Peut-on aller encore plus loin

avec les antagonistes de l’Angiotensine II ?

Antoine Sarkis, MDAntoine Sarkis, MD

Associate Professor of Associate Professor of CardiologyCardiology

Hotel Dieu de France HospitalHotel Dieu de France Hospital

RAAS Blockade

Angiotensin Converting

Enzyme Inhibitors

ACE-I

Angiotensin Receptor Blockers

ARBs

Ang II: Influence on structure, function, and atherosclerosis

Weir MR, Dzau VJ. Am J Hypertens. 1999;12:205S-213S.

Angiotensin II

Growth

Smooth musclecell growth

and migration

Plateletaggregation

Endothelialdysfunction

Thrombosis

Ang II effect in target organ Ang II effect in target organ damagedamage

McFarlane SI et al. Am J Cardiol. 2003;91(suppl):30H-7.

Angiotensinogen

Angiotensin I

Angiotensin II

Renin

ACE

Aldosterone(Adrenal/CV tissues)

Stroke HFKidneyfailure

BP

VSMC

Fat cells

Reduced baroreceptor sensitivity

Angiotensinogen

Ang I ACE

Bradykinin

ATn

ReninRenin Inactivepeptides

Ang II

•Vasodilator•Anti-thrombotic•Anti-atherogenic

•Vasoconstriction•Hypertrophy•Angiogenesis•Apoptosis

Endothelium

SMC

AT2AT1

NO

B2

Angiotensinogen

Ang I ACE

Bradykinin

ATn

ACEI

ReninRenin Inactivepeptides

Ang II

•Vasodilator•Anti-thrombotic•Anti-atherogenic

•Vasoconstriction•Hypertrophy•Angiogenesis•Apoptosis

Endothelium

SMC

AT2AT1

NO

B2

Angiotensinogen

Ang I ACE

Bradykinin

ATn

ARBs

ReninRenin Inactivepeptides

Ang II

•Vasodilator•Anti-thrombotic•Anti-atherogenic

•Vasoconstriction•Hypertrophy•Angiogenesis•Apoptosis

Endothelium

SMC

AT2AT1

NO

B2

Angiotensin IIAngiotensin II

ReninReninReninRenin

Converting enzymeConverting enzyme

AngiotensinAngiotensinreceptorsreceptors

AngiotensinAngiotensinreceptorsreceptors

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

Circulating(Liver)

Local(Tissue)

Non-renin pathways• t-PA• Cathepsin G• Tonin

Non-renin pathways• t-PA• Cathepsin G• Tonin

Non-ACE pathways• Chymase• CAGE• Cathepsin G

Non-ACE pathways• Chymase• CAGE• Cathepsin G

Escape phenomena

ANGIOTENSIN II

Vasoconstriction Proliferative Action

Vasodilatation Antiproliferative Action

AT1 AT2 ….

AT1 Receptor Blockers

RECEPTORS

Angiotensin II Receptor Blockers (ARBs)

ATn

• ARBs more effective than ACE-I due to:

- Better RAAS Blockade

- Absence of angiotensin II escape

- Placebo like side effects

Potential advantages of ARBsPotential advantages of ARBs

Effects of A II at ATEffects of A II at AT11 and AT and AT22 Receptors Receptors

Sensitive to blockade by ARBs

AT2AT1

VasoconstrictionAldosterone releaseOxidative stressVasopressin releaseSNS activationInhibits renin release Renal Na+ & H2O reabsorptionCell growth & proliferation

VasodilationAntiproliferationApoptosisAntidiuresis/antinatriuresisBradykinin productionNO release

Siragy H. Am J Cardiol. 1999;84:3S-8S.

?

Postulated role of ATPostulated role of AT22R and MMP-1 in R and MMP-1 in plaque destabilizationplaque destabilization

Strauss MH, Hall AS. Circulation. 2006;114:838-54.

Destabilization Rupture ACS

Extracellularmatrix

Leukocyteactivation

Vascular smooth muscle cells

Ang II

ARB

AT1

AT2

MMP-1

Intracellular inflammation

Endothelium

ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD

Turnbull F. 15th European Meeting on Hypertension. 2005.Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54.

CHD = MI and CV death

Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysisN = 137,356; 21 randomized clinical trials

ACEI

ARB

Stroke -1% (9% to -10%)

HF 10% (10% to 0%)

CHD 9% (14% to 3%)

Stroke 2% (33% to -3%)

HF 16% (36% to -5%)

CHD -7% (7% to -24%)

30% 0 30%Decrease Increase

StrokeP = 0.6

HFP = 0.4

CHDP = 0.001

Risk

RRR (95%)

Similar Similar

Greater Greater with with amlodipine amlodipine (2.0/1.6 mm Hg)(2.0/1.6 mm Hg)

Losartan Losartan vs atenololvs atenolol

Valsartan Valsartan vs vs amlodipinamlodipinee

Essential HTNEssential HTN

N = 9193N = 9193

(4.8 years)(4.8 years)

Essential Essential HTN, high CV HTN, high CV riskrisk

N = 15,245N = 15,245

(4.3 years)(4.3 years)

LIFE (2002)LIFE (2002)

VALUE VALUE (2004) (2004)

BPBPTreatmeTreatmentnt

Patients Patients

(Follow-(Follow-up)up)

Trial Trial (year)(year)

HTN = hypertension

13% 13% in primary outcome in primary outcome (CV death, MI, stroke) with (CV death, MI, stroke) with ARB (P = 0.021) driven by ARB (P = 0.021) driven by 25% 25% in stroke (P = 0.001) in stroke (P = 0.001)

No difference in CV death/MINo difference in CV death/MI

Primary outcome similar Primary outcome similar at study endat study end

Trend favors amlodipine Trend favors amlodipine at 3 and 6 monthsat 3 and 6 months

Difficult to interpret due Difficult to interpret due to BP differenceto BP difference

Dahlöf B et al. Lancet. 2002;359:995-1003. Julius S et al. Lancet. 2004;363:2022-31.

CV outcomes

Clinical trials of ARBs in HTN: CV outcomes

Algorithm for Treatment of Hypertension Algorithm for Treatment of Hypertension (JNC 7) (JNC 7) JAMA, May 2003JAMA, May 2003

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension 2-drug combination

for most

Stage 1 Hypertension Thiazide-type diuretics

for most.

May consider ACEI, ARB, BB, CCB, or

combination

Without Compelling Indications

2003 ESH/ESC Hypertension Guidelines2003 ESH/ESC Hypertension Guidelines

Consider:Consider:

Untreated BP levelUntreated BP level

Presence or absence of TOD and risk factorsPresence or absence of TOD and risk factors

Choose between

Single agent at Single agent at low doselow dose

Two-drug combination Two-drug combination at low-doseat low-dose

Previous agent at Previous agent at full dosefull dose

Switch to different Switch to different agent at low doseagent at low dose

Previous combination Previous combination at full doseat full dose

Add a third drug at Add a third drug at low doselow dose

Two-to three drug Two-to three drug combinationcombination

Full dose Full dose monotherapymonotherapy

Three drug combination at Three drug combination at effective doseseffective doses

If goal BP not achieved

If goal BP not achieved

Choosing drugs for patients newly diagnosed Choosing drugs for patients newly diagnosed with hypertensionwith hypertension

BHS Guidelines (June 2006)BHS Guidelines (June 2006)

Younger than 55 years55 years or olderOr black patients of any age

A C or D

A+C or A+D

A+C+D

Add •further diuretic therapy•Or alpha blocker•Or Beta Blocker•Consider seeking specialist advice

Abbreviations:

A: ACE-I (or ARB if ACE intolerant)

C: CCB

D: thiazide type diuretic

Step 1

Step 2

Step 3

Step 4

Hypertension and DiabetesRecommendations of the American Diabetic

Association

• Treat to BP <130/80 mmHg

• All patients with diabetes and hypertension should be treated with a regimen that includes either an ACEi or an ARB.

• If needed to achieve blood pressure targets, a thiazide diuretic should be added.

American Diabetes Association. Diabetes Care. 2005; 28 (Suppl 1): S10 – S17.

Conditions favoring the use of ARBs

Type 2 diabetic nephropathyType 2 diabetic nephropathy Diabetic microalbuminuriaDiabetic microalbuminuria ProteinuriaProteinuria Left ventricular hypertrpphyLeft ventricular hypertrpphy ACE-I induced coughACE-I induced cough

Specific considerations about Candesartan

Pharmacological propertiesPharmacological properties Delaying new onset of hypertension Delaying new onset of hypertension

in pre-hypertensive patientsin pre-hypertensive patients Preventing diabetesPreventing diabetes End Organ protective effects (CHF)End Organ protective effects (CHF)

Pharmacological propertiesPharmacological properties

1. Candesartan binds unsurmountably to AT1 receptor1. Candesartan binds unsurmountably to AT1 receptor

2. Longest lasting AT1-receptor binding 2. Longest lasting AT1-receptor binding ►►T/ P Ratio almost T/ P Ratio almost 100%100%

In the latest JNC 7:In the latest JNC 7:Candesartan 8-32 mg Once dailyCandesartan 8-32 mg Once daily

Losartan 25-100 mg Once to Twice dailyLosartan 25-100 mg Once to Twice daily

Valsartan 80-320 mg Once to Twice dailyValsartan 80-320 mg Once to Twice daily

JNC 7, Hypertension, 2003JNC 7, Hypertension, 2003

Use in pre-hypertensive Use in pre-hypertensive patients?patients?

TROPHYTROPHY hypothesis hypothesis The TRial Of Preventing HYpertension

(TROPHY) is an investigator-initiated trial.

Aim: To examine whether early treatment of high-normal blood pressure values (according to JNC VI) with 16 mg Candesartan would prevent or postpone the development of stage 1 hypertension.

Julius et al, Hypertension 2004Julius et al, Hypertension 2004

TROPHYTROPHY – study design – study design

Two Years Two Years

Qualifying period*

Placebo

Non-pharmacological treatment

Non-pharmacological treatment

Candesartan cilexetil16 mg

n 400

n 400

Placebo

Placebo

*Clinic BP reading of 130-139/ 89 mm Hgor 139/85-89 mm Hg

Julius et al, Hypertension 2004

40,4

63,0

13,6

53,2

0

20

40

60

80

Year 2 Year 4

Patients (%)

Placebo Candesartan 16 mg qd

TROPHY: Reduction in new-onset hypertension

66%*

16%*

Candesartan vs Placebo Placebo only

*Relative risk reduction†P < 0.001; ‡P = 0.007 Julius S et al. N Engl J Med. 2006;354:1685-97.

†

‡

N = 772

Adipocyte and vasculature interactions

Courtesy of W. Hseuh; 2005.

IL-6

PAI-1TNF-

AdiponectinLeptin

Insulin sensitivity Insulin resistance

Vascular inflammation Endothelial dysfunction

Angiotensinogen

FFA

Visfatin

Furuhashi M et al. Hypertension. 2003;42:76-81.

• Insulin sensitivity, BMI, and HDL-C independent determinants of adiponectin concentrations

• ACEI and ARB increased insulin sensitivity and adiponectin (P < 0.05)

• Changes in insulin sensitivity correlated with changes in adiponectin (r = 0.59, P < 0.05)

*P < 0.05

N = 16 with essential hypertension and insulin resistance

RAAS blockade increases RAAS blockade increases adiponectinadiponectin

6

4

10

Adiponectin(µg/mL)

0

8

2

Before After Before After

6

4

10

0

8

2

Temocapril 4 mg(n = 9)

Candesartan 8 mg(n = 7)

*

*

Candesartan in preventing Candesartan in preventing Diabetes development…Diabetes development…

ALPINE Study Design

TimeTime -4-4 00 12m12m4w4w 8w8w 12w12w 6m6m

No other antihypertensive drugs allowedNo other antihypertensive drugs allowedGoal BP: <135/<85; 65+ <140/<90 mm HgGoal BP: <135/<85; 65+ <140/<90 mm Hg

HCTZ 25 mgHCTZ 25 mg

HCTZ 25 mg + Atenolol 50 mgHCTZ 25 mg + Atenolol 50 mg

HCTZ 25 mg + Atenolol 100 mgHCTZ 25 mg + Atenolol 100 mg

Candesartan 16 mgCandesartan 16 mg

Candesartan 16 mg + Felodipine 2.5 mgCandesartan 16 mg + Felodipine 2.5 mg

Candesartan 16 mg + Felodipine 5 mgCandesartan 16 mg + Felodipine 5 mg

RRPlaceboPlacebo

Lindholm et al 2003

ALPINE study…New onset ALPINE study…New onset of diabetesof diabetes

0

1

2

3

4

5

6

7

8

9p < 0.05

No ofpatients

HCTZ

4Candesartan

Lindholm LH J Hypertens 2003

Development of new Development of new diabetes – CHARM studydiabetes – CHARM study

01020304050607080

No. of cases

developing new

Diabetes

Controlcandesartan

40%p=0.005

Lancet, 2003

Possible mechanisms involved in Possible mechanisms involved in the prevention of diabetesthe prevention of diabetes

GLUCOSE ABSORPTION

MUSCLE

PANCREAS

ADIPOSE TISSUE

LIVER

INTESTINE

HYPERGLYCEMIA DECREASED PERIPHERAL

GLUCOSE UPTAKE

INCREASED GLUCOSE

PRODUCTION

DECREASED INSULIN

SECRETION

“Candesartan improved insulin sensitivity and hence reduce the development of DM in hypertensive patients ”

Circulation, July 2005

End Organ Protective End Organ Protective effects of Candesartaneffects of Candesartan

Congestive Heart failureCongestive Heart failure

Renin-Angiotensin-Aldosterone System in CHF

RAASRAAS is activated early in the is activated early in the course of heart failure and course of heart failure and plays an important roleplays an important role in the in the progression of the syndromeprogression of the syndrome

ACE-I IndicationsACE-I Indications

Symptomatic heart failure Symptomatic heart failure (stage C)(stage C) Asymptomatic ventricular dysfunction Asymptomatic ventricular dysfunction

with LVEF <35-40 % with LVEF <35-40 % (stage B)(stage B) Patients with recent or remote history of Patients with recent or remote history of

MI regardless of EF or presence of HFMI regardless of EF or presence of HF

Class I recommendation(therapy is recommended)(therapy is recommended)

Level of evidence A

AHA / ACC HF guidelines 2005AHA / ACC HF guidelines 2005

ESC HF guidelines 2005ESC HF guidelines 2005

However: 4-year mortality remains ~40%

1. Davies MK et al. BMJ. 2000;320:428-431 (meta-analysis: 32 trials, N = 7105). 2. Gibbs CR et al. BMJ. 2000;320:495-498 (meta-analysis: 18 trials, N = 3023).

HF: Mortality Remains High

ACEIACEI Risk reduction 35% (mortality and Risk reduction 35% (mortality and

hospitalizations)hospitalizations)11

ß-blockersß-blockers Risk reduction 38% (mortality and Risk reduction 38% (mortality and

hospitalizations)hospitalizations)22

SpironolactoneSpironolactone Mortality reduction 23%Mortality reduction 23%

Substitute or adjunctive therapy to ACE

inhibitors ?

Angiotensin Receptor Angiotensin Receptor

Blockers (ARBs) in Blockers (ARBs) in Heart FailureHeart Failure

Pitt B, et al. Lancet. 2000;355:1582-1587.

All-cause mortality

Pro

bab

ility

o

f S

urv

ival 1.0

0.80.60.40.20.0

All-cause mortality or hospital admission

Ev

ent-

fre

e

Pro

bab

ility

Sudden death or resuscitated arrest

Ev

ent-

fre

e

Pro

bab

ility

1.00.80.60.40.2

0

1.00.80.60.40.2

0

0 100 200 400300 500 600 700

Follow-up (days)

P P = .16= .16

P P = .08= .08

P P = .18= .18

LosartanCaptopril

Comparative trial: ELITE IIComparative trial: ELITE II

1.0

0.9

0.8

0.6

13% risk reduction p= 0.009

0

Even

t-fre

e pr

obab

ility

Placebo

Valsartan

3 6 9 12 211815 24 27Time since randomisation (months)

0.7

1.0

0.9

0.8

0.7

Time since randomisation

(months)

p = 0.80

Surv

ival

pro

babi

lity

(%)

0 3 6 9 12 211815 24 27

All-cause mortality and morbidity All-cause mortality

Cohn et al. NEJM 2001;345:1667

Add-on trial: Val-HeFT.Add-on trial: Val-HeFT.Valsartan 160 mg Bid vs placebo on Valsartan 160 mg Bid vs placebo on

top of standard therapytop of standard therapy

CHARM Added

CHARMPreserved

CHARM ProgramCHARM ProgramCandesartan vs placebo

in patients with symptomatic heart failure

CHARMAlternative

n=2028

LVEF 40%ACE inhibitor

intolerant

n=2548

LVEF 40%ACE inhibitor

treated

n=3025

LVEF >40%ACE inhibitor

treated/not treated

Primary outcome for Overall Programme: All-cause death

Primary outcome for each trial: CV death or CHF hospitalisation

Granger CB et al. Lancet. 2003;362:772-777

0 1 2 3Years

50

HR 0.77 p=0.00040

40

30

20

10

Candesartan

Placebo

CV

Dea

th o

f H

ospi

taliz

atio

n fo

r H

F

2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE-I randomized to candesartan (32 mg) or placebo over 34 months

CHARM Alternative trial

0 1 2 3

0

10

20

30

40

50

3.5

HR 0.85, p=0.011

Candesartan

Placebo

CV

Dea

th o

f H

ospi

taliz

atio

n fo

r H

F

Years

McMurray JJ et al. Lancet. 2003;362:767-71

2,548 patients with symptomatic HF and LVSD (EF <40%) randomized to candesartan (32 mg) or placebo in addition

to an ACE-I over 34 months

CHARM Added Trial

CHARM ProgramCHARM Program Mortality and morbidityMortality and morbidity

0.7 0.8 0.9 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2

All Cause MortalityCV Death or

CHF Hospitalisation

Hazard ratio Hazard ratio

p heterogeneity=0.43

Alternative

Added

Preserved

Overall

p heterogeneity=0.37

p=0.0004

p=0.055

p=0.011

p=0.118

p<0.0001

0.77

0.85

0.89

0.840.91

CHARM LVEF CHARM LVEF 40% 40% (CHARM-Alternative and CHARM-(CHARM-Alternative and CHARM-

AddedAdded))

All-cause death 0.88 0.79-0.98 0.018

CV death 0.84 0.75-0.95 0.005

HR CI p-value

Pfeffer et al, Lancet 2003

12%12%

ReductionReduction

16%16%

FDA approved candesartan cilexetil on top of ACE inhibitor for HF

NYHA class II-IV heart failureNYHA class II-IV heart failure Dose: initial dose of 4 mg once daily Dose: initial dose of 4 mg once daily

to a target dose of 32 mg once daily, to a target dose of 32 mg once daily, achieved by doubling the dose at achieved by doubling the dose at approximately two-week intervals, as approximately two-week intervals, as toleratedtolerated

May 19, 2005

ARB Indications in CHF

Patients intolerant to ACE-Inhibitors: (Class I recommendation in stage C, class IIa in stage B, class I in stage B post MI)

Use of ARB instead of ACE-I in stage C heart failure:Class IIa recommendation (reasonable, should be considered)

On top of ACE I and B Blockers in patients who remain symptomatic: optional, because of discrepancy in guidelines:Class I (ESC, CCS), IIa (HFSA), and IIb (ACC/AHA)

CHARM-OverallNon-fatal MI

3803 3521 3206 2163 7443796 3413 3101 2088 722

0

1

3

4

5

6

7

2

0 1 2 3 3.5 yrs

Hazard ratio 0.77(95% CI 0.60 – 0.98), p=0.032

placebo

candesartan

Number at riskCandesartanPlacebo

Cumulative events%

2323 % % reduction ofreduction of Non Fatal MINon Fatal MI

Demers C et al. JAMA 2005; 294: 1794-1798.

Clinical trials continue with ARBs…

ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

ONTARGET: Study ONTARGET: Study designdesign

Ramipril 10 mg Telmisartan 80 mg

N = 25,620≥55 years with coronary, cerebrovascular, or peripheral vascular disease,

or diabetes + end-organ damage

Results anticipated in 2007

Ramipril 10 mg + telmisartan 80 mg

Primary end point:CV death, MI, stroke, hosp for HF

Secondary end point:Newly diagnosed diabetes

ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial

Diabetic retinopathy is the most common Diabetic retinopathy is the most common cause of blindness in people aged 30-69 cause of blindness in people aged 30-69 in developed countriesin developed countries

Laser photocoagulation reduces the risk Laser photocoagulation reduces the risk of blindness, but is performed only when of blindness, but is performed only when advanced vascular damage is presentadvanced vascular damage is present

Only current established treatment Only current established treatment involves careful glycaemic controlinvolves careful glycaemic control strict glycaemic control reduces both onset and strict glycaemic control reduces both onset and

progression of retinopathyprogression of retinopathy

Diabetic retinopathy

Beneficial effect of ACE-inhibition

3 small studies, non-significant results, positive tendency (Larsen et al 1990, Chase et al 1993, Ravid et al 1993).

EUCLID, n = 354, Lisinopril 10-20 mg or placebo, 2 year follow-upProgression reduced by 50% (p=0.02)Incidence reduced by 31% (n.s.)(Chaturvedi et al 1998)

Study question

Does blockade of the RAS system with Candesartan cilexetil prevent incidence and progression of retinopathy in type 1 and type 2 diabetes?

DIRECT programmeThe Diabetic REtinopathy Candesartan

Trials

3 separate studies - each sufficiently powered to establish treatment effects on retinopathy in the respective study population

Pooling of the three populations to detect effects on microalbuminuria

Results expected in 2007

JRAAS 2002;3:255-261

DIRECT Design

I. Type 1 diabetic patients without diabetic retinopathy

Endpoint: Development of retinopathy II. Type 1 diabetic patients with diabetic

retinopathy Endpoint: Progression of retinopathy III. Type 2 diabetic patients with diabetic

retinopathy Endpoint: Progression of retinopathy Pooled populations of all three studies Endpoint: Incidence of microalbuminuria

In conclusion The controversial dilemma between ACE-I

and ARBs is not settled ARBs have suffered from their introduction

late after ACE-I were well established However a placebo-like tolerability has

extended their indications in daily practice irrespective of guidelines

Candesartan is a potent ARB with solid data in end organ protection

Need for earlier intervention in the natural history of HTN? (targeting subclinical organ damage)