1. Heart failure is a major public health problem, affecting over 5 million Americans. It is primarily a condition of the elderly and costs Medicare billions of dollars annually. 2. The VALIANT trial compared the ARB valsartan to the ACE inhibitor captopril and their combination in over 14,000 patients with heart failure or left ventricular dysfunction following a myocardial infarction. It found valsartan to be noninferior to captopril in reducing cardiovascular mortality and morbidity. 3. The presentation discusses the role of the renin-angiotensin system in cardiovascular disease and how ARBs like valsartan can provide beneficial blockade of this system in heart failure and post-myocardial infarction

1. 1
From Myocardial Infarction to
Heart Failure
And
Use of ARBs
Prof Samir Abd Elkader
Professor of cardiology
Assuit University

2. 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. 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. 4
Definition of Heart Failure
HF is a complex clinical syndrome that can
result from any structural or functional
cardiac disorder that impairs the ability of
the ventricle to fill with or eject blood.

5. 5
“Heart Failure” vs. “Congestive Heart Failure”
Because not all patients have volume overload at
the time of initial or subsequent evaluation, the
term “heart failure” is preferred over the older
term “congestive heart failure.”

6. 6

7. 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

8. 8

9. From AMI to HF:
Emerging Role of Valsartan

10. Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.
Risk factors
Diabetes, hypertension
Atherosclerosis
and LVH
Myocardial
infarction
Remodeling
Ventricular
dilation
Heart failure
End-stage
heart disease
Death
The Cardiovascular Continuum

11. Effects of A II at ATEffects of A II at AT11 and ATand AT22 ReceptorsReceptors
Sensitive to blockade
by ARBs
AT2AT1
Vasoconstriction
Aldosterone release
Oxidative stress
Vasopressin release
SNS activation
Inhibits renin release
Renal Na+
& H2O reabsorption
Cell growth & proliferation
Vasodilation
Antiproliferation
Apoptosis
Antidiuresis/antinatriuresis
Bradykinin production
NO release
Siragy H. Am J Cardiol. 1999;84:3S-8S.

12. *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
PlasmaACE,
nmol/mL/min
100
80
60
40
20
0
*
* * * * * * *
30
20
10
0
PlasmaAII,
pg/mL
*
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)

13. Valsartan Heart Failure Trial
Valsartan in Heart
Failure

14. 5,010 HF patients
>18 yr; EF <40%; NYHA II-
IV
906 deaths (events recorded)
Valsartan
40 mg bid titrated to
160 mg bid
Placebo
Randomized to
Receiving usual therapy including
ACEi, diuretics, digoxin, β blockers
(stratified randomization)
Cohn et al. J Card Fail 1999;5:155-160
Val-HeFT design: valsartan added to usual therapy
for HF

15. Results:
Primary endpoints

16. 1.0
0.9
0.8
0.6
13.2% risk reduction
p= 0.009
Significant benefits on combined
mortality / morbidity endpoint
0
Event-freeprobability
Placebo
Valsartan
3 6 9 12 211815 24 27
Time since randomization (months)
0.7
Cohn et al. NEJM 2001 345:1667

17. Reduction in Mortality with Valsartan
(No ACEI Subgroup)
50
100
0 3 6 9 12 15 18 21 24 27 30
Valsartan
(N = 185)
ProportionSurvived
(%)
P value (log-rank) = .0171
60
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)

18. Reduction in Combined Morbidity Endpoint* with
Valsartan
(No ACEI Subgroup)
Event-FreeProbability
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)

19. 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

20. Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.
Risk factors
Diabetes, hypertension
Atherosclerosis
and LVH
Myocardial
infarction
Remodeling
Ventricular
dilation
Heart failure
End-stage
heart disease
Death
From AMI to HF
Valsartan has a definite role
with proven Cardiac Protection

21. Inhibition of theInhibition of the
ReninReninAngiotensin SystemAngiotensin System
in Cardiovascular Diseasein Cardiovascular Disease

22. Heart attack
remains a major
factor of high
Mortality Rate
ACUTE MYOCARDIAL INFARCTION

23. 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 &1st
dose hypotension.
3-Proper Blockade of ACE & non ACE Pathways.

24. 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

25. 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.

26. Captopril
4909
4871 (99.2%)
Vital status
unknown:
38 (0.8%)
Enrollment and Follow-up
Median follow-up: 24.7 months
Valsartan
4909
4856 (98.9%)
Vital status
unknown:
53 (1.1%)
14,808 Patients Randomized
4837 (99.0%)
Vital status
unknown:
48 (1.0%)
Combination
4885
Informed consent
not ensured: 105 patients
14,703 Patients
13

27. Cap 6.25 mg
Val 20 mg
Cap 12.5 mg
Val 20 mg
Cap 25 mg
Val 40 mg
Cap 50 mg (tid)
Val 80 mg (bid)
COMBINATION
Cap 6.25 mg
Cap 12.5 mg
Cap 25 mg
Cap 50 mg (tid)
CAPTOPRIL (tid)
Val 20 mg
Val 40 mg
Val 80 mg
Val 160 mg (bid)
VALSARTAN (bid)
Step I
GOAL by 3 months
Step IVStep IIIStep II
Study Drug
Dose Titration
Am Heart J. 2000;140:727–734.

28. 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

29. 24 Countries. 931 Sites. 14,703 Patients.
Europe:
5163
Australia/
New Zealand:
443
Brazil and
Argentina:
848
South
Africa:
58
Russia:
3135Canada:
1092
USA:
3964

30. Results

31. 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 = 0.369
0
0.1
0.2
0.3
0.4
0 6 12 18 24 30 36
ProbabilityofEvent
Valsartan
Valsartan + Captopril

32. Noninferior
ityVal Superior
to Cap
Cap Superior
to Val
Noninferiorit
y not
Demonstrate
d
Cardiovascular
Mortality 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

33. Captopril
0
0.1
0.2
0.3
0.4
0 6 12 18 24 30 36
Months
ProbabilityofEvent
Study Drug
Discontinuation
Overall
Due to
Adverse
Events
*P < 0.05 vs Captopril
Valsartan + Captopril
*
*
Valsartan
*

34. In patients with MI complicated by heart failure, left
ventricular 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

36. Tareg is The First & The
Only ARB approved in H.F
and Acute M.I

37. Than
k You
Thank You