1. Update on Valsartan Špinar J.

2. System renin-angiotensin-aldosteron angiotensinogen angiotensin I angiotensin II aldosteron ANP,BNP thirst resorp. Na + vasoconstriction RENIN rec. AT 1 ACE proliferation Retention Na + vasodilatation

3. System renin-angiotensin-aldosteron angioteninogen angiotensin I angiotensin II aldosteron RENIN rec. AT 1 ACE renin inhibitors beta-bloc. ACE - I ARB Aldosteron inhib.

4. Indications for AT 1 receptor blocade - EBM HYPERTENSION LIFE CORD VALUE MYOCARDIAL INFARCTION OPTIMAAL VALIANT Brno remodeling trial Brno first dose hypotension trial HEART FAILURE Exercise trials ELITE ELITE II Val HeFT RENAL FALIURE RENAAL MARVAL

5. Indications for AT 1 receptor blocade - EBM HYPERTENSION LIFE CORD VALUE MYOCARDIAL INFARCTION OPTIMAAL VALIANT Brno remodeling trial Brno first dose hypotension trial HEART FAILURE Exercise trials ELITE ELITE II Val HeFT RENAL FALIURE RENAAL MARVAL

6. Indications for AT 1 receptor blocade - EBM HEART FAILURE Exercise trials ELITE ELITE II Val HeFT

7. Val-HeFT

8. valsartan+ACE-I vs placebo+ACE-I 5010 patients EF < 40%, ICHS 57 % NYHA II 62% NYHA III 36% NYHA IV 2%

9. 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/no n=227 yes/no n=3038 no/yes n=139 yes/yes n=1606 placebovalsartan Treatment (ACE inhibitors/beta-blocker) AIIA+B ACE+B

10. CONSENSUS I MORTALITY PL=126 ACE-I=127 P=0.001 RR=31 % % MONTHS PL=181 AT=185 P=0.0002 RR=44.5 % Val HeFT (ACE-I NAIVE) M ORTALITY %

11. Adverse events Mortality studies in Heart Failure with ACE-I + ELITE II + Val HeFT (without placebo)% p=NS p=0,001

12. Indications for AT 1 receptor blocade - EBM MYOCARDIAL INFARCTION OPTIMAAL VALIANT Brno remodeling trial Brno first dose hypotension trial

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

15. 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 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

16. Captopril 0 0.05 0.1 0.15 0.2 0.25 0.3 061218243036 Probability of Event VALIANT - MORTALITY Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 Valsartan490944644272400726481437357 Months Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 Captopril490944284241401826351432364 Valsartan + Cap488544144265399426481435382 Valsartan Valsartan + Captopril

17. Captopril 0 0.1 0.2 0.3 0.4 061218243036 Months Probability of Event Study Drug discontinuation Overall Due to Adverse Events *P < 0.05 vs Captopril Valsartan + Captopril * * Valsartan *

18. Conclusion In patients with MI complicated by heart failure, left ventricular 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 effective alternative to an ACE inhibitor.

19. Indications for AT 1 receptor blocade - EBM HYPERTENSION LIFE CORD VALUE

20. 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 achieved Julius et al. Lancet 2004;363:2022-2031

21. VALUE: primary endpoint CV morbidity a mortality

22. VALUE TRIAL : Valsartan-based Regimen is Associated with Less Incidence of New-onset Diabetes New-Onset Diabetes (% of patients in treatment group) 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%

23. Number at risk Valsartan Amlodipine 7596 7649 7486 7485 7444 7312 7176 7169 6874 6852 7033 7012 6702 6671 6100 6072 3823 3860 1511 1513 6534 6498 Time (months) 0612182430364248546066 98765432109876543210 Valsartan-based regimen Amlodipine-based regimen HR = 0.89; 95% CI = 0.77–1.03; P = 0.12 Proportion of Patients With First Event (%) Julius S et al. Lancet. June 2004;363. VALUE: Heart Failure Hospitalisation for HF or Death From HF

24. VALUE: Tolerability *With an incidence >3% and a difference between treatment groups >1%. † Reported as serious. P Value(%) 0.045 <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 12.915.2Headache 14.316.5Dizziness 32.914.9Peripheral Oedema AmlodipineValsartan Data on file. Novartis Pharmaceuticals. Discontinuations due to AE <0.0001 0.1197 <0.0001

25. 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

26. Indications for AT 1 receptor blocade - EBM RENAL FALIURE RENAAL MARVAL

27. 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 excretion Viberti G et al. Circulation 2002;106(6):672-8

28. 0 5 10 15 20 25 30 35 Amlodipine 14.5% 29.9%* Normoalbuminuria = UAER < 20  g/min; * P = 0.001 vs. amlodipine Viberti G. Circulation. 2002;106:672-678. % of Patients Returning to Normoalbuminuria Valsartan VALSARTAN CORRECTS MICROALBUMINURIA IN TYPE 2 DM

29. 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

30. Indications for AT 1 receptor blocade - EBM UPDATE 2010 HEAL KYOTO NAVIGATOR

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42. NAVIGATORNAVIGATOR Valsartan had no effect on CV disease but moderately reduced progression to diabetes.

43. Thank you for your atention