Transcript Management of heart Failure

Management of
Chronic Heart Failure
DR.SAMEER AMBAR
DEPT OF CARDIOLOGY
JNMC BELGAUM, INDIA
[email protected]
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Asses the functional class
BP <130/80 mm of Hg
Good glycaemic control
LIPIDS LDL < 100 (IHD) <70 (DM)
Avoid smoking, alcohol
Sodium restriction <2gms /day
Fluid restriction ,2 Litres/day
ACEI
MECHANISM OF ACTION
VASOCONSTRICTION
VASODILATATION
ALDOSTERONE
PROSTAGLANDINS
VASOPRESSIN
tPA
Kininogen
SYMPATHETIC
Kallikrein
Angiotensinogen
RENIN
Angiotensin I
A.C.E.
ANGIOTENSIN II
Inhibitor
BRADYKININ
Kininase II
Inactive Fragments
ACEI IN POST MI HF
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SAVE (NEJM 1992 327:669-677)
2231 pts EF<40%, 3-16d post MI, without sx of heart
failure,
Up to 50 mg Captopril tid for 42 mo
AIRE (Lancet 1993:342:821)
2006 patients 3-10 days post MI with any evidence of
post infarct clinical HF,
Up to 5 mg Ramipril bid for 15 mos
TRACE (NEJM 1995; 333: 1670-1676)
1749 pts 3-7 days post MI with EF<=35%, with or
without symptomatic HF
trandolapril for 24-50 mos
Mortality
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SAVE: 25% (placebo) vs 20% (captopril) - 19% RRR
AIRE: 23% (placebo) vs 17% (ramipril) - 27% RRR
TRACE: 42.3% (placebo) vs 34.7% (trandolapril)- 24% RRR
HFSA 2006 Practice Guideline (7.10)
Pharmacologic Therapy:
Angiotensin Receptor Blockers
ARBs are recommended for routine
administration to symptomatic and
asymptomatic patients with an
LVEF  40% who are intolerant to
ACE inhibitors for reasons other than
hyperkalemia or renal insufficiency.
Strength of Evidence = A
Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive
Heart Failure Guideline. J Card Fail 2006;12:e1-e122.
ARBs Clinical Study:
1.Elite-II. Study:
Enrolled Target: CHF P’t
Drug: losartan v.s. captopril
Primary Endpoint:CHF Improvement
Result: losartan is not better than captopril
2.Va-HeFT Study:
Enrolled Target: CHF P’t
Drug: valsartan + Usual Group v.s. Usual Group
Primary Endpoint: CHF Event-Free Probability
Result: Reduce M/M by 13.3%
CHARM-Alternative
Primary outcome of CV death or CHF hospitalization
Proportion With CV Death
or CHF Hospitalization (%)
50
406 (40.0%)
Placebo
40
334 (33.0%)
30
Candesartan
20
10
HR 0.77 (95% CI 0.67-0.89), P=.0004
Adjusted HR 0.70, P<.0001
0
0
Number at risk
Candesartan
Placebo
1
2
3
3.5
Years
1,013
1,015
929
887
Granger CB, et al. Lancet. 2003;362:772-776.
831
798
434
427
122
126
CHARM Added Trial
CV Mortality
CV Mortality or
CHF hospitalization
50%
50%
HR 0.84
p=0.02
HR 0.85
p=0.011
30%
42.3%
42.3%
40%
40%
27.3%
23.7%
37.9%
37.9%
20%
30%
30%
20%
20%
10%
10%
10%
0%
0%
Candesartan
Candesartan
www. Clinical trial results.org
Placebo
Placebo
0%
55% on BB
Candesartan
Placebo
European
European Society
Society of
of Cardiology
Cardiology 2003
2003
When to use Angiotensin receptor blockers
1. There has been no definite mortality or
morbility advantage of ARBs over ACE
inhibitors demonstrated
2. Consider ARB in patient who is ACE inhibitor
eligible if the patient is intolerant of ACE
inhibitors because of cough, renal insufficiency,
or hyperkalemia
When to use Angiotensin receptor blockers
3. In the patient who is apparently ACE inhibitor
intolerant, rule out other causes of presumed side effect:
a. Cough-evaluate for pulmonary edema
b. Hyperkalemia-concurrent potassium supplementation,
potassium-sparing diuretic use
c. renal insufficiency-evaluate for prerenal azotemia,
NSAID use
4. The incidence of cough and hyperkalemia is lower with
ARBs versus ACE inhibitors
There does not appear to be a significant difference in
incidence of renal insufficiency
Beta blockade in Heart failure
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Beta receptor levels in heart failure
 Normal
Heart
 Severe Heart Failure
B1 80 : B2 20
B1 60 : B2 40
B1 receptors to selectively down-regulate secondary to
high levels of catecholamine
 B2 agonists retain full inotropic activity mediated through
a B2 population that is not significantly decreased
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Effect of Sympathetic
Activation in Heart Failure
CNS Sympathetic Outflow
Cardiac sympathetic Activity
1
Receptors
2
Receptors
Sympathetic activity to
kidneys & blood vessels
1
Receptors
Myocyte death
Increased arrhythmias
Disease Progression
Activation
of RAS
Vasoconstriction
Sodium retention
Benefit Of Beta Blockers
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Improve symptoms and clinical status
Increase LV ejection fraction
Little effect on exercise tolerance
Reduce frequency of hospitalizations for heart
failure
Decrease mortality
Action
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Time dependant improvement in LV
remodelling
Reduce cetecholamine myocyte toxicity
Improved B1 signaling
Antiapoptosis
antiarrthymic
RAAS inhibition
Sympathetic Activation
B1
Receptors
B2
Receptors
A1
Receptors
Metoprolol
Propranolol
Cardiotoxicity
Carvedilol
Clinical Trials
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Prospective Randomized Evaluation of Carvedilol on Symptoms and
Exercise (PRECISE)
 278 patients with chronic stable symptomatic heart failure
EF<35% despite diuretics and ACE
 Carvedilol group was associated with greater improvement in
NYHA Class
 39% reduction in combined risk of death/hospitalization for any
reason
 46% reduction in risk of hospitalization for cardiovascular
reason
Circulation 1996;94:2793-2799
Clinical Trials
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Merit-HF Trial( metaprolol randomised
interventional trial in CHF)
 3991 patients with an ischemic or
nonischemic cardiomyopathy (NYHA Class
II or III) randomized to either Metoprolol XL
up to 200mg/day or placebo.
 Metoprolol XL was associated with a 35%
reduction in mortality
Amer J Cardiol 1997;80:54J-58J
MERIT-HF
METOPROL-XL: Mortality and Morbidity
MERIT-HF Study Group. Lancet. 1999;353:2001-2007
MERIT-HF
Post-MI Patients with
Severe Heart Failure (n= 384)
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NYHA III/IV
EF <0.25
Jánosi A et al, Am Heart J 2003;146:721-8
MERIT-HF
Post-MI Patients
Total Mortality
20
Placebo
15
p = 0.0004
Metoprolol CR/XL
10
5
Risk reduction = 40%
0
0
3
6
9
12
Months of follow-up
15
18
Jánosi A et al, Am Heart J 2003;146:721-8
MERIT-HF
Post-MI Patients
Sudden Death
12
Placebo
9
p = 0.0004
6
Metoprolol CR/XL
3
Risk reduction = 50%
0
0
3
6
9
12
Months of follow-up
15
18
Jánosi A et al, Am Heart J 2003;146:721-8
MERIT-HF
Post-MI Patients
Death from Worsening Heart Failure
5
Placebo
4
p = 0.021
3
Metoprolol CR/XL
2
Risk reduction = 49%
1
0
0
3
6
9
12
Months of follow-up
15
18
Jánosi A et al, Am Heart J 2003;146:721-8
MERIT-HF
Post-MI Patients
Total Number of Hospitalizations
600
Placebo
Metoprolol CR/XL
400
200
0
All-cause
-8%
ns
CV cause
-17%
Heart failure
-32%
p=0.037
p=0.006
Jánosi A et al, Am Heart J 2003;146:721-8
MERIT-HF
Post-MI Patients
Total mortality
Risk
reduction
Events
Plac/Beta
All Post-MI patients
122/74
Post-MI severe CHF
History of revasc.
44/24
40%
37/26
(PTCA or CABG)
Cardiac death/nonfatal MI
All Post-MI patients
Post-MI severe CHF
History of revasc.
(PTCA or CABG)
45%
132/74
46/22
42/27
0.0
1.0
Relative risk and 95% CI
Jánosi A et al, Am Heart J 2003;146:721-8
MERIT-HF
Effect of metoprolol and placebo treatment on
survival and hospitalization risk in class III and IV
HF
Endpoint
Metoprolol
(N)
Placebo
(N)
Risk
reduction
(%)
p value
Total mortality
45
72
39%
0.0086
CV mortality
40
70
44%
0.0028
Sudden death
22
39
45%
0.024
Death from worsening HF
13
28
55%
0.015
Total hospitalizations
273
363
27%
0.0037
Total hospitalizations due to
worsening HF
105
187
45%
<0.0001
Goldstein S et al. J Am Coll Cardiol 2001; 38(4):932-8
MERIT-HF
Comparison of findings in subanalysis
and entire MERIT-HF cohort
Endpoint
Reductions in
entire MERIT-HF
cohort
Reductions in class
III and IV MERITHF subset
Total mortality
-34%
-39%
Sudden death
-41%
-45%
Death due to worsening HF
-49%
-55%
Goldstein S et al. J Am Coll Cardiol 2001; 38(4):932-8
MERIT-HF
Post-MI Patients
Summary
Mortality/Hospitalizations
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40% reduction in Total Mortality
50% reduction in Sudden Death
32% reduction in number of hospitalizations for
Worsening Heart Failure
Jánosi A et al, Am Heart J 2003;146:721-8
Carvedilol Prospective Randomized
Cumulative Survival Trial
(COPERNICUS)
• Enrolled 2289 patients with severe HF (LVEF <25%)
• Randomized to carvedilol in a target dose of 25 mg bid for up to
29 months
35% reduction in the risk of all-cause mortality among
patients with severe congestive heart failure (CHF) treated
with carvedilol compared to placebo
COPERNICUS and
CAPRICORN
COPERNICUS: Effect of carvedilol on the
combined risk of morbidity and mortality
Endpoint
Relative risk
reduction
Odds ratio
p value
Death or
hospitalization for
any reason
24%
0.76
0.00004
Death or
hospitalization for a
CV reason
27%
0.73
0.00002
Death or
hospitalization for
HF
31%
0.69
0.000004
Beta Blockers
Post MI LV dysfunction
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CAPRICORN( carvedilol post infarct
survival control in LVD)
1959 pts post MI LVEF<40%
 Randomized to carvedilol or placebo
 Results:
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Lower all cause mortality (12% vs. 15%)
 Lower non-fatal MI
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Lancet 2001; 357: 1385–90
CAPRICORN All-Cause Mortality
Carvedilol Post-Infarct Survival Control in LV Dysfunction
1.00
Carvedilol n=975
Proportion Event-free
0.90
0.80
Placebo n=984
Risk reduction
23%
0.70
(2%, 40%)
0.60
Mortality Rates: Placebo 15%; Carvedilol 12%
0
0
0.5
1
1.5
Years
The CAPRICORN Investigators. Lancet. 2001;357:1385-1390.
2
2.5
Clinical Use Of Beta Blockers
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Recommended for patients with NYHA class II-IV
General contraindications:
 Decompensated heart failure
 Severe claudication
 Bronchospasm
 Advanced heart block
 Use with caution if patient requires inotropes for
support of circulatory function
Beta-Blockade
Cardiac Output
Renal
Blood Flow
Sodium
Retention
Worsening
Heart Failure
Considerations in selecting a betablocker
1.
2.
3.
Patients should be clinically stable and
euvolemic before initiating beta-blocker
therapy
Start at low doses and titrate upward gradually
(doubling every 2-4 weeks)
Patients may experience an initial exacerbation
of heart failure symptoms because of
transient worsening of cardiac output
Clinical Use Cont . . .
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Clinical response may not be seen until 2 to 3
months after initiation of therapy
Abrupt withdrawal can lead to dramatic
deterioration
Patient education paramount
Outcome in Post-MI Patients with Heart Failure
CAPRICORN and MERIT-HF
pvalue
Plac/Beta
Risk
reduction
CAPRICORN
151/116
23%
p=0.03
MERIT-HF
122/74
40%
p=0.0004
All-cause mortality
Carvedilol 1 2 (1)
Metoprolol CR/XL 1
All-cause mortality/CV hosp.1
CAPRICORN
367/340
8%
ns
MERIT-HF
326/258
22%
p=0.002
Carvedilol 1 2 (1)
Metoprolol CR/XL 1
0.0
1.0
Relative risk and 95% CI
1Time
to first event
The CAPRICORN Investigators, Lancet 2001;357:1385-90
Jánosi A et al, Am Heart J 2003;146:721-8
LVEF: Change From Baseline
Within Treatment-arm Comparison
5
Carvedilol &
Enalapril
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Enalapril
***
4
 LVEF (%)
Carvedilol
***
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**
3
*
2
1
0
-1
M6
M12
M18
* P < 0.05; ** P < 0.01; *** P < 0.001
M6
M12 M18
M6
M12
M18
Diuretics
Diuretics
HFSA 2006 Practice Guideline (7.14-7.15)
Pharmacologic Therapy:
Aldosterone Antagonists
An aldosterone antagonist is recommended for
patients on standard therapy, including diuretics,
who have:
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NYHA class IV HF (or class III, previously class IV)
due to LV systolic dysfunction (LVEF  35%)
One should be considered in patients post-MI
with clinical HF or diabetes and an LVEF < 40%
who are on standard therapy, including an ACE
inhibitor or an ARB.
Strength of Evidence = A
Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive
Heart Failure Guideline. J Card Fail 2006;12:e1-e122.
RALES(randomised aldactone
evaluation study)
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1663 patients Class
3-4 CHF, LVEF<35%
on ACEinhibitor/diuretic/dig
randomized to 25
mg spironolactone
vs. placebo
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issues:
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only 10% of
patients on beta
blockers
NEJM 1999:341:709-17
RALES
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Results: 46% mortality
placebo vs 35%
spironolactone (30%
RRR)
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adverse effects:
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10% of pts in
spironolactone group
developed gynecomastia.
-serious hyperkalemia
(K>6) 14% vs 10% (not
statist sig)
EPHESUS(eplerenone post AMI
HF efficacy and survival study)
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6642 patients:
a) 3-14 days post MI,
b) EF<40,
c) CHF (rales, pulm venous congestion
seen on CXR, 3rd heart sound) OR
Diabetes
randomized to 25 mg eplerenone titrated
up to 50 mg po qd
NEJM 2003;348:1309-21
EPHESUS
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Results:
 One year mortality: 15% risk reduction (11.8% vs 13.6%)
 CV death or cardiovascular hospitalizations (26% vs
30.0%)
(75% of patients on beta blockers)
adverse effects:
 serious hyperkalemia (K>6) Epler- 5.5% vs plac- 3.9%
(p=.002)
 serious hypokalemia (K<3.5) Epler- 8.4% plac- 13.1%
(p<.001)
 gynecomastia- 0.5% vs 0.6%
Criteria for treatment with spironolactone
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New York heart Association class 3-4
Left ventricular ejection fraction <35%
Serum creatinine <2.5 mg/dL
Serum potassium <5 mmol/L
Baseline treatment with ACE inhibitor (or other
vasodilator if ACE inhibitor intolerance), loop
diuretic, and digoxin as indicated
Digoxin
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Digoxin has a significant role in improving
symptoms and rehospitalization rate
No impact on the total and cardiovascular
mortality
Usually used only in severe CHF or in patients
who remain symptomatic with optimal
treatment
Digoxin is useful in CHF with atrial fibrillation
Digoxin
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DIG trial
6800 pts EF <45%
0.25 mg/day
22% reduction in hospitalisation
No mortlity benefit
28% RRR of death in post hoc analysis
Nesiritide
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Identical to human BNP
Causing vasodilation and decrease LV filling
pressure
Decrease pulmonary capillary wedge pressure
Improves patients’ symptoms
Improvement in hemodynamics VMAC trial 5.8
mm of hg decrease on PCW
Nesiritide
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2 mcg/kg bolus infusion 0.01-0.03 mcg/kg/min
for 3 hrs
Improved safety profile compared with
dobutamine with fewer arrhythmias and better
outcomes
It should not be used in patients who are
overdiuresed, hypotensive, or present with other
signs of inadequate perfusion -Worsening of renal
failure (45%)
Inotropes
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Inotropes: direct adrenergic agonists,
phosphodiesterase inhibitors, and dopaminergic
agonists
Inotropes improve short term hemodynamics,
they do not improve and in several cases may
worsen long-term survival
Oral inotropic agents have resulted in excess
mortality in patients with HF
Amiodarone
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Antiarrhythmic effect
Low dose amiodarone was safe and significantly
reduced 2-year mortality (33.5% vs 41.4%, p=0.02)
in patients with moderate to severe HF (GESICA
trial)
Another trial did not demonstrate mortality
benefit, either all-cause or sudden death
Anticoagulation
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LVEF < 30%
LV thrombus
Atrial fibrillation
INR 2-3
Thank you