1 Item code: 2008.229 Print date: Not applicable 1.

1Item code: 2008.229 Print date: Not applicable

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3

RAAS SUPPRESSION Cardio Renal Protection

ByProfessorDr Intekhab AlamDepartment of MedicineLady Reading Hospital, Peshawar


4

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?


5

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


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


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


8

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


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


10

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.


11

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


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


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


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


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


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


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


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


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


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


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


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


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


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


ARBs

ACE

Non ACE pathways

ACEIs

Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006


(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


Nguyen G, et al. 2001



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)


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)


0

−10

−5

−15

−20

Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP


***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)


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


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


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


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)


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)


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


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


†

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

*


Aliskiren monotherapy provides significantly greater reductions in BP compared with HCTZ monotherapy


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)


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


Aliskiren alone or in combination with ramipril reduces BPin patients with microalbuminuria


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


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


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)


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)


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)


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


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


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


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


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


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


Aliskiren provides prolonged BP-lowering

Placebo (n=163)

Aliskiren 150 mg (n=167)



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)


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)


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)

§

*** §

***


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


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


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


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.


Questions?


THANK YOU



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

1 Item code: 2008.229 Print date: Not applicable 1.

Documents

mmhg slide

print date

item code

bp slide

mmhg reduction

applicable patients

trial slide

applicable raas