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.     

Inhibiting the renin-angiotensin system in myocardial infarction and heart failure: lessons from SAVE, VALIANT and CHARM, and other clinical trials

PURPOSE OF REVIEW: Inhibition of the renin-angiotensin-aldosterone system has become a cornerstone of modern heart failure and myocardial infarction therapy. This article will review the background and major clinical trials that have shaped this field over the past 15 years. RECENT FINDINGS: Major clinical trials have firmly established angiotensin converting enzyme (ACE) inhibitors as the standard of care in patients with heart failure and following myocardial infarction. Over the past several years, a number of trials have tested the hypothesis that an angiotensin II receptor blocker (ARB) could be as effective as, or more effective than, ACE inhibitors in these clinical settings. The results of these trials, while establishing a clear role for ARBs, have been subtly different in distinct patient populations. SUMMARY: The most recent trials of ARBs in heart failure and myocardial infarction patients suggest a role for angiotensin receptor blockers in patients with heart failure who are intolerant to ACE inhibitors and who are on optimal ACE inhibitor therapy. In patients with acute high-risk myocardial infarction, the VALIANT trial has established that the ARB was as effective as an ACE inhibitor following myocardial infarction. These studies have thus provided clinicians with alternatives to ACE inhibitors in these important clinical syndromes.     

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.     

Efficacy of Angiotensin Receptor Blockers in Cardiovascular Disease

The cardiovascular continuum describes the progression of pathophysiologic events from cardiovascular risk factors to symptomatic cardiovascular disease (CVD) and life-threatening events. Pharmacologic intervention early in the continuum may prevent or slow CVD development and improve quality of life. The renin–angiotensin–aldosterone system (RAAS) is central to the pathophysiology of CVD at many stages of the continuum. Numerous clinical trials of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have shown that RAAS blockade provides benefits to patients across the continuum. ARBs are as effective as ACE inhibitors in the treatment of hypertension; however tolerability and adherence to therapy appear to be improved with ARBs. Large clinical trials have shown that ARBs may provide therapeutic benefits beyond blood pressure control in patients with diabetes, heart failure or at risk of heart failure following a myocardial infarction. In addition, ARBs have been shown to provide protective effects in patients with impaired renal function or left ventricular hypertrophy. Additional clinical trials are ongoing to further characterize the role of ARBs in CVD management.     

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in atherosclerosis

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) effectively interfere with the renin-angiotensin system and exert various beneficial actions on cardiac and vascular structure and function, beyond their blood pressure-lowering effects. Randomized, controlled clinical trials have shown that ACE inhibitors improve endothelial function, cardiac and vascular remodeling, retard the anatomic progression of atherosclerosis, and reduce the risk of myocardial infarction, stroke, and cardiovascular death. Therefore, these agents are recommended in the treatment of a wide range of patients at risk for adverse cardiovascular outcomes, including those with coronary disease, prior stroke, peripheral arterial disease, high-risk diabetes, hypertension, and heart failure. ARBs are effective blood pressure-lowering and renoprotective agents and can be used in heart failure in patients who do not tolerate ACE inhibitors. The role of ARBs in the prevention of atherosclerosis and its sequelae is currently under investigation. The use of combined ACE inhibitor plus ARB therapy offers theoretical advantages over the use of each of these agents alone and is also under investigation in large, randomized clinical trials.     

Establishing a new option for target-organ protection: rationale for ARB plus ACE inhibitor combination therapy

Activation of the renin-angiotensin system (RAS) plays an important role in the promotion of cardiovascular disease and target-organ damage, mediated in part by hypertension. Combination therapy targeting RAS activation may reduce target-organ damage and provide superior blood pressure (BP) control; combining angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) represents one possible approach. In monotherapy studies, both ACE inhibitors and ARBs have demonstrated similar positive effects on BP and on RAS-related target-organ damage, including nephropathy and congestive heart failure. Studies of combination therapy, most of which involved addition of an ARB to existing ACE inhibitor therapy, have demonstrated benefits among patients with congestive heart failure and renal disease. However, variances in study design and populations, dosing and titration methods, and clinical end points, in addition to inherent differences between agents, limit the ability to reach clinically meaningful conclusions about the value of dual RAS inhibition. Trials designed to document such efficacy are currently underway.     

The addition of angiotensin receptor blockers to angiotens-inconverting enzyme inhibitors—What has time told us?

The neurohormonal hypothesis for the pathogenesis of heart failure found an early champion in the angiotensinconverting enzyme (ACE) inhibitors. More recently, the β-blockers and aldosterone receptor antagonists have provided significant support by demonstrating marked additive clinical benefit. Within this context, angiotensin receptor blockers (ARBs) were specifically designed to antagonize one of the most potent contributors to the development and progression of heart failure, angiotensin. This review discusses the recent evidence for the addition of ARBs to standard therapy with ACE inhibitors and suggests how this evidence may be used to care for patients.     

The role of ACE inhibitors and angiotensin receptor blockers in the treatment of hypertension and cardiovascular disease

Pharmacologic attenuation of the renin-angiotensin-aldosterone system (RAAS) either through angiotensin-converting enzyme (ACE) inhibition or angiotensin II receptor blockade now occupies a central role in the management of hypertension, diabetes, heart failure, and cardiovascular and renal disease. Although our understanding and use of these agents has expanded significantly over the past decade, the relative and differential benefits of ACE inhibitors and angiotensin receptor blockers (ARBs) are still not entirely clear. The data continue to support the first-line use of ACE inhibitors for all indications. Results for combination ACE inhibitor and ARB therapy in clinical outcome trials have been disappointing and do not support its use. New strategies for RAAS modulation bring hope for further progress in the treatment of hypertensive and 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.     

Have angiotensin receptor blockers lived up to expectations?

Angiotensin receptor blockers (ARBs) were introduced after clinical trials showed angiotensin-converting enzyme inhibitors (ACEIs) to have extensive clinical benefits in a wide range of diseases. Consequently, it has been more difficult for clinical trials to demonstrate similar, enhanced or additive benefits of ARBs. However, ARBs were introduced with the hypothesis that they were likely a more effective method of interrupting the renin-angiotensin system and would result in enhanced outcomes. Clinical trials in high-risk vascular patients (after myocardial infarction), patients with heart failure and patients with nephropathy show the benefits of ACE inhibition. ARBs likely have similar benefits as ACEIs when used after myocardial infarction, in patients with heart failure and for management of diabetic nephropathy. However, ARBs generally remain a second-line treatment because it has been more difficult to demonstrate that ARBs prevent acute vascular events, such as myocardial infarction, together with the greater clinical trial evidence for ACE inhibition. The primary application of ACEIs over ARBs is reflected in the Canadian clinical guidelines for the management of patients with diabetes, hypertension, heart failure and following myocardial infarction. Until the completion of clinical trials, such as the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), that examine whether ARBs have vascular protective properties similar to ACEIs, it is unlikely that the clinical guidelines will change.     

Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors

Angioedema is a rare, potentially life-threatening adverse event of renin-angiotensin system inhibitors. The objective of the present study was to determine the risk of angioedema from randomized clinical trials. A PubMed/CENTRAL/EMBASE search was made for randomized clinical trials from 1980 to October 2011 in patients on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or direct renin inhibitor (DRI). Trials with a total number of patients ≥100 and a duration of ≥8 weeks were included for analysis. Incidence of angioedema was pooled by weighing the incident rate of each trial by the inverse of the variance. Twenty-six trials with 74,857 patients in the ACE inhibitor arm with 232,523 person-years of follow-up, 19 trials with 35,479 patients on ARB with 122,293 person-years of follow-up, and 2 trials with 5,141 patients on DRI with 1,735 person-years of follow-up met the inclusion criteria and were included in the analysis. In head-to-head comparison in 7 trials, risk of angioedema with ACE inhibitors was 2.2 times higher than with ARBs (95% confidence interval [CI] 1.5 to 3.3). With ACE inhibitors and ARBs, incidence of angioedema was higher in heart failure trials compared to hypertension or coronary artery disease trials without heart failure (p <0.0001). Weighted incidence of angioedema with ACE inhibitors was 0.30% (95% CI 0.28 to 0.32) compared to 0.11% (95% CI 0.09 to 0.13) with ARBs, 0.13% (95% CI 0.08 to 0.19) with DRIs, and 0.07% with placebo (95% CI 0.05 to 0.09). In conclusion, incidence of angioedema with ARBs and DRI was <1/2 than that with ACE inhibitors and not significantly different from placebo. Incidence of angioedema was higher in patients with heart failure compared to those without heart failure with ACE inhibitors and ARBs.     

The clinical use of angiotensin-converting enzyme inhibitors

Through an integrative understanding of cardiovascular pathophysiologic characteristics at the multiorgan level, significant achievements in cardiovascular therapeutics have been achieved and enabled the rationale design and development of drugs such as the angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). In this article, we present a detailed review of the physiologic features of the renin-angiotensin-aldosterone system (RAAS), ACE inhibitors and ARB clinical pharmacologic characteristics, and specific diseases in which they are considered to be the standard of the care as supported by important clinical trial data. It is envisioned that an updated and detailed understanding of ACE inhibitors and ARBs will facilitate their successful use in the treatment of heart failure, myocardial infarction, hypertension, renal failure, and diabetic nephropathy.     

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.     

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.     

Role of angiotensin receptor blockers in the prevention and treatment of arrhythmias

The renin-angiotensin system is a key regulatory system that is activated in many forms of cardiovascular disease. It is well established that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are important therapeutic agents in the treatment of hypertension, myocardial infarction, and congestive heart failure. More recent research has suggested that renin-angiotensin system activation may also play a critical role in the genesis of atrial and ventricular arrhythmias. The possible role of renin-angiotensin system activation in arrhythmogenesis suggests that ACE inhibitors and ARBs may be important therapeutic agents in the prevention and treatment of arrhythmias. This review summarizes the current evidence for the use of ARBs in the treatment of atrial and ventricular arrhythmias.     

Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials

OBJECTIVES: We sought to investigate the role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in preventing the new onset of type 2 diabetes mellitus. BACKGROUND: Diabetes is a public health problem of epidemic proportions and its prevalence is on the rise. The typical American born today has a one in three chance of developing type 2 diabetes. This diagnosis is associated with an adverse cardiovascular prognosis and is considered the risk equivalent of established coronary disease. Even in high-risk individuals, diabetes is a preventable disease. Several studies have shown that ACE inhibitors and ARBs decrease the incidence of new-onset type 2 diabetes. However, the exact role of these agents in diabetes prevention has not yet been fully elucidated. METHODS: We conducted a meta-analysis of 12 randomized controlled clinical trials of ACE inhibitors or ARBs, identified through a MEDLINE search and a review of reports from scientific meetings, to study the efficacy of these medications in diabetes prevention. RESULTS: This showed that ACE inhibitors and ARBs were associated with reductions in the incidence of newly diagnosed diabetes by 27% and 23%, respectively, and by 25% in the pooled analysis. CONCLUSIONS: The use of an ACE inhibitor or ARB should be considered in patients with pre-diabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease.     

Role of the renin-angiotensin-aldosterone system in atrial fibrillation and cardiac remodeling

PURPOSE OF REVIEW: This review summarizes recent clinical trial evidence showing a reduction in the development and recurrence of atrial fibrillation with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor-blocking agents (ARBs). It then explores the possible mechanisms for this effect based on current animal models and limited human study. RECENT FINDINGS: Post hoc analyses of trials in patients with heart failure, hypertension, or myocardial infarction have observed reductions in atrial fibrillation among patients treated with ACE inhibitors or ARBs. Recent studies of these agents in animal models of atrial fibrillation suggest that they may prevent atrial fibrillation by reversing the cardiac structural and electrical changes, known as cardiac remodeling, that lead to the development of atrial fibrillation. This concept is also supported by two prospective studies showing that ACE inhibitors and ARBs prevent the recurrence of atrial fibrillation after electrical cardioversion. SUMMARY: Inhibition of the renin-angiotensin-aldosterone system is a novel concept for the treatment of atrial fibrillation that may target the underlying substrate of atrial fibrillation. Further human research is required to determine whether ACE inhibitors and ARBs prevent atrial fibrillation, and if so, whether this is a result of blood pressure lowering alone or a specific effect of these agents. Ongoing research will establish whether ACE inhibitors or ARBs have specific benefits in patients with atrial fibrillation.     

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-Converting Enzyme Inhibitors in Hypertension: To Use or Not to Use?

Most guidelines for the management of patients with cardiovascular disease recommend angiotensin-converting enzyme (ACE) inhibitors as first-choice therapy, whereas angiotensin receptor blockers (ARBs) are merely considered an alternative for ACE inhibitor–intolerant patients. The aim of this review was to compare outcomes and adverse events between ACE inhibitors and ARBs in patients. In patients with hypertension and hypertension with compelling indications, we found no difference in efficacy between ARBs and ACE inhibitors with regard to the surrogate endpoint of blood pressure and outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. However, ACE inhibitors remain associated with cough and a very low risk of angioedema and fatalities. Overall withdrawal rates because of adverse events are lower with ARBs than with ACE inhibitors. Given the equal outcome efficacy but fewer adverse events with ARBs, risk-to-benefit analysis in aggregate indicates that at present there is little, if any, reason to use ACE inhibitors for the treatment of hypertension or its compelling indications.     

Modulating atherosclerosis through inhibition or blockade of angiotensin

Angiotensin-convertng enzyme (ACE) inhibitors are well recognized for their benefits in treating hypertension and congestive heart failure and preventing postmyocardial infarction heart failure or left ventricular (LV) dysfunction. Recently, blockade of the angiotensin II type 1 (AT1) receptor was shown to reduce cardiovascular events in hypertensive subjects with LV hypertrophy. Several lines of evidence are now converging to show that ACE inhibitors may affect the atherosclerotic process itself. Emerging clinical data indicate that angiotensin-receptor blockers (ARBs) may possibly modulate atherosclerosis as well. The antiatherogenic properties of ACE inhibitors and ARBs may derive from inhibition or blockade of angiotensin II, now recognized as an agent that increases oxidative stress.Angiotensin-converting enzyme inhibition and angiotensin-receptor blockade also increase endothelial nitric oxide formation, which improves endothelial function. In contrast to the effects of ARBs, the vascular effects of ACE inhibitors may, in part, be mediated by an increase in bradykinin. This article reviews some of the biologic mechanisms whereby ACE inhibitors and ARBs may modulate atherosclerosis.