Heart Failure Hospitalizations The Number of Heart Failure

Heart Failure Hospitalizations The Number of Heart Failure Hospitalizations Is Increasing in Both Men and Women Annual Discharges 600, 000 500, 000 400, 000 300, 000 200, 000 Women Men 100, 000 0 '79 '81 '83 '85 '87 '89 '91 '93 '95 '97 Year AHA. 2002 Heart and Stroke Statistical Update. 2001. '99

Evidence of improving survival from heart failure in the general population JACC Vol. 44, No. 12, 2004: 2398 -405

Recent trends in hospital admissions for heart failure demonstrating recent plateau or decline JACC Vol. 44, No. 12, 2004: 2398 -405

Renin-Angiotensin Aldosterone System Non-ACE pathways · · (eg, chymase) Vasoconstriction Cell growth Na/H 2 O retention Sympathetic activation Angiotensinogen Renin AT 1 Angiotensin II ACE Cough, angioedema Benefits? Bradykinin Aldosterone Inactive fragments AT 2 · Vasodilation · Antiproliferation (kinins)

Valsartan + ACE-I in HF: Valsartan Heart Failure Trial (Val-He. FT) 5010 patients 18 years; EF <40%; NYHA II–IV; LVIDd >2. 9 cm/m 2 Receiving standard therapy ACE inhibitors (93%), diuretics (86%), digoxin (67%), β-blockers (36%) Randomized to Valsartan 40 mg bid titrated to 160 mg bid 906 deaths (events recorded) EJ = ejection fraction; LVIDd = left ventricular internal diastolic diameter. Cohn JN et al. Eur J Heart Fail. 2000; 2: 439 -446. Placebo

Effect of Valsartan on Combined Mortality and Morbidity End Point* in Overall Population 100 Valsartan (n = 2511) Placebo (n = 2499) 95 90 Probability of Event-Free Survival 13. 2% risk reduction P = 0. 009 85 80 75 70 65 0 0 3 6 9 12 15 18 21 24 27 30 Months Valsartan significantly reduces the combined endpoint of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure, when added to prescribed therapy. *All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators. Cohn JN et al. N Engl J Med. 2001; 345: 1667 -1675.

Val-He. FT: Heart Failure-Related Hospitalizations* 100 Valsartan (n = 2511) 95 Placebo (n = 2499) 90 85 Event-Free Probability 80 75 27. 5% risk reduction P <0. 001 70 65 0 0 3 6 9 12 15 Months *First hospitalization. Cohn JN et al. N Engl J Med. 2001; 345: 1667 -1675. 18 21 24 27 30

Val-He. FT: Hospitalization for Heart Failure No. (%) Patients With Events Valsartan Placebo P = 0. 02 No ACE-I 20 (17. 9) 35 (30. 7) ACE-I < median 97 (13. 7) 141 (20. 8) P = 0. 0002 ACE-I median 127 (15. 6) 174 (21. 4) P = 0. 005 0. 2 0. 4 0. 6 Adapted with permission from Carson P et al. J Card Fail. 2003; 9: 164 -171. 0. 8 1. 0 1. 2

Val-He. FT: Combined Morbidity End Point Subgroup without ACE-I background therapy 1. 000 0. 914 Valsartan (n = 185) 0. 829 Event-Free Probability 0. 743 0. 657 44% risk reduction* P <0. 0002 0. 571 0. 486 Placebo (n = 181) 0. 400 0 3 6 9 12 15 18 Time Since Randomization (mo) *For morbidity; 34% RR for mortality. Adapted from Maggioni AP et al. J Am Coll Cardiol. 2002; 40: 1414 -1421. 21 24 27

Val-He. FT: Change in Plasma Brain Natriuretic Peptide Over Time 30 n = 844 20 Plasma BNP* (pg/m. L) Placebo Baseline = 177. 6 pg/m. L n = 1710 10 n = 1890 0 P <0. 0001 -10 P <0. 0001 -20 n = 823 -30 -40 P <0. 0001 n = 1633 n = 1850 0 4 12 Time (mo) *R et Mean ± SEM. Latini al. Circulation. 2002; 106: 2454 -2458. 24 Valsartan Baseline = 183. 5 pg/m. L

Val-He. FT: Neurohormones – Change in Plasma NE Over 40 (n = 1894) (n = 1713) Time (n = 840) Placebo Baseline = 472 pg/m. L 30 D Plasma NE* (pg/m. L) 20 P = 0. 003 10 P = 0. 002 (n = 1855) P = 0. 002 (n = 1635) 0 (n = 816) -10 0 4 NE = norepinephrine. *Mean ± SEM. Latini R et al. Circulation. 2002; 106: 2454 -2458. 12 Time (mo) 24 Valsartan Baseline = 456 pg/m. L

Val-He. FT: Change From Baseline in Plasma Aldosterone 30 Placebo 20 n = 1749 n = 1541 P <0. 0001 n = 731 10 DPlasma Aldosterone (pg/m. L) 0 -10 Least Squares Mean ± -20 P <0. 0001 Valsartan -30 n = 727 -40 n = 1718 Baseline 4 months Anand I et al. AHA 75 th Scientific Session. 2002; A 1763. n = 1459 12 months 24 months

VALUE: Design Elective titration to target BP (<140/90 mm. Hg) Valsartanbased regimen V 160 mg + HCTZ 12. 5 mg V 160 mg + HCTZ 25 mg + "Free" add-on V 160 mg + HCTZ 25 mg V 160 mg V 80 mg Rollover from previous therapy A 5 mg (92%) A 10 mg + HCTZ 12. 5 mg Amlodipinebased regimen Month 0. 5 0 1 2 Screening Randomisation *Patient visits every 6 months for months 6– 72. Julius S et al. Lancet. June 2004; 363. 3 A 10 mg + HCTZ 25 mg 4 A 10 mg + HCTZ 25 mg + "Free" add-on 6 * 72 End of treatment adjustment period

Proportion of Patients With First Event (%) 14 VALUE: Primary Composite Cardiac Endpoint Valsartan-based regimen 12 Amlodipine-based regimen 10 8 6 4 HR = 1. 03; 95% CI = 0. 94– 1. 14; P = 0. 49 2 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Number at risk Valsartan 7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3765 1474 Amlodipine 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474 Julius S et al. Lancet. June 2004; 363.

VALUE: Outcome and SBP Differences at Specific Time Periods: Primary Endpoint Time Interval (months) SBP mm. Hg Overall study 0– 3 3– 6 6– 12 12– 24 24– 36 36– 48 Study end 2. 2 3. 8 2. 3 2. 0 1. 8 1. 6 1. 4 1. 7 PRIMARY ENDPOINT Odds Ratios and 95% CIs 0. 5 Favours valsartan Julius S et al. Lancet. June 2004; 363. 1. 0 2. 0 4. 0 Favours amlodipine

VALUE: Heart Failure Hospitalisation for HF or death from HF Proportion of Patients With First Event (%) 9 8 Valsartan-based regimen 7 Amlodipine-based regimen 6 5 4 3 2 0 Number at risk HR = 0. 89; 95% CI = 0. 77 -1. 03; P = 0. 12 1 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Valsartan 7649 7485 7444 7312 7169 7012 6852 6671 6498 6072 3860 1513 Amlodipine 7596 7486 7444 7312 7176 7033 6874 6702 6534 6100 3823 1511 Julius S et al. Lancet. June 2004; 363.

VALUE: Outcome and SBP Differences at Specific Time Periods: Heart Failure Time interval (months) SBP (mm. Hg) Overall study 0– 3 3– 6 6– 12 12– 24 24– 36 36– 48 Study end 2. 2 3. 8 2. 3 2. 0 1. 8 1. 6 1. 4 1. 7 Heart Failure Odds Ratios and 95% CIs 0. 25 0. 5 Favours valsartan Heart Failure: Hospitalisation for HF or death from HF. Julius S et al. Lancet. June 2004; 363. 1. 0 2. 0 4. 0 Favours amlodipine

VALUE: Analysis of Results Based on BP Control at 6 Months Patients Treated With Valsartan Patients Treated With Amlodipine Odds Ratio Fatal/Non-fatal cardiac events 0. 76 (0. 66– 0. 88) ** Fatal/Non-fatal stroke ** 0. 50 (0. 39– 0. 64) ** ** 0. 79 (0. 69– 0. 91) Heart failure hospitalisations 0. 62 (0. 50– 0. 77) ** 0. 6 Controlled patients* (n = 5253) 0. 8 1. 0 1. 2 Non-controlled patients (n = 2396) Hazard Ratio 95% CI *SBP < 140 mm. Hg at 6 months. **P < 0. 01. Weber MA et al. Lancet. 2004; 363: 2047– 49. 0. 79 (0. 69– 0. 92) 0. 91 (0. 71– 1. 17) 0. 83 (0. 66– 1. 03) Myocardial infarction 0. 4 0. 73 (0. 63– 0. 85) ** 0. 60 (0. 48– 0. 74) ** All-cause death Odds Ratio ** 0. 4 0. 6 Controlled patients* (n = 5502) 0. 8 0. 64 (0. 52– 0. 79) 1. 0 1. 2 Non-controlled patients (n = 2094) Hazard Ratio 95% CI

VALUE: Analysis of Results Based on BP Control at 6 Months Pooled Treatment Groups Odds Ratio ** Fatal/Non-fatal cardiac events ** Fatal/Non-fatal stroke 0. 75 (0. 67– 0. 83) 0. 55 (0. 46– 0. 64) ** All-cause death Myocardial infarction 0. 79 (0. 71– 0. 88) 0. 86 (0. 73– 1. 01) ** Heart failure hospitalisations 0. 4 0. 6 0. 8 Controlled patients* (n = 10755) *SBP < 140 mm. Hg at 6 months. **P < 0. 01. Weber MA et al. Lancet. 2004; 363: 2047– 49. 0. 64 (0. 55– 0. 74) 1. 0 1. 2 1. 4 Non-controlled patients (n = 4490) Hazard Ratio 95% CI

VALUE: Major Study Endpoints in 5006 Patient Pairs (N = 10, 012) on Valsartan- or Amlodipine-Based Therapies Using Serial Median Matching Hazard Ratio (95% CI) P Composite cardiac events 0. 90 (0. 79– 1. 03) 0. 111 Stroke 1. 02 (0. 81– 1. 28) 0. 899 Death 0. 96 (0. 84– 1. 10) 0. 566 Myocardial infarction 0. 97 (0. 80– 1. 19) 0. 791 Heart failure 0. 81 (0. 66– 0. 99)* 0. 040 0. 6 *P < 0. 05. 0. 8 Favours valsartan Weber MA et al. Lancet. 2004; 363: 2047– 49. 1. 0 1. 2 1. 4 Favours amlodipine

Acute MI (0. 5– 10 days)—SAVE, AIRE or TRACE eligible (either clinical/radiologic signs of HF or LV systolic dysfunction) double-blind active-controlled Captopril 50 mg tid (n = 4909) Valsartan 160 mg bid (n = 4909) Captopril 50 mg tid + Valsartan 80 mg bid (n = 4885) median duration: 24. 7 months event-driven Primary Endpoint: All-Cause Mortality Secondary Endpoints: CV Death, MI, or HF Other Endpoints: Safety and Tolerability

Mortality by Treatment 0. 3 Captopril Valsartan Probability of Event 0. 25 Valsartan + Captopril 0. 2 0. 15 0. 1 0. 05 Valsartan vs. Captopril: HR = 1. 00; P = 0. 982 Valsartan + Captopril vs. Captopril: HR = 0. 98; P = 0. 726 0 Months 0 Captopril 4909 Valsartan + Cap 4885 6 4428 4464 4414 12 4241 4272 4265 18 4007 3994 24 2635 2648 1432 1437 1435 30 36 364 357 382 Pfeffer, Mc. Murray, Velazquez, et al. N Engl J Med 2003; 349

All-Cause Mortality: Non-Inferiority Analyses Hazard Ratio (97. 5% CI) P-value noninferiority margin (noninferiority) Intention-to-Treat Patient Population (n = 14, 703) 0. 004 Per Protocol Patient Population (n = 14, 285) 0. 002 Noninferiority not Demonstrated Noninferiority Val Superior to Cap 0. 8 Cap Superior to Val 1 Favors Valsartan 1. 13 Favors Captopril 1. 2

Mortality in SAVE, TRACE, AIRE, and VALIANT Hazard Ratio for Mortality SAVE TRACE Valsartan preserves 99. 6% of mortality benefit of captopril. AIRE Combined VALIANT (imputed placebo) 0. 5 Favors Active Drug 1 Favors Placebo 2 Pfeffer, Mc. Murray, Velazquez, et al. N Engl J Med 2003; 349

CV Death, MI, or HF by Treatment 0. 4 Captopril Valsartan Probability of Event Valsartan + Captopril 0. 3 0. 2 0. 1 Valsartan vs. Captopril: HR = 0. 96; P = 0. 198 Valsartan + Captopril vs. Captopril: HR = 0. 97; P = 0. 369 0 Months 0 6 12 18 24 30 36 Pfeffer, Mc. Murray, Velazquez, et al. N Engl J Med 2003; 349

Cardiovascular Mortality and Morbidity Hazard Ratio (97. 5% CI) P-value noninferiority margin (noninferiority) CV Death 0. 001 (1657 events) CV Death or MI 0. 00001 CV Death or HF 0. 0001 (2234 events) (2661 events) CV Death, MI, or HF 0. 000001 (3096 events) Noninferiority not Demonstrated Noninferiority Val Superior to Cap 0. 8 Cap Superior to Val 1 Favors Valsartan 1. 13 Favors Captopril 1. 2

0. 26 2709 7528 0. 85 0. 96 Ratios (95% CI) Hazard 2266 5642 0. 68 0. 55 Death, MI, or HF for CV 4149 4618 5200 6738 3080 7088 2730 Median 7564 < 65 Age ³ 65 2254 Sex Male 5632 Female 4182 Prior MI 4970 No Yes 4837 DM No 2718 Yes 4747 1687 SBP £ median >619 median Serum Cr £ median > median Killip Class I II IV 4908 0. 93 4878 # of Pts. 0. 48 2805 0. 12 4675 2910 1655 6882 618 0. 71 P-Value (interaction) # of 0. 92 Pts. P-Value (interaction) 0. 11 0. 56 0. 67 0. 84 Beta. No Blocker Yes 0. 5 Favors Valsartan 1 Favors Captopril 2 0. 5 1 Favors Combination Favors Captopril Pfeffer, Mc. Murray, Velazquez, et al. N Engl J Med 2003; 349: 1893– 1906 2

Hazard Ratios (95% CI) for. Favors CV Valsartan Death, MI, or HF Favors Captopril P-Value (interaction) 0. 48 Valsartan vs. Captopril: No Beta-Blocker (n = 2907) Beta-Blocker (n = 6911) Combination vs. Captopril: 0. 56 No Beta-Blocker (n = 2910) Beta-Blocker (n = 6882) Favors Combination 0. 5 Favors Captopril 1 2 Pfeffer, Mc. Murray, Velazquez, et al. N Engl J Med 2003; 349: 1893– 1906

CHARM Programme 3 component trials comparing candesartan to placebo CHARM Alternative CHARM Added CHARM Preserved n=2028 n=2548 n=3025 LVEF £ 40% ACE inhibitor intolerant LVEF £ 40% ACE inhibitor treated LVEF >40% ACE inhibitor treated/not treated Primary outcome: CV death or CHF hosp

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 50 % 406 (40. 0%) Placebo 40 30 334 (33. 0%) Candesartan 20 10 0 HR 0. 77 (95% CI 0. 67 -0. 89), p=0. 0004 Adjusted HR 0. 70, p<0. 0001 0 Number at risk Candesartan 1013 Placebo 1015 1 2 3 929 887 831 798 434 427 3. 5 years 122 126

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 50 % 406 (40. 0%) Placebo 40 30 334 (33. 0%) Candesartan 20 10 0 HR 0. 77 (95% CI 0. 67 -0. 89), p=0. 0004 Adjusted HR 0. 70, p<0. 0001 0 Number at risk Candesartan 1013 Placebo 1015 1 929 887 2 831 798 3 434 122 427 126 3. 5 years

CHARM-Alternative Secondary outcomes p-value Candesartan Placebo CV death CHF hosp. 219 207 CV death, CHF hosp, MI 353 CV death, CHF hosp, MI, stroke 369 CV death, CHF hosp, MI, stroke, revasc 396 0. 85 252 286 0. 072 0. 68 <0. 0001 0. 78 420 0. 0007 0. 80 432 0. 001 0. 81 456 0. 8 candesartan better 0. 002 1. 0 Hazard ratio 1. 2 1. 4 placebo better

CHARM-Alternative Investigator reported CHF hospitalisations Proportion of patients (%) Number of episodes p<0. 0001 Patients hospitalised Placebo Candesartan p=0. 0001 Hospitalisations

CHARM Programme 3 component trials comparing Candesartan to placebo CHARM Alternative CHARM Added CHARM Preserved n=2028 n=2548 n=3025 LVEF £ 40% ACE inhibitor intolerant LVEF £ 40% ACE inhibitor treated LVEF >40% ACE inhibitor treated/not treated Primary outcome: CV death or CHF hosp

CHARM-Added: Primary outcome CV death or CHF hospitalisation 50 % 538 (42. 3%) 483 (37. 9%) Placebo 40 30 Candesartan 20 10 0 HR 0. 85 (95% CI 0. 75 -0. 96), p=0. 011 Adjusted HR 0. 85, p=0. 010 0 Number at risk Candesartan 1276 Placebo 1272 1 1176 1136 2 1063 1013 3 948 906 3. 5 years 457 422

CHARM-Added: Primary outcome CV death or CHF hospitalisation 50 % 538 (42. 3%) 483 (37. 9%) Placebo 40 30 Candesartan 20 10 0 HR 0. 85 (95% CI 0. 75 -0. 96), p=0. 011 Adjusted HR 0. 85, p=0. 010 0 Number at risk Candesartan 1276 Placebo 1272 1 1176 1136 2 1063 1013 3 948 457 906 422 3. 5 years

CHARM-Added Secondary outcomes p-value Candesartan Placebo CV death CHF hosp. 302 0. 84 347 309 356 CV death, CHF hosp, 495 MI 550 CV death, CHF hosp, MI, stroke 512 559 CV death, CHF hosp, MI, stroke, revasc 548 0. 029 0. 83 0. 014 0. 85 0. 010 0. 87 0. 020 0. 87 596 0. 8 candesartan better 0. 015 1. 0 Hazard ratio 1. 2 1. 4 placebo better

CHARM-Added Prespecified subgroups, CV death or CHF hosp. p-value for treatment interaction Candesartan Placebo Beta. Yes blocker No 223/702 260/574 274/711 264/561 0. 14 Recom. Yes dose of No ACE inhib. 232/643 251/633 275/648 263/624 0. 26 All patients 483/1276 538/1272 0. 6 0. 8 candesartan better 1. 0 Hazard ratio 1. 2 1. 4 placebo better

CHARM-Added Investigator reported CHF hospitalisations Proportion of patients (%) Number of episodes p=0. 008 Patients hospitalised Placebo Candesartan p=0. 002 Hospitalisations

Diastolic Heart Failure: Effects of Age on Prevalence and Prognosis Age, y <50 50 -70 >70 Prevalence 15 33 50 Mortality 15 33 50 Morbidity 25 50 50

Patients with Preserved Versus Depressed EF Smith et al. J Am Coll Cardiol 2003

Outcomes in Hf Patients with Preserved EF Smith GL et al. J Am Coll Cardiol 2003

Definition of Diastolic Dysfunction and HF Ø Diastolic HF is a clinical syndrome characterized by the symptoms and signs of HF, a preserved EF and abnormal diastolic function. Ø Diastolic dysfunction occurs when the time period during which the myocardium loses its ability to generate force and shorten and returns to an unstressed length and force, is prolonged, slowed or incomplete. Ø Systolic and diastolic HF occurs when patients have a modest decrease in EF and a modest increase in end-diastolic volume but a marked increase in end-diastolic pressure and a diastolic pressure-volume relationship that reflects decreased chamber compliance. Zile MR et al. Circulation 2002

CHARM Programme 3 component trials comparing candesartan to placebo CHARM Alternative CHARM Added CHARM Preserved n=2028 n=2548 n=3025 LVEF £ 40% ACE inhibitor intolerant LVEF £ 40% ACE inhibitor treated LVEF >40% ACE inhibitor treated/not treated Primary outcome: CV death or CHF hosp

CHARM-Preserved: Primary outcome CV death or CHF hospitalisation 30 % Placebo 25 20 366 (24. 3%) 333 (22. 0%) Candesartan 15 10 HR 0. 89 (95% CI 0. 77 -1. 03), p=0. 118 Adjusted HR 0. 86, p=0. 051 5 0 0 Number at risk Candesartan 1514 Placebo 1509 1 1458 1441 2 1377 1359 3 833 182 824 195 3. 5 years

CHARM-Preserved Primary and secondary outcomes Covariate adjusted p-value Candesartan Placebo CV death, CHF hosp. - CV death - CHF hosp. CV death, CHF hosp, MI, stroke, revasc 333 170 241 365 388 460 366 170 276 399 0. 89 0. 99 0. 85 0. 90 0. 88 429 0. 91 497 0. 8 candesartan better 1. 0 Hazard ratio 0. 118 0. 051 0. 918 0. 072 0. 635 0. 047 0. 126 0. 051 0. 078 0. 037 0. 123 0. 13 1. 2 placebo better

CHARM-Preserved: Primary outcome CV death or CHF hospitalisation 30 % Placebo 25 20 366 (24. 3%) 333 (22. 0%) Candesartan 15 10 HR 0. 89 (95% CI 0. 77 -1. 03), p=0. 118 Adjusted HR 0. 86, p=0. 051 5 0 0 Number at risk Candesartan 1514 Placebo 1509 1 1458 1441 2 1377 1359 3 833 182 824 195 3. 5 years

CHARM-Preserved Primary and secondary outcomes Covariate adjusted p-value Candesartan Placebo CV death, CHF hosp. - CV death - CHF hosp. CV death, CHF hosp, MI, stroke, revasc 333 170 241 365 388 460 366 170 276 399 0. 89 0. 99 0. 85 0. 90 0. 88 429 0. 91 497 0. 8 candesartan better 1. 0 Hazard ratio 0. 118 0. 051 0. 918 0. 072 0. 635 0. 047 0. 126 0. 051 0. 078 0. 037 0. 123 0. 13 1. 2 placebo better

CHARM-Preserved Investigator reported CHF hospitalisations Proportion of patients (%) Number of episodes p=0. 017 Patients hospitalised Placebo Candesartan p=0. 014 Hospitalisations