1 renin inhibitor the new way for the blood pressure control, anti-proteinuria, and renal protection...
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1
Renin Inhibitor Renin Inhibitor
The new way for the blood pressure control, The new way for the blood pressure control,
anti-proteinuria, and renal protectionanti-proteinuria, and renal protection
Chang-Chyi JenqChang-Chyi Jenq
2010-12-62010-12-6
2
Renin Angiotensin System Inhibition
Renin Angiotensin SystemRenin Angiotensin SystemPathophysiologic EffectsPathophysiologic Effects
ACEACE
ReninRenin
NaNa++/H/H22O retentionO retentionVasoconstrictionVasoconstrictionHypertensionHypertension
ATAT11 Receptor Receptor
AldosteroneAldosterone
AngiotensinogenAngiotensinogen
Ang IAng I
Ang IIAng II
Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006
GlomerularGlomerularvasoconstrictionvasoconstriction
InflammationInflammation Fibrosis Fibrosis
KidneyKidney
HypertrophyHypertrophy FibrosisFibrosis VasoconstrictionVasoconstriction
HeartHeart
VasoconstrictionVasoconstriction
BrainBrain
Hyperplasia hypertrophyHyperplasia hypertrophy InflammationInflammation OxidationOxidation Fibrosis Fibrosis
VesselsVessels
Biological effectsBiological effects
ACEisACEis
Non ACE pathwaysNon ACE pathways
ARBsARBs
PRAPRA
Direct renin inhibitorDirect renin inhibitor
PRAPRA
(Pro)renin(Pro)reninreceptorreceptor
Target cellTarget cell
VasoconstrictionVasoconstriction RemodellingRemodelling
VesselsVessels
KidneyKidney
HeartHeart
Direct renin inhibitorDirect renin inhibitor
Azizi M et al. 2006;
Feedback LoopFeedback Loop
Renin Angiotensin SystemPhysiologic Effects
3
Wood JM, et al. 2003
Aliskiren: Aliskiren: the first orally available direct the first orally available direct
renin inhibitorrenin inhibitor
Molecular weight = 609.8Molecular weight = 609.8 High solubility in High solubility in water water and biological and biological
fluidsfluids Non-peptide drug Non-peptide drug suitable for oral suitable for oral
administrationadministration
O
NH
CONH2
OH
H2N
CH3O
O
CH3O
4
Angiotensinogen
Aliskiren binds to the active Aliskiren binds to the active site of reninsite of renin
Aliskiren binds to a pocket in the renin molecule, blocking cleavage of angiotensinogen to angiotensin I
Renin
Aliskiren
Adapted from Wood JM, et al. 2003
5Aliskiren –Aliskiren – the next generation in the next generation in
antihypertensive treatmentantihypertensive treatment First direct renin inhibitor for hypertensionFirst direct renin inhibitor for hypertension
First major new treatment since the introduction of ARBs First major new treatment since the introduction of ARBs in 1994in 1994
Uniquely lowers PRA in monotherapy and combinationUniquely lowers PRA in monotherapy and combination Effective and sustained monotherapyEffective and sustained monotherapy Additional BP lowering when combined with other Additional BP lowering when combined with other
antihypertensivesantihypertensives Sustained 24-hour BP control with prolonged effectSustained 24-hour BP control with prolonged effect after after
withdrawalwithdrawal Placebo-like safety and tolerability profilePlacebo-like safety and tolerability profile Potential for improved Potential for improved end-organ protection end-organ protection viavia optimal optimal
suppression of the renin systemsuppression of the renin system BNP reduction in heart failureBNP reduction in heart failure LVH regression in hypertensive obesity LVH regression in hypertensive obesity Proteinuria reduction in DM nephropathyProteinuria reduction in DM nephropathy ASPIRE HIGHER program ASPIRE HIGHER program
6Unlike ACEIs and ARBs, aliskiren Unlike ACEIs and ARBs, aliskiren reducesreduces
Ang I, Ang II and PRAAng I, Ang II and PRA
↓↑↓↓Aliskiren
↑↑↑↑ARB
↑↑↓↑ACEI
PRAReninAng IIAng I
Feedback Loop
AT1 Receptor
ReninAng I
Angiotensinogen
Ang II
Direct renin inhibitor
ARBs
ACE
Non ACE pathways
ACEIs
Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006
Vasoconstriction Remodelling
Vessels
Kidney
Heart
7Elevated PRA may be associated Elevated PRA may be associated with increased risk of with increased risk of myocardial infarctionmyocardial infarction
†Risk factors defined as: smoking, cholesterol >6.3 mg/dL, or left ventricular hypertrophy
MI rate/1000 person-years40
10
20
30
Low risk:No additionalrisk factors†
Moderate risk:1 additional risk factor†
High risk:2 additionalrisk factors†
Plasma renin activity (PRA)HighNormalLow
Alderman et al. Am J Hypertens 1997.
For every 2-unit increase in PRA, there was an overall 25% increase in MI incidence
0
8Elevated PRA predicts cardiac Elevated PRA predicts cardiac events in patients receiving events in patients receiving
optimal HF treatmentoptimal HF treatment
1.0
0.8
0.6
0.4
0.2
0Cu
mu
lati
ve s
urv
ival
Follow-up (days)
0 500 1000 1500 2000 2500 3000
PRA >5.48 nmol/L/h (>7.11 ng/mL/h)
PRA <5.48 nmol/L/h (<7.11 ng/mL/h)
p<0.001
n=147
n=517
Vergaro et al. Eur Heart J 2008;29(Suppl.):393 [Abstract]
PRA and cardiac events (n=699, patients on treatment for heart failure)
9
Tryggvason et al. (2006) N Engl J Med.
Podocyte Podocyte 足細足細胞胞
GBMGBM
Fenestrated Fenestrated endothelium endothelium
Shankland SJ (2006) Kidney Int
albumin
albumin
細胞骨骼支撐細胞骨骼支撐
Other protein
10
RAS inhibition reduces Proteinuria RAS inhibition reduces Proteinuria • 蛋白尿能預測慢性腎病的進展及心 ( 腦 ) 血管疾病死亡率。• 使用 ARB/ACEi/DRi 等腎素 - 血管張力素系統抑制劑,能減低
蛋白尿的嚴重程度,並有效延緩慢性腎衰竭的進展。• 足細胞的致病機制和蛋白尿的發生機制息息相關。• 腎絲球若有外來的 stress ,足細胞的 RAS 會活化以因應 。• 長期 RAS 過度活化對足細胞的影響:導致足細胞的細胞骨骼重
組變化, 也引起腎絲球過濾選擇性的通透性增加。• 這個訊息傳導是由血管張力素第一型受體 (AT1R) 傳遞:
– 導致細胞內的 reactive oxygen species ( 氧化壓力 ) 上升– 也導致附著蛋白 actinin-4 的過度消耗及生成減少– 也導致抗氧化蛋白 Prdx2 生成減少,增加足細胞凋亡– 持續的 RAS 過度活化會不可逆的傷害並減少足細胞
• 基礎醫學實驗支持 RAS i 是很好的高血壓基礎治療藥物
11
Rasilez® neutralizes the rise in Rasilez® neutralizes the rise in PRA induced by agents that PRA induced by agents that
stimulate renin releasestimulate renin release
Taylor A, et al. J Am Coll Cardiol 2007 (Pooled analysis)
−50
50
150
Rasilez® (mg)
Other treatment (mg)
−100
n=
Mean change from baseline in PRA after 8 weeks of treatment (%)
100
0101
12
−75 −72 −75
111***
aPlacebo from aliskiren/valsartan study***p<0.0001 vs pooled placebo; †p<0.001, ‡p<0.0001 vs placeboa
Pooled placebo
Rasilez®
150 300 600
107 186 64
72
38
HCTZ
25
39
−62
25
300
***
75
−44
74
Ramipril
300
10 10
****** *** ***
18
51
Placeboa
320
Valsartan
320300
160
59
†
61
−44‡
12
40
0
−20
−80
−100
−60
−40
20
Suppression of PRA is maintained Suppression of PRA is maintained following discontinuation of following discontinuation of
aliskiren treatmentaliskiren treatment
Herron J, et al. 2006 (Study 2308)
Mean change from baseline in PRA (%)
Week100 8
Placebo (n=66)
Aliskiren 150 mg (n=66)
Aliskiren 300 mg (n=66)
Aliskiren 600 mg (n=66)
Double-blind treatmentTreatment-free
withdrawal
13
The ASPIRE HIGHER The ASPIRE HIGHER clinical study programmeclinical study programme
OverviewOverview
14
15AVOIDAVOID Population and Population and
objectivesobjectivesStudy population:Study population: Patients with mild-to-moderate hypertension, type 2 Patients with mild-to-moderate hypertension, type 2
diabetes and nephropathy (UACR 200–3500 mg/g)diabetes and nephropathy (UACR 200–3500 mg/g)
Primary objective:Primary objective: Change in UACR from baseline to study endChange in UACR from baseline to study end with with
aliskiren when added to losartan 100 mg once daily aliskiren when added to losartan 100 mg once daily and optimal antihypertensive therapy, compared with and optimal antihypertensive therapy, compared with placeboplacebo
Secondary objectives included:Secondary objectives included: Proportion of patients with Proportion of patients with ≥≥50% reduction in UACR at 50% reduction in UACR at
study endstudy end Effect of treatment on BPEffect of treatment on BP Safety and tolerabilitySafety and tolerability
UACR – urinary albumin-to-creatinine ratio Parving H-H, et al. 2008 (AVOID)
16
Aliskiren in the eValuation of Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) prOteinuria In Diabetes (AVOID)
studystudy
All patients continue to receive All patients continue to receive open-label losartan 100 mg and open-label losartan 100 mg and optimal antihypertensive therapy optimal antihypertensive therapy during the double-blind periodduring the double-blind period
Patients force-titrated after 3 Patients force-titrated after 3 monthsmonths
All treatments administered once All treatments administered once dailydaily
3 months
Placebo
Aliskiren 150 mg
+
3 months 3 months
Placebo
Aliskiren 300 mg
Randomization
Open-label Double-blind
Losartan 100 mg + optimal antihypertensive therapy
Parving H-H, et al. 2008 (AVOID)
17
Optimal antihypertensive therapy +
VariableAliskiren(n=301)
Placebo (n=298)
Mean sitting blood pressure, mmHg
Systolic 135 ± 12 134 ± 12
Diastolic 78 ± 8 77 ± 9
Geometric mean UACR, mg/g 513 (463–569) 553 (502–609)
Geometric mean UAER, μg/min 495 (440–557) 520 (469–576)
Mean eGFR, mL/min/1.73 m2 68.5 ± 25.7 66.8 ± 24.5
Baseline laboratory variables were Baseline laboratory variables were similar in the aliskiren and placebo similar in the aliskiren and placebo
groupsgroups
UAER – urinary albumin excretion rateeGFR – estimated glomerular filtration rateData are presented as mean ± SD, except for UACR and UAER, which are shown as geometric mean (95% CI) Parving H-H, et al. 2008 (AVOID)
18
BP remained similar in the aliskiren and BP remained similar in the aliskiren and placebo groups throughout the course of placebo groups throughout the course of
the studythe study
60
140
Mean sitting BP (mmHg)
130
120
110
20161284–2Week
24
Systolic
Diastolic
100
90
80
70
22181410620
Aliskiren PlaceboOptimal antihypertensive therapy +
Parving H-H, et al. 2008 (AVOID)
19
Optimal treatment + aliskiren 300 mg
Mean change from baseline§ in UACR at Month 6 (%)
0
−15
−20
−10
−5
n=289n=287
−18
52
*Optimal treatment
+ placebo
Aliskiren provides significantly greater Aliskiren provides significantly greater reductions in UACR compared with reductions in UACR compared with
placeboplacebo
§Baseline UACR values – aliskiren 513 pg/mL, placebo 553 pg/mL; baselinewas Week −2 value; data are shown as percentage change in geometric mean*p<0.001 vs placebo
Parving H-H, et al. 2007 (AVOID)Parving H-H, et al. 2008 (AVOID)
20% reductionin UACRVs. placebo
20% reductionin UACRVs. placebo
20
Patients with ≥50% reduction in UACR from baseline at Month 6 (%)
25
10
0
15
20
30
12.5
5
n=298n=301
24.7*
Optimal treatment + aliskiren 300 mg
Optimal treatment+ placebo
Significantly more patients achieve Significantly more patients achieve ≥50% reduction in UACR from ≥50% reduction in UACR from
baseline with aliskiren than with baseline with aliskiren than with placeboplacebo
*p<0.001 vs placeboBaseline was Week –2 valuen values represent number of patients randomized to each group Parving H-H, et al. 2008 (AVOID)
21
Aliskiren provides greater reductions in Aliskiren provides greater reductions in UACR than placebo across different patient UACR than placebo across different patient
subgroupssubgroups
Data are shown as geometric mean with 95% CI for the ratio of the treatment effect for aliskiren:placebo
MalesFemales
Gender
Non-CaucasianCaucasian
Race
< median≥ median
Age, years
Interaction p-value
0.63
0.77
0.28
Favoursaliskiren
Favoursplacebo
0.1 1 10
eGFR, mL/min/1.73 m2
≥ median< median
UACR, mg/g
< median≥ median
< median≥ median
SBP, mmHg
0.89
0.29
1.00
Interaction p-value
0.1 1 10
Favoursaliskiren
Favoursplacebo
Parving H-H, et al. 2008 (AVOID)
22Aliskiren provides effective BP-Aliskiren provides effective BP-lowering lowering
in patients with impaired renal in patients with impaired renal function: pooled analysisfunction: pooled analysis
Mean change from baseline in mean sitting BP after 8 weeks (mmHg)
Weir MR, et al. 2007 (Pooled analysis)
Aliskiren 300 mgAliskiren 150 mg
eGFR <60
–14.9
0
5
10
15 –14.7
–10.4–9.4
–11.2–10.1
–11.5
n=25 n=740 n=736n=26 n=25 n=740 n=736 n=26
–11.4
eGFR <60 eGFR ≥60 eGFR ≥60
DBP SBP
eGFR: estimated glomerular filtration rate (assessed in mL/min/1.73 m2)
23Addition of Rasilez® to losartan Addition of Rasilez® to losartan and optimal antihypertensive and optimal antihypertensive
therapy was generally well tolerated therapy was generally well tolerated during the studyduring the studyOptimal antihypertensive
therapy +
Rasilez® (n=301)
Placebo(n=298)
Any adverse event (AE), n (%) 201 (66.8) 200 (67.1)
Any serious AE, n (%) 27 (9.0) 28 (9.4)
Discontinuations due to AEs, n (%) 17 (5.6) 19 (6.4)
Deaths, n (%) 0 2 (0.7)
AEs reported by ≥5% of patients in either treatment group, n (%)
Headache 18 (6.0) 11 (3.7)
Nasopharyngitis 18 (6.0) 15 (5.0)
Dizziness 15 (5.0) 10 (3.4)
Hyperkalaemia 15 (5.0) 17 (5.7)
Peripheral oedema 13 (4.3) 23 (7.7)
Data are shown for the double-blind period
Parving HH et al. N Eng J Med 2008
24
Effect of study treatments Effect of study treatments on laboratory valueson laboratory values
Optimal antihypertensive therapy +
Aliskiren (n=299)
Placebo(n=297)
Potassium <3.5 mmol/L, n (%) 15 (5.0) 11 (3.7)
>5.5 mmol/L, n (%) 41 (13.7) 32 (10.8)
≥6.0 mmol/L, n (%) 14 ( 4.7) 5 (1.7)
Creatinine >2.0 mg/dL, n (%) 37 (12.4) 54 (18.2)
BUN >40.0 mg/dL, n (%) 65 (21.7) 66 (22.2)
BUN – blood urea nitrogenData are presented as number of patients with pre-specified abnormallaboratory values at any time during the double-blind period
• The incidence of serum potassium >6.0 mEq/L was numerically, but not significantly greater with aliskiren compared with placebo (p=0.06)
Parving H-H, et al. 2008 (AVOID)
25
AVOIDAVOIDSummarySummary
In patients with hypertension, type 2 diabetes and In patients with hypertension, type 2 diabetes and nephropathy, receiving losartan 100 mg once-daily and nephropathy, receiving losartan 100 mg once-daily and optimal antihypertensive therapy aliskiren 300 mg optimal antihypertensive therapy aliskiren 300 mg provided a significant additional mean reduction in UACR provided a significant additional mean reduction in UACR from baseline of 20% compared with placebofrom baseline of 20% compared with placebo
As differences in BP between the aliskiren and placebo As differences in BP between the aliskiren and placebo groups were small and not considered clinically groups were small and not considered clinically meaningfulmeaningful, the effect of aliskiren on UACR appears to be , the effect of aliskiren on UACR appears to be independent of the level of BP control, suggesting a independent of the level of BP control, suggesting a potential renoprotective effect for aliskirenpotential renoprotective effect for aliskiren
Aliskiren has Aliskiren has tolerabilitytolerability comparable to placebo when comparable to placebo when administered to patients with hypertension, type 2 administered to patients with hypertension, type 2 diabetes and nephropathy, receiving losartan 100 mg and diabetes and nephropathy, receiving losartan 100 mg and optimal antihypertensive therapyoptimal antihypertensive therapy
26
27
Anti-proteinuric effect of aliskiren in Anti-proteinuric effect of aliskiren in patients with hypertension and Type patients with hypertension and Type
2 diabetes – 2 diabetes – Study designStudy design
Day 1 Day 28 Day 56
*slow-release furosemide; UACR: urinary albumin-to-creatinine ratio
28 day washout 28 day treatment 28 day washout
Furosemide* Aliskiren 300 mg odFurosemide Furosemide
Patients with Type 2 diabetes, hypertension and albuminuria received stable doses of furosemide throughout the study
• Aims: to investigate the time course of the anti-proteinuric effect and the antihypertensive effect of aliskiren 300 mg/day
Persson F, et al. 2008
28
Aliskiren significantly reduces Aliskiren significantly reduces UACR from baseline in patients UACR from baseline in patients with diabetes and albuminuriawith diabetes and albuminuriaGeometric mean UACR (mg/g)
200
50
100
150
01
2–45–7
8–1011–13
14–1617–19
20–2223–25
26–2829–31 53–54
32–3435–37
38–4041–43
44–4647–49
50–52
Washout phaseTreatment phase
Day*p=0.04; **p<0.001; †p=0.02 vs baseline; NS: not statistically significant (p=0.14)
*
**†**
NS
Persson F et al. Kidney Int 2008
44% reduction in UACR from baseline at Day 28
Effect persisted 11 days
44% reduction in UACR from baseline at Day 28
Effect persisted 11 days
29
Aliskiren significantly reduces UACR Aliskiren significantly reduces UACR from baseline in patients with Type 2 from baseline in patients with Type 2
diabetes and albuminuriadiabetes and albuminuria
*p<0.05; **p<0.001 vs baseline
Aliskiren 300 mg + furosemide
Days 2–4 Days 8–10 Days 26–28
n=15 n=15 n=15
−17
−31
−44
Mean change from baseline in UACR (%)
−50
0
−40
−30
−20
−10
*
**
**
Persson F, et al. 2008
30
Values are mean±SEM* p≤0.05 vs baseline
Aliskiren significantly reduces Aliskiren significantly reduces 24-h SBP from baseline in 24-h SBP from baseline in patients with diabetes and patients with diabetes and
albuminuriaalbuminuria
**
* *
Mea
n (
SE
)S
BP
(m
mH
g)
130
135
140
145
150
Day
-1 7 14 21 28 35 42 49 56 Treatment phase Washout phase
Persson F, et al. Kidney Int 2008
Max. ↓ in av. 24-h SBP on day 14
Reduction persisted for 3 days after
treatment disc.
Max. ↓ in av. 24-h SBP on day 14
Reduction persisted for 3 days after
treatment disc.
31
comprised of three studiescomprised of three studies• The AVOID2 programme consists of three studies in diabetic The AVOID2 programme consists of three studies in diabetic
and non-and non-diabeticdiabetic patients, with and without patients, with and without nephropathynephropathy• Study #1 (SPP100A2243)Study #1 (SPP100A2243)
• Evaluating the effect of Evaluating the effect of aliskiren monotherapy and aliskiren monotherapy and aliskiren/ARB aliskiren/ARB combination therapy on albuminuriacombination therapy on albuminuria
• Study #2 (SPP100A2329)Study #2 (SPP100A2329)• Evaluating the effect of aliskiren compared with ACEI Evaluating the effect of aliskiren compared with ACEI
or ARB therapy or ARB therapy on renal blood flow and glomerular on renal blood flow and glomerular filtration ratefiltration rate
• Study #3 (SPP100A2260)Study #3 (SPP100A2260) • Evaluating the Evaluating the anti-proteinuric effect of aliskiren, anti-proteinuric effect of aliskiren,
on top of ACEI therapy and hydrochlorothiazide on top of ACEI therapy and hydrochlorothiazide
Persson F, et al. Diabetes Care 2009 doi:10.2337/dc09-0168 (Study 2243)Clinicaltrials.gov http://clinicaltrials.gov/ct2/show/NCT00660309 (Study 2329); Data on File 2009 (Study 2260)
32
AVOID2 Study #1
33Antiproteinuric effect of aliskiren compared, and Antiproteinuric effect of aliskiren compared, and in combination, with irbesartan in patients with in combination, with irbesartan in patients with Type 2 diabetes, hypertension and albuminuria – Type 2 diabetes, hypertension and albuminuria –
Study designStudy design
Randomization*4 weeks
Placebo
8 weeks
Irb 300
Alis 300
Run-in
8 weeks 8 weeks8 weeks
Ali/Irb 300/300
Placebo
Irb 300
Alis 300
Ali/Irb 300/300
Irb 300 Ali/Irb 300/300
Placebo Irb 300
Ali/Irb 300/300 Alis 300
Alis 300 Placebo
Furosemide# 40–60 mg
Double-blind
*Patients randomized to one of the treatment sequences#Furosemide administered to control fluid retention and BP Persson F, et al. 2008
34
−75
−100
−50
−25
0n=26n=26
*
n=26
–48%–58%
*–71%
* ‡
Mean change in UAER relative to placebo§ at Week 8 (%)
§Placebo UAER at baseline: 258 mg/day*p<0.001 vs placebo‡p<0.05 vs component monotherapies
Aliskiren300 mg
Irbesartan300 mg
Aliskiren/irbesartan300/300mg
Aliskiren/irbesartan combination Aliskiren/irbesartan combination provides significantly greater provides significantly greater
reductions in UAER than either reductions in UAER than either component monotherapycomponent monotherapy
Persson F, et al. 2008
35
Change in mean sitting BP relative to placebo at Week 8 (mmHg)
DBP SBP
Aliskiren 300 mg Irbesartan 300 mg Aliskiren/irbesartan300/300 mg
−14
–2
–8
−12
–6
–4
0
–10
n=26 n=26n=26
–3.9
n=26
–7.2
n=26
–3.6
n=26
–6.4
–7.6
–11.8
Placebo BP at endpoint: 135/78 mmHg*p<0.05 vs placebo
Aliskiren/irbesartan combination provides Aliskiren/irbesartan combination provides numerically greater reductions in BP than numerically greater reductions in BP than
either component monotherapyeither component monotherapy
*
**
*
*
Persson F, et al. 2008
36
Aliskiren neutralises the rise in PRA Aliskiren neutralises the rise in PRA induced by irbesartan in patients with Type induced by irbesartan in patients with Type 2 diabetes, hypertension and albuminuria 2 diabetes, hypertension and albuminuria
Mean change in PRA relative to placebo at Week 8 (%)
Aliskiren300 mg
Aliskiren/irbesartan300/300 mg
Irbesartan300 mg
Persson F, et al. 2008
n=26
**
−200
0
200
400
n=26
–87
**
n=26
321
–47
*
*p<0.01; **p<0.001 vs placebo
37
AVOID2 – Study #2AVOID2 – Study #2Effect on renal blood flow and GFR: Effect on renal blood flow and GFR: Design overviewDesign overview
GFR = glomerular filtration rateClinicaltrials.gov http://clinicaltrials.gov/ct2/show/NCT00660309 (Study 2329)
2 weeks2 weeks
Randomization
1 daysingle dose
High sodium diet (3 days)
Wash-out Captopril25 mg n=36
Aliskiren 300 mg n=18
Irbesartan 300 mg n=18
High sodium Diet (3 days)
Open-label treatment period
38
39
Effect of aliskiren on renal plasma Effect of aliskiren on renal plasma flow in healthy volunteers – flow in healthy volunteers – Study Study
designdesign
Fisher ND, et al. 2008
Single-blind study in 20 healthy volunteersSingle-blind study in 20 healthy volunteers Subjects tested on 3 separate days, separated Subjects tested on 3 separate days, separated
by 48 hour intervalsby 48 hour intervals On each day of testing, subjects were assigned to On each day of testing, subjects were assigned to
receive a single dose of aliskiren (75, 150, 300, or receive a single dose of aliskiren (75, 150, 300, or 600 mg) or placebo600 mg) or placebo
RPF* assessed using clearance of PAH**RPF* assessed using clearance of PAH** On each study day, basal RPF determined after On each study day, basal RPF determined after
which aliskiren administered as a single dosewhich aliskiren administered as a single dose
*RPF – renal plasma flow**PAH – para-aminohippurate
40
Aliskiren provides dose-Aliskiren provides dose-dependentdependent
increases in peak RPFincreases in peak RPF
0
50
100
150
200
250
n=7 n=7 n=15 n=19 n=7
Peak change† from baseline in RPF after a single dose (mL/min/1.73 m2)
Placebo 75 mg 150 mg 300 mg
Aliskiren
600 mg
†Peak change determined from hourly assessmentsof RPF made over 6 hours post-doseBaseline RPF – 575 mL/min/1.73 m2; *p<0.05 vs baseline
197
124
93
33
169
Fisher ND, et al. 2008
*
*
**
41
RPF remains above baseline 48 RPF remains above baseline 48 hours after aliskiren hours after aliskiren
administrationadministration
Placebo 75 mg 150 mg 300 mg
Aliskiren
Change in RPF from baseline 48-hours post-dose (mL/min/1.73 m2)
*p<0.05 vs baseline
100
0n=8n=15
n=6n=3
*
**
50
-50
Fisher ND, et al. 2008
42
Change in renal plasma flow in response to Change in renal plasma flow in response to ACE inhibition, angiotensin receptor ACE inhibition, angiotensin receptor blockade and Direct Renin Inhibitionblockade and Direct Renin Inhibition
0 50 100 150 200Change in RPF (ml/min/1.73 m2)
1. Hollenberg et al. 2000; 2. Fisher et al. 1994; 3. Lansang et al. 2000;4. Fisher & Hollenberg 1995; 5. Cordero et al. 1991; 6. Fisher et al. 2008
Enalapril 5–20 mg1
Captopril 25 mg2
Candesartan 16 mg3
Zankiren 250 mg4
Enalkiren 0.5 mg/kg2
Enalkiren* 36 mg5
Aliskiren 300 mg6
ACEI
ARB
DRI
*mean dosage based on patient weight
43Rasilez®/ramipril combination Rasilez®/ramipril combination therapy demonstrates a lower therapy demonstrates a lower
incidence of cough compared with incidence of cough compared with ramipril monotherapyramipril monotherapyRamipril
monotherapy*
(n=278)
Rasilez®monotherapy*
(n=282)
Rasilez®/ramipril
combination therapy* (n=277)
Any AE, (%) 33.8 32.3 30.0
Serious AEs, (%) 2.2 2.8 1.4
Discontinuation due to AEs, (%) 4.0 3.9 2.2
Treatment-related AEs, (%) 11.9 7.4 6.1
Most frequent AEs (³2% in any group), (%)
Headache 6.1 3.2 2.9
Cough 4.7 2.1 1.8
Nasopharyngitis 1.8 3.2 1.1
Diarrhoea 2.5 1.1 1.1
Uresin Y, et al. JRAAS 2007
*Patients received Rasilez® 150 mg, ramipril 5 mg, or Rasilez®/ramipril 150/5 mg od. After 4 weeks, patients were titrated to Rasilez® 300 mg, ramipril 10 mg or Rasilez®/ramipril 300/5 mg for an additional 4 weeks
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RasilezRasilez®® (Aliskiren) 150-300 mg daily (Aliskiren) 150-300 mg daily –– new generation in antihypertensive treatment new generation in antihypertensive treatment
First direct renin inhibitor for hypertensionFirst direct renin inhibitor for hypertension
Uniquely lowers PRA in monotherapy and combinationUniquely lowers PRA in monotherapy and combination
Effective and sustained monotherapyEffective and sustained monotherapy
Additional BP lowering when combined with other Additional BP lowering when combined with other antihypertensivesantihypertensives
Sustained 24-hour BP control with prolonged effectSustained 24-hour BP control with prolonged effect after after withdrawalwithdrawal
Placebo-like safety and tolerability profilePlacebo-like safety and tolerability profile
Potential for improved end-organ protection viaPotential for improved end-organ protection via optimal optimal suppression of the renin systemsuppression of the renin system BNP reduction in heart failureBNP reduction in heart failure LVH regression in hypertensive obesity LVH regression in hypertensive obesity Proteinuria reduction in DM nephropathyProteinuria reduction in DM nephropathy