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.     

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.     

Aliskiren in the treatment of hypertension and organ damage

Hypertension is one of the most important risk factor and cause of cardiovascular diseases (CVD). Chronic activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development of hypertension, cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors such aliskiren offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity; by contrast, ACEI and ARBs increase plasma renin activity. The efficacy of aliskiren in the reduction of major clinical events is being tested in large ongoing clinical trials. This review examines the efficacy, safety, and tolerability of aliskiren, and considers the evidence for the potential organ protection benefits of this treatment.     

Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies

The renin-angiotensin-aldosterone system (RAAS) is critical in regulating systemic blood pressure, water and electrolyte balance, and pituitary gland hormones. These physiologies appear to be primarily mediated by the angiotensin II/AT₁ receptor subtype system. Overstimulation of this system can predispose cardiovascular disease (CVD) characterized by excessive vasoconstriction, fibrosis, and cardiac remodeling. If untreated, the patient typically displays a continuum of pathophysiologic conditions progressing from atherosclerosis to left ventricle hypertrophy (LVH), coronary thrombosis, myocardial infarcts, with heart failure as an endpoint. Intervention with antihypertensive therapy is necessary to inhibit this progression. RAAS blocking drugs appear to be the most effective approach. Diastolic heart failure patients benefit from treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin AT₁ receptor blockers (ARBs). Elderly CVD patients evidence age-related changes in body composition that alter the distribution and half-life of medications, thus presenting special challenges to treatment. The presence of comorbidities such as diabetes, renal dysfunction, liver insufficiency further complicates any therapeutic strategy. In addition, noncompliance because of cognitive impairment, depression, confusion due to the complexity of dose regimens, and lack of an appropriate social support system can disrupt positive outcome. The present review discusses the roles of an overactive RAAS and sympathetic nervous system as primary contributors to CVD. In addition, treatment strategies are discussed, focusing on middle aged and elderly hypertensive and heart failure patients.     

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.     

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-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.     

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 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 renin-angiotensin system and its blockade in diabetic renal and cardiovascular disease

Diabetic nephropathy, the most common cause of end-stage renal disease in the United States, is also associated with increased cardiovascular mortality. The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development and progression of kidney disease and cardiovascular disease. Randomized, controlled trials have demonstrated renoprotection with the use of angiotensin receptor blockers (ARBs) in type 2 and angiotensin-converting enzyme inhibitors (ACEIs) in type 1 diabetes. More recent studies have demonstrated similar cardiovascular bene.ts with the use of ARBs compared with ACEIs. The combination of the two classes of RAAS blockers has been investigated in large studies of patients with heart failure and after myocardial infarction, and a few small studies of patients with diabetic nephropathy. In this review, we summarized the results of the studies on the benefits of ARBs, ACEIs, and their combination in patients with diabetic nephropathy or cardiovascular diseases.     

为什么血管紧张素转化酶抑制剂能降低高血压患者死亡率?

最新荟萃分析发现,肾素-血管紧张素(Ang)-醛固酮系统(RAAS)抑制剂能降低高血压患者死亡率,其治疗获益全部源于血管紧张素转化酶(ACE)抑制剂(ACEIs),而非血管紧张素受体拮抗剂(ARBs)。RAAS可以归纳为2条轴:ACE-AngⅡ(1-8)-AT1受体轴和ACE2-Ang(1-7)-Mas受体轴,ACEIs对RAAS的2条轴均发挥良好作用,而ARBs主要作用于前者。各个指南推荐高血压相关心血管疾病治疗优先选择ACEIs,对不能够耐受者选择ARBs。我们应当重视ACEIs在高血压、冠心病、心肌梗死和心力衰竭防治中的应用,目的是降低心血管疾病患病率和死亡率的风险。     

Reducing cardiorenal risk through combination therapy with a direct renin inhibitor

Interruption of the renin-angiotensin-aldosterone system (RAAS) cascade with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or more recently direct renin inhibitors (DRIs) is a safe and effective antihypertensive strategy that is in routine clinical use. The clinical utility of these agents in cardiorenal end-organ protection is increasingly being recognized. Although both ACE inhibitors and ARBs demonstrate substantial benefit in patients with cardiovascular and/or renal disease, considerable evidence indicates that they only partially suppress the RAAS pathway due to feedback upregulation of plasma renin activity. With the goal of providing more comprehensive RAAS blockade, combination ACE inhibitor/ARB therapy has been evaluated. However, this approach has not shown the anticipated improvements in composite cardiovascular and renal outcomes and appears to be associated with significant toxicity. Due to a unique mechanism of action, the combination of a DRI with an ACE inhibitor or ARB may represent an effective end-organ-protective therapeutic strategy.     

The role of angiotensin receptor blockers in the management of chronic heart failure

Clinical and basic science research has repeatedly confirmed the importance of the renin-angiotensin-aldosterone system in the pathophysiology of chronic heart failure. Accordingly, blockade of this system by angiotensin-converting enzyme (ACE) inhibitors has assumed a central role in the treatment of heart failure. Recently, angiotensin II receptor blockers (ARBs) have gained prominence as a possible substitute for ACE inhibitors in therapy for heart failure. However, clinical data compiled on this use of ARBs have shown them to be useful only as alternative therapy in ACE inhibitor-intolerant patients. Continuing large-scale clinical investigations may lead to an expansion of their role in therapy for various cardiovascular diseases.     

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.     

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.     

Preserving cardiac function in the hypertensive patient: why renal parameters hold the key.

The relationship between cardiovascular and renal pathologies is well recognized in advanced nephropathy and heart failure, but in early disease it has received less attention. Consequently, microalbuminuria screening and interventions that treat early nephropathy remain under-utilized cardioprotective strategies in the hypertensive patient. Agents that delay the progression of renal disease are likely to be cardioprotective by lessening the systemic consequences of renal dysfunction and may have additional cardioprotective effects by exerting beneficial effects on endothelia elsewhere in the body and within the heart. A critical driving factor within both renal and wider cardiovascular pathologies is overactivation of the renin-angiotensin-aldosterone system (RAAS). Accordingly, RAAS-directed antihypertensive agents including both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have been demonstrated to have renoprotective effects. In major prospective trials, two ARBs, losartan and irbesartan, have been demonstrated to be renoprotective in patients with frank proteinuria, and one ARB, irbesartan, has been shown to have renoprotective properties in patients with microalbuminuria. For patients with incipient or frank renal dysfunction, an aggressive RAAS-based approach to hypertension management, combining potent blood pressure control with proven renoprotection, may therefore constitute a key component of therapy targeted towards long-term cardioprotection.     

Pleiotropic Effects of Inhibitors of the RAAS in the Diabetic Population: Above and Beyond Blood Pressure Lowering

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are indispensable therapeutic agents for treating hypertension and proteinuria in patients with diabetes mellitus. Studies have shown that the renin-angiotensin-aldosterone system (RAAS) has effects on various organ systems, including the central nervous system, heart, and kidneys. Angiotensin II has major deleterious effects on vascular compliance, vascular relaxation, and plasma markers of inflammation, which are surrogate markers of cardiovascular disease. Evidence is established from major trials that ACE inhibitors and ARB therapy improve these surrogate markers and reduce cardiovascular disease, renal disease, and stroke. Accumulating evidence also supports the newer class of medication, the direct renin inhibitor aliskiren, as beneficial in hypertensive persons with diabetes mellitus. In this article, we review the mechanisms through which inhibitors of the RAAS benefit persons with hypertension and decrease the development of cardiovascular and renal disease above and beyond blood pressure lowering.     

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.     

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.