Angiotensin II receptor blockers for the treatment of hypertension

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.     

ACE inhibitors,angiotensin receptor blockers and direct renin inhibitors in combination: a review of their role after the ONTARGET trial

ABSTRACT

Background: Clinical trials have shown organ-protective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); however, cardiovascular mortality and morbidity rates, and decline in renal function remain high. In the ONTARGET trial in patients with hypertension at high cardiovascular risk, ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy, and was associated with a worse safety and tolerability profile. These results raise the question of whether ACE inhibitor/ARB, direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value.

Scope: Using PubMed and EMBASE databases, we conducted a systematic review of clinical trials published before June 2008 evaluating dual intervention with ACE inhibitors and ARBs, and compared these with trials of DRI/ACE inhibitor or DRI/ARB combinations.

Findings: A total of 70 studies met the inclusion criteria for this analysis. In patients with hypertension, ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure (BP) over monotherapy. Outcomes benefits were unclear: VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure, but at the expense of poorer tolerability. Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension, and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy, with generally similar safety and tolerability to the component monotherapies. No morbidity and mortality data for DRI/ACE inhibitor or DRI/ARB combinations are currently available.

Conclusions: ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes. DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage, but longer-term trials are required to establish whether more complete renin--angiotensin--aldosterone system control with aliskiren-based therapy translates into improved outcome benefits.     

Angiotensin receptor blockers and risk of dementia: cohort study in UK Clinical Practice Research Datalink

Aims

This was a cohort study to evaluate whether individuals exposed to angiotensin receptor blockers have a reduced risk of dementia compared with those exposed to angiotensin-converting enzyme inhibitors.

Methods

The study included new users of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (from 1995 to 2010) from UK primary care practices contributing to the Clinical Research Practice Datalink. The association between exposure to angiotensin receptor blockers and the risk of incident dementia was analysed using a Cox model, adjusting for age, sex, body mass index, diabetes, hypertension, heart failure, statin use, socioeconomic status, alcohol, smoking, number of consultations and calendar year.

Results

A total of 426 089 persons were included in the primary analysis, with 45 541 persons exposed to angiotensin receptor blockers and the remainder to angiotensin-converting enzyme inhibitors. The total number of new diagnoses of dementia was 6517. There was weak evidence of a decreased risk of dementia with exposure to angiotensin receptor blockers, with follow-up beginning at 1 year after the start of treatment (adjusted hazard ratio 0.92, 95% confidence interval 0.85–1.00). An analysis restricted to the first 12 months after the index date showed a larger effect on dementia risk (adjusted hazard ratio 0.60, 95% confidence interval 0.50–0.72).

Conclusions

A small reduction in dementia risk was seen with angiotensin receptor blockers in comparison to angiotensin-converting enzyme inhibitors. However, the strongest association was seen in early follow-up, suggesting that the inverse association is unlikely to be causal, but instead reflects other important but unmeasured differences between angiotensin receptor blocker and angiotensin-converting enzyme inhibitor users.     

Angiotensin II receptor blockers in the prevention of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. While antiarrhythmic agents and electrical cardioversion are highly effective in restoring sinus rhythm, the results obtained in prevention of recurrences are disappointing. Recently, angiotensin II has been recognized as a key factor in atrial structural and electrical remodeling associated with AF. So there are several potential mechanisms by which inhibition of the renin-angiotensin-aldosterone system may reduce AF. In this review, we report the results of studies evaluating the effect of angiotensin II receptor blockers (ARBs) in various clinical settings (i.e., lone AF, hypertension, high-risk patients, congestive heart failure, secondary prevention). However, many of these studies are small and retrospective and have a limited follow-up; moreover, since AF is related to several causes, chiefly heart diseases, patients with different characteristics have often been enrolled. Thus, it is not surprising that the results obtained are frequently conflicting. With these limitations and considering only the results of larger studies with longer follow-up, ARBs are effective in preventing AF in patients with congestive heart failure or hypertension with left ventricular hypertrophy or coronary artery/cerebrovascular disease. In any case, the use of ARBs is not recommended at present in clinical practice to prevent AF.     

Angiotensin receptor blockers in acute myocardial infarction

It has been established from multiple randomised, placebo-controlled trials that angiotensin-converting enzyme inhibitors reduce the risk of death and major non-fatal cardiovascular events after acute myocardial infarction, especially when these agents are used for long-term treatment in high-risk patients. Angiotensin receptor blockers represent a theoretically appealing class of drugs for use in combination with or as alternatives to angiotensin-converting enzyme inhibitors in such patients. The Valsartan in Acute Myocardial Infarction (VALIANT) trial compared the effects of valsartan, captopril and the combination of both in a population of high-risk patients with evidence of left ventricular dysfunction after acute myocardial infarction. This article discusses this important study and its implications for the clinical management of these high-risk patients.     

血管紧张素Ⅱ受体拮抗剂和他汀类联合应用的前景

血管紧张素Ⅱ受体拮抗剂(ARBs)和他汀类为临床广泛使用的两类心血管药物。两者能否联合使用或制成复合制剂,将成为心血管药物研究领域一大新的课题。目前,有研究结果表明,两者联合应用存在广泛前景。     

An update of the blockade of the renin angiotensin aldosterone system in clinical practice

Introduction: Cardiovascular disease (CVD) is the leading cause of death worldwide. Blockade of this system is commonly used in the treatment of cardiovascular (CV) and renal disease.

Areas covered: Data from multiple clinical trials have provided good evidence about the benefit of blocking the system as a therapeutic target to reduce CV and renal events. We have reviewed all the tested combinations of different drugs counteracting the effects of the renin–angiotensin–aldosterone system.

Expert opinion: Monotherapy with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) remains valid in all the guidelines, whereas their dual combination has been discarded due to the absence of proven benefits in high CV risk patients and in patients with chronic kidney disease (CKD). The combination of the standard therapy with an ACEi or an ARB with a mineralocorticoid receptor blocker is a valid option, but has the inconvenience of frequent hyperkalemia in patients with CKD. Similarly, the addition of the direct renin inhibitor, aliskiren, to this standard therapy is not particularly supported in diabetic patients. New dual-acting blockers, for example, those combining valsartan and neprilysin inhibitors (LCZ696-Novartis) or endothelin converting enzyme inhibitors and neprilysin inhibitors (ECEI, Daglutril-Solvay), are currently under investigation.     

Renal protective effect of RAAS blockade across the renal continuum,with a review of the efficacy and safety of valsartan

Abstract

Objective:

The purpose of this report is to review key data on the angiotensin receptor blocker (ARB) valsartan, along with data from several pivotal studies with other ARBs and angiotensin-converting enzyme (ACE) inhibitors, to highlight the beneficial class effects of renin–angiotensin–aldosterone system (RAAS) blockade throughout the renal continuum.     

The renal protective effect of angiotensin receptor blockers depends on intra-individual response variation in multiple risk markers

Aims

Angiotensin receptor blockers (ARBs) are renoprotective and targeted to blood pressure. However, ARBs have multiple other (off-target) effects which may affect renal outcome. It is unknown whether on-target and off-target effects are congruent within individuals. If not, this variation in short term effects may have important implications for the prediction of individual long term renal outcomes. Our aim was to assess intra-individual variability in multiple parameters in response to ARBs in type 2 diabetes.

Methods

Changes in systolic blood pressure (SBP), albuminuria, potassium, haemoglobin, cholesterol and uric acid after 6 months of losartan treatment were assessed in the RENAAL database. Improvement in predictive performance of renal outcomes (ESRD or doubling serum creatinine) for each individual using ARB-induced changes in all risk markers was assessed by the relative integrative discrimination index (RIDI).

Results

SBP response showed high variability (mean –5.7 mmHg, 5^th to 95^th percentile –36.5 to +24.0 mmHg) between individuals. Changes in off-target parameters also showed high variability between individuals. No congruency was observed between responses to losartan in multiple parameters within individuals. Using individual responses in all risk markers significantly improved renal risk prediction (RIDI 30.4%, P < 0.01) compared with using only SBP changes. Results were successfully replicated in two independent trials with irbesartan, IDNT and IRMA-2.

Conclusions

In this post hoc analysis we showed that ARBs have multiple off-target effects which vary between and within individuals. Combining all ARB-induced responses beyond SBP provides a more accurate prediction of who will benefit from ARB therapy. Prospective trials are required to validate these findings.     

我院血管紧张素Ⅱ受体拮抗剂的用药分析

目的:分析血管紧张素Ⅱ受体拮抗剂(ARB)的临床用药情况。方法:分别统计ARB药品用药频度(DDDs)、销售金额和平均日费用;比较2004-2006年ARB与血管紧张素转化酶抑制药(ACEI)的使用情况。结果:2001-2003年ARB平均日费用为7.66元,2004-2006年为6.81元,下降9.79%。ARB类药物每年销售总金额和DDDs均在增长,但增长速度逐年减弱,2004-2006年期间缬沙坦、厄贝沙坦2药的DDDs占总ARB类药物的DDDs的百分比分别为81.20%,82.05%,80.08%。平均日费用ARB类药物是ACEI的1.85倍。结论:ARB作为新型降压药,发展潜力巨大,但其日均费用较高,影响了临床使用。     

肾素-血管紧张素系统抑制药和慢性肾脏疾病

肾素-血管紧张素系统激活在慢性肾脏疾病的发生、发展中发挥重要作用。大量研究表明血管紧张素转换酶抑制药和血管紧张素Ⅱ受体1拮抗药在降低血压的同时可减少蛋白尿、降低血清肌酐、延缓慢性肾脏疾病的进展。合用血管紧张素转换酶抑制药和血管紧张素Ⅱ受体1拮抗药可更有效地降低蛋白尿。     

Clinical trials evaluating angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the setting of acute myocardial infarction

There is strong evidence from controlled clinical trials that in the setting of acute myocardial infarction complicated by heart failure or isolated left ventricular dysfunction, angiotensin-converting enzyme inhibitors started late during hospitalisation and continued in the long term, significantly reduced mortality and improved the prognosis. On the other hand, administration of angiotensin-converting enzyme inhibitors during the first 24 h in unselected patients with acute myocardial infarction provided only a slight benefit in terms of mortality. Angiotensin-II receptor blockers have and are being examined in the setting of acute myocardial infarction with left ventricular dysfunction and can provide an alternative for patients who cannot tolerate angiotensin-converting enzyme inhibitors. In this article, an evidence-based review of these major trials and suggestions for clinical application are presented.     

Effects of angiotensin receptor blockers on endothelial nitric oxide release: the role of eNOS variants

AIM

Angiotensin II receptor blockers (ARBs) improve endothelial cell (EC)-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide (NO) synthase (eNOS) function. To investigate this question, we tested the effects of various ARBs on NO release in ECs from multiple donors, including those with eNOS genetic variants linked to higher cardiovascular risk.

METHODS

The effects of ARBs (losartan, olmesartan, telmisartan, valsartan), at 1 µm, on NO release were measured with nanosensors in human umbilical vein ECs obtained from 18 donors. NO release was stimulated with calcium ionophore (1 µm) and its maximal concentration was correlated with eNOS variants. The eNOS variants were determined by a single nucleotide polymorphism in the promoter region (T-786C) and in the exon 7 (G894T), linked to changes in NO metabolism.

RESULTS

All of the ARBs caused an increase in NO release as compared with untreated samples (P < 0.01, n = 4–5 in all eNOS variants). However, maximal NO production was differentially influenced by eNOS genotype. Olmesartan increased maximal NO release by 30%, which was significantly greater (P < 0.01, n = 4–5 in all eNOS variants) than increases observed with other ARBs.

CONCLUSIONS

The ARBs differentially enhanced NO release in ECs in a manner influenced by eNOS single nucleotide polymorphisms. These findings provide new insights into the effects of ARBs on EC-dependent vasodilation and eNOS function.     

Telmisartan for the management of patients at high cardiovascular risk

Abstract

Background:

Cardiovascular disease (CVD) places a significant burden on healthcare providers. High blood pressure (BP) is the single most prevalent risk factor for CVD worldwide and is responsible for more deaths than any other risk factor. ‘Cardiovascular (CV) high-risk patients’ make up the broad cross-section of patients in the middle of the risk spectrum for CVD progression that is referred to as the CV continuum and includes those with atherothrombotic disease, those with target organ damage associated with type 2 diabetes and those with multiple risk factors. Angiotensin II is involved in CVD progression at every stage of the CV continuum, making the renin–angiotensin system a rational target for pharmacologic intervention. Angiotensin II receptor blockers (ARBs) offer a better tolerated alternative to angiotensin converting enzyme inhibitors, with greater long-term adherence. The ARB telmisartan recently received an indication for CV prevention.     

The short‐term effects of angiotensin II receptor blockers on albuminuria and renal function in Korean patients

Each angiotensin II receptor blocker (ARB) asserts independent molecular effects. No study has compared the renoprotective potency of different types of ARBs in Korea. This study evaluated the differences among medications for treating albuminuria. Data were obtained from electronic medical records of adult patients who underwent albuminuria test and received treatment with either angiotensin‐converting enzyme inhibitors (ACEIs) or ARBs between January 2009 and June 2016. Patients' albuminuria and renal function data were observed for three months after treatment initiation. In total, 1475 patients were included. Patients treated with ACEIs had no significant changes in albuminuria (from 127.7 ± 55.1 mg/g to 46.7 ± 18.7 mg/g, P = .127), but those treated with ARBs showed significant improvement (from 491.2 ± 33.2 mg/g to 372.0 ± 28.0 mg/g, P < .001). The ARB group had significantly more patients with normal albuminuria after treatment (from 55.8% to 59.3% for normal albuminuria, from 16.7% to 18.5% for moderately increased albuminuria and from 27.5% to 22.2% for severely increased albuminuria, P = .005), but renal function did not change significantly. Subgroup analysis of ARB types showed that candesartan (from 712.5 ± 71.1 to 489.8 ± 57.8 mg/g, P < .001) and irbesartan (from 522.6 ± 65.7 to 352.6 ± 54.3 mg/g, P < .001) had significant effects. Candesartan improved albuminuria in patients older than 60 years (from 506.9 ± 84.2 to 371.9 ± 70.6 mg/g, P = .004) and irbesartan improved albuminuria in patients with glomerular filtration rate <60 (from 551.6 ± 100.0 to 392.4 ± 76.2, P = .007). Only irbesartan and candesartan could reduce albuminuria, suggesting that all ARBs do not have the same outcome. This indicates the importance of optimizing ARB selection, considering both patient condition and organ‐specific characteristics of medications.