Journal of Renin Angiotensin Aldosterone System 2008 Dietz 163 75

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Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension1
Rainer Dietz, Ralf Dechend, Chuek-Man Yu, Manesh Bheda, Jessica Ford, Margaret F. Prescott and Deborah L. Keefe Journal of Renin-Angiotensin-Aldosterone System 2008 9: 163 DOI: 10.1177/1470320308096411 The online version of this article can be found at: http://jra.sagepub.com/content/9/3/163
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Paper
Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension1
Rainer Dietz,* Ralf Dechend, Chuek-Man Yu,# Manesh Bheda,^ Jessica Ford,^ Margaret F. Prescott, Deborah L. Keefe
Key words: aliskiren, beta-blocker, plasma renin activity, pulse pressure, reninangiotensin system
* Charit Universittsmedizin, Berlin, Germany.
Franz Volhard Clinic, Berlin, Germany.
# Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong.
Novartis Pharma AG, Basel, Switzerland.
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Correspondence to: Deborah L. Keefe Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 079361080, USA. Tel: +1 862 778 0202 Fax: +1 973 781 6619 E mail: debor ah.keef e@ novar t is.com
Journal of the ReninAngiotensinAldosterone System (Including other Peptidergic systems) September 2008 Volume 9 Number 3
Abstract Introduction. Aliskiren is the first in a new class of direct renin inhibitors to be approved for the treatment of hypertension. Patients and methods. In this double-blind, multicentre trial, 694 patients with hypertension (mean sitting diastolic blood pressure [BP] 95 and < 110 mmHg) were randomised to once-daily aliskiren 150 mg (n=231), atenolol 50 mg (n=231) or the combination (150/50 mg; n=232) for six weeks, followed by a further six weeks on double the initial doses of aliskiren and atenolol. Efficacy (reduction from baseline in mean sitting systolic and diastolic BP) and tolerability of study treatments were assessed; plasma renin activity (PRA) was measured in a subset of patients. Results. At Week 12 endpoint, aliskiren, atenolol and aliskiren/atenolol lowered systolic and diastolic BP from baseline by 14.3/11.3, 14.3/13.7 and 17.3/14.1 mmHg, respectively. Systolic BP reductions with aliskiren/atenolol were significantly greater than those with aliskiren (p=0.039) or atenolol (p=0.034) alone, and diastolic BP reductions were greater than with aliskiren alone (p<0.001). Diastolic BP changes were larger with atenolol than with aliskiren (p=0.003, correlating with the large reductions in pulse rate (> 10 bpm) observed with atenolol. Aliskiren, atenolol and aliskiren/atenolol reduced geometric mean PRA from baseline by 65%, 52% and 61%, respectively. In patients with moderate or high baseline PRA ( 0.65 ng/ml/hour), PRA was reduced to low levels (< 0.65 ng/ml/hour) at Week 12 endpoint in a greater proportion of patients receiving aliskiren (11/15 patients, 73.3%) or aliskiren/atenolol (18/23, 78.3%) than with atenolol (10/21, 47.6%). Aliskiren treatment was associated with numerically lower rates of adverse events and discontinuations due to adverse events compared with atenolol or combination treatment, and unlike atenolol was not associated with bradycardia. Conclusions. Direct renin inhibition with aliskiren may be an appropriate substitute for beta-blocker
SAGE Publications 2008 Los Angeles, London, New Delhi and Singapore
treatment in patients with uncomplicated hypertension. Aliskiren also represents an attractive option for dual therapy with atenolol to improve systolic BP/pulse pressure reductions and BP control with maintained tolerability compared with atenolol alone.
Introduction The renin system plays a key role in regulating sodium levels and intravascular volume, but it is now widely recognised that increased renin system activity may be a key factor in the pathophysiology and development of increased blood pressure (BP), renal disease, atherosclerosis, diabetes and heart failure.1 Aliskiren is the first in a new class of direct renin inhibitors to be approved for the treatment of hypertension. Aliskiren inhibits the renin system by preventing the binding of angiotensinogen to renin,2 thus decreasing plasma renin activity (PRA) and inhibiting the formation of angiotensin I and angiotensin II.3 Clinical studies in patients with hypertension have shown that aliskiren at the approved once-daily doses of 150 and 300 mg provides effective, dose-dependent reductions in BP similar to those observed with angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), with an overall tolerability profile similar to that of placebo.4,5 Moreover, combination of aliskiren with an ACE inhibitor (ACE-I), ARB or thiazide diuretic provides clinically significant additional BP reduction, and prevents the reactive rise in PRA that is generally observed when these agents are administered alone.6-8 Beta-blockers have been widely used as first-line agents for the treatment of hypertension for three decades. Although the exact mechanism by which beta-blockers lower BP remains unclear, one contributing factor may be the ability of these drugs to reduce renin secretion, and thereby lower PRA.9-11 The 2004 guidelines for the treatment of hypertension from the British Hypertension Society (BHS)
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Paper recognised this effect of beta-blockers in their AB/CD algorithm, in which beta-blockers (B) were grouped with ACE-Is and ARBs (A) as drugs that target the renin system.12 However, the effectiveness of beta-blockers as treatments for primary hypertension was called into question by the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which showed that, compared with antihypertensive therapy based on the calcium channel blocker amlodipine and the ACE-I perindopril, treatment based on the beta-blocker atenolol and a thiazide diuretic was associated with a significantly higher incidence of fatal and non-fatal stroke, total cardiovascular events and procedures, all-cause mortality and new-onset diabetes.13 Subsequent meta-analyses of clinical outcome trials showed that beta-blockers were significantly less effective than other antihypertensive classes in reducing the incidence of stroke and other major cardiovascular outcomes,14,15 and were associated with a higher rate of discontinuations due to adverse events (AEs).16 The UK National Institute for Health and Clinical Excellence (NICE) and the BHS responded to these findings by issuing a revised A/CD algorithm for the treatment of hypertension, under which beta-blockers are no longer considered a suitable option for first-line therapy in patients with uncomplicated hypertension.17,18 Despite these changes to UK guidelines, the 2007 European Society of Hypertension-European Society of Cardiology guidelines still allow for the use of beta-blockers as an established first-line treatment for hypertension, although possible contraindications include patients with metabolic syndrome or glucose intolerance.19 The present study was therefore performed to compare the BP-lowering effects and tolerability of aliskiren and the beta-blocker atenolol in patients with hypertension, and to evaluate the efficacy and safety of combination treatment with both drugs. The effects of these treatments on PRA and plasma renin concentration (PRC) were also assessed in order to compare, for the first time, the effectiveness of direct renin inhibition, betaadrenoceptor blockade, and their combination on renin system activity. any condition that might alter the absorption, distribution, metabolism, or excretion of study drugs. Patients with contraindications to the use of betablockers (including bronchospastic disease) were also excluded. All patients provided written informed consent, and the study protocol was approved by local ethical committee and/or appropriate institutional review boards. The study was conducted in accordance with Good Clinical Practice guidelines and in compliance with the Declaration of Helsinki (2002). Study design This was a randomised, double-blind trial conducted in 85 centres in China, Germany, India, South Africa, Spain and Turkey. After screening and a two-week washout for patients receiving antihypertensive medication, eligible patients entered a two- to four-week single-blind, placebo run-in period. Patients with msDBP 95 and < 110 mmHg and a < 10 mmHg difference in msDBP between the last two visits of this period were randomised 1:1:1 to once-daily, double-blind aliskiren 150 mg, atenolol 50 mg or the combination. Randomisation was performed using the interactive voice response system provider. After six weeks, the doses of aliskiren and atenolol were doubled and treatment continued for a further six weeks. As abrupt discontinuation of atenolol is not recommended, all patients entered a seven-day treatment-tapering period after the last dose of active treatment. Patients who had been receiving atenolol 100 mg (alone or in combination) received atenolol 50 mg, while patients on aliskiren alone received placebo. All study medications were taken with water at approximately 8:00 a.m. (except on the morning of clinic visits) using a double-dummy technique to maintain double-blind conditions. Drugs indicated for the treatment of hypertension or that could interfere with study safety or efficacy evaluations were prohibited. The doses of aliskiren used in this study were the starting (150 mg) and maximum dose (300 mg) approved for the treatment of hypertension by the United States Food and Drug Administration and the European Union. Atenolol treatment was also given at the usual starting (50 mg) and maximum dose (100 mg) for the treatment of hypertension. BP measurements Automated BP measurements were made with the Omron 705IT (HEM-759P-E) monitor in accordance with BHS guidelines.12 Sitting BP was
Patients and methods Eligible patients were men and women aged 18 years with hypertension (mean sitting diastolic BP [msDBP] 95 and < 110 mmHg at baseline). Patients with msDBP > 110 mmHg or mean sitting systolic BP (msSBP) > 180 mmHg were excluded, as were patients with secondary hypertension, type 1 or 2 diabetes mellitus with HbA1C > 9% at screening, severe or life-threatening disease, or
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Paper measured at trough (243 hours post-dose) at each clinic visit in the arm that recorded the higher BP measurement at the first visit. After sitting for five minutes, DBP and SBP were measured three times at one- to two-minute intervals, and the mean value was taken as the average sitting BP for that visit. Pulse rate was measured for 30 seconds just prior to the first sitting BP measurement. Biomarker assessments PRA (radioimmunoassay of generated angiotensin I [DiaSorin kit; DiaSorin, Stillwater, Minnesota, USA]) and PRC (radioimmunometric assay [Renin III Generation; CIS bio international, Gif sur Yvette, France]) were measured in patients at selected centres at baseline and Week 12. Blood samples for biomarker assessments were drawn from patients in the fasted state who had been supine for at least 20 minutes, and were collected between 7:00 and 10:00 a.m. at baseline and at the same time (1 hour) at Week 12. Blood samples were collected into EDTA tubes stored at room temperature (to avoid cryoactivation); plasma was extracted within five minutes by centrifugation at 1,300 g for 10 minutes at room temperature, and stored at 20C until analyses were performed. The assay lower limits of quantification (LOQ) were 0.20 ng/ml/hour for PRA and 1 ng/L for PRC. Safety and tolerability assessments Safety assessments consisted of recording of AEs, measurement of vital signs, routine laboratory investigations, physical examination, and ECG. The safety population comprised all patients who received at least one dose of double-blind study medication. Statistical analyses A sample size of 603 patients completing doubleblind treatment (randomised population 672 patients assuming 10% dropout rate) was targeted with equal randomisation among treatment groups. Assuming SD for msDBP of 8 mmHg, this provided 90% power to detect a 3 mmHg treatment difference in change in msDBP between aliskiren/ atenolol and aliskiren or atenolol alone (primary efficacy comparison). No statistical adjustment was required for the two pairwise comparisons as the combination must be superior to both monotherapies to be considered more effective. Changes from baseline in msDBP and msSBP at Week 6 endpoint and Week 12 endpoint (using last observation carried forward for missing values) were analysed for the intent-to-treat population (all randomised patients with a baseline measurement and 1 post-baseline efficacy measurement) using a two-way ANCOVA model with treatment and region as factors and baseline as covariate. Changes from baseline in pulse rate and mean pulse pressure were assessed at the Week 12 endpoint. BP control rates (< 140/90 mmHg) were analysed using a logistic regression model with treatment and region as factors and baseline as covariate. As PRA and PRC are not normally distributed, changes were calculated from geometric means at baseline and Week 12 endpoint and compared between groups by ANCOVA using log-transformed data. PRA was reduced to below the assay LOQ in many patients, and so a post hoc shift analysis was performed to compare effects of study treatments on PRA in more detail. Patients were divided into subgroups of PRA below the assay LOQ (< 0.20 ng/ml/hour), or low (0.200.65 ng/ml/hour), medium (> 0.654.5 ng/ml/hour) or high (> 4.5 ng/ml/hour) PRA according to the classification used previously by Alderman and co-workers.20 Shifts between PRA subgroups at baseline and Week 12 endpoint were assessed within each treatment group. Formal statistical comparisons were not performed for safety and tolerability data, with the exception of comparison of the proportion of patients who exhibited a low pulse rate (< 55 bpm) at Week 12 of double-blind treatment in each group (logistic regression model). All statistical tests were performed at a two-sided significance level of 0.05, and 95% confidence intervals (CI) were provided for differences between treatment groups. Data were analysed by Novartis using SAS version 8.2 (SAS Institute, Cary, NC, USA).
Results Patient disposition A total of 694 patients were randomised to receive study treatment, of whom 629 (90.6%) completed the study (figure 1). The most common reasons for discontinuation of double-blind treatment were AEs, protocol violations and unsatisfactory therapeutic effect. There were fewer withdrawals owing to AEs in the patients taking aliskiren alone (5/231 patients, 2.2%) than in those taking atenolol (10/231, 4.3%) or the combination of both drugs (14/232, 6.0%). Patient baseline and demographic characteristics Baseline and demographic characteristics were generally well matched across the three treatment groups. The proportions of males and patients aged 75 years were greater in the aliskiren group than in the other groups (table 1). Overall,
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Figure 1 Patient flow diagram. AE = adverse event; ITT = intent-to-treat.
Table 1 Patient baseline and demographic characteristics (randomised population). Aliskiren (n = 231) Atenolol (n = 231) Aliskiren/atenolol (n = 232)
Parameter
Age, years 65 years, n (%) 75 years, n (%) Male, n (%) Race, n (%) Caucasian Asian Black Other BMI, kg/m2 Obesity, n (%) Metabolic syndrome, n (%) Duration of hypertension, years Mean sitting DBP, mmHg Mean sitting SBP, mmHg PRA, ng/ml/houra
55.811.9 56 (24.2%) 14 (6.1%) 134 (58.0%) 191 (82.7%) 29 (12.6%) 11 (4.8%) 0 28.94.5 85 (36.8%) 81 (35.1%) 6.86.7 99.73.8 157.612.3 0.59 (0.40, 0.87)
54.711.5 55 (23.8%) 8 (3.5%) 113 (48.9%) 196 (84.8%) 24 (10.4%) 5 (2.2%) 6 (2.6%) 29.25.1 97 (42.0%) 94 (40.7%) 6.35.6 99.43.8 155.912.9 0.76 (0.52, 1.12)
55.210.9 48 (20.7%) 7 (3.0%) 120 (51.7%) 194 (83.6%) 26 (11.2%) 8 (3.4%) 4 (1.7%) 29.55.0 98 (42.2%) 87 (37.5%) 7.06.8 99.53.8 157.312.3 0.51 (0.36, 0.73)
Key: Values are presented as meanSD unless otherwise stated. aPRA values are presented as geometric mean (95% confidence interval) for aliskiren (n = 48), atenolol (n = 45) and aliskiren/atenolol (n = 50). Obesity was defined as BMI 30 kg/m2. BMI = body mass index; DBP = diastolic blood pressure; PRA = plasma renin activity; SBP = systolic blood pressure.
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Figure 2 Changes from baseline in (a) mean sitting DBP, (b) mean sitting SBP, (c) mean pulse pressure and (d) mean pulse rate at Week 12 endpoint (ITT population). Figure presents (a, b, d) least-squares meanSEM and (c) meanSEM changes with aliskiren (filled bars), atenolol (open bars) and the aliskiren/atenolol combination (striped bars). bpm = beats per minute; DBP = diastolic blood pressure; ITT = intent-to-treat; SBP = systolic blood pressure. *p < 0.05, **p < 0.01 and ***p < 0.001 in pairwise comparisons.
most patients were Caucasian (83.7%), and mean age was 55.2 years. The proportion of obese patients was high (40.3%). Changes in msSBP and msDBP At Week 12 endpoint, aliskiren 300 mg/atenolol 100 mg lowered msSBP from baseline by 17.31.1 mmHg (figure 2b), a significantly greater reduction than that observed with either aliskiren (least-squares mean [LSM] difference 2.9 mmHg; 95% CI 5.7, 0.1, p = 0.039) or atenolol alone (LSM difference 3.0 mmHg; 95% CI 5.8, 0.2, p = 0.034). There was no significant difference between msSBP reductions with aliskiren and atenolol monotherapy (LSM difference 0.1 mmHg; 95% CI 2.9, 2.7, p = 0.954). Aliskiren 300 mg/atenolol 100 mg lowered msDBP from baseline by 14.10.6 mmHg (figure 2a), significantly more than aliskiren alone (LSM
difference 2.9 mmHg; 95% CI 4.5, 1.3, p < 0.001), but not atenolol alone (LSM difference 0.5 mmHg; 95% CI 2.1, 1.1, p = 0.545). Reductions in msDBP with atenolol 100 mg were larger than those observed with aliskiren 300 mg (LSM difference 2.4 mmHg; 95% CI 0.8, 4.0, p = 0.003). At Week 6 endpoint, the aliskiren 150 mg/ atenolol 50 mg combination lowered BP from baseline by 14.5/12.3 mmHg. Aliskiren 150 mg alone lowered BP by 10.8/9.2 mmHg (p = 0.005 and p < 0.001 vs. aliskiren/atenolol for msSBP and msDBP, respectively), while atenolol 50 mg alone lowered BP by 11.3/12.5 mmHg (p = 0.013 and p = 0.798 vs. aliskiren/atenolol for msSBP and msDBP, respectively). Reductions in msDBP with atenolol 50 mg were significantly greater than those observed with aliskiren 150 mg (p < 0.001), but there was no significant difference in msSBP reductions (p = 0.738).
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Figure 3 Changes in (a) plasma renin concentration and (b) plasma renin activity at Week 12 endpoint (ITT population). Figure presents percentage changes in geometric mean values from baseline to Week 12 endpoint with aliskiren (filled bars), atenolol (open bars) and the aliskiren/atenolol combination (striped bars). Error bars indicate 95% confidence intervals. ITT = intent-to-treat.
BP control rates Rates of BP control (< 140/90 mmHg) at Week 12 endpoint were higher with the aliskiren 300 mg/atenolol 100 mg combination (51.3%) than with either aliskiren (36.1%, p < 0.001) or atenolol alone (42.2%, p = 0.009). There was no significant difference in BP control rates between aliskiren and atenolol alone (p = 0.388). Changes in pulse pressure and pulse rate At Week 12 endpoint, mean pulse pressure was reduced by approximately 3.0 mmHg by treatment with the aliskiren/atenolol combination or aliskiren
monotherapy (figure 2c). Atenolol monotherapy had no notable effect on pulse pressure. Aliskiren monotherapy had no notable effect on pulse rate at Week 12 endpoint (figure 2d). By contrast, significant mean reductions in pulse rate of > 10 bpm were observed with atenolol monotherapy and the aliskiren/atenolol combination (both p < 0.001 vs. aliskiren monotherapy). Activation of the renin system Geometric mean PRC at baseline was 8.3, 10.7 and 9.4 ng/L in the aliskiren, atenolol and
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Figure 4 Distribution of PRA at baseline and Week 12 endpoint in patients randomised to (a) aliskiren, (b) atenolol and (c) aliskiren/atenolol. Figure presents proportion of patients in each treatment group with PRA below the assay LOQ (< 0.20 ng/ml/hour; open bars), or with low (0.200.65 ng/ml/hour; stippled bars), moderate (> 0.654.5 ng/ml/hour; striped bars) or high (> 4.5 ng/ml/hour; hatched bars) PRA according to the classification used previously by Alderman and co-workers.20 PRA was measured in a subset of patients at baseline (left-hand panels) and Week 12 endpoint (right-hand panels) as described in the Methods. LOQ = limit of quantification; PRA = plasma renin activity.
aliskiren/atenolol groups, respectively. Aliskiren increased PRC by 241% at Week 12 endpoint; a smaller increase in PRC was observed with aliskiren/
atenolol (85%; p = 0.010 vs. aliskiren), while atenolol alone decreased PRC by 24% (p < 0.001 vs. aliskiren and aliskiren/atenolol; figure 3a).
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Table 2 Safety and tolerability of study treatments (safety population). Aliskiren (n = 231) Atenolol (n = 231) Aliskiren/atenolol (n = 231)
Parameter
Any AE Any serious AE Discontinuations due to AE Deaths Most frequent individual AEs ( 2%) Headache Nasopharyngitis Diarrhoea Dizziness Fatigue Back pain Influenza Asthenia Blood urea increased Bradycardia Laboratory abnormalities BUN > 14.28 mmol/L Creatinine > 176.8 mmol/L Potassium > 5.5 mmol/L Potassium 6.0 mmol/L Potassium < 3.5 mmol/L
98 (42.4) 5 (2.2) 6 (2.6) 0 10 8 8 6 3 6 2 1 0 0 (4.3) (3.5) (3.5) (2.6) (1.3) (2.6) (0.9) (0.4)
111 (48.1) 7 (3.0) 10 (4.3) 0 14 15 6 7 2 2 5 5 5 5 (6.1) (6.5) (2.6) (3.0) (0.9) (0.9) (2.2) (2.2) (2.2) (2.2)
103 2 14 1 13 3 5 4 10 6 5 3 3 3 1 0 11 7 3
(44.6) (0.9) (6.1) (0.4) (5.6) (1.3) (2.2) (1.7) (4.3) (2.6) (2.2) (1.3) (1.3) (1.3) (0.4) (4.8) (3.0) (1.3)
0 0 8 (3.5) 4 (1.7) 6 (2.6)
0 0 11 (4.8) 9 (3.9) 5 (2.2)
Key: Values represent the number (%) of patients experiencing at least one AE or laboratory abnormality. AE = adverse event; BUN = blood urea nitrogen.
Geometric mean PRA at baseline was 0.59, 0.76 and 0.51 ng/ml/hour in the aliskiren, atenolol and aliskiren/atenolol groups, respectively. At Week 12 endpoint, aliskiren, atenolol and aliskiren/ atenolol reduced PRA by 65%, 52% and 61%, respectively (figure 3b). However, geometric mean PRA at Week 12 endpoint following treatment with aliskiren (0.19 ng/ml/hour) or aliskiren/ atenolol (0.21 ng/ml/hour) was close to the assay LOQ (0.20 ng/ml/hour), indicating that the calculated percent reductions in PRA may have underestimated the true effect on PRA of these treatments. Indeed, in patients with baseline PRA above the assay LOQ, a greater proportion had their PRA levels reduced to below the LOQ (< 0.20 ng/ml/hour) at Week 12 endpoint with aliskiren (17/34 patients, 50.0%) and aliskiren/atenolol (22/37, 59.5%) than with atenolol alone (13/37, 35.1%). A post hoc shift analysis divided patients into subgroups of PRA below the assay LOQ (< 0.20 ng/ml/hour), or low (0.200.65 ng/ml/hour), medium (> 0.654.5 ng/ml/hour) or high PRA (> 4.5 ng/ml/hour). This analysis showed that treatment groups were generally well matched for PRA distribution at baseline (figure 4). In patients with moderate or high PRA at baseline ( 0.65 ng/ml/hour), the proportion who had PRA levels reduced to levels that were low (0.200.65 ng/ml/hour) or below assay LOQ (< 0.20 ng/ml/hour) was greater with aliskiren (11/15 patients, 73.3%)
and aliskiren/atenolol (18/23, 78.3%) than with atenolol (10/21, 47.6%). Few patients had high PRA at baseline, but all of those in the aliskiren (4/4 patients) or aliskiren/ atenolol (2/2 patients) groups had PRA reduced to low levels (< 0.65 ng/ml/hour) by Week 12 endpoint; by contrast, only two of the five patients with high baseline PRA in the atenolol group had low PRA at study endpoint. Safety and tolerability Study treatments were generally well tolerated; the majority of AEs were mild or moderate in severity. The proportion of patients who experienced an AE during double-blind treatment was lowest in the aliskiren group and highest in the atenolol group (table 2). Nasopharyngitis was the most common individual AE in the atenolol group, and headache was the most common event in the aliskiren and aliskiren/atenolol groups. Fatigue occurred in a greater proportion of patients receiving aliskiren/ atenolol (4.3%) than aliskiren or atenolol alone (1.3% and 0.9%, respectively).
The rate of discontinuations due to AEs was low in all treatment groups (table 2). No individual AE type was associated with study discontinuation in more than two patients in any treatment group. Bradycardia was reported as an AE only in the atenolol treatment groups, and not during treatment with aliskiren alone; two patients discontinued the study due to
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Paper bradycardia in each of aliskiren/atenolol groups. the atenolol and patients [2.4%]), and the only individual AEs reported by more than one patient in any treatment group were palpitations (two patients receiving atenolol) and headache (two patients receiving aliskiren/atenolol).
There was one death in the study. A 65-year-old man with a history of chronic obstructive pulmonary disease and ventricular hypertrophy experienced cerebral haemorrhage and ischaemic stroke on Day 9 of treatment with aliskiren/ atenolol; the patient was hospitalised and study medication was permanently discontinued, but he experienced cerebral infarction and respiratory failure starting on Day 11, supraventricular tachycardia starting on Day 13, and died on Day 14. All of these serious AEs and the death were suspected by the investigator to be related to study drug treatment. Overall, the incidence of serious AEs was low; these events were not clustered in any particular organ system, and there were no notable differences between the groups. In addition to the death and preceding serious AEs described above, one patient in the aliskiren group developed gastroenteritis and a transient ischaemic attack (both suspected to be related to study treatment) on Day 8 of double-blind treatment; the patient was hospitalised and study medication was permanently discontinued. No patient discontinued study treatment because of abnormal laboratory values. No patient exhibited serum creatinine elevations > 176.8 mol/L, and elevations in blood urea nitrogen (> 14.28 mmol/L) were observed in only one patient receiving aliskiren/atenolol (table 2). The proportions of patients exhibiting serum potassium elevations to > 5.5 or 6.0 mmol/L were similar in all treatment groups (with no increase with the combination compared with atenolol alone), and none of the elevations was judged to be clinically relevant or associated with AEs. The proportion of patients who exhibited a low pulse rate (< 55 bpm) at Week 12 of double-blind treatment was markedly higher in the atenolol (13.0%) and aliskiren/atenolol (10.1%) groups than in the aliskiren group (1.9%; p < 0.0001 vs. atenolol and p = 0.002 vs. aliskiren/atenolol). There were no notable differences between groups in orthostatic BP changes. Tapered withdrawal of atenolol and aliskiren/ atenolol at the end of the study was well tolerated. The rate of AEs during the taper period was similar with aliskiren (six patients [2.8%]), atenolol (eight patients [3.7%]) and aliskiren/atenolol (five
Discussion This is the first clinical study to compare the BPlowering effects of a direct renin inhibitor (aliskiren) and a beta-blocker (atenolol), and the first to evaluate the efficacy and safety of combining the two drug classes in patients with hypertension. Aliskiren in combination with atenolol provided significant additional reductions in msSBP compared with either drug alone, and greater msDBP reductions than aliskiren alone. The aliskiren/atenolol combination thus lowered pulse pressure to a significantly greater extent than atenolol alone. Direct renin inhibition with aliskiren lowered PRA more effectively than atenolol, and combination of aliskiren with atenolol provided no further suppression of PRA compared with aliskiren alone. The aliskiren/atenolol combination showed similar tolerability to atenolol monotherapy, but both treatments were less well tolerated than aliskiren monotherapy. The selection of msDBP as the primary efficacy variable for this study was in line with current regulatory preferences for the design of studies for submission to European Health Authorities. The greater reduction in msDBP with atenolol compared with aliskiren is not unexpected, given the large reductions in pulse rate (> 10 bpm) observed in the present study. It is well known that betablockers lower DBP more effectively than SBP, probably because of the effect of these drugs to lower pulse rate and thus increase diastolic runoff.21 However, SBP and pulse pressure are better predictors of cardiovascular outcomes than DBP, particularly in elderly patients.22-25 In the present study, aliskiren and atenolol monotherapy provided similar reductions in msSBP, and combination of aliskiren with atenolol led to a further 3 mmHg reduction compared with atenolol alone. As a result, aliskiren/atenolol reduced pulse pressure by approximately 3 mmHg, whereas atenolol failed to reduce pulse pressure. There is currently considerable interest in the effects of different antihypertensive drug classes on pulse pressure, and in particular central aortic pulse pressure. Inhibitors of the renin system may provide greater reductions in central pulse pressure than beta-blockers, indicating decreased stiffness of peripheral arteries and a reduction in wave reflection.26,27 Indeed, the Conduit Artery Function Evaluation (CAFE) substudy showed that greater central pulse pressure
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Paper reductions with calcium channel blocker/ACE-I treatment compared with beta-blocker/thiazide diuretic treatment may have contributed to the superior outcome benefits of calcium channel blocker/ACE-I therapy in ASCOT.28 Further studies are required to investigate the effect of direct renin inhibition with aliskiren on central aortic pulse pressure. The effect of study treatment on biomarkers of renin system activity (PRA and PRC) is of interest because, aside from aliskiren, beta-blockers are the only other antihypertensive drugs that act to reduce renin activity.29,30 In the present study, atenolol treatment reduced PRC and PRA, consistent with the known effect of beta-blockers to reduce renin secretion.11,31,32 Reductions in PRA observed with aliskiren (65%) and aliskiren/ atenolol (61%) were slightly greater than those observed with atenolol (52%). However, geometric mean PRA at study endpoint in the aliskiren and aliskiren/atenolol groups was around the LOQ of the PRA assay (0.20 ng/ml/hour). Indeed, the proportion of patients with PRA below the LOQ at the end of the study was markedly higher in the aliskiren (58.1%) and aliskiren/atenolol groups (66.7%) than in the atenolol group (40.5%). Hence, the percent reduction in PRA was probably underestimated to a greater extent in the aliskiren groups. A post hoc shift analysis was therefore performed to assess reductions in PRA in more detail by dividing patients into subgroups of PRA below the LOQ, or low (0.200.65 ng/ml/hour), moderate (> 0.654.5 ng/ml/hour) or high PRA (> 4.5 ng/ml/hour) according to the classification used previously by Alderman and co-workers.20 This analysis showed that, in the subgroup of patients with moderate or high PRA at baseline, treatment with aliskiren or aliskiren/atenolol reduced PRA to low levels in approximately three-quarters of patients, whereas atenolol alone achieved low PRA in less than half of the patients. These results suggest that direct renin inhibition with aliskiren controls renin system activity (PRA) more effectively than beta-blockade with atenolol. Moreover, for all PRA analyses the results for the aliskiren and aliskiren/atenolol groups were essentially identical, indicating that combination with a betablocker did not further suppress PRA than direct renin inhibition with aliskiren alone. Hence, whereas beta-blockers inhibit renin release stimulated by sympathetic activation,10 direct renin inhibition reduces renin activity independent of the mechanism(s) stimulating renin release. Further evidence for the superiority of direct renin inhibition over beta-blockade for reducing PRA comes from other studies investigating combination treatment with diuretics, drugs that stimulate renin release and thus increase PRA.33 Whereas aliskiren significantly reduces PRA in combination with a diuretic,6 combination of a beta-blocker with a diuretic does not significantly decrease PRA.10 Combination of aliskiren with atenolol attenuated the reactive rise in PRC observed with aliskiren; however, the clinical relevance of increases in PRC with aliskiren is uncertain. At least some of the rise in measured PRC can be attributed to an assay artefact by which aliskiren binding can shift prorenin to the open conformation, which although bound to aliskiren and therefore still enzymatically inactive34 renders prorenin molecules measurable as renin by the standard renin immunoassay.35,36
All treatments were generally well tolerated in this study. One patient in the aliskiren/atenolol group died during the study as a result of a cerebrovascular accident that was suspected by the investigator to be related to study treatment, and he had a total of six serious AEs that were suspected to be study drug-related. This patient had a history of ventricular hypertrophy and chronic obstructive pulmonary disease, and had smoked for 29 years. Overall, the incidence of AEs and discontinuations due to AEs was numerically lowest in the aliskiren group. Combination of aliskiren with atenolol was not associated with any notable differences in safety or tolerability compared with atenolol alone, with the exception of an increased incidence of fatigue with the combination (4.3% vs. 1.3% and 0.9% with aliskiren and atenolol alone, respectively). It is notable that fatigue is a known side effect of beta-blocker therapy; a systematic review of this drug class showed that beta-blocker treatment was associated with a significantly higher incidence of fatigue than other antihypertensive drug classes.16 The present study also demonstrated the well-known effect of beta-blocker treatment to decrease pulse rate. Bradycardia was reported as an AE in a total of eight patients receiving atenolol treatment (alone or in combination with aliskiren); four of these patients discontinued study treatment as a result of the AE, and one instance of bradycardia was reported as a serious AE. By contrast, no patient receiving aliskiren alone exhibited bradycardia as an AE. There were no notable changes in laboratory values in the study; although elevations of serum potassium to greater than 5.5 mmol/L on at least one occasion were observed in 3.54.8% of patients, the incidence was similar in all treatment groups, with no increase with the combination compared with atenolol alone. Sampling haemolysis might explain
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Paper some of these abnormalities, as none of the elevations were judged to be clinically relevant or associated with AEs. An important factor in the decision of NICE/BHS not to recommend beta-blockers as first-line options for patients with uncomplicated hypertension was the safety profile of this drug class.17 ASCOT not only showed that beta-blocker-based treatment was less effective than a calcium channel blocker/ACE-I regimen at reducing the risk of cardiovascular outcomes, but also that beta-blockerbased treatment was associated with a 30% higher rate (p<0.0001) of new-onset diabetes.13 It is well known that beta-blockers have adverse metabolic effects that may increase the risk of developing diabetes, particularly when used in combination with thiazide diuretics.37 By contrast, renin system inhibitors appear to have beneficial effects on the metabolic profile that reduce the risk of new-onset diabetes,38,39 although this has not yet been demonstrated specifically with a direct renin inhibitor. The beta-blocker regimen in ASCOT was also associated with significantly higher rates of AEs such as bradycardia, dizziness, fatigue and erectile dysfunction.13 Tolerability is a very important consideration for antihypertensive drug treatment, because hypertension is generally an asymptomatic condition and so treatment-related AEs or safety concerns may cause patients to stop taking their medication. Aliskiren treatment at the approved doses of 150 and 300 mg daily has demonstrated a tolerability profile similar to that of placebo in short-term trials in patients with hypertension.4,40,41 A long-term, open-label study has also demonstrated the safety and tolerability of aliskiren-based treatment for up to 12 months.42 Although the comparison of the safety and tolerability of aliskiren and atenolol was not the primary objective of this study, the lower rate of discontinuations due to AEs with aliskiren is consistent with the findings of systematic reviews that patients receiving beta-blockers are more likely to discontinue treatment due to AEs than patients receiving a renin system inhibitor.16,43 In conclusion, aliskiren was as effective at lowering SBP as atenolol, although DBP reductions were larger with the beta-blocker. Direct renin inhibition with aliskiren reduced PRA more effectively than beta-blockade with atenolol. Taken together with the lower rate of AEs and discontinuations due to AEs with aliskiren monotherapy compared with atenolol monotherapy, these findings suggest that aliskiren may be an appropriate substitute for beta-blocker treatment in patients with uncomplicated hypertension. Aliskiren also represents an attractive option for dual therapy with a beta-blocker such as atenolol, as combination of aliskiren with atenolol provided significant additional reductions of approximately 3 mmHg in SBP and pulse pressure, and improved BP control rates, with similar tolerability to atenolol alone.
Acknowledgements This study was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Manesh Bheda, Jessica Ford, Margaret F. Prescott and Deborah L. Keefe are Novartis employees and as such may be eligible for Novartis stock and stock options. Rainer Dietz, Ralf Dechend and ChuekMan Yu have no conflicts of interest to disclose. The authors take full responsibility for the content of the paper, but thank Dr Richard White (Oxford PharmaGenesisTM Ltd) for assistance in collating and incorporating comments from all authors and editing the final manuscript; this role was funded by Novartis.
Appendix List of study investigators: Germany: Clothilde Hohberg (IKFE Mainz, Mainz); Gisela Schirrmeister (Potsdam); Markus Bruckhaus-Walter (Herne); Alexandra Eckartz (Universitaet Witten, Zentrum fr klinische Forschung, Witten); Uwe Desaga (Hamburg); Helen Arievich (Medars GmbH, Berlin); Clemens Bauknecht (Rottweil); Julia Chevts (Karlsruhe); Gerhard Scholz (Offenbach); Juergen Stockhausen (Rednitzhembach); Wolfgang Krause (Grimma); Hans-Gert Weber (Borna); Karin Seifert (Bitterfeld); Katja Przytarski (Berlin); Evelyn Geschke (Erkner); Karin Haase (Berlin); Alexander Deines (Hannover); Eva-Maria Boenninghoff (Beckum); Marianne Buhr (Berlin); Juergen Matthes (Heilbronn); Joachim Weimer (Reinfeld); Otto Armann (Eisfeld); Klaus Weyland (Ingelheim); Bernd Drewelow (Zentrum fur Pharmakologie und Toxikologie Institut fur Klinische Studien, Rostock); Klaus Kleinertz (Med. Beratungs und Therapiezentrum Chemnitz GmbH, Chemnitz); Ralf Bodenschatz (Pharmakologisches Studienzentrum Chemnitz, Chemnitz); Uwe Laemmel (Nobitz); Lutz Schulze (Belgershain); Andrea Ansorge (Erfurt); Juergen Merke (Bensheim); Rainer Dietz (Helios Kliniken, Berlin); Michael Setzkorn (Rostock); Axel Dettmer (Munich); Karlheinz Engels (Augsburg); Bruno Kronschnabl (Regen); Martin Laser (Nurenberg); Renate Meissner (Nurenberg); Ernest Schell (Nurenberg); Ralf Schipper (Monheim); Markus Vollmuth (Nurenberg); Hans Wozny (Hamburg); Matthias Kaiser (Parsberg); Gerhard Stuchlik (Vilshofen);
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Paper Hans-Peter Unterberg (Hohenau); Thomas Kammermeier (Bogen); Ingo Senftleber (Messkirch); Holger Samer (Haag); Bernhard Egerndorfer (Munich); Wolfgang Rechl (Weiden); Michael Stern (Ruhmannsfelden); Wendelin Trs (Riedlhuette); Hubert Attenberger (Gars/Inn); Roland Braun (Unterschneidheim); Rainer Fernandez-Mayer (Diessen/Ammersee); Wilma Grosskopf (Wallerfing); Joachim Hirsch (Kaufbeuren); Irmgard Maier-Bosse (Munich); Natascha Juchert (Munich); Hans Reitner (Unterschweinbach); Reinhard Schorten (Dachau); Georg Mahl (Schrobenhausen); Robert Franz (Strasskirchen); Hong Kong: Cheuk-Man Yu (The Chinese University of Hong Kong, Shatin, New Territories); India: Balaraju Banda (Osmania General College, Hyderabad, Andhra Pradesh); Balram Bhargava (All India Institute of Medical Sciences, Ansari Nagar, New Delhi); Sandhya Kamath (B.Y.L. Nair Hospital & T.N. Medical College, Mumbai, Maharastra); Kamesh Kuchimanchi (CARE Hospital Critical Care, Hyderabad, Andhra Pradesh); Narinder Singh (Maulana Azad Medical College & LNJP, Bahadur Shah Zafar, Marg Delhi); Nityananda Chowta (Kasturba Medical Hospital, Mangalore, Karnataka); Sudha Vidyasagar (Kasturba Medical Hospital, Manipal, Karnataka); South Africa: J Jacovides (Midrand Medical Centre, Midrand, Gauteng); Esme Venter (Scion Clinical Research, Pretoria, Gauteng); M Mpe (Pretoria Heart Hospital, Pretoria, Gauteng); P Naicker (Chelmsford Medical Centre, Durban, KwaZulu/ Natal); G Latiff (Maxwell Centre, Durban, KwaZulu/Natal); Spain: Luis De Teresa (Hospital San Vicente De Raspeig, Lillo Juan); Silvia Narejos (EAP Centelles, Barcelona); Juan Garcia Puig (Hospital Universitario La Paz, Planta); Juan Salvatierra (Centro de Salud, Castellon); Juan Menarguez (Centro de Salud, Murcia); Lluis Martinez (ABS Peraleda, Peraleda); Jose Sabater (Centro De Salud LAlcora, LAlcora); Vicente Cabedo (Centro De Salud Barranquet, Castellon); Jose Vaquer (Centro De Salud De Petrel, Petrel); Jose Martinez (Centro De Salud Cabo Huertas, Alicante); Isidro Lopez (Centro de Salud Begonte, Begonte); Joan Cerda (CAP Sant Andreu de Manresa, Manresa); Carlos Calvo (Hospital Clinical Universitario Santiago de Compostela, Choupana); Turkey: Hakan Kultursay (Ege University Medical Faculty, Izmir); Bengi Yaymaci (Kosuyolu Kartal Hospital, Istanbul); Haldun Muderrisoglu (Baskent University, Ankara Hospital, Ankara); Tevfik Ecder (Istanbul University, Istanbul Medical Faculty, Istanbul); Tarkan Tekten (Adnan Menderes University Medical Faculty, Aydin); Yagiz Uresin (Istanbul University, Istanbul Medical Faculty, Istanbul); Sema Guneri (Dokuz Eylul University Medical Faculty, Izmir). References
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19. Mancia G, De Backer G, Dominiczak A et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105-87. 20. Alderman MH, Cohen HW, Sealey JE, Laragh JH. Plasma renin activity levels in hypertensive persons: their wide range and lack of suppression in diabetic and in most elderly patients. Am J Hypertens 2004;17:1-7. 21. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. II. Results of long-term therapy. JAMA 1982;248:2004-11. 22. Psaty BM, Furberg CD, Kuller LH et al. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. Arch Intern Med 2001;161:1183-92. 23. Vaccarino V, Holford TR, Krumholz HM. Pulse pressure and risk for myocardial infarction and heart failure in the elderly. J Am Coll Cardiol 2000;36:130-8. 24. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham heart study. Circulation 1999;100: 354-60. 25. Blacher J, Staessen JA, Girerd X et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med 2000;160:1085-9. 26. Hirata K, Vlachopoulos C, Adji A, ORourke MF. Benefits from angiotensin-converting enzyme inhibitor beyond blood pressure lowering: beyond blood pressure or beyond the brachial artery? J Hypertens 2005;23:551-6. 27. Chen CH, Ting CT, Lin SJ et al. Different effects of fosinopril and atenolol on wave reflections in hypertensive patients. Hypertension 1995;25:1034-41. 28. Williams B, Lacy PS, Thom SM et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213-25. 29. Buhler FR, Laragh JH, Baer L, Vaughan ED Jr, Brunner HR. Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med 1972;287:1209-14. 30. Nilsson OR, Karlberg BE, Ohlsson O, Thulin T, Tolagen K. Atenolol administered once daily in primary hypertension. Effects on blood pressure in relation to pre-treatment plasma renin activity. Acta Med Scand 1979;206:303-8. 31. Michelakis AM, McAllister RG. The effect of chronic adrenergic receptor blockade on plasma renin activity in man. J Clin Endocrinol Metab 1972;34:386-94. 32. Bravo EL, Tarazi RC, Dustan HP. On the mechanism of suppressed plasma-renin activity during beta-adrenergic blockade with propranolol. J Lab Clin Med 1974;83:119-28. 33. Lijnen P, Fagard R, Staessen J, Amery A. Effect of chronic diuretic treatment on the plasma renin-angiotensinaldosterone system in essential hypertension. Br J Clin Pharmacol 1981;12:387-92. 34. Batenburg WW, de Bruin RJ, van Gool JM et al. Aliskiren-binding increases the half life of renin and prorenin in rat aortic vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2008;28:1151-7. 35. Menard J, Guyene TT, Peyrard S, Azizi M. Conformational changes in prorenin during renin inhibition in vitro and in vivo. J Hypertens 2006;24:529-34. 36. Schalekamp MA, Derkx FH, Deinum J, Danser AJ. Newly developed renin and prorenin assays and the clinical evaluation of renin inhibitors. J Hypertens 2008;26:928-37. 37. Mason JM, Dickinson HO, Nicolson DJ, Campbell F, Ford GA, Williams B. The diabetogenic potential of thiazidetype diuretic and beta-blocker combinations in patients with hypertension. J Hypertens 2005;23:1777-81. 38. Gillespie EL, White CM, Kardas M, Lindberg M, Coleman CI. The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes. Diabetes Care 2005;28:2261-6. 39. Weycker D, Edelsberg J, Vincze G et al. Risk of diabetes in a real-world setting among patients initiating antihypertensive therapy with valsartan or amlodipine. J Hum Hypertens 2007;21:374-80. 40. Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007;49: 1157-63. 41. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111:1012-18. 42. Sica D, Gradman AH, Lederballe O, Meyers M, Cai J, Keefe DL. 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Franz Volhard Clinic, Berlin, Germany.

# Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong.

Novartis Pharma AG, Basel, Switzerland.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Figure 1 Patient flow diagram. AE = adverse event; ITT = intent-to-treat.

0 0 8 (3.5) 4 (1.7) 6 (2.6)

0 0 11 (4.8) 9 (3.9) 5 (2.2)

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