Cardiac Protection across the cardiac continuum

Dong-Ju Choi, MD, PhD College of Medicine Seoul National University Renin Angiotensin Cascade

↑ Nitric oxide (NO) Angiotensinogen •t-PA Renin •Cathepsin G A I ↑ Bradykinin CAGE •Tonin ACE Cathepsin G Chymase Degradation A II products ACEI site of action

AT1 receptor AT2 receptor

• Hypertrophy/proliferation • Antiproliferation • Vasoconstriction • NO Release • Aldosterone release • Differentiation • Antidiuretic hormone release • Vasodilation 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

Abnormal ↑PAI-1/ vasoconstriction thrombosis

↑Contractility Platelet aggregation

Activate SNS Superoxide AngiotensinAngiotensin IIII production ↑Aldosterone Vascular smooth ↑Vasopressin muscle growth

↑Endothelin Myocyte growth ↑Collagen

Burnier M, Brunner HR. Lancet. 2000;355:637–645. Adverse Effects of RAS on CV System

Vascular change 1. Vascular remodeling 2. Endothelial dysfunction 3. Inflammation

Myocardial damage 1. Myocyte sequestration 2. Myocyte isolation Increase BP

Ang II Vascular Remodeling AngII-induced Inflammation The 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:

Mechanisms and Mediators

Oxidative Target Organ Stress/Endothelial Myocardial Pathological Tissue Injury Tissue Loss Damage Dysfunction Infarction Remodeling

VascularCAD Disease TargetVentricular Organ DysfunctionEnlargement

AtherosclerosisVascular DysfunctionHypertrophy HeartEnd-stage Failure Organ Failure

Risk Factors: ANGIOTENSIN II Death Clinical Trials with ACE inhibitors

MI

CONSENSUS,

Vascular and CAD ISIS-4, GISSI-3

HOPE, QUIET, SMILE, SAVE

EUROPA, PEACE AIRE, TRACE

Myocardial Pathological Infarction Remodeling

CAD Ventricular Enlargement

Atherosclerosis Hypertrophy Heart Failure Hypertension HF SOLVD Risk Factors: CAPPP, ALLHAT Diabetes DM V-HeFT II Hypertension Hyperlipdemia ABCD, REIN, AASK SAVE, Death ATLAS Clinical Trials with ARB

DM/Renal Post-MI RENAAL, IDNT VALIANT, IRMAII, ARVAL OPTIMAL ABCD-2V, VAL-PREST NAVIGATOR

Myocardial Pathological Infarction Remodeling

Ventricular CAD, Nephropathy Enlargement

Atherosclerosis Hypertrophy Heart Failure Hypertension HF Risk Factors: SCOPE, Diabetes ELITE I&II Hypertension VALUE, Hyperlipdemia Val-HeFT Death TROPHY, LIFE CHARM Val-Syst Trial: Powerful Double-digit BP Reductions with Valsartan-based Therapy in Patients with ISH Aged 60–80 Randomised, double-blind, titration to effect study of patients (aged 60–80 years) with ISH: 24 weeks’ treatment SBP DBP DIOVAN- Amlodipine- DIOVAN- Amlodipine- based based based based (n=166) (n=163) (n=166) (n=163) 0 –5 –6.0 –6.5 –10 NS –15 ƒ Patients were randomised to DIOVAN –20 80 mg or amlodipine 5 mg –25 ƒ After 8 weeks, patients with SBP ≥140 mmHg were titrated to DIOVAN –30 160 mg/d or amlodipine 10 mg ƒ After an additional 8 weeks, HCTZ 12.5 mg Mean change in BP (mmHg) –35 –33.4 –33.5 NS was added to treatment in patients with SBP ≥140 mmHg Val-Syst: Valsartan in Isolated Systolic Hypertension (ISH); Per protocol population data shown; NS = not significant Clin Ther 2003;25:2765–80 Time Course of Morning BP Changes Mediated by ARBs

Morning home BP

165 Patients with essential hypertension: 4 weeks’ treatment

155

145 SBP (mmHg)

135 –7 0 7 14 21 28

Day Start of treatment

Valsartan 40–80 mg (n=18) Losartan 25–100 mg (n=18) Telmisartan 10–40 mg (n=18) Candesartan 2–12 mg (n=18)

Clin Exp Hypertens 2005;27:477–89 TheThe rolerole ofof arterialarterial stiffnessstiffness

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

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

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

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

Randomised study of patients with hypertension: 3 months’ treatment

Nifedipine 20 mg (n=20) Diovan 80 mg (n=21) 0

–50

–100 –69 –150

–200 p=0.02

Brachial–ankle PWV* (cm/sec) –250 –195

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

Am J Hypertens 2004;17:1050–5 Reduces Arterial Stiffness

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

Diovan 80 mg HCTZ 25 mg Placebo 0 –0.3 –3.2 (n=20) –10 (n=20) from baseline

† –20 • Diovan improves arterial compliance in AIx –21.7* patients with hypertension –30 (n=20) • Effects are independent of BP reduction (BP reductions similar for Diovan and HCTZ) Change in –40 †Augmentation index (AIx), a measure of arterial function *p<0.01 vs HCTZ and vs placebo J Hypertens 2002;20:2423–8 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 0 77% 3.5 increase* 3.24 -0.5 3 -1 -1.5 2.5 1.51 -2 2 2.39 -2.5 -2.2 1.5 -3 -3.1 1 -3.5 0.55 -3.6

0.5 Change in baseline RDS from -4 44% -3.9 0 reduction* Change in small artery elasticity from baseline (mL/mmHg x100) 6 months 12 months Placebo DIOVAN 160 mg od for 6 months DIOVAN 160 mg od for 12 months

#Individuals completing the study with or without antihypertensive or lipid lowering medications, BP <140/90 mmHg; *p<0.000; RDS=Rasmussen Disease Score Duprez et al. JACC 2007;50:published online Val-MARC: Managing BP Aggressively and Evaluating Reductions in hsCRP

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

ƒ 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

ƒ 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 DIOVAN 320 mg DIOVAN 320 mg (n=807) (plus optional HCTZ 12.5 mg) DIOVAN 160 mg (n=836) Screening 0–7 days Co-DIOVAN 160/12.5 mg (n=832) Co-DIOVAN 320/12.5 mg Co-DIOVAN 320/12.5mg (n=808) (or optional Co-DIOVAN 320/25mg)

Week 0 Week 2 Week 6 Week 12 Visit 1 Visit 2 Visit 3 Visit 4 (randomisation) (End of study)

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) 6 4.4% 4 2 0 -2 -4 -6

from baseline to 6 weeks* -8 -10

Change in hsCRP plasma level (%) -8.9% DIOVAN Co-DIOVAN 160 - 320 mg od 160/12.5 - 320/12.5 mg od (n=807, median change -0.12) (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. Hypertension 2006;48:73-79 VALUE: Elective Titration to Target BP(<140/90 mmHg)

Patients aged ≥50 years, with treated or untreated hypertension DIOVAN 160 mg + and at high risk of CV events HCTZ 25 mg + ‘Free’ add-on Co-DIOVAN DIOVAN-based Co-DIOVAN 160/25 mg regimen 160/12.5 mg DIOVAN 160 mg DIOVAN 80 mg Rollover from previous therapy Amlo 5 mg (92%) Amlo 10 mg Amlodipine- Amlo 10 mg + based regimen HCTZ 12.5 mg Amlo 10 mg + HCTZ 25 mg Amlo 10 mg + HCTZ 25 mg + ‘Free’ add-on Month –0.5 0 1 2 3 4 6 * 72

Screening Randomisation End of treatment adjustment period

*Patient visits every 6 months for Months 6–72; Amlo = amlodipine Lancet 2004;363:2022–31 VALUE: Rate of Cardiac Events Did not Differ Between the Vasarta and Amlodipine Groups

14 DIOVAN-based regimen 12 Amlodipine-based regimen 10

8

6

first event (%) event first 4

Proportion of patients with 2 HR=1.03; 95% CI=0.94–1.14; p=0.49

0 0 6 12 18 24 30 36 42 48 54 60 66 Number at risk Time (months) DIOVAN 7,649 7,459 7,407 7,250 7,0856,906 6,732 6,5366,349 5,911 3,765 1,474 Amlodipine 7,596 7,469 7,424 7,267 7,1176,955 6,772 6,5766,391 5,959 3,725 1,474

Lancet 2004;363:2022–31 LIFE : The Losartan Intervention For Endpoint Reduction in Hypertension Study Patients aged ≥55 years, with treated or untreated hypertensionand at high risk of CV events * Titration to target blood pressure: <140 / 90 mmHg Losartan 100 mg + HCTZ 12.5- 25 mg + others** Losartan 100 mg + HCTZ 12.5 mg* Losartan 50 mg + HCTZ 12.5 mg*

Placebo Losartan 50 mg Atenolol 50 mg Atenolol 50 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ 12.5 mg* Atenolol 100 mg + HCTZ 12.5- 25mg + others**

Day Day Day Mth Mth Mth Mth Yr Yr Yr Yr Yr Yr Yr Yr −14 −7 1 1 2 4 6 1 1.5 2 2.5 3 3.5 4 5

* 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 Lancet 2002;359;995-1003-1010 LIFE : BP reductions

180 Atenolol Losartan 160

Systolic 140

120

100 Mean arterial mmHg

80 Diastolic

60

40 0 6 12 18 24 30 36 42 48 54 Time (months)

Lancet 2002;359;995-1003-1010 LIFE tnll()48 4441 39428 431 4349 4392 4414 4460 4494 4588 4524 Atenolol (n) 4605 (n) Losartan StudyStudy Day Month0 121824 6 30364248546066 :

0.00 0.02 0.04 Endpoint0.06 0.08 Rate0.10 0.12 0.14 0.16 Primary Composite Endpoint 8 6 4 2 0 1080 900 720 540 360 180 0 Intention-to-Treat Unadjusted Risk Reduction14·6%,p=0·009 Adjusted RiskReduction 13·0%,p=0·021 2543 0639 8115 876 901 1854 1888 3821 3895 3992 4045 4066 4110 4135 4189 4205 4247 9 2 2014 6010 1980 1800 1620 1440 1260 Atenolol Lancet 2002;359;995-1003-1010 Losartan Atrial fibrillation accounts for 1/3 of all patients discharges with arrhythmia as principal diagnosis

6% PSVT 6% PVCs 18% 4% Unspecified Atrial Flutter 34% 9% SSS Atrial Fibrillation

8% Conduction Disease 10% 3% SCD VT 2% VF

J Am Coll Cardiol. 1992;19(3):41A. Relative Risk of Stroke and Mortality in Patients with AF vs. without AF

8 Stroke Mortality

6

4

2 Relative Risk (times) Risk Relative (Patients without AF) 0 Whitehall Whitehall Regional Heart Study Framingham (no Heart Disease) Framingham Framingham (overall) Manitoba Stroke rate in Non-Rheumatic HD with AF : ↑5% / year Lancet 1987;1:526 Am Heart J 1983;106:389 Am J Med 1995;98:476 VALUE - AF : Reduces the risk of new onset AF by 16%

•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

J Hypertens 2008, 26:403–411 VALIANT: Study Design and Inclusion Criteria

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-I Double-blind active-controlled, stepwise titration

Captopril 50 mg tid + Captopril 50 mg tid DIOVAN 160 mg bid DIOVAN 80 mg bid (n=4,909) (n=4,909) (n=4,885)

Median duration: 24.7 months Event-driven

Primary endpoint: All-cause mortality Secondary endpoints: CV morbidity and mortality Other endpoints: Safety and tolerability Am Heart J 2000;140:727–50 N Engl J Med 2003;349:1893–906 VALIANT: Risk of Mortality is Similarly Reduced with Valsartan and Captopril

Patients with acute MI complicated by either HF or LVSD Captopril 50 mg tid* (n=4,909) 0.30 DIOVAN 160 mg bid* (n=4,909) 0.25 DIOVAN 80 mg bid + captopril 50 mg tid* (n=4,885) 0.20 *titration to target dose

0.15

0.10 from any cause

Probability ofdeath 0.05 DIOVAN vs captopril: HR=1.00; p=0.98 DIOVAN + captopril vs captopril: HR=0.98; p=0.73 0 0 6 12 18 24 30 36 Time (months) 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 + 4,885 4,414 4,265 3,994 2,648 1,435 382 captopril LVSD = left ventricular systolic dysfunction HF = heart failure N Engl J Med 2003;349:1893–906 OPTIMAAL(Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan)

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 2,733 Losartan Captopril

459 discont’d 424 discont’d

2,744 analysed 2,733 analysed

Lancet 2002;360:752–60 OPTIMAAL: No Difference in Mortality Risk Between Losartan and Captopril

25 Losartan (n= 2,744) 20 Captopril (n=2,733)

15

10 Relative risk 1.13 Endpoint rate (%) (85% CI 0.99–1.28) p=0.069 5

0 Months 0 6 12 18 24 30 36

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

Receiving standard therapy

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

Randomised to

DIOVAN 40 mg bid titrated Placebo to 160 mg bid

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

EF = ejection fraction NYHA = New York Heart Association LVIDd = left-ventricular internal diastolic diameter N Engl J Med 2001;345:1667–75 Val-HeFT: Improves CV Outcomes* in CHF

Results from a 23-month mean follow-up study in 5,010 patients with CHF on standard therapy (Val-HeFT study) 100 95 90 85 DIOVAN‡ (n=2,511) 80 13.2% risk 75 reduction† 70 Placebo (n=2,499) Event-free probability (%) Event-free 65 RR=0.87; 97.5% CI: 0.77-0.97 0 0 3 6 9 12 15 18 21 24 27 Time (months)

*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 bid Cohn et al. N Engl J Med 2001;345:1667-1675 ELITE II :Evaluation of Losartan in the Elderly Study

Randomised trial of losartan versus captopril in patients over 65 with heart failure ≥ 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

Captopril Event Driven Losartan 50 mg 3 times daily Targeting 510 deaths 50 mg daily n = 1574 estimate 2 yrs n = 1578 median follow-up 555 days

Primary Endpoint : All-cause Mortality Secondary Endpoint : Sudden cardiac death and/or Resuscitated Arrest Other : All-cause Mortality / Hospitalizations Safety and Tolerability

Lancet 2000;355:1582–87 ELITE II:

Risk of All-cause Mortality or Hospital Admission is Similarly Reduced with Losartan and Captopril 1.0

0.8

0.6

0.4 Losartan (n=1578) Captopril (n=1574) 0.2 Event-free probability p=0.18

0 0 100 200 300 400 500 600 700 Follow-up (days)

Lancet 2000;355:1582–87 JIKEI HEART : Valsartan-based Therapy Improved Outcomes in Japanese Patients with HT and/or Coronary Heart Disease and/or HF

+ non-ARB Valsartan-based therapy group treatment (n=1541) + valsartan 40–160 mg daily Run-in + valsartan Conventional 40–80 mg daily treatment (non-ARB)

Conventional treatment (non-ARB) + non-ARB

Non-ARB treatment arm + non-ARB (n=1540) + non-ARB

–4 Randomisation Titration Titration End of study 0 8–12 12–16 (median follow-up Weeks was 3.1 years)

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

CV mortality Hospitalisation Hospitalisation and morbidity† Stroke/TIA for HF for angina 0

39* 40* 47* 65* 20

40 p=0.0002 p=0.0280 p=0.0293

Risk reduction (%) Risk reduction 60

p=0.0001 80

TIA = transient ischemic attack *With DIOVAN-based therapy compared † with non-ARB therapy; primary endpoint Lancet 2007;369:1431–9 Mortality and Morbidity Endpoint Trials with ARB

60,000 VALUE1 ONTARGET8 CHARM14 2 8 15 50,345 VALIANT TRANSEND SCOPE 50,000 NAVIGATOR3 LIFE9 SCAST*16 Val-HeFT4 OPTIMAAL10 CASE-J17 JIKEI HEART5,6 ELITE II11 I-Preserve18 40,000 KYOTO HEART*7 RENAAL12 IDNT19 NCT00090259*13 ACTIVE*20 29,400 30,000 SUPPORT*21 22,991 MOSES22 19,768 20,000 Number of patients 14,815

10,000

1,000 1,405 0 DIOVAN Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan

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

Summary:

ƒ To protect and improve vascular and cardiac structure/function • understanding the effects of angiotensin II is an important issue in HT.

ƒ 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

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