Transcript Managing congestive heart failure

MANAGING
CONGESTIVE HEART FAILURE
Annual Conference of the Lebanese Society of Family Medicine
Antoine Sarkis, MD
Associate Professor of Cardiology
Hotel Dieu de France Hospital
Guidelines




ESC 2005
HFSA 2006
CCS 2006
ACC/AHA 2005
NYHA
Classification
Four stage classification
Hypertension
Diabetes, Hyperchol.
Family Hx
Cardiotoxins
A
Heart disease
(any)
B
Stages in the Evolution
of Heart Failure.
Clinical Characteristics
Asymptomatic
LV dysfunction
Systolic / Diastolic
C
Dyspnea, Fatigue
Reduced exercise
Tolerance (current or past)
AHA / ACC HF guidelines 2001
D
Marked symptoms
at rest despite
max. therapy
Classification of Recommendation


Class I: General agreement or evidence that a
therapy is beneficial
►(therapy is recommended)
Class II: Conflicting evidence
IIa: evidence in favor of efficacy
►( therapy should be considered)
 IIb: evidence less well established
►( therapy may be considered)


Class III: Not recommended, may be harmful
Level of evidence



Level A: multiple randomized clinical trials or
meta-analysis
Level B: single randomized trial, or non
randomized studies
Level C: Consensus opinion of experts
Treatment Objectives
Mainly decrease symptoms and prolong life
 But also:

 Decrease
morbidity (hospital admissions,
embolism…)
 Increase exercise capacity and improve quality of
life
 Control neurohormonal changes
 Retard progression of CHF
Treatment of CHF
•
•
•
•
Selected patients
All
•
•
•
•
•
•
•
Control of risk factors
Life style
Treat etiologic cause / aggravating factors
Drug therapy
Revascularization
ICD (Implantable Cardiac Defibrillator)
Ventricular resynchronization (CRT)
Ventricular assist devices
Heart transplant
Artificial heart
Neoangiogenesis, Gene therapy
Correction of reversible causes
 Ischaemia
 Valvular
heart disease
 Thyrotoxicosis and other high output status
 Shunts
 Arrhythmia
 Atrial
fibrillation, flutter,
 Medications
 Ca
channel blockers, some antiarrhythmics
Pharmacologic Therapy
Diuretics
 ACE inhibitors
 Beta Blockers
 ARBs




Digitalis
Spironolactone
Other
Diuretics. Indications
Symptomatic HF, with fluid retention
• Peripheral edema
• Dyspnea/ Pulmonary edema (Xray)
• Jugular distension
• Hepatomegaly
AHA / ACC HF guidelines 2005
ESC HF guidelines 2005
Adverse Effects of Diuretics.
•
K+, Mg+ (15 - 60%) (sudden death ???)
•
Na+
• Hyperuricemia (15 - 40%)
• Stimulation of neurohormonal activity
• Hypotension. Pre-renal azotemia, Ototoxicity,
Gastrointestinal, Metabolic Alkalosis.
• Skin rashes, Neutropenia, Thrombocytopenia
Inhibitors of renin-angiotensinaldosterone system
 Renin-angiotensin-aldosterone
system is
activated early in the course of heart failure and
plays an important role in the progression of the
syndrome
RAAS
Blockade
Angiotensin
Converting
Enzyme Inhibitors
Angiotensin
Receptor
Blockers
(ACE-I)
(ARB)
ACE-I. Clinical Effects in CHF
• Improve symptoms
• Reduce remodeling / progression
• Reduce hospitalization
• Improve survival
CONSENSUS
N Engl J Med 1987;316:1429
ACE-I
0.8
0.7
Placebo
0.6
Probability of
Death
p< 0.001
0.5
0.4
p< 0.002
0.3
253 patients
NYHA IV
Enalapril
0.2
31 %
0.1
0
0
1
2
3
4
5
6
7
Months
8
9
10 11 12
SOLVD (Treatment)
N Engl J M 1991;325:293
ACE-I
50
p = 0.0036
Placebo
n=1284
40
% Mortality
30
Enalapril
n=1285
20
N = 2589 CHF
- NYHA II-III
- EF < 35 %
10
0
0
6
12
18
24
30
Months
36
42
48
SAVE
N Engl J Med 1992;327:669
ACE-I
30
Asymptomatic
ventricular
dysfunction post MI
Placebo
n=1116
Mortality % 20
Captopril
n=1115
N = 2231
3 - 16 days post AMI
EF < 40 %
12.5 --- 150 mg / day
10
² -19%
p=0.019
0
0
1
2
Years
3
4
AIRE
Lancet 1993;342:821
ACE-I
Placebo
30
Mortality % 20
Ramipril
10
N = 2006
HF after AMI
p = 0.002
0
0
6
12
18
Months
24
30
ACE-I Indications



Symptomatic heart failure (stage C)
Asymptomatic ventricular dysfunction
 LVEF <35-40 % (stage B)
Patients with recent or remote history of MI
regardless of EF or presence of HF (stage B)
AHA / ACC HF guidelines
ESC HF guidelines
Class I recommendation
Level of evidence A
ACE-I. Practical Use

Start with very low dose

Renal function & serum K+ after 1-2 w
In the absence of fluid retention, ACE-I should be
given first / In the presence of fluid retention
together with diuretics

Dose NOT determined by symptoms. ACE-I
should be up-titrated to dosages shown to be
effective in clinical trials

ACE-I. Adverse Effects
• Hypotension (1st dose effect)
• Worsening renal function, Hyperkalemia
• Cough
• Angioedema
• Rash, ageusia, neutropenia, …
• Pregnancy is a contra indication
Angiotensin Receptor
Blockers (ARBs) in
Heart Failure
Substitute or adjunctive therapy
to ACE inhibitors ?
Potential advantages of ARBs
• ARBs more effective than ACE-I due to:
- Better RAAS Blockade
- Absence of angiotensin II escape
- Placebo like side effects
Event-free Event-free Probability
Probability Probability of Survival
ELITE II: Endpoint Results
1.0
0.8
0.6
0.4
0.2
0.0
P = .16
1.0
0.8
0.6
0.4
0.2
0
P = .08
1.0
0.8
0.6
0.4
0.2
0
P = .18
All-cause mortality
Losartan
Captopril
Sudden death or resuscitated arrest
All-cause mortality or hospital admission
0
100
200
300
400
500
Follow-up (days)
(Reprinted with permission from Pitt B, et al. Lancet. 2000)
600
700
Val-HeFT:
Study Design and Inclusion Criteria
5010 patients
EF < 40%; NYHA II - IV
Receiving background therapy
ACEIs (93%), diuretics (86%),
digoxin (67%), beta-blockers (35%)
Randomized to
Valsartan 40 mg bid
titrated to 160 mg bid
(Cohn JN, et al. N Engl J Med. 2001)
Placebo
Effect of Valsartan on Combined Mortality and
Morbidity End Point* in Overall Population
All-cause mortality and morbidity
All-cause mortality
1.0
Survival probability (%)
Event-free probability
1.0
Valsartan
0.9
0.8
p = 0.80
0.9
0.8
0.7
Placebo
0
3
6
9
12 15 18 21
Time since randomisation
(months)
0.7
13% risk reduction p= 0.009
0.6
0
3
6
9
12
15
18
21
Time since randomisation (months)
Cohn et al. NEJM 2001;345:1667
24
27
24
27
CHARM Program
3 component trials comparing Candesartan
to placebo in patients with symptomatic heart failure
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
CHARM Program
Mortality and morbidity
All Cause Mortality
0.77
Alternative
p=0.0004
0.85
Added
p=0.011
0.89
Preserved
Overall
CV Death or
CHF Hospitalisation
0.91
p=0.055
0.7 0.8 0.9 1.0 1.1 1.2
Hazard ratio
p heterogeneity=0.37
0.84
p=0.118
p<0.0001
0.6 0.7 0.8 0.9 1.0 1.1 1.2
Hazard ratio
p heterogeneity=0.43
ARB Indications in CHF



Patients intolerant to ACE-Inhibitors:
(Class I recommendation in stage C)
On top of ACE I and B Blockers in patients who
remain symptomatic: optional (discrepancy in
guidelines):
Class I (ESC, CCS), IIa (HFSA), and IIb (ACC/AHA)
Use of ARB instead of ACE-I is a Class IIa
recommendation (reasonable, should be
considered) in stage C heart failure
RALES
Spironolactone
NEJM 1999;341:709
1.0
Annual Mortality
Aldactone 18%; Placebo 23%
0.9
Survival
0.8
Aldactone
0.7
N = 1663
NYHA III-IV
Mean follow-up 2 y
p < 0.0001
0.6
0.5
Placebo
months
0
6
12
18
24
30
36
Spironolactone. Indications
Moderate-severe symptoms/advanced heart
failure
 Class I recommendation, level of evidence
B
 Routine combination of ACE-I, ARB and
aldosterone antagonist is not recommended
(Class III)

Spironolactone. Practical use

Do not use if hyperkalemia, renal insuficieny

Monitor serum K+ at “frequent intervals”

Start ACE-i first

Start with 25 mg / 24h
ß-Blockers


Has been traditionally contraindicated in
pts with CHF
Now they are a corner stone in treatment
of CHF
ß-Adrenergic Blockers
Mechanism of action
• Density of ß1 receptors
• Inhibit cardiotoxicity of catecholamines
• Neurohormonal activation
• HR
• Anti-ischemic
• Anti-hypertensive
• Anti-arrhythmic
ß-Adrenergic Blockers
Clinical Effects in CHF
• Improve symptoms (only long term)
• Reduce remodeling / progression
• Reduce hospitalization
• Reduce sudden death
• Improve survival
ß-Adrenergic Blockers
US Carvedilol HF
NEJM 1996; 334: 1349-55
1.0
Carvedilol
(n=696)
0.9
Survival %
p<0.001
0.8
0.7
I-II NYHA
HF
Placebo
(n=398)
Risk reduction = 65%
0.6
0
50
100 150 200 250 300 350 400
Days
CIBIS-II
ß-Adrenergic Blockers
Lancet 1999;353:9
1
Bisoprolol
0.9
11.8%
0.8
P< 0.00005
Survival
Placebo
0.7
17.3%
NYHA III-IV
n=2647
0.6
Annual Mortality: bisoprolol=8.2%; placebo=12%
Mean Follow-up 1.4 years
0.5
0
200
400
Days
600
800
MERIT-HF
ß-Adrenergic Blockers
Lancet 1999; 353: 2001
Placebo
15
p=0.0062
Mortality %
Metoprolol
10
5
Risk
Reduction 34%
NYHA II-IV
N=3991
0
0
3
6
9
12
Months
15
18
21
COPERNICUS
ß-Adrenergic Blockers
NEJM 2001;344:1651
100
90
80
Survival%
Carvedilol
70
N = 2289
III-IV NYHA
p=0.00014
35% RR
60
Placebo
50
0
4
8
12
16
Months
20
24
28
CAPRICORN
ß-Adrenergic Blockers
Lancet 2001;357:1385
1
HR 0.77 (0.60 - 0.98) p<0.031
0.95
0.9
Carvedilol
Survival
116 / 975 (12%)
0.85
0.8
LVD / HF 0.75
Post AMI
Placebo
151 / 984 (15%)
0.7
0
0.5
1
1.5
Years
2
2.5
ß-Adrenergic Blockers
Indications
• Symptomatic heart failure (stage C)
• Asymptomatic ventricular dysfunction
- LVEF < 35 - 40 % (stage B)
• After AMI
AHA / ACC HF guidelines 2005
ESC HF guidelines 2005
Class I recommendation
ß-Adrenergic Blockers
When to start ?
• Patient stable
• No physical evidence of fluid retention
• No need for I.V. inotropic drugs
• Start ACE-I / diuretic first
• Start Low, Increase Slowly
• Increase the dose every 2 - 4 weeks
ß-Adrenergic Blockers
Drugs and Dose (mg)
Initial
Target
Bisoprolol
1.25 / 24h
10 / 24h
Carvedilol
3.125 / 12h
25 / 12h
Metoprolol succinnate 12,5-25 / 24h
200 / 24h
Nebivolol (ESC, elderly) 1.25/24h
10 mg/24h
ß-Adrenergic Blockers
Adverse Effects
• Hypotension
• Fluid retention / worsening heart failure
• Fatigue
• Bradycardia / heart block
• Review treatment (+/-diuretics, other drugs)
• Reduce dose
• Consider cardiac pacing
• Discontinue beta blocker only in severe cases
Digitalis Glycosides


The role of digitalis has declined somewhat
because of safety concern
Recent studies have shown that digitals does not
affect mortality in CHF patients but causes
significant
 Reduction in hospitalization
 Reduction in symptoms of HF
Digitalis
DIG
N Engl J Med 1997;336:525
50
40
Mortality %
30
Placebo
20
N=6800
NYHA II-III
n=3403
10
p = 0.8
Digoxin
n=3397
0
0
12
24
Months
36
48
Digitalis. Indications
• Sinus rythm: When no adequate response
to ACE-i + diuretics + beta-blockers
• Atrial Fibrillation: to slow AV conduction
Dose 0.125 to 0.250 mg / day
Narrow therapeutic to toxic ratio !!
Other Drugs.
(only in selected patients)
• Inotropics: refractory HF
• Nitrates: ischemia, angina, pulmonary congestion
• Antiarrhythmics: (only amiodarone) H risk arrhyth.
• Anticoagulants: High risk of embolism e.g Atrial Fibr.
• Ca channel blockers (only amlodipine): ischemia,
hypertension
Devices


Cardiac
Resynchronization
Therapy (CRT)
Implantable Cardiac
Defibrillator (ICD)
Cardiac Resynchronization
Therapy for Heart Failure (CRT)


Ventricular Dysynchrony
 Electrical: Inter- or Intraventricular
conduction delays typically
manifested as left bundle branch
block
 Mechanical: Regional wall motion
abnormalities compromising
ventricular mechanics
Cardiac Resynchronization
 Modification of interventricular,
intraventricular, and atrioventricular activation sequences
Tavazzi L. Eur Heart J 2000;21:1211-1214
Primary and secondary outcomes in
CARE-HF: 409 CRT-treated patients as
compared with 404 control patients
Outcomes
Hazard ratio
(95% CI)
p
All-cause mortality
0.64
(0.48-0.85)
0.0019
All-cause mortality/HF
hospitalization
0.54
(0.43-0.68)
<0.0001
Cleland JG. NEJM 2005; 352: 1539-1549
Cardiac Resynchronization Therapy
(CRT)


NYHA class III or IV, LVEF < 0.35 and
dyssynchrony (QRS >= 120 ms)
Class I recommendation, Level A
Intra Cardiac Defibrillator.
Indications in Secondary
Prevention
 Patients
with sustained
VT or SCD → ICD
Intracardiac Defibrillator
Mortality outcomes over five years in SCD-HeFT
(Sudden Cardiac Death in Heart Failure Trial)
Parameter
ICD,
n=829
Amiodarone,
n=845
Placebo,
n=847
All-cause mortality 22
(%)
28
29
Mortality risk vs
placebo, HR
(97.5% CI)
1.06
(0.86-1.30),
p=0.53
—
0.77
(0.62-0.96),
p=0.007
* randomized 2521 patients with NYHA class 2-3 HF and an LVEF <35%
Bardy GH et al. N Engl J Med 2005; 352:225-237.
ICD indications
Primary prevention
NYHA class II or III and LVEF <= 30 %
 With a reasonable life expectancy > 1 year
 Class I recommendation
 However may be indicated even in stage B
(NYHA class I) especially in ischemic
aetiology

Heart Transplant. Indications
• Refractory cardiogenic shock
• Documented dependence on IV inotropic support
• Severe symptoms of ischemia not amenable to
revascularization
• Recurrent symptomatic ventricular arrhythmias
refractory to all therapeutic modalities
 Treat risk factors.
 ACE-I (or ARB) in
appropriate pts for
vascular disease or
diabetes
 ACE-I, ARB,
-Blockers in
appropriate pts.
 ICD in selected pts.
A
Stages in the Evolution
of Heart Failure.
Treatment
AHA / ACC HF guidelines 2005
B (Asymptomatic LV Systolic Dysfunction)
C (Symptomatic LV Systolic Dysfunction)
 Routine: ACE-I,  blockers,
Diuretics
 In selected pts: aldost
antag, ARB, Digitalis, nitrates
ICD, CRT
D
(Refractory End-Stage HF)
CRT
Mech. Assist device
Heart Transplant