Rationale for the use of angiotensin II receptor blockers in patients with left ventricular dysfunction (part I of II)

Almost 5 million individuals in the United States are diagnosed with chronic heart failure (HF), and the prevalence is increasing. Angiotensin-converting enzyme (ACE) inhibitors and beta blockers, neurohormonal antagonists that block the renin-angiotensin system (RAS) and the sympathetic nervous system, respectively, have been shown in clinical trials to reduce morbidity and mortality in patients with HF, and these therapies are now integral components of standard HF treatment. Yet, morbidity and mortality rates in HF remain unacceptably high, and the limitations of current standard therapies are becoming increasingly apparent. About 10% of patients with HF are unable to tolerate ACE inhibitors, often because of cough. In addition, ACE inhibition may not completely block the RAS because angiotensin II, the main end product of the RAS, can be generated via non-ACE enzymatic pathways. Angiotensin II receptor blockers (ARBs) may exert more complete RAS blockade than ACE inhibitors by interfering with the binding of angiotensin II at the receptor level, regardless of the enzymatic pathway of production. They are also better tolerated than ACE inhibitors and have been shown to improve symptoms and function in clinical trials in patients with HF. These factors provide a strong rationale for the study of the clinical effects of ARBs in patients with HF.     

Rationale for the use of combination angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy in heart failure

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality in the United States. The renin-angiotensin system (RAS) plays a major role in its pathophysiology, and angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of therapy. However, HF continues to progress despite this therapy, perhaps because of production of angiotensin II by alternative pathways, which lead to direct stimulation of the angiotensin II receptor. Angiotensin II receptor blocker (ARB) therapy alone or in combination with the ACE inhibitor is a promising approach to block the RAS and slow HF progression more completely. METHODS: The current medical literature on the pathophysiology of HF and the use of ACE inhibitors and ARBs was extensively reviewed. RESULTS: Evidence from basic science, experimental animals, and clinical trials provides data on the safety and efficacy of RAS inhibition with ACE inhibitors and ARBs as monotherapy and in combination. Data from the Evaluation of Losartan in the Elderly (ELITE) II trial indicate that ARBs alone do not appear to be more effective than ACE inhibitors in HF, but studies evaluating their use in combination are currently ongoing. CONCLUSIONS: The addition of an ARB offers more complete angiotensin II receptor blockade of the RAS than can be obtained by ACE inhibitors alone. Combination therapy preserves the benefits of bradykinin potentiation offered by ACE inhibitors while providing potential antitrophic influences of AT(2) receptor stimulation and may play an increased role in the treatment of chronic HF in the future.     

Angiotensin II receptor blockers in the treatment of heart failure

Heart failure treatment centers on antagonism of the renin-angiotensin-aldosterone system and adrenergic nervous system. Angiotensin-converting enzyme (ACE) inhibitors have been shown to benefit patients with left ventricular systolic dysfunction irrespective of symptoms. Despite ACE inhibitor use, left ventricular dysfunction continues to progress in most patients. In addition, ACE inhibitors are substantially underused in patients who would benefit, in large part due to physician concern over potential adverse effects. Angiotensin receptor blockers (ARBs) have been proposed as either potential substitutes for ACE inhibitors or as additive therapy for heart failure patients. The authors will review the importance of the renin-angiotensin-aldosterone system in the progression of heart failure, as well as the mechanisms by which ACE inhibitors and ARBs counteract this effect. The clinical evidence to date supporting the use of ARBs in heart failure also will be reviewed. Based on current trials, ARBs are suitable substitutes for ACE inhibitors in patients who have true ACE inhibitor intolerance, but ACE inhibitors should still be considered first-line therapy in the treatment of left ventricular systolic dysfunction and heart failure. ARBs are a reasonable additive therapy in patients on maximal ACE inhibitor therapy who remain symptomatic, especially in patients unable to tolerate beta blockade.     

Angiotensin receptor blockers: evidence for preserving target organs

Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.     

The role of angiotensin II receptor blockers in the treatment of heart failure patients

Evidence from large, randomized, controlled clinical trials supports the use of angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and spironolactone to reduce mortality and morbidity. Despite these effective therapies, event rates related to heart failure remain high. Although ACE inhibitors reduce angiotensin II production, they do not fully suppress the increased angiotensin II production in heart failure. Angiotensin II receptor blockers (ARBs) directly block the effect of angiotensin II, derived from any source, at the receptor level and have the potential to be as effective or even more effective than ACE inhibitors. The results of a number of clinical studies have demonstrated ARBs are effective and well tolerated. However, no studies have demonstrated a convincing decrease in mortality with ARB use, although a decrease has been observed for heart failure hospitalization. The results from further studies are awaited to clarify the role of ARBs in the treatment of heart failure.     

A hard look at angiotensin receptor blockers in heart failure

Multiple trials over the past several years have examined indications for angiotensin receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet despite these data, there is still confusion regarding the efficacy of ARBs as monotherapy in these patient populations, as well as the specific indications for combination ARB/angiotensin-converting enzyme (ACE) inhibitor therapy. We examine the key differences among the trials-including the ACE inhibitor dose, the ARB and its dose, blood pressure reduction, and patient populations-to present our perspective on ARB use, alone or in combination with ACE inhibitors, in patients with chronic heart failure and post-myocardial infarction left ventricular dysfunction. We conclude that ACE inhibitors remain the first-line therapy for left ventricular dysfunction. Angiotensin receptor blockers should be reserved for monotherapy in ACE intolerant patients and for combination therapy in symptomatic class II/III patients with chronic heart failure.     

ACE-Inhibition and Angiotensin II Receptor Blockers in Chronic Heart Failure: Pathophysiological Consideration of the Unresolved Battle

Reducing the effects of angiotensin II by blockade of AT1-receptors may be superior to inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors in chronic heart failure (CHF) patients. However, the results of several trials did not fulfil this expectation. In both ELITE II with symptomatic CHF patients and in OPTIMAAL involving high risk patients after acute myocardial infarction, angiotensin II type I (AT1) receptor blocker (ARB) losartan did not prove to be superior to captopril. There are several potential reasons, why ARBs did not fare better than ACE inhibitors. Although AT1-receptor blockade may block the effects of non-ACE pathways of tissue angiotensin II formation, no clinical evidence is available that a more powerful inhibition of the tissue renin-angiotensin system brings improved survival. The choice of patients for clinical trials of HF therapy is not based on the level of neurohumoral activation. Thus, the more effective attenuation of angiotensin II action with ARBs may not bring additional benefits. The potential antiremodeling effect of ARBs through the stimulation of AT2 receptors by angiotensin II could be counterbalanced by a failure of AT1-receptor blockers to enhance bradykinin, nitric oxide and prostacyclin formation with antigrowth properties. Although ACE-inhibitors seem to have slightly better results at present than AT1 blockers in the battle on heart failure patient, future trials will decide which is the definitive winner.     

Angiotensin II receptor blockers in congestive heart failure

The benefits of angiotensin-converting enzyme (ACE) inhibitors for the treatment of congestive heart failure (CHF) are well-established. A newer class of medications, angiotensin II receptor blockers (ARBs), may be a suitable replacement for ACE inhibitors as a result of a more complete inhibition of angiotensin II and better tolerability among patients. To examine the current literature on the efficacy and safety of ARBs in the setting of CHF, a Medline search was conducted of the English language literature for the years 1987 to 2005. Clinical trials that reported data on cardiac outcomes were reviewed. The earlier trials were direct ARB to ACE inhibitor comparisons (ELITE I and ELITE II). These studies indicated that ARBs do not confer an improvement in cardiac outcomes over ACE inhibitors. RESOLVD, Val-HeFT, and the 3 separate trials of the CHARM program investigated the addition of an ARB to standard therapy. The RESOLVD trial showed no significant differences in clinical events among ACE inhibitor, ARB, and their combination. Although no mortality benefit was evident in the Val-HeFT trial, a substantial reduction in CHF rehospitalizations was reported among patients who were not receiving ACE inhibitor therapy. The CHARM-Overall program demonstrated a significant benefit in cardiovascular death and hospital admissions for CHF with the addition of ARB to standard therapy, a benefit that was more pronounced in patients with depressed left ventricular ejection fraction. In the setting of CHF, rates of cardiac outcomes do not differ substantially between ARBs and ACE inhibitors. However, their combination may improve outcomes for patients with CHF.     

The role of the renin angiotensin system blocking in the management of atrial fibrillation

OBJECTIVE: The objective of the study was to review the current available clinical evidence for the role of renin-agiotensin system (RAS) blockade in the treatment of atrial fibrillation (AF). METHOD: We conducted a pubmed and medline literature search (January 1980 through May 2007) to identify all clinical trials published in English involving the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for preventing the occurrence or recurrence of AF. Discussing pathophysiology and experimental evidence in detail is beyond the scope of this article. CONCLUSION: There is no solid evidence to support using ACE inhibitors or ARBs as antiarrhythmic therapy in patients with AF. However, in view of the possible benefits and the low incidence of side effects with ACE inhibitors and ARBs, they might be given in patients with recurrent AF, particularly if there are other indications for their use such as hypertension, HF, or diabetes mellitus. Possible benefits from pre-treatment argue in favour of using ACE inhibitors and ARB as first-line therapy in patients with hypertension.     

Suppression of the renin-angiotensin-aldosterone system in chronic heart failure: choice of agents and clinical impact

Chronic heart failure (CHF) has taken on epidemic proportions in the United States, with approximately 550,000 new cases annually. With the evolution of pharmacotherapy targeting neurohormonal pathways over the past 2 decades, the annual mortality in subjects with New York Heart Association (NYHA) class IV has dramatically improved from 52% in the seminal CONSENSUS trial to less than 20% in more recent trials in CHF. Suppression of the renin-angiotensin system (RAS) with various angiotensin-converting enzyme (ACE) inhibitors has been proven to save lives in several large-scale trials of CHF, and all of them can be used at doses tested in clinical trials without clear preference of one over another. Angiotensin receptor blockers (ARBs) can be used in place of ACE inhibitors in the case of ACE inhibitor intolerance with comparable results. However, some inconsistencies exist between trials with ARBs, and it is uncertain if the ARBs tested in clinical trials provide comparable clinical benefit whether used in place of or in combination with ACE inhibitors. Once ACE inhibition has been started, beta blockade should follow for all subjects with symptomatic CHF. Triple neurohormonal blockade can then be accomplished with the addition of an aldosterone receptor or ARB. Regardless of the exact agent used or sequence of initiation, the critical importance of careful monitoring of neurohormonal blockade cannot be overstated. Renal failure and hyperkalemia are the most important complications of suppression of the renin-angiotensin-aldosterone system (RAAS), and an increase in hospital admissions and death from hyperkalemia after publication of the RALES trial illustrates the danger of "casual" use of neurohormonal blockers. In light of the tremendous benefits of neurohormonal blockade, the only conclusion from these data is to initiate RAAS-blocking agents following the safety precautions tested in the respective clinical trials.     

From evidence to rationale: cardiovascular protection by angiotensin II receptor blockers compared with angiotensin-converting enzyme inhibitors

Clinical trials have shown the efficacy of angiotensin II receptor blockers (ARBs) in patients with hypertension and have suggested that ARBs are noninferior to angiotensin-converting enzyme (ACE) inhibitors in patients with ischemic heart disease and heart failure. The Heart Outcomes Prevention Evaluation (HOPE), a landmark study in high cardiovascular risk management, demonstrated the cardioprotection of the ACE inhibitor ramipril. Thus, in the recent Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET?) ramipril was selected as a comparator when exploring the cardioprotective potential of telmisartan in the first head-to-head comparison of an ACE inhibitor and an ARB in a broad cross-sectional cohort of cardiovascular high-risk patients. ONTARGET showed that telmisartan is as effective as ramipril in the management of these patients but is better tolerated. The combination of ramipril and telmisartan did not confer a further benefit but did bring about an increased rate of adverse events such as renal dysfunction. In previous ARB outcome trials, cardiovascular risk profile, nature and severity of the underlying cardiovascular disease, dosing regimens and concomitant therapies, follow-up, and endpoints have varied greatly so that caution is warranted in extrapolating evidence gained from high-risk patients to other conditions such as acute myocardial infarction or chronic heart failure.     

Renin-angiotensin-system blockade in the prevention of diabetes

Type 2 diabetes often occurs in association with hypertension and cardiovascular disease, and markedly increases cardiovascular risk. Strategies to reduce the incidence of diabetes in patients with cardiovascular disease or at high risk for such disease are therefore important. Certain classes of antihypertensive agents, namely the thiazide diuretics and beta-blockers, have an adverse impact on the metabolic profile and increase the risk for new-onset diabetes in hypertensive subjects. In contrast, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which are blockers of the renin-angiotensin system (RAS), have been shown to increase insulin sensitivity. They may also reduce the risk of diabetes in patients with hypertension or cardiovascular disorders. Some of the evidence in favour of ACE inhibitors and ARBs has come from studies with active comparators that have potential adverse metabolic effects. However, the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme demonstrated that the ARB candesartan reduced the incidence of diabetes in heart failure patients in comparison to placebo. The mechanisms responsible for the beneficial effects of RAS blockade remain to be established. Nevertheless, a treatment that can control hypertension and reduce the risk of onset of type 2 diabetes at the same time is certainly desirable.     

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, the 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. (c)2000 by CHF, Inc.     

Renin-angiotensin-aldosterone blockade for cardiovascular disease prevention

The renin-angiotensin-aldosterone system (RAAS) plays a significant role in pathophysiology of multiple disease states. RAAS blockade is beneficial in patients with hypertension, acute myocardial infarction, chronic heart failure, stroke, and diabetic renal disease. RAAS blockade with the combination angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has demonstrated conflicting results in recent clinical trials. This article reviews the latest evidence of isolated ACEI or ARB use, their combination, and the role of aldosterone blockers and direct renin inhibitors in patients at risk, and makes recommendations for their use in the prevention of morbidity and mortality in cardiovascular disease.     

Use of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy to reduce cardiovascular events in high-risk patients: Part 1

Cardiovascular disease is understood as a continuum; risk factors induce a pathophysiologic cascade that culminates in end-organ failure. The renin-angiotensin system (RAS) influences multiple aspects of the pathophysiology via hemodynamic and nonhemodynamic effects. Many long-term clinical trials provide overwhelming evidence of benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) across the cardiovascular continuum, including benefits regarding hypertension, myocardial infarction, stroke, renal disease, and heart failure. Trials also indicate additive or synergistic effects of combination therapy in renal disease and heart failure, a possibility supported by the basic biochemistry of the agents. Discussion of these trials is included in part 1 of this 2-part review. Part 2 of the review will discuss the extensive interaction of the RAS with the cellular and molecular pathophysiology of cardiovascular disease and the cross-continuum effects of ARBs and ACE inhibitors, which raise the possibility that RAS inhibition can offer protection in high-risk patients who do not have symptoms. The benefits of combined ACE inhibitor/ARB therapy in high-risk patients await confirmation; ongoing clinical research in this area will be discussed.     

Aldosterone receptor blockers in the treatment of heart failure

Opinion statement Heart failure is associated with neurohormonal activation, including activation of the renin-angiotensin-aldosterone system. Plasma aldosterone levels are elevated in patients with heart failure in spite of the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers because of angiotensin-independent stimuli for aldosterone production. In addition to its long recognized role in sodium retention, aldosterone has a number of other deleterious effects, including the increase in myocardial and vascular fibrosis and myocardial remodeling in patients with heart failure. Based on strong clinical trial data, low-dose aldosterone receptor blockers are recommended to improve morbidity and mortality in patients with severe chronic heart failure due to left ventricular systolic dysfunction and in patients with heart failure associated with left ventricular systolic dysfunction after acute myocardial infarction, and in patients already on standard therapy including ACE inhibitors (or angiotensin receptor blockers) and β blockers. In view of the potential for serious hyperkalemia with the use of aldosterone receptor blockers, it is essential to monitor serum potassium closely and to adjust the dose of aldosterone antagonists based on serum potassium levels. Close adherence to the dosing regimens used in the clinical trials (RALES [Randomized Aldactone Evaluation Study] and EPHESUS [Eplerenone Post-AMI Heart Failure Efficacy and Survival Study]) is recommended. These agents should not be initiated in patients with severe renal insufficiency and closer monitoring is warranted in those with mild to moderate renal insufficiency or diabetes.     

Treatment of high-risk diabetic patients with angiotensin II receptor blockers

In the United States, approximately 16 million people have diabetes; 90-95% have type 2 diabetes. They are at increased risk of developing hypertension and cardiovascular disease (CVD). The benefits of treating hypertension in diabetic patients and the potential to delay complications and reduce mortality have been demonstrated in clinical trials. Increasing evidence shows that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) may be equally effective in delaying progressive renal disease in diabetic patients. Large, multicentre trials are ongoing to confirm the efficacy and superior safety profile of ARBs in this population.     

American College of Cardiology/American Heart Association Chronic Heart Failure Evaluation and Management guidelines: relevance to the geriatric practice

BACKGROUND: Heart failure (HF) is the only cardiovascular disease with increasing incidence and prevalence. Most HF patients are older adults. With the aging of the population and effective treatment of hypertension and coronary artery disease, the two major underlying causes of HF, the number of older Americans with HF is expected to rise significantly in the coming decades. HF is the number one hospital discharge diagnosis for older adults. It is one of the causes of frequent hospital readmissions, reflecting acute decompensation and compromised quality of life for patients and increased cost and resource use for the healthcare system. It is also associated with approximately 300,000 deaths annually, most in older adults. Advances in the management of HF in the past several decades have significantly decreased the mortality and morbidity associated with this condition. Randomized controlled trials have demonstrated the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, and spironolactone on survival and quality of life of HF patients, but there is evidence of underuse of evidence-based care for HF. Several national guidelines have been published since 1994 that recommended evidence-based evaluation and management of HF. In 1995, the American College of Cardiologists (ACC) and the American Heart Association (AHA) published their first HF guidelines that recommended left ventricular (LV) function evaluation for all patients presenting with HF and use of ACE inhibitors for all patients with LV systolic dysfunction (LVSD) unless contraindicated. The guidelines recommended the use of hydralazine and isosorbide dinitrate in patients who could not use ACE inhibitors. In addition, digoxin was recommended in patients with HF due to LVSD but not adequately responsive to ACE inhibitors and diuretics and in those with atrial fibrillation and rapid ventricular rates. Diuretic use was recommended for symptomatic patients with evidence of fluid overload. Use of anticoagulation was restricted to patients with atrial fibrillation or to those with a history of systemic or pulmonary embolism. Beta-blockers were reserved for HF patients after acute myocardial infarctions. Recent advances in the management of HF called for a revision of the guidelines. PURPOSE: The purpose of revising the 1995 ACC/AHA guidelines was to incorporate recent advances in pharmacological and nonpharmacological approaches to HF treatment and to assist physicians in clinical decision-making in the management of HF. METHODS: The ACC/AHA invited representatives from the American College of Chest Physicians, the Heart Failure Society of America, the International Society for Heart and Lung Transplantation, the American Academy of Family Physicians, and the American College of Physicians-American Society of Internal Medicine to participate in the preparation of the guidelines. The writing committee searched pertinent medical literature in English using computerized databases such as MEDLINE and EMBASE and manually searching the bibliographies of the selected articles. The writing committee classified HF into four stages, including patients who are at high risk for developing HF. According to this new classification, Stage A and B represent asymptomatic patients, the former at high risk for developing HF but no structural disorder, the latter with structural disorders of the heart. Stage C encompasses patients with underlying structural heart disorders who are symptomatic, either currently or in the past. Stage D includes end-stage HF patients. This new classification is intended to complement the New York Heart Association (NYHA) functional classification of HF into Class I (asymptomatic), Class II (symptomatic on less than ordinary exertion), Class III (symptomatic on ordinary exertion), and Class IV (symptomatic at rest). RESULTS: The recommendations are categorized into those for evaluation and management.     

Angiotensin blockade or aldosterone blockade as the third neuroendocrine-blocking drug in mild but symptomatic heart failure patients

Recent clinical trials have explored whether angiotensin receptor blockers (ARBs) or aldosterone blockade should be added to standard angiotensin-converting enzyme (ACE) inhibitor/beta blocker treatment in heart failure. Both strategies are of some value but it is unclear which strategy should be used first in patients with mild but symptomatic heart failure. The arguments for and against each strategy are discussed. The strongest argument for aldosterone blockade is the consistency in the results of the RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study) studies, but what is lacking is a trial of aldosterone blockade in patients with mild, symptomatic heart failure as such. The strongest argument for ARBs is that the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Added trial result was positive in the precise patient population of interest (mild, symptomatic heart failure). The strength of this argument is diminished by the somewhat different results in Val-HeFT (Valsartan Heart Failure Trial). A third possibility is to use neither an ARB nor an aldosterone blocker and arguments can be marshalled for this position also. Clinicians should now assess these various arguments to select what they believe would be best for their patients.