IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM CARDIOVASCOLARE DOPO TRENT’ANNI DI CARDIOVASCOLARE DOPO TRENT’ANNI DI

ESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORIESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORI

I sartani non sono inferiori ed insieme possono fare meglioI sartani non sono inferiori ed insieme possono fare meglio

Pasquale Perrone FilardiPasquale Perrone Filardi Università Federico II di NapoliUniversità Federico II di Napoli

HEART FAILURE & Co.HEART FAILURE & Co.Ninth International SymposiumNinth International Symposium

Milano, 17 – 18 aprile 2009Milano, 17 – 18 aprile 2009

ARBs, morbidity and mortality along the cardiovascular continuum

Risk factorsDiabetes

Hypertension

Atherosclerosisand LVH

Myocardialinfarction

Remodeling Ventriculardilation

Congestiveheart failure

End-stage micro-vascular

andheart disease

Death

Adapted from Dzau V, Braunwald E. Am Heart J 1991; 121: 1244–1263

ELITE II Val-HeFTCHARM

NAVIGATOR

RENAALIDNTIRMA-2MARVAL

LIFE ONTARGETTRANSCEND

VALUESCOPE

OPTIMAAL VALIANT

DIRECT

BIOLOGICAL EFFECTS OF RASBIOLOGICAL EFFECTS OF RAS

Angiotensin IIAngiotensin II

Angiotensin IAngiotensin I

ACE ACE InhibitorsInhibitorsKininase IIKininase II

Inactive Inactive FragmentsFragments

( - )( - )

Angiotensin II Escape Angiotensin II Escape (Chymase, Cathepsin G, (Chymase, Cathepsin G,

CAGE)CAGE)

BradykininBradykinin

t-PAt-PA

BB22 Receptor Receptor

Natriuresis, VasodilationNatriuresis, Vasodilation&&

Anti-Inflammatory EffectsAnti-Inflammatory Effects

NO, NO, PGIPGI22, ,

HPFHPF AT-IIAT-II AT-IAT-I

DephosphorylationDephosphorylation

Anti-Proliferative Anti-Proliferative EffectsEffects

PhosphorylationPhosphorylation

Proliferative Proliferative EffectsEffects

CNS CNS StimulationStimulation

AldosteronAldosteronEndothelin releaseEndothelin release

VasoconstrictionVasoconstriction

NADPH OxidaseNADPH Oxidase

InflammationInflammation

ROLE OF ARBs IN CARDIOVASCUAR PROTECTION ROLE OF DUAL RAS BLOCKADE IN CARDIOVASCULAR PROTECTION

TARGET ORGANS HEART

Patients at high cardiovascular risk without LV dysfunction

Post-MI ischemic dysfunction Patients with chronic LV systolic dysfunction Patients with chronic LV diastolic dysfunction

KIDNEY EYE BRAIN

QUESTIONS

The ONTARGET Trial ProgrammeOutcome:

Primario: mortalità CV , IMA, Ictus, ospedalizzazione per scompenso cardiaco

Secondario: mortalità CV , IMA, Ictus (outcome HOPE)

Teo K., et al. Am Heart J 2004;148:52–61

Screening

n = 7,800Telmisartan80 mg/day +placebo

n = 7,800Ramipril

10 mg/day +placebo

Randomisation (n=23,400) * Randomisation (n= 6,000) †

n = 7,800Telmisartan80 mg/day +

Ramipril10mg/day

n = 3,000Placebo

Follow-up at 6 weeks

Follow-up at 6 months for 5.5 years

n = 3,000Telmisartan80 mg/day

Follow-up at 6 weeks

Follow-up at 6 months for 5.5 years

*planned. Actual = 25,620 †planned. Actual = 5,926

ONTARGET TRANSCEND

5.5

Yea

rs

NO PLACEBO YES PLACEBO

Tempo al Primary OutcomeONTARGET

Years of Follow-up

Cum

ula

tive

Haz

ard

Ra

tes

0.0

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4

Telmisartan

Ramipril

# at Risk Yr 1 Yr 2 Yr 3 Yr 4T 8542 8176 7778 7420 7051R 8576 8214 7832 7473 7095

IS RAS INHIBITION STILL USEFUL IN CONTEMPORARY PATIENTS AT HIGH

CARDIOVASCULAR RISK?

TRANSCEND patients on “2008 standard care, so called placebo arm”, were almost as protected as with ramipril in HOPE

0

5

10

15

20

HOPE control HOPE ramipril TRANSCEND control TRANSCENDtelmisartan

14% 14,8%13%

17,8%

The Lancet, published on line Aug 31, 2008 N Engl J Med 2000;342:145-53

-17% absolute risk reduction

TRANSCENDPrimary and Key Secondary Outcomes

Telm Plac RR (CI) P

Primary 465 (15.7%) 504 (17.0%) 0.92 (0.81-1.05) 0.216

HOPE 384 (13.0%) 440 (14.8%) 0.87 (0.76-1.00) 0.048

CV death 227 (7.7%) 223 (7.5%) 1.03 (0.85-1.24) 0.778

MI 116 (3.9%) 147 (5.0%) 0.79 (0.62-1.01) 0.059

Stroke 112 (3.8%) 136 (4.6%) 0.83 (0.64-1.06) 0.136

CHF hosp 134 (4.5%) 129 (4.3%) 1.05 (0.82-1.34) 0.694

Tempo al Primary OutcomeONTARGET

Years of Follow-up

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4

Ramipril

Telmi & Ram

# at Risk Yr 1 Yr 2 Yr 3 Yr 4R 8576 8214 7832 7473 7095T&R 8502 8134 7740 7377 7023

Modifiche della PA (mmHg)ONTARGET e HOPE

Ramipril Telmisartan Combinazione

Sistolica -6.0 -6.9 -8.4

Diastolica

HOPE

-4.6

-3/-2

-5.2 -6.0

Dogma Disputed: Can Agressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery

Disease Be Dangerous?Messerli et al Ann Intern Med 2006

ARBs AND DUAL RAS BLOCKADE IN LEFT VENTRICULAR SYSTOLIC

DYSFUNCTION

Post-ischemic (OPTIMA; VALIANT)Chronic (VAL-HeFT; CHARM)

0.0

0.1

0.2

0.3

0.4

0 6 12 18 24 30 36

VALSARTAN, CAPTOPRIL, OR BOTH IN MYOCARDIAL VALSARTAN, CAPTOPRIL, OR BOTH IN MYOCARDIAL INFARCTION COMPLICATED BY HEART FAILURE, LV INFARCTION COMPLICATED BY HEART FAILURE, LV

DYSFUNCTION OR BOTHDYSFUNCTION OR BOTHPfeffer et al for the Pfeffer et al for the VALIANTVALIANT Investigators. Investigators. N Engl J MedN Engl J Med 2003 2003

ValsartanValsartanValsartan and CaptoprilValsartan and CaptoprilCaptoprilCaptopril

Prob

abil

ity

of E

vent

MonthsNo.at RiskValsartan 4909 4464 4272 4007 2648 1437 357Valsartan and Captopril 4885 4414 4265 3994 2648 1435 382Captopril 4909 4428 4241 4018 2635 1432 364

n=14808n=14808f.u. 24.7 mf.u. 24.7 m

p = n.s. for all comparisonsp = n.s. for all comparisons

CHARM-Overall All-cause death

0 1 2 3 years3.50

10

20

30

Placebo

5

15

25

35 %

HR 0.91 (95% CI 0.83-1.00), p=0.055Adjusted HR 0.90, p=0.032

945 (24.9%)886 (23.3%)

Candesartan

-9%( p=0,055)

ANNUAL MORTALITY: 8.8 % (PL) VS 8.1 % ANNUAL MORTALITY: 8.8 % (PL) VS 8.1 % (CANDESARTAN)(CANDESARTAN)

00 11 22 33 yearsyears

55

1010

1515

2020

2525

3030

%%

00

CV deathCV deathHR 0.88 (95% CI 0.79-0.97), p=0.012HR 0.88 (95% CI 0.79-0.97), p=0.012

Adjusted HR 0.87, p=0.006Adjusted HR 0.87, p=0.006

Non-CV deathNon-CV deathp=0.45p=0.45

PlaceboPlacebo

CandesartanCandesartan

PlaceboPlacebo

CandesartanCandesartan

3.53.5

Number at riskNumber at risk

CandesartanCandesartan 3803 3803

PlaceboPlacebo 3796 3796Lancet. September 6, 2003Lancet. September 6, 2003

CHARM-Overall: CV Death and non-CV Death

CHARM: EFFECTS ON MORTALITY IN PTS WITH REDUCED EF

(Alternative + Added)

Placebo708 (31.0%)

Candesartan642 (28.0%)

anni3.50 1 2 3

0

10

20

30

All

-cau

se d

eath

(%

)

5

35

25

15

40

HR 0.88 (95% CI 0.79 – 0.98)

p=0.018

Young et al Circulation 2004; 110: 2618-26

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

%

HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001

3.5

406 (40.0%)

334 (33.0%)

-23%( p=0,0004)

MOST RECENT AND UPCOMING RANDOMIZED CLINICAL TRIALS IN HEART FAILURE

TRIAL INTERVENTION RESULTS YEAR

PEP-CHF perindopril NEUTRAL 2006 EVEREST tolvaptan NEUTRAL 2007 CORONA rosuvastatin NEUTRAL 2008 ACCLAIM immunomodulation NEUTRAL 2008 Anemia darbopoetin NEUTRAL 2008 AFCHF rhytm vs rate control NEUTRAL 2008 DSG dronaderone NEUTRAL

2008 BEAUTIFUL ivabradine NEUTRAL

2008 GISSI-HF rosuvastatin, omega-3 NEUTRAL 2008 I-PRESERVE irbesartan NEUTRAL

2008 EMPHASIS eplerenone ongoing TOPCAT anti-aldosterone ongoing RED-HF darbopoetin ongoing

ACE-Is, ARBs AND DUAL RAS BLOCKADE IN LEFVT VENTRICULAR

DIASTOLIC DYSFUNCTIONACE-Is (PEP-CHF)

ARBs (I-PRESERVE; CHARM PRESERVED)

Dual blockade (no studies)

Left ventricular morphology and

function in patients with heart failure with reduced or normal ejection fraction

Maeder et al. Journal of the American College of Cardiology 2009;53: 905-918

EFFECTS OF PERINDOPRIL IN ELDERLY PEOPLE WITH DIASTOLIC HEART FAILURE

Cleland et al for the PEP-CHF Investigators Eur Heart J 2006; 27: 2338–2345

Irbesartan in Patients with Heart Failureand Preserved Ejection FractionI-PRESERVE N Engl J Med 2008;359:2456-67

Death or hospitalization for cardiovascular causes

IRMA 2IRMA 2MARVALMARVAL

Prevention Protection

ESRD ESRD

Early Stage Late Stage End Stage

Microalbuminuria Microalbuminuria ProteinuriaProteinuria

IRMA 2: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria MARVAL: Microalbuminuria Reduction with Valsartan IDNT: Irbesartan Diabetic Nephropathy TrialRENAAL: Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan ESRD: End-stage renal disease

Cardiovascular morbidity and mortalityCardiovascular morbidity and mortality

Angiotensin Receptor Antagonists Trials Across The Whole Spectrum Of Type 2 Diabetic Renal Disease Progression

IDNTIDNTRENAALRENAAL

Effects of ramipril, telmisartan or both on renal outcomes (dialysis, doubling of serum creatinine, and death) in the

ONTARGET trial

Mann et al. The Lancet 2008; 372: 547-553

DIRECT-Protect 2: Retinopathy regressionC

um

ula

tive

pro

po

rtio

n

No at riskPlacebo 954 812 760 713 510 93 1Candesartan 951 811 755 692 492 100 0

0.0

0.1

0.2

0.3

0.4

p=0.009p=0.009

Time from randomisation (years)0 1 2 3 4 5 6

PlaceboPlaceboCandesartanCandesartan

CONCLUSIONS

ARBs (telmisartan) have demonstrated to be as efficacious as ACE-Is in patients at high cardiovascular risk without LV dysfunction, and in patients with post-ischemic (valsartan) and chronic LV systolic dysfunction (valsartan, candesartan)

ARBs (candesartan, irbesartan) have not demonstrated to be efficacious in patients with LV diastolic dysfunction, similarly to ACE-Is

ARBs (losartan, valsartan, irbesartan) have demonstrated to provide renal protection in patients with pre-clinical and clinical diabetic nephropathy

ARBs (candesartan) have demonstrated to induce retinopathy regression in type II diabetics (but needs confirmation)

Dual RAS blockade was ineffective and potentially harmful in patients without LV dysfunction and this association should be used with caution and strict surveillance of renal function

Dual RAS blockade (valsartan, candesartan) reduces mortality/morbidity in patients with chronic LV systolic dysfunction