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Things we knew, things we did… Things we have learnt, things we should do Alain Wajman M.D., Cardiologist Prat Hosp. Clin. Spe Rothschild Hospital APHP,

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Presentation on theme: "Things we knew, things we did… Things we have learnt, things we should do Alain Wajman M.D., Cardiologist Prat Hosp. Clin. Spe Rothschild Hospital APHP,"— Presentation transcript:

1 Things we knew, things we did… Things we have learnt, things we should do Alain Wajman M.D., Cardiologist Prat Hosp. Clin. Spe Rothschild Hospital APHP, Paris Post MI Heart Failure with Left Ventricular Dysfunction Management and Aldosterone Blockade

2 2 Heart Failure Disease with the highest prevalence in the next decade 50% of elderly (age ) 50%: ischaemic heart disease (post MI and LVD) High costs for public health Prognosis: poor but improving One-year mortality 5% NYHA class I 25-30% NYHA class IV

3 3 Jessup M and Brozena S. N Engl J Med 2003;348: Ventricular REMODELING After Acute Infarction

4 4 Neurohormonal changes: VC > VD Vasoconstriction: 1.Noradrenaline 2.Renin Angiotensine System 3.Endothelin 4.Arginin Vasopressin 5.Cytokines Vasoconstriction: 1.Noradrenaline 2.Renin Angiotensine System 3.Endothelin 4.Arginin Vasopressin 5.Cytokines Vasodilation / Antiproliferative substances: 1.Natriuretic peptides 2.Bradykinines 3.NO 4.Adrenomedulline Vasodilation / Antiproliferative substances: 1.Natriuretic peptides 2.Bradykinines 3.NO 4.Adrenomedulline

5 5 Jessup M and Brozena S. N Engl J Med 2003;348: Targets for Heart Failure Treatment Diuretics ACE I, AIIRAs Beta-blockers Anti-aldosterone Antiarrhytmics CCBs AIIRAs Antiplatelets Anticoagulants Statins?

6 6 Jessup M and Brozena S. N Engl J Med 2003;348: Severity of Systolic Heart Failure And Therapeutic Options

7 7 Diuretics in Post MI HF with LVD Always mandatory, ++++ if congestion Natriuretics Furosemide: mg IV, 40 to 250 mg/d Renal vasodilation Hyponatremia Hypokalemia Alkalosis Hyperuricemia Hypertriglyceridemia

8 8 Beta-blockers in Post MI HF with LVD If EF < 35 % to 40 % Mandatory, start late, 4 to 6 weeks after acute phase …. In combination with ACE I Carvedilol Bisoprolol Metoprolol Nebivolol Start Late, Low, and go Slow Control: HR, BP, Diuresis, Body weight

9 9 ACE I or ARBs (AIIRAs) sartans in HF with low ejection fraction Candesartan, CHARM trial: 7000 patients with heart failure already receiving an ACE I or intolerant to an ACE I and low EF < 40% Significant mortality and rehospitalization reduction No benefit if EF > 40% Candesartan: 4.8 mg then 16 to 32 mg/d

10 10 Weber K. N Engl J Med 2001;345: The Renin-Angiotensin-Aldosterone System

11 11 Dluhy R and Williams G. N Engl J Med 2004;351:8-10 Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt Levels

12 12 Ernst M and Moser M. N Engl J Med 2009;361: Sites of Diuretic Action in the Nephron

13 13 Weber K. N Engl J Med 2001;345: Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth-Muscle Cells in an Intramyocardial Coronary Artery

14 14 Weber K. N Engl J Med 2001;345: Coronary Vascular Remodelling in Hyperaldosteronism in Rats

15 15 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Objective To evaluate the effects of eplerenone (a selective aldosterone blocker): on morbidity and mortality in patients with acute myocardial infarction (MI) complicated by left ventricular dysfunction and heart failure Reference Pitt B, Remme W, Zannad F et al. for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–21.

16 16 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - TRIAL DESIGN - Design Multicentre, multinational, randomized, double-blind, placebo-controlled Patients 6632 patients 3 – 14 days after acute MI, who had left ventricular ejection fraction <40% and were receiving optimal treatment, which could include ACE inhibitors, angiotensin receptor blockers, diuretics (other than K + - sparing diuretics) and beta-blockers Follow-up and primary endpoints Primary endpoints: all-cause mortality; death from cardiovascular cause or first hospitalization for cardiovascular event. Mean 16 months follow-up. Treatment Placebo or eplerenone titrated to target dose 50 mg daily

17 17 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Age (years) a Male (%) History Left ventricular ejection fraction (%) a Days from MI to randomization a Symptoms of heart failure Medications ACE inhibitor or angiotensin-receptor blocker Beta-blockers Diuretics Aspirin Statins Baseline characteristics Placebo (n=3313) Eplerenone (n=3319) Pitt et al.N Engl J Med 2003;348:1309–21. a Mean

18 18 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS - Both primary endpoints significantly reduced in eplerenone group compared with placebo: all-cause mortality: 14.4 vs. 16.7% (RR 0.85, P=0.008) death or hospitalization due to cardiovascular event: 26.7 vs. 30.0% (RR 0.87, P=0.002) Significantly fewer hospitalizations for cardiovascular events in eplerenone group, attributable to significant reduction in hospitalizations for heart failure Incidence of gynecomastia in the two groups was similar. Incidence of serious hyperkalemia significantly higher in eplerenone group; serious hypokalemia significantly lower Drug well tolerated as defined by withdrawal rate from trial: only marginally higher with eplerenone

19 19 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS, continued - Months after randomization Cumulative incidence (%) All-cause mortality Pitt et al.N Engl J Med 2003;348:1309–21. Placebo Eplerenone RR=0.85 (95% CI=0.75–0.96) P=0.008

20 20 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS, continued - Primary and selected secondary endpoints Pitt et al.N Engl J Med 2003;348:1309–21. P Primary endpoints All-cause mortality Cardiovascular death or hospitalization for cardiovascular events Secondary endpoints (No.) Hospitalization for cardiovascular events Acute MI Heart failure Stroke Ventricular arrhythmia 0.85 (0.75–0.96) 0.87 (0.79–0.95) (14.4) 885 (26.7) No. (%) Eplerenone (n=3319) 554 (16.7) 993 (30.0) No. (%) Placebo (n=3313) Relative risk (95% CI) or ratio

21 21 Pitt B et al. N Engl J Med 2003;348: EPHESUS main results Deaths from any cause Deaths from CV cause or hospitalizations Sudden death from cardiac causes -15% -21% -13%

22 22 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS, continued - P Gynecomastia Serious hyperkalemia (serum potassium >6 mmol/L) Serious hypokalemia (serum potassium <3.5 mmol/L) Adverse events No. (0.5) (5.5) (8.4) <0.001 (%) Eplerenone (n=3307) No. (0.6) (3.9) (13.1) (%) Placebo (n=3301) Pitt et al.N Engl J Med 2003;348:1309–21.

23 23 EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - SUMMARY - In patients with acute myocardial infarction (MI) complicated by left ventricular dysfunction and heart failure, eplerenone: Reduced all-cause mortality, and reduced death or hospitalization due to cardiovascular events Had no effect on the incidence of gynecomastia Increased the incidence of serious hyperkalemia but decreased serious hypokalemia NEJM 2003

24 24 Post MI Heart failure with LVD Take-home messages 1.Clinical examination 2.X-ray 3.Cardiac ultrasound (ejection fraction) 4.BNP or NT-Pro BNP 5.Body weight 6.Blood pressure control 7.Repeat ionograms ( Na, K, …) 8.Kidney function 9.Use drugs at the right dosages 10.Eplerenone at top of standard treatment (EPHESUS)

25 Things we knew, things we did… Things we have learnt, things we should do Questions? ~ Answers! International Congress of Medicine for Everyday Practice

26 26 NT pro-BNP and heart failure <300 HF Probablilty LOW >75 yrs 50-75yrs <50 yrs ng/l HF and AGE G.Meune 2008

27 27 Weber K. N Engl J Med 2001;345: Compensated and Decompensated Heart Failure, as Indicated by the Presence or Absence of Urinary Sodium Retention, Together with Symptoms and Signs of Expanded Intravascular and Extravascular Volume


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