor antagonist for >7 days within three months prior to randomization. No statistically significant difference in total mortality, sudden cardiac death, or hospitalization was demonstrated between the two groups (Fig. 2). 33 More patients tolerated losartan (91%) when compared to captopril (86%) (p< 0.001). The RESOLVD study compared the safety and efficacy of candesartan and enalapril (10 mg bid) either alone (candesartan 4, 8, or 16 mg daily) or in combination (candesartan 4 or 8 mg daily) in 786 patients with NYHA Class II IV CHF and a left ventricular EF of <40%. 34 The study had a two stage design. Stage I involved titration of enalapril and/or candesartan, while stage II, which began after 19 weeks of candesartanplacebo therapy, involved a second randomization to metoprolol or placebo. The duration of follow up for the complete study was 43 weeks. A nonsignificant increase in mortality was noted in the groups receiving either monotherapy (6.1%) or combination therapy (8.7%) with candesartan when compared to those receiving enalapril alone (3.7%) (p=0.15). However, ventricular remodeling as determined by systolic and diastolic ventricular volumes was significantly less in the candesartan-enalapril group. Diastolic Dysfunction A discussion of the role of any class of drugs in heart failure would be incomplete without the inclusion of diastolic dysfunction. Warner et al 35 recruited 20 patients with diastolic dysfunction from a cohort undergoing exercise testing for the evaluation of coronary artery disease (CAD) as a cause of dyspnea. A diagnosis of diastolic dysfunction was made if the patients met all of the following criteria: 1) EF >50%; 2) no evidence of ischemia on stress echo; 3) a transmitral E/A <1; 4) resting SBP <150 mm Hg; and 5) exercise SBP >200 mm Hg. Patients were randomized to either losartan 50 mg daily or placebo in a crossover design. Exercise testing was performed at baseline and after two weeks of therapy or placebo. Resting systolic and diastolic blood pressures, heart rate, and echocardiographic measurements were not altered by placebo or losartan. Losartan significantly increased exercise duration by 1.3 minutes when compared to placebo (p<0.005) and improved quality of life. Peak systolic blood pressure during exercise was reduced on losartan to 193 mm Hg compared to placebo, 217 mm Hg (p<0.005). These effects were seen even in the six patients receiving ACE inhibitors. The authors proposed that the rise in angiotensin II that occurs during exercise, which is incompletely blocked by ACE inhibitors, slows the rate of left ventricular relaxation, raises blood pressure, and increases left ventricular end diastolic pressure during exercise. Blockade of the angiotensin II receptor may blunt this effect and improve relaxation and diastolic function, exercise duration, and reduce symptoms. Ongoing Trials Four ongoing trials, Valsartan in Heart Failure Trial (Val-HeFT), Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity

108 ARBS IN HF CHF MARCH/APRIL 2000 (CHARM), Optimal Therapy In Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTI- MAAL) study, and Valsartan In Acute Myocardial Infarction (VALIANT), are evaluating the role of ARBs either alone or in combination with ACE inhibitors in left ventricular dysfunction, in the setting of either acute myocardial infarction or chronic heart failure. The Val-HeFT is evaluating the effect of valsartan in addition to ACE inhibitors (unless ACE inhibitor intolerant) on mortality and morbidity in patients with NYHA Class II IV heart failure. 36 Patients must have a left ventricular EF 40% and left ventricular dilatation 2.9 cm/m 2. The target dose of valsartan of 160 mg twice daily was selected, based on the hemodynamic data previously described. A number of parameters are being assessed serially (left ventricular dimensions, neurohormones, Holter, etc.) to further our understanding of mechanisms in heart failure. This 5005 patient trial, which began in April 1997, is expected to be completed in late 2000. The CHARM study is evaluating the effect of candesartan on mortality and morbidity in 6500 patients with NYHA Class II IV heart failure and either systolic or diastolic dysfunction. 37 The target dose of candesartan is 32 mg daily. This trial has three arms representing three different patient groups: 1) depressed left ventricular systolic function with an EF 40% and treated with an ACE inhibitor; 2) depressed left ventricular systolic function and intolerant of ACE inhibitor; and 3) preserved left ventricular function with an EF 40% who are not treated with an ACE inhibitor. The trial, which began in March of 1999, is expected to complete in March 2001. The OPTIMAAL is comparing the effects of losartan 50 mg daily and captopril 50 mg tid on mortality in patients with an acute myocardial infarction; randomization must occur within 10 days of the infarct. 38 Patients must meet one of the following entry criteria: 1) clinical heart failure; 2) anterior wall Q waves; or 3) ejection fraction <35%. Patients scheduled for percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery are excluded. This 5000 patient study is expected to be completed early next year. The VALIANT study is comparing the effects of valsartan 160 mg bid, valsartan 80 mg bid combined with captopril 50 mg tid, and captopril 50 mg tid on mortality in 14,500 patients with a recent acute myocardial infarction (3 14 days) and clinical heart failure or left ventricular systolic dysfunction. 39 Enrollment began in October 1998 and follow up is expected to be completed in 2002. Conclusions The current role of ARBs in the management of heart failure can be summarized from the recent Action Heart Failure Recommendations 40 that were developed prior to the presentation of the ELITE II results: Because of the lack of conclusive evidence supporting the efficacy of angiotensin II receptor antagonists in heart failure, it is reasonable to prescribe these drugs instead of ACE inhibitors only in patients who are intolerant of ACE inhibitors due to angioedema or intractable cough. Ongoing clinical trials with more than 30,000 patients will determine whether ARBs are of benefit in any patients with left ventricular dysfunction. Whether extensive use of this class of agents is indicated in all patients with heart failure, or just in selected patients, with systolic dysfunction, diastolic dysfunction, or ACE inhibitor intolerance, as either stand-alone therapy or in combination with ACE inhibitors, will be determined by the results of ongoing trials. 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