Download A comparison of the tolerability of the direct renin inhibitor

Journal of Human Hypertension (2007) 21, 780–787
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ORIGINAL ARTICLE
A comparison of the tolerability of the
direct renin inhibitor aliskiren and
lisinopril in patients with severe
hypertension
RH Strasser1, JG Puig2, C Farsang3, M Croket4, J Li5 and H van Ingen4
1
Technical University Dresden, Heart Center, University Hospital, Dresden, Germany; 2Department of
Internal Medicine, La Paz Hospital, Madrid, Spain; 31st Department of Internal Medicine, Semmelweis
University, Budapest, Hungary; 4Novartis Pharma AG, Basel, Switzerland and 5Novartis Institutes for
Biomedical Research, Cambridge, MA, USA
Patients with severe hypertension (4180/110 mm Hg)
require large blood pressure (BP) reductions to reach
recommended treatment goals (o140/90 mm Hg) and
usually require combination therapy to do so. This
8-week, multicenter, randomized, double-blind, parallelgroup study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren
with the angiotensin converting enzyme inhibitor
lisinopril in patients with severe hypertension (mean
sitting diastolic blood pressure (msDBP)X105 mm Hg
and o120 mm Hg). In all, 183 patients were randomized
(2:1) to aliskiren 150 mg (n ¼ 125) or lisinopril 20 mg
(n ¼ 58) with dose titration (to aliskiren 300 mg or
lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required.
Aliskiren-based treatment (ALI) was similar to lisinoprilbased treatment (LIS) with respect to the proportion of
patients reporting an adverse event (AE; ALI 32.8%; LIS
29.3%) or discontinuing treatment due to AEs (ALI 3.2%;
LIS 3.4%). The most frequently reported AEs in both
groups were headache, nasopharyngitis and dizziness.
At end point, ALI showed similar mean reductions from
baseline to LIS in msDBP (ALI 18.5 mm Hg vs LIS
20.1 mm Hg; mean treatment difference 1.7 mm Hg
(95% confidence interval (CI) 1.0, 4.4)) and mean sitting
systolic blood pressure (ALI 20.0 mm Hg vs LIS
22.3 mm Hg; mean treatment difference 2.8 mm Hg
(95% CI 1.7, 7.4)). Responder rates (msDBPo90 mm Hg
and/or reduction from baselineX10 mm Hg) were 81.5%
with ALI and 87.9% with LIS. Approximately half of
patients required the addition of HCTZ to achieve BP
control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone,
or in combination with HCTZ, exhibits similar tolerability
and antihypertensive efficacy to LIS alone, or in
combination with HCTZ, in patients with severe hypertension.
Journal of Human Hypertension (2007) 21, 780–787;
doi:10.1038/sj.jhh.1002220; published online 31 May 2007
Keywords: aliskiren; renin–angiotensin system; angiotensin converting enzyme inhibitor; severe hypertension; thiazide
diuretic; combination therapy
Introduction
Patients with severe hypertension are at particularly
high cardiovascular risk due to the direct and
independent relationship between blood pressure
(BP) and the risk of mortality due to stroke and
ischaemic heart disease.1 Current treatment guidelines define severe hypertension as BP4160/100 mm
Hg (stage 2 hypertension) or 4180/110 mm Hg (grade
Correspondence: Professor RH Strasser, Technische Universität
Dresden, Herzzentrum Dresden, Universitätsklinik, Fetscherstr.
76, 01307 Dresden, Germany.
E-mail: [email protected]
Trial registry: This trial is registered at ClinicalTrials.gov with
trial identifier NCT00219050.
Received 31 October 2006; revised 16 March 2007; accepted 17
March 2007; published online 31 May 2007
3 hypertension),2,3 with a treatment target of o140/
90 mm Hg. Due to the large BP reductions required
for patients with severe hypertension to reach their
treatment goals, combination therapy is almost
invariably required.
Existing antihypertensive therapies are associated
with high rates of discontinuation, despite the
proven clinical benefit of reducing BP.4,5 A recent
population-based study of 4100 000 patients with
hypertension found that compliance with older drug
classes, such as diuretics, b-blockers and calcium
channel blockers, was as low as 36–59% after
1 year.5 Compliance was better with newer treatments,
such as angiotensin converting enzyme (ACE)
inhibitors (62%) and angiotensin receptor blockers
(ARBs; 71%).5 These differences are suspected to be
due to the poor tolerability of some of these drugs.5
Tolerability of aliskiren in patients with severe hypertension
RH Strasser et al
781
Significant adverse events (AEs) associated with
conventional antihypertensive drug classes include
fatigue or dizziness in 16% of patients receiving
b-blockers,6 Oedema in up to 70% of patients
receiving calcium channel blockers6,7 and a dry,
non-productive cough in 5–35% of patients receiving treatment with ACE inhibitors.6,8,9 However, this
does not explain the poor compliance observed with
diuretics, which have few symptomatic side effects.5
Inhibitors of the renin system, such as ACE
inhibitors and ARBs, do not provide optimal
suppression of the renin system as they stimulate a
reactive increase in plasma renin activity, which
may ultimately lead to elevated angiotensin II
levels.10 Consequently, direct inhibition of renin
(that is, targeting the renin system at its point of
activation) has long been proposed as the most
promising means of inhibiting the renin system.11
Aliskiren will be the first in a new class of oral
direct renin inhibitors for the treatment of hypertension. Aliskiren is a highly potent inhibitor of human
renin in vitro (IC50 ¼ 0.6 nmol/l) and in healthy
volunteers.12,13 Studies in patients with mildto-moderate hypertension (ESH-ESC grade 1 or 2,
or JNC7 stage 1) have shown that aliskiren provides
similar antihypertensive efficacy and tolerability to
ARBs,14,15 and that addition of hydrochlorothiazide
(HCTZ) to aliskiren produces significant additional
BP-lowering effects with maintained good tolerability.16 Aliskiren alone or in combination with HCTZ
has also been shown to provide highly effective BP
lowering with excellent tolerability over X1-year
period of treatment.17
The aim of the present study was to assess the
tolerability and antihypertensive efficacy of aliskirenbased treatment compared with treatment based on
the ACE inhibitor, lisinopril, in patients with severe
hypertension.
Materials and methods
Study population
This study enrolled 194 patients aged X18 years
with uncomplicated severe hypertension (mean
sitting diastolic blood pressure (msDBP)X105 mm Hg
and o120 mm Hg) from 12 study centres in
Germany, 9 in Spain and 5 in Hungary.
Exclusion criteria included a history or evidence
of secondary hypertension; antihypertensive treatment with more than three classes of antihypertensive medication; diabetes mellitus requiring insulin
treatment; type II diabetes mellitus with poor
glucose control (HbA1C48% at Visit 1); diagnosed
heart failure; history of myocardial infarction, coronary bypass surgery, or any percutaneous coronary
intervention; angina pectoris; potentially lifethreatening arrhythmia or symptomatic arrhythmia
or other life-threatening disease; any surgical or
medical condition that might significantly alter the
absorption, distribution, metabolism or excretion of
the study drugs; and known or suspected contraindications to the study medications.
The study was performed in compliance with the
Guidelines for Good Clinical Practice and the
Declaration of Helsinki of the World Medical
Association, and received approval by the appropriate independent ethics committees. All participants gave written informed consent before any
study-related procedure.
Study design
This was an 8-week, randomized, double-blind,
active-controlled, parallel-group study of aliskiren
compared with lisinopril (both with the optional
addition of HCTZ to achieve BP control) in adult
patients with uncomplicated severe hypertension.
Owing to the severity of the disease, the use of a
placebo treatment was not employed. Lisinopril was
selected as an active control because it is commonly
used to treat patients with severe hypertension.
The primary objective of this study was
to compare the tolerability of aliskiren-based treatment with treatment based on the ACE inhibitor,
lisinopril. The BP-lowering efficacy of these two
treatments was a secondary objective of this study.
The study consisted of three periods (Figure 1).
Eligibility for study entry was assessed at an initial
study visit and eligible patients then entered a
washout phase (period 1) of up to 10 days, during
which all other antihypertensive medications were
withdrawn. However, due to the severity of hypertension, and the potential increased cardiovascular
risk associated with the withdrawal of antihypertensive medication, the washout period was designed to minimize the length of time patients
remained untreated. Consequently, antihypertensive
medications were withdrawn for a minimum of 3
days and all participants with an msDBPX105 mm
Hg and o120 mm Hg at the end of the washout
period proceeded immediately to the active treatment phase of the study (period 3). Patients with
msDBPX85 mm Hg and o105 mm Hg after the
washout phase entered a single-blind placebo runin of 1–3 weeks (period 2). During this period, BP
was monitored weekly up to a maximum of 3 weeks
to assess eligibility for randomization (msDBPX
105 mm Hg and o120 mm Hg). Participants who
failed to meet the eligibility criteria after 3 weeks
were discontinued from the study. Any patient with
an msDBPX120 mm Hg and/or a mean sitting
systolic blood pressure (msSBP)X200 mm Hg at
any time during the washout or single-blind placebo
run-in periods was immediately discontinued from
the study.
In period 3, all patients who met the inclusion
criteria were randomized in a 2:1 ratio to receive
aliskiren 150 mg or lisinopril 20 mg once daily. BP
was assessed weekly for the first 2 weeks and
every 2 weeks thereafter. For patients with msDBPX
110 mm Hg or msSBPX180 mm Hg at the end of
Journal of Human Hypertension
Tolerability of aliskiren in patients with severe hypertension
RH Strasser et al
782
Figure 1 Study design. Dashed arrows represent titration of treatment doses for patients whose BP was not controlled to the appropriate
target levels at weeks 1 or 2. Solid arrows indicate titration of drug doses at week 4 for patients who did not undergo early titration, but
whose BP was not controlled to target level at week 4. BP, blood pressure.
week 1, or with msDBPX95 mm Hg or
msSBPX160 mm Hg at the end of week 2, the
treatment dose was doubled (to aliskiren 300 mg or
lisinopril 40 mg). Subsequent addition of HCTZ
25 mg was permitted for these patients if msDBP
was X95 mm Hg or msSBP remained X160 mm Hg
at weeks 2 or 4, or if msDBP was X90 mm Hg or
msSBP was X140 mm Hg at week 6 (Figure 1). For
patients who did not require early titration at weeks
1 or 2, doses were increased to aliskiren 300 mg, or
lisinopril 40 mg at the end of week 4 if BP was not
controlled to target levels (msDBPo90 mm Hg and
msSBPo140 mm Hg).
Aliskiren 150 mg and matching placebo were
provided as film-coated tablets. Lisinopril 20 mg,
lisinopril 40 mg and matching placebo were provided as identically appearing capsules, as were
HCTZ 25 mg and matching placebo. Patients were
requested to take the study medication orally with
water at approximately 0800 hours, except on the
day of a study visit.
Randomization was performed by the interactive
voice response system provider using a validated
system that automates the random assignment of
treatment groups to randomization numbers. All
patients, investigator staff, persons performing the
assessments and data analysts remained blinded to
the identity of the treatment from the time of
randomization until database lock.
Each investigator site was supplied with a
computer loaded with electronic data capture software and investigator site staff were trained to use
this system by Novartis personnel. All required data
were entered into the electronic case report forms
(eCRFs) by designated investigator site personnel
before transfer to Novartis via a secure Virtual
Private Network. Novartis staff reviewed the eCRFs
entered by investigational staff for completeness and
Journal of Human Hypertension
accuracy and instructed the site personnel to make
any required corrections or additions. Quality
control audits of all key safety and efficacy data in
the database were carried out before database lock.
Tolerability assessments
The safety population was defined as all randomized patients who received at least one dose of
study medication. All AEs, serious adverse events
(SAEs) and use of concomitant medications were
recorded at each study visit. Non-directive questioning was used to elicit information on AEs; for all
AEs, the severity, relationship to study drug and
duration were assessed, and any action taken was
recorded.
Evaluations of routine blood chemistry, haematology and urine values, as well as a physical
examination, vital signs and ECG recordings, were
performed at screening, randomization (start of
period 3) and after the completion of the study.
Efficacy assessments
BP and pulse rate were measured at follow-up visits
on weeks 1, 2, 4, 6 and 8 of the double-blind
treatment period. Sitting and standing BP was
measured at trough (2473 h post-dose) from the
arm in which the highest sitting DBP was found at
the first study visit, using a calibrated standard
sphygmomanometer. Three measurements were
taken at each visit and the average of the three
measurements was used for analysis. Pulse rate was
measured for 30 s immediately before the first sitting
BP measurement.
Statistical analyses
Patients were randomized in a 2:1 ratio between
aliskiren and lisinopril treatment groups, respec-
Tolerability of aliskiren in patients with severe hypertension
RH Strasser et al
783
tively. The lisinopril treatment group contained
fewer patients as lisinopril served solely as a
reference drug for the evaluation of the tolerability
of aliskiren. A sample size of 153 completed patients
(102 patients in the aliskiren-based treatment group
and 51 patients in the lisinopril-based treatment
group) was considered sufficient to evaluate the
overall tolerability profile of the aliskiren- and
lisinopril-based regimens and to satisfy the regulatory requirement for the assessment of safety.
Assuming a dropout rate of 15%, a total of X180
patients were to be randomized. No precise power
computations were carried out as this was a safety
study and was not powered for any specific end
point. There were no pre-set margins for the
assessment of safety in terms of AE rates or other
safety parameters.
The primary assessment of tolerability was based
on the frequency of AEs, laboratory abnormalities
and SAEs. The frequency distribution of patients
who experienced orthostatic BP changes (a decrease
of at least 20 mm Hg in SBP or a decrease of at least
10 mm Hg in DBP when moving from a sitting to a
standing position) was also assessed.
All efficacy variables were analysed for the intentto-treat population, which was defined as all
randomized patients who had a baseline (start of
period 3) measurement and at least one post-baseline efficacy measurement. The key efficacy variables were change from baseline in msDBP and
msSBP. The proportion of responders (patients with
msDBPo90 mm Hg and/or X10 mm Hg reduction
from baseline in msDBP) was also assessed.
Descriptive statistics were provided for each
efficacy variable. For each patient, the last postbaseline measurement of a variable during the
double-blind period was carried forward as the
end point measurement for the variable to be
analysed. The study was not powered for efficacy
comparisons.
Results
Patient characteristics
A total of 194 patients were enrolled in the study, of
whom 183 were randomized to receive active
treatment (aliskiren, n ¼ 125; lisinopril, n ¼ 58). Of
these, 138 patients were randomized directly into
the active treatment phase. Fifty-six patients entered
the optional single-blind run-in period, of whom 45
were subsequently randomized to receive study
treatment; the other 11 patients were excluded for
abnormal test procedure results (n ¼ 7; this includes
patients who did not meet BP inclusion criteria),
withdrawal of consent (n ¼ 3) and administrative
problems (n ¼ 1).
The treatment groups were generally similar with
respect to demographics and baseline characteristics
(Table 1). All but one of the patients in the study was
Caucasian (99.5%) and a little more than half of the
patients were male (56.8%). The mean age of
patients was 55 years with a mean duration of
hypertension of 9 years. Nearly half of patients were
obese with 46.4% of patients having a body mass
index of at least 30 kg/m2. The msDBP and msSBP
values at baseline were 108.3 and 162.8 mm Hg,
respectively, and these values were similar between
the two treatment groups.
Most randomized patients (83.1%) had one or more
past or continuing medical conditions, the most
common of which was hypercholesterolaemia. There
were no notable differences between the two treatment groups in the incidence of past or continuing
medical conditions (Table 1) or in the use of
concomitant medications (55.2% in each group).
Mean exposure to drug treatment was similar for
both treatment groups (aliskiren, 52.2 days; lisinopril, 53.9 days) and close to the planned duration of
treatment of 56 days. Overall, 165 patients completed the study and the completion rate was similar
in the two treatment groups (aliskiren, 88.8%;
lisinopril, 93.1%). The main reasons for discontinuation were AEs (n ¼ 6; 3.3%), withdrawal of
consent (n ¼ 5; 2.7%) and unsatisfactory therapeutic
effect (n ¼ 3; 1.6%). At the end of the study, 33
patients (26.4%) were receiving aliskiren 150 mg, 25
patients (20.0%) were being treated with aliskiren
300 mg and 67 patients (53.6%) were receiving
aliskiren 300 mg plus HCTZ 25 mg. In the lisinopril
group, 20 patients (34.5%) were being treated with
lisinopril 20 mg, 12 patients (20.7%) were receiving
lisinopril 40 mg and 26 patients (44.8%) were
receiving lisinopril plus HCTZ 25 mg.
Tolerability
Adverse events. Aliskiren- and lisinopril-based
treatments were well tolerated. The incidence of
AEs was similar in the two treatment groups; 32.8%
of patients in the aliskiren group and 29.3% of
patients in the lisinopril group reported at least one
AE during the double-blind treatment period. There
were no notable differences between treatment
groups in the type of AEs observed (Table 2) and
the majority of AEs were mild or moderate in
severity. The most frequently reported AEs were
headache (8.7%), nasopharyngitis (2.7%), dizziness
(1.6%) and fatigue (1.6%). Only 3.3% of patients
withdrew from the study due to AEs with no more
than one person reporting the same AE as a reason
for discontinuation.
The proportion of patients reporting AEs that
were suspected by the investigator to be related to
the study drugs was similar in the aliskiren group
(5.6%) and the lisinopril group (5.2%). The only
individual AE suspected to be related to study
treatment in more than one patient was headache
(two patients in the aliskiren group and one in the
lisinopril group).
No deaths occurred during the study. Three SAEs
were reported by two patients, both in the lisinopril
Journal of Human Hypertension
Tolerability of aliskiren in patients with severe hypertension
RH Strasser et al
784
Table 1 Patient baseline characteristics
Parameter
Age (years)
X65 years, n (%)
X75 years, n (%)
Gender
Male, n (%)
Female, n (%)
Race, n (%)
Caucasian
Other
Weight (kg)
Height (cm)
BMI (kg/m2)
X30 kg/m2, n (%)
Diagnosis of diabetes,a n (%)
Diagnosis of metabolic syndrome,b n (%)
Duration of hypertension (years)
Medical history and continuing medical conditions, n (%)
Hypercholesterolaemia
Hyperuricaemia
Prior medications, n (%)
b-blocking agents
Dihydropyridine CCBs
ACE inhibitors
ARBs
ACE inhibitors and diuretic combinations
ARBs and diuretic combinations
Concomitant medications, n (%)
HMG CoA reductase inhibitors
Acetylsalicylic acid
Topical anti-inflammatory preparations
NSAIDs
Biguanides
ACE inhibitorsc
Dihydropyridine derivatives
Mean sitting DBP (mm Hg)
Mean sitting SBP (mm Hg)
Mean sitting pulse rate (b.p.m.)
Aliskiren (n ¼ 125)
Lisinopril (n ¼ 58)
Total (n ¼ 183)
55.3712.3
28 (22.4)
9 (7.2)
55.6711.1
12 (20.7)
3 (5.2)
55.4711.9
40 (21.9)
12 (6.6)
70 (56.0)
55 (44.0)
34 (58.6)
24 (41.4)
104 (56.8)
79 (43.2)
124 (99.2)
1 (0.8)
86.0716.6
168710
30.575.3
60 (48.0)
15 (12.0)
66 (52.8)
9.179.3
103 (82.4)
21 (16.8)
8 (6.4)
111 (88.8)
39 (31.2)
29 (23.2)
33 (26.4)
24 (19.2)
20 (16.0)
15 (12.0)
69 (55.2)
23 (18.4)
15 (12.0)
10 (8.0)
8 (6.4)
7 (5.6)
2 (1.6)
2 (1.6)
108.473.1
163.4713.5
74.9710.8
58 (100)
0 (0)
84.9720.0
16779
30.376.3
25 (43.1)
8 (13.8)
34 (58.6)
9.877.4
49 (84.5)
9 (15.5)
5 (8.6)
48 (82.8)
21 (36.2)
18 (31.0)
12 (20.7)
13 (22.4)
4 (6.9)
5 (8.6)
32 (55.2)
12 (20.7)
8 (13.8)
3 (5.2)
3 (5.2)
4 (6.9)
1 (1.7)
1 (1.7)
108.072.5
161.7712.6
74.4711.2
182 (99.5)
1 (0.5)
85.6717.7
16879
30.575.6
85 (46.4)
23 (12.6)
100 (54.6)
9.378.7
152 (83.1)
30 (16.4)
13 (7.1)
159 (86.9)
60 (32.8)
47 (25.7)
45 (24.6)
37 (20.2)
24 (13.1)
20 (10.9)
101 (55.2)
35 (19.1)
23 (12.6)
13 (7.1)
11 (6.0)
11 (6.0)
3 (1.6)
3 (1.6)
108.373.0
162.8713.2
74.7710.9
Abbreviations: ACE, angiotensin converting enzyme; ARBs, angiotensin receptor blockers; BMI, body mass index; b.p.m., beats per minute; CCBs,
calcium channel blockers; DBP, diastolic blood pressure; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; NSAIDs, non-steroidal antiinflammatory drugs; SBP, systolic blood pressure.
Values are presented as mean7s.d. unless otherwise stated.
a
From medical history.
b
Metabolic syndrome was defined as any three of the following: waist circumference 4102 cm for men or 488 cm for women; triglycerides
X1.69 mmol/l (X150 mg/dl); high-density lipoprotein cholesterol o1.04 mmol/l (o40 mg/dl) for men or o1.29 mmol/l (50 mg/dl) for women;
SBPX130 or DBPX85 mm Hg; fasting glucoseX6.1 mmol/l (X110 mg/dl).
c
Other than lisinopril given as part of this study.
group; one patient suffered severe angina pectoris
and myocardial infarction (leading to hospitalization and percutaneous coronary intervention with
stent implantation) and one patient suffered appendicitis. These events were not suspected to be
related to study treatment.
Laboratory values and physical signs
Notable changes in vital signs occurring at singletime points included an increase in mean SBP for
one patient in the aliskiren group, and decreased
pulse rate for one patient in the lisinopril group;
neither of these changes was reported as an AE. The
incidence of patients with orthostatic BP changes at
each visit was low (less than 7% at any visit in any
treatment group) and similar to baseline, and there
Journal of Human Hypertension
were no notable differences between treatment
groups.
There were no notable changes in haematological
parameters in patients receiving aliskiren-based
treatment (n ¼ 125) during the course of the study.
In the lisinopril treatment group (n ¼ 58), three
patients recorded abnormal haematological values:
one patient demonstrated an elevated (475%)
platelet count, one patient demonstrated an elevated
white blood cell count (450%) and, as is often
observed with ACE inhibitor therapy,18–20 one
patient recorded a 420% decrease in haemoglobin
level. The haematological profiles of all other
patients in the lisinopril treatment group remained
normal throughout the course of the study.
For most biochemistry parameters, changes from
baseline were small and there were no meaningful
Tolerability of aliskiren in patients with severe hypertension
RH Strasser et al
785
Table 2 Safety and tolerability
Aliskiren (n ¼ 125)
Lisinopril (n ¼ 58)
Total (n ¼ 183)
Any AE
Discontinuations due to AE
SAE
Discontinuations due to abnormal lab values
41
4
0
0
(32.8)
(3.2)
(0)
(0)
17
2
2
0
(29.3)
(3.4)
(3.4)
(0)
58
6
2
0
(31.7)
(3.3)
(1.1)
(0)
AEs by primary system organ class (X2% of total in any group)
Nervous system disorders
Infections and infestations
Gastrointestinal disorders
General disorders and administration site conditions
Musculoskeletal and connective tissue disorders
Skin and subcutaneous tissue disorders
Respiratory, thoracic and mediastinal disorders
13
6
5
4
3
6
4
(10.4)
(4.8)
(4.0)
(3.2)
(2.4)
(4.8)
(3.2)
6
3
2
3
4
0
1
(10.3)
(5.2)
(3.4)
(5.2)
(6.9)
(0)
(1.7)
19
9
7
7
7
6
5
(10.4)
(4.9)
(3.8)
(3.8)
(3.8)
(3.3)
(2.7)
Most common individual AEs (X1% of total in any group)
Headache
Nasopharyngitis
Dizziness
Fatigue
Peripheral edema
Vertigo
Back pain
Cough
Neck pain
11
3
1
1
2
2
1
1
1
(8.8)
(2.4)
(0.8)
(0.8)
(1.6)
(1.6)
(0.8)
(0.8)
(0.8)
5
2
2
2
0
0
1
1
1
(8.6)
(3.4)
(3.4)
(3.4)
(0.0)
(0.0)
(1.7)
(1.7)
(1.7)
16
5
3
3
2
2
2
2
2
(8.7)
(2.7)
(1.6)
(1.6)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
Abbreviations: AEs, adverse events; SAE, serious adverse event.
Table shows the number (%) of patients with an AE.
differences between treatment groups. Overall,
mean uric acid levels increased from baseline in
both treatment groups (by 39.2 and 45.7 mmol/l for
the aliskiren and lisinopril groups, respectively).
There was a slight increase in creatinine levels in
the aliskiren group (1.5 mmol/l) compared with a
slight decrease in the lisinopril group (0.6 mmol/l).
Few individual patients showed notable abnormal
laboratory values. Low serum potassium levels
(o3.5 mmol/l) occurred in three patients (5.2%) in
the lisinopril group and three patients (2.5%) in the
aliskiren group. There was only one case each of
serum potassium elevation (45.5 mmol/l) and blood
urea nitrogen elevation (414.28 mmol/l), both in the
aliskiren group. None of the abnormal laboratory
values was reported as an AE.
Antihypertensive efficacy
Of the 125 patients randomized to receive the
aliskiren-based treatment regimen, the majority
was titrated from 150 to 300 mg (n ¼ 92; 73.6%),
and a little more than half (n ¼ 67; 53.6%) received
add-on treatment with HCTZ 25 mg. Similar rates of
titration (n ¼ 38; 65.5%) and add-on therapy (n ¼ 26;
44.8%) were observed with lisinopril-based treatment (Figure 2).
At the week 8 end point, aliskiren-based treatment
and lisinopril-based treatment provided similar reductions from baseline (mean7s.d.) in msDBP (aliskiren
18.578.7 mm Hg vs lisinopril 20.177.9 mm Hg; mean
treatment difference 1.7 mm Hg (95% CI 1.0, 4.4))
and msSBP (aliskiren 20.0715.3 mm Hg vs lisinopril
Figure 2 Proportion of patients with severe hypertension
receiving monotherapy vs add-on therapy with HCTZ during
the active treatment phase of the study. Graph shows proportion
of patients who stayed on aliskiren (150 or 300 mg) or lisinopril
(20 or 40 mg) monotherapy compared with the proportion who
required add-on therapy with HCTZ 25 mg for additional BP
control. BP, blood pressure; HCTZ, hydrochlorothiazide.
22.3714.6 mm Hg; mean treatment difference
2.8 mm Hg (95% CI 1.7, 7.4)).
Marked reductions in msDBP and msSBP were
observed after 1 week of treatment in both groups,
and absolute BP values in the aliskiren- and
lisinopril-based treatment groups were similar at
all time points during this study (Figure 3).
The majority of patients in both treatment groups
exhibited a successful response to treatment
(msDBPo90 mm Hg, and/or X10 mm Hg reduction
from baseline) at the week 8 end point. The
proportion of responders for the aliskiren-based
Journal of Human Hypertension
Tolerability of aliskiren in patients with severe hypertension
RH Strasser et al
786
Figure 3 Effect of study treatment on msDBP and msSBP
throughout the active-treatment phase in patients with severe
hypertension. Graph shows absolute blood pressure values in
patients receiving aliskiren-based therapy (filled squares) or
lisinopril-based therapy (open circles). Blood pressure was
measured at weeks 1, 2, 4, 6 and 8. Values are presented as
mean7s.d. msDBP, mean sitting diastolic blood pressure; msSBP,
mean sitting systolic blood pressure.
regimen (81.5%) was similar to that observed with
the lisinopril-based regimen (87.9%).
ability of aliskiren monotherapy or combinations of
aliskiren and HCTZ in patients with mild-tomoderate hypertension (JNC7 stage 1, or ESH-ESC
grade 1 or 2).14,16 Aliskiren, alone or in combination
with HCTZ, also demonstrated excellent long-term
tolerability in a 12-month clinical trial in patients
with mild-to-moderate hypertension.17
The design of the present study allowed for the
addition of HCTZ 25 mg in patients who did not
achieve BP control with aliskiren or lisinopril
monotherapy. Although the present study was not
designed to have sufficient statistical power for
comparisons of antihypertensive efficacy, aliskirenbased therapy provided BP-lowering effects similar
to those of lisinopril-based treatment in patients
with severe hypertension.
In conclusion, the results of the present study
show that aliskiren-based treatment (with the addition of HCTZ as needed for BP control) is well
tolerated and provides highly effective BP lowering
similar to that of a lisinopril-based treatment regimen in patients with severe hypertension. An
antihypertensive regimen based on the direct renin
inhibitor aliskiren therefore represents a well-tolerated and effective option for the treatment of severe
hypertension.
Discussion
Characteristics that physicians look for when
choosing an antihypertensive drug include sustained BP lowering efficacy (both alone and in
combination with other agents), a good tolerability
profile, and convenient dosing to ensure good
compliance. This is the first study to investigate
the tolerability and efficacy of the orally effective,
direct renin inhibitor aliskiren in patients with
severe hypertension (JNC7 stage 2, or ESH-ESC
grade 3). The study showed that aliskiren-based
therapy (with the optional addition of HCTZ to
achieve BP control) was well tolerated by patients
with severe hypertension, and provided similar
BP-lowering effects to therapy based on the ACE
inhibitor lisinopril.
The incidence of AEs with aliskiren-based treatment was low, and similar to that observed with
lisinopril-based therapy. Moreover, the most frequently reported AEs in both groups were headache,
nasopharyngitis and dizziness, events that are
commonly observed in studies of antihypertensive
drugs in patients with severe hypertension.21–23
Aliskiren-based treatment did not result in any
significant changes in laboratory or biochemistry
values. Despite ACE inhibitors being commonly
associated with a dry non-productive cough
(5–35% of patients), the incidence of cough following lisinopril-based treatment was unusually low in
this study (2%).
The good tolerability of aliskiren-based therapy
observed in the present study in patients with severe
hypertension is consistent with previous studies
that have shown the placebo-like safety and tolerJournal of Human Hypertension
What is known about the topic
K Patients with severe hypertension (4180/110 mm Hg) require
large reductions in BP to achieve recommended BP levels and
as a result combination antihypertensive therapy is almost
invariably required.
K The renin system is a key regulator of volume and BP
homeostasis and inhibitors of the renin system (for example,
ACE inhibitors, angiotensin receptor blockers (ARBs)) are
widely used in the treatment of hypertension.
K The direct renin inhibitor (DRI), aliskiren, will be the first in a
new class of antihypertensive therapy. Studies in patients
with mild-to-moderate hypertension have shown that
aliskiren provides similar antihypertensive efficacy and
tolerability to ARBs.
What this study adds
This is the first study to evaluate the tolerability and efficacy
of a direct renin inhibitor in patients with severe
hypertension.
K Aliskiren, with the optional addition of the diuretic,
hydrochlorothiazide, is well tolerated in patients with severe
hypertension.
K Aliskiren-based treatment provides effective BP reductions in
patients with severe hypertension, similar to an equivalent
regimen based on the ACE inhibitor, lisinopril.
K
Acknowledgements
This study was supported by Novartis Pharma AG.
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