V. GercClinic for Heart Disease and

RheumatismSarajevo

Advantages of renin-angiotensin system blockade in the treatment

of cardiovascular disease

The cardiovascular continua in cardiovascular disease

The pathophysiological continua incardiovascular disease

Angiotensin II is central to atherosclerotic mechanisms

Oxidative Stress Inflammation

Endothelial dysfunction Tissue remodelling

Vascular permeability ↑ Leucocyte infiltration ↑

Activation of signalling pathways

Production of inflammatory mediators

Proliferation of VSMCs

Matrix deposition

MMP activationPlatelet aggregationPAI-1 activation

Vasoconstriction

Nitric oxide ↓

LDL peroxidation ↓

LDL peroxidation ↑

Reactive oxygen species ↑

NAD(P)H oxidase activity ↑

Angiotensin II

Schmieder et al. Lancet 2007;369:1208−1219

Vascular Risk Factors and Endothelial Dysfunction

Role of oxidative stress:

Hypertension

Angiotensin II Smoking

Diabetes

Homocysteine

oxLDL

Endothelial Dysfunction

-Bradykinin/NO

mod. from Gibbons GH, Clin Cardiol 20 (1997)

- Antioxidants (?)

oxidative stress

Long-term cardiovascular effects of angiotensin II

Metabolism of the Renin-Angiotensin System

Component Half-life in circulation Degrading enzyme(s)

Renin 15–20 min —

Angiotensinogen 4–16 h Renin

Angiotensin I 1–2 min Angiotensin-converting enzyme

Angiotensin II Seconds Aminopeptidase A, endopeptidase,

Prolylcarboxy-peptidase

Mechanism of action of angiotensin-converting enzyme inhibitors

EFFECTS OF ANGITENSIN II

vasoconstriction (”afterload” ) reabsorption of Na+ and water (“preload” ) coronary constriction

syntesis of cellular proteins (HLV)

fibroblastic hyperplasia (myocardial fibrosis)

apoptosis of myocites

diastolic dysfunction of the heart

EFFECTS OF ANGIOTENSIN II

endothelial dysfunction

PAI-1 ( fibrinolysis)

tissue factor

proliferation and migration of smooth

muscles

sympathetic, vagal activity

adrenocortex ( catecholamine, aldosterone)

Potential pathogenic propertiesof Angiotensin II

• Heart• Myocardial hypertrophy• Interstitial fibrosis

Potential pathogenic propertiesof Angiotensin II

• Coronary Arteries

• Endothelial dysfunction with decreased release of nitric oxide

• Coronary constriction via release of noradrelanine

• Increased oxidative stress; oxygen derived free radicals formed via NADH

• Promotion of inflamatory response and atheroma

Potential pathogenic propertiesof Angiotensin II

• Kidneys• Increased intraglomerular pressure• Increased protein leak• Glomerular growth and fibrosis• Increased sodium reabsorption

Potential pathogenic propertiesof Angiotensin II

• Adrenals• Increased formation of aldosterone

Potential pathogenic propertiesof Angiotensin II

• Coagulation system• Increased fibrinogen• Increased PAI-1

Inhibition of the RAS

• Inhibition of the RAS is established for the treatment and now prevention of a wide range of cardiovascular disease. The basic concept hinges on the adverse effects of excess angiotensin II and increase protective bradykinin.

Renin – Angiotensin - Aldosterone system:where inhibitors act

Dual role of ACE inhibitors, both preventing and treating cardiovascular disease

Pharmacodynamic effects of ACEI

Hemodynamic: vasodilation (AII, BK, PGI, NO)Sympatholytic: Ach NAEndothel: PGI, NO, AII, endothelinAntiproliferative: AII, aldo, c-fos, c-mycAntithrombotic: PAI-1Antiatherogenic: the above + antioxidants

Indications for ACEI, based on trial data

• 1.Heart failure, all stages• 2. Hypertension• 3.AMI, postinfarct LV dysfunction• 4.Nephropathy, nondiabetic and diabetic• 5. Diabetes type 2, lessens new

microalbuminuria and LV hypertrophy

ACE

Blood pressure

Oxidative stress

Inflammation

Endothelian dysf.

Nitric oxide

Growth of the plaque

Fibrinolysis

tPA

PAI-1

Re

du

ction

of

card

iov

asc

ula

r eve

nts

Antiatherosclerotic effect of LISINOPRIL

Pleiotropic effects of renin-angiotensin system blockers

Pleiotropic effects

Statins ACEI

Early effects(hours, days)

LDL,TG;HDLNOS, O-

AII, BK, PGO-

Intermediaryeffects (weeks)

Viscosity Tr aggregation

PAI-1

Fibrinolysis Tr activation

BMP-2

Late effects(months)

Cell migration, proliferation;

stabilisation of the plaque

Cell migration, proliferation;

stabilisation of the plaque

Angiotensin-converting enzyme inhibitors in hypertensive patients at high cardiovascular risk

ACEI

ACE inhibitors in hypertension

• ACEI are effective as monotherapy in BP reduction in most patients. There are few side effects and contraindication

ACE inhibitors in hypertension

• A particulary attractive combination is that with diuretics, because diuretics increase circulating renin activity and angiotensin II levels, wich ACEI counterregulate by inhibiting the conversion of angiotensin I to angiotensin II.

RAAS, ACEIs, and ARBs: Summary

• RAAS is a major regulator of CV and renal function

• RAAS blockade – Reduces BP– Exerts antiatherosclerotic effects– Delays or avoids onset of T2DM

• ACEIs and ARBs are the major RAAS blockers in use

• ACEIs do not inhibit Ang II formation by non-ACE pathways

• ACEIs block AT1 and AT2 receptors, whereas ARBs inhibit AT1 receptors and leave AT2 receptors open for stimulation

Schmieder RE et al. Lancet. 2007;369:1208-19.

Role of ARB in the treatment of cardiovascular diseases, with a

special reference to LOSARTAN

Arguments favoring development of ARBs

• ACE inhibitors are not specific

• ACE inhibitors do not provide

complete blockade of RAS

• Alternative pathways for angiotensin

II formation

• Significant incidence of cough

Arguments favoring development of ARBs

• ACE inhibitors are not specific

• ACE inhibitors do not provide

complete blockade of RAS

• Alternative pathways for angiotensin

II formation

• Significant incidence of cough

Angiotensin II formation in the heart mediated by chymase v.s. formation mediated by angiotensin

converting enzyme

Balcells E, et al. Am J Physiol. 1997;273:H1769–H1774.

A II fo

rmati

on, %

Mouse

Rabbit

Rat Dog Human

0

40

60

80

100

20

ACE mediatedChymase mediated

“Escape” of angiotensin II despite ACE inhibition

Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4(6):966-972.

Plasma Ang II(pg/mL)

Plasma ACE(nmoL/mL/min)

*

********

0

10

20

30

Placebo 4 h 24 h 1 2 3 4 5 6

Hospital Months

020406080

100

*P <.001 vs placebo

Inhibition of the RAS

• ARBs directly block the angiotensin II receptor (AT1), thereby largely avoiding the side effects of excess bradykinin such as cough and angioedema.

Mechanism of action of angiotensin receptor blockers

Effects of Angiotensin II upon AT1 i AT2 receptors

AT2AT1

VasoconstrictionAldosteron releaseOxidative stressVasopresin release Activation of SNS Inhibition of renin release Renal reabsorption of Na+ i H2OCell growth and proliferation

VasodilationAntiproliferative effectApoptosisAntidiuresis/antinatriuresisBradykinin formationRelease of NO

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

ARBs currently available for clinical use

Generic name Trade name Drug company

LosartanLosartan H

TenlopTenlop H

Bosnalijek

Valsartan Diovan, Tareg, Nisis

Novartis

Irbesartan Aprovel, Avapro, Karvea

Bristol-Myers, Squibb, Sanofi

Candesartan Atacand, Kenzen, Blopress

AstraZeneca/ Takeda

Telmisartan Micardis, Pritor Glaxo Smith Kline

Eprosartan Teveten Glaxo Smith Kline

Olmesartan Benycar, Daiichi Sankyo

Pharmacology of Angiotensin Receptor Blockers

Drug Half-life, h

Bioavailabili

ty %

Volume of distributio

n

Renal/hepatic

clearance, %

Candesartan 9 15 0.13 L/kg 60/40

Eprosartan 5 13 13 L 30/70

Irbesartan 11–15 60–80 53–93 L  1/99

Losartan 2 33 34 L 10/90

E-3174 6–9 − 12 L 50/50

Olmesartan 10–15 28 17 L 45/55

Telmisartan 24 42–58 500 L  1/99

Valsartan 6 ∼25 17 L 30/70

ARBs currently available for clinical use

Drug Recommended initial dosage

Dosage range Tablet/capsule

Losartan,Tenlop

50 mg once daily 25-50 mg, once daily, or 100 mg once daily

tablet12,5, 50, 100 mg

Valsartan 80 mg once daily 80-320 mg once or twice daily

capsule80,160 mg .

Irbesartan 150 mg once daily 150-300mg once daily

tablet75,150, 300 mg

Candesartan 8 mg once daily 8-16 mg once or twice daily;32 mg once daily

tablet4,8,16,32 mg

Eprosartan 400 mg once daily 400-800 mg once daily

tablet200, 400 mg

Telmisartan 40 mg once daily 40-80 mg once daily

tablet 40,80 mg

Olmesartan 20 mg once daily 20-40 mg once daily tablet 20,40 mg

ARBsIndications

• Hypertension• Heart failure• Secondary prevention following

myocardial infarction• Diabetic nephropathy• Proteinuria/microalbuminuria• Left ventricle hypertrophy• Atrial fibrilation• Cough caused by ACEI

Losartan and hypertension

Studies with Losartan

The Losartan Heart Failure n=722

Study (ELITE)

The Losartan Hypertension n=9194

Survival Study (LIFE)

The Losartan Heart Failuren=3152

Survival Study (ELITE II)

The Losartan Post-MI Survival n=5000

Study (OPTIMAAL)

The Losartan Renal Protectionn=1520

Study (RENAAL)

19,588

Comparison of efficacy of candesartan and losartan in the

treatment of hypertension : results at trough

-20

-16

-12

-8

-4

0

4

SPmmHg

Plac Los CC CC 50 8 16

*

**

* p<0.001 vs plac ; # p>0.05 vs Los-20

-16

-12

-8

-4

0

4

DPmmHg

Plac Los CC CC 50 8 16

**

* #

85 83 82 84n

Andersson, 1998

Comparison of efficacy of candesartan and losartan in the treatment of hypertension : results at peak

Andersson, 1998

-20

-16

-12

-8

-4

0

4

-20

-16

-12

-8

-4

0

4

DPmmHg

SPmmHg

Plac Los CC CC 50 8 16

Plac Los CC CC 50 8 16

**

*

*

*

*

* p<0.001 vs plac 85 83 82 84n

Comparison of efficacy of ARBs and amlodipine in the treatment of mild and

moderate hypertension

mmHg

mmHg

-16

-12

-8

-4

0

-16

-12

-8

-4

0

-16

-12

-8

-4

0

-16

-12

-8

-4

0

Los 50 Amlo 10 Vals 80 Amlo 5

Irbe 75 - 300 Amlo 2.5 - 10 CC 8 Amlo 10 Plac

SP

DP

Comparison of efficacy of ARBs and enalapril in the treatment of mild and moderate

hypertension

mmHg

-16

-12

-8

-4

0

-16

-12

-8

-4

0

mmHg

-16

-12

-8

-4

0

-16

-12

-8

-4

0Los 50 Enal 20 Vals 80 Enal 20

Irbe 75-300 Enal 10- 40 CC 4- 8 Enal 10-20

SP

DP

Comparison of efficacy of ARBs and hydrochlorothiazide in the treatment of

hypertension

-16

-12

-8

-4

0

-16

-12

-8

-4

0

0

-16

-12

-8

-4

Los 50 HCTZ 12.5 Vals 80 HCTZ 25

CC 8 HCTZ 25

mmHg

mmHg

SP

DP

Comparison of efficacy of ARBs and atenolol in the treatment of mild and moderate

hypertension

mmHg

-14

-12

-10

-8

-6

-4

-2

0

Los 50 Atenolol 50

SP

DP

-14

-12

-10

-8

-6

-4

-2

0

Irbes75-150

Atenolol50-100

Dijastolni P.

Angiotensin receptor blockers and hypertension: meta-analysis

Meta-analysis of CV events with ARBsvs comparators

BPLTTC. Lancet. 2003;362:1527-35.

Blood Pressure Lowering Treatment Trialists’ Collaboration4 trials; N = 16,791

Relative risk of event with ARB vs comparator

Stroke CHD Heart failure Major CV event

1.2

1.0

0.8

0.6

Efficacy vs. Tolerability

AT1- Receptor Antagonists

DOSETherapeuticWindow

Tolerability

Efficacy

excellent

low

50 %

Compliance With Antihypertensive

Treatment at 1 Year

38

43

50

58

*64

Co

mp

lian

ce a

t 1

Yea

r (%

)

ThiazideDiuretics

BetaBlockers

CCBs ACEInhibitors

ARBs

35

40

45

50

55

60

65

0

ARBs: Evolution of protective benefits

↓BP

↓Stroke

↑Glycemic control

↓Heart failure

↓Renal dysfunction

↓CHD (?)

ARBs: Evolution of protective benefits

↓BP

↓Stroke

↑Glycemic control

↓Heart failure

↓Renal dysfunction

↓CHD (?)

Combination antihypertensive therapy and cardiovascular event rate: amlodipine and

renin-angiotensin system blockade

Baseline Control Rates37.2 37.9

ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy

ACEI / HCTZN=5733

Co

ntr

ol

rate

(%

)

CCB / ACEIN=5713

10

20

30

40

50

60

70

80

9078.5

81.7

P<0.001 at 30 months follow-up Control defined as <140/90 mmHg

Kaplan Meier for Primary Endpoint

Cum

ulat

ive

even

t ra

te

HR (95% CI): 0.80 (0.72, 0.90)

20% Risk Reduction

Time to 1st CV morbidity/mortality (days)

p = 0

ACEI / HCTZ

CCB / ACEI650

526

.0002

I

0.5 1.0 2.0

Primary Endpoint and Components

Composite CV mortality/morbidity

Cardiovascular mortality

Non-fatal MI

Non-fatal stroke

Hospitalization for unstable angina

Coronary revascularization procedure

Resuscitated sudden death

Risk Ratio(95%)

Favors CCB / ACEI

Favors ACEI / HCTZ

0.80 (0.72–0.90)

0.81 (0.62-1.06)

0.81 (0.63-1.05)

0.87 (0.67-1.13)

0.74 (0.49-1.11)

0.85 (0.74-0.99)

1.75 (0.73-4.17)

Clinical trials of RAAS manipulation with ARBs

CAD/MI

VALIANTOPTIMAALVal-PREST

Hypertension

VALUESCOPETROPHYLIFE

CHF

ELITE 1 and 2Val-HEFTCHARM

Stroke

SCOPEMOSES

Dzau V. J Hypertens. 2005.Dahlof B. Am J Cardiol. 2007.

Barnett AH et al. N Engl J Med. 2004.Bakris G et al. ASH 2007 Scientific Sessions.

Diabetes and/or renal disease

RENAAL ABCD-2V AMADEOIDNT DETAILIRMA-2 MARVAL

LIFE study• The Losartan Intervention For Endpoint reduction in

hypertension study

• Prospective, multinational, double-blind, controlled, random study, intention-to-treat study

• 9.193 patients with hypertension and ecg signes of LVH

• Losartan compared to atenololom

Dahlöf B. et al, Lancet 2002.; 359:995-1003.

LIFE: Losartan and atenolol reduced comparably blood pressure

Systolic

Diastolic

Mean arterial pressuremm

Hg

180

160

140

120

100

40

80

60

Duration (months)

423624 3012 1860 48 54

Dahlöf B et al Lancet 2002;359:995–1003.

AtenololLosartan

Composite of CV Death, Stroke and MI

Pro

port

ion

of P

atie

nts

with

Fir

st E

vent

(%

)0

2

4

6

8

10

12

14

16

0 6 12 18 24 30 3642 48 5460 66

Adjusted Risk Reduction: 13.0%, P = 0.021

Months

LIFE: LVH Regression and Primary Endpoint

Ch

ang

e fr

om

Ba

selin

e (

%)

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

P < 0.0001

P < 0.0001

4.4%

10.2%

15.3%

9.0%

LosartanAtenolol

Dahlöf B et al. Lancet. 2002;359:995-1003.

Cornell Voltage-Duration Product

Sokolow-LyonVoltage

LIFE – significant regression of LVH in

comparison to baseline values

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Cornell Product Sokolow-Lyon

Mea

n ch

ange

s in

the

bas

elin

e va

lues

(%

)

losartan

atenolol

p<0.0001

10.2 %

9.0 %

15.3 %

4.4 %

p<0.0001

Reduction of left ventricular mass stratified according to various antihypertensive regimens

Klingbeil et al Am J Med 2003

reduction in left ventricular mass LV (%)

Diuretics Beta-blockers

Calciumantagonist

*

ACEinhibitors

**

ARBs

*

*p<0.05; **p<0.001 vs beta-blocker

0

5

10

15

20

0

2

4

6

8

10

12

14

16

% o

f p

ati

en

ts w

ith

th

e f

irs

t s

ign

es

of

hy

pe

rte

ns

ive

co

mp

lic

ati

on

sCardiovascula death, stroke and myocardial

infarction miokarda

Losartan

Atenolol

Months 0 6 12 18 24 30 36 42 48 54 60 66

Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted risk reduction 13.0%, p=0.021Non-adjusted risk reduction 14.6%, p=0.009

Dahlöf B i sur. Lancet 2002;359:995-1003.

No. of patients with risk

13%

Losartan reduces CV complications with equal antihypertensive efficacy

Losartan

Atenolol

Adjusted risk reduction 24.9%, p=0.001Non-adjusted risk reduction 25.8%, p=0.0006

Months 0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8

Dahlöf B i sur. Lancet 2002;359:995-1003.

Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897

Stroke with and without death

% o

f p

ati

en

ts w

ith

th

e f

irs

t s

tro

ke

25%

Losartan reduces more efectively stroke with equal antihypertensive efficacy

Angiotensin receptor blockers and stroke risk

MOSES: ARB surpasses CCB for secondary stroke prevention

Schrader J et al. Stroke. 2005;36:1218-26.

N = 1405 with HTN and prior cerebral event

-21

-25 -25-30

-25

-20

-15

-10

-5

0

Primary compositeoutcome*

*Cerebrovascular, CV events, and all-cause death †Events per 100 person-years, including recurrent events

Fatal/nonfatalCV events

Fatal/nonfatalstroke

RRR Eprosartan vs nitrendipine†

(%)

P = 0.014

P = 0.061 P = 0.026

Meta-analysis of CV events with ARBsvs comparators

BPLTTC. Lancet. 2003;362:1527-35.

Blood Pressure Lowering Treatment Trialists’ Collaboration4 trials; N = 16,791

Relative risk of event with ARB vs comparator

Stroke CHD Heart failure Major CV event

1.2

1.0

0.8

0.6

Intention-to-Treat

LIFE: New Onset Diabetes

Losartan

Atenolol

En

dp

oin

t R

ate

Study Day 0 180 360 540 720 900 1080 1260 1440 1620 1800 19800.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

Adjusted Risk Reduction 25%, p<0.001Unadjusted Risk Reduction 25%, p<0.001

B Dahlof et al. Lancet 2002;359:995-1003

Months 0 6 12 18 24 30 36 42 48 54 60 66Losartan (n) 586 569 558 548 532 520 513 501 484 459 237 127Atenolol (n) 609 588 562 552 540 527 507 486 472 434 204 99

24

20

16

12

8

4

0

LH Lindholm, et al Lancet 2002; 359:1004-1010

Atenolol n= 139 (23%)

Losartann= 103 (18%)

Cardiovascular death, stroke and myocardial infarction in diabetics

25%

Adjusted risk reduction = 24,5%; p=0,031Non- adjusted risk reduction = 26,7%; p=0,017

% o

f p

ati

en

ts w

ith

th

e

firs

t o

ns

et

of

co

mp

lic

ati

on

s

0 6 12 18 24 30 36 42 48 54 60 66

Study Month

Pro

po

rtio

n o

f p

atie

nts

, %

24

20

16

12

8

4

0

RRR 39%

p = 0.002

LIFE: Diabetes Subgroup (n = 1195) Total Mortality

(secondary endpoint)

Losartan

Atenolol

(from Lindholm LH et al., Lancet 359: 1004-1010, 2002)

The role and importance of Losartan in the treatment of diabetic nephropathy with

proteinuria

Lewis EJ et al. N Engl J Med 1993;329:1456-1462.

Progression to death,

dialysis or transplant

(%)

Captopril

Placebo

Follow-up (y)0 1 2 3 4

0

10

20

30

40

*

Effect of ACE Inhibition on Nephropathy in Patients with Type 1 Diabetes

Collaborative Study Group* p = 0.006 vs placebo.

M e ta - re g re s s io n a n a ly s is o f 1 0 0 s tu d ie s to ta l in g 2 ,4 9 4 p a t ie n tsw ith ty p e 1 a n d t y p e 2 d ia b e te s .* p < 0 .0 5 v s c a lc iu m c h a n n e l b lo c k e rs .† p < 0 .0 5 v s c o n tro l.

E ffe c t o f B P R e d u c t io n v s A C E In h ib it io n o n P ro te in u r ia a n d R e n a l F u n c t io n in P a t ie n ts w ith D ia b e te s

K a s is k e B L e t a l. A n n In te rn M e d 1 9 9 3 ;1 1 8 :1 2 9 -1 3 8 .

Renal protection beyond RR ?

RR

Risk ESRF

Other drugs

ACEIor

ARB

DHP- Ca Antag.

Intraglomerular pressure may stay unchanged

DHP- CaAntag

Ang II

Dilation ofafferentarteriole

RR

Reduction of intraglomerular pressure

ACEI or ARB

Ang II

RR

Dilation of efferent

artheriole

Studies with ARBs in diabetics

RENAAL (Reduction in Endpoints in NIDDM with Angiotensin II Antagonist Losartan)

IDNT (Irbesartan in Diabetic Nephropathy Trial)

IRMA2 (Irbesartan Micro-Albuminuria type 2 diabetes mellitus in hypertensive patients

RENAAL study

The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study

Brenner BM et al. N Engl J Med 2001; 345(12):861-869.

Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):328-335.

RENAALProgression of renal disease

Losartan Placebo0

-.02

-.04

-.06

-.08

dl/m

g/ye

ar -0.056

-0.069

p=0.0118% reduction

Brenner BM et al New Engl J Med 2001 ;345(12):861-869.

RENALL – Results

Patients in the losartan group had a reduction in proteinuria of 35%, while the patients in the placebo group had an increase in proteinuria (P=<0.001)

Brenner et al. NEJM. 2001.

RENALL – Conclusions

• Losartan has renoprotective effects by reducing risk of doubling creatinine AND by reducing progression to ESRD

• Losartan reduces episodes of CHF

• Effects reported as independent of blood pressure

ARBs decrease renal complications in T2DM

ESRD/Cr 2/all deaths:16% vs placebo (P = 0.02)

Losartan/ placebo

Nephropathy(1513)

RENAAL

UAER at 24 weeks: 44% valsartan vs 8% amlodipine (P < 0.001)

Valsartan/amlodipine

Microalbuminuria(332)

MARVAL

ESRD/ Cr 2/mortality: 20% vs placebo (P = 0.02) 23% vs amlodipine (P = 0.006)

Irbesartan/amlodipine/placebo

Nephropathy(1715)

IDNT

Time to nephropathy: 39% (150 mg, P = 0.08) 70% (300 mg, P < 0.001)

Irbesartan150/300 mg vs placebo

Microalbuminuria(590)

IRMA-2

Primary outcomeTreatmentT2DM (N)

Adapted from Sharma AM. Hypertension. 2004;44:12-19.Cr = creatinineUAER = urinary albumin excretion rate

Combination treatment

• ACEI+ARB: different mechanisms of action make combination treatment useful owing to complete RAS blockade,

CALM

Objectives: To assess and compare the effects of candesartan or lisinopril, or both, on blood pressure and urinary albumin excretion in patients with microalbuminuria, hypertension, and type 2 diabetes

Design: 12 weeks' monotherapy with candesartan or lisinopril followed by 12 weeks' monotherapy or combination treatment199 patients aged 30-75 yearsCandesartan 16 mg od or lisinopril 20 mg

Outcome: Blood pressure and urinary albumin:creatinine ratio

(Candesartan And Lisinopril Microalbuminuria study)

CALM Mean difference at week 24

Candesartan Lisinopril Combination

Sitting DBP (mm Hg) 10.4 10.7 16.3

Sitting SBP (mm Hg) 14.1 16.7 25.3

Urinary albumin/creatinine ratio (%) 24 39 50

Mogensen et al. BMJ 321; 1440

p=0.005p=0.003

p=0.002p=0.02

p=0.04p>0.20

CALM

• Conclusions– Candesartan 16 mg od has similar effect to

lisinopril on BP and microalbuminuria in hypertensive patients with type 2 diabetes

– Combination treatment ACEI+ARB is more effective than either monotherapy at reducing BP and urinary albumin/creatinine ratio

Mogensen et al. BMJ 321; 1440

Pharmacokinetic differences between angiotensin-converting enzyme inhibitors and angiotensin

receptor blockers in renal failure Parameter ACE

inhibitorsAngiotensin receptor

antagonists

Proteinuria ↓↓ ↓↓

Uric acid ↓ ↓↓

Glomerular filtration rate ↓↓ ↓↓

Hyperkalemia ↑↑ ↑

Blood pressure reduction ↓↓ ↓↓

Systemic accumulation Yes No

AT2-receptor stimulation

Possibly ↑↑

Renal and Pharmacokinetic Aspects of ACE Inhibitor and Angiotensin Receptor Antagonist

Therapy in End-stage Renal Disease Parameter ACE

inhibitorsAngiotensin receptor

antagonists

Angioneurotic edema Yes Yes, but much less frequently

Dialyzer reactions Yes No

Residual renal function ↓↓ ↓↓

Dialyzability Yes No

Hyperkalemia ↑↑ ↑↑

Blood pressure reduction ↓↓ ↓↓

Systemic accumulation Yes No

AT2-receptor stimulation

Possibly ↑↑

Landmark studies with ACEI and ARBs and clinical significance of RAAS blockade in hypertension, coronary disease, MI and heart failure

Reduction of mortality (%)

7

12

29

1922

27

0

5

10

15

20

25

30

35

GISSI-3 SMILE SAVE TRACE AIREISIS-4

ACEI in post-MI

> 100 000 patients !

ACEI in early phase AMI

• ACE inhibitors achieve a modest but statistically significant reduction in mortality ( 6% to 11%). Best results are obtained in higher risk patients treated long term, such as those with large infarcts, in whom ACEI give a striking reduction of 26% in mortality

ACE Inhibitors• ACEI in patients with heart failure

reduce– morbidity– mortality

• ACEI in sedondary prevention of MI reduce

– morbidity– mortality

– - development of HF

Studies: CONSENSUS, SOLVD, SAVE, AIRE, ISSIS-4

ARBs and chronic heart failure

®

Studies of ARBs in chronic heart failure

ELITE

ELITE II

Val-HeFT

CHARM

ELITE study

• Application of 50 mg losartan, in comparison with captopril, in patients with heart failure reduced mortality by 46% and sudden cardiac death by 64%

ARBs and heart failure

• ARBs have been tested in an era when ACE inhibitors were already the established therapy of choise for heart failure. Had the ARBs come earlier, they would probably have been first choise.

Combination therapy with ACE inhibitors and

ARB• Adding the ARB to the ACEI gave better

results in more severe heart failure with the mean ejection fraction about 25% (Val-HeFT and CHARM trials). In diabetes and diabetic renal disease, the combination is advised when monotherapy fails to reduce proteinuria sufficiently.

Indication and evidence forcombining ACEI and ARB

Indication Indication for dual RAS inhibition

Hypertension Not standard, possibly in LVH, microalbuminuria, DM

Systolic heart failure Yes, when symptoms persist despite diuretic, beta blocker, and ACEI

Post myocardial infarction No

Nephroprotection (diabetics) Yes

Nephroprotection (non -diabetics) Da

ONgoing Telmisartan Alone and in combination

with Ramipril Global Endpoint Trial

The telmisartan trial in cardiovascular protection

Sponsored by Boehringer Ingelheim

ONgoing Telmisartan Alone and in combination

with Ramipril Global Endpoint Trial

The telmisartan trial in cardiovascular protection

Sponsored by Boehringer Ingelheim

Indication and evidence forcombining ACEI and ARB

Indication Indication for dual RAS inhibition

Hypertension Not standard, possibly in LVH, microalbuminuria, DM

Systolic heart failure Yes, when symptoms persist despite diuretic, beta blocker, and ACEI

Post myocardial infarction No

Nephroprotection (diabetics) Yes

Nephroprotection (non -diabetics) Yes

Less new diabetes

• An important finding with ACE inhibitors and ARBs, especially when compared with beta blockers or diuretics, is the decreased developement of new diabetes.

Effect of ACEIs and ARBs on new-onset diabetes

Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.

Meta-analysis: 12 randomized controlled trials; N = 72,333 patients without 72,333 patients without T2DM at baselineT2DM at baseline

CAPPPSTOP-2

HOPELIFE

ALLHATANBP2SCOPEALPINECHARMSOLVDVALUEPEACE

All pooledACEI pooledARB pooled

0.125 0.25 0.5 1 2

Less likely to develop T2DM

Relative risk (95% CI)

More likely to develop T2DM

New-onset diabetes rate reduced by renin-angiotensin-aldosterone system modulation

Risk of new-onset diabetes in hypertension: comparison of antihypertensive drug classes

Drug related new diabetes

Inhibitors of renin-angiotensin-aldosterone system

• Several analyses of retrospective clinical trials suggest benefit of ACE inhibitors or AT1 blockers in prevention of atrial fibrillation, especially in patients with left ventricular hypertrophy or dysfunction.

Atrial Fibrillation (AF) - Primary Prevention

• In 2007 ESH / ESC guidelines recommendation to preferentially use ARBs / ACEIs

• Evidence mainly from post-hoc analyses

Atrial Fibrillation

• In a meta-analysis on almost 12.000 patients with systolic HF BBs were found to reduce (-27%) AF

• In patients with an AF history and systolic HF BBs are a specific indication

Angiotensin receptor blockers in atrial fibrillation: losartan versus atenolol

Pleiotropic effects of renin-angiotensin system blockers

Inhibitors of renin-angiotensin-aldosterone system

• Plasma aldosterone concentracions increase in patients with atrial fibrillation and atrial expression of the aldosterone receptor is higher in these patients than in those without the disorder.

Inhibitors of renin-angiotensin-aldosterone system

• Patients with primary hyperaldosteronism have a 12-fold greater risk of atrial fibrillation than do controls matched for blood pressure.

Inhibitors of renin-angiotensin-aldosterone system

• Hence blockade of aldosterone receptors could be a therapeutic option for patients with atrial fibrillation, but data from trials are not available.