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.     

Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution?

This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.     

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosteron system (RAAS), through increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Recpetor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflmmatory effect of drugs bocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors.     

The Role of Angiotensin Receptor Blocker and Calcium Channel Blocker Combination Therapy in Treating Hypertension

Hypertension remains a significant health problem, affecting approximately 30% of the US population. Of these, only 36.8% have BP controlled to recommended levels of <140/90mmHg for uncomplicated hypertension and <130/80 mmHg for patients with diabetes mellitus or renal disease. For those with uncontrolled hypertension, the risk of diabetes, renal disease, stroke, and cardiovascular disease is increased. Therapeutic options for the treatment of hypertension include several major classes of drugs: diuretics, ß-adrenoceptor antagonists (ß-blockers), ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), renin inhibitors, calcium channel blockers, and central sympatholytics, alone or in combination. Guidelines recommend thiazide diuretics as preferred first-line monotherapy. However, only 50% of patients will respond adequately to this therapy and the rest will require two or more antihypertensive agents to achieve BP goals. Clinical evidence demonstrates that some drugs have advantages when used in combination rather than as monotherapy. Drugs that block the renin-angiotensin-aldosterone system not only provide BP control but may also provide vascular protection and are metabolically neutral. This is a concise review of the safety and efficacy of ARBs in combination with amlodipine for the treatment of hypertension, with focus on the telmisartan-amlodipine combination. A MEDLINE search of the English literature from 2006 to 2009 of amlodipine in combination with ARBs revealed six publications, which are included in this review.     

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.     

Safety and efficacy of aliskiren in the treatment of hypertension and associated clinical conditions

Aliskiren is the first known representative of a new class of non-peptide orally active renin inhibitors that blocks the renin-angiotensin-aldosterone-system (RAAS) at its rate-limiting step. It induces a net reduction in plasma renin activity (PRA), angiotensin II and aldosterone levels. Aliskiren is effective in reducing blood pressure (BP) and is well tolerated. The incidence of adverse events and the number of study discontinuations as a result of adverse events during aliskiren treatment were relatively low and generally not dissimilar from placebo. In placebo-controlled studies, aliskiren showed a dose-related systolic/diastolic BP lowering effect at doses between 75 and 300 mg/day. When compared to active treatments, aliskiren was generally as effective as hydrochlorothiazide, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers, in reducing BP. Aliskiren exhibits synergistic effects when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE inhibitors or ARBs. Although in clinical studies aliskiren proved to reduce proteinuria, the early termination of the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) confirms previous concerns about the full suppression of the RAAS, in this case with aliskiren combined with ACE-inhibitors or ARBs, in patients with diabetes and concomitant renal impairment. This review summarizes the available data on its safety profile and its clinical development for treatment of arterial hypertension, diabetes and nephropathy.     

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.     

Targeting the renin–angiotensin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Agents that counteract the negative impact of the renin–angiotensin–-aldosterone system (RAAS) are effective antihypertensives and reduce the risk of developing Type 2 diabetes. Contrary to common perception, angiotensin-converting enzyme inhibitors do not share the apparent benefit of angiotensin II receptor blockers (ARBs) in reducing risk of cardiovascular-disease outcomes, particularly stroke, in randomised clinical trials. RAAS agents, especially ARBs, are well tolerated. Use of ARBs alone or in combination with other classes of antihypertensive agents to lower blood pressure and/or medications to control other conditions (e.g., insulin sensitivity) reduces risk of cardiovascular disease outcomes and Type 2 diabetes with excellent tolerability. Selected issues related to use of RAAS agents as antihypertensive therapies (e.g., Type 2 diabetes, global risk management, multiple drug therapy and coronary heart disease) are addressed.     

Arterial stiffness and the renin-angiotensin-aldosterone system.

Arterial stiffness has recently been recognised as an independent risk factor for cardiovascular morbidity and mortality in hypertension. Many of the complications seen with angiotensin II (Ang II) excess or hyperaldosteronism--an increased event rate, left ventricular hypertrophy, endothelial dysfunction and target organ damage--are also associated with arterial stiffness. It is possible that reduced arterial compliance may be one mechanism whereby increased activity of the renin-angiotensin-aldosterone system (RAAS) produces adverse vascular effects. Common pathophysiological processes, altered collagen turnover and increased fibrosis may underlie both arterial stiffness and RAAS-associated vascular damage. While it is recognised that patients with hyperaldosteronism have increased arterial stiffness, the role of the RAAS in modulating arterial compliance in essential hypertension and in normotensive subjects is less clear cut. There is, however, more consistent data which show that drugs that interfere with Ang II or aldosterone, namely angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aldosterone antagonists, all reduce arterial stiffness. In many cases, this is to a greater extent than predicted from the extent of reduction in blood pressure (BP), suggesting a role for RAAS in vascular stiffness in hypertensive subjects. There is also evidence that combined ACE inhibitors (ACE-Is) and ARBs may have an additive effect in reducing stiffness. The reduction in cardiovascular mortality in end-stage renal disease patients treated with ACE-Is was preferentially seen in those who had reduced arterial stiffness. These data suggest that, in addition to regulation of vascular biology and BP, the RAAS is an important determinant of arterial stiffness in health and, more particularly, in disease.     

Angiotensin Antagonism in Patients with Heart Failure

Chronic heart failure (CHF) is a major cause of morbidity and mortality in western society. It is now widely accepted that the renin-angiotensin-aldosterone system (RAAS) and, in particular, angiotensin II (A-II) play a key role in the pathophysiology of CHF. Large-scale clinical trials have demonstrated that inhibitors of angiotensin-converting enzyme (ACE), the principal enzyme responsible for A-II production, improve symptoms and survival in patients with CHF. This enzyme is also responsible for the breakdown of the vasodilator hormone bradykinin. Administration of ACE inhibitors is associated with increased plasma bradykinin levels and this is thought to contribute to the vascular changes associated with ACE inhibitor therapy. However, RAAS inhibition with ACE inhibitors remains incomplete because ACE inhibitors do not block the non-ACE-mediated conversion of angiotensin I to A-II. Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) antagonize the action of A-II at the A-II type 1 (AT(1)) receptor, whilst allowing the potentially beneficial actions of A-II mediated via the A-II type 2 (AT(2)) receptor. Evidence that the clinical benefit demonstrated with ACE inhibitors in patients with CHF may extend to ARBs has only emerged recently. Combination therapy with both an ACE inhibitor and an ARB has a number of potential advantages and has been investigated in several large-scale clinical trials recently. In patients with CHF, first-line therapy should include an ACE inhibitor and a beta-adrenoceptor antagonist. The addition of an ARB provides symptomatic relief but has not been shown to improve survival. Where an ACE inhibitor is not tolerated, treatment with an ARB would seem an appropriate alternative. There is insufficient data to support the routine use of ARBs as first-line therapy in the management of CHF.     

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.     

Perindopril versus angiotensin II receptor blockade in hypertension and coronary artery disease: implications of clinical trials

The renin-angiotensin-aldosterone system (RAAS) is now known to play a key role in the pathogenesis of hypertension and a range of other cardiovascular diseases. Two groups of drugs, the ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been developed with the aim of improving clinical outcomes by regulating the RAAS in patients with cardiovascular disease. Initial assumptions were that these two drug types might be interchangeable, but ongoing research has revealed differences between them in terms of pharmacology and outcomes in clinical trials. Although both groups of drugs lower blood pressure, studies of the ACE inhibitor perindopril have revealed preservation of beneficial vascular and endothelial effects mediated by bradykinin and nitric oxide. The selective blockade exerted by ARBs is not associated with these effects. Furthermore, examination of clinical endpoints in major clinical trials has provoked discussion about outcomes comparing ACE inhibitors and ARBs, with recent debate focusing on the incidence of myocardial infarction (MI) in patients receiving these agents. Whether there is an actual difference in protection from MI remains unresolved, although available data confirm the benefit and safety of ACE inhibitors, in particular perindopril, for myocardial protection.     

Targeting the renin-angiotensin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Agents that counteract the negative impact of the renin-angiotensin-aldosterone system (RAAS) are effective antihypertensives and reduce the risk of developing Type 2 diabetes. Contrary to common perception, angiotensin-converting enzyme inhibitors do not share the apparent benefit of angiotensin II receptor blockers (ARBs) in reducing risk of cardiovascular-disease outcomes, particularly stroke, in randomised clinical trials. RAAS agents, especially ARBs, are well tolerated. Use of ARBs alone or in combination with other classes of antihypertensive agents to lower blood pressure and/or medications to control other conditions (e.g., insulin sensitivity) reduces risk of cardiovascular disease outcomes and Type 2 diabetes with excellent tolerability. Selected issues related to use of RAAS agents as antihypertensive therapies (e.g., Type 2 diabetes, global risk management, multiple drug therapy and coronary heart disease) are addressed.     

ACE Inhibitors in Heart Failure

ACE inhibitors have significantly decreased cardiovascular mortality, myocardial infarction (MI), and hospitalizations for heart failure (HF) in patients with asymptomatic or symptomatic left ventricular (LV) systolic dysfunction. Furthermore, the extended 12-year study of the SOLVD (Studies Of Left Ventricular Dysfunction) Prevention and Treatment trials (X-SOLVD) demonstrated a significant benefit with a reduction of cumulative all-cause death compared with placebo (50.9% vs 56.4%) [hazard ratio (HR) 0.86; 95% CI 0.79, 0.93; p < 0.001]. The survival benefits and significant reductions in cardiovascular morbidity related to treatment with ACE inhibitors are likely achieved by titrating the dose of ACE inhibitors to the target dose achieved in clinical trials. Although the ATLAS (Assessment of Treatment with Lisinopril And Survival) study, which randomly allocated HF patients to low- or high-dose lisinopril, showed no significant difference between groups for the primary outcome of all-cause mortality (HR 0.92; 95% CI 0.82, 1.03), the predetermined secondary combined outcome of all-cause mortality and HF hospitalization was reduced by 15% for the patients receiving high-dose lisinopril compared with low-dose (p < 0.001) with a 24% reduction in HF hospitalization (p = 0.002). Despite the use of ACE inhibitors, blockade of the renin angiotensin aldosterone system (RAAS) remains incomplete, with evidence of continued production of angiotensin II by non-ACE-dependent pathways. The safety and potential benefits of angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) in patients with impaired systolic function have been assessed in moderate to large clinical trials. In patients with impaired LV systolic function and HF, combination therapy with ARBs with recommended HF therapy including ACE inhibitors in patients who remain symptomatic may be considered for its morbidity benefit. Based on the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity)-Added data, candesartan cilexetil in addition to standard HF therapy results in a further reduction of cardiovascular mortality. Close monitoring of renal function and serum potassium levels is needed in this setting. The VALIANT (VALsartan In Acute myocardial iNfarction Trial) results suggest that valsartan is as effective as captopril in patients following an acute MI with HF and/or LV systolic dysfunction and may be used as an alternative treatment in ACE inhibitor-intolerant patients. There was no survival benefit with valsartan-captopril combination compared with captopril alone in this trial. Despite these results, ACE inhibitors remain the first-choice therapeutic agent in post-MI patients, and ARBs can be used in patients with clear intolerance. Although the use of ACE inhibitors may be appealing in patients with HF and preserved LV systolic function, there is currently no evidence from large clinical trials to support this.     

Angiotensin II receptor blockade and ventricular remodelling.

Cardiac remodelling is the expression of molecular, cellular and interstitial changes in response to cardiac injury, manifesting as adverse alterations in the size, shape and function of the ventricle. Several clinical studies have documented significant elevations in the levels of renin, angiotensin II (Ang II) and aldosterone attending acute myocardial infarction and/or congestive heart failure. Similar to catecholamines, markedly elevated activity of the renin-angiotensin-aldosterone system (RAAS) is associated with poor prognosis. The effects of Ang II upon cardiac tissue are related to two primary receptors, Ang II type 1 (AT1) and Ang II type 2 (AT2). The AT1-receptor appears to mediate many of the deleterious effects of chronic RAAS activity, while the AT2-receptor is increasingly shown to have potential cardioprotective effects. Attenuating the deleterious effects of sustained Ang II stimulation can be achieved by direct inhibition of angiotensin- converting enzyme (ACE) and/or direct antagonism of AT receptors. ACE inhibition reduces left ventricular (LV) volumes, retards the progression of LV dilatation and hypertrophy and increases systolic function in systolic dysfunction. By blocking at the receptor level, Ang II receptor blockers (ARBs) provide an alternative and more direct approach to inhibiting the effects of Ang II; however, data relating to their effects upon ventricular remodelling, whether used in isolation or in combination with ACE inhibitors (ACE-Is), are less convincing. Data arising from several recent clinical trials suggest that simultaneous use of ACE-Is and ARBs maybe of more benefit in attenuating ventricular remodelling than either agent alone.     

Pharmacoeconomics of angiotensin II antagonists in type 2 diabetic patients with nephropathy: implications for decision making

Angiotensin II receptor antagonists (angiotensin II receptor blockers; ARBs) are a class of antihypertensive drugs that are generally considered comparable to ACE inhibitors in the prevention of heart and kidney failure. However, these two classes of agents do interfere in different stages of the renin-angiotensin system. In patients with type 2 diabetes mellitus, advantages for ARBs over conventional (non-ACE inhibitor) therapy on progression from micro- to macroalbuminuria and overt nephropathy and end-stage renal disease have been shown in clinical trials. In patients with type 2 diabetes and end-stage renal disease, the need for dialysis and/or transplantation results in the use of major healthcare resources. This paper reviews the available economic evidence on treatment with ARBs in type 2 diabetic patients with advanced renal disease.Within-trial analytic and Markov model economic evaluations of the RENAAL (Reduction of Endpoint in Non-insulin dependent diabetes mellitus with Angiotensin II Antagonist Losartan), IDNT (Irbesartan Diabetic Nephropathy Trial) and IRMA (IRbesartan in type 2 diabetes with MicroAlbuminuria)-2 studies suggest that treatment with ARBs in patients with type 2 diabetes with overt or incipient nephropathy confers health gains and net cost savings compared with conventional (non-ACE inhibitor) therapy. For reimbursement and reference pricing decisions, there is a need for a head-to-head comparison of an ACE inhibitor with ARBs to model all possible costs and effects of ACE inhibitors and ARBs. This will result in a proper pharmacoeconomic outcome, where both types of drugs can be compared for healthcare decisions.     

Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention

ObjectiveTo review the available literature on the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients.Data sourcesA Medline search was conducted using the search terms stroke and antihypertensives, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers from 1985 to August 17, 2009.Study selectionRandomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients.Data synthesisThe prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a renin–angiotensin–aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies.ConclusionA growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention.     

The biochemical pharmacology of renin inhibitors: Implications for translational medicine in hypertension, diabetic nephropathy and heart failure: Expectations and reality

The renin-angiotensin-aldosterone system (RAAS) plays a dominant role in the pathophysiology of hypertension, Diabetes mellitus (DM), chronic kidney disease (CKD) and chronic heart failure (CHF). Therefore, drugs that block key components of the RAAS such as ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) have gained wide clinical use for these indications. Despite progress, the morbidity and mortality of patients treated with ACEi or ARBs remain high. Small molecules that directly inhibit renin (DRI) and are orally active have also been developed and one such drug, aliskiren, was introduced into clinical use for treatment of hypertension in 2007. Further clinical trials aimed to expand the therapeutic use of aliskiren are in progress for CKD-DM and CHF. In this review we analyze and review the translational medicine prospects of aliskiren in respect to the biochemical pharmacology of the RAAS, the marketed RAAS modulators and the new emerging science regarding the role of prorenin, renin and renin receptors in cardiovascular biology and disease. The information already gained with aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEis and ARBs, their potential added value in combination with other RAAS modulators and other unproven benefits in relation to prorenin and renin receptor biology. This review will also indicate basic and clinical research needs that are critical to determine whether DRIs can provide meaningful added medical benefits over contemporary medicines that regulate the RAAS, and the need to identify patients that are more likely to benefit from DRIs and any possible long term adverse effects.     

The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure

The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.     

Improving treatment adherence to antihypertensive therapy: the role of single-pill combinations

INTRODUCTION: The majority of patients with hypertension require combination therapy to achieve their blood pressure (BP) goal. Studies have consistently shown that polypharmacy and complex treatment regimens have a detrimental effect on treatment compliance, adherence and persistence (herein referred to as treatment adherence). AREAS COVERED: This paper reviews the available clinical evidence, as well as guidelines, which propose combinations of an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor plus a calcium channel blocker (CCB) or diuretic. EXPERT OPINION: ARBs are associated with better tolerability compared with ACE inhibitors, and data suggest that ARB/CCB combinations may be better tolerated than CCB monotherapy. The use of true once-daily single-pill combination therapy with effective and well-tolerated agents will reduce pill burden, simplify treatment regimens and improve treatment adherence, which will, in turn, help patients to reach and maintain their BP target and achieve the short- and long-term treatment goal of cardiovascular risk reduction.