Clinical update: the role of angiotensin II receptor blockers in patients with left ventricular dysfunction (Part II of II)

Almost 5 million individuals in the United States have chronic heart failure (HF), which is increasing in prevalence. Angiotensin-converting enzyme (ACE) inhibitors are standard therapies for HF, although more than 10% of patients with HF are unable to tolerate these agents. Furthermore, ACE inhibitors may not provide complete blockade of the renin-angiotensin system (RAS) in the long term. Because angiotensin II receptor blockers (ARBs) may block the RAS more completely than ACE inhibitors and are better tolerated, several large-scale ARB trials have been performed exploring their potential role in treating patients with symptomatic HF and left ventricular systolic dysfunction. The Losartan Heart Failure Survival Study (ELITE II) demonstrated no significant differences in morbidity and mortality between the ARB losartan and the ACE inhibitor captopril among elderly patients with HF. The Valsartan Heart Failure Trial (Val-HeFT) demonstrated reductions in hospitalizations for HF with the ARB valsartan when added to standard HF therapy, with no effect on mortality. Both trials suggested a potential negative interaction between ARB and beta-blocker therapy. The Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program demonstrated significant reductions in morbidity and mortality with the ARB candesartan in patients with HF due to systolic dysfunction, with or without ACE inhibitors and with or without beta blockers. Thus, the addition of ARBs to the treatment regimen of patients with symptomatic HF should be strongly considered.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Renin inhibition: A new modality for hypertension management

Renin is the first and rate-limiting step cleaving angiotensinogen to angiotensin I, thus influencing angiotensin II (Ang II) formation. Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is effective in management of several cardiovascular diseases; however, control continues to be difficult and requires multiple drug therapy. Use of RAS inhibitors does not totally prevent Ang II formation, which could continue to contribute to development of end-organ damage. Over the past two decades, renin inhibition seemed to be an attractive approach for complete blockade of the RAS. Recently, aliskiren, a renin inhibitor, was approved as the first of a new class of antihypertension drugs. Clinical trials demonstrated significant blood pressure reduction in hypertensive patients with aliskiren used alone or combined with hydrochlorothiazide, ACE inhibitors, or ARBs. Studies are in progress to evaluate the potential role for renin inhibition in management of kidney and cardiac diseases.     

Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense?

Both angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) interfere with the activity of the renin-angiotensin system (RAS) in a different way. Theoretically, one might expect beneficial effects when they are used in combination, as a more complete suppression of the RAS can be achieved. But can this additional effect still be seen in patients on full-dose ACE-inhibition? Several controlled trials demonstrated that combination therapy can have additional benefits in hypertensive patients, in chronic heart failure patients, and in both diabetic and non-diabetic nephropathy patients. However, the clinical benefit was not always as pronounced as expected and not every patient will benefit from dual blockade of the RAS. There is some evidence of a less pronounced effect of combination therapy when a full dose of the ACE-inhibitor is given. However, it is well known that ACE-inhibitors cannot completely suppress the formation of angiotensin II, in particular, when the RAS is activated. Indeed, clinical trials indicated that add-on therapy with an ARB was especially of use when the RAS remained activated despite full-dose ACE-inhibitor treatment. In summary, combination of a full-dose ACE-inhibitor and an ARB can be a rational choice in selected patients.     

Benefits and Risks of Aliskiren Treatment in Patients With Type 2 Diabetes: Analyses of the 3A Registry

The authors sought to retrospectively analyze the real‐world evidence on aliskiren in diabetic patients with or without concomitant renin‐angiotensin system (RAS) blocker use based on the Registry for Ambulant Therapy With RAS Inhibitors in Hypertension Patients in Germany (3A). Of 14,986 patients included, 3772 patients had diabetes and 28.5% received aliskiren, 14.3% received angiotensin‐converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), 35.4% received aliskiren plus an ACE inhibitor/ARB, and 10.5% received other drugs. Ambulatory blood pressure (BP) monitoring (baseline BP 148±15.8/84.0±10.9 mm Hg) revealed stronger diastolic BP reduction for aliskiren plus ACE inhibitor/ARB than aliskiren alone in the low (2.8±0.5 vs 0.6±0.6; P=.004) and intermediate (5.9±0.5 vs 4.5±0.5; P=.04) baseline BP groups. There was a lesser ambulatory BP reduction observed for patients receiving non‐RAS in the high baseline category for both systolic (12.5±1.8 vs 17.1±1.0; P=.02) and diastolic (6.9±1.0 vs 9.8±0.6; P=.01) BP. In patients with hypertension and type 2 diabetes, aliskiren was beneficial in lowering BP, with no observed increases in major adverse effects compared with RAS‐blocking therapy alone.     

Rationale and design of a study to evaluate management of proteinuria in patients at high risk for vascular events: the IMPROVE trial

Declining kidney function predicts increasing cardiovascular risk in people with hypertension. Microalbuminuria is a marker for cardiovascular risk and declining kidney function. Agents that block the renin-angiotensin-aldosterone system (RAAS), notably angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure and slow the progression of proteinuric kidney disease. Evidence is accumulating that the combination of an ACE inhibitor and an ARB is the optimal means of RAAS blockade in this setting, slowing the progression of nephropathy independently of blood pressure lowering to a greater degree than can be achieved using maximum approved doses of either agent alone. However, the emerging therapeutic potential of ACE inhibitor/ARB combination therapy in hypertensive kidney disease requires further characterization. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events trial aims to determine definitively whether the combination therapy of an ARB, irbesartan and an ACE inhibitor, ramipril, is more effective than ramipril alone in reducing the urinary albumin excretion rate in patients at high cardiovascular risk with hypertension and proteinuria or microalbuminuria.     

Effectiveness of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers on total and cardiovascular mortality and morbidity in primary prevention: A nationwide study based on French Health Insurance Data (SNDS)

Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) both inhibit the renin‐angiotensin system (RAS) but have different sites of action. Whether clinically meaningful differences exist is still debated. The authors set up a population‐based nationwide retrospective cohort study with at least 5 years of follow‐up based on the comprehensive French Health Insurance Database linked to the French hospital discharge database. Patients aged 50 or above, identified as ARB or ACE inhibitor new users in 2009 (at least one delivery during the year and no such delivery in 2008) were eligible. Exclusion criteria included history of cancer, cardiovascular disease, or chronic renal insufficiency. Main outcome measure was overall mortality. Secondary outcomes were cardiovascular deaths, major cardiovascular events, and major or other cardiovascular events. Out of 407 815 eligible patients, 233 682 (57%) were ARB users; two‐third had no previous exposure to antihypertensive drug. Based on propensity‐score based Cox model, ARB new user group had a better overall (HR: .878, 95%CI, .854 to .902), and cardiovascular (HR: .841, 95%CI, .800 to .84) survival and had a lower risk for major cardiovascular events (HR: .886, 95%CI, .868 to .905). Statistically significant quantitative interactions were detected with diabetes. Considering subgroup analyses, ARBs had a better survival than ACE inhibitors in nondiabetic patients.     

The pathophysiologic role of the brain renin-angiotensin system in stroke protection: clinical implications

The brain possesses the same renin-angiotensin system (RAS) as the systemic circulation. Recent experimental studies have shown that the brain RAS plays an important role in stroke and neuronal protection through its effector peptide angiotensin (Ang) II. Ang II exerts its stroke-protective effects through stimulation of Ang II type 2 (AT2) receptors. Angiotensin receptor blockers (ARBs) exert a dual influence, which is important in their stroke protective effects. They selectively block the Ang II type 1 (AT1) receptors, decreasing local vasoconstriction, and allow free Ang II to stimulate the unoccupied AT2 receptor and increase local vasodilation, resulting in the alleviation of local brain ischemia and limiting the volume and extent of brain loss. In contrast, angiotensin-converting enzyme (ACE) inhibitors, by decreasing the amount of Ang II production, may diminish the stroke-protective effects of Ang II. This perhaps could be a reason for the inferior stroke-protective effect of ACE inhibitors compared with ARBs, which has been demonstrated in several clinical trials. The evidence for this effect of ARBs compared with ACE inhibitors, however, is only indirect. Ongoing clinical trials with head-to-head comparisons of ARBs and ACE inhibitors will hopefully provide the needed information.     

Optimal strategies for preventing progression of renal disease: Should angiotensin converting enzyme inhibitors and angiotensin receptor blockers be used together?

Interruption of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT₁ receptor blockers has been shown to delay progression in a variety of renal diseases, suggesting that the RAS, and its major effector molecule, angiotensin II, are important players in renal pathophysiology. Both antagonists combine inhibition of deleterious effects of angiotensin II with activation of potentially beneficial pathways mediated by nitric oxide and prostaglandins. Some concerns have been raised about the completeness of the RAS blockade achieved by these agents. ACE-independent pathways can generate angiotensin II, whereas increases in angiotensin II levels may compete with the AT₁ receptor blocker at the receptor site. It has been suggested that an ACE inhibitor/AT₁ receptor blocker combination offers a better therapeutic effect than treatment with either agent alone. In this review, we focus on mechanisms of actions of ACE inhibitors and AT₁ receptor blockers, implicate them in the rationale for the use of an ACE inhibitor/AT₁ receptor blocker combination, and discuss evidence evaluating the renal effects of the combination as compared to the effects of a single agent. There is a surprising lack of information about the nephroprotective potential of the combination, allowing no consistent conclusions about the superiority of the combination over the single agent. Several experimental and clinical reports suggest that in some conditions, the combination may be beneficial. Rather than providing unequivocal evidence for the use of combination treatment in the renal disease, these studies should be considered as stimuli for more detailed exploration of this issue.     

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.     

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.