Transcript Atherosclerotic Plaque - Cardiologie francophone

Therapeutic Algorithm in Heart Failure
Joseph Elias, MD
May 22, 2004
Beirut - LEBANON
Prevalence and Prognosis of HF in USA
• 2 million Heart Failure patients in the US
in 1997
• 28 billions US$ in 1996 for congestive HF
• 400,000 new cases per year
• Sudden cardiac death (SCD) may occur
in as many as 40% of all Heart Failure
patients
Prevalence and Prognosis of HF in
Europe
• Estimates range from 0.4% to 2%
• Increase rapidly with age
• High prevalence
– 10 million patients with HF
– 10 million patients with myocardial dysfunction
• 50% of patients with HF will die within 4 years
• > 50% of patients with severe HF will die within
1 year
Task force for the Diagnostic and Treatment of Chronic Heart Failure
ESC. European Heart Journal 2001;22:1527-1560
Prevalence and Prognosis of HF in
France
• 500,000 Heart Failure patients in France in 2001
• Increase by 120,000 per year
• The incidence rises from:
– 0.4% of male and 0.3% of females aged between 55 and 64 years
to
– 5% of males and 8.5% of females aged between 85 to 94 years
• 3.5 million consultations and 150,000
hospitalizations for HF per year
• The cost linked to HF represents more than 1% of
total medical cost
Prevalence and Prognosis of HF in
Lebanon
The Epidemiological Aspects and Etiological Basis of
Heart Failure
Alan J. Cowley
in: International Handbook of Heart Failure, 1994, pp 13-17
percent
70
Ischemic Heart Disease (IHD)
Dilated cardiomyopathy (CMO)
Primary valvular disease
60
50
40
30
n = 552
20
10
0
IHD
R.W. Timmers, M.D.
CMO
Valvular
Hypertension
Other
The two main endpoints in progressive Heart
Failure are:
Sudden Cardiac Death (SDC) is the leading cause of
death in NYHA class I and II
Progressive left ventricular dysfunction leading to death by
pump failure, occurring mainly in
NYHA class III and IV
R.W. Timmers, M.D.
Primary prevention of Sudden Cardiac Death (SCD) in Heart Failure
B. F. Uretsky et al. J. Am Coll. Cardiol. Dec 1997;30:1589-97
Sudden Death by severity of Heart Failure symptoms
NYHA Class
II
Annual Mortality(%) SCD (%)
5-15
50-80
(Mainly arrythmias)
III
20-50
30-50
IV
30-70
5-30
(Mainly pump failures)
R.W. Timmers, M.D.
Aim of the Treatment
• Prevention of disease leading to heart failure.
• Prevention of progression to heart failure.
• Morbidity: maintenance or improvement in
quality of life.
• Mortality: increase duration of life.The aims of
CHF therapy are to improve hemodynamics and
tolerance of exercise.
Non Pharmacological
Therapy
• General advise and measures.
• Educate patients and family.
• Weight Control.
• Dietary Measures.
• Smoking
• Travelling
• Sexual activity
• Exercise and exercise training
Pharmacological Therapy
•
•
•
•
•
•
•
•
•
•
•
Diuretics.
ACE inhibitors.
Cardiac Glycosides.
β-Blockers.
ARBS
Aldosterone antagonists
Vasodialtor agents
Positive inotropic agents
Anticoagulation
Antiarrhythmic agents
Oxygen
Device and surgery Therapy
•
•
•
•
•
Pace maker therapy
Biventricular stimulation
Heart Surgery
Circulation Support Systems
AICD
Diuretics
LOOP DIURETICS, THIAZIDES AND METOLAZONE
Diuretics are essential for symptomatic treatment when fluid overload is
present, although there are no controlled randomized trials that have
assessed the effect on survival of these agents
They should always be administered in combination with ACE inhibitors
Aldosterone receptor Antagonists – Spironolactone
Aldosterone antagonist is recommended in advance HF in addition to
ACE inhibitors and Diuretics to improve survival and morbidity
The RALES mortality trial showed that low dose Spironolactone (12.5 – 50
mg) on top of an ACE inhibitor and a loop diuretic markedly and
progressively improved survival of patients in advanced NYHA III/IV HF,
irrespective of aetiology
β-BLOCKERS
There are different types of β-Blockers:
• Those that selectively inhibit Beta1 receptors.
• Those that inhibit Beta1 and Beta2 receptors.
• Those that inhibit Beta1, Beta2 and Alpha1
receptors.
β-BLOCKERS
Interfere with the endogenous nervous
system.
Inhibit the effects of the sympathetic nervous
system (epinephrine and nor epinephrine).
Reduce sympathetic activity:
- Prevention of catecholamine toxicity.
- Reduction of myocardial ischemia.
- Reduction of arrhythmias.
β Blockade in Heart Failure
• Consensus recommendations
– all patients with class II-III heart failure due to left ventricular
systolic dysfunction should receive a β blocker (in addition to
an ACE inhibtor) unless they have contraindication to its use
or cannot tolerate treatment with the drug
– The results fo the CIBIS II study with Bisoprolol and the
COPERNICUS study with Carvedilol have considerably
contributed to increasing the evidence regarding the use of βblockers in NYHA IV patients
Primary prevention of Sudden Cardiac Death (SCD) in Heart Failure
B. F. Uretsky et al. J. Am Coll. Cardiol. Dec 1997;30:1589-97
ACE inhibitors for the prevention of SDC in Heart Failure
SUDDEN DEATH MORTALITY
Study
NYHA
Class
Consensus 1
IV
SOLVD RX
SOLVD Prev.
Overall
R.W. Timmers, M.D.
Follow-up
(mo)
Mortality
Decrease
ACE
no ACE
12
27% (p=0.003)
11.0
11.0
> 0.25
II, III
41
16% (p=0.004)
8.2
8.8
> 0.25
I, II
37
8% (p=0.30)
4.6
5.0
0.10
6.2
6.6
0.09
p
Primary prevention of Sudden Cardiac Death (SCD) in Heart Failure
B. F. Uretsky et al. J. Am Coll. Cardiol. Dec 1997;30:1589-97
ACE inhibitors for the prevention of SDC in Post-MI
w/o clinical signs of heart failure (early intervention)
SUDDEN DEATH MORTALITY
Study
NYHA
Class
SAVE
I
TRACE
SMILE.
Overall
Mortality
Decrease
ACE
no ACE
42
19% (p=0.019)
5.6
6.7
> 0.25
I, II
24-50
22% (p=0.001)
12.0
15.2
0.025
I, II
1.5
22% (p=0.17)
0.5
1.4
0.17
7.7
9.7
(Including AIRE Study)
R.W. Timmers, M.D.
Follow-up
(mo)
p
0.015
ACE inhibition in Myocardial Infarction, LV Dysfunction and Heart Failure:
Mortality Studies
Trials
Myocardial infarction
< 24 hrs
Odds Ratio (& C. Limits)
+ 10 + 9
- 11 + 5
-5 +3
-3 +6
-6+2
Consensus-2
GISSI-3
ISIS-4
Chinese AMI
Subtotal:
MI with LV dysfunction
Days
Months
Subtotal:
MI and Heart Failure
Days
- 19 + 9
- 22 + 7
-8 +8
- 13 + 6
SAVE
TRACE
SOLVD
- 27 + 9
AIRE
- 8 %+ 2
Overall
Treatment effect 2P = 0.003
R.W. Timmers, M.D.
Risk Reduction %
0.5
0.75
1.0
1.25
Angiotensin Receptor
Blockers (ARBs) in Heart
Failure
Substitute or adjunctive
therapy to ACE inhibitors ?
ARBs in Heart Failure
A meta-analysis of 17 studies in HF
(n=12 469)
 Patients with HF NYHA class II to IV
 Studies comparing ARBs to placebo or ACE inhibitors
 Randomized, blinded, parallel-group studies
 Treatment duration of at least 4 weeks
 Studies reporting death and hospitalization for HF
Jong P et al. J Am Coll Cardiol 2002;39:463-70
ARBs in Heart Failure
Conclusions of the Metaanalysis
 ARBs were not superior to controls in the pooled
rates of death or hospitalization
 There was a NS trend in favor of ARBs over placebo in
reducing mortality and hospitalization when given without
background ACEIs
 When compared directly with ACEIs, ARBS were not
superior in reducing either mortality or hospitalization
 ARB+ACEI combinations were superior to ACEIs alone
reducing hospitalization but not mortality
Jong P et al. J Am Coll Cardiol 2002;39:463-70
in
CHARM-Alternative:
Primary outcome CV death or CHF
hospitalisation
%
50
406 (40.0%)
Placebo
40
334 (33.0%)
30
Candesartan
20
10
HR 0.77 (95% CI 0.67-0.89), p=0.0004
Adjusted HR 0.70, p<0.0001
0
0
Number at risk
Candesartan 1013
Placebo
1015
1
929
887
2
831
798
3
434 122
427 126
3.5 years
CHARM-Alternative
Secondary outcomes
p-value
Candesartan Placebo
CV death
CHF hosp.
CV death, CHF hosp,
MI
CV death, CHF hosp,
MI, stroke
CV death, CHF hosp,
MI, stroke, revasc
219
207
353
369
396
0.85
252
286
0.072
0.68
<0.0001
0.78
420
0.0007
0.80
432
0.001
0.81
456
0.6
0.8
candesartan
better
0.002
1.0
Hazard
ratio
1.2
1.4
placebo
better
CHARM-Added: Primary outcome
CV death or CHF hospitalisation
50
%
538 (42.3%)
483 (37.9%)
Placebo
40
30
Candesartan
20
10
HR 0.85 (95% CI 0.75-0.96), p=0.011
Adjusted HR 0.85, p=0.010
0
0
Number at risk
Candesartan 1276
Placebo
1272
1
1176
1136
2
1063
1013
3
948 457
906 422
3.5 years
CHARM-Added
Secondary outcomes
p-value
Candesartan Placebo
CV death
CHF hosp.
302
309
CV death, CHF hosp, 495
MI
CV death,CHF hosp,
MI, stroke
CV death,CHF hosp,
MI, stroke, revasc
512
548
0.84
347
0.029
0.83
356
0.014
0.85
550
0.010
0.87
559
0.020
0.87
596
0.6
0.8
candesartan
better
0.015
1.0
Hazard
ratio
1.2
1.4
placebo
better
VALLIANT study
CV Death, MI, or HF by Treatment
0.4
Captopril
Valsartan
Valsartan + Captopril
Probability of Event
0.3
0.2
0.1
Valsartan vs. Captopril: HR = 0.96; P = 0.198
Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369
0
Months
0
6
12
18
24
30
36
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Summing up ACEI & ARBs in post MI
Mortality in SAVE, TRACE, AIRE, and VALIANT
Hazard Ratio for Mortality
SAVE
TRACE
Valsartan
preserves
99.6% of
mortality
benefit of
captopril.
AIRE
Combined
VALIANT
(imputed placebo)
0.5
Favors
Active Drug
1
Favors
Placebo
2
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Primary prevention of Sudden Cardiac Death (SCD) in Heart Failure
B. F. Uretsky et al. J. Am Coll. Cardiol. Dec 1997;30:1589-97
Antiarrythmics for the prevention of SDC in Heart Failure
Class I Antiarrythmics:
CAST 1 & 2 showed no evidence of preventing SCD in Heart Failure (Encainide, Flecainide)
BASIS study (moricizine) showed a non significant increase in mortality...
Amiodarone
showed mixed results in primary SCD prevention in Heart Failure:
CHF-STAT (US) trial showed no difference, except for non-ischemic cardiomyopathy Heart Failure
patients (trend-wise)
GESICA (Argentina) showed a significant mortality reduction for both pump failure and SCD. (60% of
patients had non-ischemic cardiomyopathy)
CAMIAT(Canada), and EMIAT(UK) trials in post MI showed a significant 35% reduction in SCD
but no decrease in overall mortality...
R.W. Timmers, M.D.
Cardiac Glycosides
• Cardiac glycosides are indicated in AF and at any
degree of symptomatic HF
• In sinus rhythm, cardiac glycosides are
recommended to improve the clinical status of
patients with persisting HF symptoms due to LV
systolic dysfunction despite ACE inhibitors and
diuretic treatments
• In the DIG Trial in 6,800 patients wth an ischaemic
and non-ischaemic cardiomyopathy and mild to
moderate HF, with long term digoxin, reduced
symptoms, improved clinical status without any
impact on survival
Surgery
• Surgical treatment should be directed towards the
underlying aetiology and mechanisms. In addition
to revascularization, it is important to approach
patients with significant valvular disease before
they develop significant LV dysfunction
• Cardiomyoplsty cannot be recommended for
treatment of HF
• Heart transplantation is an accepted mode of
treatment for end stage HF. Although, controlled
trials have never been conducted, it is considered
to significantly increase survival and quality of life
(5 years survival70-80%)
Cardiac Resynchronization
Therapy for Heart Failure
Mechanisms, Clinical Outcomes
and Patient Selection
Ventricular Dysynchrony and
Cardiac Resynchronization
• Ventricular Dysynchrony1
– Electrical: Inter- or
Intraventricular conduction delays typically manifested as left bundle
branch block
– Structural: disruption of myocardial collagen matrix impairing electrical
conduction and mechanical efficiency
– Mechanical: Regional wall motion abnormalities with increased workload
and stress—compromising ventricular mechanics
• Cardiac Resynchronization
– Therapeutic intent of atrial synchronized biventricular pacing
» Modification of interventricular, intraventricular, and atrialventricular activation sequences in patients with ventricular
dysynchrony
» Complement to optimal medical therapy
1
Tavazzi L. Eur Heart J 2000;21:1211-1214
Proposed Mechanisms of
Cardiac Resynchronization
Cardiac Resynchronization
Improved Intraventricular
Synchrony
Improved Atrioventricular
Synchrony
Yu C-M, Chau E, Sanderson J, et al. Circulation 2002;105:438-445
Improved Interventricular
Synchrony
Summary of Proposed
Mechanisms
Cardiac Resynchronization
Intraventricular
Synchrony
 dP/dt,  EF,  CO
( Pulse Pressure)
 LVESV
Atrioventricular
Synchrony
 MR
 LA
Pressure
 LV Diastolic
Filling
 LVEDV
Reverse Remodeling
Yu C-M, Chau E, Sanderson J, et al. Circulation 2002;105:438-445
Interventricular
Synchrony
 RV Stroke
Volume
HF and CRT Clinical Studies – Observational and
Randomized
CRT Improves Quality of Life
Score and NYHA Functional Class
QoL
PATH-CHF1 (n=41)
+
+
InSync (Europe)2 (n=103)
+
+
InSync ICD (Europe)3 (n=84)
+
+
MUSTIC4 (n=67)
+
MIRACLE5 (n=453)
+
+
MIRACLE ICD6 (n=364)
+
+
+

Blank
1 Auricchio
Statistically significant improvement with CRT (p  0.05)
Not statistically significant or No statistical analysis performed on data
Indicates test neither performed nor reported
A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026-
2033
Gras D, Leclercq C, Tang A, et al. Eur J Heart Failure 2002;4:311-320
3 Kuhlkamp V. JACC 2002;39:790-797
4 Linde C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118
2
NYHA
5 Abraham
W, Fisher W, Smith A, et al.
N Engl J Med. 2002;346:1845-1853
6 Leon A. NASPE Scientific Sessions – Late Breaking
Clinical Trials. May 2002; Medtronic Inc. data on file
CRT Improves Exercise Capacity
6 Min Walk
+
InSync (Europe)2 (n=103)
+
InSync ICD (Europe)3 (n=84)
+
MUSTIC4 (n=67)
+

MIRACLE5 (n=453)
+
+
+

+
+
+

Blank
+
Statistically significant improvement with CRT (p  0.05)
Not statistically significant or No statistical analysis performed on data
Indicates test neither performed nor reported
A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026-
2033
Gras D, Leclercq C, Tang A, et al. Eur J Heart Failure 2002;4:311-320
3 Kuhlkamp V. JACC 2002;39:790-797
4 Linde C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118
2
Exercise
Time
PATH-CHF1 (n=41)
MIRACLE ICD6 (n=364)
1 Auricchio
Peak VO2
5 Abraham
W, Fisher W, Smith A, et al.
N Engl J Med. 2002;346:1845-1853
6 Leon A. NASPE Scientific Sessions – Late Breaking
Clinical Trials. May 2002; Medtronic Inc., data on file
CRT Improves Cardiac
Function/Structure
LVEF
MR
Other
+ LVEDP
+ LV dP/dtmax
PATH-CHF1 (n=41)
InSync (Europe)2 (n=103)
+
InSync ICD (Europe)3 (n=84)
+
MUSTIC4 (n=67)

MIRACLE5 (n=453)
+
+
+ LVEDD,
+ LVEDV, LVESV
MIRACLE ICD6 (n=362)

+
+ LVESV,
+ LVEDV
+

Blank
1 Auricchio
+ Filling Time

 LVEDD,LVESD
 Filling Time
Statistically significant improvement with CRT (p  0.05)
Not statistically significant or No statistical analysis performed on data
Indicates test neither performed nor reported
A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026-
2033
Gras D, Leclercq C, Tang A, et al. Eur J Heart Failure 2002;4:311-320
3 Kuhlkamp V. JACC 2002;39:790-797
4 Linde C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118
2
+ Filling Time
5 Abraham
W, Fisher W, Smith A, et al.
N Engl J Med. 2002;346:1845-1853
6 Young J. ACC Scientific Sessions – Late Breaking
Clinical Trials III. March 2002; Medtronic Inc.,
data on file
Cardiac Resynchronization
Outcomes
Sustained for at least 12 months
InSync European and
Canadian Study1
(n=67, followed to 12 months)
NYHA
QoL
6 Minute
Walk
+
+
+
PATH-CHF Study2
(n=29, followed to 12 months)
+
+
+
+
+
+
+
MUSTIC Study3
(n=42 in sinus rhythm group,
n=33 in atrial fibrillation group
followed to 12 months)
+

Blank
1

Statistically significant improvement with CRT (p  0.05)
No statistically significant improvement with CRT
Indicates test neither performed nor reported
Gras D, Leclercq C, Tang A, et al. Eur J Heart Fail 2002;4:311-320
A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026-2033
3 Linde C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118
2 Auricchio
Peak VO2
Cardiac Resynchronization
Benefits
Relative to Hospitalization
PATH-CHF1
•
•
MUSTIC2
•
•
1 year prior to implant, 22 patients hospitalized for HF
with average stay of 18.5 days
One year following implant, 9 patients hospitalized for
HF with average stay of 4.5 days
Sinus Rhythm Group: 7 times fewer hospitalizations
for HF (12 month F/U)
AF Group: 4 times fewer hospitalizations for HF (12
m/fu)
MIRACLE3
•
Number of HF-hospitalizations significantly reduced
(p = 0.02)
•
Length of stay for HF-hospitalizations significantly
reduced (p = 0.05)
MIRACLE ICD4
1 Auricchio
A. Stellbrink C, Sack S., et al. J Am Coll Cardiol 2002;39:2026-2033
C, Leclercq C, Rex S, et al. J Am Coll Cardiol 2002;40:111-118
3 Abraham W, Fisher W, Smith A, et al. N Engl J Med. 2002;346:1845-1853
4 Leon A. DeLurgioD, Smith A, et al. PACE 2002;25(4), Part II:647
2 Linde
In Summary
Cardiac Resynchronization therapy offers an
adjunctive approach for treating selected patients
with ventricular dysynchrony and moderate to
severe heart failure who remain symptomatic
despite optimal, stable medical therapy.
CHF- Choice of Pharmacological therapy
LV Systolic
Dysfunction
ACE
inhibitors
Beta-blocker
Diuretic
Aldosterone
antagonists
Asymptomati
c LV
Dysfunction
Indicated
Post MI
Not indicated
Not indicated
Symptomatic
HF NYHA II
Indicated
Indicated
Indicated if fluid
retention
Not indicated
Worsening
HF
NYHA III/IV
Indicated
Indicated
(under specialist
care)
Indicated
combination of
diuretics
Indicated
End stage HF Indicated
NYHA IV
Indicated
(under specialist
care)
Indicated
combination of
diuretics
Indicated
CHF- Choice of Pharmacological therapy
LV Systolic
Dysfunction
Angiotensin II
receptor
antagonist
Cardiac Glygosides Vasodilator
(Hydralazine/isoso
rbide dinitrate)
Asymptomatic LV
Dysfunction
Not indicated
With AF
Not indicated
Symptomatic HF
NYHA II
If ACE inhibitors are
not tolerated and +/added to ACE
a. With AF
b. When improved
from more severe
HF in sinus
ryhthm
If ACE inhibitors and
ARBs not tolerated
Worsening HF
NYHA III/IV
If ACE inhibitors are
not tolerated and +/added to ACE
Indicated
If ACE inhibitors and
ARBs not tolerated
End stage HF
NYHA IV
If ACE inhibitors are
not tolerated and +/added to ACE
Indicated
If ACE inhibitors and
ARBs not tolerated
Conclusion
Therapeutic Algorithm in Heart Failure
For symptoms
For
survival/morbidity
NYHA I
Reduce/stop diuretic
NYHA II
+/- diuretic
depending on fluid
retention
Continue ACE
inhibitor if
asymptomic. Add if post MI
ACE inhibitor as first ARB if ACE inhibitor
line treatment
intolerant
NYHA III
Add - if still
symptomatic
+ diuretics + digitalis ACE inhibitor and if still symptomatic
and spironolactone
+ nitrates/hydralzine
if tolerated
NYHA IV Diuretic + digitalis +
nitrates/hydralazine
if tolerated +
temporary inotropic
support +/- devices
ACE inhibtor and and spironolactone
+/- devices
For symptoms if
intolerance to ACE
or -
Or ACE inhibitor +
ARB if - intolerant
ARB if ACE inhibitor
intolerant
Or ACE inhibitor +
ARB if - intolerant
ARB if ACE inhibitor
intolerant
Or ACE inhibitor +
ARB if - intolerant