what do the antagonists of aldosteronereceptors have to...

What do the antagonists of aldosteronereceptors

have to offer in the treatment of heart failure?

Director Cardiology Department, Director Cardiology Department, AsclepeionAsclepeion Hospital, Hospital, Athens,GreeceAthens,Greece

Adj. Assistant Professor, Hypertension and Atherosclerosis SectAdj. Assistant Professor, Hypertension and Atherosclerosis Section, ion,

Boston University Medical School, Boston, USABoston University Medical School, Boston, USA

Adj. Associate Professor of Cardiology, Emory University, AtlantAdj. Associate Professor of Cardiology, Emory University, Atlanta, USAa, USA

Athanasios J. ManolisAthanasios J. Manolis

Heart Failure: PathophysiologyHeart Failure: Pathophysiology

Neurohormonal AdaptationSympathetic nervous system

HRContractilityCO

COSystemic perfusionPulmonary pressurePulmonary congestion

Stimulation of RAA system

AngII, aldosterone

Na+ and H2O retentionEndothelial dysfunctionOrgan fibrosisLV dilatation and hypertrophyOxidative stressVascular remodelingImmune system activation

LVSD

Aims of Heart Failure Patient Aims of Heart Failure Patient ManagementManagement

• Alleviate symptoms• Improve quality of life• Delay disease progression• Prolong patient survival• Reduce sudden cardiac death• Minimise hospital admissions/hospital

care (costs)

Heart Failure Drug Treatment Options Heart Failure Drug Treatment Options

Symptom Relieving

• Diuretics• Digoxin

Disease Modifying

• ACE inhibitors /angiotensinII receptor antagonists

• Beta-blockers• Aldosteronereceptor

antagonists

Present Challenges in TreatmentPresent Challenges in TreatmentDespite use of ACE inhibitors + β-blockers

• Risk of death remains high (≥12% per year)

• Risk of death or cardiovascular

hospitalization remains high (≥25% per year)

• Risk of disability remains high

Optimize

What Is the Next Step?What Is the Next Step?

ACE inhibitor β-blocker+

Choice of dose Choice of drug

What Is the Next Step?What Is the Next Step?

Optimize

ACE inhibitor β-blocker+

Optimization of ACE InhibitionOptimization of ACE InhibitionATLAS TrialRandomized comparison of low dose(2.5 mg to 5 mg daily) and high-dose lisinopril(32.5 mg to 35 mg daily)

• 8% lower risk of death (P=0.128)• 15% lower risk of death or hospitalization

for heart failure (P=0.001)• Greater risk of hypotension, renal

insufficiency, and hyperkalemia with high dose

Packer M, et al. Circulation. 1999;100:2312-2318.

MortalityCardiovascularHospitalization

* †

‡

* **

CarvedilolBID CarvedilolBID

Effect of Different Doses of Effect of Different Doses of CarvedilolCarvedilolon Morbidity and Mortality (MOCHA)on Morbidity and Mortality (MOCHA)

Placebo

6.25 mg

12.5 mg

25 mg

16

12

8

4

0

0.4

0.3

0.2

0.1

0

Placebo

6.25 mg

12.5 mg

25 mg

Bristow MR, et al. Circulation. 1996;94:2807-2816.

*P<0.05 vs placebo†P=0.07 vs placebo‡P<0.001 vs placebo

*P=0.01

What Is the Next Step?What Is the Next Step?

Choice of dose Choice of drug

Optimize

ACE inhibitor β-blocker+

ACE Inhibitors vs Angiotensin ACE Inhibitors vs Angiotensin Receptor Blockers in Multicenter TrialsReceptor Blockers in Multicenter Trials

0.161.13(0.95,1.35)

280/1,578250/1,574ELITE II2(chronic HF)

0.071.13(0.99,1.28)

499/2,744447/2,733OPTIMAAL1

(post-MI CHF)

PValue

HazardRatioLosartanCaptopril

1.Dickstein K, et al. Lancet. 2002;360:752-760.2.Pitt B, et al. Lancet. 2000;355:1582-1587.

Optimization of Optimization of ββ--BlockadeBlockade

COMET TrialRandomized comparison of metoprolol(50 mg BID) and carvedilol(25 mg BID)

• 17% lower risk of death (P=0.0017)• 11% lower risk of death or

hospitalization for heart failure (P=0.02)

• Similar risk of adverse events

Poole-Wilson PA, et al. Lancet. 2003;362:7-13.

What Is the Next Step?What Is the Next Step?

Add a third agent

ACE inhibitor β-blocker+

Angiotensinreceptor blocker

Aldosteroneantagonist

What Is the Next Step?What Is the Next Step?

ACE inhibitor β-blocker+

Val-HeFT

VALIANT

CHARM

What Is the Next Step?What Is the Next Step?

Angiotensinreceptor blocker

ACE inhibitor β-blocker+

ValVal--HeFTHeFT: ARBs Added to ACE Inhibitors: ARBs Added to ACE Inhibitors

Months

Even

t-fre

e su

rviv

al (%

)

100

0 6 12 18 24

70

80

90 Valsartan

P=0.80

6 12 18 240

Valsartan

100

90

80

70

60Placebo

P=0.009

Months

All-Cause Mortality Death or CHF Hospitalization

↓ 13%Placebo

Cohn JN, et al. N Engl J Med. 2001;345:1667-1675.

Alternative

Added

Preserved

Overall

0.7 0.8 0.9 1.0 1.1 1.2

Hazard ratio

HR=0.89 (0.77-1.02) P=0.086

HR=0.91 (0.83-1.00) P=0.055

CHARM Program: CHARM Program: AllAll--Cause MortalityCause Mortality

PfefferMA, et al. Lancet. 2003;362:759-766.

0 1 2 3Years

0

10

20

30

40

50

Placebo

Candesartan

HR 0.85 (95% CI 0.75-0.96), P=0.011

%

CHARMCHARM--Added: Added: Cardiovascular Cardiovascular DDeatheath or Hospitalization for CHFor Hospitalization for CHF

McMurray JJV, et al. Lancet. 2003;362:767-771.

Hypertrophy, apoptosis, ischemia,arrhythmias, remodeling, fibrosis

Angiotensin II Norepinephrine

Aldosterone

The Pathophysiology of Heart Failure The Pathophysiology of Heart Failure Results from Neurohormonal ActivationResults from Neurohormonal Activation

EPHESUS

RALES

What Is the Next Step?What Is the Next Step?

Aldosteroneantagonist

ACE inhibitor β-blocker+

RRandomized andomized AlAldactonedactone EEvavalluation uation SStudy : Study Designtudy : Study Design

NYHA III or IV heart failureLVEF ≤ 35%

ACEI + loop diuretic ± digoxin

Placebo(n=841)

Spironolactone25-50 mg/day

(n=822)

Primary Endpointl All-cause mortalitySecondary Endpointsl Cardiac mortalityl Cardiac hospitalisationl Cardiac mortality or cardiac hospitalisationl Changes from baseline in NYHA classification

3 years

Pitt B et al, N EnglJ Med 1999; 341: 709-717

RALES: AllRALES: All--Cause MortalityCause Mortality1.00

0.90

0.80

0.70

0.60

0.50

0.400 6 12 18 24 30 36

Placebo

Spironolactone

Surv

ival

(%)

Months

RR=0.70 (0.60-0.82) P<0.001

Pitt B, et al. N Engl J Med. 2003;341:709-717.

RALES: Cardiovascular Mortality or RALES: Cardiovascular Mortality or Cardiovascular HospitalizationCardiovascular Hospitalization

1.00

0.90

0.80

0.70

0.60

0.50

0.40

Months

RR=0.68 (0.59-0.78) P<0.001

Placebo

Spironolactone

Surv

ival

(%)

0 6 12 18 24 30 363 9 15 21 27 33

Pitt B, et al. N Engl J Med. 2003;341:709-717.

Primary End Points: •All-cause mortality•CV mortality/CV hospitalisation*

Secondary End Points: •CV mortality•All-cause mortality/all-cause hospitalisations•CV hospitalisations

Placebon = 3313

1012 Deaths

Randomise3–14 Days Post–AMI

Eplerenone 25–50 mg od

n = 3319

AMI, LVEF ≤ 40%, Clinical HF, Standard Therapy

Study DesignStudy Design

*CV hospitalisation= hospitalisationfor heart failure, MI, stroke, or ventricular arrhythmiaPitt B et al. CardiovascDrugs and Therapy 2001; 15: 79-87

EPHESUS

Months since randomization

Cum

ulat

ive

inci

denc

e (%

)22

00 36

2

20

16

18

14

12

10

8

6

4

3 6 9 12 15 18 21 24 27 30 33

Eplerenone

Placebo

RR=0.85 (0.75-0.96) P=0.008

EPHESUS: AllEPHESUS: All--Cause MortalityCause Mortality

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

EPHESUS: Combined Risk of Cardiovascular EPHESUS: Combined Risk of Cardiovascular Mortality or Cardiovascular HospitalizationMortality or Cardiovascular Hospitalization

40

0

35

25

30

20

15

10

5

0 363 6 9 12 15 18 21 24 27 30 33

RR=0.87 (0.79-0.95)P=0.002

Eplerenone

Placebo

Cum

ulat

ive

inci

denc

e (%

)

Months since randomization

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

AllAll--Cause Mortality Subgroup AnalysisCause Mortality Subgroup Analysis

.1 .3.2 .4.5.6.7.8.9 1.11.0 1.2 1.51.31.4 1.61.71.8

Eplerenone Better Placebo Better

Total mortalityGender

FemaleMedian age ≤65 yr

>65 yrMedian pulse pressure <45 mmHg

≥45 mmHgMedian serum potassium <4 mmol/L

≥4 mmol/LMedian serum creatinine <96 µmol/L

≥96 µmol/LHistory of diabetes No history

Any type of diabetesHistory of hypertension No

YesMedian ejection fraction before randomisation

<35%≥35%

Reperfusion within 14 days of index AMI NoYes

Use of diuretics NoYes

Male P = 0.44

P = 0.23

P = 0.01*

P = 0.29

P = 0.03*

P = 0.35

P = 0.05

P = 0.25

P = 0.62

P = 0.34

Use of potassium supplements NoYes P = 0.71

*Statistically significant

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

EPHESUS

Objective: To assess the impact of eplerenone on mortality 30 days after randomization in patients after acute myocardial infarction (AMI) with a left ventricular ejection fraction (LVEF) ≤40%and clinical signs of heart failure (HF)

EPHESUSEPHESUSTMTM: 30: 30--Day AnalysisDay Analysis

Pitt B, White H, NicolauJ, et al. J Am CollCardiol. 2005;46:425-431.

Why Are 30Why Are 30--day Mortality day Mortality Data Important?Data Important?

Rate of Sudden Cardiac Death Post-MI

0

0.3

0.6

0.9

1.2

1.5

First 30 days >1-6 mo >6-12 mo >1-2 y >2-3 y

Adapted from Solomon SD, Zelenkofske S, McMurray JJV, et al. N EnglJ Med. 2005;352:2581-2588.

Study of 14,609 patients with LVD, HF, or both after MI to assess the timing of sudden cardiac death, using the VALIANT database.

Even

t Rat

e

Days/Months From Randomization

EPHESUSEPHESUSTMTM: All: All--Cause MortalityCause Mortalityat 30 Days Postat 30 Days Post--RandomizationRandomization

• Risk reduction in all-cause mortality seemed to occur as early as 10 days post-randomization

543210

RR=0.69 (95% CI, 0.54-0.89)

All-Cause Mortality (Primary End Point)C

umul

ativ

e In

cide

nce

(%)

Placebo + standard therapies (n=3313)

Eplerenone + standard therapies (n=3319)

31%reduction

Days From Randomization

0 10 20 30

P=.004

Pitt B, White H, NicolauJ, et al. J Am CollCardiol. 2005;46:425-431.

EPHESUSEPHESUSTMTM: Sudden Cardiac Death: Sudden Cardiac Deathat 30 Days Postat 30 Days Post--RandomizationRandomization

RR=0.63 (95% CI, 0.40-

1.00)

Sudden Cardiac Death (Secondary End Point)

Placebo + standard therapies (n=3313)

Eplerenone + standard therapies (n=3319)

37%reduction

5

4

3

2

1

0

Cum

ulat

ive

Inci

denc

e (%

)

0 10 20 30

P=.051

Pitt B, White H, NicolauJ, et al. J Am CollCardiol. 2005;46:425-431.

Days From Randomization

Aldosterone AntagonismAldosterone AntagonismEPHESUS and RALES TrialsPlacebo vs eplerenone or spironolactoneadded to ACE inhibitor and β-blocker in post-MI CHF or class III-IV heart failure

• 15% to 30% lower risk of death (P<0.01)• 15% to 30% lower risk of death or

hospitalization for heart failure in both trials, both P<0.001

• Higher risk of renal insufficiency and hyperkalemia

What Is the Next Step?What Is the Next Step?

Angiotensinreceptor blocker

Aldosteroneantagonist

ACE inhibitor β-blocker+

Should an Aldosterone Antagonist Be the Should an Aldosterone Antagonist Be the Next Step After ACE Inhibitor + Next Step After ACE Inhibitor + ββ--Blocker?Blocker?

Renal insufficiency Hyperkalemia

Renal insufficiency Hyperkalemia

Other safety

DecreaseNo changeEffect on blood pressure

10%-15%15%-30%Effect on risk of death or CHF hospitalization

5%-10%15%-30%Effect on mortality

Angiotensin Receptor Blocker

Aldosterone Antagonist

What Is the Next Step?What Is the Next Step?

ACE inhibitor β-blocker+

Aldosteroneantagonist

ESC GUIDELINES FOR HEART FAILURE ESC GUIDELINES FOR HEART FAILURE (UPDATE 2005)(UPDATE 2005)

• Aldosteroneantagonists such as eplerenoneare recommended in addition to ACEiand β-blockers in post-MI LV dysfunction with or without symptoms of HF (level of evidence IB).

• Check serum potassium <5 and creatinine<2.5. Add low dose Eplerenone25 mg. After 4-6 days if potassium is 5-5.5 reduce dose 50%. If potassium > 5.5 stop the drug. If symptoms persists and normokalaemiaexists after one month, increase to 50 mg daily. Check biochemicsafter one week.

PostPost--MI LV MI LV DysfunctionDysfunction: Current : Current therapeutic strategiestherapeutic strategies

• ACE inhibitors (SAVE, AIRE, TRADE)• Carvedilol (CAPRICORN)• ARBs alternatively to ACEi (VALIANT)• Eplerenone (EPHESUS)

- Statins- Aspirine- Nitrates?