选择性醛固酮封锁需与瞬态或永久心脏的急性心肌梗死住院期间衰竭患者

Need for Selective Aldosterone Blockade for Patients with Transient or Persistent Heart Failure During Hospitalisation for AMI Professor C Richard CONTI University of Florida College of Medicine, Gainsville, Florida (USA) Hospital Events in NRMI AMI Patients EVENT AMI + CHF (%) AMI (%) Stroke 2.2 1.4 A V block 5.7 4.6 VT or VF 11.9 9.09 Rupture/EMD 1.8 1.0 Unexpected cardiac arrest 8.3 4.4 LOS 7.1 5.3 Recurrent MI 3.0 2.7 Death 21.4 7.2 AMI and HF Conclusions from NMRI CHF and AMI is a high risk situation Despite the high risk, these patients are less frequently treated with medications with proven mortality benefit or with primary reperfusion strategies None of these patients were treated with aldactone or eplerenone Cardiac Echo performed within 24 hrs after AMI Prognosis after Myocardial Infarction GRACE: Impact of Heart Failure on Cumulative Mortality From ACS ACS = acute coronary syndromes. Steg PG et al. Circulation. 2004;109:494-499. Time to Death Within 6 Months (n = 10,771) 0.3 0.2 0.1 0.0 0 1 2 3 4 6 HR = 3.8 (95% CI, 3.33 to 4.36) Heart failure at admission No heart failure at admission Proportion Dead 5 ACE-I = angiotensin-converting enzyme inhibitor; Ang I = angiotensin I; ARB = angiotensin II blocker. Pathophysiologic effects on cardiovascular system Ang IIAng IAngiotensinogen Renin Na+/H2O retention K+, Mg+ loss Aldosterone ACE ACE-i Non-RAAS Stimulators ARB ARB Aldosterone Blockers Non-RAAS stimulatorsAlternative Pathways Aldosterone: Important Component of Renin-Angiotensin-Aldosterone System Fibrosis Fibrosis No fibrosis Adapted from Weber KT, Brilla CG. Circulation 1991;83:1849-1865. Unilateral Renal Artery Stenosis Aldosterone Infusion in Uninephric Rat Infrarenal Aortic Banding Plasma HBP LVH Fibrosis Angiotensin II Aldosterone Angiotensin II Aldosterone Angiotensin II Aldosterone Yes Yes Yes Yes Yes Yes Yes Yes No HBP = high blood pressure; LVH = left ventricular hypertrophy Aldosterone Stimulates Myocardial Fibrosis Myocardial Fibrosis in Hypertension and CHF: The Aldosterone Hypothesis Aldosterone Cardiac fibroblasts Collagen synthesis Collagen deposition Myocardial Fibrosis LV stiffness LVD CHF Aldosterone Receptor Antagonists Adapted from Hameedi and Chadow. Curr Hypertens Rep. 2000;2:378-383 Pathophysiologic Mechanisms of Aldosterone in Heart Failure VSMC = vascular smooth muscle cell; NO = nitric oxide; ET-1 = endothelin-1. Rajagopalan and Pitt. Med Clin North Am. 2003;87:441-457. Adrenal Myocardial/Vascular Angiotensin II, K+, ACTH Aldosterone Fibroblast Collagen Synthesis VSMC Hypertrophy Free Radical Production NO (in adrenal) AT1R Binding of Ang II ACE Activity PAI-1 ET-1 McKelvie et al. Circulation 1999;100:1056-64 50 40 30 20 10 0 -20 -10 -30 -40 D Aldosterone (pg/mL ) 17 weeks 43 weeks Candesartan 4 mg Candesartan 8 mg Candesartan 16 mg Candesartan+ Enalapril 4 mg/20mg Candesartan + Enalapril 8 mg/20mg Enalapril 20 mg Aldosterone Rebound Occurs Even with Combined ACE-I and AII Blocker (RESOLVD) AIRE: ACE Inhibition for Post-MI LV Dysfunction The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993;342:821-828. Placebo Ramipril Time (months) 35 30 25 20 15 10 5 0 0 6 12 18 24 30 HR 0.73 (95% CI, 0.60 to 0.89) P = .002Cumulative Mortality (%) RR: 27% LV = left ventricular; HR = hazard ratio; RR = risk reduction. 11 CAPRICORN: Beta-blockade for Post-MI LV Dysfunction (Only Event-free for All-cause Mortality) HR = hazard ratio; RR = risk reduction. The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. PlaceboCarvedilol Proportion Event-Free Years 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 0.5 1.0 1.5 2.0 2.5 HR 0.77 (95% CI, 0.60 to 0.98) P = .031 RR: 23% 12 VALIANT: ARB and/or ACEI Post MI Adapted from Pfeffer MA et al. N Engl J Med. 2003;349:1893-1906. Probability of Event 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 Months Probability of Event 12 Months 0.4 0.3 0.2 0.1 0.0 0 6 18 24 30 36 CaptoprilValsartan Valsartan and Captopril Death From Any Cause Combined Cardiovascular Endpoint 13 EPHESUS: Study Design Primary endpoints: Secondary endpoints: Total mortality CV mortality/CV hospitalizations CV mortality Total mortality/total hospitalizations Eplerenone 25 to 50 mg qd (n = 3319) Placebo (n = 3313) 6632 Patients 3 to 14 Days Post-MI 1012 Deaths Pitt B et al. N Engl J Med. 2003;348:1309-1321. Acute MI, Heart Failure, LVEF 40%, Standard Therapy 14 RR: 31% Pitt B et al. Abstract presented at: ESC Working Group on Acute Cardiac Care; 2004. EPHESUS Co-Primary Endpoint: Total Mortality (30 Days) Eplerenone + standard care Placebo + standard care Cumulative Incidence (%) Days From Randomization HR = 0.69 (95% CI, 0.54 to 0.89) (4.6%) (3.2%) P = .004 HR = hazard ratio. RR = risk reduction. EPHESUS Co-Primary Endpoint: Total Mortality (Duration of Study) Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321. Eplerenone + standard care (n = 3319) Placebo + standard care (n = 3313) Cumulative Incidence (%) 22 20 18 16 14 12 10 8 6 4 2 0 3 6 9 12 15 18 21 24 27 Months Since Randomization HR = 0.85 (95% CI, 0.75 to 0.96) P = .008 0 RR: 15% (16.7%) (14.4%) HR = hazard ratio. RR = risk reduction. HR = 0.87 (95% CI, 0.74 to 1.01) EPHESUS Co-Primary Endpoint: CV Mortality/CV Hospitalization (30 Days) Pitt B et al. Abstract presented at: ESC Working Group on Acute Cardiac Care; 2004. RR: 13% Eplerenone + standard care Placebo + standard care Cumulative Incidence (%) Days From Randomization (9.9%) (8.6%) HR = hazard ratio. RR = risk reduction. P = .074 EPHESUS Co-Primary Endpoint: CV Mortality/CV Hospitalization (Duration of Study) Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321. Eplerenone + standard care (n = 3319) Placebo + standard care (n = 3313) 40 Cumulative Incidence (%) 35 30 25 20 15 10 5 0 3 6 9 12 15 18 21 24 27 HR = 0.87 (95% CI, 0.79 to 0.95) P = .002 0 Months Since Randomization RR: 13% (30.0%) (26.7%) HR = hazard ratio. RR = risk reduction. EPHESUS: Sudden Death From Cardiac Causes Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321. Eplerenone + standard care (n = 3319) Placebo + standard care (n = 3313) 10 Cumulative Incidence (%) 8 6 5 4 3 2 1 0 3 6 9 12 15 18 21 24 27 HR = 0.79 (95% CI, 0.64 to 0.97) P = 0.03 0 9 7 Months Since Randomization RR: 21% HR = hazard ratio. RR = risk reduction. EPHESUS: Rates of Hyperkalemia and Hypokalemia Eplerenone n (%) Placebo n (%) P value Investigator reported Hyperkalemia 113 (3.4%) 66 (2.0%) 5.5 mEq/L at initiation Creatinine clearance 30 mL/min Concomitant use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir, or other drugs described in their labeling as strong inhibitors of CYP3A4 23 Eplerenone: Rates of Sex-Hormone-Related Adverse Events Eplerenone Placebo Males Gynecomastia 0.4% 0.5% Mastodynia 0.1% 0.1% Females Abnormal vaginal bleeding 0.4% 0.4% 24 Eplerenone: Potassium Monitoring Measure serum potassium Before initiating eplerenone therapy At 1 day At 1 week At 1 month Periodically thereafter Patient characteristics and serum potassium levels may prompt additional monitoring Use caution when treating patients with renal insufficiency or diabetes, including those with proteinuria, due to increased risk of hyperkalemia 25 Eplerenone: Dose Adjustments After Initiating Therapy for Post-MI HF Serum Potassium (mEq/L) Action Dose Adjustment 5.5 mmol/L): Elevated baseline serum creatinine Low baseline creatinine clearan