UPTODATE CLINICAL CARE IN HEART FAILURE

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UP-TO-DATE CLINICAL CARE IN HEART FAILURE

• Andrew Ignaszewski MD FRCPC
• Heart Function Clinic and
• Heart Transplant Program
• St. Pauls Hospital
• Vancouver BC

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Outline

• Recent advances in diagnosis of CHF
• BNP
• Recent advances in treatment of CHF
• ACEI and ARB
• CABG
• ICD and CRT
• BC Heart Failure Care
• Diagnostic algorithm
• Therapeutic algorithm

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Myocardial matrix slippage
Dissolution of collagen struts
Increased surface area of ventricle
4
LV Remodelling Post MI
5
Heart Failure after Acute MI
Cumulative HF ()
30
25
20
15
10
5
0
0
1
2
3
4
5
6
7
8
9
10
30
Days
Years
Time
Kannel et al, 1979
6
LV Remodelling Post Anteroseptal MI
Apical 4 chamber view End diastole
Sharpe N. 2000
7
Common Signs and Symptoms of CHF

• Signs
• Jugular venous
• Distention
• Peripheral edema
• Pulmonary congestion / rales
• Pleural effusions
• S3 gallop

• Symptoms
• Dyspnea on exertion
• Orthopnea
• Paroxysmal nocturnal
• Dyspnea
• Fatigue
• abdominal fullness
• Anorexia, nausea, vomiting

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Origin of Symptoms in Chronic Heart Failure
1. Lungs increased stiffness due to raised
venous pressure and lymphatic distension increas
ed left atrial pressure increased physiological
dead space increased respiratory rate weakness
of diaphragm 2. Circulation reduced blood flow
to skeletal muscle increased production of
metabolites altered response to metabolites 3.
Skeletal muscle rest atrophy ischemic
atrophy activation of ergoreceptors
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Diagnoses Confused with Heart Failure

• Lung diseases (asthma, obstructive lung disease,
  bronchitis)
• Consequences of obesity
• Lack of fitness
• Fatigue/depression
• Renal disease, pulmonary emboli, shunts,
  hypertension

10
Causes of Hospitalisation in CHF
250
55
200
150
No. of patients
25
100
15
50
6
6
6
0
Sodiumretention
Angina/MI
Dysrhythmia
Hyper-tension
COPD
Infection
Bennett SJ et al. Am J Crit Care 1998
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Hospital Visits for CHF
Emergency department presentations
21
79

• Approximately 80 of ED visits for HF result in
  hospitalisations

Repeat visit
Initial episode

• Rates of hospital readmission
• 2 within 2 days
• 20 within 1 month
• 50 within 6 months

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CHF how hard to diagnose?
Opinion CHF is easy to diagnose clinically I
can diagnose it when the patient enters the door
Sensitivity
Specificity
PPV
()
()
()
Symptoms 1
21 66
52 81
2 26
Clinical picture 2
7 31
91 99
2 - 67
1 subjective 2 objective

• Fraction falsely diagnosed heart failure in
  primary health care - Framingham 40 (McKee
  1971) - Boston 42 (Carlson 1985) - Kuopio
  50 (Remes 1991)
• Echocardiogram, the current gold standard -
  expensive, time consuming, need an expert -
  cannot be used on all patients (e.g. adipositas
  and emphysema)

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Natriuretic Peptides
15
SYNTHESIS AND SECRETION OF BNP
cardiomyocyte
blood
Receptors and Endopeptidases
No known receptors or enzymes
16
POTENTIAL CLINICAL APPLICATIONS OF BNP

• Establish/rule out diagnosis of CHF
• Short and long term prognostic stratification in
  CHF and post-MI
• Screening for LV dysfunction in general
  population
• Monitoring for decompensation and hormone-guided
  therapy
• Risk stratification in acute coronary syndrome
• Monitor for cardiac transplant rejection
• Therapy for acute CHF

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Liu et al. Can J Cardiol 200319347
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BNP Levels of Patients Without CHF, With Baseline
LV Dysfunction, and With CHF
N139 N14 N97
Dao, Q., Maisel, A. et al. J. American College of
Cardiology, Vol 37, No. 2, 2001
20
BNP Levels in Patients With Dyspnea Secondary to
CHF or COPD
N56 N94
Dao, Q., Maisel, A. et al. J. American College of
Cardiology, Vol 37, No. 2, 2001
21
BNP Levels in Patients With Edema Diagnosed With
CHF or Without CHF
N44 N44
Dao, Q., Maisel, A. et al. J. American College of
Cardiology, Vol 37, No. 2, 2001
22
BNP vs. EF by Echocardiography
Davis et al. Lancet 1994343440-4.
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Plasma BNP Concentration
Survival in CHF Patients With LV Dysfunction
BNP lt 73 pg/ml
100
80
plt 0.0001
Cumulative Survival ()
60
40
BNP gt 73 pg/ml
20
0
Months
0
10
20
30
40
50
Tsutamoto T. et al. Circulation 199796509-516
24
NT-proBNP Monitoring and Guidance of CHF Therapy
Improves Outcomes
Heart failure or death
Cardiovascular events
100
100
NT-proBNP
NT-proBNP
90
90
Clinical
Clinical
80
80
Event free ()
70
70
60
60
50
50
P 0.049
P 0.034
40
40
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Time after randomisation (days)
Time after randomisation (days)
Troughton RW et al. Lancet 2000
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Heart Failure Care
BC HF Guideline draft April 23,03
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Management Algorithm for Heart Failure
1. Establish that patient has heart
failure 2. Determine aetiology of heart
failure 3. Identify concomitant disease relevant
to heart failure 4. Assess severity of
symptoms 5. Predict prognosis 6. Anticipate
complications 7. Choose appropriate
treatment 8. Monitor progress and tailor treatment
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Investigations and Assessment in HF
Lifestyle Laboratory Outcome Symptoms ECG and
CXR Mortality NYHA Echocardiogram Morbidity Qo
L creatinine Hb and FBS Physical
signs Thyroid function Liver function,
lipids, ? exercise test Radionuclide
study Heart Catheterization
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Polypharmacy From a Guideline Perspective
The cardiovascular continuum
NYHA Class
Risk factor
0 I II III IV
LV dysfunction
Heart Failure
ASA Statins ? blockers ACE inhibitors CCB
Mild
Diuretics ACE inhibitors ? blockers ARB Spironolac
tone Digoxin
Moderate
Severe
Time
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Goals of Treatment in CHF

• Improve Prognosis
• Mortality
• Morbidity
• Disease progression
• Improve Quality of Life
• Reduce symptoms
• Manage adverse effects

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Mortality Reduction with ACEi
50 40 30 20 10 0
54
ACE Inhibitor Control
40
39
35
Mortality ()
25
23
20
17
Enalapril 20 mg bid p0.003
Enalapril 10 mg bid plt0.0036
Captopril50 mg tid p0.019
Ramipril 5 mg bid p0.002
Follow up times were 6 and 12 months 48
months 6 months. The CONSENSUS Trial Study
Group. N Engl J Med 19873161429-1435. The SOLVD
Investigators. N Engl J Med 1991325293-302. The
SAVE Investigators. N Engl J Med
1992327669-677. AIRE Investigators. Lancet
1993342821-828.
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ACE Inhibitors - Hospitalization Benefit
Benzapril, Cilazapril, Penndopril Adapted from
Garg R. et al. JAMA 19952731450-1456.
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Use of ACEi for Treatment of Heart Failure

• Introduce as soon as safely possible
• Following acute MI, unless contraindicated or not
  tolerated, for 6 weeks, or indefinitely in those
  with LVEF lt 40 or clinical evidence of CHF
• All asymptomatic patients with LVEF lt 35-40,
  unless contraindicated or not tolerated
• All patients with symptomatic CHF, NYHA Class
  II-IV unless contraindicated or not tolerated
• Target dose should be either the dosage used in
  trials or maximum tolerated dose

Canadian Cardiovascular Society Guideline Update
for the Management Prevention of CHF 2001.
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ACEI Indicated for HF in BC
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MOCHA - Effect of Carvedilol on LVEF
p?0.05 vs. placebo. plt0.0001 vs. placebo

plt0.001


??LVEF (EF units)
Placebo
25 mg bid
6.25 mg bid
12.5 mg bid
Carvedilol
Patients receiving diuretics, ACE inhibitors,
digoxin follow-up 6 months placebo (n84),
carvedilol (n261). Multicenter Oral Carvedilol
Heart Failure Assessment. Adapted from Bristow
MR, et al. Circulation. 19969428072816.
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All-cause mortality
Beta blockers in CHF
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COPERNICUS
Survival
All-cause mortality
100
90
Carvedilol
80
Placebo
70
60
Nominal p0.00014 35 risk reduction
50
24
0
20
16
12
8
4
28
Months
.
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Major Clinical Trials with Beta-blockers with
Heart Failure
Canadian Cardiovascular Society Guideline Update
for the Management Prevention of CHF 2001.
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Effect of Bucindolol on Mortality by Race
1.0
p0.014
0.8
Nonblacks
Probabilityof Survival
Blacks
0.6
Hazardratio 1.31
0.4
0
6
12
18
24
30
36
42
Months Post-randomization
Eichhorn EJ et al. Circulation.
2000102(Suppl)II-778. Abstract 3759.
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Principal RCTs of ? Blockers in CHF
Entry Criteria
Minimum
Minimum
Stable
Open-label
Minimum LVEF
systolic BP
heart rate
(weeks)
challenge
(units)
(mmHg)
(bpm)
MDC
stable
4
40
90
45
CIBIS-I
6 (3)
4
40
100
65
4
ANZ
4
45
90
50
US carvedilol
8 (4)
4
35
85
68

CIBIS-II
6
35
100
60

MERIT-HF
2
40
100
68
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Change in Heart Rate and CHF Mortality
Change in mortality ()
60
PROFILE
40
XAMOTEROL
PROMISE
20
VHeFT (Prazosin)
0
CIBIS
VHeFT (HDZ/ISDN)
-20
SOLVD
BHAT
-40

NOR TIMOLOL
CONSENSUS
ANZ
-60
US CARVEDILOL
-80
MOCHA

GESICA
-100
-20
-16
-12
-8
-4
0
4
8
12
Change in heart rate (bpm)
Kjekshus Gullestad (1999)
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Effect of Carvedilol on Risk of a Clinical Event
in Subgroups Defined by Baseline SBP
All-cause Mortality
85-95 mm Hg
Interaction p0.64
96-105 mm Hg
106-115 mm Hg
116-125 mm Hg
gt 125 mm Hg
Death or CHF hospitalizations
Interaction p0.80
Hazard Ratio
0
0.2
0.4
0.6
0.8
1
1.2
1.4
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Target Doses and Outcomes in Trials of Beta
Blockers
Effect onMortality
Dose Range(mean dose)
Metoprolol

MDC1
100150 mg (108 mg)
No ?
(tartrate)
MERIT-HF2
200 mg (159 mg)
? 34
(succinate)
Bisoprolol
5 mg (3.8 mg)
CIBIS3
NS
10 mg (7.5 mg)
CIBIS II4
? 34
plt0.01. The combined endpoint of mortality
and need for transplantation was significantly
reduced. 1. MDC Trial Study Group. Lancet.
199334214411446. 2. MERIT-HF Study Group.
Lancet. 199935320012007. 3. CIBIS
Investigators. Circulation. 19949017651773. 4.
CIBIS II Investigators. Lancet. 1999353913.
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Recommendations for the Use of Beta-blockers in
Heart Failure

• All NYHA class II-III HF and LVEF ? 40, unless
  contraindicated to reduce mortality,
  hospitalizations, and to improve cardiac function
  and quality of life
• Patients with stable class IV HF
• Patients who are NYHA class I asymptomatic with
  LV systolic function with LVEF ? 40,
  particularly
• post-MI

Canadian Cardiovascular Society Guideline Update
for the Management Prevention of CHF 2001.
46
Starting beta Blockade in CHF
Dose titration - Bisoprolol
10.0 mg bid
7.5 mg bid
5.0 mg bid
2.5 mg bid
1.25 mg bid
Increments every 24 weeks or more
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?-blocking Therapy in CHF
a Matter of Understanding, Timing and Patience

• START LOW (initial doses used in CIBIS II, MERIT,
  US CARVEDILOL, COPERNICUS in stable patients)
• GO SLOW (up-titrate every 1-4 weeks
  depending on clinical status)
• DO NOT INTERRUPT TOO
  QUICKLY AND ABRUPTLY (try to achieve
  stability altering other therapies first)
• ? ?-blockade needs months to establish efficacy

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Beta Blocker Uptitration

• Prior to next dose increase assess for following
  signs of intolerance
• Worsening volume overload
• Symptomatic hypotension
• Symptomatic bradycardia
• Most of these negative effects are transient and
  resolve within 2-4 weeks but can return with each
  up-titration of beta-blocker medication.
• Patients often need support to continue
  medication through this start-up phase.
• Suggestions for management of transient symptoms
  include
• Taking beta-blocker at night (if once daily)
• Taking other vasodilator medications at alternate
  times (e.g. ACE Inhibitor at noon)
• Taking beta-blocker with food.

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Starting Beta Blockade in CHF
Presumed time course of effects
Clinical benefits
Clinical deterioration
12
34
56
78
910
1112
0
Months
50
Starting beta Blockade in CHF
Actions in case of adverse reactions
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Beta Blocker Symptom Management
52
Beta-Blocking Drugs for HF in BC
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Treatments to Reduce Mortality in CHF
ACE Inhibitors 39 Trials n8,308 1,361
deaths OR24 NNT/year 74
Beta blockers 26 Trials n10,502 1,172
deaths OR36 NNT/year 29
ACE-I beta blockers NNT/year 21
Cleland Freemantle (1999)
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Dose-titration and visit schedule
Candesartan/matching placebo once daily
32 mg
16 mg
8 mg
32 mg
4 mg
16 mg
8 mg
Every 4 months until study end
Time
0 w
2 w
4 w
6 w
6 m
Visit
1
2
3
4
5
55
CHARM-Alternative
Baseline characteristics
Candesartan Placebo n1013 n1015
Reason for ACE-I intolerance () cough 70 74
hypotension 14 12 renal dysfunction 13 10
angioedema/anaphylaxis 4 4 other 10 11
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CHARM-Alternative
CV death or CHF hospitalisation
50

RRR23
406 (40.0)
Placebo
40
334 (33.0)
30
Candesartan
20
10
HR 0.77 (95 CI 0.67-0.89), p0.0004Adjusted HR
0.70, plt0.0001
0
0
1
2
3
years
3.5
Number at risk Candesartan 1013 929 831 434 122 P
lacebo 1015 887 798 427 126
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CHARM-Alternative
Secondary outcomes
p-value
Candesartan
Placebo
0.85
CV death 219 252 CHF hosp. 207 286 CV death,
CHF hosp, 353 420 MI CV death, CHF
hosp, 369 432 MI, stroke CV death, CHF
hosp, 396 456 MI, stroke, revasc
0.072
0.68
lt0.0001
0.78
0.0007
0.80
0.001
0.81
0.002
0.6
0.8
1.0
1.2
1.4
candesartan better
Hazard ratio
placebo better
58
CHARM-Alternative
Permanent study drug discontinuations
Percent of patients
Placebo
25
23.1
Candesartan
20
15
13.6
12.0
9.1
10
(1/39)
4.2
5
2.6
1.0
0.5
0.3
0
0
Hypo-tension
Increased creatinine
Cough
Increasedpotassium
Angioedema
59
CHARM-Added
CV death or CHF hospitalisation
50

RRR15
538 (42.3)
Placebo
40
483 (37.9)
30
Candesartan
20
10
HR 0.85 (95 CI 0.75-0.96), p0.011Adjusted HR
0.85, p0.010
0
0
1
2
3
years
3.5
Number at risk Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422
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CHARM-Added
Secondary outcomes
p-value
Candesartan
Placebo
0.84
CV death 302 347 CHF hosp. 309 356 CV death,
CHF hosp, 495 550 MI CV death,CHF
hosp, 512 559 MI, stroke CV death,CHF
hosp, 548 596 MI, stroke, revasc
0.029
0.83
0.014
0.85
0.010
0.87
0.020
0.87
0.015
0.6
0.8
1.0
1.2
1.4
candesartan better
Hazard ratio
placebo better
61
CHARM-Added,
Prespecified subgroups
p-value for treatment interaction
Candesartan
Placebo
Beta- Yes 223/702 274/711blocker No 260/574 264/
561 Recom. Yes 232/643 275/648dose
of No 251/633 263/624ACE inhib. All
patients 483/1276 538/1272
0.14
0.26
0.6
0.8
1.0
1.2
1.4
CV death or CHF hosp.
candesartan better
Hazard ratio
placebo better
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CHARM-Preserved
Primary and secondary outcomes
Covariate adjustedp-value
p-value
Candesartan
Placebo
0.89
0.118
0.051
CV death, CHF hosp. 333 366 - CV death 170 170
- CHF hosp. 241 276 CV death, CHF
hosp, 365 399 MI CV death,CHF hosp, 388 429
MI, stroke CV death,CHF hosp, 460 497 MI,
stroke, revasc
0.99
0.918
0.635
0.85
0.072
0.047
0.90
0.126
0.051
0.88
0.078
0.037
0.91
0.123
0.13
0.8
1.0
1.2
candesartan better
Hazard ratio
placebo better
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Algorithm for Heart Failure Neurohormonal
Inhibiting Drug Therapy
Heart Failure (digoxin, diuretics as indicated)
ACE-I
Tolerated
Not tolerated
Add beta blocker
ARB
Tolerated
Tolerated
Not tolerated
Follow-up
Beta blocker
ARB
Follow-up
Follow-up
Follow-up
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Effects of Adding ?-Blockers or Angiotensin
Receptor Blockers vs Increasing ACE Inhibitor
Dose in HF
Symptoms Hospitalization Mortality Increase
dose No ? 12 8 NS of ACE inhibitor1 effect Ad
d angiotensin Improvement ? 27 No receptor
blocker2 effect Add ?-blockade3
Improvement ? 20-35 ? 35
vs. low dose ACE Not recommended for patients
receiving ACEI and ?-blockade. vs.
recommended ACE dosage. 1. Packer M et al.
Circulation. 199910023122318. 2. Cohn JN et
al. N Engl J Med. 20013451667-1675. 3. Lechat P
et al. Circulation. 19989811841191.
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CHF Disease Management
Control Volume Slow Disease Progression

Diuretic
RAAS Inhibition
Beta-Blockade
Treat residual symptoms
DIGOXIN
SPIRONOLACTONE
Am J Cardiol 199983(suppl 2A)9A-38A
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Heart Failure Care
BC HF Guideline draft April 23,03
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Prognosis in LV Systolic Dysfunction

• Prognosis for patients with ischemic
  cardiomyopathy is poor despite all medical Rx
• 5 yr survival rates range 50-60 at best
• Survival is worse with
• Increasing age
• Decreasing LVEF
• Extent of CAD

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Non-contracting Myocardium
Dead
Alive
Infarcted
Stunned
Ischemic
Hibernating
69
LV Systolic Dysfunction

• Stunned Myocardium
• prolonged impairment of LV contractility after
  a period of transient ischemia
• Hibernating Myocardium
• depressed myocardial contractility at rest due
  to persistently impaired coronary blood flow
• sufficient blood flow to sustain viability but
  inadequate to maintain systolic contraction
• Infarcted Myocardium DEAD MEAT

70
Improved LVEF after Revascularization
Hibernating Myocardium
71
Survival in Based on MCR
Treatment Strategy
Plt0.02
Plt0.007
Survival ()
Chaudhry et al., JACC, 1999.
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Cognitive Function and CHF

• What people know about their disease

Patients
78
Heart Failure- Cause for Hospital Admission
Other
Non compliance
Ischemia
Arrhythmia
Volume overload
0
10
20
30
40
of Patients
79
ACC / AHA Guidelines
Stage A High risk for CHF No structural heart
disease or CHF symptoms
Stage B Structural heart disease No CHF symptoms
Stage C Structural heart disease Prior or
current CHF symptoms
Stage D Refractory CHF requiring
special interventions
Development of CHF symptoms
Refractory symptoms of CHF at rest
Structural heart failure
eg, Patients who have marked symptoms at rest
despite maximal medical therapy (eg, those who
are recurrently hospitalised or cannot be safely
discharged from the hospital without
specialised interventions)
eg, Patients with hypertension, coronary
artery disease, diabetes mellitus, or patients
using cardiotoxins or with FHx CM
eg, Patients with known structural heart
disease, shortness of breath and fatigue reduced
exercise tolerance
eg, Patients with previous MI LV systolic
dysfunction asymptomatic valvular disease
Therapy treat hypertension, encourage smoking
cessation, treat lipid disorders, encourage
regular exercise, discourage alcohol intake and
illicit drug use, ACE inhibition in appropriate
patients
Therapy All measures under Stages A, B and C,
mechanical assist devices, heart
transplantation, continuous iv inotropic infusions
for palliation, hospice care
Therapy All measure under stage A, drugs for
routine use (diuretics, ACE inhibitors, b
blockers, digitalis), dietary salt restriction
Therapy All measures under Stage A, ACE
inhibitors in appropriate patients, b blockers
in appropriate patients
80
DIAGNOSTIC CHALLENGE OF CHF

• Symptoms are vague and non-specific
• Especially in early stages
• gt60 CHF patients are NYHA Class I - II
• Fraction falsely diagnosed CHF in primary health
  care - Framingham 40 (McKee 1971)
  - Boston 42 (Carlson 1985) -
  Kuopio 50 (Remes 1991)
• Misdiagnosis of CHF in Emergency Department -
  Multicenter BNP 26 (Maisel, ACC, 2002)

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Actions in Case of Adverse Reactions to BB in HF
Evaluate symptoms
Caused by direct or indirect effects by ? blocker
therapy? Symptom Action Dyspnea Increase
diuretics / adjust b blocker Fluid
retention Increase diuretics Bradycardia Adjust
dogoxin / b blocker Hypotension Adjust
ACE-inhibitor / ? blocker
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Heart Failure

• Clinical successes
• Better prevention? (primary and secondary)
• RCTs showing
• Effective relief of symptoms
• Reduction in hospitalisation
• Increased life expectancy

• Clinical failures
• Rising incidence prevalence
• Increases in hospitalisation
• Diagnosis
• High continuing mort/morb
• Implementing effective therapy
• Polypharmacy (and myths)
• Over-utilisation of unproven technology/surgery
• Delivery of message to the public
• Many others

83
Heart Failure Future Issues

• Rising prevalence
• Ageing of the population
• Prevention
• Diagnosis
• Implementation
• Rationalisation
• New diagnostic groups
• New treatments