Cardiac Protectionacross the cardiac continuum

Dong-Ju Choi, MD, PhDCollege of MedicineSeoul National University

• t-PA•Cathepsin G•Tonin

Angiotensinogen

A IRenin

A IIA II

CAGECathepsin GChymase

• Antiproliferation• NO Release• Differentiation• Vasodilation

• Hypertrophy/proliferation• Vasoconstriction• Aldosterone release• Antidiuretic hormone release

AT1 receptor AT2 receptor

ACEI site of action

ACE

Degradation products

↑ Bradykinin

↑ Nitric oxide (NO)

Renin Angiotensin Cascade

de Gasparo M, et al. Hypertension. Pathophysiology, Diagnosis, and Management. 2nd ed. New York, NY: Raven Press; 1995:1695–1720. Dzau VJ. J Hypertens. 1989;7:933-936.

Pathophysiologic Effects of Angiotensin II

Burnier M, Brunner HR. Lancet. 2000;355:637–645.

AngiotensinAngiotensin IIII

Abnormalvasoconstriction

Activate SNS

↑Aldosterone

↑Vasopressin

↑Collagen

↑Contractility

↑PAI-1/thrombosis

Platelet aggregation

Superoxideproduction

↑Endothelin

Vascular smooth muscle growth

Myocyte growth

Adverse Effects of RAS on CV System

Vascular change1. Vascular remodeling2. Endothelial dysfunction3. Inflammation

Myocardial damage1. Myocyte sequestration2. Myocyte isolation

Increase BP

Ang II

Vascular Remodeling

AngII-induced InflammationThe inflammatory response by AngII:

1) Increase in vascular permeability,

2) Infiltration of leukocytes, and

3) Tissue remodeling.

Myocardial Damage by RAS

1. Myocyte sequestration• Hypertrophy• Apoptosis• Necrosis

2. Myocyte isolation• Interstitial fibrosis • Conduction disturbance

Blocking RAS is critical to prevent

1. Vascular change (Vascular remodeling, endothelial dysfunction and inflammation)

and

2. Myocardial damage(Myocyte sequestration and myocyte isolation)

The Cardiovascular Continuum:

Risk Factors:

Vascular Dysfunction

Vascular Disease

Tissue Injury

Target OrganDysfunction

End-stageOrgan Failure

Death

Oxidative Stress/EndothelialDysfunction

Target OrganDamageTissue Loss

ANGIOTENSIN II

AtherosclerosisHypertrophy

CAD

MyocardialInfarction

PathologicalRemodeling

Ventricular Enlargement

Heart Failure

Mechanisms and Mediators

Clinical Trials with ACE inhibitors

Risk Factors:DiabetesHypertensionHyperlipdemia Death

AtherosclerosisHypertrophy

CAD

MyocardialInfarction

PathologicalRemodeling

VentricularEnlargement

Heart FailureHypertension

CAPPP, ALLHAT

DM

ABCD, REIN, AASK

Vascular and CAD

HOPE, QUIET,

EUROPA, PEACE

MI

CONSENSUS,

ISIS-4, GISSI-3

SMILE, SAVE

AIRE, TRACE

HF

SOLVD

V-HeFT II

SAVE,

ATLAS

Clinical Trials with ARB

Risk Factors:DiabetesHypertensionHyperlipdemia Death

AtherosclerosisHypertrophy

CAD, Nephropathy

MyocardialInfarction

PathologicalRemodeling

VentricularEnlargement

Heart FailureHypertension

SCOPE,

VALUE,

TROPHY, LIFE

DM/Renal

RENAAL, IDNT

IRMAII, ARVAL

ABCD-2V,

NAVIGATOR

Post-MI

VALIANT,

OPTIMAL

VAL-PREST

HF

ELITE I&II

Val-HeFT

CHARM

Amlodipine-based

(n=163)

DIOVAN-based

(n=166)

Amlodipine-based

(n=163)

DIOVAN-based

(n=166)

–6.5–6.0

–33.4 –33.5Mea

n ch

ange

in B

P (m

mH

g)

NS

NS

0

–5

–10

–15

–20

–25

–30

–35

Patients were randomised to DIOVAN 80 mg or amlodipine 5 mg

After 8 weeks, patients with SBP ≥140 mmHg were titrated to DIOVAN 160 mg/d or amlodipine 10 mg

After an additional 8 weeks, HCTZ 12.5 mg was added to treatment in patients with SBP ≥140 mmHg

DBPSBP

Randomised, double-blind, titration to effect study of patients (aged 60–80 years) with ISH: 24 weeks’ treatment

Val-Syst: Valsartan in Isolated SystolicHypertension (ISH);Per protocol population data shown; NS = not significant Clin Ther 2003;25:2765–80

Val-Syst Trial:Powerful Double-digit BP Reductions with Valsartan-based Therapy in Patients with ISH Aged 60–80

Time Course of Morning BP Changes Mediated by ARBs

Day

SBP

(mm

Hg)

–7 0 7 14 21 28

165

155

145

135

Valsartan 40–80 mg (n=18)Telmisartan 10–40 mg (n=18)

Losartan 25–100 mg (n=18)Candesartan 2–12 mg (n=18)

Start of treatment

Morning home BP

Patients with essential hypertension: 4 weeks’ treatment

Clin Exp Hypertens 2005;27:477–89

The role of arterial stiffness as the major cause of cardio-vascular risk can be seen in recent outcome data.

Pulse Wave Velocity

aortic pulse wave velocity on entry was used to stratify arterial stiffness in a cohort of ESRD patients into tertiles

1st tertile has almost normal results; 3rd tertile has 6x risk of “all cause’ mortality

The role of arterial stiffnessThe role of arterial stiffness

Clin Exp Hypertens. 2004 Oct-Nov;26(7-8):689-99

Reduces Arterial Stiffness

Am J Hypertens 2004;17:1050–5

Bra

chia

l–an

kle

PWV*

(cm

/sec

)

–195

–69

Nifedipine 20 mg (n=20) Diovan 80 mg (n=21)

p=0.02

0

–50

–100

–150

–200

–250

Randomised study of patients with hypertension: 3 months’ treatment

*Brachial-ankle pulse wave velocity (PWV), a measure for systemic arterialstiffness

Reduces Arterial Stiffness

†Augmentation index (AIx), a measure of arterial function*p<0.01 vs HCTZ and vs placebo

Randomised, double-blind, parallel-group design study of patients with essential hypertension: 6 weeks’ treatment

J Hypertens 2002;20:2423–8

• Diovan improves arterial compliance in patients with hypertension

• Effects are independent of BP reduction (BP reductions similar for Diovan and HCTZ)

–21.7*(n=20)

–3.2(n=20)

–0.3(n=20)

Cha

nge

inA

Ix†

from

bas

elin

e

Diovan 80 mg HCTZ 25 mg Placebo0

–10

–20

–30

–40

DETECTIV : Valsartan Increases Small Artery Elasticity in Asymptomatic Risk Patients with High CV Risk

Results from a 12-month study in 76 asymptomatic patients# with RDS ≥6 and controlled BP and cholesterol levels (DETECTIV study)

6 months 12 months

Cha

nge

in R

DS

from

bas

elin

e

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

44%reduction*

-2.2

-3.1

-3.9-3.6-3.6

#Individuals completing the study with or without antihypertensive or lipid lowering medications, BP <140/90 mmHg; *p<0.000; RDS=Rasmussen Disease ScoreDuprez et al.

DIOVAN 160 mg od for 12 monthsDIOVAN 160 mg od for 6 monthsPlacebo

6 months 12 monthsCha

nge

in s

mal

l art

ery

elas

ticity

from

bas

elin

e (m

L/m

mH

g x1

00)

0

0.5

1

1.5

2

2.5

3

3.577%

increase*

0.55

1.51

2.39

3.24

JACC 2007;50:published online

DIOVAN 160 mg(n=836)

Co-DIOVAN160/12.5 mg(n=832) Co-DIOVAN 320/12.5 mg

(n=808)

DIOVAN 320 mg(n=807)

Week 0Visit 1

(randomisation)

Week 2Visit 2

Week 6Visit 3

Week 12Visit 4

(End of study)

DIOVAN 320 mg (plus optional HCTZ 12.5 mg)

Co-DIOVAN 320/12.5mg (or optional Co-DIOVAN 320/25mg)

Screening

0–7 days

Val-MARC: Managing BP Aggressively and Evaluating Reductions in hsCRP

Multicentre, open-label, randomised, parallel-group study of patients with Stage II hypertension

Objectives, to determine: • If BP reduction with DIOVAN/Co-DIOVAN is effective at reducing hsCRP levels• If there is a difference between moderate and aggressive BP reduction in terms of hsCRP change

Primary endpoints:• Change in SBP from baseline to Week 6 with DIOVAN vs Co-DIOVAN• Change in hsCRP from baseline to Week 6 with DIOVAN vs Co-DIOVAN• Change in hsCRP from baseline to Week 12 in the overall group

Hypertension 2006;48:73-79

Val-MARC : DIOVAN Reduces hsCRP Levels Independent of Blood Pressure Reduction

Results from a 6-week study* in 1,615 patients with stage II HTN#

(Val-MARC study)C

hang

e in

hsC

RP

plas

ma

leve

l (%

)fr

om b

asel

ine

to 6

wee

ks*

DIOVAN 160 - 320 mg od

(n=807, median change -0.12)

Co-DIOVAN 160/12.5 - 320/12.5 mg od

(n=808, median change +0.05)

#SBP ≥160 mmHg or DBP ≥100 mmHg, patients completing the study; *Study duration 12 weeks, after 6 weeks of treatment, HCTZ 12.5 mg/day allowed at discretion in both groups to reach BP <140/90 mmHg); p<0.001 for DIOVAN vs. Co-DIOVAN Ridker et al.

-8.9%

4.4%

-10

-8

-6

-4

-2

0

2

4

6

Hypertension 2006;48:73-79

Month –0.5 0 1 2 3 4 6 * 72

Amlo 10 mg +HCTZ 25 mg

Amlo 5 mg

Amlo 10 mg +HCTZ 12.5 mg

Amlo 10 mg

DIOVAN 80 mg

DIOVAN 160 mg

Co-DIOVAN 160/12.5 mg

Co-DIOVAN 160/25 mg

Amlodipine-based regimen

DIOVAN 160 mg +HCTZ 25 mg + ‘Free’ add-on

Amlo 10 mg +HCTZ 25 mg + ‘Free’ add-on

DIOVAN-based regimen

ScreeningRandomisation End of treatment adjustment period

Rolloverfromprevious therapy(92%)

*Patient visits every 6 months forMonths 6–72; Amlo = amlodipine

VALUE: Elective Titration to Target BP(<140/90 mmHg)

Lancet 2004;363:2022–31

Patients aged ≥50 years, with treated or untreated hypertensionand at high risk of CV events

Number at risk

Amlodipine 7,596 7,469 7,424 7,267 7,117 6,7726,955 6,576 5,959 3,725 1,4746,391

DIOVAN 7,649 7,459 7,407 7,250 7,085 6,7326,906 6,536 5,911 3,765 1,4746,349

Time (months)0 6 12 18 24 30 36 42 48 54 60 66

Prop

ortio

n of

pat

ient

s w

ith

first

eve

nt (%

)DIOVAN-based regimenAmlodipine-based regimen

HR=1.03; 95% CI=0.94–1.14; p=0.49

14

12

10

8

6

4

2

0

VALUE: Rate of Cardiac Events Did not Differ Between the Vasarta and Amlodipine Groups

Lancet 2004;363:2022–31

LIFE :The Losartan Intervention For Endpoint Reduction in Hypertension Study

* Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg but was mandatory if SiBP >160 / 95 mmHg**Other antihypertensives excluding ACEIs, A II antagonists, beta blockers

Day −14

Day−7

Day1

Mth1

Mth2

Mth4

Mth6

Yr1

Yr1.5

Yr2

Yr2.5

Yr3

Yr3.5

Yr4

Yr5

* Titration to target blood pressure: <140 / 90 mmHg

Placebo Losartan 50 mg

Atenolol 50 mg

Losartan 50 mg + HCTZ 12.5 mg*

Losartan 100 mg + HCTZ 12.5 mg*

Losartan 100 mg + HCTZ 12.5- 25 mg + others**

Atenolol 50 mg + HCTZ 12.5 mg*

Atenolol 100 mg + HCTZ 12.5 mg*

Atenolol 100 mg + HCTZ 12.5- 25mg + others**

Lancet 2002;359;995-1003-1010

Patients aged ≥55 years, with treated or untreated hypertensionand at high risk of CV events

LIFE : BP reductions

Time (months)

Lancet 2002;359;995-1003-1010

Systolic

Diastolic

Mean arterialmm

Hg

180

160

140

120

100

40

80

60

423624 3012 1860 48 54

AtenololLosartan

Endp

oint

Rat

e

LIFE : Primary Composite Endpoint

0 180 360 540 720 900 1080 1260 1440 1620 1800 1980Study Day0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

Intention-to-Treat

Losartan

Atenolol

Study Month 0 6 12 18 24 30 36 42 48 54 60 66Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4110 4045 3895 1888 901Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876

Adjusted Risk Reduction 13·0%, p=0·021Unadjusted Risk Reduction 14·6%, p=0·009

Lancet 2002;359;995-1003-1010

Atrial fibrillation accounts for 1/3 of all patientsdischarges with arrhythmia as principal diagnosis

2% VF

J Am Coll Cardiol. 1992;19(3):41A.

34% Atrial

Fibrillation

18% Unspecified

6% PSVT

6% PVCs

4%Atrial

Flutter

9% SSS

8%Conduction Disease

3% SCD10% VT

Relative Risk of Stroke and Mortality in Patients with AF vs. without AF

Lancet 1987;1:526Am Heart J 1983;106:389 Am J Med 1995;98:476

0

2

4

6

8

Whitehall

Framingham(no Heart Disease)

Framingham (overall)

Manitoba

Whitehall

Regional Heart Study

Framingham

Stroke MortalityR

ela

tive R

isk (

tim

es)

Stroke rate in Non-Rheumatic HD with AF : ↑5% / year

(Patients without AF)

VALUE - AF :Reduces the risk of new onset AF by 16%

J Hypertens 2008, 26:403–411

•DIOVAN significantly reduces the risk of new-onset AF by 16% compared with amlodipine

•DIOVAN significantly reduces the risk of persistent AF by 32% compared with amlodipine

VALIANT: Study Design and Inclusion Criteria

Primary endpoint: All-cause mortalitySecondary endpoints: CV morbidity and mortalityOther endpoints: Safety and tolerability

Captopril 50 mg tid(n=4,909)

DIOVAN 160 mg bid(n=4,909)

Captopril 50 mg tid + DIOVAN 80 mg bid

(n=4,885)

0.5–10 days after acute MI – SAVE, AIRE or TRACE eligible(either clinical/radiological signs of HF or LVSD)

Major exclusion criteria

– Serum creatinine >2.5 mg/dL

– DBP <100 mmHg

– Prior intolerance of an ARB or ACE-IDouble-blind active-controlled, stepwise titration

Median duration: 24.7 monthsEvent-driven

Am Heart J 2000;140:727–50N Engl J Med 2003;349:1893–906

VALIANT: Risk of Mortality is Similarly Reduced with Valsartan and Captopril

N Engl J Med 2003;349:1893–906

0.30

Prob

abili

ty o

f dea

th

from

any

cau

se

0

0.05

0.10

0.15

0.20

0.25

0 6 12 18 24 30 36Time (months)

DIOVAN vs captopril: HR=1.00; p=0.98

Captopril 50 mg tid* (n=4,909)DIOVAN 160 mg bid* (n=4,909) DIOVAN 80 mg bid + captopril 50 mg tid* (n=4,885) *titration to target dose

DIOVAN + captopril vs captopril: HR=0.98; p=0.73

Patients with acute MI complicated by either HF or LVSD

Captopril 4,909 4,428 4,241 4,018 2,635 1,432 364 Diovan 4,909 4,464 4,272 4,007 2,648 1,437 357 Diovan + captopril

4,885 4,414 4,265 3,994 2,648 1,435 382

LVSD = left ventricular systolic dysfunctionHF = heart failure

OPTIMAAL(Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan)

Lancet 2002;360:752–60

　 50 years of age AMI-patients with heart failure or anterior Q-wave AMI

31,738 assessed

26,261 excluded

5,477 randomised

2,744 Losartan

2,733 Captopril

2,744 analysed 2,733 analysed

459 discont’d 424 discont’d

25

20

15

10

5

0

Endp

oint

rate

(%)

0 6 12 18 24 30 36

Losartan (n= 2,744)Captopril (n=2,733)

Relative risk 1.13 (85% CI 0.99–1.28) p=0.069

OPTIMAAL: No Difference in Mortality Risk Between Losartan and Captopril

Months

Lancet 2002;360:752–60

Val-HeFT (The Valsartan in Heart Failure Trial )

5,010 patients with HF ≥18 years; EF <40%; NYHA II–IV; LVIDd >2.9 cm/m2

ACE-I (93%), diuretics (86%),digoxin (67%), beta-blockers (36%)

DIOVAN 40 mg bid titrated to 160 mg bid

Two primary endpoints: 1) Mortality 2) Combined endpoint of mortality and morbidity

Randomised to

Receiving standard therapy

Placebo

EF = ejection fractionNYHA = New York Heart Association LVIDd = left-ventricular internaldiastolic diameter N Engl J Med 2001;345:1667–75

Val-HeFT: Improves CV Outcomes* in CHF

Time (months)

100

95

90

85

80

75

70

65

0

Even

t-fre

e pr

obab

ility

(%)

DIOVAN‡ (n=2,511)

Placebo (n=2,499)

13.2%risk

reduction†

*Combined 1° endpoint: all-cause mortality, cardiac arrest with resuscitation, hospitalization for worsening HF, or therapy with intravenous inotropes or vasodilators; †p=0.009 vs. placebo; 1° endpoint of mortality was not significantly different between valsartan and placebo; ‡DIOVAN regimen started at 40 mg bid after placebo run-in, doubled every 2 weeks to target 160 mg bidCohn et al.

0 3 6 9 12 15 18 21 24 27

Results from a 23-month mean follow-up study in 5,010 patients with CHF on standard therapy (Val-HeFT study)

RR=0.87; 97.5% CI: 0.77-0.97

N Engl J Med 2001;345:1667-1675

≥ 60 yrs; NYHA II - IV; EF ≤ 40 %ACEI naive or < 7 days in 3 months prior to entry

Standard Rx ( ± Dig / Diuretics ), ß - blocker stratification

Captopril50 mg 3 times daily

n = 1574

Losartan50 mg daily

n = 1578

Event DrivenTargeting 510 deaths

estimate 2 yrsmedian follow-up 555 days

Primary Endpoint : All-cause MortalitySecondary Endpoint : Sudden cardiac death and/or Resuscitated ArrestOther : All-cause Mortality / Hospitalizations

Safety and Tolerability

ELITE II :Evaluation of Losartan in the Elderly Study

Lancet 2000;355:1582–87

Randomised trial of losartan versus captoprilin patients over 65 with heart failure

1.0

0.8

0.6

0.4

0.2

00 100 200 300 400 500 600 700

Follow-up (days)

Even

t-fre

e pr

obab

ility

Losartan (n=1578)Captopril (n=1574)

p=0.18

ELITE II:

Lancet 2000;355:1582–87

Risk of All-cause Mortality or Hospital Admission is Similarly Reduced with Losartan and Captopril

JIKEI HEART : Valsartan-based Therapy Improved Outcomes in Japanese Patients with HT and/or Coronary Heart Disease and/or HF

Run-in

Conventional treatment (non-ARB)

Conventional treatment (non-ARB) + non-ARB

+ non-ARB

+ non-ARB

+ valsartan 40–80 mg daily

+ valsartan40–160 mg daily

+ non-ARBtreatmentValsartan-based therapy group

(n=1541)

Non-ARB treatment arm(n=1540)

Randomisation 0

Titration 8–12

Titration 12–16

End of study(median follow-up

was 3.1 years)

–4

Weeks

Mochizuki et al. Lancet 2007;369:1431–9

40*

Stroke/TIA

JIKEI HEART R

isk

redu

ctio

n (%

) 65*

Hospitalisation for angina

47*

Hospitalisation for HF

39*

CV mortality and morbidity†

0

20

40

60

80TIA = transient ischemic attack*With DIOVAN-based therapy comparedwith non-ARB therapy; †primary endpoint Lancet 2007;369:1431–9

p=0.0002 p=0.0280p=0.0293

p=0.0001

0

10,000

20,000

30,000

40,000

50,000

60,000VALUE1

VALIANT2

NAVIGATOR3

Val-HeFT4

JIKEI HEART5,6

KYOTO HEART*7

Num

ber o

f pat

ient

s

DIOVAN Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan

50,345

29,400

22,99119,768

1,000 1,405

CHARM14

SCOPE15

SCAST*16

CASE-J17

I-Preserve18

IDNT19

ACTIVE*20

SUPPORT*21

MOSES22

1Julius et al. Lancet 2004;363:2022–31; 2Pfeffer et al. NEJM 2003;349:1893–906; 3www.novartis.com; 4Cohn et al. NEJM 2001;345:1667–75; 5Mochizuki et al. J Hypertens 2006;24(Suppl. 4):S31; 6Mochizuki et al. Cardiovasc Drugs Ther 2004;18:305–9; 7http://clinicaltrials.gov (NCT00149227) 8www.ontarget-micardis.com; 9Dahlof et al. Lancet 2002;359:955–1003; 10Dickstein et al. Lancet 2002;360:752–60; 11Pitt et al. Lancet 2000;355:1582–7; 12Brenner et al. NEJM 2001;345:861–9; 13http://clinicaltrials.gov (NCT00090259) 14www.atacand.com; 15Papademetriou et al. J Am Coll Cardiol 2004;44:1175–80; 16http://clinicaltrials.gov (NCT00120003); 17Ogihara J Hypertens 2006;24(Suppl. 4):S30; 18Carson et al. J Card Fail 2005;11:576–85; 19Lewis et al. NEJM 2001;345:851–60; 20http://clinicaltrials.gov (NCT00249795); 21http://clinicaltrials.gov (NCT00417222); 22Schrader et al. Stroke 2005;36:1218–26*Expected enrolment

ONTARGET8

TRANSEND8

LIFE9

OPTIMAAL10

ELITE II11

RENAAL12

NCT00090259*13

14,815

Mortality and Morbidity Endpoint Trials with ARB

Summary:To protect and improve vascular and cardiac structure/function• understanding the effects of angiotensin II is an important issue

in HT.

Blocking the negative effects of angiotensin II at the AT1 receptor• improves endothelial function,• improves inflammation,• reduces oxidative stress• improves left ventricular remodeling and function

ARB has proven clinical benefits from HT to HF patients in the spectrum of CV continuum.

ARB provides proven cardioprotective benefits.