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

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. 2002 Heart and Stroke Statistical Update. 2001. Annual Discharges 0 100,000 200,000 300,000 400,000 500,000 600,000 '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: 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 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;2:439-446.

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;345:1667-1675. Months 369121518212427 0 65 70 75 80 85 90 95 100 Probability of Event-Free Survival 030 Valsartan (n = 2511) Placebo (n = 2499) P = 0.009 13.2% 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;345:1667-1675. 369121518212427 0 65 70 75 80 85 90 95 100 Months Event-Free Probability P <0.001 27.5% risk reduction 0 Valsartan (n = 2511) Placebo (n = 2499) Val-HeFT: Heart Failure-Related Hospitalizations* 30

Val-HeFT: Hospitalization for Heart Failure 0.20.60.81.00.41.2 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 = 0.0002 P = 0.005 No ACE-I ACE-I < median ACE-I  median ValsartanPlacebo Adapted with permission from Carson P et al. J Card Fail. 2003;9:164-171.

Val-HeFT: Combined Morbidity End Point P < 0.0002 44% risk reduction* Subgroup without ACE-I background therapy 0.400 0.486 0.571 0.657 0.743 0.829 0.914 0369121518212427 1.000 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;40:1414-1421.

Val-HeFT: Change in Plasma Brain Natriuretic Peptide Over Time *R et Mean ± SEM. Latini al. Circulation. 2002;106:2454-2458.  Plasma BNP* (pg/mL) Time (mo) n = 844 n = 1890 n = 1710 n = 1850 n = 1633 n = 823 P <0.0001 0412 24 -40 -30 -20 -10 0 10 20 Placebo Baseline = 177.6 pg/mL Valsartan Baseline = 183.5 pg/mL 30

Time (mo) (n = 1894)(n = 1713)(n = 840) (n = 1855) (n = 1635) (n = 816) 041224 -10 0 10 20 30 40 P = 0.003   Plasma NE* (pg/mL) P = 0.002 Val-HeFT: Neurohormones – Change in Plasma NE Over Time NE = norepinephrine. *Mean ± SEM. Latini R et al. Circulation. 2002;106:2454-2458. Placebo Baseline = 472 pg/mL Valsartan Baseline = 456 pg/mL

Val-HeFT: Change From Baseline in Plasma Aldosterone 4 months12 months24 months -30 -20 -10 0 10 20 30 -40 Baseline   Plasma Aldosterone (pg/mL) Least Squares Mean ± P <0.0001 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 ) Month0.501234 6 *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 14 12 10 8 6 4 2 0 Time (months) 0 6121824303642 48 54 60 66 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 7596 7649 7469 7459 7424 7407 7267 7250 7117 7085 6772 6732 6955 6906 6576 6536 5959 5911 3725 3765 1474 6391 6349

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 1.02.00.5 PRIMARY ENDPOINT Odds Ratios and 95% CIs  SBP mmHg 1.4 1.6 1.8 2.0 3.8 1.7 2.2 3–62.3 Favours valsartan 4.0 Julius S et al. Lancet. June 2004;363.

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 VALUE: Heart Failure 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. 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 1.02.00.5 Heart Failure Odds Ratios and 95% CIs  SBP (mmHg) 1.4 1.6 1.8 2.0 3.8 1.7 2.2 2.3 0.254.0 36–48 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 < 0.01. Patients Treated With ValsartanPatients Treated With Amlodipine Hazard Ratio 95% CI 0.40.60.81.01.2 Controlled patients* (n = 5253) Non-controlled patients (n = 2396) ** 0.40.60.81.01.2 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 0.40.60.81.01.21.4 Controlled patients* (n = 10755) Non-controlled patients (n = 4490) Hazard Ratio 95% CI *SBP < 140 mmHg at 6 months. Pooled Treatment Groups ** **P < 0.01. 0.75 (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 0.60.81.01.21.4 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)0.111 1.02 (0.81–1.28)0.899 0.96 (0.84–1.10)0.566 0.97 (0.80–1.19)0.791 0.81 (0.66–0.99)*0.040 *P < 0.05. 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 0 0.05 0.1 0.15 0.2 0.25 0.3 061218243036 Probability of Event Mortality by Treatment 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

All-Cause Mortality: Non-Inferiority Analyses 0.811.2 Hazard Ratio (97.5% CI) 1.13 P-value (noninferiority) 0.002 Per Protocol Patient Population (n = 14,285) 0.004 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;349 0.512 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 = 0.198 Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369 0 0.1 0.2 0.3 0.4 061218243036 Probability of Event Valsartan Valsartan + Captopril

Noninferiority Val Superior to CapCap Superior to Val Noninferiority not Demonstrated Cardiovascular Mortality and Morbidity 0.811.2 Hazard Ratio (97.5% CI) 1.13 P-value (noninferiority) noninferiority margin CV Death (1657 events) 0.001 CV Death or HF (2661 events) 0.0001 CV Death or MI (2234 events) 0.00001 CV Death, MI, or HF (3096 events) 0.000001 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 0.512 Favors Valsartan Favors Captopril # of Pts.P-Value (interaction) 0.512 # of Pts.P-Value (interaction) 4618 5200 6738 3080 7088 2730 7564 2254 5632 4182 4970 4837 2718 4747 1687 619 0.96 0.55 0.93 0.12 0.71 0.67 0.84 4675 5119 6768 3026 7085 2709 7528 2266 5642 4149 4908 4878 2805 4675 1655 618 1.00 0.47 0.26 0.85 0.68 0.92 0.11 2907 6911 0.48 2910 6882 0.56

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) 0.5 12 Favors CaptoprilFavors Valsartan Favors CaptoprilFavors Combination 0.56 0.48 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 0 10 20 30 40 50 Placebo Candesartan % HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 Number at risk Candesartan 1013 929 831 434 122 Placebo 1015 887 798 427 126 3.5 406 (40.0%) 334 (33.0%)

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 0123years 0 10 20 30 40 50 Placebo Candesartan % HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 Number at risk Candesartan 1013929831434122 Placebo 1015887798427126 3.5 406 (40.0%) 334 (33.0%)

CHARM-Alternative Secondary outcomes CV death219252 CHF hosp. 207286 CV death, CHF hosp,353420 MI CV death, CHF hosp,369432 MI, stroke CV death, CHF hosp,396456 MI, stroke, revasc Candesartan Placebo candesartan better Hazard ratio placebo better 0.60.81.01.21.4 p-value 0.072 <0.0001 0.0007 0.001 0.002 0.85 0.68 0.78 0.80 0.81

CHARM-Alternative Investigator reported CHF hospitalisations Placebo Candesartan Proportion of patients (%) Patients hospitalised Hospitalisations p<0.0001 p=0.0001 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 0 10 20 30 40 50 Placebo Candesartan Number at risk Candesartan127611761063 948 457 Placebo127211361013 906 422 3.5 HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010 483 (37.9%) 538 (42.3%) %

CHARM-Added: Primary outcome CV death or CHF hospitalisation 0123years 0 10 20 30 40 50 Placebo Candesartan Number at risk Candesartan127611761063948457 Placebo127211361013906422 3.5 HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010 483 (37.9%) 538 (42.3%) %

CHARM-Added Secondary outcomes CV death302347 CHF hosp.309 356 CV death, CHF hosp,495550 MI CV death,CHF hosp,512559 MI, stroke CV death,CHF hosp,548596 MI, stroke, revasc candesartan better Hazard ratio placebo better 0.60.81.01.21.4 p-value 0.029 0.014 0.010 0.020 0.015 Candesartan Placebo 0.84 0.83 0.85 0.87

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 patients483/1276538/1272 Candesartan Placebo candesartan better Hazard ratio placebo better 0.60.81.01.21.4 p-value for treatment interaction 0.14 0.26

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 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

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 151414581377833182 Placebo 150914411359824195 3.5 0 10 20 30 Placebo Candesartan 5 15 25 HR 0.89 (95% CI 0.77-1.03), 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.333 366 - CV death170170 - CHF hosp. 241276 CV death, CHF hosp,365399 MI CV death,CHF hosp,388429 MI, stroke CV death,CHF hosp,460497 MI, stroke, revasc candesartan better Hazard ratio placebo better 0.81.01.2 p-value 0.918 0.072 0.118 0.126 0.078 0.123 Covariate adjusted p-value 0.635 0.047 0.051 0.037 0.13 Candesartan Placebo 0.89 0.99 0.85 0.90 0.88 0.91

CHARM-Preserved: Primary outcome CV death or CHF hospitalisation 0 123years Number at risk Candesartan 151414581377833182 Placebo 150914411359824195 3.5 0 10 20 30 Placebo Candesartan 5 15 25 HR 0.89 (95% CI 0.77-1.03), 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.333 366 - CV death170170 - CHF hosp. 241276 CV death, CHF hosp,365399 MI CV death,CHF hosp,388429 MI, stroke CV death,CHF hosp,460497 MI, stroke, revasc candesartan better Hazard ratio placebo better 0.81.01.2 p-value 0.918 0.072 0.118 0.126 0.078 0.123 Covariate adjusted p-value 0.635 0.047 0.051 0.037 0.13 Candesartan Placebo 0.89 0.99 0.85 0.90 0.88 0.91

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

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

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

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