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HEART FAILURE & Co. Ninth International Symposium Milano, 17 – 18 aprile 2009. IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM CARDIOVASCOLARE DOPO TRENT’ANNI DI ESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORI I sartani non sono inferiori ed insieme possono fare meglio Pasquale Perrone Filardi

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HEART FAILURE & Co.

Ninth International Symposium

Milano, 17 – 18 aprile 2009

IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM CARDIOVASCOLARE DOPO TRENT’ANNI DI ESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORI

I sartani non sono inferiori ed insieme possono fare meglio

Pasquale Perrone Filardi

Università Federico II di Napoli


ARBs, morbidity and mortality along the cardiovascular continuum

OPTIMAAL

VALIANT

ELITE II

Val-HeFT

CHARM

LIFE

ONTARGET

TRANSCEND

Ventricular

dilation

Remodeling

DIRECT

Congestive

heart failure

Myocardial

infarction

End-stage micro-vascular and

heart disease

Atherosclerosis

and LVH

NAVIGATOR

RENAAL

IDNT

IRMA-2

MARVAL

Risk factors

Diabetes

Hypertension

Death

VALUE

SCOPE

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


BIOLOGICAL EFFECTS OF RAS continuum

 Bradykinin

Angiotensin I

ACE Inhibitors

Angiotensin II Escape

(Chymase, Cathepsin G, CAGE)

Kininase II

( - )

Inactive Fragments

Angiotensin II

NO, PGI2, HPF

t-PA

B2 Receptor

AT-II

AT-I

Natriuresis, Vasodilation

&

Anti-Inflammatory Effects

Dephosphorylation

Anti-Proliferative Effects

Phosphorylation

CNS Stimulation

Endothelin release

Vasoconstriction

NADPH Oxidase

Inflammation

Aldosteron

Proliferative Effects


Questions
QUESTIONS continuum

  • 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


The ONTARGET Trial Programme continuumOutcome:Primario: mortalità CV , IMA, Ictus, ospedalizzazione per scompenso cardiacoSecondario: mortalità CV , IMA, Ictus (outcome HOPE)

ONTARGET

TRANSCEND

NO PLACEBO

YES PLACEBO

Screening

Randomisation (n= 6,000) †

Randomisation (n=23,400) *

Because of an extraordinary effort by investigators in 40 countries, it was possible to complete recruitment for the ONTARGET study in May 2003, seven months ahead of the scheduled timeline.

The ONTARGET trial currently recruited 25,621 patients.

n = 7,800Telmisartan80 mg/day +placebo

n = 7,800Ramipril10 mg/day +placebo

n = 7,800Telmisartan80 mg/day +

Ramipril10mg/day

n = 3,000Telmisartan80 mg/day

n = 3,000Placebo

5.5 Years

Follow-up at 6 weeks

Follow-up at 6 weeks

Follow-up at 6 months for 5.5 years

Follow-up at 6 months for 5.5 years

*planned. Actual = 25,620

†planned. Actual = 5,926

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


Tempo al primary outcome
Tempo al Primary Outcome continuum

ONTARGET

# at Risk

Yr 1

Yr 2

Yr 3

Yr 4

T

8542

8176

7778

7420

7051

0.25

R

8576

8214

7832

7473

7095

0.20

IS RAS INHIBITION STILL USEFUL IN CONTEMPORARY PATIENTS AT HIGH CARDIOVASCULAR RISK?

0.15

Telmisartan

Cumulative Hazard Rates

Ramipril

0.10

0.05

0.0

0

1

2

3

4

Years of Follow-up


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

-17% absolute risk reduction

17,8%

14,8%

14%

13%

The Lancet, published on line Aug 31, 2008

N Engl J Med 2000;342:145-53


Transcend primary and key secondary outcomes
TRANSCEND continuumPrimary and Key Secondary Outcomes


Cumulative Hazard Rates continuum

Years of Follow-up

Tempo al Primary Outcome

ONTARGET

# at Risk

Yr 1

Yr 2

Yr 3

Yr 4

0.25

8576

8214

7832

7473

7095

R

8502

8134

7740

7377

7023

T&R

0.20

0.15

Ramipril

0.10

Telmi & Ram

0.05

0.0

0

1

2

3

4


Modifiche della pa mmhg ontarget e hope
Modifiche della PA (mmHg) continuumONTARGET e HOPE


Dogma Disputed: Can Agressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?

Messerli et al Ann Intern Med 2006



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

Pfeffer et al for the VALIANT Investigators. N Engl J Med 2003

0.4

Valsartan

Valsartan and Captopril

Captopril

n=14808

f.u. 24.7 m

0.3

0.2

Probability of Event

0.1

p = n.s. for all comparisons

0.0

0

6

12

18

24

30

36

No.at Risk

Months

Valsartan 4909 4464 4272 4007 2648 1437 357

Valsartan and Captopril 4885 4414 4265 3994 2648 1435 382

Captopril 4909 4428 4241 4018 2635 1432 364


Charm overall all cause death
CHARM-Overall COMPLICATED BY HEART FAILURE, LV DYSFUNCTION OR BOTHAll-cause death

%

35

30

945 (24.9%)

Placebo

25

886 (23.3%)

20

Candesartan

15

-9%( p=0,055)

10

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

Adjusted HR 0.90, p=0.032

5

0

0

1

2

3

3.5

years

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


Charm overall cv death and non cv death
CHARM-Overall: COMPLICATED BY HEART FAILURE, LV DYSFUNCTION OR BOTHCV Death and non-CV Death

CV death

HR 0.88 (95% CI 0.79-0.97), p=0.012Adjusted HR 0.87, p=0.006

30

25

Placebo

20

Candesartan

%

15

10

Non-CV death

p=0.45

Candesartan

5

Placebo

0

0

1

2

3

3.5

years

Number at risk

Candesartan 3803

Placebo 3796

Lancet. September 6, 2003


Charm effects on mortality in pts with reduced ef alternative added
CHARM: EFFECTS ON MORTALITY IN PTS WITH REDUCED EF COMPLICATED BY HEART FAILURE, LV DYSFUNCTION OR BOTH(Alternative + Added)

40

35

30

25

All-cause death (%)

20

15

10

5

0

0

1

2

3

3.5

anni

Placebo

708 (31.0%)

Candesartan

642 (28.0%)

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
CHARM-Alternative: Primary outcome COMPLICATED BY HEART FAILURE, LV DYSFUNCTION OR BOTHCV death or CHF hospitalisation

%

50

406 (40.0%)

Placebo

40

334 (33.0%)

30

Candesartan

20

-23%( p=0,0004)

10

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

0

0

1

2

3

3.5

years


Most recent and upcoming randomized clinical trials in heart failure
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



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 Failure HEART FAILURE

and Preserved Ejection Fraction

I-PRESERVE N Engl J Med 2008;359:2456-67

Death or hospitalization for cardiovascular causes


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

Prevention

Protection

Microalbuminuria

Proteinuria

ESRD

Cardiovascular morbidity and mortality

Early Stage

Late Stage

End Stage

IRMA 2

MARVAL

IDNT

RENAAL

IRMA 2: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria

MARVAL: Microalbuminuria Reduction with Valsartan

IDNT: Irbesartan Diabetic Nephropathy Trial

RENAAL: Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan

ESRD: End-stage renal disease


Effects of ramipril, telmisartan or both on renal outcomes Spectrum Of Type 2 Diabetic Renal Disease Progression (dialysis, doubling of serum creatinine, and death) in theONTARGETtrial

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


Direct protect 2 retinopathy regression
DIRECT-Protect 2: Retinopathy regression Spectrum Of Type 2 Diabetic Renal Disease Progression

0.4

Placebo

Candesartan

0.3

0.2

Cumulative proportion

0.1

p=0.009

0.0

0

1

2

3

4

5

6

Time from randomisation (years)

No at risk

Placebo 954 812 760 713 510 93 1

Candesartan 951 811 755 692 492 100 0


Conclusions
CONCLUSIONS Spectrum Of Type 2 Diabetic Renal Disease Progression

  • 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


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