Angiotensin II-receptor blockers: clinical relevance and therapeutic role.

The limitations of angiotensin-converting-enzyme (ACE) inhibitors and the role of angiotensin II-receptor blockers (ARBs) in the treatment of hypertension, heart failure, and diabetic nephropathy are discussed. Although ACE inhibitors are generally well tolerated, two important class-related adverse effects are cough, which is common, and angioedema, which is rare but serious. Cough and angioedema appear to be less frequent with ARBs than with ACE inhibitors. ARBs seem to be as capable as ACE inhibitors of producing renal dysfunction. ARBs may offer more complete inhibition of angiotensin II than ACE inhibitors. The mechanism of action is based on selective binding to angiotensin type 1 receptors. Many clinical studies have shown that ARBs lower blood pressure as effectively as other antihypertensive agents, including ACE inhibitors. ARBs do not appear to have a greater clinical effect than ACE inhibitors in patients with heart failure. Some studies of combination ARB and ACE inhibitor therapy for heart failure indicate advantages of the combination over therapy with either class. ARBs may exert renal protective effects in diabetic nephropathy. ARBs offer an alternative to ACE inhibitors in the management of hypertension, especially for ACE-inhibitor-intolerant patients. ACE inhibitors remain the drugs of choice for patients with heart failure, left ventricular dysfunction after MI, and diabetic nephropathy; ARBs offer these patients an alternative when ACE inhibitor therapy is not tolerated.     

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for prevention and treatment of nephropathy associated with type 2 diabetes mellitus

Renal complications resulting from type 2 diabetes mellitus are costly and common. Finding optimal therapy is important for the prevention and management of diabetic nephropathy. Research has focused on antihypertensive agents that modify the renin-angiotensin-aldosterone system. Because of their effects on the glomerulus, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have been studied as interventions at various stages of diabetic nephropathy. The ACE inhibitors may delay the progression to microalbuminuria and then clinical albuminuria. The ARBs decrease albuminuria in patients with microalbuminuria and decrease adverse renal events, specifically the progression to end-stage renal disease in patients with clinical albuminuria and hypertension. Limited data suggest that combination therapy with ACE inhibitors and ARBs may slow the progression of microalbuminuria to clinical albuminuria. Because of the variability in degree of albuminuria evaluated and in study designs (numbers of patients, study duration, drug dosages, and outcomes measured), a detailed review of the available literature about ACE inhibitors and ARBs in the prevention or treatment of diabetic nephropathy may provide insight to clinicians.     

A Comparison of Two Multiple-Characteristic Decision-Making Models for the Comparison of Antihypertensive Drug Classes

BACKGROUND: Multiple-characteristics decision-making (MCDM) models can be used to calculate a score, based on a set of characteristics, for a number of alternative drugs or drug classes to allow comparison between them and thus enhance evidence-based pharmacotherapy. OBJECTIVE: To compare two MCDM models, Simple Additive Weighting (SAW) and Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS), in determining first-line antihypertensive drug class. METHODS: Five different classes of antihypertensive drugs were analyzed: diuretics, beta-adrenoceptor antagonists (beta-blockers), dihydropyridine calcium channel blockers (DHP-CCBs), ACE inhibitors, and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). Four characteristics were deemed relevant for the determination of first-line antihypertensive drug class: effectiveness, persistence with treatment as a measure of tolerability, cost, and clinical experience. Weight factors were determined by sending questionnaires to cardiologists, pharmacists, general practitioners (GPs), and internists in The Netherlands. Absolute scores for the characteristics were determined from literature (effectiveness and persistence) and health insurance data (costs and clinical experience). RESULTS: Ninety-two cardiologists (33% of those sent the questionnaire), 90 GPs (31%), 87 internists (31%), and 123 pharmacists (43%) completed the questionnaire. Among all professions, according to both SAW and TOPSIS, ACE inhibitors were ranked as the first-line antihypertensive drug class, typically followed by beta-blockers. CONCLUSION: Both SAW and TOPIS analyses, using weight factors assigned by cardiologists, pharmacists, GPs, and internists from The Netherlands, rank ACE inhibitors as the first choice among antihypertensive drug classes for the treatment of uncomplicated hypertension. Both methods are valuable tools in the development of evidence-based pharmacotherapy.     

Antihypertensive efficacy of olmesartan medoxomil alone and in combination with hydrochlorothiazide

Angiotensin receptor blockers (ARBs) are highly effective antihypertensive agents with excellent safety profiles. ARBs have been shown to improve cardiovascular morbidity and mortality in hypertensive patients with heart failure or diabetic nephropathy. For this later class of patients, the American Diabetes Association recommends ARBs as the primary treatment option. The ARBs function by blocking the binding of angiotensin-II (A-II) to its receptor, thereby inhibiting the action of A-II. Unlike the angiotensin-converting enzyme (ACE) inhibitors, which block the production of A-II through the ACE pathway, the ARBs effectively inhibit A-II regardless of whether it is produced through ACE or some alternate enzyme pathway. This difference in action offers a distinct advantage of ARBs over ACE inhibitors. Olmesartan medoxomil, the latest addition to the ARB class, is a long-acting, safe and well-tolerated antihypertensive drug. The combination of olmesartan medoxomil with a low-dose diuretic, potentiates the blood pressure lowering effect of either agent alone and is highly effective in achieving the recommended blood pressure goals in the majority of patients treated.     

Antihypertensive efficacy of olmesartan medoxomil alone and in combination with hydrochlorothiazide

Angiotensin receptor blockers (ARBs) are highly effective antihypertensive agents with excellent safety profiles. ARBs have been shown to improve cardiovascular morbidity and mortality in hypertensive patients with heart failure or diabetic nephropathy. For this later class of patients, the American Diabetes Association recommends ARBs as the primary treatment option. The ARBs function by blocking the binding of angiotensin-II (A-II) to its receptor, thereby inhibiting the action of A-II. Unlike the angiotensin-converting enzyme (ACE) inhibitors, which block the production of A-II through the ACE pathway, the ARBs effectively inhibit A-II regardless of whether it is produced through ACE or some alternate enzyme pathway. This difference in action offers a distinct advantage of ARBs over ACE inhibitors. Olmesartan medoxomil, the latest addition to the ARB class, is a long-acting, safe and well-tolerated antihypertensive drug. The combination of olmesartan medoxomil with a low-dose diuretic, potentiates the blood pressure lowering effect of either agent alone and is highly effective in achieving the recommended blood pressure goals in the majority of patients treated.     

The Role of Direct Renin Inhibition in Clinical Practice

Monotherapy with most antihypertensive agents reduces systolic BP by about 10 mmHg (‘Rule of 10’). Thus, the majority of hypertensive patients require combination therapy to achieve BP goals. In this review, we provide a brief overview of the renin-angiotensin-aldosterone system (RAAS) and discuss the rationale, clinical evidence, and shortcomings related to the use of angiotensin-converting enzyme (ACE) inhibitors in combination with angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We summarize the rationale and clinical evidence supporting the use of the direct renin inhibitor (DRI) aliskiren, particularly in combination with other antihypertensive classes, including in high-risk patients with diabetes mellitus and with or without diabetic nephropathy. DRIs may be useful in combination with ACE inhibitors or ARBs as they provide a more complete blockade of the RAAS, effectively suppressing residual angiotensin II production and the counter-regulatory increase in plasma renin activity observed in patients receiving monotherapy with ACE inhibitors or ARBs.     

Recent advances in pharmacological management of hypertension in diabetic patients with nephropathy. Effects of antihypertensive drugs on kidney function and insulin sensitivity.

Hypertension is often seen in Type 1 and Type 2 diabetic patients, particularly in those with nephropathy, and the progression of diabetic nephropathy is closely related to blood pressure elevation. Thus, the effects of antihypertensive drugs on kidney function and insulin sensitivity in diabetic patients are of great clinical importance. Successful antihypertensive treatment has been shown to slow the progression of diabetic nephropathy. Several results from short term studies have suggested that angiotensin converting enzyme (ACE) inhibitors may be advantageous over other conventional antihypertensive agents in reducing albuminuria in both hypertensive and normotensive diabetics with microalbuminuria or persistent proteinuria. However, the decline in glomerular filtration rate during ACE inhibitor treatment is comparable to that during effective treatment with conventional antihypertensive drugs in hypertensive Type 1 diabetic patients with overt nephropathy. Whether ACE inhibitors possess a specific effect in preventing the development of diabetic nephropathy remains to be seen in properly designed long term studies. Although calcium antagonists may preserve kidney function or possess a renoprotective effect in hypertensive Type 2 diabetics with nephropathy, firm evidence supporting this contention seems to be lacking and also requires long term evaluation. Increasing attention is being directed toward the effect of antihypertensive drugs on insulin sensitivity in diabetic patients: ACE inhibitors and alpha 1-adrenoceptor blocking agents have been shown to improve this sensitivity. Despite the widespread involvement of calcium in hormone secretion and action, calcium antagonists appear to have little effects on the glucoregulatory and calcium-regulatory hormones within the drug dosages used in clinical practice. Several clinical variables, such as the presence or absence of hypertension, overt nephropathy and microalbuminuria, or a combination of variables should be accounted for when evaluating critically the cumulative data on the effects of antihypertensive drugs on kidney function and albuminuria in the variety of diabetic patient groups. Understanding the pharmacokinetic and pharmacodynamic characteristics of antihypertensive drugs will be of clinical importance in diabetic patients with advanced nephropathy (glomerular filtration rate of less than 30 ml/min) and/or other complications, such as impaired gastric motility or gastroparesis, and will thereby lead to a more rational management of hypertension in those patients.     

Renin-angiotensin system blockade at the level of the angiotensin converting enzyme or the angiotensin type-1 receptor: similarities and differences

The development of drugs which block the renin-angiotensin system (RAS) has been proven a major advance in cardiovascular medicine. Angiotensin converting enzyme (ACE) inhibitors, which block the formation of angiotensin II from the inactive angiotensin I, are widely used as first line treatment in hypertension, heart failure and diabetic nephropathy. More recently, selective antagonists of the angiotensin type-1 receptor (AT1R) have become available for clinical use. Accumulating evidence suggests that AT1R antagonists have similar effects to ACE inhibitors in hypertension, heart failure and diabetic nephropathy. Although ACE inhibitors and AT1R antagonists block the same system, experimental evidence suggest that their mechanisms of action differ in several respects, such as increased bradykinin and angiotensin 1-7 levels with ACE inhibitors and AT2R activation with AT1R antagonists. Nevertheless, the clinical significance of these differences remains largely unknown and, in practice, the only clear advantage of AT1R antagonists over ACE inhibitors is the absence of cough as a side effect. Recent clinical data suggest that combined ACE inhibition and AT1R antagonism offer additive effects in reducing blood pressure in hypertension, in reducing proteinuria in nephropathy and in improving prognosis in heart failure. Further evidence suggests that some hypertensive patients may have a good antihypertensive response with ACE inhibition but not with AT1R antagonism, or the reverse. These data suggest that these two drug classes have important similarities, because they act on the same system, but they also appear to have important differences, which are not only of theoretical but also of clinical importance.     

Drug treatment for hypertension in Finnish primary health care

Objective: To analyse the prescribing patterns of antihypertensive drugs in Finnish primary health care and to describe the profiles of monotherapy and combination therapy in relation to the duration of high blood pressure. Methods: Thirty out of 250 primary health care centres were randomly selected for the study. All doctors (n?=?337) from the participating health centres recorded all hypertensive patients (n?=?4405) during a 2-week period in May 1995. Adequate information was obtained concerning 4294 hypertensives, of whom 65% were women with a mean age for the total study population of 64 years. 85% of the patients (n= 3638) had antihypertensive medication which was classified into five main categories: diuretics, beta blocking agents, calcium channel blockers, ACE inhibitors and hypotensives. Results: Of the patients using antihypertensive medication, 48% were undergoing monotherapy and 52% combination therapy. Beta blocking agents were the most frequently prescribed drugs for hypertension, being used by half of the patients. ACE inhibitors and diuretics were prescribed in a different manner for male and female hypertensives, with men receiving more ACE inhibitors and women more diuretics. The number of antihypertensive drugs increased with the duration of hypertension, though 38% of the patients having hypertension for over 10 years were still undergoing monotherapy. Among patients undergoing combination therapy, 75% received two different agents, most often a diuretic with a beta blocking agent. Conclusions: With increasing duration of hypertension, the number of antihypertensive drugs also increased. Beta blocking agents were the drug of choice for all patients. For women, combination therapy more frequently included diuretics, whereas ACE inhibitors were favoured for men.     

Dual Therapy in Hypertensive Patients with Coronary Artery Disease: The Role of Calcium Channel Blockers and β-Blockers

BP is the most important determinant of the risk of stroke. A small reduction in BP results in a substantial reduction of both ischemic and hemorrhagic stroke. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental evidence has linked the renin-angiotensin system (RAS) to the development and progression of cerebrovascular disease. Inhibition of the RAS has beneficial cerebrovascular effects and may reduce the risk of stroke in a manner possibly independent from the alterations of BP. Some clinical trials even suggest that ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) exert cerebroprotective effects beyond BP lowering, but the evidence is controversial. Studies on specific protective actions of antihypertensive drugs are generally hampered by the fact that any treatment-related difference in BP may play a dominant role in the prevention of stroke. There are also indications that the protective potency of ARBs might be superior to that of ACE inhibitors, due to their differential activation of angiotensin II type 2 receptors, but the clinical relevance of this mechanism is unclear. Some studies in primary prevention of stroke, acute stroke, and secondary prevention show advantages for ARBs beyond controlling BP alone. In primary prevention, the LIFE randomized trial showed a significant difference in stroke rate in favor of losartan compared with atenolol despite similar reductions in BP. In acute stroke, the role of hypertension and its treatment remains controversial. ACCESS, however, suggested that an ARB is safe in hypertensive acute stroke patients and may offer advantages independent from BP control. In secondary stroke prevention, there are very few antihypertensive trials. These trials show that BP lowering is at least as successful as in primary prevention, but the absolute stroke risk is much higher. An ACE inhibitor was effective compared with placebo in the PROGRESS trial. The MOSES study showed that eprosartan prevented vascular events more effectively than nitrendipine, despite similar BP-lowering effects. Hypertension is not only the most important risk factor for stroke, but is also closely correlated with cognitive decline and dementia. Therefore, prevention of cognitive decline or even improvement of slightly diminished brain function should be an important goal for antihypertensive treatment in the future. Some clinical data suggest advantages for ACE inhibitors, ARBs, and calcium channel antagonists. Currently, however, the existing data are not sufficient for clinical recommendations. Therefore, ongoing trials will further define the exact role of inhibitors of the RAS and are urgently needed in secondary prevention, in acute stroke, and in the prevention of cognitive decline.     

Non-steroidal anti-inflammatory drugs (NSAIDs) and hypertension treatment intensification: a population-based cohort study

Purpose

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to antagonize the effects of antihypertensive drugs, and these associations can lead to an increase in arterial blood pressure. However, the impact of NSAIDs on hypertension treatment management in large-scale populations remains poorly evaluated. We examined whether the introduction of NSAID into the treatment regimen would induce an intensification of hypertension treatment (defined as the introduction of a new antihypertensive drug).

Methods

We conducted a cohort study involving 5,710 hypertensive subjects included in the French health insurance system database who had been treated and stabilized with their antihypertensive therapy and not exposed to any NSAID between 1 April 2005 and 1 April 2006. The maximum follow-up duration was 4?years.

Results

Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95?% confidence interval (CI) 1.05–1.71] for NSAIDs in general, 1.79 (95?% CI 1.15–2.78) for diclofenac and 2.02 (95?% CI:1.09–3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACEIs; HR? 4.09, 95?% CI 2.02–8.27) or angiotensin receptor blockers (ARBs; HR?3.62, 95?% CI 1.80–7.31), but not with other antihypertensive drugs.

Conclusions

Exposure to NSAIDs leads to an intensification of hypertension treatment, especially in patients treated with ACEIs or ARBs. Renin–angiotensin system blockers should be avoided whenever NSAIDs are prescribed.     

Angiotensin receptor blockers: RAAS blockade and renoprotection

ABSTRACT

Introduction: Chronic kidney disease (CKD) is an increasingly prevalent public health concern and is associated with a high risk of adverse cardiovascular outcomes. Renal impairment is frequently associated with hypertension and there is compelling evidence of the benefits of antihypertensive therapy for reducing progression of kidney disease. The central role of the renin-angiotensin-aldosterone system (RAAS) in hypertension and renal disease has led to interest in the ability of RAAS-blocking agents to provide benefits beyond blood pressure control.

Scope: This review explores the mechanisms involved in CKD development, assesses markers of CKD progression, explores the role of the RAAS in renal disease, and examines RAAS blockade as a therapeutic option for renoprotection. For this purpose, a non-systematic literature review was conducted using the Medline database.

Findings: Studies in patients with diabetic renal disease have shown that RAAS blockade with angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs) reduces progression of renal disease. Similarly, several studies have demonstrated the benefits of ACE inhibitors in non-diabetic renal disease, although few studies have been conducted with ARBs in this setting. At present, there is little evidence to determine the relative merits of ARBs and ACE inhibitors in terms of clinical outcomes, although ARBs appear to have advantages in terms of renal haemodynamics and measures of renal function.

Conclusions: The beneficial effects of ARBs, which result from a combination of antihypertensive, haemodynamic, antiproteinuric and pleiotropic mechanisms, provide a strong rationale for considering the use of these agents in the treatment of high-risk patients.     

Can the renin-angiotensin system protect against stroke? A focus on angiotensin II receptor blockers

From a patient's perspective, stroke is the most devastating form of cardiovascular disease, representing the number one cause of permanent disability in the United States. Treatment of hypertension significantly reduces the risk of stroke; however, it is unclear whether all antihypertensive agents are equivalent in this regard. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of cardiovascular events, including stroke. Although attenuation of the renin-angiotensin system (RAS) is often credited with the blood pressure-independent effects of this class of agents, this hypothesis has not been confirmed with regard to the end point of stroke. In fact, drugs that activate the RAS, such as diuretics and dihydropyridine calcium channel blockers, are as effective or superior to ACE inhibitors for stroke prevention. Angiotensin II receptor blockers (ARBs) selectively block the angiotensin II subtype I receptor, which results in a reflexive increase in levels of angiotensin II and unopposed activation of angiotensin II subtype 2 receptors. Clinical trials comparing ARBs with active controls have reported significant reductions in stroke in ARB-treated patients. Data on ARBs and other drugs that activate the RAS (diuretics and dihydropyridine calcium channel blockers) support a potential role for the RAS in protecting against stroke. Ongoing trials with ARBs are evaluating stroke as a primary end point, and results should help to further elucidate the role of ARBs in this disease. Until then, it is prudent to treat hypertension with an agent or combination of agents that are likely to result in a rapid and sustained reduction in blood pressure, taking into consideration patient characteristics, comorbidities, tolerability, and cost.     

National antidepressant prescribing in children and adolescents with mental health disorders after an FDA boxed warning

BackgroundIn October 2004, the U.S. Food and Drug Administration (FDA) issued a boxed warning about an increased risk of suicidality (i.e., suicidal ideation, behavior, or attempts) related to all antidepressants in children and adolescents.ObjectiveTo describe national antidepressant prescribing patterns in children and adolescents before, during, and after the introduction of the FDA boxed warning.MethodsCross-sectional data from the 2002–2009 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) were used to describe antidepressant prescribing patterns within a nationally-representative sample of 4035 physician visits for children and adolescents diagnosed with depression or other psychiatric disorder(s) [i.e., anxiety disorders or attention deficit/hyperactivity disorder (ADHD)].ResultsIn 2002–2003, antidepressants were prescribed in 4.1 million (36.1%) visits, followed by 3.2 million (28.8%) visits in 2004–2005 and 2.8 million (26.8%) visits in 2006–2007. However, antidepressant prescribing patterns reversed during 2008–2009, with an increase to 3.6 million (32.5%) visits. Compared to the period preceding the FDA boxed warning (2002–2003), a significant decline in visits related to antidepressant prescribing detected in the immediate post-FDA boxed warning period (2006–2007) (AOR = 0.67, 95% CI: 0.47–0.96). No association between the FDA boxed warning and antidepressant prescribing visits was detected during the FDA boxed warning period (2004–2005) (AOR = 0.80, 95% CI: 0.53–1.21) and in the late post-FDA boxed warning period (2008–2009) (AOR = 1.01, 95% CI: 0.63–1.60).ConclusionsAfter a 2-year lag period, antidepressant prescribing for visits of children and adolescents diagnosed with depression or other psychiatric disorder(s) in community-based and outpatient clinic settings declined when compared to the period preceding the FDA boxed warning. This decline was not sustained in the period of five years after implementation of the FDA boxed warning.     

The concern about ACE/ARB and COVID-19: Time to hold your horses!

Concern about coronavirus 2019 (COVID-19) morbidity and mortality has drawn attention to the potential role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) because the SARS-CoV-2 uses the ACE2 receptor as its point of entry into the body. It is not clear if and to what degree the SARS-CoV-2 virus affects the renin-angoiotensin system. Early studies from China which speculated on the role of ACE inhibition and ARBs did not evaluate the drug regimens. A vast body of evidence supports the use of ACE inhibitors and ARBs in hypertensive patients and patients with heart failure, and very little evidence has been acquired about their role in COVID-19. There is good evidence in support of the use of ACE inhibitors and ARBs in indicated patients with hypertension and heart failure, and clinicians should be reticent about abruptly withdrawing these drugs based on a paucity of evidence.     

The cost effectiveness of ACE inhibitors as first-line antihypertensive therapy

BACKGROUND: Current hypertension guidelines differ in their recommendations for first-line antihypertensive therapy. OBJECTIVE: To evaluate the cost effectiveness of ACE inhibitor therapy as antihypertensive first-line therapy as compared with conventional antihypertensive therapy with beta-adrenoceptor antagonists or diuretics. STUDY DESIGN: Cost-effectiveness analysis based on data from randomised trials and observational studies comparing the effectiveness of ACE inhibitor and conventional antihypertensive therapy, we constructed a Markov model to compare four strategies in the management of uncomplicated hypertension: (i) prescribing ACE inhibitor therapy to all patients; (ii) prescribing conventional therapy to all patients; (iii) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on electrocardiography (ECG); or (iv) individualised antihypertensive therapy based on the presence or absence of left ventricular hypertrophy on echocardiography. METHODS: Cost data were derived from the medical literature and focus groups, and utility values were derived from patients on antihypertensive monotherapy. All costs were calculated in 1999 Canadian dollars, but are reported in US dollars according to the 1999 purchasing power parity rate for medical and healthcare. The effectiveness of ACE inhibitor therapy in the presence of left ventricular hypertrophy was derived from observational studies. The time horizon was over a lifetime. PERSPECTIVE: Third-party payer. PATIENTS/PARTICIPANTS: A cohort of men aged 40 years without cardiovascular comorbidity requiring antihypertensive drug therapy. MAIN OUTCOME MEASURES AND RESULTS: In the baseline analysis, all four strategies resulted in expected discounted QALYs that differed from each other only at the third decimal point (i.e. less than 0.003). Given the uncertainties in the variable estimates and the small size of the differences, these differences are extremely small and unlikely to represent real differences. Even accepting the small gains as real, the resulting cost-effectiveness ratios are unattractively high: $US 200,000 per QALY gained for the echocardiography strategy (compared with ECG), and $US 700,000 for the "ACE inhibitor for all" strategy (compared with ECG). The incremental cost effectiveness of prescribing ACE inhibitor therapy to everybody was never less than $US 100,000/QALY in the sensitivity analysis. CONCLUSIONS: Prescribing ACE inhibitors as antihypertensive first-line therapy in patients without cardiovascular morbidity cannot be recommended at the present time unless the acquisition costs of ACE inhibitors become substantially more attractive.