Tissue angiotensin‐converting enzyme inhibitors: Are they more effective than serum angiotensin‐converting enzyme inhibitors?

Since their discovery in the 1980s, angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease angiotensin formation, prevent breakdown of bradykinin, and may also act on peptides of the renin-angiotensin system. They are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure, and have been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. They may preserve endothelial function and counteract initiation and progression of atherosclerosis. Broadly, ACE inhibitors can be divided into tissue specific or serum ACE inhibitors. Tissue-specific ACE inhibitors as a group are not superior to serum ACE inhibitors in the treatment of coronary artery disease. Pending direct comparator clinical trials between a tissue ACE inhibitor and a plasma ACE inhibitor, both ramipril and perindopril can be recommended for secondary risk prevention, based on the evidence.     

Are angiotensin converting enzyme inhibitors and angiotensin receptor blockers becoming the treatment of choice in African-Americans?

African-American patients constitute a significant and important group who are at high risk for developing hypertension-related complications. The proportion of African-American patients succumbing to or suffering from cardiovascular, renal, and neurologic sequelae is unacceptably high. Therefore, it is extremely crucial to develop appropriate therapeutic strategies for this vital subset of our society. The renin-angiotensin system may play a role in the pathophysiology of hypertension-related diseases, and therefore drugs that block this system, ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, may have a special indication for African-American patients. Although these drugs may not be the most efficacious agents in terms of blood pressure reduction, they have a major benefit in offering target organ protection and arresting disease progression in the African-Americans. Hence, contrary to the old notions, drugs blocking the renin-angiotension system have an important place in the management of hypertension and related disorders in African-American patients.     

Beyond ONTARGET: angiotensin‐converting enzyme inhibition and angiotensin II receptor blockade in combination,a lesser evil in some?

Aim: Following the recent Ongoing Telmistartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) finding of adverse renal outcomes, dual renin‐angiotensin blockade has fallen out of favour, despite antihypertensive and antiproteinuric efficacy. However, in high‐risk severe hypertension, not studied in ONTARGET, whether combination treatment should be withheld or withdrawn is not clear. We examine the renal effects of angiotensin‐converting enzyme inhibitor (ACE‐I) and angiotensin II receptor blocker (ARB) monotherapy versus combination therapy in patients with type 2 diabetes and varying degrees of hypertension. Methods: Subjects attending a hospital diabetes centre were selected as case (combination therapy, n = 120) and control (monotherapy, n = 480). Subjects were matched for age, gender, ethnicity, estimated glomerular filtration rate (eGFR), blood pressure (BP) and study duration. Patients were stratified by BP, hypertension stage 1 (BP < 160/100, n = 506) and stage 2 (≥160/100, n = 94), and by treatment group. Data were analysed for the primary renal outcome of eGFR decline ≥20 ml/min, over a median of 3.7 years. Results: In keeping with the ONTARGET study, for stage 1 hypertension, combination treatment is significantly worse than monotherapy for the primary outcome of eGFR decline ≥20 ml/min (20 vs. 10.7%, p = 0.01). In contrast, for stage 2 hypertension, this endpoint was reached less often for combination versus monotherapy (12.0 vs. 23.2%, p = 0.2). Combination treatment was also not detrimental in patients with proteinuria or eGFR < 60 ml/min and was associated with fewer macrovascular events. Conclusion: Given that hypertension control is paramount and in the spirit of primum non nocere, these data are reassuring should clinicians choose to use ACE‐I and ARB combination therapy in the very hypertensive diabetic patient.     

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.     

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.     

Do angiotensin II receptor antagonists substitute angiotensin converting enzyme inhibitors in the treatment of high blood pressure?

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AIIA) are both pharmacological groups that inhibit the actions of angiotensin II. ACEI prevent the formation of angiotensin II from angiotensin I, whereas A II A inhibit the final crucial step of angiotensin II binding with the AT1 receptor site. A similar antihypertensive efficacy has been described for both groups but A II A drugs have a better safety profile above all due to the absence of dry cough. Despite the fact that evidence with ACEI is more conclusive, A II A seems to achieve the same protective effects on the target organ damage in hypertensive patients. At present, ACEI are the drugs of choice in the treatment of patients with cardiac dysfunction and failure. The information of ongoing trials with A II A will be of great value in deciding the optimal treatment for hypertensive patients with different cardiovascular diseases.     

Optimizing target-organ protection in patients with diabetes mellitus: Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers?

High blood pressure in the setting of type 1 and type 2 diabetes is commonly associated with the earlier development of target-organ damage, including cardiovascular and cerebrovascular disease and progressive renal insufficiency. The major goal of treating high blood pressure in this population is to prevent or reduce the likelihood of targetorgan damage. The treatment goal for high blood pressure, therefore, has to be defined based on optimal means of preventing cardiovascular and renal events. The reduction of high blood pressure with pharmacologic therapy is associated with reduction of cardiovascular events, renal disease, and associated mortality. However, many questions remain. Some of the basic and important questions include the following: What should be the goal of treated blood pressure in the diabetic, and are there preferred agents that should be used in the hypertensive diabetic population? How do angiotensin-converting enzyme inhibitors and angiotensin receptor blockers fit in? Are there advantages of one class over the other? The goal of this review is to summarize the recent clinical trial findings and try to provide recommendations based on the evidence of these trials to help the clinician better choose blood pressure goals and treatment strategies in the diabetic population.     

Are angiotensin converting enzyme inhibitors beneficial in patients with aortic stenosis?

Angiotensin converting enzyme (ACE) inhibitors may become an accepted form of treatment for aortic stenosis in the future.     

Renovascular hypertension in 2007: Where are we now?

Hypertension in patients with renovascular disease poses a major clinical challenge. Renal arterial disease accelerates hypertension by activation of multiple pressor systems. Although younger individuals with fibromuscular lesions often respond well to angioplasty with minor associated risks, care must be taken in cases of complex vascular anomalies, such as renal artery aneurysms. More than 85% of patients referred for revascularization have atherosclerotic renal artery stenosis; most are older patients with preexisting hypertension, diabetes, and vascular disease. The benefits of stent revascularization in this group are controversial. Antihypertensive therapy works best with drugs that block the renin-angiotensin system; however, most patients require multiple agents. Detailed analysis of the literature and small prospective trials failed to identify major benefits with renal artery angioplasty as compared with intensive drug therapy. The CORAL study and others seek to randomly assign subjects with high-grade renovascular lesions to optimal medical management with and without stenting.     

Renin-angiotensin-aldosterone system blockade and renal protection: angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers?

Renal function is closely associated with cardiovascular risk, to the extent that even minor renal abnormalities, which are present in 10% of the general population, carry a greatly elevated risk of cardiovascular disease, target-organ damage and death. Reducing blood pressure by 20 mmHg or more in patients with severe hypertension (>160/100 mmHg) and advanced renal disease is sufficient to ensure a considerable reduction in proteinuria. In patients with less severe disease, however, blockade of the renin-angiotensin-aldosterone system (RAAS) is necessary to restore normal renal function. Clinical studies have shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), which both overcome the activity of angiotensin II, provide renoprotection in diabetics and non-diabetic populations. Which class of drugs is more effective remains a subject of debate, but the evidence favours ARBs for providing more effective renoprotection in patients at risk of diabetic nephropathy. The ARBs preserve renal haemodynamics and reduce progression to end-stage renal disease by around 25% in patients with overt nephropathy and prevent progression to overt disease by up to 70% in patients with mild renal impairment. The combination of ARBs and ACE inhibitors is even more protective, halving the number of patients with progression of renal impairment compared with either monotherapy. Long-term clinical studies now under way will help to establish the relative efficacies of the ARBs and ACE inhibitors and provide greater insight into the benefits of combination therapy.     

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.     

Does angiotensin‐converting enzyme gene polymorphism affect blood pressure? Findings after 6 years of follow‐up in healthy subjects

BACKGROUND: There has been an increase in research into the association between angiotensin-converting enzyme (ACE) gene deletion polymorphism and cardiovascular disease, with conflicting results. The present prospective long-term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects, over 6 years of follow-up. METHODS: Population: 684 healthy volunteers (aged, 25-55 years): normotensive and free of cardiovascular diseases, with acceptable echocardiographic window. All subjects had to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at entry. STUDY PROTOCOL: All subjects underwent a complete physical examination, 12-lead ECG and ECHO, and venous blood samples were drawn for DNA analysis and cholesterol. All subjects had a clinical evaluation each year for the 6 year duration of the study. RESULTS: All 684 subjects completed 6 years of follow-up. We identified three genetically distinct groups. The ACE-DD group (n=225, 80F/145M, mean age 43.4+/-7.6 years) had 42 hypertensive subjects (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary syndromes (ACS). There was no association between family history, smoking habit, hypercholesterolemia and events. The ACE-ID group (n=335, 116F/219M, mean age 43.6+/-7 years) had 16 hypertensive subjects (4.7%) and 3 subjects with ACS. The ACE-II group (n=124, 45F/79M, mean age 42.5+/-6.9 years) had 2 hypertensive subjects (1.6%) and 1 HF subject. The incidence of hypertension and cardiovascular events was significantly higher in the ACE-DD group (53 cases, 23%) than in the ACE-ID and ACE-II groups (20 and 3 cases, 5.9 and 2.4%, respectively), P=0.0001. The higher incidence of hypertension was observed in the older age groups (36-45 and 46-55 years) with ACE-DD and ACE-ID genotypes. CONCLUSION: Our data suggest that ACE-DD polymorphism is associated with a higher incidence of hypertension in baseline healthy subjects, irrespective of other risk factors. The higher incidence of hypertension was apparent predominantly in the older age groups.     

Why are angiotensin converting enzyme inhibitors underutilised in the treatment of heart failure by general practitioners?

Treatment with angiotensin converting enzyme inhibitors confers significant morbidity and mortality benefits in patients with heart failure, yet previous studies have repeatedly shown that these drugs are underutilised in general practice. To investigate why this is the case, we conducted an anonymous questionnaire survey of 515 general practitioners in the Nottingham Health District. The response rate was 60.2%. We found that although 39.3% of respondents underestimated the poor prognosis associated with heart failure, 98% were aware of the prognostic benefits conferred by angiotensin converting enzyme inhibitors. However, 46.3% of respondents expressed concern about the potential adverse effects associated with angiotensin converting enzyme inhibitors, the main fears being hypotension and renal impairment. General practitioners who were concerned about adverse effects were significantly less likely to have initiated an angiotensin converting enzyme inhibitor for heart failure than those who were not (P<0.01). Further research is needed to identify which patients can safely be commenced on angiotensin converting enzyme inhibitors in general practice. In the meantime, general practitioners should be encouraged to refer patients whenever they are concerned about initiating angiotensin converting enzyme inhibitors in the community.     

Does the antihypertensive response to angiotensin converting enzyme inhibition predict the antihypertensive response to angiotensin receptor antagonism?

To test the hypothesis that the antihypertensive response to angiotensin converting enzyme (ACE) inhibition can predict the response to angiotensin II type I receptor (AT₁R) antagonism, 33 hypertensive patients were randomized to receive lisinopril (20 mg) or losartan (50 mg) for 5 weeks. Patients were then crossed-over to the alternative treatment for a second 5-week period. Twenty-four-hour ambulatory BP (ABP) was measured before randomization and on the final day of each period. The agreement in ABP response between the two drugs was assessed using the following approaches: Subjects were classified as responders and nonresponders using as a threshold an arbitrary level of response (ABP fall ≥ 10 mm Hg systolic or ≥ 5 mm Hg diastolic) or the median ABP response achieved by each of the drugs. Disagreement between the two drugs in the responders-nonresponders classification was expressed as the proportion of subjects whose ABP responded to one of the drugs only. Lisinopril was more effective than losartan in reducing ABP (mean difference 4.7 ± 8.1/3.3 ± 5.7 mm Hg, systolic/diastolic, P < .05). Disagreement in the antihypertensive response between the two drugs was found in 39%/33% of subjects for systolic/diastolic ABP using the arbitrary response criterion (33%/39% using the median response criterion). Significant correlations were found between the responses to lisinopril and losartan (r = 0.47/0.59, systolic/diastolic, P < .01). We conclude that in more than one third of hypertensive subjects, the BP response to ACE inhibition fails to predict the response to AT₁ R antagonism and vice versa. These data suggest that there are differences between these two drug classes that are not only of theoretical but also of practical significance.     

Cardiovascular risk reduction and diabetes education: what are we telling our patients?

PURPOSE: The purpose of this study was to determine the extent to which diabetes education encounters include evidence-based content aimed at reducing the risk of cardiovascular disease. METHODS: During a 2-week period in November 2001, 3 certified diabetes educators (CDEs) listed the statements they made while teaching patients. These statements/comments were then assigned to the 7 outcome areas identified by the Diabetes Self-Management Assessment Report Tool (D-SMART). All educational encounters completed during that same month by 21 educators were reviewed for content areas or modules consistent with the American Diabetes Association National Standards. RESULTS: Of all statements made by the 3 CDEs, 63% were about glycemic control while only 5% were directly relevant to cardiovascular risk reduction. There were 1043 educational encounters in November 2001, of which only 10% targeted cardiovascular risk. Educators focused most of their educational efforts (62%) on glycemic control. CONCLUSIONS: Despite its potential impact and strong evidence base, diabetes education gives little attention to the reduction of cardiovascular risk. Diabetes educators should emphasize interventions that are most likely to be effective in reducing cardiovascular morbidity and mortality in patients with diabetes.     

Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both?

Aortic stenosis is the most common adult heart valve condition seen in the Western world and its incidence continues to rise. No established disease modifying treatments retard progression of the stenotic process. Recent insights into the pathogenesis of calcific aortic stenosis suggest that the disease mimics atherosclerosis. The natural history and progression of calcific aortic stenosis are described with particular emphasis on new and emerging medical treatments that may modify the disease process. In particular, statins and angiotensin converting enzyme inhibitors appear to hold promise but definitive evidence from large clinical trials is awaited.