Correspondence Graziano Riccioni, M.D., Ph.D., Via G. De Rogatis, 12, 71016 San Severo (FG), Italia. Tel.: +39 882 227022; Fax: +39 882 227022; E-mail: email@example.com
Hypertension is one of the most important risk factor and cause of cardiovascular diseases (CVD). Chronic activation of the renin–angiotensin–aldosterone system (RAAS) plays a key role in the development of hypertension, cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEI) 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 such aliskiren offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity; by contrast, ACEI and ARBs increase plasma renin activity. The efficacy of aliskiren in the reduction of major clinical events is being tested in large ongoing clinical trials. This review examines the efficacy, safety, and tolerability of aliskiren, and considers the evidence for the potential organ protection benefits of this treatment.
Hypertension is a major cardiovascular risk factor associated with significant morbidity and mortality worldwide and will increase in importance as a public health problem by 2020 . The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) establishes that the goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality . Although the past two decades have seen significant improvement in antihypertensive drugs to treat this patient population, adequate control of high blood pressure (BP) has yet to be achieved .
Control of BP involves complex interactions among the kidney, the central nervous system (CNS), peripheral nervous system (PNS), the vascular endothelium throughout the body, as well as a variety of the other organs, such as the adrenal and pituitary glands. The sympathetic nervous system (SNS), the renin–angiotensin–aldosterone system (RAAS), vasopressin (VP), nitric oxide (NO), and a host of a vasoactive peptides, including endothelin, adrenumedullin, others produced by the heart, and many different cells (endothelial and vascular smooth cells) modulate the responses of these systems and help maintain BP over a range commensurate with optimum physical and mental activity. Additionally, these systems affect the ability of the kidney to handle sodium (Na+) and fluid volume, which some feel is the primary controller of BP .
Hypertension and RAAS
The mechanism of primary (essential) hypertension includes genetic predisposition, endothelial cell dysfunction, SNS hyperactivity, abnormalities in RAAS function, hyperinsulinemia, and insulin resistance. In particular, RAAS is likely involved in the pathogenesis of hypertension and has been shown to play a significant role in BP regulation. Renin is a low molecular weight enzymatic protein that is synthesized from juxtaglomerular cells (JGC) in the form of the preprohormone prorenin when BP is low.
The (pro)renin receptor ([P]RR) is a new component of the RAAS that has attracted much attention as a potential new therapeutic target. This receptor binds renin and the inactive proenzyme form of renin, prorenin, and the binding triggers the activation of the mitogen-activated protein kinase p42/p44 followed by upregulation of the expression of profibrotic genes. In addition, prorenin bound to (P)RR undergoes a conformational change and becomes catalytically active . Numerous in vitro and in vivo animal studies using the (pro)renin receptor (P)RR blocker handle region peptide have suggested an important role of (P)RR in the pathogenesis of end-stage organ damage in patients with diabetes and hypertension. In addition, a limited number of clinical studies have suggested an association between (P)RR gene polymorphisms and BP levels and between (P)RR mRNA levels and angiotensin-converting enzyme mRNA levels in human arteries .
Renin is synthesized as preprorenin, which is converted to prorenin on insertion to endoplasmic reticulum. The majority (75%) of prorenin is secreted constitutively, whereas the reminder is targeted to dense core secretory granules. In the secretory granules, an acidic pH is created by vacuolar H+-adenosine triphosphatases (ATPases) to optimize the activity of the proteases (cathepsin B, prohormone convertases) that cleave off the 43-amino acid prosegment to yield renin. Mature renin is stored in granules in the JGC and is released by an exocytotic process involving stimulus-secretion coupling between the renal and the systemic circulation. Active renin secretion is regulated principally by four interdependent factors: (1) a renal baroreceptor mechanism in the afferent arteriole; (2) changes in delivery of sodium chloride (NaCl) to the macula densa cells of the distal tubule (which lie close to the JGC and, together, form the juxtaglomerular apparatus); (3) sympathetic nerve stimulation via β1-adrenergic receptors; and (4) negative feedback by a direct action of angiotensin II (Ang II) on the JGC and by an increase in sympathetic activity .
Renin acts on angiotensinogen, cleaving it to obtain a decapeptide, angiotensin I (Ang I), which is biologically inert. In fact, the biologically active molecule is obtained through hydrolysis of Ang I by the action of angiotensin converting enzyme (ACE), which forms Ang II , whereas the renin remains in the blood system for 30 to 60 min and continues to induce the production of Ang I. Other metabolites of Ang I and II may have significant biological activity, particularly in tissues. Ang III and IV are formed by the sequential removal of amino-acids from the N-terminus of Ang II. Ang III is present in the CNS and is involved in kidney damage in mesangial cells and renal injury. Some studies have shown that the angiotensin degradation product Ang III presents some biological activities. In renal interstitial fibroblasts Ang III induces c-fos gene expression, suggesting a potential role of Ang III in the control of cell proliferation . Ang IV, a major metabolite of Ang III, exerts central actions well known to include the increase of memory recall and learning in passive and conditional avoidance behavioral studies  (Figure 1).
Preclinical studies have suggested a cooperative effect of Ang IV in Ang II signaling . It has been shown by several studies and experiments that Ang II is the primary effector of a variety of RAAS-induced physiological and pathophysiological actions. At least four angiotensin receptor subtypes have been described . The type 1 (AT1) receptor mediates actions on the cardiovascular system (CVS) (vasoconstriction, increased BP, increased cardiac contractility, vascular and cardiac hypertrophy), kidney (renal tubular sodium reabsorption and inhibition of renin release), SNS (promotion of thirst, regulation of VP secretion, and modulation of sympathetic outflow) , and adrenal cortex (stimulation of aldosterone synthesis) . This receptor is widely distributed on many cell types in Ang II target organs. The type 2 (AT2) receptor is abundant during fetal life in the brain, kidney, and other sites, and its levels decrease markedly in the postnatal period. It may mediate vasodilatation, antiproliferative, and apoptotic effects in vascular smooth muscle and inhibit growth and remodeling in the heart [10,12]. The importance of any of these AT2-mediated actions remains uncertain. The type 4 (AT4) receptors are thought to mediate the release of plasminogen activator inhibitor 1 by Ang II and by the N-terminal truncated peptides (Ang III and Ang IV), but the function of the type 3 (AT3) receptors is unknown . Ang II also stimulates the production of aldosterone, which is a major regulator of sodium and potassium balance and thus plays a major role in regulating extracellular volume. It enhances the reabsorption of sodium and water in the distal tubules and collecting ducts and thereby promotes potassium excretion . Thus, RAAS plays a key role in regulation of circulatory homeostasis, but continued or inappropriate activation of the system is thought to contribute to the pathophysiology of disease such as hypertension. There is evidence that perturbations of the RAAS are involved in essential hypertension as well as in the responses of cardiovascular and renal tissue to hypertensive and nonhypertensive injury [7,8].
Approximately 15% of patients with essential hypertension have mild-to-moderate increases in plasma renin activity (PRA), with several postulated mechanisms, including increased sympathetic activity and mild volume depletion . The majority (50–60%) of essential hypertension patients have PRA within the normal range, although it has been argued that a normal renin level in the face of hypertension (which ought to suppress renin secretion) may be inappropriate. PRA, also called plasma renin assay, may be used to screen for hypertension of kidney origin, and may help plan treatment of essential hypertension. PRA is also used to further evaluate a diagnosis of excess aldosterone, a hormone secreted by the adrenal cortex, in a condition called Conn's Syndrome. A determination of the PRA and a measurement of the plasma aldosterone level are used in the differential diagnosis of primary and secondary hyperaldosteronism. Patients with primary hyperaldosteronism (caused by an adrenal tumor that overproduces aldosterone) will have an increased aldosterone level with decreased renin activity. Conversely, patients with secondary hyperaldosteronism (caused by certain types of kidney disease) will have increased levels of renin. The plasma renin concentration (PRC) measure the maximum renin effect. Therapeutic responses to RAAS blocking agents indicate that maintenance of normal renin levels may indeed contribute to BP elevation, suggesting that renin-dependent mechanisms may be involved in more than 70% of patients with essential hypertension. On the other hand, about 25–30% have evidence of low or suppressed renin levels, a finding that may be an expected response. Alternatively, in some cases it may reflect, by analogy to primary aldosteronism, sodium, or volume excess (so-called “volume-dependent” hypertension). Low-renin hypertension is more common among older people with hypertension, women, African–Americans’, and patients with type 2 diabetes, as well as among patients with chronic renal parenchymal disease. Although such patients often have a lower BP lowering benefit from RAAS blocking agents, there is evidence that the circulating levels of PRA might not necessarily reflect tissue activities of the system .
Drugs Interact with RAAS: ACE Inhibitors, Angiotensin 1 Receptor Blockers, and Renin Inhibitor
The pharmacological inhibition of the RAAS can be obtained through three different basic mechanisms: (1) inhibition of Ang II generation from Ang I, achieved through inhibition of ACE; (2) inhibition of the action of Ang II at the level of its receptor(s); and (3) inhibition of Ang I generation from angiotensinogen obtained by direct inhibition of renin .
After a discussion of a new prospective on the blockade of RAAS via its rate-limiting step for better control of hypertension, we briefly show the results already demonstrated and accepted regarding the drugs operating on ACE and on Ang II receptors. Several trials also showed not only their utility for lowering BP but they also suggest benefits beyond BP control, such as preventing progression of renal dysfunction  and decreasing cardiovascular diseases (CVD) mortality and morbidity [16,17].
ACE inhibitors (ACE-I) block the action of ACE, a bivalent dipeptidyl carboxyl metallopeptidase that cleaves the C-terminal dipeptide from Ang I and bradykinin. Because Ang II cannot be formed and Ang I is inactive, the ACE-I paralyses the classic RAAS, thereby removing the effects of most endogenous Ang II as both a vasoconstrictor and a stimulant to aldosterone synthesis. Interestingly, with long-term use of ACE-I, their plasma Ang II levels return to previous values while the BP remains lowered, which suggests that the antihypertensive effect may involve other mechanisms . The use of ACE-I in the treatment of hypertension has steadily expanded as they have been shown to provide special advantages in a large group of hypertensive patients. Angiotensin I receptor blockers (ARB) displaces Ang II from its specific AT1 receptor, antagonizing all of its known effects and resulting in both a dose-dependent fall in peripheral resistance and little change in heart rate or cardiac output . As a consequence of the competitive displacement, circulating level of Ang II increase and, at the same time the blockade of the renin–angiotensin mechanism is more complete, including any Ang II that is generated through pathways that do not involve ACE. An important and obvious difference between ARB and ACE-I is the absence of an increase in kinin levels that may be responsible for some of the beneficial effects of ACE-I and their side effects .
Aliskiren is the most advanced of the new class of orally active, nonpeptide, low molecular weight renin inhibitors [21,22]. The development of aliskiren was preceded by other similar drugs, such as enalakiren, remikiren, and zankiren , all of which were limited by their poor oral bioavailability, weak antihypertensive effect, and short duration of action .
Many published studies have demonstrated a relation between PRA and acute myocardial infarction (AMI) , chronic heart failure (CHF) , left ventricular hypertension (LVH) , modification of function renal indexes , and development of hypertension in obese subjects . Phase II and III clinical trials have demonstrated the efficacy of once-daily administration of aliskiren in the treatment of patients with mild-to-moderate hypertension (diastolic BP [DBP]≥95 mmHg and <110 mmHg), either as monotherapy or in combination with diuretics, calcium channel blockers (CCBs), ACE-Is, or ARBs, or as monotherapy in the treatment of severe hypertension (DBP ≥105 mmHg and <120 mmHg) .
Aliskiren and Hypertension
Aliskiren in Monotherapy
Oh et al. , in a randomized placebo-controlled study involving 672 mild-to-moderate hypertensive patients, demonstrated that all doses of aliskiren in monotherapy (150, 300, or 600 mg or placebo once daily for 8 weeks) gave greater reductions in mean sitting systolic BP (MSSBP) and mean sitting diastolic BP (MSDBP) by 13.0/10.3 mmHg (150 mg), 14.7/11.1 (300 mg), and 15.8/12.5 mmHg (600 mg), respectively, versus 3.8/4.9 mmHg (placebo). In this study the treatment with aliskiren provided significant antihypertensive efficacy with no rebound effects on BP after treatment withdrawal. The BP lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal (see Table 1).
In a 4-week randomized double-blind study with 236 mild-to-moderate hypertensive patients Stanton et al.  compared aliskiren (37.5, 75, 150, or 300 mg once daily) with losartan (100 mg once daily). The authors showed dose-dependent reductions in daytime ambulatory systolic BP (SBP) by −0.4 mmHg (37.5 mg), −5.3 mmHg (75 mg), −8.0 mmHg (150 mg), and −11.0 mmHg (300 mg). All doses of aliskiren also led to significant dose-dependent decreases of PRA between −55 and −83%, whereas PRA increased by 110% with losartan.
Also Gradman et al.  in a randomised, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial involving 652 patients with mild-to-moderate hypertension demonstrated that treatment with aliskiren (150, 300, and 600 mg once daily) significantly reduced MSDBP and MSSBP compared to placebo. In this study the mean reductions in trough DBP were 9.3 mmHg (150 mg), 11.8 mmHg (300), and 11.5 mmHg (600 mg) versus 6.3 mmHg for placebo. The mean reductions in trough SBP were 11.4 mmHg (150 mg), 15.8 mmHg (300 mg), and 15.7 mmHg (600 mg), respectively, versus 5.3 mmHg for placebo. In the same study, the antihypertensive effect of aliskiren 150 mg once daily was comparable to that of irbesartan (150 mg/day), and the treatment with aliskiren (300 and 600 mg once daily) lowered MSDBP significantly more than irbesartan (150 mg/daily) with comparable safety and tolerability profile (see Table 1).
Aliskiren Versus ACE-I
In a 8-week, multicenter, randomized, double-blind, parallel-group study Strasser et al.  compared the tolerability and antihypertensive efficacy of aliskiren with lisinopril in patients with severe hypertension (MSDBP ≥105 mmHg and ≤120 mmHg). In this study 183 patients were randomized to aliskiren treatment (150 mg once daily) or lisinopril (20 mg once daily) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren showed similar mean reductions from baseline to lisinopril in MSDBP (−18.5 mmHg vs. −20.1 mmHg) and MSSBP (−20.0 mmHg vs. −22.3 mmHg). This study showed that the treatment with aliskiren alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to lisinopril alone, or in combination with HCTZ, in patients with severe hypertension.
Andersen et al.  in a 26-week double-blind study compared long-term efficacy, safety, and tolerability of aliskiren and ramipril alone and combined with HCTZ in patients with hypertension. In this study 842 patients (MSDBP 95–109 mmHg) were randomized to receive aliskiren (150 mg once daily) or ramipril (5 mg once daily). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent HCTZ addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18, and 21 when BP control was inadequate. At week 26, aliskiren-based therapy produced greater mean reductions in MSSBP (17.9 vs. 15.2 mmHg) and MSDBP (13.2 vs. 12.0 mmHg). Aliskiren-based therapy produced sustained BP reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy. The treatment with aliskiren was well tolerated with adverse event rates similar to ramipril (see Table 1).
Aliskiren Versus Combination Therapy
The efficacy of aliskiren was demonstrated by further trials not only as a drug in monotherapy but also in combination therapy (see Table 2). Jordan et al.  evaluated the treatment with aliskiren in obese patients (body mass index [kg/m2]≥30) with hypertension (MSDBP 95–109 mmHg) who had not responded to four treatment weeks with HCTZ (25 mg/day). In this study, after a 2- to 4-week washout period, 560 patients received single-blind HCTZ (25 mg once daily) for 4 weeks and 469 nonresponders were randomly assigned to double-blind aliskiren (150 mg once daily), irbesartan (150 mg once daily), amlodipine (5 mg once daily), or placebo for 4 weeks plus HCTZ (25 mg once daily). Then, this treatment was followed by 8 weeks on double the initial doses of aliskiren (300 mg), irbesartan (300 mg), or amlodipine (10 mg). After 8 weeks of double-blind treatment, aliskiren/HCTZ lowered BP by 15.8/11.9 mmHg, significantly more than placebo/HCTZ (8.6/7.9 mmHg). Aliskiren/HCTZ provided BP reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/10.3 mm Hg, respectively). The combination treatment with aliskiren resulted in a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve BP control with first-line thiazide diuretic treatment.
Uresin et al.  demonstrated the antihypertensive efficacy and safety of the combination of aliskiren and ramipril in patients with diabetes and hypertension. In this double-blind, multicenter trial, 837 patients with diabetes mellitus and hypertension (95 < MSDBP < 110 mmHg) were randomized to receive once-daily aliskiren (150 mg titrated to 300 mg after 4 weeks), ramipril (5 mg titrated to 10 mg), or the combination (aliskiren 300 mg/ramipril 10 mg). After 8 weeks of treatment, aliskiren, ramipril, and aliskiren/ramipril lowered MSDBP by 11.3, 10.7, and 12.8 mmHg, and MSSBP by 14.7, 12.0, and 16.6 mmHg, respectively. The combination therapy provided a greater reduction in MSDBP than either drug alone in patients with diabetes and hypertension.
Pool et al.  investigated the BP lowering effects of aliskiren, alone or in combination with valsartan. In this multicenter, randomized, placebo-controlled, 8-week trial, 1123 patients with mild-to-moderate hypertension were randomized to receive once-daily oral treatment with placebo, aliskiren monotherapy (75, 150, or 300 mg), valsartan monotherapy (80, 160, or 320 mg), aliskiren, and valsartan in combination, or valsartan/HCTZ (160 mg/12.5 mg). Once-daily oral treatment with aliskiren (300 mg) significantly lowered MSDBP and MSSBP compared with placebo. Aliskiren monotherapy demonstrated a safety and tolerability profile comparable to placebo aliskiren and valsartan alone and in combination produced dose-related reductions in MSDBP and MSSBP. Coadministration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone and was comparable in magnitude to the effect of valsartan/HCTZ, with similar tolerability to the component monotherapies and to placebo. In a subset of 581 patients Yarrows et al.  demonstrated that combination therapy with aliskiren (150 mg) and valsartan (160 mg) for 4 weeks provided significantly greater BP reductions than aliskiren or valsartan monotherapy and is an appropriate option for management of BP in patients with stage 2 hypertension. Further, Geiger et al.  investigated the efficacy and safety of several different multidrug regimens including aliskiren, valsartan, and HCTZ in patients not adequately responsive to HCTZ as monotherapy. After 4 weeks of HCTZ treatment, 641 patients whose DBP was ≥95 mmHg were treated for 8 weeks with aliskiren/valsartan/HCTZ, aliskiren/HCTZ, valsartan/HCTZ, or HCTZ alone. The aliskiren/valsartan/HCTZ combination produced statistically significant additional reductions in SBP/DBP when compared with other groups. At the week 8 endpoint, reductions in SBP/DBP in the respective treatment groups were 22/16, 15/11, 18/14, or 6/6 mmHg. Aliskiren/valsartan/HCTZ produced significantly better BP control compared with other treatment groups. The safety profile of aliskiren/valsartan/HCTZ was similar to the two-drug combinations, with a greater BP lowering effect in patients who had not responded to HCTZ monotherapy.
Oparil et al.  compared the effects of aliskiren and valsartan alone or in combination in a double-blind study involving 1797 hypertensive patients (MSDBP 95–109 mmHg). All patients were randomized to receive once-daily aliskiren 150 mg, valsartan 160 mg, a combination of aliskiren 150 mg and valsartan 160 mg, or placebo for 4 weeks, followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks. At the week 8 endpoint, the combination of aliskiren (300 mg) and valsartan (320 mg) lowered MSDBP from baseline by 12.2 mmHg, which was significantly more than either monotherapy (aliskiren 300 mg 9.0 mmHg decrease; valsartan 320 mg, 9.7 mmHg decrease), or placebo (4.1 mmHg decrease). This study demonstrated that the combination of aliskiren and valsartan at the maximum recommended doses provides significantly greater reductions in BP than does monotherapy with either agent in patients with hypertension, with a tolerability profile similar to that of aliskiren or valsartan alone.
In a 52-week, open-label, multicenter, parallel-group study, Kushiro et al.  showed the long-term safety, tolerability, and efficacy of aliskiren-based therapy in 345 Japanese patients with mild-to-moderate hypertension. This study had two periods: (1) an 8-week, dose-titration period and (2) a 44-week, fixed-dose period with an optional addition of a diuretic or a CCB. A clinically meaningful reduction of 17.6/12.8 mmHg from baseline values was achieved in the mean sitting BP at the endpoint with aliskiren, irrespective of the dose and additional treatments, and showed the safety and efficacy of aliskiren-based therapy.
Blumenstein et al.  investigated the efficacy, safety, and tolerability of a single-pill combination (SPC) of aliskiren with HCTZ in hypertensive patients nonresponsive to HCTZ 25 mg/daily therapy. In this study, 722 patients with inadequate response to 4 weeks of HCTZ 25 mg/daily (MSDBP ≥ 90 < 110 mmHg) were randomized to once-daily, double-blind treatment for 8 weeks with an SPC of aliskiren/HCTZ 300/25 mg/daily or 150/25 mg/daily, or continued HCTZ 25 mg/daily monotherapy. Aliskiren/HCTZ 300/25 mg and 150/25 mg SPCs lowered MSSBP/DBP from baseline by 16.7/10.7 and 12.9/8.5 mmHg, respectively, both significantly greater reductions than HCTZ 25 mg alone (7.1/4.8 mmHg). Rates of BP control (<140/90 mmHg) were also significantly higher with aliskiren/HCTZ 300/25 mg (58%) and 150/25 mg (49%) than with HCTZ (26%; both P < 0.001). Aliskiren/HCTZ 300/25 mg provided significantly greater MSSBP/DBP reductions and rates of BP control than the 150/25 mg SPC dose.
Finally Shmieder et al.  in a randomized, double-blind, multicenter study assessed the long-term efficacy and safety of aliskiren in comparison with HCTZ in patients with essential hypertension. After a 2- to 4-week placebo trial, 1124 patients (MSDBP 95–109 mmHg) were randomized to aliskiren 150 mg (n = 459), HCTZ 12.5 mg (n = 444), or placebo (n = 221) once daily. Forced titration (to aliskiren 300 mg or HCTZ 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or HCTZ 25 mg. At week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. BP reductions (MSSBP/MSDBP) were significantly greater with aliskiren versus HCTZ-based treatment at week 26 (−20.3/−14.2 vs. −18.6/−13.0 mm Hg) and were also greater at week 52 (−22.1/−16.0 vs. −21.2/−15.0 mm Hg). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to HCTZ 25 mg in reducing BP (−17.4/−12.2 vs. −14.7/−10.3 mmHg). The authors concluded that aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective HCTZ regimens.
Aliskiren Versus CCBs
Drummond et al.  have demonstrated that treatment with aliskiren (150 mg once daily) plus amlodipine (5 mg once daily) significantly reduced the MSDBP and MSSBP of their patient group (n = 545). Meanwhile, those patients treated with amlodipine 5 mg alone did not have fully controlled hypertension. At the end of the study, MSSBP and MSDBP reductions with the combination of aliskiren (11.0 mmHg–150 mg) and amlodipine (8.5 mmHg–5 mg) were significantly greater than with amlodipine (5.0 mmHg–5 mg) alone. In addition, a significantly greater proportion of patients who were treated with aliskiren 150 mg plus amlodipine 5 mg achieved BP levels of <140/90 mmHg compared with amlodipine 5 mg alone.
Also, Littlejohn et al.,  in a 54-week clinical trial involving 556 hypertensive patients who require antihypertensive combination therapy to achieve BP control, investigated the safety and efficacy of aliskiren combined with amlodipine. Overall, 556 patients with 95 ≤ MSDBP ≤ 110 mmHg received aliskiren/amlodipine 150/5 mg once daily for 2 weeks, followed by forced titration to aliskiren/amlodipine 300/10 mg once daily for 52 weeks. Add on HCTZ was permitted from week 10 to achieve BP control (<140/90 mmHg). Four hundred fifty-two patients completed 54 weeks of treatment with aliskiren/amlodipine 300/10 mg with or without add-on HCTZ. Aliskiren/amlodipine combination therapy provided a mean BP reduction from baseline to week 54 of 24.2/15.5 mmHg; 74.3% of patients achieved BP control. In the subgroup of patients with stage 2 hypertension (baseline MSSBP ≥160 mmHg and/or MSDBP ≥100 mmHg), the mean BP reduction at week 54 was 29.1/17.1 mmHg, and 67.0% of patients achieved BP control. The authors of the study showed that aliskiren/amlodipine 300/10 mg combination therapy, with or without add-on HCTZ, effectively reduced BP, particularly in patients with stage 2 hypertension.
Aliskiren Versus β-Blockers
In a double-blind, multicenter trial Dietz et al.  randomized 694 hypertensive patients (MSDBP ≥ 95 ≤ 110 mmHg) to once-daily aliskiren 150 mg (n = 231), atenolol 50 mg (n = 231), or the combination (150/50 mg; n = 232) for 6 weeks, followed by a further 6 weeks on double the initial doses of aliskiren and atenolol. At the week 12 endpoint, aliskiren, atenolol, and aliskiren/atenolol lowered SBP and DBP from baseline by 14.3/11.3, 14.3/13.7, and 17.3/14.1 mmHg, respectively. SBP reductions with aliskiren/atenolol were significantly greater than those with aliskiren or atenolol alone, and DBP reductions were greater than with aliskiren alone. In this study, the therapy with aliskiren has demonstrated to be an appropriate substitute for β-blocker treatment in patients with uncomplicated hypertension and an attractive option for dual therapy with atenolol to improve SBP/pulse pressure reductions.
Aliskiren and Cardio-Renal Organ Damage
The role of RAAS in regulating the volume and composition of extracellular fluid and BP, as well as onset and progression of cardiovascular and renal diseases, has been studied for more than 150 years. The compounds that block the vital stages of the RAAS cascade, such as ACE-I, ARB, and aldosterone receptor antagonists, importantly extended our treatment options. However, the positive therapeutic effects of these compounds also have certain negative consequences. Administration of ACE-Is and ARBs interrupts physiological feedback for renal renin release and leads to reactive elevation of circulating active renin and greater production of Ang I and Ang II with subsequent return of aldosterone secretion to the pretreatment levels (“escape” phenomenon). These possible adverse effects of the intermediary products of incomplete RAAS blockade leading to organ complications have facilitated efforts to develop compounds blocking the initial stages of the rennin–angiotensin cascade such aliskiren. Aliskiren reduces PRA and neutralizes HCTZ -induced RAAS activation. Once-daily administration of the drug leads to greater than 24-h activity and its prolonged blocking effects on the kidneys are the basis for its reno-protectivity. Aliskiren has demonstrated favorable effects on vascular inflammation, remodeling, and neurohumoral mediators of various forms of cardiovascular complications, including CHF and proteinuria in diabetic patients.
Aliskiren and Heart
The development of alternative approaches to the blockade of the RAAS was encouraged by the success of ACE-I in the treatment of CHF, one of the most serious cardiac problem encountered in clinical practice. This success is the basis of the evidence that supports the use of ACE-I for the reduction of morbidity and mortality in mild-to-severe CHF and in LVD following an AMI. It is not known, however, whether the benefit of ACE inhibition is solely attributable to the blockade of Ang II production, or if it is also related to bradykinin accumulation.
Seed et al.  studied the neurohumoral effects of aliskiren (300 mg once daily) versus placebo or ramipril (10 mg once daily) for 5 weeks in 27 patients (aged >50 years) with symptomatic CHF (New York Heart Association [NYHA] class II–IV, ejection fraction [EF] < 35%). Plasma BNP, Ang II, aldosterone, PRA concentration, biochemical and hematological measurements, and other assessments were measured at baseline and during 5 weeks of randomized therapy. Aliskiren significantly suppressed the BNP values more than ramipril in short-term treatment.
In a 4-week randomized double-blind study with 236 mild-to-moderate hypertensive patients, Stanton et al.  showed that PRA was reduced from baseline values by 55% with 37.5 mg of aliskiren, by 60% with 75 mg, by 77% with 150 mg, and by 83% with 300 mg (contrasting with a 110% rise in PRA with losartan). In this study, the authors founded a comparable reduction (−60%) in PRA with aliskiren in patients with CHF (compared with a 165% increasing with ramipril). PRA was suppressed by aliskiren, but it did not change with placebo; even if it increased with ramipril as expected, this increase occurred either in the first week or in the fifth one. The reduction of PRA is important because PRA is related and CHF .
In the Aliskiren in Left Ventricular Hypertrophy (ALLAY) study, Solomon et al.  showed that aliskiren was as effective as losartan in reducing left ventricular mass (LVM), an important measure of end-organ damage, in 465 overweight (BMI >25), hypertensive patients randomized to receive aliskiren 300 mg, losartan 100 mg, or their combination daily for 9 months. Aliskiren was as effective as losartan in promoting LVM regression. Reduction in LVM with the combination of aliskiren plus losartan was not significantly different from that with losartan monotherapy, independent of BP. Aliskiren was effective as losartan in attenuating LVM in hypertensive patients with LVH.
Aliskiren and Kidney
The incidence of chronic kidney disease (CKD), like diabetic nephropathy, is increasing all over the world. Preclinical studies have shown that aliskiren, similar to other RAAS inhibitors, has renoprotective effects in both diabetic and nondiabetic models of CKD. It has also been shown to induce a dose-dependent BP diminution and prevent progressive albuminuria in streptozotocin-treated TG(mRen-2)27 rats  as compared to double transgenic rats . The renoprotective effect of aliskiren in these studies was attributed to its extensive distribution to the kidney, achieving a kidney/plasma concentration ratio of over 60 at 2 weeks of treatment. Aliskiren may inhibit kidney fibrosis by suppressing (pro)renin receptor gene expression and, thus, reduce receptor number and attenuate (pro)renin-induced profibrotic signaling. This is achieved by preventing the activation of (pro)renin and by negating the gain in catalytic activity of receptor bound renin. In one study, aliskiren was compared to valsartan in preventing target-organ damage in dTGR. Both low- and high-dose aliskiren and high-dose valsartan lowered BP, reduced albuminuria and creatinine levels, attenuated LVH, and increased survival . Antiinflammatory effects of aliskiren and the ARB losartan were also demonstrated in the kidneys of dTGR . In another rat model of advanced diabetic nephropathy, aliskiren reduced albuminuria and other markers of renal damage including expression of TGF-β and collagens III and IV types .
In the past 20 years, inhibitors of the RAAS became an important method of treatment of hypertension. Similarly, RAAS inhibitors were increasingly being used in patients with underlying renal disease, and there was evidence that some agents had an antiproteinuric effect that was independent from BP lowering . This effect is considered important for two reasons: (1) observations deriving several large interventional studies uniformly found that proteinuria represents a major risk factor for the progression of renal disease [54,55] and (2) the reduction of proteinuria in patients with underlying diabetic nephropathy was associated with a decreased risk for end-stage renal disease [56,57]. A similar observation was seen in patients with nondiabetic kidney disease with lower levels of baseline proteinuria .
An exploratory study investigated the time course of the antiproteinuric and antihypertensive effects of aliskiren in 15 patients with type 2 diabetes and microalbuminuria or microalbuminuria alone . After starting treatment with aliskiren 300 mg once daily, there was a progressive reduction from baseline levels in the urinary albumin/creatinine ratio (UACR). The mean 24-h SBP was significantly lower than baseline levels after 7, 14, and 28 days of treatment. The mean 24-h DBP was not significantly different from baseline levels during the period of the treatment, but the baseline DBP was lower (75 mmHg). Importantly, there was no significant correlation between the relative change in UACR and in 24-h BP from the baseline. Significant changes in UACR occurred earlier (days 2–4) than changes in 24-h SBP (day 7), and over the duration of the treatment with aliskiren, there was a progressive reduction from the baseline in UACR but not in BP. Findings of this exploratory study suggest that the antiproteinuric effect of aliskiren is, in part, BP independent.
In the AVOID trial, a randomized, double-blind, placebo-controlled study including hypertensive patients with type 2 diabetes and nephropathy, the authors evaluated the renoprotective effects of a dual blockade of the RAAS by adding treatment with aliskiren to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. Five hundred ninety-nine patients were randomized to receive 6 months of treatment with aliskiren (150 mg once daily for 3 months, followed by an increase in dosage to 300 mg once daily for another 3 months) or placebo, in addition to losartan. Treatment with aliskiren (300 mg once daily), as compared with placebo, reduced the mean UACR by 20%, with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo. The total numbers of adverse and serious events was similar in both treatment groups. Aliskiren has demonstrated renoprotective effects independent of its BP-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment . The addition of aliskiren provided an incremental antiproteinuric effect that appeared to be independent from BP lowering in hypertensive diabetic patients who had residual proteinuria, despite the treatment with an ARB .
Aliskiren and Microvascular System
Less well appreciated is the impact of hypertension on microvascular complications. Current opinion holds that, beyond hypertension, hyperglycemia directly damages arterioles and smaller blood vessels of diabetic patients, resulting in microvascular complications like nephropathy, retinopathy, and neuropathy. It is important to diagnose and treat these conditions before they manifest themselves as microvascular diseases of the retina, kidneys, and nervous system. A growing body of evidence suggests that shared pathophysiologic mechanisms initiate and promote dysfunction in the micro/macro-vasculature in individuals with diabetes and hypertension. Despite the frequent concomitance of nephropathy, retinopathy, and neuropathy, it is increasingly apparent that these three conditions may progress independently of one another .
Diabetic nephropathy is a progressive kidney disease characterized by proteinuria, diminished glomerular filtrate rate (GFR), and elevated arterial BP . It follows a prodrome of microalbuminuria and increasing BP . Histopathologic damage associated with diabetic nephropathy is characterized by an increase of glomerulus volume, proliferation, and sclerosis of mesangial cells, and increasing vasoactive agents, such as Ang II. These observations could help to explain the growing body of evidence that blockers of the RAAS may slow the progression of glomerulosclerosis in patients with diabetes and hypertension .
The primary mechanism of retinopathy in individuals with type 2 diabetes is centrally involved in diabetic macular edema (DME), defined as vascular leakage and subsequent edema that affects the center of the macula which can occur at any level of diabetic retinopathy .
Diabetic retinopathy is divided into 2 categories: nonproliferative diabetic retinopathy (NPDR) that produces an increasing of capillary permeability, hemorrhages, and DME, and proliferative diabetic retinopathy (PDR), which produces neovascularization on the vitreous surface of the retina, in the vitreous cavity, and on the iris (which can result in neovascular glaucoma). Vision loss occurs as a consequence of the progression of NPDR to PDR, or the development of DME at any stage of retinopathy . Hypertensive retinopathy is a well-characterized series of changes in retinal microvasculature . It can coexist with diabetic retinopathy and can increase the risk of vision loss. Risk factors for diabetic retinopathy and DME include the duration and magnitude of hyperglycemia, hypertension, and functional renal impairment. Persistent hyperglycemia triggers biochemical changes that collectively lead to altered retinal hemodynamics and, as PDR progresses, to the formation of new but fragile blood vessels on the surface of the retina. Vision loss can occur through vitreous hemorrhage and fibrotic changes in the vitreous gel leading to the contraction of newly formed blood vessels and the vitreous gel, which in turn can lead to subsequent traction and retinal detachment [63,65].
The specific pathophysiologic mechanisms of diabetic retinopathy are not well understood. In studies of spontaneously hypertensive rats early inflammatory responses were documented in the retina . Further studies regarding the same animal model have documented an enhanced expression of fibronectin and vascular endothelial growth factor, breakdown of the blood-retinal barrier, and withdrawal of neuroprogenitor cells from the cell cycle . Another study supports the idea that microvascular damage to the retina is directly attributable to diabetes and is exacerbated by hypertension suggesting that the AT1 receptor activation contributes to blood-retinal barrier dysfunction . Furthermore, the blockade of the RAAS could help to ameliorate this damage at the earliest stages of the disease. The attainment of aggressive BP target levels in patients, especially in the ones with diabetes, has been shown to improve microvascular complications. The United Kingdom Prospective Diabetes Study (UKPDS 36) correlated each 10-mmHg reduction in MSSBP with average reductions in risk rates for microvascular complications of retinopathy (13%) and nephropathy (13%) . Risk factors, like hypertension, may be an important link between microvascular and macrovascular outcomes. An early and aggressive management of hypertension, which includes RAAS blockage, has been associated with benefits extending beyond macrovascular disease, and may reduce the development and progression of microvascular diseases, such as retinopathy and nephropathy.
A more complete inhibition of RAAS may be the object for new therapeutic targets for the treatment of hypertensive disease. Published studies suggested that alternative pathways to the ACE exist for Ang I generation in the heart, large arteries, and the kidney. In vitro studies in intact tissues, homogenates, or membrane isolates from the heart and large arteries have repeatedly demonstrated such pathways, but the issue remains unresolved because the approaches used have not made it possible to extrapolate from the in vitro to the in vivo situation. Hollenberg et al.  studied the renal vasodilator response to three angiotensin-converting enzyme inhibitors (ACEI), two renin inhibitors, and two ARBs at the top of their respective dose–response relationships in young and healthy human volunteers. Both renin inhibitors and both ARBs that were studied induced a renal vasodilator response of 140–150 mL/min/1.73 m2, approximately 50% larger than the maximal renal hemodynamic response to ACE inhibition, which was 90–100 mL/min/1.73 m2. These findings indicate that in the intact human kidney, virtually all Ang II generation is renin-dependent but at least 40% of Ang I is converted to Ang II by pathways other than ACE, presumably a chymase, although other enzyme pathways exist. One implication of these studies is that at the tissue level, direct renin inhibitors and Ang II antagonists have much greater potential for blocking the RAAS than does ACE inhibition.
Others classes of patients are included in the trial previously named, like patients with CHF, diabetes, and so on, and it may be important to consider the treatment and adverse or benefit long-term effects about attendant diseases. Two ongoing trials, Aliskiren in VIsceral obesity AT risk patients Outcomes Research (AVIATOR) and Aliskiren Trial in Type 2 Diabetic nephropathy (ALTITUDE), will assess cardiovascular events and diabetic complications with aliskiren; the results will be available between 2011 and 2013.
The ongoing ALTITUDE trial is expected to provide definitive outcomes data on the effects of direct renin inhibition with aliskiren in patients with type 2 diabetes on renal and CV morbidity and mortality. ALTITUDE will determine whether a dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEI or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes .
Besides other trials, ATMOSPHERE (Aliskiren Trial to Minimise OutcomeS in Patients with HEart FailurE), will examine the potential clinical benefit of aliskiren in addition to other RAAS blocking agents as well as it will compare aliskiren head-to-head to ACEI therapy. This study should answer key questions regarding the clinical utility of direct renin inhibitor in CHF settings and, depending on the mechanistic substudies that have to be performed, may also investigate how these agents exert any observed benefits. Further to this, aliskiren will also be investigated in the ASTRONAUT (Aliskiren Trial on Acute Heart Failure Outcomes), which will evaluate whether an early therapy with aliskiren delays cardiovascular death and CHF rehospitalization within 6 months and posthospitalization for episodes of acute decompensated CHF .