Aliskiren Group Research Articles

Addition of Aliskiren to Angiotensin Receptor Blocker Improves Ambulatory Blood Pressure Profile and Cardiorenal Function Better than Addition of Benazepril in Chronic Kidney Disease

An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

Therapeutic effects of the direct renin inhibitor, aliskiren, on non-alcoholic steatohepatitis in fatty liver Shionogiob/obmale mice

Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome in the liver that is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The renin-angiotensin system (RAS) appears to play important roles in NASH. Direct renin inhibitors (DRI) reduce plasma renin activity (PRA) through interaction with the active site of the enzyme and reduce the formation of angiotensin-II (AT-II). Therefore, the DRI aliskiren may further suppress the RAS. This study examined the effects of aliskiren on NASH in fatty liver Shionogi (FLS)-ob/ob male mice that are the closest animal model of metabolic syndrome-related NASH in humans. Aliskiren (100 mg/kg per day, aliskiren group) or a placebo (control group) was p.o. administrated to eight FLS-ob/ob mice each for 16 weeks and factors including steatosis, fibrosis, inflammation and oxidative stress were compared between the two groups. Amounts of hepatic fibrosis were significantly lower in the aliskiren group than in the control group. Areas of α-smooth muscle actin positivity, the numbers of F4/80 positive, 8-hydroxy-2-deoxyguanosine positive cells and immunohistochemical staining of 4-hydroxynonenal were also significantly decreased in the aliskiren group. Levels of RNA expression for transforming growth factor-β1, connective tissue growth factor and monocyte chemoattractant protein-1 were significantly lower in the aliskiren group. Aliskiren attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate and Kupffer cells and by reducing oxidative stress.

Aliskiren Effect on Plaque Progression in Established Atherosclerosis Using High Resolution 3D MRI (ALPINE): A Double‐Blind Placebo‐Controlled Trial

BackgroundThe renin–angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high-risk patients with preexisting cardiovascular disease.Methods and ResultsThis was a single-center, randomized, double-blind, placebo-controlled trial in patients with established cardiovascular disease. After a 2-week single-blind placebo phase, patients were randomized to receive either placebo (n=37, mean±SD age 64.5±8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean±SD age 63.9±11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark-blood, 3-dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo). Aliskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31±6.57 vs 0.15±4.39 mm3, P=0.03, and percentage wall volume 3.37±2.96% vs 0.97±2.02%, P=0.04) compared with placebo. In a subgroup analysis of subjects receiving ACEI/ARB therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group.ConclusionsMRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving ACEI/ARB therapy.Clinical Trial RegistrationURL: http://ClinicalTrials.gov Unique identifier: NCT01417104.

Long‐term Effects of Aliskiren versus Hydrochlorothiazide on Left Ventricular Diastolic Function in Elderly Hypertensive Patients

A direct rennin inhibitor, Aliskiren, has been found to improve cardiac function in animals with myocardial infarction. We tested whether Aliskiren would modulate left ventricular (LV) diastolic function in elderly hypertensive patients, and compared it to hydrochlorothiazide (HCTZ). Mild hypertensives [65 ± 4 (SD) yrs] were randomly assigned to Aliskiren (n = 10) or HCTZ (n = 7) for 6 months. Blood pressure (BP), cardiac output (Qc), stroke volume (SV) and echocardiographic variables, such as early (E) and late (A) mitral inflow velocity, tissue Doppler velocities of the early (E’) and late (A’) mitral annulus, and color M‐mode propagation velocity (Vp) were recorded before and after treatment. BP decreased to a similar extent in both groups (p < 0.001). Qc, SV, and LV end‐diastolic volume remained unchanged in both groups. In the HCTZ group, E (77 ± 14 vs 69 ± 13 cm/s, p = 0.044) and Vp significantly decreased with a small decrease in E/A ratio (0.97 ± 0.24 vs. 0.87 ± 0.17) and E’ (7.8 ± 1.4 vs 7.3 ± 2.0 cm/s). However, A’ (10.9 ± 1.4 vs 11.7 ± 1.4 cm/s, p = 0.018) significantly increased, suggesting a compensatory increase in late diastolic filling to maintain stroke volume. In the Aliskiren group, no changes were observed in E, E/A ratio, E’, A’, or Vp. Thus, HCTZ decreased early diastolic filling most likely due to decreased LA driving pressure, while Aliskiren had no effects on early or late diastolic filling in hypertensive seniors.

Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure

Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality. To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients. International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥ 400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥ 1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012. All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months. In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), β-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo. Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge. clinicaltrials.gov Identifier: NCT00894387.

Time course of antiproteinuric effect of aliskiren in arterial hypertension associated with type 2 diabetes and microalbuminuria

Objective: The aim was to compare the antiproteinuric effect of aliskiren and ramipril in hypertensive patients with type 2 diabetes and microalbuminuria.Research design and methods: A total of 138 patients were treated with aliskiren 300 mg/day or ramipril 10 mg/day for 12 weeks and checked after 1, 2, 4, 8 and 12 weeks and 2 and 4 weeks after treatment withdrawal.Main outcome measures: Clinic and ambulatory BP, urinary albumin excretion rate (UAER) and plasma aldosterone were measured.Results: Both aliskiren and ramipril induced a similar lowering in clinic and ambulatory BP (p < 0.001 vs baseline). However, such a lowering persisted longer after stopping aliskiren than after stopping ramipril regimen. Both treatments reduced UAER, but the decrease in UAER associated with aliskiren was more pronounced, the difference vs ramipril being maximal at week 12 (−42 vs −15%, p < 0.01). Two weeks after stopping therapy, UAER remained below baseline values with aliskiren, but not in the ramipril group. Plasma aldosterone decreased in the aliskiren group, whereas in the ramipril group it decreased until week 8 and thereafter increased toward baseline values.Conclusions: Aliskiren has a greater and more prolonged antiproteinuric effect than R; it might partly be related to a higher degree of intrarenal renin–angiotensin–aldosterone system blockade.

Effects of antihypertensive therapy on glucose, insulin metabolism, left ventricular diastolic dysfunction and renin system in overweight and obese hypertensives

We attempted to test the hypothesis that the direct renin inhibitor aliskiren can improve diastolic dysfunction, glucose, and insulin metabolism (GIM) in overweight and obese hypertensive patients. Seventy-eight hypertensive patients were divided into two groups: 38 treated with aliskiren for six months, and 40 treated without aliskiren but with only traditional anti-hypertensive therapy, as controls. Doppler mitral flow velocity patterns were assessed before and after aliskiren during a six-month period. GIM (three-hour intravenous glucose tolerance test) was measured after four to six weeks of washout and six months of treatment. The mitral E/A ratio increased from 0.65 ± 0.11 to 0.75 ± 0.19. None of the indexes changed in the control group. In the control group, GIM parameters, fasting glucose levels (5.3 ± 0.9 to 6.0 ± 1.5 mmol/l; p = 0.003), fasting insulin levels (121 ± 121 to 189 ± 228 pmol/l; p = 0.03), and most other relevant metabolic measures (p < 0.05 for all) significantly worsened. Aliskiren did not affect GIM. In the control group LVM/height was not affected (119 ± 12 to 120 ± 17 g/m; p = 0.8), whereas aliskiren significantly reduced LVM/height (120 ± 13 to 111 ± 19 g/m; p = 0.04). Optimal target BP was achieved in the group as a whole and in both obese patient groups, while benefits to cardiac structure were of a smaller magnitude. In high-risk, overweight/obese patients with hypertension, traditional therapy provides significantly greater BP- versus aliskiren-lowering throughout the 24-hour dosing interval. Therefore in obese, hypertensive individuals, adequate and similar blood pressure control was achieved with aliskiren; however, the aliskiren group and not the control group was associated with a more favorable GIM profile and led to a significant regression of LVM; overall aliskiren-based treatment offers sustained control of PRA.

Antiatherosclerotic potential of aliskiren: its antioxidant and anti-inflammatory effects in rabbits: a randomized controlled trial

Background: Aliskiren is a direct renin inhibitor. It counteracts renin-angiotensin system and is used to treat hypertension. This study aims to evaluate the effect of aliskiren on the progression of atherosclerosis in domestic rabbits. Methods: Twenty-one local domestic rabbits were divided into three groups each group had special dietary regimen for 8 weeks: Group I (normal control), Group II (atherogenic control) and Group III (2% Cholesterol + aliskiren 40mg/kg/day orally). Blood samples were collected at the end of experiment (8 weeks) for measurement of serum lipid profile, plasma high sensitive C-reactive protein (hs-CRP), plasma malondialdehyde (MDA) and plasma reduced glutathione (GSH). Immunohistochemical analysis including vascular cell adhesion molecule-1 (VCAM-1); monocyte chemoattractant protein-1 (MCP-1); tumor necrotic factor - α (TNF-α); and interleukin – 17 (IL-17). Histopathologic assessment of aortic atherosclerotic changes were also performed. Results: Compared to normal control group, there is a significant increase in the level of lipid profile, hs-CRP (134.1±1.2ug/L), and malondialdehyde (0.561±0.136umol/L) in the atherogenic diet group, while GSH was significantly reduced (0.58±0.024mmol/L) at (p ≤ 0.05). Immunohistochemical analysis showed that expression of aortic VCAM-1; MCP-1; TNF-α; and interleukin–17 were significantly increased in atherogenic control group compared to normal control group (p<0.001). In addition, animals on atherogenic diet have significant atherosclerotic lesion compared to normal control group. Aliskiren group appears to have no significant effect on lipid profile compared to atherogenic control group, but it has statistically significant reduction in hs-CRP (73.1±3.88ug/L) and MDA (0.261±0.15umol/L) at (p ≤ 0.05). Aliskiren treatment failed to significantly increase the level of plasma reduced glutathione. In addition, aliskiren treatment significantly reduced the expression of VCAM-1; MCP-1; TNF-α; and IL–17 (p≤0.05). Histopathological examination of aortic arch showed that aliskiren significantly reduced atherosclerotic lesion (p≤0.005). Conclusion: We can conclude that aliskiren is helpful in reducing lipid peroxidation, systemic inflammation and aortic expression of inflammatory markers used in this study and hence reduces the progression of atherosclerotic plague.

Effect of the Direct Renin Inhibitor Aliskiren on Urinary Albumin Excretion in Spontaneous Type 2 Diabetic KK- Mouse

Objective. Although angiotensin II-mediated inflammation and extracellular matrix accumulation are considered to be associated with the progression of diabetic nephropathy, these processes have not yet been sufficiently clarified. The objective of this study was to determine whether the correction of the abnormal renal expression of MMPs and its inhibitors (MMPs/TIMPs) and cytokines following the administration of aliskiren to KK-A y mice results in a renoprotective effect. Methods. KK-A y mice were divided into two groups, that is, untreated (saline) and treated (aliskiren) groups. Systolic BP, HbA1c levels, and the albumin-creatinine ratio (ACR) were measured. The renal expression of MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (pro)renin receptor ((P)RR) was examined using real-time PCR and/or immunohistochemical staining. Renal MAPK and NF-κB activity were also examined by Western blot analyses and ELISA, respectively. Results. Significant decreases in systolic BP and ACR levels were observed in treated KK-A y mice compared with the findings in untreated KK-A y mice. Furthermore, increases in MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (P)RR expression, in addition to MAPK and NF-κB activity, were significantly attenuated by aliskiren administration. Conclusions. It appears that aliskiren improves albuminuria and renal fibrosis by regulating inflammation and the alteration of collagen synthesis and degradation.

Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

BackgroundThis study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.MethodsIn a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting–enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.ResultsThe trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons).ConclusionsThe addition of aliskiren to standard therapy with renin–angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.)

Abstract 9767: Direct-renin-inhibitor Aliskiren Therapy Consistently Suppresses Enhanced Cardiac Sympathetic Activity and Improves Left Ventricular Remodeling in Patients with Systolic Heart Failure

Introduction: Adding aliskiren to heart failure (HF) therapy was reported to reduce plasma brain natriuretic peptide (BNP) concentration. However, the effects of aliskiren on cardiac sympathetic nerve activity and on cardiac function have not yet been clarified. Hypothesis: We assessed the hypothesis that adding aliskiren to standard therapy would be effective to suppress cardiac sympathetic nerve function and improve cardiac function. Methods: We enrolled 38 patients with mild HF (NYHA class II). The inclusion criteria were: 1) in stable condition for at least six months; 2) receiving standard therapy including an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker and a beta-blocker; 3) have systolic dysfunction (left ventricular ejection fraction: LVEF of &lt; 45%); 4) without diabetes; and 5) without renal dysfunction (serum creatinine of &gt; 1.2 mg/dL). We randomly assigned 18 patients to receive additional aliskiren treatment of 150 mg/d (aliskiren group), while 20 patients continued standard therapy (control). All patients underwent neurohormonal measurements, echocardiography and 123I-metaiodobenzylguanidine (MIBG) imaging. In the MIBG images, the heart/mediastinum (H/M) ratio and cardiac washout rate (WR) were determined for evaluating cardiac sympathetic activity. The follow-up data were obtained three and 12 months later. Results: In the aliskiren group, plasma renin activity and BNP fell significantly. MIBG analysis showed a consistent decrease in WR and a consistent increase in H/M ratio over 12 months only in the aliskiren group (WR %: 39.6 ± 3.1 vs 32.0 ± 2.1, 32.8 ± 3.7, p = 0.013, H/M: 2.80 ± 0.16 vs 3.12 ± 0.22, 3.05 ± 0.20 p = 0.015 at each follow-up period). The LVEF improved although not significantly (p = 0.074). The LV end-diastolic volume (EDV) and end-systolic volume (ESV) improved significantly (EDV index mL/m2: 92.8±6.4 vs 79.7±5.8, 82.3±5.3, p = 0.042 and ESV index: 56.6±4.8 vs 46.4±4.5, 48.6±4.4, p = 0.021). In the control group, these data remained unchanged. Conclusions: In HF patients receiving standard therapy but still continuing to have cardiac dysfunction, the addition of aliskiren consistently suppresses cardiac sympathetic activity over 12 months and improves left ventricular remodeling.

Aliskiren reduces home blood pressure and albuminuria in patients with hypertensive nephrosclerosis

The aim of this study was to investigate the antialbuminuric and antihypertensive effects of aliskiren by monitoring home blood pressure (BP) in comparison with the effects of the angiotensin receptor blocker (ARB) valsartan in patients with hypertensive nephrosclerosis and albuminuria. We conducted an open-label, randomized trial to compare the effects of aliskiren with those of valsartan. Patients with BP <150/90mmHg, an estimated glomerular filtration rate of 90-30mL/min/1.73m(2), and albuminuria >30mg/g, despite treatment with a 160mg daily dose of valsartan, were randomly assigned to the following two groups: the aliskiren group, who switched from 160mg/day valsartan to 150mg/day aliskiren, which was later increased to 300mg/day (n=20); and the valsartan group, who continued with 160mg/day valsartan (n=20). After 12weeks of treatment, although there was no significant difference in clinic BP between groups, a significant reduction in morning and evening systolic BP was observed in the aliskiren group. The decrease in albuminuria in the aliskiren group was significantly better than that in the valsartan group, and a significant correlation was noted between the change in morning systolic BP and the change in albuminuria in the aliskiren group (r=0.564, P=0.0084). We showed that aliskiren treatment leads to a greater reduction in albuminuria and home systolic BP values than valsartan in patients with nephrosclerosis. We propose that aliskiren therapy should be considered as a therapeutic modality to complement ARBs in hypertensive patients with nephrosclerosis.

Efficacy of aliskiren and valsartan in hypertensive patients with albuminuria: a randomized parallel-group study

Blockade of the renin-angiotensin system (RAS) is a critical approach to the management of hypertension, especially in proteinuric patients. It is well proven that the direct renin inhibitor aliskiren shows comparable clinical efficacy to the angiotensin II receptor blocker valsartan on blood pressure control and albuminuria. However, there is only limited data on the hand-to-hand effectiveness of these two RAS blockers in improving arterial stiffness. We tested whether aliskiren or valsartan would improve arterial stiffness in hypertensive patients with albuminuria who are already on antihypertensive therapy. Thirty-four patients with hypertension and albuminuria < 1 g, after a wash-out period of three weeks, were randomized to aliskiren or valsartan in a 24-week randomized parallel-group study. A nonsignificant difference in blood pressure was seen between the two treatment groups. Albuminuria was significantly reduced in both groups (56% for the aliskiren group, p < 0.05, and 38% for the valsartan group, p < 0.05). Only valsartan but not aliskiren significantly reduced carotid-femoral pulse wave velocity (-1.1 ± 0.8 m/s (p = 0.02) for valsartan and +0.1 ± 0.7 m/s (ns) for aliskiren). The results of our study showed that valsartan improves arterial stiffness to a significantly greater extent than aliskiren, despite a similar antihypertensive and antiproteinuric effect.

Results from the ALTITUDE Trial

The addition of aliskiren, a novel direct renin inhibitor that lowers plasma renin activity, to standard therapy (an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker) did not improve outcomes for people with type 2 diabetes and renal impairment who are at high risk for cardiovascular and renal events. This finding is among the preliminary results of Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints [ALTITUDE; NCT00549757], which was stopped early in December 2011 because of futility and a high rate of adverse events in the aliskiren group.

Effect of add-on direct renin inhibitor aliskiren in patients with non-diabetes related chronic kidney disease

BackgroundThe renin-angiotensin-aldosterone system (RAAS) plays an important role in the progression of chronic kidney disease (CKD). Although dual RAAS inhibition results in worse renal outcomes than monotherapy in high risk type 2 diabetes patients, the effect of dual RAAS inhibition in patients with non-DM CKD is unclear. The aim of this study was to evaluate the potential renoprotective effect of add-on direct renin inhibitor in non-DM CKD patients.MethodsWe retrospectively enrolled 189 non-DM CKD patients who had been taking angiotensin II receptor blockers (ARBs) for more than six months. Patients were divided into an add-on aliskiren group and an ARB monotherapy group. The primary outcomes were a decline in glomerular filtration rate (GFR) and a reduction in urinary protein-to-creatinine ratio at six months.ResultsThe baseline characteristics of the two groups were similar. Aliskiren 150 mg daily reduced the urinary protein-to-creatinine ratio by 26% (95% confidence interval, 15 to 37%; p < 0.001). The decline in GFR was smaller in the add-on aliskiren group (−2.1 vs. -4.0 ml/min, p = 0.038). Add-on aliskiren had a neutral effect on serum potassium in the non-DM CKD patients. In subgroup analysis, the proteinuria-reducing effect of aliskiren was more prominent in patients with a GFR less than 60 ml/min, and in patients with a urinary protein-to-creatinine ratio greater than 1.8. The effect of aliskiren in retarding the decline in GFR was more prominent in patients with hypertensive nephropathy than in those with glomerulonephritis.ConclusionAdd-on direct renin inhibitor aliskiren (150 mg daily) safely reduced proteinuria and attenuated the decline in GFR in the non-DM CKD patients who were receiving ARBs.

Anti-fibrotic effect of Aliskiren in rats with deoxycorticosterone induced myocardial fibrosis and its potential mechanism

The objective of our study was to investigate the effect of Aliskiren, a renin inhibitor, on the deoxycorticosterone (DOCA) induced myocardial fibrosis in a rat model and its underlying mechanism. A total of 45 Sprague-Dawley (SD) rats underwent right nephrectomy and were randomly assigned into 3 groups: control group (CON group: silicone tube was embedded subcutaneously); DOCA treated group (DOC group: 200 mg of DOCA was subcutaneously administered); DOCA and Aliskiren (ALI) treated group (ALI group: 200 mg of DOCA and 50 mg/kg/d ALI were subcutaneously and intragastrically given, respectively). Treatment was done for 4 weeks. Sirius red staining was employed to detect the expression of myocardial collagen, and the myocardial collagen volume fraction (CVF) and perivascular collagen volume area (PVCA) were calculated. Radioimmunoassay was carried out to measure the renin activity (RA) and content of angiotensin II (Ang II) in the plasma and ventricle. Western blot assay was done to detect the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (PERK1/2) and matrix metalloproteinase 9 (MMP-9). In the DOC group and ALI group, the CVF and PVCA were significantly increased; the RA and Ang II levels in the plasma and ventricle were remarkably lowered when compared with the CON group. The RA and Ang II levels in the ventricle of the ALI group were significantly lower than those in the DOC group. Moreover, the expressions of ERK1/2, PERK1/2 and MMP9 were the lowest in the CON group, but those in the ALI group were significantly reduced as compared to the DOC group. ALI can inhibit the DOCA induced myocardial fibrosis independent of its pressure-lowing effect, which may be related to the suppression of RA and Ang II production, inhibition of ERK1/2 phosphorylation and MMP9 expression in the heart.

Additive renoprotective effects of aliskiren on angiotensin receptor blocker and calcium channel blocker treatments for type 2 diabetic patients with albuminuria

This open-label, randomized, parallel-controlled study investigated the effects of the direct renin inhibitor aliskiren on 64 hypertensive type 2 diabetic patients with chronic kidney disease (CKD) and stable glycemic control who were already being treated with fixed doses of antihypertensive agents over a 24-week period. These agents were 80 mg of the angiotensin II receptor blocker (ARB) telmisartan and 5 mg of the calcium channel blocker (CCB) amlodipine. Patients were randomly assigned to two groups: the aliskiren group, receiving 150 mg per day aliskiren, which was increased to 300 mg per day (n=32), and the CCB group, which received an increased dose (7.5 mg per day) of amlodipine that was increased to 10 mg per day (n=32). Urinary albumin excretion and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) were investigated in each group. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, but percent changes of urinary albumin/creatinine ratios, 8-OHdG and L-FABP levels decreased significantly in the aliskiren group compared with the CCB group. Plasma aldosterone levels were significantly decreased in the aliskiren group, which correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of aliskiren to the maximal recommended dose of ARB and usual dose of amlodipine is more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than increasing the dose of amlodipine.

Aliskiren, ALTITUDE, and the implications for ATMOSPHERE

Blockade of the renin–angiotensin system (RAS) is a core therapeutic strategy in systolic heart failure.1 The value of angiotensin-converting enzyme (ACE) inhibitors was proven in two pivotal trials conducted >20 years ago. More recently, angiotensin receptor blockers (ARBs) have also been shown to be beneficial in systolic heart failure both as an alternative to and when added to an ACE inhibitor. Separately, mineralocorticoid receptor antagonists (MRAs) reduce mortality and morbidity when added to an ACE inhibitor or ARB (MRAs are not considered further here). The latest approach to RAS blockade to be tested in clinical practice is renin inhibition. Currently the efficacy and safety of the renin inhibitor aliskiren is being tested in two clinical trials in heart failure, the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failure (ATMOSPHERE) and the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT), described previously in this journal.2,3 However, on 20 December 2011, treatment in another study, the Aliskiren Trial In Type 2 Diabetes Using Cardio-Renal Disease Endpoints (ALTITUDE), was stopped on the recommendation of its Data Monitoring Committee (DMC).2,3 ALTITUDE was comparing placebo or aliskiren 300 mg once daily, added to background ACE inhibitor or ARB therapy in patients with diabetes and either (i) increased urinary albumin excretion or (ii) both a reduced estimated glomerular filtration rate (eGFR 30–60 mL/min/1.73 m2) and established cardiovascular disease. The primary outcome in ALTITUDE is a composite of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, end-stage renal disease, renal death, or doubling of baseline serum creatinine concentration, sustained for at least a month. As a result of the DMC recommendation, ALTITUDE is currently being closed out in an orderly fashion. The basis of the DMC recommendation was futility (i.e. no prospect of demonstrating the treatment benefit anticipated in the protocol) as well as safety concerns. These concerns included renal dysfunction, hyperkalaemia, and hypotension (which are unsurprising) as well as an excess of strokes. In the publically released information, the number of patients experiencing a non-fatal stroke in the placebo group was 85 (2.0%) and 112 (2.6%) in the aliskiren group (nominal, unadjusted, P-value 0.04).6 Although this unexpected finding has provoked concern and discussion, the reported numbers do not represent the final number of events in ALTITUDE (at the time of the DMC's recommendation it was estimated that approximately a third of events remained to be collected and adjudicated). Consequently, while the apparent imbalance in strokes may persist or increase, it may also attenuate. Furthermore, given all prior data relating use of antihypertensive therapy to a reduced incidence of stroke in patients with diabetes, it is also possible that the imbalance in strokes represents a chance finding.7–9 In response to these findings it has been recommended that dual aliskiren and ACE inhibitor/ARB therapy not be used in patients with both hypertension (the current indication for aliskiren) and diabetes or moderate to severe renal dysfunction (eGFR <60 mL/min/1.73 m2).10 This recommendation has led to questions about the use of dual aliskiren therapy in patients with diabetes in the ongoing ATMOSPHERE trial (and, to a lesser extent, also the ASTRONAUT trial which has almost finished recruitment and will complete follow-up this year). In ATMOSPHERE, patients with systolic heart failure and an elevated B-type natriuretic peptide (BNP) or N-terminal pro BNP ( NT-proBNP) concentration are randomized in equal proportions to receive either enalapril 10 mg twice daily, aliskiren 300 mg once daily, or the combination of both drugs.3 ATMOSPHERE is an event-driven trial with a primary composite outcome of cardiovascular death or heart failure hospitalization. We believe that the preliminary results of ALTITUDE should not lead to any alteration in the conduct of ATMOSPHERE. The reasons for taking this view are discussed in detail below.

Local delivery of a direct renin inhibitor into the kidney ameliorates progression of experimental glomerulonephritis

Increasing evidence indicates that locally blocking renin-angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN. Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system. Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS+aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels. This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis.

Aliskiren for the treatment of essential hypertension under real-life practice conditions: design and baseline data of the prospective 3A registry

The renin-angiotensin system (RAS) is a key target for blood pressure control and for cardiovascular and renal protection. Aliskiren is the first-in-class direct oral inhibitor of renin that controls the rate-limiting step in the RAS cascade. So far little is known about the use and efficacy of aliskiren in the treatment of essential hypertension under clinical practice conditions. The 3A registry was an open, prospective cohort study (observational registry) of 14,988 patients in 899 offices throughout Germany. Consecutive patients were eligible for inclusion if their physician had decided to modify their antihypertensive therapy. This included treatment with aliskiren or an angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB) or agents not blocking the RAS, alone or on top of an existing drug regimen. Mean age of patients was 65 years, their mean body mass index was 28.2 kg/m(2) 53.5% were men, 36% working, 90% in statutory health insurance and 26% in any disease management programme. Patients in the aliskiren and the RAS groups compared with the non-RAS group were older, more often men, had a longer history of hypertension, and had a higher prevalence of comorbidities (diabetes, chronic heart failure, ischaemic heart disease, renal disease). Mean systolic, but not diastolic blood pressure was substantially higher in the aliskiren group (158/91 mmHg vs. 154/89 mmHg in ACE-I/ARB vs. 152/89 mmHg in non-RAS). Mean number of antihypertensive drugs was higher in the aliskiren group compared with the other groups (3.0 drugs vs. 2.5 in ACE-I/ARB vs. 1.6 in non-RAS; p < 0.0001). In this large cohort of outpatients with hypertension, aliskiren was used mainly in patients with more severe stages of hypertension and those with concomitant diseases such as diabetes mellitus and impaired renal function. The 3A registry will provide important information about the use and efficacy of aliskiren in a real-life setting.