Update on Valsartan

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


HYPERTENSION

LIFECORD

VALUE

MYOCARDIAL INFARCTION

OPTIMAALVALIANT


HEART FAILURE

Exercise trialsELITE ELITE II

Val HeFT

RENAL FALIURE

RENAALMARVAL


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


MYOCARDIAL INFARCTIONOPTIMAALVALIANT


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%)


14,808 Patients Randomized

4837 (99.0%)


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.


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


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


UPDATE 2010HEAL

KYOTONAVIGATOR

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

Update on Valsartan

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