Recent changes in the landscape of combination RAS blockade

The renin–angiotensin system (RAS) is a prime target for cardiovascular drug therapy. Inhibition of the RAS lowers blood pressure and confers protection against cardiovascular and renal events. These latter benefits cannot be entirely attributed to blood pressure lowering. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) have been studied extensively and, while there is irrefutable evidence that these agents mitigate the risk for cardiovascular and renal events, their protection is incomplete. In outcomes studies that have employed ACE-inhibitors or ARBs there has been a relatively high residual event rate in the treatment arm and this has been ascribed, by some, to the fact that neither ACE-inhibitors nor ARBs completely repress RAS. For this reason, combined RAS blockade with an ACE-inhibitor and ARB has emerged as a therapeutic option. In hypertension, combined RAS blockade elicits only a marginal incremental drop in blood pressure and it does not further lower the risk for cardiovascular events. In chronic heart failure and proteinuric renal disease, combining these agents in carefully selected patients is associated with a reduction in clinical events. Irrespective of the setting, dual RAS blockade is associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The emergence of the direct renin inhibitor, aliskiren, has afforded clinicians a new strategy for RAS blockade. Renin system blockade with aliskiren plus another RAS agent is the subject of ongoing large-scale clinical trials and early studies suggest promise for this strategy. Currently, combined RAS blockade with an ACE-inhibitor and an ARB should not be routinely employed for hypertension; however, the combination of an ACE-inhibitor or ARB with aliskiren might be considered in some patients given the more formidable blood pressure-lowering profile of this regimen. In carefully selected patients with heart failure or kidney disease, combination therapy with two RAS inhibitors should be considered.     

Current possibilities of ACE inhibitor and ARB combination in arterial hypertension and its complications

The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in blood pressure regulation and hypertension-related complications. Angiotensin-converting enzyme inhibitors (ACEIs) were the first to be used to block the RAAS and now have many compelling indications in the treatment of hypertension and its cardiovascular and renal complications. Angiotensin II receptor blockers (ARBs), introduced 20 years later, have been shown to be equally as effective as antihypertensive treatment and are also associated with a lower number of side effects. Furthermore, in clinical trials ARBs and ACEIs were associated with comparable benefits for their most typical indications. This was confirmed in the 2007 New European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of hypertension by comparable specific recommendations for ARB and ACEI treatment. There is sufficient theoretical background and, in some cases, also clinical evidence that combination therapy with ACEIs and ARBs may be more beneficial than monotherapy with either of the groups alone, both in uncomplicated hypertension and with concomitant heart failure or renal dysfunction. However, the combination of ACEI and ARB was not recommended in the ESH/ESC 2007 Guidelines. This may change after the publication of the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) study, the preliminary results of which have just been presented. In heart failure, recent studies have shown that the combination of ACEI and ARB decreases cardiovascular mortality and the number of hospitalizations due to aggravation of heart failure. These results have been reflected in the newest ESC guidelines of the heart failure treatment. Nephroprotective properties of the combination of ACEs and ARBs have been proved both in studies on nondiabetic and diabetic nephropathy. The potential benefits, indications in prespecified groups of patients, the most recent data from clinical trials and latest research regarding dual blockade of RAAS will be reviewed in this article.     

Aliskiren,the future of renin–angiotensin system blockade?

The suppression of the renin–angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been proven in many studies to treat hypertension and reduce cardiovascular events; however, reducing angiotensin I receptor stimulation results in the loss of the negative-feedback signal, leading to increased plasma renin activity. Numerous direct renin inhibitors were synthesized, but abandoned owing to low potency, poor bioavailability and short half-life. Aliskiren, a direct renin inhibitor of a novel structural class, inhibits the activity of the renin produced and, thus, its capacity to form angiotensin I, as measured by plasma renin activity. Aliskiren has been recently shown to be efficacious in hypertensive patients at once-daily oral dosing with favorable pharmacokinetics and the potential to improve end-organ protection.     

Hypertension and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

Hypertension is a common problem in patients with autosomal dominant polycystic kidney disease affecting both renal and patient survival. Activation of the renin–angiotensin–aldosterone system due to cyst expansion and local renal ischemia has been proposed to play an important role in the development of hypertension in autosomal dominant polycystic kidney disease. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with autosomal dominant polycystic kidney disease. Both hypertension and the activation of the renin–angiotensin–aldosterone system play a role in the development of left ventricular hypertrophy in these patients. Prospective randomized results indicate that aggressive control of blood pressure is important for the optimal reversal of left ventricular hypertrophy, thereby diminishing a major risk factor for cardiovascular morbidity and mortality of patients with autosomal dominant polycystic kidney disease. There is also substantial epidemiological support for aggressive control of blood pressure in slowing renal disease progression in autosomal dominant polycystic kidney disease patients. Blockade of the renin–angiotensin–aldosterone system should be the initial approach in the treatment of hypertension in these patients.     

Antihypertensive strategy based on angiotensin II receptor blockers: a new gateway to reduce risk in hypertension

Effective treatment of high blood pressure levels represents a key strategy for reducing global cardiovascular risk. Other factors, beyond blood pressure control, however, appear to be of potential relevance in reducing the risk related to hypertension. Recent clinical trials have demonstrated that those pharmacological agents that counteract the renin–angiotensin system may confer additional clinical benefits across the spectrum of cardiovascular disease, beyond their blood pressure-lowering properties. These studies are largely based on the use of an antihypertensive strategy, based on the association between angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ARBs) and low-dose thiazide diuretics or calcium channel blockers. Over the last few decades, clinical trials have also tested the potential effects of combination therapy based on the association between angiotensin-converting enzyme inhibitors or ARBs and other renin–angiotensin system-blocking agents, including mineralocorticoid receptor antagonists and, more recently, renin inhibitors. This review highlights the evidence derived from recent clinical trials, supporting a role for pharmacological strategies based on ARBs in primary and secondary prevention of cardiovascular and renal disease.     

Recent advances in the treatment of hypertension

Uncontrolled blood pressure remains the single most common cause of death accounting for more than 7 million deaths per year worldwide. Despite the availability of potent lifestyle and pharmacologic approaches, rates of control of blood pressure are unsatisfactory and additional strategies to curb the burden of hypertension are warranted. Several novel pharmacological- and device-based approaches have recently been tested and may prove helpful to achieve better blood pressure control rates and thereby improve cardiovascular outcomes in patients with hypertension.     

Aliskiren,the first approved renin inhibitor: Clinical application and safety in the treatment of hypertension

Hypertension is one of the most important risk factors for, and causes of, cardiovascular disease. The difficulty in achieving a normal blood pressure range in some patients makes the rate of cardiovascular disease high. For some years renin-angiotensin system inhibitors such as angiotensin-converting enzyme (ACE) and angiotensin receptor blockade have been objects of interest for treatment of cardiovascular disease. Aliskiren, the first approved renin inhibitor to reach the market, is a low molecular weight, orally active, hydrophilic nonpeptide molecule, which blocks angiotensin I generation. However it might also become a reasonable therapeutic choice in a broad number of clinical conditions, as stable coronary artery disease, cerebrovascular and cardiorenal disease, diabetes, and peripheral arterial disease. The aim of this review is to describe the effectiveness and safety of aliskerin in the treatment of hypertension.     

Hyperuricemia as a risk factor for cardiovascular disease

Chronic activation of the renin–angiotensin–aldosterone system (RAAS) plays a key role in the development of hypertension, and cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity (PRA); by contrast, ARBs and ACE inhibitors increase PRA. Elevated PRA is independently associated with cardiovascular morbidity and mortality. A single-pill combination of the direct renin inhibitor, aliskiren, and the ARB, valsartan, at once-daily doses of 150/160 mg and 300/320 mg, has recently been approved by the US FDA for the treatment of hypertension in patients not adequately controlled on aliskiren or ARB monotherapy, and as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. This article examines the efficacy, safety and tolerability of aliskiren/valsartan combination therapy, and considers the evidence for the potential organ-protection benefits of this treatment.     

Angiotensin receptor blockers and secondary stroke prevention: the MOSES study

Hypertension control is critical to prevent stroke. With several clinical trials conducted over the last decade, it seems that the use of an angiotensin-modulating antihypertensive agent conveys benefits beyond blood pressure reduction. Currently, there is evidence supporting the use of either an angiotensin receptor blocker or an angiotensin-converting enzyme inhibitor in the primary-prevention context. However, in the secondary prevention of stroke, the choice of agent is less clear. There is evidence that intensive blood pressure reduction with a combination of an angiotensin-converting enzyme inhibitor and a diuretic can reduce stroke recurrence, but do angiotensin receptor blockers have the same ability? The Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) trial endeavors to answer this question and strives to demonstrate the benefit of angiotensin receptor blockers in the secondary prevention of stroke.     

Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.     

The role of renin–angiotensin– aldosterone system inhibition in chronic kidney disease

Chronic kidney disease (CKD) is emerging as a new health pandemic. Underlying the global rise in CKD is an increase in diabetes, hypertension and other cardiovascular risk factors leading to progressive renal dysfunction. Emerging evidence strongly suggests that achieving target blood pressure goals via inhibition of the renin–angiotensin–aldosterone system confers significant renal and cardioprotection for patients with CKD. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) lower blood pressure, reduce proteinuria and reduce both the progression of CKD and adverse cardiovascular events. The role of aldosterone inhibition and combination therapy, such as ACEI/ARB, in CKD are under investigation. As our understanding of the basic mechanisms underlying CKD progression advances, novel therapies targeting post-translational endothelial and mesangial messengers downstream from angiotensin II and aldosterone may become available for clinical use.     

Vaccines in the management of hypertension

Importance of the field: In the USA only 35% of patients with hypertension achieve adequate blood pressure control. Non-compliance is one of the main barriers to treatment. Vaccine against hypertension is an innovative treatment, injected every 4 – 6 months, to combat non-compliance.

Areas covered in this review: Pathogenesis of hypertension and progress towards developing a hypertension vaccine, including the virus-like-particle-based approach, new adjuvant molecules and the potential toxicity of hypertension vaccine.

What the reader will gain: The pathogenesis of hypertension is multifactorial. The most common cause is disruption of the Renin–angiotensin–aldosterone system (RAAS), and the first vaccine study was carried out against renin. While the vaccine reduced blood pressure in animal models, it also caused autoimmune disease. In the last decade, vaccines against angiotensin I, angiotensin II, and angiotensin II-type 1 receptors have demonstrated acceptable safety profiles in animal and human studies.

Take home message: Reduction in blood pressure can be achieved by inducing immunity against targets in the RAAS. The target antigen and selection of adjuvant are crucial factors determining effectiveness and safety of the vaccine. CYT006-AngQb (angiotensin II vaccine) reduced blood pressure in humans but the results were not reproducible with more frequent dosing. Vaccines for hypertension are still in the early phase. We hope for an effective vaccine for hypertension in the years to come.     

Angiotensin II,tissue factor and the thrombotic paradox of hypertension

Tissue factor (TF), the physiologic initiator of blood coagulation, may contribute to the increased risk of thrombotic complications that characterizes arterial hypertension, as suggested by hypertensive animal models showing evidence for TF activation, and clinical studies in hypertensive patients at higher cardiovascular risk with increased circulating levels of TF and thrombogenic microparticles. Angiotensin II stimulates TF expression both in vitro and in vivo, an effect abolished by ACE or angiotensin II receptor inhibition. Moreover, renin–angiotensin system blockers, including aliskiren, a direct renin inhibitor, are able to modulate TF expression in monocytes and vascular endothelial cells activated by inflammatory cytokines. This behavior is suggestive of anti-inflammatory and anti-thrombotic properties of renin–angiotensin system blockers, and is compatible with the possibility that blocking local renin–angiotensin system activation might downregulate TF, thus reducing the risk of ischemic complications in hypertensive patients.     

AT1 receptor blockade for the prevention of cardiovascular events after myocardial infarction

Myocardial infarction is associated with high morbidity and mortality. Multiple therapeutic modalities have been shown to be effective in reducing adverse postmyocardial infarction outcomes. The most prominent drugs that have been used in this group of patients are those that oppose the effects of the renin–angiotensin–aldosterone system. These drugs include β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone blockers. Following initial success with angiotensin-converting enzyme inhibitors in reducing mortality and cardiac remodeling in postmyocardial infarction patients, recent focus has been on adjunctive or alternative use of angiotensin II-receptor antagonists. Multiple large-scale, randomized trials have been conducted in order to compare angiotensin II-receptor antagonists with a combination of angiotensin II-receptor antagonists and angiotensin-converting enzyme inhibitors, and with angiotensin-converting enzyme inhibitors alone in postmyocardial infarction patients and also in heart failure. Although some results are conflicting, the weight of evidence is towards equivalency of these two groups of medicines, provided that the maximum effective dose of the angiotensin II-receptor antagonists is used. The combination of an angiotensin-converting enzyme inhibitor and an angiotensin II-receptor antagonist may have additional benefits for some, but not all, patients; for example, reducing morbidity and mortality in patients with chronic heart failure but not in postmyocardial infarction patients. Indeed, in the postmyocardial infarction setting, the combination appears simply to increase the side effects, without conferring additional benefits. Use of aldosterone antagonists as adjunctive therapy in postmyocardial infarction patients is associated with added benefits in terms of mortality reduction and will become the standard of care in this group of patients.     

Race-based therapy for hypertension: possible benefits and potential pitfalls

Hypertension is a leading risk factor for cardiovascular disease, which includes coronary heart disease, heart failure and stroke. This article examines the possible benefits and potential pitfalls of utilizing race-based categories for antihypertensive therapy. Although the use of race and ethnicity to guide antihypertensive treatment is fraught with difficulty and is, to a large extent, inadequate, there may be benefit in recognizing specific aspects of race and ethnicity when approaching patients with hypertension. Evidence from clinical trials, including drug efficacy and safety comparisons and cardiovascular outcomes, has demonstrated some differences based on race/ethnicity. American federal standards strongly encourage capturing data on race/ethnicity, and most of the current data are available for self-described African–Americans. International studies increasingly identify race/ethnicity, although the data are not as robust as in US trials. Current guidelines recommend thiazide diuretics and/or long-acting calcium channel blockers as initial treatment for Blacks, although medications for compelling indications agents should be prescribed, regardless of race/ethnicity.     

Managing complications of hypertension in aortic valve stenosis patients

ABSTRACT

Introduction: Hypertension is highly prevalent in aortic valve stenosis (AS) patients as the prevalence of both disorders increases with age. Hypertension and associated stiffening of the large arteries increase afterload and thereby influence both the transvalvular flow and the remodeling of the aortic root and the left ventricle during AS progression.

Area covered: The present review gives an overview on complications of hypertension in AS, how these can be diagnosed, and potentially may be managed.

Expert commentary: Hypertension-mediated cardiovascular (CV) damage in AS is associated with increased morbidity and a twofold higher mortality even in asymptomatic patients, and also limits the symptomatic and survival benefit from valve replacement. Data from registries and post hoc analyses from outcome studies in AS suggest that treatment with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers, respectively, is safe and associated with improved survival and reduced CV events in these patients. However, optimal blood pressure (BP) target in AS patients is not documented, and strict BP control in the early postoperative phase in AS patients treated with transcatheter aortic valve replacement (TAVR) may be associated with adverse events. Thus, randomized studies on BP management in asymptomatic AS and post-TAVR patients are highly needed.     

Whole body elemental composition in patients with essential hypertension

Abstract. The whole body content of sodium, chlorine and potassium has been measured in 30 patients with essential hypertension, using the techniques of in vivo neutron activation analysis and whole body counting. Total exchangeable sodium and potassium were also measured, and found to be well correlated with the total body amounts of these elements. Comparable measurements on normotensive subjects could not be obtained, but results for both elements were similar to those expected on the basis of published values for healthy normal body composition. Similarly, no abnormality was found in the average body content of the other major elements (chlorine, calcium, phosphorus and nitrogen). We therefore have no evidence that essential hypertension is associated with any abnormality in the mean body content of these elements. However, there was some evidence of a relationship between body sodium and blood pressure in this study group.     

The renin-angiotensin system during converting enzyme inhibition with captopril in patients with severe treatment-resistant hypertension

Abstract. The effect of captopril on blood pressure (BP) and various components of the renin-angiotensin system was assessed in ten severely hypertensive patients. Captopril acutely reduced the BP with a maximum decrease of 23% at 90–120 min.
Maintenance treatment with captopril alone could not control the BP in any of the patients. Addition of hydrochlorothiazide markedly reduced the BP, while supplementation with propranolol caused no consistent changes.
Three patients attained a supine diastolic blood pressure (SDBP) ≤90 mmHg. Only two patients had a fall in SDBP less than 10 mmHg. One patient stopped because of taste disturbances.
Monitoring the renin-angiotensin system showed suppressed plasma concentrations of angiotensin II and increased levels of angiotensin I and renin, indicating the inhibition of converting enzyme activity. Plasma concentration of renin substrate decreased significantly. This observation has important implications for the methodology of renin assays.
Captropril is an effective alternative in the treatment of hypertensive patients not readily controlled with conventional therapy.     

Manipulating the angiotensin system – new approaches to the treatment of solid tumours

Angiotensin II (Ang II), a main effector peptide in the renin–angiotensin system (RAS), plays a fundamental role as a vasoconstrictor in controlling cardiovascular function and renal homeostasis. Ang II also acts as a growth promoter or angiogenic factor via type 1 angiotensin II receptors (AT₁Rs) in certain tumour cell lines. Recent studies have shown the activation of the local RAS in various tumour tissues, including the abundant generation of Ang II by angiotensin-converting enzyme (ACE) and the upregulation of AT₁R expression. Thus, considerable attention has been paid to the role of the RAS in cancer and its blockade as a new approach to the treatment of cancer. There is increasing evidence that the Ang II–AT₁R system is involved in tumour growth, angiogenesis and metastasis in experimental models, suggesting the therapeutic potential of an ACE inhibitor and AT₁R blocker, both of which have been used as antihypertensive drugs. In addition, specific Ang II-degrading enzymes are expressed in tumours and play a regulatory role in cell proliferation and invasion. This review focuses on the role of the Ang II–AT₁R system in solid tumours, particularly in the progression of gynaecological cancer, and presents the clinical potential of manipulating the angiotensin system as a novel and promising strategy for cancer treatment.     

Aliskiren and valsartan in stage 2 hypertension: subgroup analysis of a randomized,double-blind study

Introduction  Patients with stage 2 hypertension require large absolute reductions in blood pressure (BP) to achieve recommended BP goals. Combination therapy with the direct renin inhibitor, aliskiren, and the angiotensin receptor blocker, valsartan, has been shown to produce greater BP reductions than either agent alone in a double-blind study in 1797 hypertensive patients. Methods  This post-hoc analysis evaluated the BP-lowering efficacy of aliskiren in combination with valsartan in a subset of patients (n=581) with stage 2 hypertension (baseline mean sitting systolic BP [msSBP] ≥160 mmHg). Patients were randomized to receive aliskiren/valsartan 150/160 mg, aliskiren 150 mg, valsartan 160 mg, or placebo once daily for 4 weeks followed by 4 weeks at double the initial dose. Mean changes from baseline in msSBP and mean sitting diastolic BP were assessed at week-8 endpoint (intent-to-treat population). Results  Aliskiren/valsartan 300/320 mg reduced BP from baseline by 22.5/11.4 mmHg at week-8 endpoint. BP reductions with combination therapy were significantly greater than with aliskiren 300 mg (17.3/8.9 mmHg, P<0.05), valsartan 320 mg (15.5/8.3 mmHg, P<0.01), or with placebo (7.9/3.7 mmHg, P<0.0001). BP control rates (<140/90 mmHg) were also significantly higher (P<0.05) with aliskiren/valsartan 300/320 mg (29.8%) compared with either aliskiren 300 mg (19.0%) or valsartan 320 mg (13.8%) monotherapy, or placebo (8.9%). All treatments were generally well tolerated. Conclusion  Combination therapy with aliskiren and valsartan provided significantly greater BP reductions over aliskiren or valsartan monotherapy and is an appropriate option for management of BP in patients with stage 2 hypertension.