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Arterial hypertension is the main preventable cause of premature mortality worldwide. Across Latin America, hypertension has an estimated prevalence of 25.5–52.5%, although many hypertensive patients remain untreated. Appropriate treatment, started early and continued for the remaining lifespan, significantly reduces the risk of complications and mortality. All international and most regional guidelines emphasize a central role for renin–angiotensin–aldosterone system inhibitors (RAASis) in antihypertensive treatment. The two main RAASi options are angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Although equivalent in terms of blood pressure reduction, ACEis are preferably recommended by some guidelines to manage other cardiovascular comorbidities, with ARBs considered as an alternative when ACEis are not tolerated. This review summarizes the differences between ACEis and ARBs and their place in the international guidelines. It provides a critical appraisal of the guidelines based on available evidence from randomized controlled trials (RCTs) and meta-analyses, especially considering that hypertensive patients in daily practice often have other comorbidities. The observed differences in cardiovascular and renal outcomes in RCTs may be attributed to the different mechanisms of action of ACEis and ARBs, including increased bradykinin levels, potentiated bradykinin response, and stimulated nitric oxide production with ACEis. It may therefore be appropriate to consider ACEis and ARBs as different antihypertensive drugs classes within the same RAASi group. Although guideline recommendations only differentiate between ACEis and ARBs in patients with cardiovascular comorbidities, clinical evidence suggests that ACEis provide benefits in many hypertensive patients, as well as those with other cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Cardiovascular disease accounts for more than 17 million deaths globally every year, of which complications of hypertension account for 9.4 million deaths worldwide. Early detection and management of hypertension can prevent costly interventions, including dialysis and cardiac surgery. Non-pharmacological approaches for managing hypertension commonly involve lifestyle modification, including exercise and dietary regulations such as reducing salt and fluid intake; however, a majority of patients will eventually require antihypertensive medications. In 2020, the International Society of Hypertension published worldwide guidelines in its efforts to reduce the global prevalence of raised blood pressure (BP) in adults aged 18 years or over. Currently, several classes of medications are used to control hypertension, either as mono- or combination therapy depending on the disease severity. These drug classes include those that target the renin-angiotensin-aldosterone system (RAAS) and adrenergic receptors, calcium channel blockers, diuretics and vasodilators. While some of these classes of medications have shown significant benefits in controlling BP and reducing cardiovascular mortality, the prevalence of hypertension remains high. Significant efforts have been made in developing new classes of drugs that lower BP; these medications exert their therapeutic benefits through different pathways and mechanism of actions. With several of these emerging classes in phase III clinical trials, it is hoped that the discovery of these novel therapeutic avenues will aid in reducing the global burden of hypertension. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a global health problem and is strongly associated with hypertension (HTN) and impaired quality of life. Managing HTN with agents that block the renin angiotensin aldosterone system (RAAS) remains the gold standard, however there is a misleading impression that patients with impaired renal function or those receiving hemodialysis should not be treated with RAAS inhibitors. To date, only a few data in this field are available, given that this population subset is systematically excluded from many major clinical trials. The purpose of this review was to solve the difficult equation regarding the optimal use of RAAS blockade in patients with CKD. [ABSTRACT FROM AUTHOR]

Contrast-associated acute kidney injury has multiple definitions, but is generally described as worsening renal function after administration of iodinated contrast media. It is associated with high in-hospital mortality and poor long-term survival. Furthermore, patients undergoing coronary angiography commonly have comorbidities such as hypertension or congestive heart failure, which are often treated with renin-angiotensin-aldosterone system-blocking agents such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Trials assessing the effects of these renin-angiotensin-aldosterone system-blocking agents on the subsequent development of contrast-associated acute kidney injury have shown conflicting data, suggesting both beneficial and harmful effects. Therefore, there are no clear guidelines on whether clinicians should discontinue renin-angiotensin-aldosterone system-blocking agents peri-procedurally. In this article, we review the data from trials assessing the effects of peri-procedural renin-angiotensin system-blocking agent use in patients undergoing coronary and peripheral angiography and intervention. Future studies will likely focus on the extent of damage or potential benefit of these agents on renal function, cardiac function, as well as morbidity and mortality. Currently, there is insufficient evidence to recommend discontinuation of angiotensin-converting enzyme inhibitors prior to coronary angiography. [ABSTRACT FROM AUTHOR]

For heart failure patients with cardiac implantable electronic devices (CIEDs), especially those who remain symptomatic after implantation, the best management strategy is still unclear. Although there are several concerns regarding the clinical utilization of sacubitril/valsartan, it has improved the prognosis of patients with heart failure compared with the use of renin-angiotensin system inhibitors in recent years. Recent real-world observational studies and post hoc analyses demonstrated that sacubitril/valsartan might have effects in patients with CIEDs. Given its potential underlying mechanisms, sacubitril/valsartan could improve outcomes of mortality and sudden cardiac death incidence, as well as clinical and echocardiographic evaluations. The possible antiarrhythmic effect of sacubitril/valsartan is still debated. Moreover, given that hypotension is the critical limitation of uptitration, the rise in systolic blood pressure attributed to cardiac resynchronization therapy might support the use of sacubitril/valsartan, with improved tolerance. The clinical utility of sacubitril/valsartan in heart failure patients with CIEDs requires further investigation to determine the actual effects, optimal target populations, and underlying mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: The use of renin-angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), was alleged to cause a more severe course of novel coronavirus disease 2019 (COVID-19). Methods: We systematically reviewed the published studies to assess the association of RAS inhibitors with mortality as well as disease severity in COVID-19 patients. A systematic literature search was performed to retrieve relevant original studies investigating mortality and severity (severe/critical disease) in COVID-19 patients with and without exposure to RAS inhibitors. Results: A total of 59 original studies were included for qualitative synthesis. Twenty-four studies that reported adjusted effect sizes (24 studies reported mortality outcomes and 16 studies reported disease severity outcomes), conducted in RAS inhibitor–exposed and unexposed groups, were pooled in random-effects models to estimate overall risk. Quality assessment of studies revealed that most of the studies included were of fair quality. The use of an ACEI/ARB in COVID-19 patients was significantly associated with lower odds (odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.56–0.95; n = 18,749) or hazard (hazard ratio [HR] = 0.75, 95% CI 0.60–0.95; n = 26,598) of mortality compared with non-use of ACEI/ARB. However, the use of an ACEI/ARB was non-significantly associated with lower odds (OR = 0.91, 95% CI 0.75–1.10; n = 7446) or hazard (HR = 0.73, 95% CI 0.33–1.66; n = 6325) of developing severe/critical disease compared with non-use of an ACEI/ARB. Discussion: Since there was no increased risk of harm, the use of RAS inhibitors for hypertension and other established clinical indications can be maintained in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Introduction: The long-term benefits of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on outcomes in patients with chronic congestive heart failure are well-known, making them one of the most widely prescribed medications. However, the administration of ACEIs/ARBs in acute decompensated heart failure (ADHF) can increase the risk of morbidity and mortality secondary to worsening renal function (WRF). A decrease in estimated glomerular filtration rate (eGFR) during the treatment of ADHF has been associated with an increase in mortality proportional to the degree of WRF. Aim: The aim of our study is to determine whether withholding ACEIs/ARBs during the initial 72 h of admission in patients with ADHF will prevent WRF and allow more effective diuresis. Methods: Four hundred and thirty patients will be randomized to the intervention (withholding ACEIs/ARBs) or control (continue/start ACEIs/ARBs) arms for 72 h. Primary outcomes include rates of acute kidney injury (AKI), patient global assessment, and change in kinetic eGFR over 72 h, while secondary outcomes include change in weight, fluid balance, change in signs and symptoms of congestion, change in renal function, change in urinary biomarkers (tissue inhibitor of metalloproteinases 2 [TIMP-2] × insulin-like growth factor-binding protein 7 [IGFBP7]), patients experiencing treatment failure, hospital length of stay (LOS), cost analysis, mortality within 30 days, and hospital readmissions over 30 days and 1 year. Conclusion: This prospective clinical trial will prove if withholding ACEIs/ARBs will prevent AKI in ADHF. It will help us understand the complex interactions between the heart and kidney, and delineate the best treatment strategy for ADHF. Holding ACEIs/ARBs might help preserve renal function, and decrease hospital LOS, readmission rates, and cost of care in ADHF. Registration: ClinicalTrials.gov identifier: NCT03695120. [ABSTRACT FROM AUTHOR]

There is ongoing debate on the safety of renin-angiotensin system (RAS) inhibitors in COVID-19. Recently published studies highlight a potential relationship between cardiovascular disease (CVD) and COVID-19. This article aims to summarize the evidence on the use of RAS inhibitors in CVD patients with COVID-19, focusing on safety issues of the RAS inhibitors and their relationship with COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Current guidelines recommend renin–angiotensin–aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events. Objectives: Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD. Methods: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors. Results: Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria. Conclusion: Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria. [ABSTRACT FROM AUTHOR]

The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that target the RAAS and SNS, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction (HFrEF) and suggests changes to current management paradigms. From this assessment, the evidence supports favoring sacubitril/valsartan over ACEIs or ARBs, and this therapy should be used in conjunction with beta-blockers to further decrease morbidity and mortality in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Primary care physicians play a significant role in managing heart failure (HF), with the goals of reducing mortality, avoiding hospitalization, and improving patients’ quality of life. Most HF-related hospitalizations and deaths occur in patients with New York Heart Association functional class II or III, many of whom are perceived to have stable disease, which often progresses without clinical symptoms due to underlying deleterious effects of neurohormonal imbalance and endothelial dysfunction. Management includes lifestyle changes and stepped pharmacological therapy directed at the four stages of HF, with aggressive uptitration of therapies, including beta-blockers and inhibitors of the renin-angiotensin-aldosterone system. Recently, two new HF treatments have become available in clinical practice. Ivabradine was approved to reduce the risk of hospitalization for HF in patients with stable, symptomatic HF. Additionally, the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, was found to be significantly superior to enalapril in reducing risks of cardiovascular death and HF-related hospitalization. The respective 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America clinical practice guideline updates recommend that patients taking angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy be switched to ARNI therapy to further reduce morbidity and mortality. For HF management to be maximally effective, physicians must be knowledgeable about the risks and benefits of treatments and stay engaged with patients to identify signs of disease progression. This article provides an overview of the progressive nature of HF in apparently stable patients and describes areas for treatment improvement that may help to optimize patient care. [ABSTRACT FROM AUTHOR]

The availability of effective drugs targeting the major risk factors of cardiovascular disease (CVD) has reduced morbidity and mortality. Cumulative relative risk of CVD events can be reduced by 75 % with a combination of aspirin, a β-adrenoceptor antagonist (β-blocker), an HMG-CoA reductase inhibitor (statin), and an angiotensin-converting enzyme inhibitor. The principal pharmacodynamics of these drugs cannot explain the entirety of their cardioprotective action, as other drugs with similar pharmacologic targets have not been associated with favorable clinical effects. This raises the possibility that the cardioprotective drugs have a unique pleiotropic activity that contributes to their clinical efficacy. Recent data suggest that reducing cellular stress such as oxidative, inflammatory, and endoplasmic reticulum stress, might be a common denominator of the drugs with proven efficacy in reducing CVD risk. In this communication, the evidence in favor of this hypothesis is discussed, and ongoing trials with therapeutic agents targeting cellular stresses are reviewed. [ABSTRACT FROM AUTHOR]

Historically, the first described effect of an angiotensin converting enzyme (ACE) inhibitor was an increased activity of bradykinin, one of the substrates of ACE. However, in the subsequent years, molecular models describing the mechanism of action of ACE inhibitors in decreasing blood pressure and cardiovascular risk have focused mostly on the renin-angiotensin system. Nonetheless, over the last 20 years, the importance of bradykinin in regulating vasodilation, natriuresis, oxidative stress, fibrinolysis, inflammation, and apoptosis has become clearer. The affinity of ACE appears to be higher for bradykinin than for angiotensin I, thereby suggesting that ACE inhibitors may be more effective inhibitors of bradykinin degradation than of angiotensin II production. Data describing the effect of ACE inhibition on bradykinin signaling support the hypothesis that the most cardioprotective benefits attributed to ACE inhibition may be due to increased bradykinin signaling rather than to decreased angiotensin II signaling, especially when high dosages of ACE inhibitors are considered. In particular, modulation of bradykinin in the endothelium appears to be a major target of ACE inhibition. These new mechanistic concepts may lead to further development of strategies enhancing the bradykinin signaling. [ABSTRACT FROM AUTHOR]

The aim of this review article is to summarize the current knowledge about mechanisms that connect blood pressure regulation and hypercholesterolemia, the mutual interaction between hypertension and hypercholesterolemia, and their influence on atherosclerosis development. Our research shows that at least one-third of the population of Western Europe has hypertension and hypercholesterolemia. Several biohumoral mechanisms could explain the relationship between hypertension and hypercholesterolemia and the association between these risk factors and accelerated atherosclerosis. The most investigated mechanisms are the renin-angiotensin-aldosterone system, oxidative stress, endothelial dysfunction, and increased production of endothelin-1. Arterial hypertension is frequently observed in combination with hypercholesterolemia, and this is related to accelerated atherosclerosis. Understanding the mechanisms behind this relationship could help explain the benefits of therapy that simultaneously reduce blood pressure and cholesterol levels. [ABSTRACT FROM AUTHOR]

Most patients hospitalized for acutely decompensated heart failure (ADHF) present with symptoms and signs of volume overload, which are also associated with high rates of death and re-hospitalization. Several studies have investigated the possible use of extracorporeal ultrafiltration in the management of ADHF, evaluating potential clinical benefits in terms of hospitalization and survival rates versus those of conventional diuretic therapy. Though ultrafiltration remains an extremely appealing therapeutic option for patients with AHDF, some of the most recent studies have reported conflicting results. Differences in the selection of study population, heterogeneity of the indications for the use of ultrafiltration, disparity in the ultrafiltration protocols, and high variability in the pharmacologic therapies used for the control group could explain some of these contradictory findings. The purpose of the present review is to provide an overview and an update on the mechanisms and clinical effects of ultrafiltration and on currently available evidence supporting its use in ADHF. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common cardiac arrhythmia, contributing to increased morbidity and reduced survival through its associations with stroke and heart failure. AF contributes to a four- to fivefold increase in the risk of stroke in the general population and is responsible for 10-15 % of all ischemic strokes. Diagnosis and treatment of AF require considerable health care resources. Current therapies to restore sinus rhythm in AF are suboptimal and are limited either by their pro-arrhythmic effects or by their procedure-related complications. These limitations have necessitated identification of newer therapeutic targets to expand the treatment options. There has been a considerable amount of research interest in investigating the mechanisms of initiation and propagation of AF. Despite extensive research focused on the pathogenesis of AF, a thorough understanding of various pathways mediating initiation and propagation of AF still remains limited. Research efforts focused on the identification of these pathways and molecular mediators have generated a great degree of interest for developing more targeted therapies. This review discusses the potential therapeutic targets and the results from experimental and clinical research investigating these targets. [ABSTRACT FROM AUTHOR]

Hispanics are the fastest growing ethnic minority in the USA. Among Hispanics, lack of hypertension awareness and lack of effective blood pressure (BP) control are problematic, as are higher incidence rates of hypertension-related co-morbidities compared with non-Hispanic populations. Moreover, there are currently no hypertension treatment guidelines that address the unique characteristics of this ethnic group. This article discusses ethnic differences in hypertension and cardiovascular risk factors and reviews the literature on the efficacy of antihypertensive agents in Hispanic patients, with a focus on the role of renin-angiotensin-aldosterone system (RAAS) inhibition in the management of hypertension in these patients. Hypertension in Hispanic patients can be challenging to manage, in part because this population has a higher prevalence of obesity, diabetes, and metabolic syndrome compared with non-Hispanic whites. The presence of these comorbidities suggests that RAAS-inhibitor-based therapies may be particularly beneficial in this population. However, few studies have evaluated the efficacy of antihypertensive treatments in Hispanic patients. Two outcomes studies in hypertensive patients have shown the benefits of treating Hispanic patients with antihypertensive therapy and included RAAS inhibitors as part of the treatment regimen. In addition, BP-lowering trials have shown the antihypertensive efficacy of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and direct renin inhibitors, although data on the latter are more limited. Additional studies are needed to more thoroughly evaluate the effects of RAAS inhibitors (and other drug classes) on outcomes and BP lowering in the Hispanic hypertensive population. [ABSTRACT FROM AUTHOR]

Monotherapy with most antihypertensive agents reduces systolic BP by about 10mmHg ('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. [ABSTRACT FROM AUTHOR]

Hypertension in African Americans is a major clinical and public health problem because of the high prevalence and premature onset of elevated blood pressure (BP) as well as the high burden of co-morbid factors that lead to pharmacological treatment resistance (obesity, diabetes mellitus, depressed glomerular filtration rate, and albuminuria). BP control rates are lower in African Americans, especially men, than in other major race/ethnicity-sex groups; overall control rates are 29.9% for non-Hispanic Black men. Optimal antihypertensive treatment requires a comprehensive approach that encompasses multifactorial lifestyle modifications (weight loss, salt and alcohol restriction, and increased physical activity) plus drug therapy. The most important initial step in the evaluation of patients with elevated BP is to appropriately risk stratify them to allow determination of whether they are truly hypertensive and also to determine their goal BP levels. The overwhelming majority of African American hypertensive patients will require combination antihypertensive drug therapy to maintain BP consistently below target levels. The emphasis is now appropriately on utilizing the most effective drug combinations for the control of BP and protection of target-organs in this high-risk population. When BP is >15/10mmHg above goal levels, combination drug therapy is recommended. The preferred combination is a calcium antagonist/angiotensin-converting enzyme inhibitor or, alternatively, in edematous and/or volume overload states, a thiazide diuretic/angiotensin-converting inhibitor. [ABSTRACT FROM AUTHOR]

Background: Evidence is currently equivocal on the added benefits of dual blockade of the renin-angiotensin- aldosterone system with the combination of either an ACE inhibitor (ACEI) plus an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) or aliskiren, the first-in-class direct renin inhibitor, plus an ARB. Objective: To compare the compliance, persistence, healthcare resource utilization, and healthcare costs associated with aliskiren plus ARB versus ACEI plus ARB combination therapies among adult patients diagnosed with hypertension. Methods: Patients (aged ≥18 years) initiated on either combination therapy were identified in the Market- Scan Commercial and Medicare Supplemental Databases (1 July 2007 to 30 June 2008). The ARB components considered were candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. The ACEI components included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Outcomes measured during the 6-month study period included the proportion of days covered (PDC), treatment discontinuation, healthcare resource utilization, and changes in healthcare costs (study period minus 6-month baseline values). Risk-adjusted differences in outcomes between treatments and associated 95% confidence intervals (CIs) were estimated using multivariate regression models, controlling for demographics, region, co-morbidities, prescription drug use, and resource utilization during the baseline period. Results: Adjusting for baseline characteristics, aliskiren plus ARB patients (n = 1395) demonstrated a significantly higher PDC (67.0% vs 54.3%; difference 12.7%; 95% CI 10.6, 14.7) and a significantly lower discontinuation rate (50.4% vs 68.6%; odds ratio 0.46; 95% CI 0.40, 0.54) than ACEI plus ARB patients (n = 16 507). Aliskiren plus ARB patients had significantly fewer all-cause hospitalizations (adjusted incidence rate ratio [IRR] 0.73; 95%CI 0.61, 0.86) and significantly fewer all-cause emergency room (ER) visits (adjusted IRR 0.72; 95% CI 0.61, 0.85) than ACEI plus ARB patients. Compared with ACEI plus ARB therapy, aliskiren plus ARB therapy was associated with significantly larger increases in prescription costs by $US264 post therapy initiation (95% CI 153, 375), but with non-significantly greater reductions in total healthcare costs by -$583 (95% CI -2409, 1242) [2008 values]. Conclusion: In adult hypertensive patients, treatment with aliskiren plus ARB was associated with significantly better compliance/persistence and fewer hospitalizations and ER visits compared with ACEI plus ARB therapy. Reductions in total healthcare costs were non-significantly different between patients treated with aliskiren plus ARBversusACEI plusARB, despite the increased prescription costs associated with aliskiren plusARBtherapy. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers) have been shown to be effective drugs in the management of hypertension and to have beneficial effects along the cardiovascular continuum. However, due to compensatory mechanisms, both of these types of agent increase plasma renin activity, which has been reported to have deleterious effects on patient outcomes. Aliskiren is the first nonpeptide orally administered direct renin inhibitor available on the market. Reported data have shown that aliskiren effectively reduces BP alone or in combination with other antihypertensive agents, and has a good tolerability profile. Moreover, this agent reduces plasma renin activity, which in theory could have additional clinical benefits. However, clinical trials analyzing the effects of aliskiren on mortality are still ongoing. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most frequent arrhythmia found in clinical practice. The majority of patients With AF are still candidates for antiarrhythmic drug treatment, not only for acute reversion to sinus rhythm but also for long-term treatment to prevent recurrences of AF. Currently available antiarrhythmic drugs, however, are unable to provide complete efficacy in all patients, and present problematic risks of proarrhythmia. The progressively increasing prevalence of AF supports the need to develop improved therapeutic approaches for the clinical management of arrhythmia. Accordingly, new treatment techniques aimed at suppressing the origin of the arrhythmogenic foci have been developed in the last decade. However, ablative treatments are only available for selected patients. Because of these factors, and also because primary prevention of AF should be our goal, the introduction of non-antiarrhythmic agents that could prevent both new-onset AF and recurrences of AF may eventually improve patient outcomes and reduce the incidence of this epidemic disease. The potential clinical value of these non-antiarrhythmic options is currently under active investigation. There is now clinical and experimental evidence that many drugs may have beneficial effects in preventing AF through several possible mechanisms. Non-antiarrhythmic drugs, such as ACE inhibitors and angiotensin receptor blockers, HMG-CoA reductase inhibitors (statins), corticosteroids, and N-3 polyunsaturated fatty acids may have a positive effect in patients with AF or in preventing AF in patients at risk. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and Diamicro N MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy. [ABSTRACT FROM AUTHOR]

Systemic hypertension is a long-term risk factor for the development of atherosclerotic vascular disease and when uncontrolled is a short-term trigger of acute vascular events such as acute coronary syndromes and stroke. Thus, rapid reduction in BP is desirable. Patients at high risk for vascular disease, such as those with diabetes mellitus, have aggressive goal BP targets because studies have shown that achieving these targets reduces events. Given the dual goals in high-risk patients of reducing BP quickly and to aggressively low targets, the classic 'step therapy' of one drug titrated at a time to reduce BP is inadequate. Combination therapy with at least two potent medications makes more sense, and manufacturers are now increasing their offerings of single-pill combinations for hypertension. Combination pills are popular with patients and increase compliance with therapy. Many believe that renin-angiotensin aldosterone system (RAAS) blockers are the cornerstone of hypertension treatment in patients at high risk for vascular disease. The newer combination pills include a RAAS blocker and diuretics or a long-acting calcium channel antagonist (CCA). Recent studies have shown that a RAAS blocker plus a dihydropyridine CCA is superior to older diuretic-based combinations for preventing cardiovascular events. These considerations support a new approach to the higher risk hypertensive patient: effective doses of RAAS blocker/CCA combination pills to rapidly lower BP to <130/80 mmHg. [ABSTRACT FROM AUTHOR]

Most hypertensive patients will require more than one antihypertensive drug to lower BP below target levels. The combination of diuretics with renin-angiotensin system (RAS) antagonists offers several advantages to include additive BP-lowering efficacy and enhanced reductions in urinary protein excretion. Thiazide diuretics are associated with metabolic complications that are particularly evident when used in high doses. When used in combination with RAS blockade, metabolic complications such as hypokalemia are minimized. The avoidance of hypokalemia has been linked to less thiazide-induced glucose intolerance. Patient persistence on therapy is dependent on well tolerated drug combinations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Congestive heart failure (CHF) is a major public health problem that results in tremendous economic burden. Diastolic heart failure (DHF) forms an important subset with increasing incidence and prevalence. There are widely variable estimates of the prevalence, ranging from 13% to 74% of all CHF presentations, and this is predominantly a result of a lack of uniform criteria for establishing a diagnosis. New developments in management of DHF have lagged behind those for systolic heart failure (SHF), for which numerous new therapeutic and device strategies have been instituted. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of both SHF as well as DHF. The beneficial role of ACE inhibitors as well as aldosterone antagonists in SHF has been well established. Because of its unique role of the RAAS in establishing fibrosis at a molecular level, RAAS blockade provides an opportunity to expand the therapeutic options for DHF. Thus far, in patients with primary DHF only the angiotensin receptor type 1 antagonist candesartan has been reported to decrease morbidity and probably mortality. Large, ongoing randomized trials including TOPCAT (Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart) and the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) are currently underway to establish the role of aldosterone antagonists in patients with DHF. [ABSTRACT FROM AUTHOR]

BACKGROUND: The VIOS (Vascular Improvement with Olmesartan medoxomil Study) study is a randomized, parallel study to determine the relative effects of suppressing the renin-angiotensin system (RAS) with the angiotensin receptor antagonist olmesartan medoxomil versus suppressing sympathetic drive with the β-adrenoceptor antagonist atenolol on remodeling of the subcutaneous small resistance vessel. Remodeling of small resistance vessels may be the earliest pathologic finding associated with hypertension. It may predate the onset of clinically apparent hypertension. METHODS: In this study, 100 patients with stage I hypertension are characterized at baseline before being treated for 1 year to obtain a goal BP of less than 140/90mm Hg as defined by Joint National Committee (JNC)-7. Resistance vessel remodeling is determined using the gluteal fat biopsy technique in the hypertensive patients and a group of normotensive healthy volunteers. Additionally, efforts will be made to define whether noninvasive hemodynamic parameters, retinal vessel measurement changes, or biologic markers may predict and track the underlying vascular morphologic and physiologic changes induced by either regimen during the 12-month treatment period. RESULTS: The primary endpoint will be the degree of vascular remodeling as obtained from percutaneous biopsy of gluteal subcutaneous resistance vessels in each of two treatment arms compared with the normal volunteers. The design of the study and the pertinent baseline characteristics of these patients with uncomplicated essential hypertension are presented. CONCLUSION: The suppression of the RAS by the blockade of angiotensin II type 1 (AT1) receptors may demonstrate remodeling effects on the ubiquitous small resistance vessels similar to that seen in the myocardium and renal glomeruli, thus affording more complete end-organ protection. [ABSTRACT FROM AUTHOR]

Blockade of the renin-angiotensin system improves morbidity and mortality of patients with cardiovascular diseases, e.g. arterial hypertension, renal failure, following myocardial infarction and in congestive heart failure. The angiotensin II type 1 (AT1) receptor antagonists (angiotensin receptor blockers; ARBs), i.e. losartan, eprosartan, irbesartan and valsartan were developed by computer-based molecule design. Early observations already indicate that the ARBs elicit pleiotropic effects developing anti-aggregatory, anti-inflammatory and anti-mitogenic effects independent from their actions at the AT1 receptor. Losartan metabolism indicates a number of known active intermediates and pointed to further interactions of these derivatives with other receptors and cellular signaling systems. Here we discuss a compilation of detailed pharmacokinetic and pharmacodynamic data of active metabolites of ARBs indicating their mode of action and suggest novel therapeutic implications. The clinical observations that ARBs elicit potencies in patients with cardiovascular diseases via the regulation of inflammatory, growth and homeostatic factors lead us to focus on specific, reactive metabolites, which hold potential for future indications and possible drug interactions in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is well recognized for its importance in regulation of BP, electrolyte balance and vascular growth. Pharmacological suppression of the RAS, through ACE inhibition and/or angiotensin receptor blockade, is a proven effective therapeutic approach to the treatment of a range of cardiovascular diseases. Renin is the enzyme that catalyzes the first and rate-limiting step of RAS, the cleavage of angiotensinogen to angiotensin I (A-I). A-I is then further converted by ACE to the biologically active vasoconstrictor, A-II. Interruption of the generation of A-II by renin inhibitors at this highly specific initial step of the cascade would be expected to have similar but not identical effects to those of the already well established RAS antagonists. Due to the lack of effective alternative enzyme pathways, blockade of A-II production may be more effective with renin inhibition than with ACE inhibition, and because of the high specificity of renin for only one substrate, namely angiotensinogen, adverse effects would be expected to be less frequent. It is currently unclear whether blockade of angiotensin II type 1 receptors (AT1), leaving other A-II receptors unblocked, is preferable to the reduction in plasma and tissue A-II levels achieved with either ACE or renin inhibition. The development of early peptidic and peptidomimetic renin inhibitors was hampered by problems with oral bioavailability and high costs of synthesis. However recent work has led to the synthesis of a potent non-peptidic inhibitor of renin, aliskiren, which has acceptable oral bioavailability. This renin inhibitor has been shown to effectively reduce A-II levels in normal volunteers and to lower BP in patients with mild to moderate hypertension. It appears likely that aliskiren is the first of a new class of agents that may prove useful in the management of patients with nephropathy, heart failure and atherosclerosis in addition to hypertension. [ABSTRACT FROM AUTHOR]

The article presents the discussion on role of heart rate (HR) in various cardiovascular disorders. Topics include development of several therapeutic agents primarily based on the neurohormonal blockade with reninangiotensin-aldosterone system (RAAS) blocking agents; and debate in the academic community regarding the precise role of ivabradine in patients with HF in the clinic.