what do the antagonists of aldosteronereceptors have to...
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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
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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
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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)
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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
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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
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Optimize
What Is the Next Step?What Is the Next Step?
ACE inhibitor β-blocker+
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Choice of dose Choice of drug
What Is the Next Step?What Is the Next Step?
Optimize
ACE inhibitor β-blocker+
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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.
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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
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What Is the Next Step?What Is the Next Step?
Choice of dose Choice of drug
Optimize
ACE inhibitor β-blocker+
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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.
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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.
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What Is the Next Step?What Is the Next Step?
Add a third agent
ACE inhibitor β-blocker+
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Angiotensinreceptor blocker
Aldosteroneantagonist
What Is the Next Step?What Is the Next Step?
ACE inhibitor β-blocker+
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Val-HeFT
VALIANT
CHARM
What Is the Next Step?What Is the Next Step?
Angiotensinreceptor blocker
ACE inhibitor β-blocker+
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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.
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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.
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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.
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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
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EPHESUS
RALES
What Is the Next Step?What Is the Next Step?
Aldosteroneantagonist
ACE inhibitor β-blocker+
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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
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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.
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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.
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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
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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.
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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.
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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
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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.
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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
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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.
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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
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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
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What Is the Next Step?What Is the Next Step?
Angiotensinreceptor blocker
Aldosteroneantagonist
ACE inhibitor β-blocker+
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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
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What Is the Next Step?What Is the Next Step?
ACE inhibitor β-blocker+
Aldosteroneantagonist
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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.
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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?