Ποιά η Θέση των Αποκλειστών ΑΤ1 στη Θεραπεία της Καρδιακής Ανεπάρκειας Ποιά η Θέση των Αποκλειστών ΑΤ1 στη Θεραπεία της Καρδιακής Ανεπάρκειας Αθανάσιος Ι. Μανώλης MD

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

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

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

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

Valsartan + ACE-I in HF: Valsartan Heart Failure Trial (Val-HeFT) 5010 patients  18 years; EF 2.9 cm/m 2 ACE inhibitors (93%), diuretics (86%), digoxin (67%), β-blockers (36%) Valsartan 40 mg bid titrated to 160 mg bid 906 deaths (events recorded) Randomized to Receiving standard therapy Placebo EJ = ejection fraction; LVIDd = left ventricular internal diastolic diameter. Cohn JN et al. Eur J Heart Fail. 2000;2:

Effect of Valsartan on Combined Mortality and Morbidity End Point* in Overall Population *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: Months Probability of Event-Free Survival 030 Valsartan (n = 2511) Placebo (n = 2499) P = % risk reduction 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.

*First hospitalization. Cohn JN et al. N Engl J Med. 2001;345: Months Event-Free Probability P < % risk reduction 0 Valsartan (n = 2511) Placebo (n = 2499) Val-HeFT: Heart Failure-Related Hospitalizations* 30

Val-HeFT: Hospitalization for Heart Failure No. (%) Patients With Events 20 (17.9) 97 (13.7) 127 (15.6) 35 (30.7) 141 (20.8) 174 (21.4) P = 0.02 P = P = No ACE-I ACE-I < median ACE-I  median ValsartanPlacebo Adapted with permission from Carson P et al. J Card Fail. 2003;9:

Val-HeFT: Combined Morbidity End Point P < % risk reduction* Subgroup without ACE-I background therapy Time Since Randomization (mo) Event-Free Probability Valsartan (n = 185) Placebo (n = 181) *For morbidity; 34% RR for mortality. Adapted from Maggioni AP et al. J Am Coll Cardiol. 2002;40:

Val-HeFT: Change in Plasma Brain Natriuretic Peptide Over Time *R et Mean ± SEM. Latini al. Circulation. 2002;106:  Plasma BNP* (pg/mL) Time (mo) n = 844 n = 1890 n = 1710 n = 1850 n = 1633 n = 823 P < Placebo Baseline = pg/mL Valsartan Baseline = pg/mL 30

Time (mo) (n = 1894)(n = 1713)(n = 840) (n = 1855) (n = 1635) (n = 816) P =   Plasma NE* (pg/mL) P = Val-HeFT: Neurohormones – Change in Plasma NE Over Time NE = norepinephrine. *Mean ± SEM. Latini R et al. Circulation. 2002;106: Placebo Baseline = 472 pg/mL Valsartan Baseline = 456 pg/mL

Val-HeFT: Change From Baseline in Plasma Aldosterone 4 months12 months24 months Baseline   Plasma Aldosterone (pg/mL) Least Squares Mean ± P < Anand I et al. AHA 75 th Scientific Session. 2002;A1763. n = 1749 n = 1541 n = 731 n = 1718 n = 1459 n = 727 Placebo Valsartan

VALUE: Design Elective titration to target BP (<140/90 mmHg ) Month *72 A 10 mg + HCTZ 25 mg A 5 mg A 10 mg + HCTZ 12.5 mg A 10 mg V 80 mg V 160 mg V 160 mg + HCTZ 12.5 mg V 160 mg + HCTZ 25 mg Amlodipine- based regimen V 160 mg + HCTZ 25 mg + "Free" add-on A 10 mg + HCTZ 25 mg + "Free" add-on Valsartan- based regimen Screening Randomisation End of treatment adjustment period Rollover from previous therapy (92%) *Patient visits every 6 months for months 6–72. Julius S et al. Lancet. June 2004;363.

VALUE: Primary Composite Cardiac Endpoint Time (months) Proportion of Patients With First Event (%) Valsartan-based regimen Amlodipine-based regimen HR = 1.03; 95% CI = 0.94–1.14; P = 0.49 Julius S et al. Lancet. June 2004;363. Number at risk Valsartan Amlodipine

VALUE: Outcome and SBP Differences at Specific Time Periods: Primary Endpoint Time Interval (months) Overall study 36–48 24–36 12–24 6–12 0–3 Study end Favours amlodipine PRIMARY ENDPOINT Odds Ratios and 95% CIs  SBP mmHg –62.3 Favours valsartan 4.0 Julius S et al. Lancet. June 2004;363.

Number at risk Valsartan Amlodipine VALUE: Heart Failure Time (months) Valsartan-based regimen Amlodipine-based regimen HR = 0.89; 95% CI = ; P = 0.12 Proportion of Patients With First Event (%) Julius S et al. Lancet. June 2004;363. Hospitalisation for HF or death from HF

VALUE: Outcome and SBP Differences at Specific Time Periods: Heart Failure Time interval (months) Overall study Study end Heart Failure Odds Ratios and 95% CIs  SBP (mmHg) –48 24–36 12–24 6–12 0–3 3–6 Favours amlodipineFavours valsartan Julius S et al. Lancet. June 2004;363. Heart Failure: Hospitalisation for HF or death from HF.

VALUE: Analysis of Results Based on BP Control at 6 Months Fatal/Non-fatal cardiac events Fatal/Non-fatal stroke All-cause death Myocardial infarction Heart failure hospitalisations *SBP < 140 mmHg at 6 months. **P < Patients Treated With ValsartanPatients Treated With Amlodipine Hazard Ratio 95% CI Controlled patients* (n = 5253) Non-controlled patients (n = 2396) ** Controlled patients* (n = 5502) Non-controlled patients (n = 2094) Hazard Ratio 95% CI ** 0.76 (0.66–0.88) 0.60 (0.48–0.74) 0.79 (0.69–0.91) 0.83 (0.66–1.03) 0.62 (0.50–0.77) Odds Ratio 0.73 (0.63–0.85) 0.50 (0.39–0.64) 0.79 (0.69–0.92) 0.91 (0.71–1.17) 0.64 (0.52–0.79) Odds Ratio Weber MA et al. Lancet. 2004;363:2047–49.

VALUE: Analysis of Results Based on BP Control at 6 Months Fatal/Non-fatal cardiac events Fatal/Non-fatal stroke All-cause death Myocardial infarction Heart failure hospitalisations Controlled patients* (n = 10755) Non-controlled patients (n = 4490) Hazard Ratio 95% CI *SBP < 140 mmHg at 6 months. Pooled Treatment Groups ** **P < (0.67–0.83) 0.55 (0.46–0.64) 0.79 (0.71–0.88) 0.86 (0.73–1.01) 0.64 (0.55–0.74) Odds Ratio Weber MA et al. Lancet. 2004;363:2047–49.

Composite cardiac events Stroke Death Myocardial infarction Heart failure Favours valsartanFavours amlodipine 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 0.90 (0.79–1.03) (0.81–1.28) (0.84–1.10) (0.80–1.19) (0.66–0.99)*0.040 *P < Weber MA et al. Lancet. 2004;363:2047–49.

Primary Endpoint:All-Cause Mortality Secondary Endpoints:CV Death, MI, or HF Other Endpoints:Safety and Tolerability Captopril 50 mg tid (n = 4909) Valsartan 160 mg bid (n = 4909) Captopril 50 mg tid + Valsartan 80 mg bid (n = 4885) 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 median duration: 24.7 months event-driven

Captopril Probability of Event Mortality by Treatment Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 Valsartan Months Valsartan vs. Captopril: HR = 1.00; P = Valsartan + Captopril vs. Captopril: HR = 0.98; P = Captopril Valsartan + Cap Valsartan Valsartan + Captopril

All-Cause Mortality: Non-Inferiority Analyses Hazard Ratio (97.5% CI) 1.13 P-value (noninferiority) Per Protocol Patient Population (n = 14,285) Intention-to-Treat Patient Population (n = 14,703) Noninferiority Val Superior to CapCap Superior to Val Noninferiority not Demonstrated noninferiority margin Favors Valsartan Favors Captopril

Mortality in SAVE, TRACE, AIRE, and VALIANT Hazard Ratio for Mortality Favors Active Drug Favors Placebo Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003; Combined TRACE SAVE AIRE VALIANT (imputed placebo) Valsartan preserves 99.6% of mortality benefit of captopril.

Captopril CV Death, MI, or HF by Treatment Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 Months Valsartan vs. Captopril: HR = 0.96; P = Valsartan + Captopril vs. Captopril: HR = 0.97; P = Probability of Event Valsartan Valsartan + Captopril

Noninferiority Val Superior to CapCap Superior to Val Noninferiority not Demonstrated Cardiovascular Mortality and Morbidity Hazard Ratio (97.5% CI) 1.13 P-value (noninferiority) noninferiority margin CV Death (1657 events) CV Death or HF (2661 events) CV Death or MI (2234 events) CV Death, MI, or HF (3096 events) Favors Valsartan Favors Captopril

Hazard Ratios (95% CI) for CV Death, MI, or HF Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:1893–1906 Favors Combination Favors Captopril Median  65 Age  65 SexMale Female Prior MINo Yes DMNo Yes SBP  median  median Serum  median Cr  median Killip I ClassII III IV Beta- No BlockerYes Favors Valsartan Favors Captopril # of Pts.P-Value (interaction) # of Pts.P-Value (interaction)

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

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

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 0123years Placebo Candesartan % HR 0.77 (95% CI ), p= Adjusted HR 0.70, p< Number at risk Candesartan Placebo (40.0%) 334 (33.0%)

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 0123years Placebo Candesartan % HR 0.77 (95% CI ), p= Adjusted HR 0.70, p< Number at risk Candesartan Placebo (40.0%) 334 (33.0%)

CHARM-Alternative Secondary outcomes CV death CHF hosp CV death, CHF hosp, MI CV death, CHF hosp, MI, stroke CV death, CHF hosp, MI, stroke, revasc Candesartan Placebo candesartan better Hazard ratio placebo better p-value <

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

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

CHARM-Added: Primary outcome CV death or CHF hospitalisation 0123years Placebo Candesartan Number at risk Candesartan Placebo HR 0.85 (95% CI ), p=0.011 Adjusted HR 0.85, p= (37.9%) 538 (42.3%) %

CHARM-Added: Primary outcome CV death or CHF hospitalisation 0123years Placebo Candesartan Number at risk Candesartan Placebo HR 0.85 (95% CI ), p=0.011 Adjusted HR 0.85, p= (37.9%) 538 (42.3%) %

CHARM-Added Secondary outcomes CV death CHF hosp CV death, CHF hosp, MI CV death,CHF hosp, MI, stroke CV death,CHF hosp, MI, stroke, revasc candesartan better Hazard ratio placebo better p-value Candesartan Placebo

CHARM-Added Prespecified subgroups, CV death or CHF hosp. Beta- Yes223/702274/711 blockerNo260/574264/561 Recom.Yes232/643275/648 dose ofNo251/633263/624 ACE inhib. All patients483/ /1272 Candesartan Placebo candesartan better Hazard ratio placebo better p-value for treatment interaction

CHARM-Added Investigator reported CHF hospitalisations Placebo Candesartan p=0.002 p=0.008 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes

Diastolic Heart Failure: Effects of Age on Prevalence and Prognosis Age, y 70 Age, y 70 Prevalence Mortality Morbidity

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

Zile MR et al. Circulation 2002 Definition of Diastolic Dysfunction and HF  Diastolic HF is a clinical syndrome characterized by the symptoms and signs of HF, a preserved EF and abnormal diastolic function.  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.  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.  Diastolic HF is a clinical syndrome characterized by the symptoms and signs of HF, a preserved EF and abnormal diastolic function.  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.  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.

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

CHARM-Preserved: Primary outcome CV death or CHF hospitalisation 0123years Number at risk Candesartan Placebo Placebo Candesartan HR 0.89 (95% CI ), p=0.118 Adjusted HR 0.86, p=0.051 % 366 (24.3%) 333 (22.0%)

CHARM-Preserved Primary and secondary outcomes CV death, CHF hosp CV death CHF hosp CV death, CHF hosp, MI CV death,CHF hosp, MI, stroke CV death,CHF hosp, MI, stroke, revasc candesartan better Hazard ratio placebo better p-value Covariate adjusted p-value Candesartan Placebo

CHARM-Preserved: Primary outcome CV death or CHF hospitalisation 0 123years Number at risk Candesartan Placebo Placebo Candesartan HR 0.89 (95% CI ), p=0.118 Adjusted HR 0.86, p=0.051 % 366 (24.3%) 333 (22.0%)

CHARM-Preserved Primary and secondary outcomes CV death, CHF hosp CV death CHF hosp CV death, CHF hosp, MI CV death,CHF hosp, MI, stroke CV death,CHF hosp, MI, stroke, revasc candesartan better Hazard ratio placebo better p-value Covariate adjusted p-value Candesartan Placebo

CHARM-Preserved Investigator reported CHF hospitalisations Placebo Candesartan p=0.014 p=0.017 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes