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http://jra.sagepub.com/content/9/3/163The online version of this article can be found at:

DOI: 10.1177/1470320308096411

2008 9: 163Journal of Renin-Angiotensin-Aldosterone Systemainer Dietz, Ralf Dechend, Chuek-Man Yu, Manesh Bheda, Jessica Ford, Margaret F. Prescott and Deborah L. Keefe

hypertension1Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with

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AbstractIntroduction.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, atenololand 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 10 bpm) observed

with atenolol. Aliskiren, atenolol andaliskiren/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 wasnot associated with bradycardia.

Conclusions. Direct renin inhibition with 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 atenolol to

improve systolic BP/pulse pressure reductions

and BP control with maintained tolerability

compared with atenolol alone.

IntroductionThe renin system plays a key role in regulatingsodium levels and intravascular volume, but it isnow widely recognised that increased reninsystem activity may be a key factor in thepathophysiology and development of increasedblood pressure (BP), renal disease, atherosclerosis,diabetes and heart failure.1Aliskiren is the first in

a new class of direct renin inhibitors to beapproved for the treatment of hypertension.Aliskiren inhibits the renin system by preventingthe binding of angiotensinogen to renin,2 thusdecreasing plasma renin activity (PRA) andinhibiting the formation of angiotensin I andangiotensin II.3 Clinical studies in patients withhypertension have shown that aliskiren at theapproved once-daily doses of 150 and 300 mgprovides effective, dose-dependent reductions inBP similar to those observed with angiotensin-converting enzyme (ACE) inhibitors and angiotensin

receptor blockers (ARBs), with an overalltolerability profile similar to that of placebo.4,5

Moreover, combination of aliskiren with an ACEinhibitor (ACE-I), ARB or thiazide diureticprovides clinically significant additional BPreduction, and prevents the reactive rise in PRAthat is generally observed when these agents areadministered alone.6-8

Beta-blockers have been widely used as first-lineagents for the treatment of hypertension for threedecades. Although the exact mechanism by whichbeta-blockers lower BP remains unclear, one con-

tributing factor may be the ability of these drugs toreduce renin secretion, and thereby lower PRA.9-11

The 2004 guidelines for the treatment of hypertensionfrom the British Hypertension Society (BHS)

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(Including otherPeptidergic systems)

September 2008

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SAGE Publications 2008 Los Angeles, London, New Delhi and Singapore 10.1177/1470320308096411

* 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 07936-

1080, USA.Tel: +1 862 778 0202

Fax: +1 973 781 6619

Email:

deborah.keef e@novar

tis.com

Effects of the direct renin inhibitor aliskirenand atenolol alone or in combination in patientswith 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,

renin-

angiotensin

system

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recognised this effect of beta-blockers in theirAB/CD algorithm, in which beta-blockers (B) weregrouped with ACE-Is and ARBs (A) as drugs thattarget the renin system.12 However, the effective-ness of beta-blockers as treatments for primaryhypertension was called into question by the

Anglo-Scandinavian Cardiac Outcomes Trial(ASCOT), which showed that, compared with anti-hypertensive therapy based on the calcium channelblocker amlodipine and the ACE-I perindopril,treatment based on the beta-blocker atenolol and athiazide diuretic was associated with a significantlyhigher incidence of fatal and non-fatal stroke, totalcardiovascular events and procedures, all-causemortality and new-onset diabetes.13 Subsequentmeta-analyses of clinical outcome trials showedthat beta-blockers were significantly less effectivethan other antihypertensive classes in reducing the

incidence of stroke and other major cardiovascularoutcomes,14,15 and were associated with a higherrate of discontinuations due to adverse events(AEs).16 The UK National Institute for Health andClinical Excellence (NICE) and the BHS respondedto these findings by issuing a revised A/CD algo-rithm for the treatment of hypertension, underwhich beta-blockers are no longer considered asuitable option for first-line therapy in patients withuncomplicated hypertension.17,18

Despite these changes to UK guidelines, the 2007

European Society of Hypertension-EuropeanSociety of Cardiology guidelines still allow for theuse of beta-blockers as an established first-linetreatment for hypertension, although possiblecontraindications include patients with metabolicsyndrome or glucose intolerance.19 The presentstudy was therefore performed to compare theBP-lowering effects and tolerability of aliskirenand the beta-blocker atenolol in patients withhypertension, and to evaluate the efficacy andsafety of combination treatment with both drugs.The effects of these treatments on PRA andplasma renin concentration (PRC) were alsoassessed in order to compare, for the first time,the effectiveness of direct renin inhibition, beta-adrenoceptor blockade, and their combination onrenin system activity.

Patients and methodsEligible patients were men and women aged 18years with hypertension (mean sitting diastolicBP [msDBP] 95 and < 110 mmHg at baseline).Patients with msDBP > 110 mmHg or mean sittingsystolic BP (msSBP) > 180 mmHg were excluded,

as were patients with secondary hypertension,type 1 or 2 diabetes mellitus with HbA1C > 9% atscreening, severe or life-threatening disease, or

any condition that might alter the absorption,distribution, metabolism, or excretion of study drugs.Patients with contraindications to the use of beta-blockers (including bronchospastic disease) were alsoexcluded. All patients provided written informedconsent, and the study protocol was approved by

local ethical committee and/or appropriate institu-tional review boards. The study was conducted inaccordance with Good Clinical Practice guidelinesand in compliance with the Declaration ofHelsinki (2002).

Study designThis was a randomised, double-blind trial con-ducted in 85 centres in China, Germany, India,South Africa, Spain and Turkey. After screeningand a two-week washout for patients receivingantihypertensive medication, eligible patients

entered a two- to four-week single-blind, placeborun-in period. Patients with msDBP 95 and< 110 mmHg and a < 10 mmHg difference inmsDBP between the last two visits of this periodwere randomised 1:1:1 to once-daily, double-blindaliskiren 150 mg, atenolol 50 mg or the combina-tion. Randomisation was performed using theinteractive voice response system provider. Aftersix weeks, the doses of aliskiren and atenolol weredoubled and treatment continued for a further sixweeks. As abrupt discontinuation of atenolol is notrecommended, all patients entered a seven-day

treatment-tapering period after the last dose ofactive treatment. Patients who had been receivingatenolol 100 mg (alone or in combination) receivedatenolol 50 mg, while patients on aliskiren alonereceived placebo.

All study medications were taken with water atapproximately 8:00 a.m. (except on the morningof clinic visits) using a double-dummy techniqueto maintain double-blind conditions. Drugs indi-cated for the treatment of hypertension or thatcould interfere with study safety or efficacy eval-

uations were prohibited.

The doses of aliskiren used in this study were thestarting (150 mg) and maximum dose (300 mg)approved for the treatment of hypertension bythe United States Food and Drug Administrationand the European Union. Atenolol treatment wasalso given at the usual starting (50 mg) andmaximum dose (100 mg) for the treatment ofhypertension.

BP measurements

Automated BP measurements were made withthe Omron 705IT (HEM-759P-E) monitor inaccordance with BHS guidelines.12 Sitting BP was

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measured at trough (243 hours post-dose) ateach clinic visit in the arm that recorded thehigher BP measurement at the first visit. After sit-ting for five minutes, DBP and SBP were meas-ured 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 measuredfor 30 seconds just prior to the first sitting BPmeasurement.

Biomarker assessmentsPRA (radioimmunoassay of generated angiotensinI [DiaSorin kit; DiaSorin, Stillwater, Minnesota,USA]) and PRC (radioimmunometric assay [ReninIII Generation; CIS bio international, Gif surYvette, France]) were measured in patients atselected centres at baseline and Week 12. Bloodsamples for biomarker assessments were drawn

from patients in the fasted state who had beensupine for at least 20 minutes, and were collectedbetween 7:00 and 10:00 a.m. at baseline and at thesame time (1 hour) at Week 12. Blood sampleswere collected into EDTA tubes stored at roomtemperature (to avoid cryoactivation); plasma wasextracted within five minutes by centrifugation at1,300 g for 10 minutes at room temperature, andstored 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 assessmentsSafety assessments consisted of recording of AEs,measurement of vital signs, routine laboratoryinvestigations, physical examination, and ECG.The safety population comprised all patients whoreceived at least one dose of double-blind studymedication.

Statistical analysesA sample size of 603 patients completing double-blind treatment (randomised population 672patients assuming 10% dropout rate) was targeted

with equal randomisation among treatment groups.Assuming SD for msDBP of 8 mmHg, this pro-vided 90% power to detect a 3 mmHg treatmentdifference in change in msDBP between aliskiren/atenolol and aliskiren or atenolol alone (primaryefficacy comparison). No statistical adjustmentwas required for the two pairwise comparisons asthe combination must be superior to bothmonotherapies to be considered more effective.Changes from baseline in msDBP and msSBP atWeek 6 endpoint and Week 12 endpoint (using lastobservation carried forward for missing values)

were analysed for the intent-to-treat population(all randomised patients with a baseline meas-urement and 1 post-baseline efficacy measure-ment) using a two-way ANCOVA model with

treatment and region as factors and baseline ascovariate. Changes from baseline in pulse rateand mean pulse pressure were assessed at theWeek 12 endpoint. BP control rates (< 140/90mmHg) were analysed using a logistic regressionmodel with treatment and region as factors and

baseline as covariate.

As PRA and PRC are not normally distributed,changes were calculated from geometric meansat baseline and Week 12 endpoint and comparedbetween groups by ANCOVA using log-trans-formed data. PRA was reduced to below theassay LOQ in many patients, and so a post hocshift analysis was performed to compare effectsof study treatments on PRA in more detail.Patients were divided into subgroups of PRAbelow the assay LOQ (< 0.20 ng/ml/hour), or low

(0.200.65 ng/ml/hour), medium (> 0.654.5ng/ml/hour) or high (> 4.5 ng/ml/hour) PRAaccording to the classification used previously byAlderman and co-workers.20 Shifts between PRAsubgroups at baseline and Week 12 endpointwere assessed within each treatment group.

Formal statistical comparisons were not performedfor safety and tolerability data, with the exceptionof comparison of the proportion of patients whoexhibited a low pulse rate (< 55 bpm) at Week 12of double-blind treatment in each group (logisticregression model). All statistical tests were per-formed at a two-sided significance level of 0.05,and 95% confidence intervals (CI) were providedfor differences between treatment groups. Datawere analysed by Novartis using SAS version 8.2(SAS Institute, Cary, NC, USA).

ResultsPatient dispositionA total of 694 patients were randomised to receivestudy treatment, of whom 629 (90.6%) completed

the study (figure 1). The most common reasonsfor discontinuation of double-blind treatmentwere AEs, protocol violations and unsatisfactorytherapeutic effect. There were fewer withdrawalsowing to AEs in the patients taking aliskirenalone (5/231 patients, 2.2%) than in those takingatenolol (10/231, 4.3%) or the combination ofboth drugs (14/232, 6.0%).

Patient baseline and demographiccharacteristicsBaseline and demographic characteristics were

generally well matched across the three treatmentgroups. The proportions of males and patientsaged 75 years were greater in the aliskirengroup than in the other groups (table 1). Overall,

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Figure 1Patient flow diagram.

AE = adverse event; ITT = intent-to-treat.

Table 1

Patient baseline and demographic characteristics (randomised population).

Aliskiren Atenolol Aliskiren/atenolol

Parameter (n = 231) (n = 231) (n = 232)

Age, years 55.811.9 54.711.5 55.210.9 65 years, n (%) 56 (24.2%) 55 (23.8%) 48 (20.7%)

75 years, n (%) 14 (6.1%) 8 (3.5%) 7 (3.0%)Male, n (%) 134 (58.0%) 113 (48.9%) 120 (51.7%)Race, n (%)

Caucasian 191 (82.7%) 196 (84.8%) 194 (83.6%)Asian 29 (12.6%) 24 (10.4%) 26 (11.2%)Black 11 (4.8%) 5 (2.2%) 8 (3.4%)Other 0 6 (2.6%) 4 (1.7%)

BMI, kg/m2 28.94.5 29.25.1 29.55.0Obesity, n (%) 85 (36.8%) 97 (42.0%) 98 (42.2%)

Metabolic syndrome, n (%) 81 (35.1%) 94 (40.7%) 87 (37.5%)Duration of hypertension, years 6.86.7 6.35.6 7.06.8Mean sitting DBP, mmHg 99.73.8 99.43.8 99.53.8Mean sitting SBP, mmHg 157.612.3 155.912.9 157.312.3PRA, ng/ml/houra 0.59 (0.40, 0.87) 0.76 (0.52, 1.12) 0.51 (0.36, 0.73)

Key: Values are presented as meanSD unless otherwise stated. aPRA values are presented as geometric mean (95% confi-dence 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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most patients were Caucasian (83.7%), and meanage was 55.2 years. The proportion of obesepatients was high (40.3%).

Changes in msSBP and msDBPAt Week 12 endpoint, aliskiren 300 mg/atenolol100 mg lowered msSBP from baseline by17.31.1 mmHg (figure 2b), a significantly greaterreduction 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 differencebetween msSBP reductions with aliskiren andatenolol monotherapy (LSM difference 0.1 mmHg;95% CI 2.9, 2.7, p = 0.954).

Aliskiren 300 mg/atenolol 100 mg lowered msDBPfrom 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 0.654.5 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.



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Geometric mean PRA at baseline was 0.59, 0.76and 0.51 ng/ml/hour in the aliskiren, atenololand aliskiren/atenolol groups, respectively. At

Week 12 endpoint, aliskiren, atenolol andaliskiren/ atenolol reduced PRA by 65%, 52% and61%, respectively (figure 3b). However, geometricmean PRA at Week 12 endpoint following treatmentwith aliskiren (0.19 ng/ml/hour) or aliskiren/atenolol (0.21 ng/ml/hour) was close to the assayLOQ (0.20 ng/ml/hour), indicating that the calcu-lated percent reductions in PRA may have underes-timated the true effect on PRA of these treatments.Indeed, in patients with baseline PRA above theassay LOQ, a greater proportion had their PRA lev-els 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%) thanwith atenolol alone (13/37, 35.1%).

Apost hocshift analysis divided patients into sub-groups of PRA below the assay LOQ (< 0.20ng/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 thattreatment groups were generally well matchedfor PRA distribution at baseline (figure 4). In patientswith moderate or high PRA at baseline ( 0.65

ng/ml/hour), the proportion who had PRA levelsreduced to levels that were low (0.200.65ng/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 withatenolol (10/21, 47.6%). Few patients had highPRA at baseline, but all of those in the aliskiren (4/4

patients) or aliskiren/ atenolol (2/2 patients) groupshad PRA reduced to low levels (< 0.65 ng/ml/hour)by Week 12 endpoint; by contrast, only two of thefive patients with high baseline PRA in the atenololgroup had low PRA at study endpoint.

Safety and tolerabilityStudy treatments were generally well tolerated; themajority of AEs were mild or moderate in severity.The proportion of patients who experienced an AEduring double-blind treatment was lowest in thealiskiren group and highest in the atenolol group

(table 2). Nasopharyngitis was the most commonindividual AE in the atenolol group, and headachewas the most common event in the aliskiren andaliskiren/atenolol groups. Fatigue occurred in agreater 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 alltreatment groups (table 2). No individual AE type wasassociated with study discontinuation in more than

two patients in any treatment group. Bradycardia wasreported as an AE only in the atenolol treatmentgroups, and not during treatment with aliskirenalone; two patients discontinued the study due to

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Table 2

Safety and tolerability of study treatments (safety population).

Aliskiren Atenolol Aliskiren/atenolol

Parameter (n = 231) (n = 231) (n = 231)

Any AE 98 (42.4) 111 (48.1) 103 (44.6)

Any serious AE 5 (2.2) 7 (3.0) 2 (0.9)Discontinuations due to AE 6 (2.6) 10 (4.3) 14 (6.1)Deaths 0 0 1 (0.4)

Most frequent individual AEs ( 2%)Headache 10 (4.3) 14 (6.1) 13 (5.6)Nasopharyngitis 8 (3.5) 15 (6.5) 3 (1.3)Diarrhoea 8 (3.5) 6 (2.6) 5 (2.2)Dizziness 6 (2.6) 7 (3.0) 4 (1.7)Fatigue 3 (1.3) 2 (0.9) 10 (4.3)Back pain 6 (2.6) 2 (0.9) 6 (2.6)Influenza 2 (0.9) 5 (2.2) 5 (2.2)Asthenia 1 (0.4) 5 (2.2) 3 (1.3)Blood urea increased 0 5 (2.2) 3 (1.3)Bradycardia 0 5 (2.2) 3 (1.3)

Laboratory abnormalitiesBUN > 14.28 mmol/L 0 0 1 (0.4)Creatinine > 176.8 mmol/L 0 0 0Potassium > 5.5 mmol/L 8 (3.5) 11 (4.8) 11 (4.8)Potassium 6.0 mmol/L 4 (1.7) 9 (3.9) 7 (3.0)Potassium < 3.5 mmol/L 6 (2.6) 5 (2.2) 3 (1.3)

Key: Values represent the number (%) of patients experiencing at least one AE or laboratory abnormality. AE = adverseevent; BUN = blood urea nitrogen.



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bradycardia in each of the atenolol andaliskiren/atenolol groups.

There was one death in the study. A 65-year-oldman with a history of chronic obstructive pul-

monary disease and ventricular hypertrophyexperienced cerebral haemorrhage and ischaemicstroke on Day 9 of treatment with aliskiren/atenolol; the patient was hospitalised and studymedication was permanently discontinued, buthe experienced cerebral infarction and respira-tory failure starting on Day 11, supraventriculartachycardia starting on Day 13, and died on Day14. All of these serious AEs and the death weresuspected by the investigator to be related tostudy drug treatment.

Overall, the incidence of serious AEs was low;these events were not clustered in any particularorgan system, and there were no notable differ-ences between the groups. In addition to thedeath and preceding serious AEs describedabove, one patient in the aliskiren group devel-oped gastroenteritis and a transient ischaemicattack (both suspected to be related to studytreatment) on Day 8 of double-blind treatment;the patient was hospitalised and study medica-tion was permanently discontinued.

No patient discontinued study treatment because ofabnormal laboratory values. No patient exhibitedserum creatinine elevations > 176.8 mol/L, andelevations in blood urea nitrogen (> 14.28 mmol/L)were observed in only one patient receivingaliskiren/atenolol (table 2). The proportions ofpatients exhibiting serum potassium elevations to> 5.5 or 6.0 mmol/L were similar in all treat-ment groups (with no increase with the combi-nation compared with atenolol alone), and noneof the elevations was judged to be clinically rele-vant or associated with AEs.

The proportion of patients who exhibited a lowpulse rate (< 55 bpm) at Week 12 of double-blindtreatment was markedly higher in the atenolol(13.0%) and aliskiren/atenolol (10.1%) groupsthan in the aliskiren group (1.9%; p < 0.0001 vs.atenolol and p = 0.002 vs. aliskiren/atenolol).There were no notable differences betweengroups in orthostatic BP changes.

Tapered withdrawal of atenolol and aliskiren/atenolol at the end of the study was well toler-

ated. The rate of AEs during the taper period wassimilar with aliskiren (six patients [2.8%]), atenolol(eight patients [3.7%]) and aliskiren/atenolol (five

patients [2.4%]), and the only individual AEsreported by more than one patient in any treat-ment group were palpitations (two patientsreceiving atenolol) and headache (two patientsreceiving aliskiren/atenolol).

DiscussionThis is the first clinical study to compare the BP-lowering effects of a direct renin inhibitor(aliskiren) and a beta-blocker (atenolol), and thefirst to evaluate the efficacy and safety of combin-ing the two drug classes in patients with hyperten-sion. Aliskiren in combination with atenololprovided significant additional reductions in msSBPcompared with either drug alone, and greatermsDBP reductions than aliskiren alone. Thealiskiren/atenolol combination thus lowered pulse

pressure to a significantly greater extent thanatenolol alone. Direct renin inhibition with aliskirenlowered PRA more effectively than atenolol, andcombination of aliskiren with atenolol providedno further suppression of PRA compared withaliskiren alone. The aliskiren/atenolol combinationshowed similar tolerability to atenolol monother-apy, but both treatments were less well toleratedthan aliskiren monotherapy.

The selection of msDBP as the primary efficacyvariable for this study was in line with current reg-

ulatory preferences for the design of studies forsubmission to European Health Authorities. Thegreater reduction in msDBP with atenolol com-pared with aliskiren is not unexpected, given thelarge reductions in pulse rate (> 10 bpm) observedin the present study. It is well known that beta-blockers lower DBP more effectively than SBP,probably because of the effect of these drugs tolower pulse rate and thus increase diastolic run-off.21 However, SBP and pulse pressure are betterpredictors of cardiovascular outcomes than DBP,particularly in elderly patients.22-25 In the presentstudy, aliskiren and atenolol monotherapy pro-vided similar reductions in msSBP, and combina-tion of aliskiren with atenolol led to a further3 mmHg reduction compared with atenolol alone.As a result, aliskiren/atenolol reduced pulse pres-sure by approximately 3 mmHg, whereas atenololfailed to reduce pulse pressure. There is currentlyconsiderable interest in the effects of different anti-hypertensive drug classes on pulse pressure, and inparticular central aortic pulse pressure. Inhibitors ofthe renin system may provide greater reductions incentral pulse pressure than beta-blockers, indicat-ing decreased stiffness of peripheral arteries and a

reduction in wave reflection.26,27 Indeed, theConduit Artery Function Evaluation (CAFE) sub-study showed that greater central pulse pressure

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reductions with calcium channel blocker/ACE-Itreatment compared with beta-blocker/thiazidediuretic treatment may have contributed to thesuperior outcome benefits of calcium channelblocker/ACE-I therapy in ASCOT.28 Further studiesare required to investigate the effect of direct renin

inhibition with aliskiren on central aortic pulsepressure.

The effect of study treatment on biomarkers ofrenin system activity (PRA and PRC) is of interestbecause, aside from aliskiren, beta-blockers arethe only other antihypertensive drugs that act toreduce renin activity.29,30 In the present study,atenolol treatment reduced PRC and PRA, consis-tent with the known effect of beta-blockers toreduce renin secretion.11,31,32 Reductions in PRAobserved with aliskiren (65%) and aliskiren/

atenolol (61%) were slightly greater than thoseobserved with atenolol (52%). However, geomet-ric mean PRA at study endpoint in the aliskirenand aliskiren/atenolol groups was around theLOQ of the PRA assay (0.20 ng/ml/hour). Indeed,the proportion of patients with PRA below theLOQ at the end of the study was markedly higherin the aliskiren (58.1%) and aliskiren/atenololgroups (66.7%) than in the atenolol group(40.5%). Hence, the percent reduction in PRAwas probably underestimated to a greater extentin the aliskiren groups.

Apost hocshift analysis was therefore performedto assess reductions in PRA in more detail bydividing patients into subgroups of PRA belowthe LOQ, or low (0.200.65 ng/ml/hour), moder-ate (> 0.654.5 ng/ml/hour) or high PRA (> 4.5ng/ml/hour) according to the classification usedpreviously by Alderman and co-workers.20 Thisanalysis showed that, in the subgroup of patientswith moderate or high PRA at baseline, treatmentwith aliskiren or aliskiren/atenolol reduced PRAto low levels in approximately three-quarters of

patients, whereas atenolol alone achieved lowPRA in less than half of the patients. These resultssuggest that direct renin inhibition with aliskirencontrols renin system activity (PRA) more effec-tively than beta-blockade with atenolol. Moreover,for all PRA analyses the results for the aliskirenand aliskiren/atenolol groups were essentiallyidentical, indicating that combination with a beta-blocker did not further suppress PRA than directrenin inhibition with aliskiren alone. Hence,whereas beta-blockers inhibit renin release stim-ulated by sympathetic activation,10 direct renin

inhibition reduces renin activity independent of themechanism(s) stimulating renin release. Furtherevidence for the superiority of direct renin inhi-bition over beta-blockade for reducing PRA

comes from other studies investigating combinationtreatment with diuretics, drugs that stimulate reninrelease and thus increase PRA.33Whereas aliskirensignificantly reduces PRA in combination with adiuretic,6 combination of a beta-blocker with adiuretic does not significantly decrease PRA.10

Combination of aliskiren with atenolol attenuatedthe reactive rise in PRC observed with aliskiren;however, the clinical relevance of increases in PRCwith aliskiren is uncertain. At least some of the risein measured PRC can be attributed to an assayartefact by which aliskiren binding can shiftprorenin to the open conformation, which although bound to aliskiren and therefore stillenzymatically inactive34 renders prorenin mole-cules measurable as renin by the standard reninimmunoassay.35,36

All treatments were generally well tolerated inthis study. One patient in the aliskiren/atenololgroup died during the study as a result of a cere-brovascular accident that was suspected by theinvestigator to be related to study treatment, andhe had a total of six serious AEs that were sus-pected to be study drug-related. This patient hada history of ventricular hypertrophy and chronicobstructive pulmonary disease, and had smokedfor 29 years. Overall, the incidence of AEs anddiscontinuations due to AEs was numericallylowest in the aliskiren group. Combination of

aliskiren with atenolol was not associated withany notable differences in safety or tolerabilitycompared with atenolol alone, with the excep-tion of an increased incidence of fatigue with thecombination (4.3% vs. 1.3% and 0.9% withaliskiren and atenolol alone, respectively). It isnotable that fatigue is a known side effect ofbeta-blocker therapy; a systematic review of thisdrug class showed that beta-blocker treatmentwas associated with a significantly higher inci-dence of fatigue than other antihypertensive drugclasses.16 The present study also demonstrated

the well-known effect of beta-blocker treatmentto decrease pulse rate. Bradycardia was reportedas an AE in a total of eight patients receivingatenolol treatment (alone or in combination withaliskiren); four of these patients discontinuedstudy treatment as a result of the AE, and oneinstance of bradycardia was reported as a seriousAE. By contrast, no patient receiving aliskirenalone exhibited bradycardia as an AE. There wereno notable changes in laboratory values in thestudy; although elevations of serum potassium togreater than 5.5 mmol/L on at least one occasionwere observed in 3.54.8% of patients, the inci-dence was similar in all treatment groups, with noincrease with the combination compared withatenolol alone. Sampling haemolysis might explain

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some of these abnormalities, as none of theelevations were judged to be clinically relevantor associated with AEs.

An important factor in the decision of NICE/BHS

not to recommend beta-blockers as first-lineoptions for patients with uncomplicated hyperten-sion was the safety profile of this drug class.17

ASCOT not only showed that beta-blocker-basedtreatment was less effective than a calcium channelblocker/ACE-I regimen at reducing the risk of car-diovascular outcomes, but also that beta-blocker-based treatment was associated with a 30% higherrate (p


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Hans-Peter Unterberg (Hohenau); ThomasKammermeier (Bogen); Ingo Senftleber(Messkirch); Holger Samer (Haag); BernhardEgerndorfer (Munich); Wolfgang Rechl (Weiden);Michael Stern (Ruhmannsfelden); Wendelin Trs(Riedlhuette); Hubert Attenberger (Gars/Inn);

Roland Braun (Unterschneidheim); RainerFernandez-Mayer (Diessen/Ammersee); WilmaGrosskopf (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 (TheChinese University of Hong Kong, Shatin, NewTerritories); India: Balaraju Banda (OsmaniaGeneral College, Hyderabad, Andhra Pradesh);Balram Bhargava (All India Institute of Medical

Sciences, Ansari Nagar, New Delhi); SandhyaKamath (B.Y.L. Nair Hospital & T.N. MedicalCollege, Mumbai, Maharastra); KameshKuchimanchi (CARE Hospital Critical Care,Hyderabad, Andhra Pradesh); Narinder Singh(Maulana Azad Medical College & LNJP, BahadurShah Zafar, Marg Delhi); Nityananda Chowta(Kasturba Medical Hospital, Mangalore,Karnataka); Sudha Vidyasagar (Kasturba MedicalHospital, 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 MedicalCentre, Durban, KwaZulu/ Natal); G Latiff (MaxwellCentre, Durban, KwaZulu/Natal); Spain: Luis DeTeresa (Hospital San Vicente De Raspeig, LilloJuan); 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 CaboHuertas, Alicante); Isidro Lopez (Centro de SaludBegonte, Begonte); Joan Cerda (CAP Sant Andreude Manresa, Manresa); Carlos Calvo (HospitalClinical Universitario Santiago de Compostela,Choupana); Turkey: Hakan Kultursay (EgeUniversity Medical Faculty, Izmir); Bengi Yaymaci(Kosuyolu Kartal Hospital, Istanbul); HaldunMuderrisoglu (Baskent University, AnkaraHospital, Ankara); Tevfik Ecder (IstanbulUniversity, Istanbul Medical Faculty, Istanbul);Tarkan Tekten (Adnan Menderes University

Medical Faculty, Aydin); Yagiz Uresin (IstanbulUniversity, Istanbul Medical Faculty, Istanbul);Sema Guneri (Dokuz Eylul University MedicalFaculty, Izmir).

References1. Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens Suppl2005;23:S9-S17.2. Wood JM, Maibaum J, Rahuel J et al. Structure-baseddesign of aliskiren, a novel orally effective renin inhibitor.Biochem Biophys Res Commun2003;308:698-705.

3. Nussberger J, Wuerzner G, Jensen C, Brunner HR.Angiotensin II suppression in humans by the orally activerenin inhibitor aliskiren (SPP100): comparison with enalapril.Hypertension2002;39:E1-E8.4. Pool JL, Schmieder RE, Azizi M et al.Aliskiren, an orallyeffective renin inhibitor, provides antihypertensive efficacyalone and in combination with valsartan. Am J Hypertens2007;20:11-20.5. Uresin Y, Taylor A, Kilo C et al. Efficacy and safety ofthe direct renin inhibitor aliskiren and ramipril alone or incombination in patients with diabetes and hypertension. JRenin Angiotensin Aldosterone Syst2007; 8: 1908.6. Villamil A, Chrysant SG, Calhoun D et al. Renin inhibi-tion with aliskiren provides additive antihypertensive efficacy

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J Hypertens2007;25:217-26.7. Kilo C, Taylor A, Tschope D, Ibram G, Fang H, PrescottMF. Aliskiren, a novel renin inhibitor for treatment of hyper-tension, enhances renin system suppression by reducingplasma renin activity alone or in combination with ramipril inpatients with diabetes. Eur Heart J2006;27(suppl):118-19 P789.8. Yarows SA, Oparil S, Patel S, Zhang J, Fang H, Satlin A.Suppression of the renin system with the oral direct renininhibitor aliskiren alone and in combination with valsartan inpatients with hypertension.J Hypertens2007; 25(suppl):S257-S2589. Nielsen I, Steiness E, Hesse B. Acute and long-term saltdepletion and beta-blockade: plasma renin activity responseand its relation to blood pressure reduction in long-termtreatment. Acta Med Scand1978;203:415-18.10. Bravo EL, Tarazi RC, Dustan HP, Lewis JW. Dissociationbetween renin and arterial pressure responses to beta-adren-ergic blockade in human essential hypertension. Circ Res1975;36:241-7.11. Blumenfeld JD, Sealey JE, Mann SJ et al. Beta-adrenergicreceptor blockade as a therapeutic approach for suppressing therenin-angiotensin-aldosterone system in normotensive andhypertensive subjects. Am J Hypertens1999;12:451-9.12. Williams B, Poulter NR, Brown MJ et al. Guidelines formanagement of hypertension: report of the fourth workingparty of the British Hypertension Society, 2004-BHS IV.J HumHypertens2004;18:139-85.13. Dahlof B, Sever PS, Poulter NRet al. Prevention of car-diovascular events with an antihypertensive regimen ofamlodipine adding perindopril as required versus atenololadding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood PressureLowering Arm (ASCOT-BPLA): a multicentre randomised con-trolled trial. Lancet2005;366:895-906.14. Lindholm LH, Carlberg B, Samuelsson O. Should betablockers remain first choice in the treatment of primary hyper-tension? A meta-analysis. Lancet2005;366:1545-53.15. Khan N, McAlister FA. Re-examining the efficacy ofbeta-blockers for the treatment of hypertension: a meta-analysis. CMAJ2006;174:1737-42.16. Wiysonge C, Bradley H, Mayosi B et al. Beta-blockersfor hypertension. Cochrane Database Syst Rev2007;CD002003.17. National Institute for Health and Clinical Excellence.Hypertension: management of hypertension in adults in pri-mary care. 2006;http://www.nice.org.uk/CG034 accessed 28th

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19. Mancia G, De Backer G, Dominiczak A et al. 2007Guidelines for the Management of Arterial Hypertension: TheTask Force for the Management of Arterial Hypertension of theEuropean Society of Hypertension (ESH) and of the EuropeanSociety of Cardiology (ESC).J Hypertens2007;25:1105-87.20. Alderman MH, Cohen HW, Sealey JE, Laragh JH. Plasmarenin activity levels in hypertensive persons: their wide range

and lack of suppression in diabetic and in most elderlypatients. Am J Hypertens2004;17:1-7.21. Veterans Administration Cooperative Study Group on

Antihypertensive Agents. Comparison of propranolol andhydrochlorothiazide for the initial treatment of hypertension.II. Results of long-term therapy. JAMA1982;248:2004-11.22. Psaty BM, Furberg CD, Kuller LH et al. Associationbetween blood pressure level and the risk of myocardialinfarction, stroke, and total mortality: the cardiovascularhealth study. Arch Intern Med2001;161:1183-92.23. Vaccarino V, Holford TR, Krumholz HM. Pulse pressureand risk for myocardial infarction and heart failure in the eld-erly.J Am Coll Cardiol2000;36:130-8.24. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Ispulse pressure useful in predicting risk for coronary heart disease?

The Framingham heart study. Circulation1999;100: 354-60.25. Blacher J, Staessen JA, Girerd Xet al. Pulse pressure notmean pressure determines cardiovascular risk in older hyper-tensive patients. Arch Intern Med2000;160:1085-9.26. Hirata K, Vlachopoulos C, Adji A, ORourke MF.Benefits from angiotensin-converting enzyme inhibitorbeyond blood pressure lowering: beyond blood pressure orbeyond the brachial artery? J Hypertens2005;23:551-6.27. Chen CH, Ting CT, Lin SJ et al. Different effects of fos-inopril and atenolol on wave reflections in hypertensivepatients. Hypertension1995;25:1034-41.28. Williams B, Lacy PS, Thom SM et al. Differential impact ofblood pressure-lowering drugs on central aortic pressure andclinical outcomes: principal results of the Conduit Artery FunctionEvaluation (CAFE) study. Circulation2006;113:1213-25.

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32. Bravo EL, Tarazi RC, Dustan HP. On the mechanism ofsuppressed plasma-renin activity during beta-adrenergicblockade with propranolol. J Lab Clin Med1974;83:119-28.33. Lijnen P, Fagard R, Staessen J, Amery A. Effect ofchronic diuretic treatment on the plasma renin-angiotensin-aldosterone system in essential hypertension. Br J ClinPharmacol1981;12:387-92.

34. Batenburg WW, de Bruin RJ, van Gool JM et al.Aliskiren-binding increases the half life of renin and proreninin rat aortic vascular smooth muscle cells. Arterioscler ThrombVasc Biol2008;28:1151-7.35. Menard J, Guyene TT, Peyrard S, Azizi M. Conformationalchanges in prorenin during renin inhibition in vitro and in vivo.

J Hypertens2006;24:529-34.36. Schalekamp MA, Derkx FH, Deinum J, Danser AJ.Newly developed renin and prorenin assays and the clinicalevaluation of renin inhibitors.J Hypertens2008;26:928-37.37. Mason JM, Dickinson HO, Nicolson DJ, Campbell F,Ford GA, Williams B. The diabetogenic potential of thiazide-type diuretic and beta-blocker combinations in patients withhypertension.J Hypertens2005;23:1777-81.38. Gillespie EL, White CM, Kardas M, Lindberg M,

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