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Update on Valsartan. Špinar J. System renin-angiotensin-aldosteron. angiotensinogen. RENIN. angiotensin I. ACE. angiotensin II. vasodilatation. rec. AT 1. aldosteron. proliferation. ANP,BNP thirst resorp. Na + vasoconstriction. Retention Na +. - PowerPoint PPT Presentation
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Update on ValsartanUpdate on Valsartan
Špinar J.
System renin-angiotensin-aldosteron
angiotensinogen
angiotensin I
angiotensin II
aldosteron
ANP,BNP thirst resorp. Na+ vasoconstriction
RENIN
rec. AT1
ACE
proliferation
Retention Na+
vasodilatation
System renin-angiotensin-aldosteron
angioteninogen
angiotensin I
angiotensin II
aldosteron
RENIN
rec. AT1
ACE
renin inhibitorsbeta-bloc.
ACE - I
ARB
Aldosteron inhib.
Indications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBMIndications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBM
HYPERTENSION
LIFECORDVALUE
MYOCARDIAL INFARCTION
OPTIMAALVALIANT
Brno remodeling trialBrno first dose hypotension trial
HEART FAILURE
Exercise trialsELITE ELITE II
Val HeFT
RENAL FALIURE
RENAALMARVAL
Indications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBMIndications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBM
HYPERTENSION
LIFECORD
VALUE
MYOCARDIAL INFARCTION
OPTIMAALVALIANT
Brno remodeling trialBrno first dose hypotension trial
HEART FAILURE
Exercise trialsELITE ELITE II
Val HeFT
RENAL FALIURE
RENAALMARVAL
Indications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBMIndications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBM
HEART FAILUREExercise trials
ELITE ELITE II
Val HeFT
Val-HeFT
Val-HeFT
valsartan+ACE-I vs placebo+ACE-I
5010 patientsEF < 40% , ICHS 57 %
NYHA II 62%NYHA III 36%
NYHA IV 2%
Mortality and morbidity(ACE inhibitor/beta-blocker subgroups)
47% 36,3% 34,8% 22%27,7% 30,9% 20,5% 25,5%
0 %
10 %
20 %
30 %
40 %
50 %
no/non=227
yes/non=3038
no/yesn=139
yes/yesn=1606
placebo valsartan
Treatment (ACE inhibitors/beta-blocker)Treatment (ACE inhibitors/beta-blocker)
AIIA+B ACE+B
CONSENSUS ICONSENSUS I MORTALITY MORTALITY
05
101520253035404550
0 2 4 6 8 10 12
PL=126
ACE-I=127
P=0.001
RR=31 %
%
MONTHS
05
101520253035404550
0 3 6 9 12 15 18 21 24
PL=181
AT=185
P=0.0002
RR=44.5 %
Val HeFTVal HeFT (ACE-I NAIVE)(ACE-I NAIVE)
MMORTALITY ORTALITY %
Adverse eventsMortality studies in Heart Failure with ACE-I
+ ELITE II + Val HeFT (without placebo)
0
2
4
6
8
10
12
14
16
Cough Other
%%
p=NS
p=0,001
Indications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBMIndications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBM
MYOCARDIAL INFARCTIONOPTIMAALVALIANT
Brno remodeling trialBrno first dose hypotension trial
Enrollment
Europe:5163
Australia/New Zealand:
443
Brazil andArgentina
:848
South Africa:
58
Russia:3135Canada:
1092
USA:3964
24 Countries. 931 Sites. 14,703 Patients.
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
Vital status ascertained in 14,564 patients (99.05%)
Vital status not ascertained in 139 patients (0.95%)
(lost to follow-up at 1 year: 0.4%; 2 years: 0.7%)
14,703 Patients
13
Captopril
0
0.05
0.1
0.15
0.2
0.25
0.3
0 6 12 18 24 30 36
Pro
bab
ilit
y o
f Even
tVALIANT - MORTALITY
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Valsartan 4909 4464 4272 4007 2648 1437 357
Months
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
Captopril 4909 4428 4241 4018 2635 1432 364
Valsartan + Cap 4885 4414 4265 3994 2648 1435 382
Valsartan
Valsartan + 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
tStudy Drug discontinuation
Overall
Due to Adverse Events
*P < 0.05 vs Captopril
Valsartan + Captopril*
*
Valsartan
*
Conclusion
In patients with MI complicated by heart failure, leftventricular dysfunction or both:• Valsartan is as effective as a proven dose of
captopril in reducing the risk of:– Death– CV death or nonfatal MI or heart failure
admission• Combining valsartan with a proven dose of
captopril produced no further reduction in mortality—and more adverse drug events.
Implications:In these patients, valsartan is a clinically effectivealternative to an ACE inhibitor.
Indications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBMIndications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBM
HYPERTENSIONLIFE
CORDVALUE
VALUE TRIAL -methods• Would valsartan reduce cardiac morbidity and
mortality more than amlodipine in hypertensive patiens at high cardiovascular risk?
• Multicenter, multinational, double-blind randomized study
• 15 245 patients 50years• treated or untreated hypertension at high risk
for CV events• Primary endpoint – First event : a composite of
cardiac morbidity and mortality• Valsartan 80mg or amlodipine 5mg initially -
titrated up to BP<140/90 was achievedJulius et al. Lancet 2004;363:2022-2031
VALUE: primary endpointCV morbidity a mortality
0
2
4
6
8
10
12
14
16
18
VALUE TRIAL : Valsartan-based Regimen is Associated with Less Incidence of New-onset Diabetes
New
-On
set
Dia
bete
s (%
of
pati
ents
in t
reatm
ent
gro
up)
Valsartan-based Regimen(n=5254)
Julius et al. Lancet 2004;363:2022-2031.
Amlodipine-based Regimen(n=5168)
23% Risk Reduction with Valsartan
P<0.0001
16.4%13.1%
Number at risk
Valsartan
Amlodipine 7596
7649
7486
7485
7444
7444
7312
7312
7176
7169
6874
6852
7033
7012
6702
6671
6100
6072
3823
3860
1511
1513
6534
6498
Time (months)0 6 12 18 24 30 36 42 48 54 60 66
9
8
7
6
5
4
3
2
1
0
Valsartan-based regimen
Amlodipine-based regimen
HR = 0.89; 95% CI = 0.77–1.03; P = 0.12
Pro
port
ion
of
Pati
en
ts
Wit
h F
irst
Even
t (%
)
Julius S et al. Lancet. June 2004;363.
VALUE: Heart FailureHospitalisation for HF or Death From HF
VALUE: Tolerability
*With an incidence >3% and a difference between treatment groups >1%.†Reported as serious.
P Value(%)(%)
0.045
<0.0001<0.0001<0.0001
2.02.4Atrial Fibrillation†
1.01.7Syncope†
6.23.5Hypokalaemia*
Prespecified adverse events
6.49.3Angina Pectoris*
3.14.4Angina Pectoris†
6.13.2Oedema Other*
6.88.8Diarrhoea*Additional common adverse events
14.513.4
Prespecified adverse evets
12.915.2Headache14.316.5Dizziness32.914.9Peripheral Oedema
Amlodipine Valsartan
Data on file. Novartis Pharmaceuticals.
Discontinuations due to AE
<0.0001<0.0001<0.0001
0.1197<0.0001<0.0001
<0.0001
Julius S et al. Lancet. June 2004;363.
• The primary composite cardiac endpoint was not different between the treatment groups
• There was a positive trend in favour of valsartan for less heart failure but this did not reach significance
• VALUE is the first trial to show a highly significant lower rate of new-onset diabetes when an ARB (valsartan) was compared to a CCB (amlodipine)
VALUE: Main Results
Indications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBMIndications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBM
RENAL FALIURERENAALMARVAL
MARVAL TRIAL
• MicroAlbuminuria Reduction With VALsartan
• 332 patients with DM2 and microalbuminuria
• With or without hypertension• 80mg/d valsartan or 5mg/d amlodipine• 24 weeks• The primary end point was the percent
change in UAER from baseline to 24 weeks.
• UAER – elevated urine albumine excretionViberti G et al. Circulation 2002;106(6):672-8
0
5
10
15
20
25
30
35
Amlodipine
14.5%
29.9%*
Normoalbuminuria = UAER < 20 g/min; *P = 0.001 vs. amlodipineViberti G. Circulation. 2002;106:672-678.
% o
f Pa
tien
ts R
etu
rnin
g to
N
orm
oa
lbu
min
uria
Valsartan
VALSARTAN CORRECTS MICROALBUMINURIA IN TYPE 2
DM
MARVAL TRIAL RESULTS
• The UAER at 24 weeks was– 56% of baseline with valsartan– 92% of baseline with amlodipine,– a highly significant between-group effect
(P0.001)
• More patients reversed to normoalbuminuria with valsartan 29.9% versus 14.5% (P0.001)
• BP reductions were similar between the two treatments
Viberti, Circulation 2002, 106;672-678
Indications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBMIndications for ATIndications for AT11 receptor blocade - EBM receptor blocade - EBM
UPDATE 2010HEAL
KYOTONAVIGATOR
NAVIGATORNAVIGATORNAVIGATORNAVIGATOR
NAVIGATORNAVIGATORNAVIGATORNAVIGATOR
NAVIGATORNAVIGATORNAVIGATORNAVIGATOR
NAVIGATORNAVIGATORNAVIGATORNAVIGATOR
Valsartan had no effect onValsartan had no effect onCV disease but moderately reducedCV disease but moderately reduced
progression to diabetes.progression to diabetes.
Thank you for your atention