Φαρμακευτική θεραπεία της μετεμφραγματικής καρδιακής ανεπάρκειας. Α. Καραβίδας Υπεύθυνος ιατρείου καρδιακής ανεπάρκειας Γ.Ν.Α Γ.

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1 Φαρμακευτική θεραπεία της μετεμφραγματικής καρδιακής ανεπάρκειας Α. Καραβίδας Υπεύθυνος ιατρείου καρδιακής ανεπάρκειας Γ.Ν.Α Γ.Γεννηματάς

2 Clinical Trials on Fibrinolysis N = AMI pts, ( GUSTO I, GUSTOIIb, GUSTO III, ASSENT III) HF at admission 12.5% HF at any time during admission 29.4% Hasdai et al. Am Heart J. 23 N = 66.5 AMI pts, National Registry of Myocardial Infarction HF at admission 2.4% HF after admission 8.6% Spencer FA et al. Circulation 22 N = 5566 pts with AMI admitted to 84 hospitals in 9 countries (VALIANT registry) HF after admission 23.1% Velazquez Velazquez EJ et al.eur Heart J 24 Heart Failure is a common occurrence after AMI

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4 Ν=7.773pts >65 years without a history of HF

5 HF-free survival N= AMI pts from 1994 to 1999, 24% underwent invasive coronary revascularization (PCI) FU mean 32 months The use of primary PCI was associated with lower rates of heart failure in hospital (17% versus 24%) and at discharge (4% versus 7%) Am J Cardiol 28

6 Heart Failure Complicating AMI Presents an Early and Sustained Increase in Mortality 3- to 4-fold 4 increase in mortality 1,2,3 NRMI-2 1 Hasdai et al 2 GRACE 3 Hospital admission 3 days 6 Months 1 National Registry Myocardial Infarction-2 Wu et al. J Am Coll Cardiol.. 22;4: Hasdai et al. Am Heart J. 23;145: Global Registry of Acute Coronary Events Steg et al. Circulation. 24;19:

7 Goals in the management of post-myocardial infarction with left ventricular dysfunction Prevent future coronary events (CAD progression) Improve symptoms Attenuate progressive pathologic LV remodeling (reduce progression of disease) Adapted from Gheorgiade and Bonow. Circulation 1998 Prolong survival by preventing CAD progression, SCD or progression of HF

8 Natural history of Congestive Heart Failure Index event 6% EF % 2% Secondary damage Neurohormonal activation Sympathetic system activity SNSnervous RAAS Endothelin Reninetc Angiotensin- Aldosterone System activity Asymptomatic Time (years) Symptomatic Mann DL.et al. Circulation 25

9 The Pathophysiology of Heart Failure Results from Neurohormonal Activation RAS activation Angiotensin II Aldosterone SNS activation Norepinephrine Hypertrophy,apoptosis,ischemia,arrhythmias, remodeling, fibrosis Mortality and disease progression

10 Early Use of ACE-Inhibitors in Post-MI Trials Patients (n) Mean Follow-up Target Dose LVEF (%) Effects on all-cause mortality SAVE Captopril yrs 5 N/A mg tid 4 AIRE Ramipril yrs 5 mg I III bid N/A TRACE yrs 4mg N/Aqd 35 Trandorapril SAVE Radionuclide EF 4% Pfeffer MA et al. N Eng J Med 1992 AIRE Clinical and/or radiographic signs of HF Acute Infarction Ramipril Efficacy study Investigators. Lancet 1993 All-cause mortality: 19%(p=.19) All-cause mortality: 27%(p=.2) All-cause mortality: 22%(p=.1) TRACE Echocardiographic EF 35% Kober L et al. N Eng J Med 1995

11 SAVE Radionuclide EF 4% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiographic EF 35%.4 All-Cause Mortality.35 Probability of Event N=5966 pts Placebo ACE-I 26% reduction Placebo: 866/2971 (29.1%) ACE-I: 72/2995 (23.4%) OR:.74 (.66.83) Years ACE-I Placebo Flather MD, et al. Lancet. 2;355:

12 4 SAVE Radionuclide EF 4% ACE-I (n = 2995) AIRE Clinical and/or radiographic signs of HF Death and Major CV Events Placebo (n = 2971) TRACE Echocardiographic EF 35% 25% reduction Events (%) % reduction.73* (.63.85) 2% reduction.8* (.69.95).75* (.67.83) 1 n = 355 n = 46 Readmission for HF n = 324 n = 391 Reinfarction n = 149 n = 1244 Death/MI or Readmission for HF *odds ratio (95% CI) Flather MD, et al. Lancet. 2;355:

13 Echocardiographic substudy of SAVE The protective effects of Captopril Ν=42 AMI pts 2D echo was performed soon after AMI and after 1 year St John SM et al. Circulation 1994

14 Echocardiographic substudy of SAVE The protective effects of Captopril Ν=42 AMI pts 2D echo was performed soon after AMI and after 1 year 35% reduction St John SM et al. Circulation 1994

15 VALIANT: Mortality by Treatment Probability of Event Months Captopril Valsartan Valsartan + Captopril N= 1473 AMI pts EF 35 on echo and/ or EF 4 on radionuclide ventriculography Mean FU 2years Valsartan vs. Captopril: HR = 1.; P =.982 Valsartan + Captopril vs. Captopril: HR =.98; P = Captopril Valsartan Valsartan + Cap Pfeffer, McMurray, Velazquez, et al. N Engl J Med 23;349

16 Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN STUDY) All-Cause Mortality N=1.959 acute MI pts, EF<4%, FU 1.3 years ACE inhibitor 97%, aspirin 86%, thrombolysis/primary angioplasty 46% 1 Proportion Event-Free % reduction P =.31 Carvedilol Placebo The CAPRICORN Investigators. Lancet 21 Years

17 CAPRICORN STUDY RR of Sudden Cardiac Death 26% 25% 41% The CAPRICORN Investigators. Lancet 21

18 Ν=127 acute MI patients with LVSD FU echo after 6 months of therapy EF had increased in the carvedilol group by 5% after 6 months of treatment with no change with placebo

19 Patients With HF Complicating AMI Receive Suboptimal Medical Treatment Medication within 24*h Beta-blockers PO IV ACE Inhibitors No HF (%) HF (% Wu et al. J Am Coll Cardiol.. 22 A review of medical records from > 2. patients with a history of MI found that only 34% received β-blockers Abraham W et al. Am J Cardiol 28

20 K Weber, N Engl J Med 21 Η Αλδοστερόνη προάγει την περιαγγειακή ίνωση και την αγγειακή αναδιαμόρφωση Αλλαγές σε μοριακό,κυτταρικό επίπεδο με προοδευτική αποδόμηση της εξωκυττάριας θεμέλειας ουσίας

21 Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS): Design patients with acute MI complicated by systolic left ventricular dysfunction ( EF < 4%) and heart failure Acute MI in prior 3-14 Days Heart Failure (in not diabetics but not required for diabetics) Eplerenone 25-5 mg QD n=3,313 Primary endpoints: Secondary endpoints: Other endpoints: Optimal medical therapy (ACE inhibitors or angiotensinreceptor blockers(87%),diuretics, and beta-blockers (75%), coronary reperfusion therapy) at mean of 16 month follow-up Placebo n=3,319 All-cause mortality CV mortality + CV hospitalization CV mortality CV hospitalization All-cause mortality + all-cause hospitalization New onset of atrial fibrillation/flutter NYHA functional class QOL AMI=acute myocardial infarction; QOL=quality of life. Reproduced with permission: Pitt B, et al. Cardiovasc Drugs Ther. 21;15:79-87.

22 Primary Endpoint: All-Cause Mortality % reduction Cumulative Incidence (%) RR =.85 (95% CI, ) P =.8 Placebo Eplerenone Months Since Randomisation Placebo Eplerenone Pitt B et al. N Eng J Med 23; 348:

23 Primary Endpoint: CV Mortality/CV Hospitalization Cumulative Incidence (%) RR =.87 (95% CI, ) P =.2 13% reduction Placebo Eplerenone Months Since Randomization Placebo Eplerenone Pitt B et al. N Eng J Med 23; 348:

24 RR of Sudden Cardiac Death 1 All Patients Cumulative incidence (%) 5 Placebo Eplerenone RR=.79 (95% CI, ) P=.3 21% reduction Months since randomization Pitt B, et al. N Engl J Med. 23;348:

25 HF Hospitalizations 2 Eplerenone Placebo 7 23% risk reduction P = % risk reduction P = Percent (%) 1 Number of Episodes Patients Hospitalized for Heart Failure Episodes of Heart Failure Hospitalization Pitt B et al. N Eng J Med 23; 348:

26 Effects on Potassium Homeostasis % absolute decrease P < ,1 1 Patients (%) % absolute increase P =.2 8,4 Eplerenone Placebo 4 2 5,5 3,9 Serious Hyperkalaemia (K + 6. mmol/l) Hypokalaemia (K + < 3.5 mmol/l) Pitt B et al. N Eng J Med 23; 348:

27 EPHESUS: Eplerenone Survival Benefits at 3 Days Support Urgency to Treat 12 13% Eplerenone Placebo Cumulative Incidence (%) % % All-cause mortality RR=.69 (95% CI,,54-,89) CV mortality CV hospitalizations RR=.87 (95% CI,,74-1,1) CV mortality RR=.68 (95% CI,,53-,88)88 Pitt et al. JACC 25;46;

28 EPHESUS TM : Sudden Cardiac Death at 3 Days Post-Randomization Sudden Cardiac Death (Secondary End Point) 5 RR=.63 (95% CI,.4-1.) Cumulative Incidence (%) Placebo + standard therapies (n=3313) Eplerenone + standard therapies (n=3319) 37% reduction Days From Randomization P=.51 Pitt B, White H, Nicolau J, et al. J Am Coll Cardiol. 25;46:

29 21% reduction All cause mortality 15% Effects of eplerenone in Pts with EF<3% 21% reduction CV mortality/hospitalization 13% 33% reduction Sudden cardiac death 21% Pitt et al. Eur J Heart Fail 26

30 Effects of eplerenone within 3 days in patients with EF<3% 29% 43% 58% Pitt et al. Eur J Heart Fail 26

31 Eplerenone suppress post-acute myocardial infarction collagen turnover changes (EPHESUS substudy) N = 476 pts PINP- PIIINP= βιολογικοί δείκτες ορού σύνθεσης κολλαγόνου Eplerenone Placebo Iraqi W et al. Crculation 29

32 Post-MI LV Dysfunction: Current therapeutic strategies ACE inhibitors (SAVE, AIRE, TRACE) Carvedilol (CAPRICORN) ARBs alternatively to ACEi (VALIANT) Eplerenone (EPHESUS) - Statins - Aspirine

33 Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation Long term Management of Heart Failure or LV Dysfunction Recommendations Oral beta-blockers in all patients without contraindications Class LOE I A ACE inhibitors in all patients without contraindications ARB (Valsartan) in all patients without contraindications who do not tolerate ACE-inhibitors Aldosterone antagonists if EF<4% and signs of heart failure or diabetes if creatinine is < 2.5mg/dL (221μmol/L) in men and < 2. mg/dl (177μmol/L) in women and potassium < 5mmol/L I A I B I B ESC GUIDELINES 28