1

From Myocardial Infarction to Heart Failure

And Use of ARBs

Prof Samir Abd Elkader

Professor of cardiology

Assuit University

2

Heart Failure is a Major and Growing Public Health Problem in the U.S.

Approximately 5 million patients in this country have HF

Over 550,000 patients are diagnosed with HF for the first time each year

Primary reason for 12 to 15 million office visits and 6.5 million hospital days each year

In 2001, nearly 53,000 patients died of HF as a primary cause

3

Heart Failure is Primarily a Condition of the Elderly

The incidence of HF approaches 10 per 1000 population after age 65

HF is the most common Medicare diagnosis-related group

More dollars are spent for the diagnosis and treatment of HF than any other diagnosis by Medicare

4

Definition of Heart Failure

HF is a complex clinical syndrome that canresult from any structural or functionalcardiac disorder that impairs the ability ofthe ventricle to fill with or eject blood.

5

“Heart Failure” vs. “Congestive Heart Failure”

Because not all patients have volume overload atthe time of initial or subsequent evaluation, theterm “heart failure” is preferred over the older term “congestive heart failure.”

6

7

Stages of Heart Failure

At Risk for Heart Failure:

STAGE A High risk for developing HF

STAGE B Asymptomatic LV dysfunction

Heart Failure:

STAGE C Past or current symptoms of HF

STAGE D End-stage HF

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From AMI to HF:

Emerging Role of Valsartan

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

Risk factorsDiabetes, hypertension

Atherosclerosisand LVH

Myocardialinfarction

Remodeling Ventriculardilation

Heart failure

End-stageheart

disease

Death

The Cardiovascular Continuum

Effects of A II at ATEffects of A II at AT11 and AT and AT22 Receptors Receptors

Sensitive to blockade by ARBs

AT2AT1

VasoconstrictionAldosterone releaseOxidative stressVasopressin releaseSNS activationInhibits renin release Renal Na+ & H2O reabsorptionCell growth & proliferation

VasodilationAntiproliferationApoptosisAntidiuresis/antinatriuresisBradykinin productionNO release

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

*P <0.001 vs placebo.Adapted with permission from Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:966-972.

A II Escape With Long-Term ACE-I Therapy

Pla

sm

a A

CE,

nm

ol/

mL/m

in 100

80

60

40

200

** * * * * * *

30

20

10

0

Pla

sm

a A

II,

p

g/m

L

*

Placebo 4 h 24 h 1 2 3 4 5 6

Hospital Months

Plasma A II levels increased with time, although plasma-

converting enzyme activity remained suppressed

(n = 9 after 24 h)

Valsartan Heart Failure Trial

Valsartan in Heart Failure

5,010 HF patients>18 yr; EF <40%; NYHA II-

IV

906 deaths (events recorded)

Valsartan40 mg bid titrated to

160 mg bidPlacebo

Randomized to

Receiving usual therapy including ACEi, diuretics, digoxin, blockers (stratified randomization)

Cohn et al. J Card Fail 1999;5:155-160

Val-HeFT design: valsartan added to usual therapy for HF

Results: Primary endpoints

1.0

0.9

0.8

0.6

13.2% risk reductionp= 0.009

Significant benefits on combined mortality / morbidity endpoint

0

Even

t-fre

e pr

obab

ility

Placebo

Valsartan

3 6 9 12 211815 24 27Time since randomization (months)

0.7

Cohn et al. NEJM 2001 345:1667

Reduction in Mortality with Valsartan (No ACEI Subgroup)

50

100

0 3 6 9 12 15 18 21 24 27 30

Valsartan(N = 185)

Pro

po

rtio

n S

urv

ived

(%

)

P value (log-rank) = .017160

70

80

90

Placebo (N = 181)

Time Since Randomization (months)

Risk reduction= 33.1%

Hazard ratio (Cox model): 0.6694

(Adapted from Maggioni AP, et al. [abstract 839-5]. J Am Coll Cardiol. 2002)

Reduction in Combined Morbidity Endpoint* with Valsartan

(No ACEI Subgroup)E

ven

t-F

ree

Pro

bab

ility

Time Since Randomization (months)Hazard ratio (Cox model) : 0.560*First morbid event, including death or hospitalization

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30

P value (log-rank) = .0002

Valsartan(N = 185)

Placebo(N = 181)

Risk reduction = 44.0%

(Adapted from Maggioni AP, et al. [abstract 839-5]. J Am Coll Cardiol. 2002)

Val-HeFT impact on FDA

Valsartan is also approved by Egypt MOH for treatment of Heart Failure.

So, Valsatan is the first & ONLY ARB approved in HF

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

Risk factorsDiabetes, hypertension

Atherosclerosisand LVH

Myocardialinfarction

Remodeling Ventriculardilation

Heart failure

End-stageheart

disease

Death

From AMI to HF Valsartan has a definite role

with proven Cardiac Protection

Inhibition of theInhibition of the

ReninReninAngiotensin System Angiotensin System in Cardiovascular Disease in Cardiovascular Disease

Heart attack remains a major

factor of high

Mortality Rate

ACUTE MYOCARDIAL INFARCTION

Unacceptable High Mortality Rate from

Acute Heart Attack

1- Under utilization of drug treatment is a major

Factor in the unaccepted high Post- Heart Attack.

2-Many patients taking ACE inhibitors suffer intolerable side

Effects such as dry irritant cough &1stdose hypotension.

3-Proper Blockade of ACE & non ACE Pathways.

Rational

VALIANT : was designed as a mortality trial in high-risk MI patients (SAVE, AIRE, TRACE) who derived particular benefits from an ACE inhibitor.

To determine whether:

the ARB valsartan was superior to captopril in improving survival

and with equal statistical power

the addition of the ARB valsartan to captopril was superior to the proven dose of captopril in improving survival

VALIANT: Endpoints

Primary Endpoints

Time to all-cause mortality

–Cardiovascular mortality

–Cardiovascular mortality, reinfarction, and hospitalization for heart failure

–Cardiovascular mortality, reinfarction, hospitalization for heart failure, resuscitated sudden death, stroke

Secondary Endpoints

Am Heart J. 2000;140:727–734.

Captopril4909

4871 (99.2%)

Vital status unknown:38 (0.8%)

Enrollment and Follow-up

Median follow-up: 24.7 months

Valsartan4909

4856 (98.9%)

Vital status unknown:53 (1.1%)

14,808 Patients Randomized

4837 (99.0%)

Vital status unknown:48 (1.0%)

Combination4885

Informed consent not ensured: 105 patients

14,703 Patients

13

Cap 6.25 mgVal 20 mg

Cap 12.5 mgVal 20 mg

Cap 25 mgVal 40 mg

Cap 50 mg (tid)Val 80 mg (bid)

COMBINATION

Cap 6.25 mgCap 12.5 mg

Cap 25 mgCap 50 mg (tid)

CAPTOPRIL (tid)

Val 20 mgVal 40 mg

Val 80 mgVal 160 mg (bid)

VALSARTAN (bid)

Step I

GOAL by 3 months

Step IVStep IIIStep II

Study DrugDose Titration

Am Heart J. 2000;140:727–734.

Lancet. 2002;360:752–760. Am J Cardiol. 1991;68:70D–79D. Lancet. 1993;342:821–828. N Engl J Med. 1995;333:1670–1676. Data on file. Novartis Pharmaceuticals.

SAVE AIRE TRACE OPTIMAAL VALIANT

2,231 1,986 1,749

5,477

14,703

0

2,000

4,000

6,000

8,000

10,000

16,000

12,000

14,000

VALIANT: B- Largest Population

24 Countries. 931 Sites. 14,703 Patients.

Europe:5163

Australia/New Zealand:

443

Brazil andArgentina

:848

South Africa:

58

Russia:3135Canada:

1092

USA:3964

Results

Captopril

25% Reduction in Mortality

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Months

Valsartan vs. Captopril: HR = 0.96; P = 0.198

Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.3690

0.1

0.2

0.3

0.4

0 6 12 18 24 30 36

Pro

bab

ilit

y o

f Even

t

Valsartan

Valsartan + Captopril

NoninferiorityVal

Superior to Cap

Cap Superior to Val

Noninferiority not

Demonstrated

CardiovascularMortality and Morbidity

0.8 1 1.2

Hazard Ratio(97.5% CI)

1.13

P-value(noninferiority)

noninferiority margin

CV Death(1657 events)

0.001

CV Death or HF(2661 events)

0.0001

CV Death or MI(2234 events)

0.00001

CV Death, MI, or HF

(3096 events)

0.000001

Favors Valsartan Favors Captopril

Captopril

0

0.1

0.2

0.3

0.4

0 6 12 18 24 30 36

Months

Pro

bab

ilit

y o

f Even

t

Study DrugDiscontinuation

Overall

Due to Adverse Events

*P < 0.05 vs Captopril

Valsartan + Captopril*

*

Valsartan

*

In patients with MI complicated by heart failure, leftventricular dysfunction or both:

25% Reduction in Mortality

Implications:

Tareg approved now MRP & in more 50 countries

As First line Treatment in Acute M.I

Conclusion

Tareg is The First & The Only ARB approved in H.F

and Acute M.I

Thank

You

Thank You