Heart Failure
Final common pathway for many cardiovascular diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunction Cardinal manifestations of heart failure include dyspnea, fatigue and fluid retention Risk of death is 5-10% annually in patients with mild symptoms and increases to as high as 3040% annually in patients with advanced disease
Main causes
Coronary artery disease Hypertension Valvular heart disease Cardiomyopathy Cor pulmonale
Compensatory changes in heart failure
Activation of SNS Activation of RAS Increased heart rate
Release of ADH Release of atrial natriuretic peptide Chamber enlargement
Myocardial hypertrophy
NYHA Classification of heart failure
Class I: No limitation of physical activity Class II: Slight limitation of physical activity Class III: Marked limitation of physical activity
Class IV: Unable to carry out physical activity without discomfort
New classification of heart failure
Stage A: Asymptomatic with no heart damage but have risk factors for heart failure Stage B: Asymptomatic but have signs of structural heart damage Stage C: Have symptoms and heart damage Stage D: Endstage disease
ACC/AHA guidelines, 2001
Types of heart failure
Diastolic dysfunction or diastolic heart failure
Systolic dysfunction or systolic heart failure
Factors aggravating heart failure
Myocardial ischemia or infarct Dietary sodium excess Excess fluid intake Medication noncompliance Arrhythmias Intercurrent illness (eg infection) Conditions associated with increased metabolic demand (eg pregnancy, thyrotoxicosis, excessive physical activity) Administration of drug with negative inotropic properties or fluid retaining properties (e. NSAIDs, corticosteroids) Alcohol
Goals of treatment
To improve symptoms and quality of life To decrease likelihood of disease progression
To reduce the risk of death and need for hospitalisation
Approach to the Patient with Heart Failure
Assessment of LV function (echocardiogram, radionuclide ventriculogram) EF < 40% Assessment of volume status Signs and symptoms of fluid retention Diuretic (titrate to euvolemic state) No signs and symptoms of fluid retention ACE Inhibitor b-blocker Digoxin
R e la tio n b e tw e e n p la s m a n o ra d re n a lin e a n d m o rta lity in p a tie n ts w ith h e a rt fa ilu re
C u m u la tive m o rta lity (% ) 100
O v e ra ll p < 0 .0 0 0 1
N o ra d re n a lin e > 9 0 0 p g /m l
80
60
N o ra d re n a lin e > 6 0 0 p g /m l a n d < 9 0 0 p g /m l
40 N o ra d re n a lin e < 6 0 0 p g /m l 20
0 0 12 24 36 48 60 M o n th s
N E JM 19 8 4 ; 311 : 8 1 9-8 2 3
Effects of SNS Activation in Heart Failure
Dysfunction/death of cardiac myocytes
Provokes myocardial ischemia Provokes arrhythmias Impairs cardiac performance
These effects are mediated via stimulation of b and a1 receptors
Am J Hypertens 1998; 11: 23S-37S
R e c e p to r d e n s itie s in h u m a n le ft v e n tric u la r m y o c a rd iu m
70
N o rm a l m yo c a rd iu m
60
Id io p a th ic d ila te d ca rd io m yo p a th y
R e ce p to r d e n s ity (fm o l/m g )
50
*p < 0 .0 5
40
*
30 *
20
10
0 b 1 b a 1
S c a n d C a rd io v a sc J 1 9 9 8 ; S u p p l 4 7 :4 5 -5 5
Carvedilol in Heart Failure
Effective receptor-blockade approach to heart failure
Negative inotropic effect counteracted by vasodilation
Provides anti-proliferative, anti-arrhythmic activity and inhibition of apoptosis
Prevents renin secretion
Drugs of Today 1998; 34 (Suppl B): 1-23.
US Multicenter Program
Placebo (n=398) Carvedilol (n=696) % Risk Reduction
All-cause 31 mortality (7.8%) Death due to progressive 13 heart failure (3.3%) Sudden death 15 (3.8%)
Risk of hospitalization for cardiovascular reasons Combined risk of mortality & hospitalization
NEJM 1996; 334:1349-1355
22 (3.2%) 5 (0.7%) 12 (1.7%)
78 (14.1%) 110 (16%)
65%
78 (19.6%) 98 (25%)
27% 38%
ANZ Multicentre Heart Failure Trial
Placebo (n=208) All-cause mortality 26 (12.5%)
Carvedilol (n=207) 20 (10%)
% Risk Reduction 24%
Risk of hospitalization for cardiovascular reasons
Combined risk of mortality & hospitalization
Lancet 1997; 349: 375-380.
84 (40%)
97 (47%)
64 (31%)
74 (36%)
28%
29%
Effect of carvedilol on progression of congestive heart failure
All randomized patients Endpoint Placebo (n=134) Carvedilol (n=232)
Primary endpoint
Death due to CHF Hospitalization due to worsening CHF Increase in CHF medication
* Placebo vs. carvedilol, p = 0.008
Drugs of Today 1998; 34 (Suppl B): 1-23.
28 (21%)
4 (3%) 8 (6%) 16 (12%)
25 (11%)*
0 (0%) 9 (4%) 16 (7%)
COPERNICUS: Effect on Mortality
20 18 16
18.5%
Mortality (%)
14 12 10 8 6 4 2 0
11.4%
35%
Carvedilol (n=1156)
Placebo (n=1133)
22nd Congress of European Society of Cardiology, August 2000
COPERNICUS: Mortality reduction in special patient groups with carvedilol
EF < 15%, hospitalised 3 or more times during prior year for worsening heart failure
0
EF<20%, hospitalised for heart failure in year prior to study entry
Mortality reduction (%)
-10 -20 -30 -40
36% 42%
-50 -60
22nd Congress of European Society of Cardiology, August 2000
Carvedilol vs. Metoprolol
12
Change in LVEF (%) from baseline
10 8 6 4 2 0
18.5%
11.4%
Metoprolol
Carvedilol
Circulation 2000; 102: 546-551
Dosage guidelines for Carvedilol in heart failure
Patient selection • Stable on background medications (diuretics, digoxin and/or ACE inhibitors) • Not in a fluid-overload state • Not hypotensive
3.125 mg bid
2 weeks
Doubled every 2 weeks
Max dose 25 mg bid (<85 kg); 50 mg bid (>85 kg)
After each new dose initiation • Observe for signs of dizziness or light headedness for one hour
Before dose increase Evaluate for • Worsening heart failure • Vasodilation • Bradycardia
Management of Complications
Transient worsening of heart failure (e.g. increasing dyspnea,
decreasing exercise capacity)
Increase dose of diuretic and/or ACE inhibitor
If necessary, reduce carvedilol dose and/or prolong titration interval Search for other possible causes (e.g. thyroid malfunction, infection, non-compliant drug intake, excessive liquid intake, etc.)
Vasodilatory Symptoms (dizziness, light headedness,
symptomatic hypotension)
Decrease diuretic dose and, if necessary, ACE inhibitor dose
If the cessation of both is not successful, reduce carvedilol dose and/or prolong titration interval
Management of Complications (Contd.)
Bradycardia (Pulse rate below 55 beats/min)
Check and eventually reduce digitalis dose
If necessary, reduce carvedilol dose and/or prolong titration interval
Withdraw carvedilol only in the event that hemodynamics are affected
Symptoms of Bronchial obstruction
Search for other possible causes (e.g., concurrent infection, subacute pulmonary edema)
Reduce dose of, or withdraw, carvedilol only after possible causes for symptoms have been ruled out
The role of angiotensin II in the progression of heart failure
Coronary artery disease Cardiomyopathy Cardiac overload
Left ventricular dysfunction
Arterial blood pressure Renin release
Angiotensin II
Aldosterone release
Vasoconstriction Peripheral organ blood flow
Na+ and water retention
Inotropy and hypertrophy of vascular and cardiac cells
Cardiac remodelling
Skeletal muscle blood flow Renal blood flow Left ventricular dilation & hypertrophy
Exercise intolerance
Oedema
Pump failure
ACE Inhibitors: physiologic benefits
Arteriovenous Vasodilatation
pulmonary arterial diastolic pressure pulmonary capillary wedge pressure left ventricular end-diastolic pressure systemic vascular resistance systemic blood pressure maximal oxygen uptake (MVO2)
ACE Inhibitors: physiologic benefits
LV function and cardiac output renal, coronary, cerebral blood flow
No change in heart rate or myocardial contractility
no neurohormonal activation resultant diuresis and natriuresis
ACE Inhibitors: clinical benefits
Increases exercise capacity improves functional class attenuation of LV remodeling post MI
decrease in the progression of chronic HF decreased hospitalization enhanced quality of life
improved survival
Asymptomatic Patients
Enalapril
SOLVD Prevention Trial
EF<35% HF progression, hospitalization
Captopril
SAVE, GISSI-3, ISIS-4 Post MI, EF <40% overall mortality, re-infarction hospitalization, HF progression
Symptomatic Patients
Hydralazine + Isosorbide dinitrate
VHeFT-I mortality, improved functional class as compared with use of digoxin and diuretics VHeFT-II proved less effective than enalapril
Dosage of ACE inhibitors: ATLAS study
Low-dose (2.5-5 mg)
Cardiovascular mortality All-cause mortality + hospitalisation for cardiovascular reason All-cause mortality + hospitalisation for heart failure 44.9%
High-dose (32.5-35mg)
42.5%
83.8%
79.7%
60.4%
55.1%
Circulation 1999;100:2312-18
AIRE
AIRE Study demonstrated efficacy of ramipril on mortality and morbidity in CHF post-MI NYHA class IIII patients
2006 patients enrolled in a double-blind,randomized, placebo-controlled study
27% reduction in the risk of death 23% decrease in progression to severe / resistant heart failure
Lancet. 1993; 342:821-828
Guidelines to ACE Inhibitor Therapy
Contraindications Renal artery stenosis Renal insufficiency (relative) Hyperkalemia Arterial hypotension Cough Angioedema Alternatives Hydralazine + ISDN, AT-II inhibitor
Guidelines to ACE Inhibitor Therapy
All patients with symptomatic heart failure and those in functional class I with significantly reduced left ventricular function should be treated with an ACE inhibitor, unless contraindicated or not tolerated
ACE inhibitors should be continued indefinitely
It is important to titrate to the dosage regimen used in the clinical trials … in the absence of symptoms or adverse effects on end-organ perfusion In very severe heart failure, hydralazine and nitrates added to ACE inhibitor therapy can further improve cardiac output
ACE Inhibitor Therapy in Heart Failure Patients
(Ejection Fraction < 0.40)
Systolic Blood Pressure
<100 mmHg (or elevated creatinine) Lowest Dose, Short-Acting
100-139 mmHg (or recent intense diuresis) Usual Starting Dose, Longor Short-Acting
>140 mmHg
Intermediate Dose, Long- or Short-Acting
Follow-Up Every 1-2 Weeks
Stable BP and Creatinine Level Stop ACE Inhibitor Therapy Increase ACE Inhibitor Dose; Follow-Up Every 1-2 Weeks
Y
Symptomatic Low BP or Rising Creatinine Level
Residual Excess Fluid?
N
Refer to specialist
Stop Diuretic and ACE Inhibitor Therapy
N Y
Target Dose Resume ACE Inhibitor Titration Return to Baseline BP and Creatinine Level ?
Diuretics
Indicated in patients with symptoms of heart failure who have evidence of fluid retention
Enhance response to other drugs in heart failure such as beta-blockers and ACE inhibitors
Therapy initiated with low doses followed by increments in dosage until urine output increases and weight decreases by 0.5-1kg daily
Digoxin
Enhances LV function, normalizes baroreceptor-mediated reflexes and increases cardiac output at rest and during exercise Recommended to improve clinical status of patients with heart failure due to LV dysfunction and should be used in conjunction with diuretics, ACE inhibitors and beta-blockers Also recommended in patients with heart failure who have atrial fibrillation Digoxin initiated and maintained at a dose of 0.25 mg daily Adverse effects include cardiac arrhythmias, GI symptoms and neurological complaints (eg. visual disturbances, confusion)
Summary of drug treatment for CHF
Asymptomatic LV dysfunction ACE inhibitor Mild to moderate CHF Digoxin Moderate to severe CHF Digoxin
Beta blocker
Diuretics ACE inhibitor Beta blocker
Diuretics ACE inhibitor Beta blocker
Spironolactone