Things we knew, things we did… Things we have learnt, things we should do Alain Wajman M.D.,...

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

Heart Failure

Disease with the highest prevalence in the next decade

50% of elderly (age 70 - 80) 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 Jessup M and Brozena S. N Engl J Med 2003;348:2007-2018

Ventricular REMODELINGAfter Acute Infarction

4

Neurohormonal changes: VC > VD

Vasoconstriction:1.Noradrenaline2.Renin Angiotensine System3.Endothelin4.Arginin Vasopressin5.Cytokines

Vasoconstriction:1.Noradrenaline2.Renin Angiotensine System3.Endothelin4.Arginin Vasopressin5.Cytokines

Vasodilation /Antiproliferative substances:1.Natriuretic peptides2.Bradykinines 3.NO4.Adrenomedulline

Vasodilation /Antiproliferative substances:1.Natriuretic peptides2.Bradykinines 3.NO4.Adrenomedulline

5 Jessup M and Brozena S. N Engl J Med 2003;348:2007-2018

Targets for Heart Failure Treatment

•Diuretics•ACE I, AIIRAs•Beta-blockers•Anti-aldosterone

AntiarrhytmicsCCBsAIIRAsAntiplateletsAnticoagulantsStatins?

6Jessup M and Brozena S. N Engl J Med 2003;348:2007-2018

Severity of Systolic Heart Failure And Therapeutic Options

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Diuretics in Post MI HF with LVD

• Always mandatory, ++++ if congestion • Natriuretics • Furosemide: 40-60 mg IV, 40 to 250

mg/d• Renal vasodilation• Hyponatremia• Hypokalemia • Alkalosis • Hyperuricemia • Hypertriglyceridemia

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

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

10Weber K. N Engl J Med 2001;345:1689-1697

The Renin-Angiotensin-Aldosterone System

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

12Ernst M and Moser M. N Engl J Med 2009;361:2153-2164

Sites of Diuretic Action in the Nephron

13

Weber K. N Engl J Med 2001;345:1689-1697

Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth-Muscle Cells in an Intramyocardial Coronary Artery

14

Weber K. N Engl J Med 2001;345:1689-1697

Coronary Vascular Remodelling

in Hyperaldosteronism in Rats

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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 failureReference

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.

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EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

- TRIAL DESIGN -

DesignMulticentre, multinational, randomized, double-blind, placebo-controlled

Patients6632 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 endpointsPrimary endpoints: all-cause mortality; death from cardiovascular cause or first hospitalization for cardiovascular event. Mean 16 months follow-up.

TreatmentPlacebo or eplerenone titrated to target dose 50 mg daily

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EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

Age (years)a

Male (%)

HistoryLeft ventricular ejection fraction (%)a

Days from MI to randomizationa

Symptoms of heart failure

MedicationsACE inhibitor or angiotensin-receptor blockerBeta-blockersDiureticsAspirinStatins

Baseline characteristics

64

70

337.390

8775618947

Placebo(n=3313)

64

72

337.390

8675608847

Eplerenone(n=3319)

Pitt et al. N Engl J Med 2003;348:1309–21.a Mean

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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

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EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

- RESULTS, continued -

Months after randomization

Cumulativeincidence

(%)

00

6 12 18 24 30 36

40

30

20

10

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

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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 endpointsAll-cause mortalityCardiovascular death or

hospitalization forcardiovascular events

Secondary endpoints (No.)Hospitalization for cardiovascular events

Acute MIHeart failureStrokeVentricular arrhythmia

0.85 (0.75–0.96)0.87 (0.79–0.95)

0.0080.002

0.03

0.960.0020.110.69

478 (14.4)885 (26.7)

No. (%)

Eplerenone(n=3319)

554 (16.7)993 (30.0)

1004

2696185463

876

2684777358

0.87

0.990.771.350.92

No. (%)

Placebo(n=3313)

Relative risk(95% CI)or ratio

21

Pitt B et al. N Engl J Med 2003;348:1309-1321

EPHESUS main results

Deaths from any cause

Deaths from CV cause or hospitalizations

Sudden death from cardiac causes

-15%

-21%

-13%

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

12

180

273

No.

(0.5)

(5.5)

(8.4)

0.70

0.002

<0.001

(%)

Eplerenone(n=3307)

14

126

424

No.

(0.6)

(3.9)

(13.1)

(%)

Placebo(n=3301)

Pitt et al. N Engl J Med 2003;348:1309–21.

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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

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Post MI Heart failure with LVD Take-home messages

1. Clinical examination 2. X-ray3. Cardiac ultrasound (ejection fraction)4. BNP or NT-Pro BNP5. Body weight 6. Blood pressure control7. Repeat ionograms ( Na, K, …) 8. Kidney function 9. Use drugs at the “right dosages”10.Eplerenone at top of standard treatment

(EPHESUS)

Things we knew, things we did… Things we have learnt, things we should do

Questions? ~ Answers!

International Congress of Medicine for Everyday Practice

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NT pro-BNP and heart failure

<300

HF ProbabliltyLOW

1800900450

>75 yrs50-75yrs<50 yrs

ng/l

HF and AGE

G.Meune 2008

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Weber K. N Engl J Med 2001;345:1689-1697

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