2. GENERAL MEASURES
• Identification and Correction of Causes:
• Hypertension, Diabetes,…
• Identification of the causes that cause decompensation of heart failure:
• dietary indiscretion
• inappropriate reduction in HF management medications
• patient-driven
• clinician-driven
• Advise to :
• Stop Smoking
• Limit Daily Alcohol to 2 SD for Men and 1 SD for Women and completely cease in those with alcohol-induced
cardiomyopathy
• avoid exposure to extreme heat and overzealous exercise
3. DRUGS TO AVOID IF POSSIBLE
• Anti-arrhythmic: cardio-depressant and pro-arrythmic effect and can cause worsening
of HF.
• only “amiodarone” and “dofetilide” have shown not to adversely affect the survival
• CCBs: increased cardiovascular events and worsening of HF
• only vasoselective ones have shown to be safe
• NSAIDs:
• water and salt retention
• decrease the efficacy and increase adverse effects of diuretics and ACE-Inhs
4. ELECTROLYTE DISTURBANCES
• Potassium:
• Hypokalemia carries the risk of:
• arrythmia
• digitalis toxicity
• activation of sympathetic nervous system and RAS can cause hypokalemia
• most drugs used in treatment of HF can alter potassium concentration
• A modest increase in potassium can ameliorate the efficacy of HF treatment
• Recommended potassium level: 4-5 mmol/L
• Those on ACE-Inh and/or Aldosterone antagonists may not need supplemental K and in fact it might
be deleterious.
5. ELECTROLYTE DISTURBANCES
• Sodium:
• Dietary sodium should be limited to 2-3g/d
• Further restriction to <2g/d in moderate-severe HF
• Fluid Restriction:
• Generally unnecessary
• Unless the patient is hyponatremic (Na <130 mmol)
• RAS activation
• Excessive AVP
• Loss of salt in excess of water due to diuretic use
6. PHARMACOLOGICAL
MANAGEMENT OF HFREF PATIENTS
• Group of Medications:
• Diuretics
• Vasodilators
• ACE-Inhs/ARBs/Aldosterone Receptor Antagonists
• Beta-Blockers
• Inotropes/Inodilators
• Digoxin
7. DIURETICS
• Loop Diuretics (Preferred Choice)
• Increase sodium excretion by up to 20-25% of filtered load of the sodium
• Enhance free water clearance
• Maintain their efficacy unless the renal function is severely impaired
• Thiazides
• Increase sodium excretion by only 5-10% of filtered load
• Decrease free water clearance
• Lose their effectiveness in patients with impaired renal function (CCL < 40 mL/min)
9. LOOP DIURETICS
Proximal Convoluted Tubule
• Reversible inhibition of Na-K-2 CL Symporter on the apical
membrane of the epithelial cells in the ascending limb of the
loop of Henle
• They are bound to plasma proteins and their delivery ot the
site of action is limited by filtration
• They need to transported into the lumen by organic acid
transport system in PCT.
Distal Proximal Convoluted Tubule
NaHCO3 NaCl
Glomerulus
• Diabetic patients need a higher dose
• The bio-availability of :
Cortex
Medulla
• Frusemide: 40-70% of the oral dose
• Bumetanide and Torsemide: > 80%
NaCl
Carbonic
anhydrase
inhibitors
Descending
limb
• more effective in advanced HF patients and those
with right-sided HF
• greater cost
• Ethacrynic Acid: Slower onset of action and delayed or partial
reversibility. It is the choice for those with sulfa allergy.
553
MECHANISMS OF ACTION. Loop
diuretics are believed to improve
symptoms of congestion by
several mechanisms. First, loop
diuretics reversibly bind to and
reversibly inhibit the action of the
Na+,K+-2Cl− cotransporter, thereby
preventing salt transport in the
thick ascending loop of Henle.
Inhibition of this symporter also
inhibits Ca2+ and Mg2+ resorption
by abolishing the transepithelial
potential difference that is the
driving force for absorption of
these cations. By inhibiting the
concentration of solute within the
medullary interstitium, these
drugs also reduce the driving force
for water resorption in the collect-ing
duct, even in the presence of
AVP (see Chaps. 25 and 27). The
decreased resorption of water by
the collecting duct results in the
production of urine that is almost
isotonic with plasma. The increase
in delivery of Na+ and water to the
distal nephron segments also
markedly enhances K+ excretion,
particularly in the presence of ele-vated
aldosterone levels.
Loop diuretics also exhibit
several characteristic effects on
intracardiac pressure and systemic
hemodynamics. Furosemide acts
as a venodilator and reduces right
Thiazides
AVP antagonists
Loop
diuretics
Ascending
limb
Ascending
limb
NaCl
gradient
Na+
Loop of Henle
Mineralocorticoid
receptor antagonist
K+
Collecting duct
H2O
H2O
Na+
Na+
K+
FIGURE 28-10 Sites of action of diuretics in the kidney. AVP = arginine vasopressin. (From Bristow MR, Linas S, Port DJ:
Drugs in the treatment of heart failure. In Zipes DP, Libby P, Bonow RO, Braunwald E [eds]: Braunwald’s Heart Disease. 7th ed.
Philadelphia, Elsevier, 2004, p 573.)
10. LOOP DIURETICS
• Diuresis
• Reduction of Pre-Load and PCWP
• This effect is lessened in the presence of NSAIDs (esp. Indomethacin) as
it is dependent on the release of vasodilatory PGs
• Increase in After-Load as the result of increase in SVR secondary to RAS
activation.
• Hence, the need for combination with vasodilators.
• K, Mg, Ca are all excreted
11. THIAZIDE AND THIAZIDE-LIKE
• Prevent maximal urine dilution,
and decrease the ability of free
water clearance.
• Dilutional Hyponatremia
• Increase Ca resorption
• Decrease Mg resorption
• Increase K and H excretion as
the result of increased NaCl
delivery to the distal tubule.
NaHCO3 NaCl
Thiazides
Ascending
limb
Proximal Convoluted Tubule
AVP antagonists
Loop
diuretics
Ascending
limb
NaCl
H2O
Na+
Na+
Na+
K+
K+
Descending
limb
Glomerulus
Carbonic
anhydrase
inhibitors
Cortex
Medulla
Distal Proximal Convoluted Tubule
12. Thiazides
MINERALOCORTICOID
AVP antagonists
RECEPTOR ANTAGONISTS
Loop
diuretics
• Mineralocorticoids:
Ascending
limb
• Na and Water retention
NaCl
• K and H gradient
excretion
Mineralocorticoid
receptor antagonist
• Spironolactone
• Eplerenone
Collecting duct
Loop of Henle
diuretics in the kidney. AVP = arginine vasopressin. (From Bristow MR, Linas S, Port H2O
H2O
Na+
Na+
K+
K+
13. • Spironolactone:
• Antiandrogenic and progesterone-like effects; hence, the
gynaecomastia, impotence, and menstrual irregularities
• Eplerenone was developed to overcome the side effects
above.
• Eplerenone also has a shorter half-life
• Their benefits are less contributed to the diuretic effects. But
their peripheral anti-aldosterone effect plays a more
important role in reduction of cardiovascular morbidity and
mortality.
14. • How does spironolactone/eplerenone work?
• blocking the aldosterone receptor which is a cytosolic
ligand-dependent transcription factor
• these receptors are involved in myocardial fibrosis,
inflammation, and calcification.
• The mechanisms which have been attributed to
spironolactone to improve outcome include:
• prevention of extracellular matrix remodelling
• prevention of hypokalemia
15. MAJOR STUDY SUPPORTING
THE ABOVE
• RALES (Randomized Aldosterone Evaluation Study)Trial
(1999):
554
• Spironolactone 25 mg/d titrated to 50 mg/d if needed
vs. Placebo
• NYHA Class III and Class IV with LVEF of <35% already
CH
being treated with ACEI, Loop Diuretics, and Digoxin 28
in
majority.
• 30% reduction in mortality in the spironolactone group
(p=0.001):
• lower risk of death from progressive pump failure
and sudden death
• 35% reduction of hospitalisation
• significant improvement in the NYHA functional call (p
< 0.001)
• Other retrospective trials have also demonstrated a trend of
improvement in overall mortality in those with better NYHA
functional class when spironolactone was added to the
management.
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.00
PROBABILITY OF SURVIVAL
A MONTHS
Spironolactone
Placebo
0 3 6 9 12 15 18 21 24 27 30 33 36
40
16. 0.65
PROBABILITY MAJOR STUDY 0.60
0.55
SUPPORTING
THE ABOVE
• EPHESUS (Eplerenone Post-Acute Myocardial
Infarction Heart Failure Efficacy and Survival Study)
2003:
• A double-blinded placebo-controlled study
• Primary End Points:
• Death from cardiovascular causes
• Hospitalization for HF, AMI, Stroke,
Ventricular Arrhythmia
• Significant decrease in the death from
cardiovascular cause in the group which
received Eplerenone
• Other end points were also reduced.
• EMPHASIS-HF (Mild HF patients with NYHA class
II and eplerenone)
0.50
0.45
0.00
A 0 3 6 9 12 15 18 21 24 27 30 33 36
MONTHS
CUMULATIVE MORTALITY (%)
B
Placebo
40
35
30
25
20
15
10
5
0
Placebo
Eplerenone
P = 0.008
RR = 0.85 (95% CI, 0.75–0.96)
0 3 6 9 12 15 18 21 24 27 30 33 36
RANDOMIZATION (mo)
FIGURE 28-11 Kaplan-Meier analysis of the probability of survival in patients
in the placebo and treatment groups in the RALES trial (A) with spironolactone,
and probability of mortality in patients in the placebo and treatment groups in
the EPHESUS (B) trial using eplerenone. (Modified from Pitt B, Zannad F, Remme
WJ, et al: The effect of spironolactone on morbidity and mortality in patients with
severe heart failure. N Engl J Med 341:709, 1999; and Pitt B, Remme W, Zannad F, et al:
Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunc-tion
17. OTHER DIURETICS
• Pottasium-Sparing Diuretics:
• Amiloride, Triamterene
• Their effect in achieving a net negative Na balance is not that great in the patients with HF as their site of
action is more in the DCT and sodium retention happens more in the PCT part of the nephrons in this group
of patients.
• Carbonic Anhydrase Inhibitors:
• only should be used to correct the metabolic alkalosis that occurs as the result of other diuretics secondary to:
• Volume contraction
• Excessive H loss in the DCT
• When used repeatedly can cause:
• Metabolic Acidosis
• Hypokalemia
18. OTHER DIURETICS
• AVP Antagonists (Vaptans):
• As increased circulating AVP in patients
with HF lead to positive water balance (V2
receptor) and increased vascular resistance
(V1a receptor)
• 4 medications : Tolvaptan (V2), Lixivaptan
(V2), Satavaptan (V2), Conivaptan (V1a, V2)
• None have shown to improve mortality
• Their use have been authorised for those
who suffer from Hypervolemic or
Euvolemic hyponatremia (<125 mmol/L)
which is symptomatic and also resistant to
conventional therapies (fluid restriction,
etc.)
Principal cell
Collecting duct
Synthesis
DNA
↑cAMP PKA
Transport
receptor
–
Gs
V2
AVP
Tolvaptan
Conivaptan
AQP
H2O
H2O
NA+
K+
NA+
NA+
AQP
K+
H2O
AQP
FIGURE 28-12 Mechanism of action of vasopressin antagonists. The binding
of AVP to V2 receptors stimulates the synthesis of aquaporin-2 (AQP) water
channel proteins and promotes their transport to the apical surface. At the cell
19. DIURETICS
CH
28
552
TABLE 28-7 Diuretics for Treating Fluid Retention in Chronic Heart Failure
DRUG INITIAL DAILY DOSAGE MAXIMUM TOTAL DAILY DOSAGE DURATION OF ACTION (HR)
Loop diuretics*
Bumetanide 0.5-1.0 mg qd or bid 10 mg 4-6
Furosemide 20-40 mg qd or bid 600 mg 6-8
Torsemide 10-20 mg qd 200 mg 12-16
Ethacrynic acid 25-50 mg qd or bid 200 mg 6
Thiazide diuretics†
Chlorothiazide 250-500 mg qd or bid 1000 mg 6-12
Chlorthalidone 12.5-25 mg qd 100 mg 24-72
Hydrochlorothiazide 25 mg qd or bid 200 mg 6-12
Indapamide 2.5 mg qd 5 mg 36
Metolazone 2.5-5 mg qd 20 mg 12-24
Potassium-sparing diuretics
Amiloride 12.5-25 mg qd 20 mg 24
Triamterene 50-75 mg bid 200 mg 7-9
AVP antagonists
Satavaptan 25 mg qd 50 mg qd NS
Tolvaptan 15 mg qd 60 mg qd NS
Lixivaptan 125 mg qd 250 mg bid NS
Conivaptan (IV) 20-mg IV loading dose, followed by
20-mg continuous IV infusion/day
40-mg IV infusion/day 7-9
Sequential nephron blockade
Metolazone 2.5 to 10 mg qd plus loop diuretic
Hydrochlorothiazide 25 to 100 mg qd or bid plus loop diuretic
Chlorothiazide (IV) 500 to 1000 mg qd plus loop diuretic
NOTE: Unless indicated, all doses are for oral diuretics.
*Equivalent doses: 40 mg furosemide = 1 mg bumetanide = 20 mg torsemide = 50 mg of ethacrynic acid.
†Do not use if estimated glomerular filtration is <30 mL/min or with cytochrome 3A4 inhibitors.
NS = not specified.
Modified from Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 112:e154, 2005.
20. COMPLICATIONS
• Electrolyte Disturbances:
• Hypo- and Hyperkalemia
• Hypomagnesemia
• Hypo- and Hypercalcemia
• Hyponatremia
• Hypotension, decreased exercise tolerance, fatigue : dose reduction can improve symptoms
• Azotemia: does not need change in dose. In fact, in patients with advanced HFrEF higher levels of Urea
and Creatinine should be tolerated to achieve the desired therapeutic effects.
• Activation of RAS
• Ototoxicity: Ethacrynic acid / tinnitus, hearing impairment, deafness / usually reversible
21. DIURETIC RESISTANCE
• The effects of diuretics as the disease progresses
becomes less and less.
22. DIURETIC RESISTANCE
• 3 mechanisms that counteract the effects:
• Most of the loop diuretics are short acting; therefore, after a period of natriuresis then
a period of antinatriuresis ensues which in the setting of excess salt use can lead to a
stronger Na retention. This effect is due to RAS and SANS activation.
• Reduced response to endogenous natriuretic peptides in patients with progressive HF.
• As the result of excessive salt delivery to the DCT the epithelial cells undergo
hypertrophy and Na, K, ATP-ase activity increases as so does the the thiazide-sensitive
NaCl cotransporters. Hence, the Na resorptive capacity increases by 3 folds.
• Development of Cardiorenal Syndrome : Worsening renal function in the setting of
worsening heart failure. This should not be dismissed as pre-renal renal impairment.
23. DIURETIC RESISTANCE
• Strategies:
• More Frequent Dosing/ Higher Doses /
Continuous Infusion
• Addition of Second Line Diuretics
• Utilisation of Device-Based Therapies such as
Ultrafiltration.
25. ACE-INHIBITORS
• ACE-Inhs:
• Should be used for symptomatic and asymptomatic HFrEF (LVEF <40%)
• Interfere with RAS:
• reduce AT-II
• inhibit kininase II : increase bradykinin which further enhances the AT suppression
• Effects:
• Stabilise LV remodelling
• Improve patient symptoms
• Prevent hospitalisation
• Prolong life
26. • Start with lower dose and titrate up to the recommended
dose by doubling every 3-5 days.
• For stable patients it is acceptable to add beta-blockers
before achieving the full dose.
• Higher doses are more effective in preventing hospitalisation.
• What to watch? BP, Electrolytes, Renal Function, esp. in those
with pre-existing azotemia, hypotension, hyponatremia,
diabetes mellitus, and those taking supplemental potassium.
• Abrupt withdrawal of treatment should be avoided as this
might lead to clinical deterioration.
27. SURVIVAL BENEFIT
• Meta-analysis of ACE-Inh CH
in
patients with depressed EF
28
following an AMI
• 3 trials
560
40
30
0
A
10
Number at risk
ACEI
Placebo
2995
2971
ACEI
2250
2184
1617
1521
892
853
223
138
20
Placebo
CUMULATIVE MORTALITY (%)
0 1 2 3 4 5
40
30
MORTALITY (%)
28. 10
CUMULATIVE SURVIVAL BENEFIT
• Meta-analysis of ACE-Inh
in HF patients with
depressed EF including
the post-infarction
patients.
• 5 trials
0
A
B
0 1 2 3 4 5
Number at risk
2250
2184
1617
1521
892
853
223
138
0 1 2 3 4 5
TIME SINCE RANDOMIZATION (yr)
ACEI
Placebo
2995
2971
40
30
20
10
0
CUMULATIVE MORTALITY (%)
FIGURE 28-15 Meta-analysis of ACE inhibitors in HF patients with a depressed EF.
A, Kaplan-Meier curves for mortality for HF patients with a depressed EF treated with
an ACEI following an acute AMI (three trials). B, Kaplan-Meier curves for mortality for
HF patients with a depressed EF treated with an ACEI in five clinical trials, including
postinfarction trials. The benefits of ACEIs were observed early and persisted long
term. (Modified from Flather MD, Yusuf S, Kober L, et al: Long-term ACE-inhibitor therapy
in patients with heart failure or left ventricular dysfunction: A systematic overview of data
30. SIDE EFFECTS
• Most adverse effects are related to suppression of the RAS
• Mild hypotension and azotemia is well tolerated.
• If hypotension is associated with dizziness then:
• If fluid retention is significant: reduce the ACE-Inh dose
• If fluid retention is not an issue then reduce the diuretic dose.
• Potassium Retention: esp. if patient is receiving potassium supplements or potassium-sparing agents. If becomes
problematic, dose reduction might be necessary.
• Kinin-potentiation related side effects:
• Non-productive cough (10-15%)
• Angio-edema (1%)
31. ANGIOTENSIN-RECEPTOR
BLOCKERS
• Similar effects on:
• LV Remodelling
• Improving patient symptoms
• Preventing Hospitalisation
• Prolonging Life
• They work on angiotensin type 1 receptor: the responsible receptor for most of the adverse effects of the
RAS on CVS
• Their effectiveness is similar to ACE-Inh
• They can be well-tolerated in those suffering from adverse effects of ACE-Inh (angioedema, cough)
• Those with ACE-Inh induced hyperkalemia, will have the same problem with ARBs and the management
should be changed to a combination of Hydralazine and and oral nitrate
32. • There are studies that support the addition of
ARBs to ACE-Inh.
• The same precautions with ACE-Inh also
applies to ARBs for routine checking of K,
Renal Function, BP, etc.
33. SURVIVAL BENEFIT
• CHARM (Candesartan
Heart Failure : Assessment
of Reduction in Mortality
and Morbidity)Trial
(2003):
CH
28
• Candesartan effect on
the mortality and
hospital admission in
patients not receiving
ACE-Inh
562
50
40
30
20
10
0
HOSPITAL ADMISSION FOR CHF (%)
CARDIOVASCULAR DEATH OR
PROPORTION WITH
Placebo
Hazard ratio 0.77
(95% Cl 0.67–0.89), P = 0.0004
Adjusted hazard ratio 0.70,
P <0.0001
Time (years)
A
Candesartan
0 1 2 3 3.5
50
40
CHF (%)
DEATH OR
Placebo
Candesartan
34. 28
HOSPITAL ADMISSION Time (years)
20
PROPORTION CARDIOVASCULAR SURVIVAL BENEFIT
• CHARM-Added Trial
(2003):
• Candesartan effect on
the mortality and
hospital admission in
patients receiving ACE-Inh
10
0
Hazard ratio 0.77
(95% Cl 0.67–0.89), P = 0.0004
Adjusted hazard ratio 0.70,
P <0.0001
A
PROPORTION WITH
HOSPITAL ADMISSION FOR CHF (%)
CARDIOVASCULAR DEATH OR
B
0 1 2 3 3.5
50
40
30
20
10
0
Placebo
Candesartan
Hazard ratio 0.85
(95% Cl 0.75–0.96), P = 0.011
Adjusted hazard ratio 0.85,
P <0.010
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Time (years)
FIGURE 28-16 Effect of candesartan on cardiovascular mortality or hospital
admission for heart failure in the CHARM-Alternative trial (A) and the CHARM-Added
trial (B). Two groups of patients who were randomized to candesartan
or placebo are depicted—patients who were not receiving an ACEI (A) and
patients who were receiving an ACEI (B). The effect size of candesartan was
36. BETA-BLOCKERS
• Beta Blockers interfere with the harmful effects of sustained ANS activation.
• Although there are some benefits in blocking all the three adrenergic receptors
(alpha-1, beta-1, and beta-2); the deleterious side effects of the activation of adrenergic
system is attributed to beta-1
• They provide added benefits to ACE-Inh
• Three well-studied Beta-Blockers:
• Metoprolol Succinate (CR) (beta-1 selective)
• Bisoprolol (beta-1 selective)
• Carvedilol (nonselective blockade)
37. SURVIVAL BENEFIT
• MERIT-HF (Metoprolol
CR/XL Randomized
Intervention Trial in
Congestive Heart Failure)
- 2001: 34% reduction in
mortality in those with
mild-moderate HF and
moderate-severe systolic
dysfunction.
50
40
30
20
10
0
Placebo
Candesartan
Hazard ratio 0.77
(95% Cl 0.67–0.89), P = 0.0004
Adjusted hazard ratio 0.70,
P <0.0001
0 1 2 3 3.5
Time (years)
50
40
30
Placebo
Candesartan
CUMULATIVE MORTALITY (%)
EFFECT OF β-BLOCKADE ON MORTALITY IN CHF
MERIT-HF
Placebo
Metoprolol CR/XL
P = 0.0062 (adjusted)
P = 0.00009 (nominal)
n = 3991
FOLLOW-UP (mo)
↓34% mortality
OF SURVIVAL
CIBIS II
20
15
10
5
0
0 3 6 9 12 15 18 21
1.0
0.9
0.8
0.7
0.6
38. SURVIVAL BENEFIT
Hazard ratio 0.77
(95% Cl 0.67–0.89), P = 0.0004
Adjusted hazard ratio 0.70,
P <0.0001
0 1 2 3 3.5
• Bisoprolol: Time a (second years)
generation beta1-
selective blocker with 120 fold higher
affinity to beta1 than to beta2.
Placebo
• CBIS-Candesartan
II (Cardiac Insufficiency Bisoprolol
Study) - 1999:
• 32% reduction in all cause mortality
(p = 0.002)
• 45% reduction of sudden cardiac
death (p = 0.001)
• 30% reduction of HF hospitalisation
(p < 0.001)
• 15% reduction of all cause
hospitalisation (p = 0.002)
20
10
0
Hazard ratio 0.85
(95% Cl 0.75–0.96), P = 0.011
Adjusted hazard ratio 0.85,
P <0.010
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Time (years)
Effect of candesartan on cardiovascular mortality or hospital
heart failure in the CHARM-Alternative trial (A) and the CHARM-Added
Two groups of patients who were randomized to candesartan
depicted—patients who were not receiving an ACEI (A) and
receiving an ACEI (B). The effect size of candesartan was
group of patients who were receiving an ACEI. (Modified from
McMurray JJ, Yusuf S, et al: Effects of candesartan in patients with
failure and reduced left-ventricular systolic function intolerant to
CUMULATIVE MORTALITY FOLLOW-UP (mo)
↓34% mortality
n = 3991
patients)
CIBIS II
COPERNICUS
PROBABILITY OF SURVIVAL
TIME (days)
↓34% mortality
Placebo
Bisoprolol
n = 2647
P = 0.00006
10
5
0
0 3 6 9 12 15 18 21
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
100
90
0 200 400 600 800
39. 0.5
0.4
0.3
0.2
0.1
0.0
PROBABILITY TIME SURVIVAL BENEFIT
Hazard ratio 0.85
(95% Cl 0.75–0.96), P = 0.011
Adjusted hazard ratio 0.85,
P <0.010
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
• Carvedilol: a non-selective blocker.
Amongst all three, this has been
able to show the greatest benefit
in mortality reduction.
• COPERNICUS (Carvedilol
Prospective Randomised
Cumulative Survival):
• 38% reduction in the mortality
20
10
0
Time (years)
Effect of candesartan on cardiovascular mortality or hospital
heart failure in the CHARM-Alternative trial (A) and the CHARM-Added
Two groups of patients who were randomized to candesartan
depicted—patients who were not receiving an ACEI (A) and
were receiving an ACEI (B). The effect size of candesartan was
group of patients who were receiving an ACEI. (Modified from
McMurray JJ, Yusuf S, et al: Effects of candesartan in patients with
failure and reduced left-ventricular systolic function intolerant to
converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet
and McMurray JJ, Ostergren J, Swedberg K, et al: Effects of candesar-tan
with chronic heart failure and reduced left-ventricular systolic func-tion
angiotensin-converting-enzyme inhibitors: The CHARM-Added trial.
amongst patients with
advanced HF and euvolemic
status with LVEF < 25%
• 31% reduction in relative risk
of death and hospitalisation
2003.)
bisoprolol on mortality in subjects with symptomatic ischemic
nonischemic cardiomyopathy. CIBIS-I showed a nonsignificant (P =
risk reduction for mortality at 2-year follow-up. Because the
for CIBIS-I was based on an unrealistically high expected
the control group, a follow-up trial with more conservative
estimates and sample size calculations was conducted. In
bisoprolol reduced all-cause mortality by 32% (11.8% versus
0.002), sudden cardiac death by 45% (3.6% versus 6.4%; P =
hospitalizations by 30% (11.9% bisoprolol versus 17.6%
0.001), and all-cause hospitalizations by 15% (33.6% versus
0.002; see Fig. 28-17). The CIBIS-III trial addressed the impor-tant
of whether an initial treatment strategy using the beta
bisoprolol was noninferior to a treatment strategy of using an
100
0 200 400 600 800
FIGURE 28-17 Kaplan-Meier analysis of the probability of survival in patients
in the placebo and beta blocker groups in the MERIT-HF (top), CIBIS II (middle),
and COPERNICUS (bottom) trials. CHF = chronic heart failure. (Data from The
Cardiac Insufficiency Bisoprolol Study II [CIBIS-II]: A randomised trial. Lancet 353:9,
1999; Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Ran-domised
Intervention Trial in Congestive Heart Failure [MERIT-HF]. Lancet 353:2001,
SURVIVAL (% of patients)
COPERNICUS
Placebo
Carvedilol
n = 2289
P = 0.00013 (unadjusted)
P = 0.0014 (adjusted)
(days)
↓34% mortality
Placebo
Bisoprolol
n = 2647
P = 0.00006
90
80
70
60
0
0 3 6 9 12 15 18 21
MONTHS
↓35% mortality
40. OTHER BETA BLOCKERS
• Bucindolol: BEST Trial showed survival benefit in non-black patients versus increase mortality in
black patients. This was due to a polymorphism in beta1-adrenergic receptor
• Nebivolol:
• Selective Beta1-Blocker with ancillary vasodilatory effects (via nitric oxide pathways)
• SENIOR (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in
Seniors with Heart Failure)
• Significant reduction in composite outcome of death and rehospitalisation in older
patients (p = 0.04)
• The effects were similar in those with depressed and preserved EF (<=35% and >35%)
42. SIDE EFFECTS
• Fluid Retention
• General Fatigue : Generally resolves within weeks or months
spontaneously
• Bradycardia or Exacerbation of Heart Block:
• dose reduction if HR < 50, development of 2nd or 3rd degree
Blocks
• Not recommended for patients with asthma or active
bronchospasm.
43. RENIN-INHIBITORS
• Aliskiren : Orally active renin inhibitor
• nonpeptide inhibitor that binds to the active site of renin and prevents
conversion of angiotensinogen to angiotensin I
• ALOFT Study ( Aliskiren Observation of Heart Failure Treatment):
• Aliskiren Vs. Placebo to patients on ACE-Inh and NYHA Class II-IV
• End Point : change of base line N-Terminal pro BNP (a prognostic biomarker
for HF) in 3 months
• The NT-ProBNP levels were significantly lower in the Aliskiren group (p <0.01)
44. TRIALS
561
TABLE 28-9 Mortality Rates in Placebo-Controlled Trials*
TRIAL NAME AGENT NYHA CLASS
NO. OF PATIENTS
IN STUDY
12-MO PLACEBO
MORTALITY (%)
12-MO EFFECT
SIZE (%)
P VALUE AT
12 MO (FULL
FOLLOW-UP)
ACEIs
HF
CONSENSUS-1 Enalapril IV 253 52 ↓31 0.01(0.0003)
SOLVD-Rx Enalapril I-III 2569 15 ↓21 0.02 (0.004)
SOLVD-Asx Enalapril I, II 4228 5 0 0.82 (0.30)
Post-MI
SAVE Captopril — 2231 12 ↓18 0.11 (0.02)
AIRE Ramipril — 1986 20 ↓22 0.01 (0.002)
TRACE Trandolapril — 1749 26 ↓16 0.046 (0.001)
ARBs
HF
VAL-HeFT Valsartan II-IV 5010 9 0 NS (0.80)
CHARM-Alternative Candesartan II-IV 2028 8 ↓14 NS
CHARM-Added Candesartan II-IV 2548 8 ↓12 NS
Aldosterone Antagonists
HF
RALES Spironolactone III, IV 1663 24 ↓25 NS (<0.001)
Post-MI
EPHESUS Eplerenone I 6632 12 ↓15 NS (0.005)
Beta Blockers
HF
CIBIS-I Bisoprolol III, IV 641 21 ↓20† NS (0.22)
U.S. Carvedilol Carvedilol II, III 1094 8 ↓66† NS (< 0.001)
ANZ-Carvedilol Carvedilol I-III 415 NS NS NS (>0.1)
CIBIS-II Bisoprolol III, IV 2647 12 ↓34† NS (0.001)
MERIT-HF Metoprolol CR II-IV 3991 10 ↓35† NS (0.006)
BEST Bucindolol III, IV 2708 23 ↓10† NS (0.16)
COPERNICUS Carvedilol Severe 2289 28 ↓38† NS (0.0001)
Post-MI
CAPRICORN Carvedilol I 1959 ↓23† NS (0.03)
BEAT Bucindolol I 343 NS ↓12† NS (0.06)
NOTE: Twelve-month mortality rates were taken from the survival curves when data were not directly available in published material.
45. STAGES OF HEART FAILURE
CH
28
548
Stage D
Refractory
symptoms
requiring
special
intervention
Inotropes
Hospice
VAD, transplantation
Aldosterone antagonist, nesiritide
Consider multidisciplinary team
Revascularization, mitral-valve surgery
Cardiac resynchronization if bundle-branch block present
Dietary sodium restriction, diuretics, and digoxin
Stage C
Structural
disease,
previous or
current
symptoms
ACE inhibitors and beta-blockers in all patients
Stage B
Structural
heart
disease, no
symptoms
ACE inhibitors or ARBs in all patients; beta-blockers in selected patients
Treat hypertension, diabetes, dyslipidemia; ACE inhibitors or ARBs in some patients
Stage A
High risk
with no
symptoms
Risk-factor reduction, patient and family education
FIGURE 28-6 Stages of heart failure and treatment options for systolic heart failure. Patients with stage A HF are at high risk for HF but do not have structural
46. RECOMMENDATIONS
CH
28
564
contractility, effects However, is to leading increased Digoxin may therefore with of 0.125 0.125 1.0 ng/renal doses recommended rhythm about pharmacokinetics, drugs supplement Although Diagnosis of HF confirmed
Assess for fluid retention
Fluid retention
Diuretic
ICD if NYHA
Class II or III
CRT if NYHA class
III-IV and QRS > 120 ms†
(*ARB if ACEI intolerant)
Evaluate comorbidities
Evaluate precipitating factors
No fluid retention
ACE inhibitor*
NYHA I-IV
Persistent
symptoms
or
special
populations
Beta blocker
ARB
Aldosterone antagonist
Hydralazine/isosorbide
Digoxin
47. STAGE A
• Class I:
• Hypertension and lipid disorders should be controlled in
accordance with contemporary guidelines to lower the
risk of HF (Level of Evidence: A)
• Other conditions that may lead to or contribute to HF,
such as obesity, diabetes mellitus, tobacco use, and known
cardiotoxic agents, should be controlled or avoided. (Level
of Evidence: C)
48. identify increased HF risk in those receiving chemotherapy
may be useful but remain unvalidated as yet (333).
Tobacco use is strongly associated with risk for incident HF
(92,320,334), and patients should be strongly advised about the
hazards of smoking, with attendant efforts at quitting. Cocaine
and amphetamines are anecdotally but strongly associated with
HF, and their avoidance is mandatory. Although it is recognized
that alcohol consumption is associated with subsequent devel-opment
STAGE B
of HF (92,139,140), there is some uncertainty about the
and reduced EF, evidence-based beta blockers used to reduce mortality (346–348). (Level of Evidence: 3. In all patients with a recent or remote history of statins should be used to prevent symptomatic cardiovascular events (104,349–354). (Level of 4. In patients with structural cardiac abnormalities, LV hypertrophy, in the absence of a history of blood pressure should be controlled in accordance clinical practice guidelines for hypertension symptomatic HF (27,94,311–313). (Level of Evidence: Table 12. Recommendations for Treatment of Stage B HF
Recommendations COR LOE In patients with a history of MI and reduced EF, ACE inhibitors or ARBs
should be used to prevent HF
I A In patients with MI and reduced EF, evidence-based beta blockers
should be used to prevent HF
I B In patients with MI, statins should be used to prevent HF I A Blood pressure should be controlled to prevent symptomatic HF I A 27,94,311–ACE inhibitors should be used in all patients with a reduced EF to prevent HF I A Beta blockers should be used in all patients with a reduced EF to prevent HF I C An ICD is reasonable in patients with asymptomatic ischemic cardiomyopathy
who are at least 40 d post-MI, have an LVEF !30%, and on GDMT
IIa B Nondihydropyridine calcium channel blockers may be harmful in patients with low LVEF III: Harm C ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; COR, Class of Recommendation; EF, ejection fraction; GDMT, guideline-medical therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; MI, myocardial and N/A, not available.
49. STAGE C
JACC Vol. 62, No. 16, 2013 Yancy et al.
October 15, 2013:e147–239 2013 ACCF/AHA Heart Failure Guideline: Full Text
HFrEF Stage C
NYHA Class I – IV
Treatment:
For NYHA class II-IV patients.
Provided estimated creatinine
>30 mL/min and K+ <5.0 mEq/dL
Class I, LOE A
ACEI or ARB AND
Beta Blocker
For persistently symptomatic
African Americans,
NYHA class III-IV
Add Add Add
Class I, LOE C
Loop Diuretics
Class I, LOE A
Hydral-Nitrates
Class I, LOE A
Aldosterone
Antagonist
For all volume overload,
NYHA class II-IV patients
e173
Figure 1. Stage C HFrEF: evidence-based, guideline-directed medical therapy. ACEI indicates angiotensin-converting enzyme inhibitor;
ARB, angiotensin-receptor blocker; HFrEF, heart failure with reduced ejection fraction; Hydral-Nitrates, hydralazine and isosorbide dinitrate;
LOE, Level of Evidence; and NYHA, New York Heart Association.
