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1、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,AMI and HF,Conclusions from NMRI CHF and
2、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,Prognos
3、is 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 admissi
4、on 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 II,Ang I,Angiotensinogen,Renin,Na+/H2O retention K+, Mg+ loss,Aldosterone,ACE,ACE-i,Non-RAAS
5、Stimulators,ARB,ARB,Aldosterone Blockers,Aldosterone,Non-RAAS stimulators,Alternative 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,Aldo
6、sterone 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 Fib
7、rosis,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,Patho
8、physiologic 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 Hypertrop
9、hy, 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,
10、Candesartan + Enalapril 8 mg/20mg,Enalapril 20 mg,Aldosterone Rebound Occurs Even with Combined ACE-I and AII Blocker (RESOLVD),11,AIRE: ACE Inhibition for Post-MI LV Dysfunction,The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993;342:821-828.,Placebo Ramipril,RR: 27%,LV
11、= left ventricular; HR = hazard ratio; RR = risk reduction.,12,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.,Placebo,Carvedilol,Proportion Event-Free,Years
12、,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%,13,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 Ev
13、ent,12,Months,0.4,0.3,0.2,0.1,0.0,0,6,18,24,30,36,Captopril,Valsartan,Valsartan and Captopril,Death From Any Cause,Combined Cardiovascular Endpoint,14,EPHESUS: Study Design,Primary endpoints:,Secondary endpoints:,Total mortality CV mortality/CV hospitalizations CV mortality Total mortality/total hos
14、pitalizations,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,RR: 31%,Pitt B et al. Abstract presented at: ESC Working Group on Acute Cardiac Car
15、e; 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 Morta
16、lity (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),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
17、 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
18、 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.
19、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 Inci
20、dence (%),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,Pitt B et al. N Engl J Med. 2003;348:1309-1321.,ACC/AHA Guidelines for Managemen
21、t of ST-Elevation MI with LV Dysfunction and HF,Aspirin Clopidogrel -Blocker ACE inhibitor Aldosterone antagonist Heparin (UFH or LMWH) GP IIb-IIIa inhibitor (if receiving PCI),Aspirin Clopidogrel -Blocker ACE inhibitor Aldosterone antagonist Statin Smoking cessation Cardiac rehabilitation,In-hospit
22、al Therapy,Discharge Therapy,LV = left ventricular; UFH = unfractionated heparin; LMWH = low-molecular-weight heparin; GP = glycoprotein; PCI = percutaneous coronary intervention.,22,Eplerenone: Post-MI Heart Failure Indication and Dosing,Indicated to improve survival of stable patients with Left ve
23、ntricular systolic dysfunction (LVEF 40%) Clinical evidence of HF after acute MI Start at 25 mg qd and titrate in a single step to target dosage of 50 mg qd, preferably within 4 weeks, as tolerated No interactions with ACE inhibitors, ARBs, beta-blockers, diuretics, aspirin, statins, or reperfusion
24、therapy May be administered with or without food,Pitt B et al. N Engl J Med. 2003;348:1309-1321.,23,Eplerenone: Post-MI Heart Failure Contraindications,Serum potassium 5.5 mEq/L at initiation Creatinine clearance 30 mL/min Concomitant use with potent CYP3A4 inhibitors such as ketoconazole, itraconaz
25、ole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir, or other drugs described in their labeling as strong inhibitors of CYP3A4,24,Eplerenone: Rates of Sex-Hormone-Related Adverse Events,25,Eplerenone: Potassium Monitoring,Measure serum potassium Before initiating eplerenone therap
26、y 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,26,Eplerenone:
27、Dose Adjustments After Initiating Therapy for Post-MI HF,*Eplerenone can be restarted at 25 mg qod when the potassium level falls to 5.5 mEq/L.,.,Conclusions,Heart failure post MI is a major public health problem Neurohormonal blockers improve the clinical course of post-MI patients with LV dysfunct
28、ion Eplerenone improves survival and reduces CV mortality/CV hospitalizations in patients with post-MI LV dysfunction and evidence of HF; these benefits are additive to those from other cardiac drugs Consider early use of eplerenone for stable patients with LVEF 40% and past or present signs or symp
29、toms of heart failure after acute MI,Who is a Good Candidate for Aldosterone Blockade after a Myocardial Infarction ?,Heart Failure Patients (Rales, S3, Chest X-ray Congestion, Symptoms) Hypokalemia Hypertension Left Ventricular Hypertrophy Dilated Cardiomyopathy,Take home message Patients post-MI w
30、ith heart failure are at high risk of death, even when treated with primary PCI early after presentation. Early initiation of therapy, i.e. before hospital discharge, can save lives !,Weber. N Engl J Med. 1999;341:752-755.,Aldosterone “escapes” ACE-inhibitor suppression May be caused by Inability of
31、 standard doses to fully suppress angiotensin-regulated adrenal production of aldosterone Patient lifestyle may counter (by stimulating renin release) Upright posture, physical activity, restriction of dietary sodium Aldosterone secretion can be independent of RAAS Potassium-dependent aldosterone se
32、cretion Reduced metabolic clearance of aldosterone and biologic activity of its metabolites,Aldosterone “Escape” and Independence of RAAS,EPHESUS: Baseline Therapy*,*At randomization (3 to 14 days after MI). Pitt B et al. N Engl J Med. 2003;348:1309-1321.,33,EPHESUS: Hospitalizations for Heart Failu
33、re,Pitt B et al. N Engl J Med. 2003;348:1309-1321.,0,100,200,300,400,500,600,700,No. of Patients,No. of Episodes,P = .002,618,477,P = .03,391,345,Eplerenone + standard care,Placebo + standard care,15% risk reduction,23% risk reduction,Stepwise logistic regression identified 4 independent risk factor
34、s for K (K+ 5.5 mmol/L): Elevated baseline serum creatinine Low baseline creatinine clearance History of diabetes mellitus Baseline use of antiarrhythmics These risk factors were not associated with a significant differential adverse effect of eplerenone vs placebo for: All-cause mortality CV death/
35、CV hospitalization CV death Sudden cardiac death,EPHESUS: Risk Factors for Hyperkalemia,Bakris G et al. American Heart Association Scientific Sessions; 2004.,EPHESUS: Worst-Case Analysis: Hyperkalemia and Mortality,Bakris G et al. American Heart Association Scientific Sessions; 2004. Pitt B et al. N Engl J Med. 2003;348:1309-1321.,