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1Item code: 2008.229 Print date: Not applicable
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RAAS SUPPRESSION Cardio Renal Protection
ByProfessorDr Intekhab AlamDepartment of MedicineLady Reading Hospital, Peshawar
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Hypertension
There is a 90% lifetime risk of becoming hypertensive for a person living in a developed country.
BP limits are different in children and pregnancy.
BP goal is different if you have diabetes or CKD.
Primary (“essential”) HTN comprises 95% of cases.
Secondary 5% of cases.
Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.
For persons over age 50, SBP is a more important than DBP as CVD risk factor.
Question: when did you last check your blood pressure?
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JNC-7 Classification
NormalNormal
PrehypertensionPrehypertension
Stage I hypertensionStage I hypertension
Stage II hypertensionStage II hypertension
SBP (mmHg)SBP (mmHg) DBP (mmHg)DBP (mmHg)BP ClassificationBP Classification
< 120< 120
120-139120-139
140-159140-159
>> 160 160
< 80< 80
80-8980-89
90-9990-99
>> 100 100
andand
oror
oror
oror
http://hin.nhlbi.nih.gov/nhbpep_slds/menu.htmhttp://hin.nhlbi.nih.gov/nhbpep_slds/menu.htm
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The majority of patients are not treated to BP goal
USTop-5 EU
countries*Japan
Top-7
countries†
Hypertension prevalence, in millions
(% of population)
65.2
(22%)
72.9
(24%)
36
(28%)
175
(24%)
Not diagnosed (%) 28% 30% 49% 33%
Diagnosed not treated (%) 26% 16% 12% 19%
Treated not at goal‡ (%) 44% 54% 74% 54%
Prevalent patients not at to goal‡ (%) 70% 73% 88% 75%
• US: NHANES 1999-2002 (NVS Analysis, Dr. Suh, Rutgers University, 2006/03); • France: Thales 2005, Decision Resources DB9; Italy: Thales 2005; Spain: TNS Cardiomonitor 2005,
• Germany: Datamonitor, IMS disease analyser; UK: Thales (2006); • Japan: Statistical analysis,CVD basic research, Datamonitor, patient diary
*Top-5 EU countries: France, Italy, Spain, Germany and UK†Top-7 countries: US, Japan and Top-5 EU countries; weighted average by population‡Goal defined as BP<140/90 mmHg
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SBP DBP
ALLHAT 1
HOPEPROGRESS
CAPPP
INSIGHT
NORDIL
HOT
STONE
STOP-2
LIFE
ALLHAT 2
ANBP2
INVEST
SCOPE
ASCOTVALUE
130
140
150
160
170
180
190
200mmHg
70
80
90
100
110
120
mmHg
Mancia G, Grassi G. J Hypertens 2002
Even in clinical trial conditions, many patients do not reach goal with current therapies
B T B T
B = baseline; T = trial
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Benefits of Lowering BP
Sustaining a 12 mmHg reduction in SBP over 10 years will prevent one death for every 11 patients treated with Stage I HTN with additional CVD risk factors
Why to treat HTN?
“The relationship between BP and CVD is positive and continuous.”
– 35-40% in stroke morbidity and mortality
– 20-25% CAD events
– 21% vascular mortality
– 52% in CHF
– 35% in LVH
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Patients with hypertension have additional co-morbidities, making treatment difficult
Obesity
Glucose intolerance
Hyperinsulinaemia
Reduced HDL-C
Elevated LDL-C
Elevatedtriglycerides3
4+
0 1
2
26%
25%
8%
22%
19%
3
4+
0 1
2
27%
24%
12%
20%
17%
>50% have two or more comorbidities
Men Women
Kannel WB, 2000
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Goals of Therapy
Adopt a holistic approach and abandon ahypertension/ Normotension dichotomy and focus on global risk reduction.
Reduce CVD and renal morbidity and mortality.
Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease.
Achieve SBP goal especially in persons >50 years of age.
• Maintain QOL and Minimize side effects.
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Works best in motivated individuals
Initiate at prehypertension classification
Obesity risk for HTN and DM
Sodium “restriction” and other diet aids:– Usual salt intake 10 gm/d = 4 gm Na+
– Reduce to 2.4 gm Na+/day
– Caution – salt substitutes contain K+
Discourage excessive consumption of coffee and other caffeine-rich products.
Stop smoking and Alcohol consumption.
Exercise/Activity:– 30-40 minutes 3-4x/wk, optimal 5x/wk
– Stress reduction / Meditation.
Lifestyle Modification
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Lifestyle Modification
ModificationModification Approximate SBP reductionApproximate SBP reduction(range)(range)
Weight reductionWeight reduction 55––2020 mmHg/10 kg weight lossmmHg/10 kg weight loss
Adopt DASH eating planAdopt DASH eating plan 88––14 mmHg14 mmHg
Dietary sodium reductionDietary sodium reduction 22––8 mmHg8 mmHg
Physical activity Physical activity 44––9 mmHg9 mmHg
Stopping alcohol Stopping alcohol consumptionconsumption
22––4 mmHg4 mmHg
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Hot topics – should these be incorporated into the guidelines?
Lower BP targets
First-line combination therapy
β-blockers no longer a first choice treatment for hypertension
The need to consider total CV risk
Acceptance of more measures of organ damage (e.g. intermediate clinical endpoints)
Dual Renin System suppression
New classes of antihypertensives
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RAAS and CV diseases
While cardiovascular (CV) diseases have long been the leading cause of death in many developed nations, the WHO estimates that it will become the leading cause in the developing world by the year 2010
The spectrum of CV diseases has been described as a‘CV continuum’
Renin-angiotensin-aldosterone system (RAAS) activationis pathologically involved throughout the CV continuum
ACEIs and ARBs, originally developed for hypertension, are drugs for which clinical trial evidence has now accumulated throughout the CV continuum
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker
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Risk factorsDiabetes
Hypertension
Atherosclerosisand LVH
Myocardialinfarction (MI)
Remodeling Ventriculardilation
Congestiveheart failure (HF)
End-stage micro-vascular andheart disease
Death
Adapted from Dzau, Braunwald. Am Heart J 1991;121:1244–63
CONSENSUSSOLVD, Val-HeFTELITE II Val-HeFTCHARM
DREAMNAVIGATOR RENAAL
IDNTIRMA-2MARVAL
HOPE, EUROPA, PEACE, LIFE ONTARGET, TRANSCEND
VALUELIFESCOPE
SAVE, AIRE, TRACEOPTIMAAL, VALIANT
DIRECT
LVH = left ventricular hypertrophy
RAAS and its inhibitors: Their role along the CV continuum
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Where are we now – the best of RAAS suppression?
Primary prevention:
In the prevention of CV events in high risk patients
Secondary prevention:
In patients with post-MI left ventricular dysfunction/HF
Tertiary prevention:
In patients with chronic HF
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The residual risk
With the best available treatments to suppress the RAAS
– 20% of patients at high risk of CV events (HOPE/ONTARGET patients), CV death, non-fatal MI ornon-fatal stroke still occur within a 5-year follow-up period
– 22% of patients with post-MI left ventricular dysfunction/failure (VALIANT patients) still die withina 3-year follow-up period
– 25% of patients with chronic HF (CHARM/Val-HeFT patients) still die or are admitted for HF within a 3-year follow-up period
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Dual Blockade of the RAAS
What do enthusiasts say?
More trials needed
“Variances in study design and populations, dosing and titration methods, and clinical end points, in addition to inherent differences between agents, limit the ability to reach clinically meaningful conclusions about the value of dual RAS inhibition”
Cohn JN, Goldman JN Am J Hypertens 2008; 21: 248 - 256
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Can we further improve patient outcomes with more complete block of the RAAS?
Residual risk may be due to the incomplete suppression of the RAAS provided by these agents
ACEIs and ARBs both increase plasma renin activity (PRA), which may limit their organ-protective effects
Aliskiren is the first Direct Renin Inhibitor (DRI), a new class of antihypertensive agents
Aliskiren suppresses the RAAS at its point of activation and therefore may provide more complete control of the RAAS than either ACEIs or ARBs
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Development of direct Renin inhibitors has been challenging
Numerous renin inhibitors have been synthesized and studied previously, including H142, ditekiren, enalkiren, zankiren and remikiren
However, these agents were not clinically effective due to:
– lack of oral availability
– low efficacy
– short half-life
– high cost of synthesis
Luther R, et al. 1991; Stanton A. 2003;Wood JM, et al. 2003; Jensen C, et al. 2008
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Classic understanding of the Renin System
Gibbons GH. 1998; Adapted from: Müller DN & Luft FC. 2006
ACE
Na+/H2O retentionVasoconstriction
Hypertension
Aldosterone
Renin
Angiotensinogen
Ang I
AT1 Receptor
Ang II
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ACEIs and ARBs cause compensatory rises in PRA
Glomerularvasoconstriction
Inflammation Fibrosis
Kidney
Hypertrophy Fibrosis Vasoconstriction
Heart
Vasoconstriction
Brain
Hyperplasia hypertrophy Inflammation Oxidation Fibrosis
VesselsFeedback Loop
AT1 Receptor
ReninAng I
Angiotensinogen
Ang II
Biological effects
ACE
Non ACE pathways
ARBs
ACEIs
PRA
Adapted from: Müller DN & Luft FC. 2006
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Angiotensinogen
Aliskiren binds to the active site 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
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Direct renin inhibition acts at the point of activation of the Renin System and neutralizes the PRA rise
Feedback Loop
AT1 Receptor
ReninAng I
Angiotensinogen
Ang II
Direct renin inhibitor
Biological effects
ACE
Non ACE pathways
PRA
Adapted from: Müller DN & Luft FC. 2006
Glomerularvasoconstriction
Inflammation Fibrosis
Kidney
Hypertrophy Fibrosis Vasoconstriction
Heart
Vasoconstriction
Brain
Hyperplasia hypertrophy Inflammation Oxidation Fibrosis
Vessels
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Unlike ACEIs and ARBs, aliskiren reducesAng 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
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(Pro)renin receptor may play an important role in cardio vascular disease by local Renin System activation
(Pro)reninreceptor
Vasoconstriction Remodelling
Vessels
Kidney
Heart
(Pro)renin receptor actions:
Binding of (pro)renin
Increased renin catalytic activity
Activates VSMC ERK1/2
Increase PAI-1
Aliskiren binds to renin Target cells
VSMC
Feedback Loop
AT1 Receptor
Renin
Angiotensinogen
Ang II
Non ACE pathways
Ang I
ACE
Direct renin inhibitor
Nguyen G, et al. 2001
Direct renin inhibitor
27Item code: 2008.229 Print date: Not applicable
1000
1
0.1
100
10
Aliskiren has a half-life of approximately 40 hours, making it suitable for once-daily dosing
Mean (plus SD) plasma aliskiren concentration profiles (n=30) after single oral administration of aliskiren to healthy subjects, semi-logarithmic scale
Concentration (ng/mL)
0Time (hours)
75 mg150 mg300 mg600 mg
1008020 40 60
Vaidyanathan S, et al. 2006 (Study 2205)
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Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP
0
−15
−5
−20
−10
n=133n=129n=130n=127n=130
** *******
p=0.005
p=0.01
Placebo 150 300 600 150
*p<0.02 vs placebo; **p<0.005; ***p<0.0005 vs placebo Gradman AH, et al. 2005 (Study 2201)
n=133n=129n=130n=127n=130
***
******
***
Aliskiren (mg)
DBP SBP
Irbesartan(mg) Aliskiren (mg)
Irbesartan(mg)
Placebo 150 300 600 150
−6.3
−9.3
−11.8 −11.5
−8.9
−5.3
−11.4
−15.8 −15.7
−12.5
Mean change from baseline in mean sitting BP at Week 8 (mmHg)
29Item code: 2008.229 Print date: Not applicable
0
−10
−5
−15
−20
Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP
Mean change from baseline in mean sitting BP at Week 8 (mmHg)
***p<0.0001 vs placebo
Placebo 150 300 600
Aliskiren (mg)
150 300 600Placebo
n=166n=166n=167n=163
***
−4.9
−10.3−11.1
−12.5*** ***
n=166n=166n=167n=163
***
−3.8
−13.0
−14.7−15.8
******
DBP SBP
Aliskiren (mg)
Oh BH, et al. 2007 (Study 2308)
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Pooled analyses in >3,500 patients demonstrate that aliskiren provides dose-dependent reductions in BP
Dahlöf B, et al. 2007 (Pooled analysis)
***p<0.0001 vs placeboValues under bars represent least square mean reductions ± standard error of the mean; values in arrows represent placebo-subtracted reductions
Mean change from baseline in mean sitting BPafter 8–12 weeks (mmHg)
0
−15
−5
−25
−10
−20
−6.2
***
DBP SBP
Placebo 150 mg
n=1180n=776 n=1603
−10.1−11.8
300 mgAliskiren
Placebo 150 mg 300 mgAliskiren
n=1180n=776 n=1603
***
−5.9
***−12.5
−15.2
***
6.6 9.33.9 5.6
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Aliskiren provides effective DBP-lowering in patients with obesity: pooled analysis
***p<0.001 vs placebo
Mean change from baseline in mean sitting DBP after 8–12 weeks (mmHg)
Prescott MF, et al. 2007 (Pooled analysis)
0
5
10
15
–6.1
–10.0–11.1
–6.2
–10.1
–11.8******
n=275 n=434 n=630 n=776 n=1180 n=1603
******
Placebo 150 300
Aliskiren (mg)
Placebo 150 300
Aliskiren (mg)
All patientsPatients with obesity
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Aliskiren provides effective SBP-lowering in patients with diabetes: pooled analysis
Taylor AA, et al. 2007 (Pooled analysis)**p<0.01; ***p<0.001 vs placebo
Mean change from baseline in mean sitting SBP after 8–12 weeks (mmHg)
0
−15
−5
−25
−10
−20
n=1180n=776 n=1603
−5.9
***−12.5
−15.2
***
n=98n=55 n=393
−6.9
**−13.2
−14.8
***
Placebo 150 300
Aliskiren (mg)
Placebo 150 300
Aliskiren (mg)
All patientsPatients with diabetes
33Item code: 2008.229 Print date: Not applicable
Aliskiren provides effective DBP-loweringin patients with metabolic syndrome: pooled analysis
†p<0.0001 vs placebo
Mean change from baseline in mean sitting DBPafter 8–12 weeks (mmHg)
White WB, et al. 2007 (Pooled analysis)
0
5
10
15
–5.8
–10.4–11.3
–6.7
–10.4–11.9
n=189 n=365 n=387 n=299 n=531 n=640
††
†
†
Placebo 150 300
Aliskiren (mg)
Placebo 150 300
Aliskiren (mg)
Patients with metabolic syndrome
Patients without metabolic syndrome
UPDATED (ref only)
34Item code: 2008.229 Print date: Not applicable
Aliskiren provides effective BP-lowering in patients with impaired renal function: 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)
35Item code: 2008.229 Print date: Not applicable
Summary- Efficacy in monotherapy
Aliskiren 150 mg is the recommended starting dose
Titration to 300 mg may provide additional benefit
Aliskiren 600 mg does not provide additional benefit compared with 300 mg and is not recommended for clinical use
Aliskiren demonstrates antihypertensive efficacy regardless of age or gender
Aliskiren demonstrates antihypertensive efficacy in patients with obesity, diabetes, impaired renal function and metabolic syndrome
36Item code: 2008.229 Print date: Not applicable
Aliskiren provides superior BP-lowering compared with ramipril in patients with stage 2 hypertension (post-hoc analysis)
Andersen K, et al. 2008 (Study 2306)Stage 2 hypertension defined as SBP ≥160 mmHg*p<0.05; †p=0.0518 for superiority vs ramipril
Mean change from baseline in mean sitting BP at Week 12 (mmHg)
†
0
−15
−5
−25
−10
−20
n=87n=88 n=87n=88
−12.7−10.2
−18.1
−22.3
DBP SBP
Aliskiren 150 or 300 mg Ramipril 5 or 10 mg
n=87n=87n=87
*
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Aliskiren monotherapy provides significantly greater reductions in BP compared with HCTZ monotherapy
Mean change from baseline in mean sitting BP at Week 12 (mmHg)
0
−15
−5
−25
−10
Pairwise comparisons: ***p<0.001 vs HCTZ
−20
n=547n=560 n=547n=560
−12.2−10.3
−17.4−14.7
***
***
DBP SBP
Aliskiren 300 mg
HCTZ 25 mg
Aliskiren 300 mg
HCTZ 25 mg
Schmieder RE, et al. 2007 (Study 2323)
38Item code: 2008.229 Print date: Not applicable
Aliskiren alone or in combination with ramipril reduces SBP irrespective of the degree of glycaemic control
Tschoepe D, et al. 2006 (Study 2307)HbA1C <7.0%, baseline SBP = 155.7 mmHg HbA1C ≥7.0%, baseline SBP = 157.1 mmHg
–20
–15
–10
–5
0
p≤0.001p≤0.05
–14.9
n = 133
–14.9
n = 146
–11.8
n = 132
–12.1
n = 142
–15.6
n = 135
–17.8
n = 138
< 7.0% < 7.0% < 7.0%≥ 7.0% ≥ 7.0% ≥ 7.0%
HbA1C level
Mean change from baseline inmean sitting SBP at Week 8 (mmHg)
Aliskiren Ramipril Aliskiren/ramipril
39Item code: 2008.229 Print date: Not applicable
Aliskiren alone or in combination with ramipril reduces BPin patients with microalbuminuria
Mean change from baseline in mean sitting BP at Week 8 (mmHg)
Aliskiren/ramipril
300/10 mgRamipril10 mg
Aliskiren300 mg
−18
−6
0
−14
DBP SBP
−8
−10
−12
−16
*p<0.05 vs ramipril monotherapy Gradman AH, et al. 2007 (Study 2307)
−20
n=67n=72n=69 n=67n=72n=69
−13.2
−11.1−10.4
−16.8
−11.8 −12.4
*
Aliskiren/ramipril
300/10 mgRamipril10 mg
Aliskiren300 mg
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Optimal treatment + aliskiren 300 mg
n=289
n=287
−18
5
0
–5
–10
–15
–20
2
Optimal treatment+ placebo
Parving H-H, et al. 2007 Parving H-H, et al. 2008 UACR: Urinary Albumin to Creatinine Ratio
Mea
n c
han
ge
fro
m b
asel
ine
in U
AC
R a
t M
on
th 6
(%
)
p<0.001
AVOID StudyIn patients treated with losartan,
adding aliskiren provides significantly greater reductions in UACR compared with placebo
41Item code: 2008.229 Print date: Not applicable
Change in renal plasma flow in response to ACE inhibition, angiotensin receptor blockade 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 & Hollenberg. 2007
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
UPDATED (ref only)
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More obese patients achieve BP control with aliskiren/HCTZ than with other combinations or HCTZ monotherapy
*
**
**
BP control defined as BP <140/90 mmHg*p<0.05, **p<0.01 vs aliskiren/HCTZClass 1/2 obesity: BMI of 30–39.9 kg/m2; class 3 obesity: BMI ≥40 kg/m2
80
60
40
20
0
Proportion of patients achieving BP control at Week 12 (%)
n=97 n=106 n=102 n=101n=16 n=10 n=16 n=12
56.7 59.453.9
34.7
68.8
43.8
16.7
50.0
Obesity 1/2 3 1/2 3 1/2 3 1/2 3class
Aliskiren/HCTZ 300/25 mg
Amlodipine/HCTZ 10/25 mg
Irbesartan/HCTZ 300/25 mg
HCTZ 25 mg alone
Prescott MF, et al. 2007 (Study 2309)
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Aliskiren/valsartan combination therapy improves BP control compared with either component monotherapy
BP control defined as BP <140/90 mmHg**p<0.0001 vs placebo; †p<0.001, ‡p<0.0001 vs aliskiren/valsartan combination
BP control rate at Week 8 (%)
0
40
20
50
3437
16
n=455 n=453 n=438n=430
60
†
****
**
30
10
49
‡
Oparil S, et al. 2007 (Study 2327)
Placebo Aliskiren 300 mg
Valsartan 320 mg
Aliskiren/valsartan
300/320 mg
UPDATED (BP control rates and ref only)
44Item code: 2008.229 Print date: Not applicable
Summary- Efficacy in comparative and add-on studies
Aliskiren 300 mg monotherapy is more effective at reducing BP than ramipril 10 mg or HCTZ 25 mg monotherapy
Aliskiren 300 mg combined with ramipril 10 mg provides significantly greater reductions in BP than component monotherapies
Aliskiren 300 mg combined with ramipril 10 mg provides significantly greater reductions in SBP than ramipril 10 mg monotherapy in patients with microalbuminuria
Aliskiren 75–300 mg provides additional BP lowering when combined with HCTZ 6.25–25 mg
Aliskiren 300 mg combined with valsartan 320 mg provides significantly greater reductions in BP than component monotherapies
For patients with hypertension and obesity who fail to respond to diuretic monotherapy, adding aliskiren provides BP reductions and improved BP control rates
Addition of aliskiren 150 mg to amlodipine 5 mg in patients not responding adequately to amlodipine 5 mg monotherapy provides additional BP reductions and improves responder and control rates
45Item code: 2008.229 Print date: Not applicable
Clinical advantages of good 24-hour BP control
24-hour ambulatory BP correlates better than office BP measurements with target organ injury1
Use of long-acting drugs or preparations providing 24-hour efficacy on a once-daily basis is recommended2
– minimization of BP variability, possibly providing greater protection against the risk of major CV events and the development of target-organ damage
1. Chobanian AV, et al. 2003;2. Mancia G, et al. 2007
46Item code: 2008.229 Print date: Not applicable
Significant reductions in mean ambulatory BP sustained over 24 hours
Mitchell J, et al. 2006 (Study 2308)
Trough to peak ratio: aliskiren 150 mg 0.64aliskiren 300 mg 0.98aliskiren 600 mg 0.86
Mean change from baseline in mean ambulatory DBP (mmHg)
Placebo (n=53)Aliskiren 150 mg (n=52)Aliskiren 300 mg (n=56)Aliskiren 600 mg (n=55)
Clock hour
5
0
−5
−10
−1508:00 12:00 16:00 20:00 0:00 04:00
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Summary-Sustained >24-hour BP control
Aliskiren once daily provides persistent and smooth 24-hour BP reduction
Aliskiren once daily demonstrates >24-hour blood pressure control, with a trough-to-peak ratio of 98% with the 300 mg dose
Adding aliskiren to valsartan provides significantly greater reductions in mean 24-hour ambulatory BP compared with either component monotherapy
Even during the early morning BP surge, aliskiren maintains sustained BP reductions
With a half-life of 40 hours, aliskiren demonstrates sustained BP reductions at every time point over 24 hours
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Aliskiren combined with valsartan provides long-term BP-lowering efficacy – interim analysis after 6 months
Mean change from baseline in mean sitting BP at Week 28 (mmHg)*
0
−15
−5
−25
−10
−20
n=182n=386 n=87n=386
−15.9
−23.8
DBP SBP
Aliskiren/valsartan 300/320 mg Aliskiren/valsartan/HCTZ 300/320/25 mg
n=87n=87n=182
−24.6
−13.9
Chrysant SG, et al. 2008 (Study 2301)*patients completing 6 months’ treatment
NEW SLIDE
49Item code: 2008.229 Print date: Not applicable
Long-term efficacy
Long-term treatment with aliskiren, alone or in combination with HCTZ, provides sustained BP reductions over a 12-month period
Long-term treatment with aliskiren in combination with valsartan provides sustained BP reductions over a 6-month period
50Item code: 2008.229 Print date: Not applicable
Aliskiren provides prolonged BP-lowering
Placebo (n=163)
Aliskiren 150 mg (n=167)
Aliskiren 300 mg (n=166)
Aliskiren 600 mg (n=166)
0
−20
−5
−10
−15
Mean change in sitting diastolic blood pressure (mmHg)
Drug discontinuation
100 1 2 3 4 5 6 7 8 9Week
Herron J, et al. 2006 (Study 2308)
51Item code: 2008.229 Print date: Not applicable
SBP returns to baseline levels more rapidly after discontinuation of ramipril compared with aliskiren
Baseline Week 1 Week 2 Week 3 Week 4
12
10
8
6
4
2
0
–2
Mean change in mean sitting SBP during the 4-week withdrawal period (mmHg)
*Following 26-weeks’ treatment, patients randomized to discontinuation received placebo for 4 weeks; †Patients continuing active treatment could be receiving aliskiren 150 or 300 mg, or ramipril 5 or 10 mg, with or without optional HCTZ (12.5 mg or 25 mg).
Aliskiren regimen discontinued (n=163)*
Aliskiren regimen continued (n=170)†
Ramipril regimen discontinued (n=177)*
Ramipril regimen continued (n=165)†
Andersen K, et al. 2008 (Study 2306)
52Item code: 2008.229 Print date: Not applicable
Aliskiren maintained BP reductions after a missed dose with significantly greater efficacy than irbesartan or ramipril (post-hoc analysis)
†Missed dose on Day 42 or Day 49, 48 hours after the last dose***p<0.0001 vs ramipril; §p<0.005 vs irbesartanData are shown as least squares mean change ± SE for the ABPM completer population
Change in mean 24-hour ambulatory BP from start to end of missed dose period† (mmHg)
0
1
2
3
4
1.0
n=171
3.6
n=152
4.0
n=155
0.7
n=171
2.2
n=152
2.6
5
n=155
DBPSBP
Ramipril 10 mgIrbesartan 300 mgAliskiren 300 mg
Palatini P, et al. 2008 (Study 2351)
§
*** §
***
53Item code: 2008.229 Print date: Not applicable
Persistence of effect
Aliskiren demonstrates persistence of effect after drug discontinuation
Return to baseline BP occurs more slowly after discontinuation of aliskiren than after discontinuation of ramipril
Aliskiren provides superior maintenance of BP-lowering effect compared with ramipril and irbesartan after a missed dose
Aliskiren maintains BP reductions after a missed dose with significantly greater efficacy than ramipril or irbesartan
54Item code: 2008.229 Print date: Not applicable
Blood Pressure Goals
Must be Less than 140/90
Ideally 120/80 or less
Less than 130/80 if
have diabetes
Lifestyle Changes
when over 135/85
55Item code: 2008.229 Print date: Not applicable
Hot topics – should these be incorporated into the guidelines?
Lower BP targets
First-line combination therapy
β-blockers no longer a first choice treatment for hypertension
The need to consider total CV risk
Acceptance of more measures of organ damage (e.g. intermediate clinical endpoints)
Dual Renin System suppression
New classes of antihypertensives
56Item code: 2008.229 Print date: Not applicable
Take home message
“stress the importance of compliance”
Many people still believe that hypertension is a disease that can be cured and that the treatment can be
stopped or reduced when the BP levels fall. Physicians need to convey the
message that Hypertension is the first and easily measurable, usually
irreversible sign that many organs in the body are under attack and that
many catastrophes can be prevented by controlling the Blood Pressure.
57Item code: 2008.229 Print date: Not applicable
Questions?
58Item code: 2008.229 Print date: Not applicable
THANK YOU
59Item code: 2008.229 Print date: Not applicable
60Item code: 2008.229 Print date: Not applicable
Rationale for selective angiotensin type 1 receptor blockade
Bradykinin/NO
Inactive fragments
ANGIOTENSIN I
ANGIOTENSIN II
ARB
AT1 RECEPTOR
VasoconstrictionSodium retention
SNS activationInflammation
Growth-promoting effects
AT2 RECEPTOR
VasodilationNatriuresis
Tissue regenerationInhibition of inappropriate
cell growth
Chymase, tPA, Cathepsin
‘Angiotensin II escape’
ACE inhibitor