Chronic Heart Failure: Diagnosis and modern management

1
Chronic Heart FailureDiagnosis and modern
management

• Dr Kris McLaughlin
• SHO 3 Cardiology
• Aberdeen Royal Infirmary

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Definition of heart failure

• A clinical syndrome comprising of dyspnoea,
  fatigue or fluid retention due to cardiac
  dysfunction, either at rest or on exertion, with
  accompanying neurohormonal activation.
• Braunwald E.

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There are many mechanisms of heart failure

• LV systolic dysfunction many causes
• Valvular heart disease
• Restrictive cardiomyopathy eg amyloid
• Pericardial constriction
• LV diastolic dysfunction
• Cardiac arrhythmias

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Epidemiology

• Prevalence of heart failure 0.4 - 2
• Prevalence of asymptomatic LVSD 0.4 - 2
• Prevalence and incidence increase with age (mean
  age 74years)
• Approximately 1 million cases in the UK
• or 100 000 in Scotland
• prevalence and incidence are increasing..
• ageing pop, better survival post MI/CHF

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Pathophysiology of Heart Failure (due to LVSD)
Coronary artery disease
Arrhythmia
Left-ventricular injury
Pathologic remodelling
Left-ventricular dysfunction
Hypertension
Death
Cardiomyopathy
Pump failure
Neurohormonal activation
Valvular disease

• Vasoconstriction
• Endothelial
• dysfunction
• Renal sodium
• retention

• Symptoms
• Dyspnoea
• Fatigue
• Oedema

Heart failure
Adapted from Fonarow GC et al. Rev Cardiovasc
Med. 2003 4(1) 8-17.
.
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Grading of heart failure
Coronary heart disease statistics heart failure
supplement., BHF 2002, http//www.heartstats.org,
accessed 25.02.04. Prevalence data is from a
population based study Davies MK et al. The
Lancet 2001 358 439-444.
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Prognosis Heart Failure vs Cancer Mortality
The one-year survival rate for heart failure is
worse than that for cancer of the breast, uterus,
prostate bladder
Coronary heart disease statistics heart failure
supplement., BHF 2002, http//www.heartstats.org,
accessed 25.02.04. Based on Quinn M et al. ONS
2001 Cowie MR et al. Heart 2000 83 505-510.
NHL Non-Hodgkins lymphoma
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Left Ventricular Function HF
Mortality
Kaplan-Meier plot showing mortality rate in 5491
patients hospitalised with congestive HF, grouped
according to wall motion index (WMI) (log-rank, P
WMI WMI 0.8-1.2
WMI 1.3-1.6
WMI 1.6
0
Years
Left ventricular systolic function is a potent
predictor of death in hospitalised heart failure
patients
Survival data from 5491 patients admitted for new
or worsening heart failure in 34 Danish centres
1993-1996. Left ventricular systolic function was
estimated using wall motion index score.
Follow-up was 5-8 years.
Gustafsson F et al. Eur Heart J 2003 24 863-870.
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Costs of HF to the UK NHS (2000)
Hospital
Primary care
inpatient care
16.5
Drugs
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Outpatient
60.5
6
investigations
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Hospital
outpatient care
Coronary heart disease statistics heart failure
supplement., BHF 2002, http//www.heartstats.org,
accessed 25.02.04.
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Average Length of Hospital Admission HF vs
Other Conditions
Coronary heart disease statistics heart failure
supplement., BHF 2002, http//www.heartstats.org,
accessed 25.02.04. Based on Hospital Episode
Statistics DOH 2001 at http//www.dh.gov.uk/publi
cationsandstatistics/statistics/hospitalepisodesta
tistics/fs/en accessed 10.03.04
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Heart failure can be easy to diagnose
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.but usually it is difficult to diagnose on
clinical grounds alone

• Studies show diagnosis incorrect in approx.
  30-40 of cases
• Chest crepitations, oedema, tachycardia not
  specific
• S3, ?JVP, displaced apex insensitive, poor
  inter-observer agreement
• Many patients have symptoms only dyspnoea,
  fatigue are non specific
• Therefore objective evidence of cardiac
  dysfunction mandatory
• Wheeldon et al QJMed 19938617-24

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Diagnosis of heart failure (ESC guidelines)

• 1 symptoms or signs of HF (rest or exercise)
• and
• 2 objective evidence of cardiac dysfunction
• and (in doubtful cases)
• 3 response to therapy (diuretics)

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Obtaining objective evidence of cardiac
dysfunction

• Echocardiography, Radionuclide ventriculography
  (RNVG/MUGA), MRI, left ventriculography
• Approx. 2-4 of the population
• Approx. 22/1000/year 11 000 for the North East
• (more in fact in view of difficulty in clinical
  diagnosis and serial studies!)
• Are screening tests the answer?

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Potential screening tests

• 12 Lead ECG
• LVSD very unlikely if ECG normal (90-95
  sensitive)
• Problems with confidence of interpretation in
  primary care, must be entirely normal or else
  loses reliability
• BNP (brain (B-type) natriuretic peptide)
• Amino acid peptide, can be measured easily in
  blood
• Elevated in heart failure, therefore low BNP
  effectively excludes heart failure
• May be useful diagnostic testmay soon come into
  widespread clinical use

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BNP as a screening test for heart failure

• Highly sensitive test for HF, stable for up to
  72hours, bedside testing available if desired,
  relatively inexpensive
• Low BNP effectively rules out heart failure or
  LVSD, elevated BNP indicates need for an
  echo/cardiac assessment
• Many published trials assessing utility of BNP in
  suspected heart failure, the general population,
  post MI vast majority suggest it is a useful
  and reliable screening test

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Relationship between BNP and echocardiographic
abnormalities in 331 patients with suspected
heart failure
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Modern treatment of chronic heart failure (LV
systolic dysfunction)

• The past - haemodynamic hypothesis
• The present - neurohormonal hypothesis
• ACE inhibitors
• Betablockers
• Aldosterone receptor blockers
• ARBs
• Beyond neurohormonal manipulation
• CRT
• Cardiac transplantation

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The Past

• Haemodynamic hypothesis damaged pump causes low
  blood pressure and back pressure causes oedema
• Liberal use of diuretics and digoxin
• Vasodilator therapy
• V-HEFT I (1986)
• Hydralazine (300mg) and ISDN (160mg) superior to
  placebo (or prazosin)
• Mortality 25.6 at 2 years v 34.3 in placebo
  (p

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DIG trial
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Neurohormonal Hypothesis

• HF is a systemic disorder cardiac dysfunction,
  renal dysfunction, skeletal muscle dysfunction,
  systemic inflammation, neurohormonal activation
  (mostly maladaptive)
• Renin-angiotensin-aldosterone system
• salt and water retention
• adverse haemodynamics
• LV hypertrophy/remodelling and fibrosis
• hypokalaemia and hypomagnesaemia
• SNS arrhythmogenic, adverse haemodynamics,
  increases renin etc

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RAAS Therapeutic Intervention Sites
Angiotensinogen secreted by the liver
Renin secreted by kidney
Angiotensin I
Angiotensin converting enzyme (ACE) from lung
tissue
ACE inhibitors
Angiotensin II - potent vasoconstrictor
Adrenal cortex
Blood vessel constriction
Angiotensin II receptor antagonists
Aldosterone release
Blood pressure?
Aldosterone receptor antagonists
Adapted from Stier CT et al. Heart Disease 2003
5 (2) 102-118 and McMahon EG. Current Opinion in
Pharmacology 2001 1 190-196.
Target organ effects
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Major Trials of ACE-Inhibitors in HF
The CONSENSUS Trial Study Group. N Eng J Med
1987 316 1429-1435., The SOLVD Investigators. N
Eng J Med 1991 325 293-302. The SOLVD
Investigators. N Eng J Med 1992 327 685-691.,
Pfeffer MA, Braunwald E, Moye LA et al. The SAVE
Investigators. N Eng J Med 1992 327 669-677.,
The Acute Infarction Ramipril Efficacy (AIRE)
Study Investigators. Lancet 1993 342 821-828.,
Køber L, Torp-Pedersen C, Carlsen JE et al.
Trandolapril Cardiac Evaluation (TRACE) Study
Group. N Eng J Med 1995 333 1670-1676.
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ACE inhibitors are the cornerstone of therapy for
heart failure due to LV systolic dysfunction
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Betablockers in Heart failure

• 15 years ago BB contraindicated in HF
• 1970s Sweden small studies suggest benefit
• US carvedilol trials (1996)- NYHA I-III (IV)
• n1094, 4 separate trials, 65 RRR in mortality
• CIBIS II - bisoprolol - NYHA III
• n2647, mortality 11.8 v 17.3 (p
• MERIT - metoprolol CR/XL - NYHA II-III
• improved mortality, morbidity and LVEF

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Major Trials of Beta-Blockade in HF
CIBIS Investigators and Committees. Circulation
1994 90 1765-1773. CIBIS-II Investigators and
Committees. Lancet 1999 353 9-13. MERIT-HF
Study Group. Lancet. 1999 35320012007. Packer
M, Bristow MR, Cohn JN et al. US Carvedilol Heart
Failure Study Group. N Eng J Med 1996 334
1349-1355. Poole-Wilson PA et al Lancet 2003
362 7-13. Capricorn Investigators. Lancet 2001
357 1385-1390.
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Carvedilol reduces risk of death or
cardiovascular hospitalisation
38 reduction in death or hospitalisation
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Are all betablockers equivalent?COMET trial

• Carvedilol non selective BB (B1,B2)
• Metoprolol selective BB (B1)

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Primary endpoint of mortality
40
Metoprolol
30
20
Carvedilol
Mortality ()
17 survival benefit RR 0.83 95 CI 0.74-0.93, P
0.0017
10
0
0
1
2
3
4
5
Time (years)
Poole-Wilson et al. COMET. Lancet 2003 3627-13
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Betablockers are the second cornerstone of
therapy for heart failure due to LV systolic
dysfunction
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Aldosterone receptor blockade
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The Role of Aldosterone in the Pathophysiology of
CVD
Classical (epithelial)
Non- classical (non-epithelial)
Aldosterone
Cardiovascular disease
Adapted from Liew D Krum H Current Opinion in
Investigational Drugs 2002 3(10) 1468-1473.
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RAAS Therapeutic Intervention Sites
Angiotensinogen secreted by the liver
Renin secreted by kidney
Angiotensin I
Angiotensin converting enzyme (ACE) from lung
tissue
ACE inhibitors
Angiotensin II - potent vasoconstrictor
Adrenal cortex
Blood vessel constriction
Angiotensin II receptor antagonists
Aldosterone release
Blood pressure?
Aldosterone receptor antagonists
Adapted from Stier CT et al. Heart Disease 2003
5 (2) 102-118 and McMahon EG. Current Opinion in
Pharmacology 2001 1 190-196.
Target organ effects
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Aldosterone not adequately suppressed by ACE
Inhibitors
100
Enalapril 20 mg bd
80
Plasma ACE (nmol/mL/min)
P 60
40








20
0
P Enalapril 20 mg bd
20
16
Plasma Aldosterone (ng/dL)
12

8
4
0
0
4 hr
24 hr
1
2
3
4
5
6
Hospital
Months
Biollaz J, et al. J Cardiovasc Pharmacol.
19824966-972
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The neurohormonal hypothesis- Proven?

• Aldosterone receptor antagonist - spironolactone
  25mg vs placebo
• RALES 1998
• n 1663
• NYHA IV (III)
• ACEI 89, Frusemide, digoxin 72
• 27 RRR in mortality
• Safe (hyperkalaemia excess 0.5)

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RALES All-Cause Mortality
1.00
Risk reduction 30 95 CI (18-40) p 0.95
0.90
0.85
0.80
Aldosterone receptor antagonist ACE inhibitor
loop diuretic digitalis
0.75
Probability of survival
0.70
0.65
Placebo ACE inhibitor loop diuretic
digitalis
0.60
0.55
0.50
0.45
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
Pitt B et al, N Engl J Med 1999 341 709-717
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EPHESUS study eplerenone post MI LVSD/HF

• 6642 patients
• LVEF
• ACEI/AR2B 87
• Betablockers 75
• Aspirin 88
• Diuretics 60
• Statin 47

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Primary Endpoint All-Cause Mortality
22
20
18
16
Placebo Eplerenone
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Cumulative Incidence ()
12
10
8
RR 0.85 (95 CI, 0.75-0.96) P 0.008
6
4
2
0
36
33
30
27
24
21
18
15
12
9
6
3
0
Months Since Randomisation
Pitt B et al. N Eng J Med 2003 348 1309-1321
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A word of caution

• Recent Canadian observational study
• Pre-RALES (1994)
• Prescription rates for spironACEI 34/1000
• Hospitalisation rates for hyperK 2.4/1000
• Post RALES (2001)
• Prescription rates 149/1000
• Hospitalisation rates for hyperK 11/1000
• Assoc. mortality rose from 0.3/1000 to 2.0/1000
• ? Inappropriate use of spironolactone (
• ? Inadequate monitoring (compared to clinical
  trial)

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Angiotensin Receptor Blockers (ARBs) why and
when

• ELITE I underpowered, ignore
• ELITE II ACEI perhaps better than losartan
  50-75mg
• Val-HeFT valsartan 160mgbd
• CHARM candasartan 32mg od

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Valsartan Heart Failure Trial

• Chronic stable HF patients (NYHA II-III)
• Valsartan added to usual heart failure therapy
  (ACEi diuretics digoxin ? blockers)
• 5,010 patients
• 302 centers in 16 countries

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Val-HeFT survival curves
1.0
p 0.80

0.9
Placebo
Survival probability ()

0.8
0.7

0
3
6
9
12
21
18
15
24
27
Time since randomization (months)
Cohn et al. NEJM 20013451667
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Significant benefits on combined mortality /
morbidity endpoint
1.0
13.2 risk reduction p 0.009
0.9
0.8
Event-free probability
Placebo
0.7
0.6
0
3
6
9
12
21
18
15
24
27
Time since randomization (months)
Cohn et al. NEJM 2001 3451667
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Primary endpoint greatest benefits in patients
not on ACE inhibitor therapyCombined all-cause
mortality / morbidity
1.0
44.5risk reductionp 0.0002

0.8
Event-free probability
0.6
Placebo (n 181)
Valsartan (n 185)
0.4
3
6
9
12
21
18
15
24
27
0
Time since randomization (months)
Cohn et al. AHA Scientific Sessions 2000
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The CHARM program

• CHARM added candesartan in addition to ACE I
  (pre-treated) in 2548 NYHA II-IV LVSD patients
• 55 on BB, 17 on spironolactone
• 15 RRR in CV death or hospitalisation for HF OR
  0.85.75-.96 p0.011)
• 14 RRR in CV death (2ndry outcome)
  OR0.840.72-0.98, p0.029
• Similar benefit whether on BB or not
• Lancet sept 2003362

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• CHARM alternative
• 2028 ACE I intolerant patients with LVEF
• 23 RRR for CV death or hospitalisation for HF
  (33 candesartan v 40 Placebo)(OR 0.87 CI
  0.67-0.89) drug discontinuation rates 30 and
  29 respectively

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The modern HF patient

• Diuretic loop (or BFZ) as low a dose as
  required
• ACE I NYHA I-IV, max. tolerated dose
• BB NYHA I-III (IV) carvedilol or bisoprolol,
  stable,compensated HF, start low, go slow aim
  for 25mgBD or 10mgOD respectively (or HR
• Spironolactone 25mg NYHA III-IV only, watch
  potassium/renal function.
• Candasartan/valsartan/?losartan good
  alternatives to ACE I if ACE I intolerant.
  Possibly add on therapy to NYHA II-IV patients if
  recurrent hospitalisations a problem and no other
  options.
• Hydralazine/nitrate if ACE I/ARB intolerant
  (usually renal failure)

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Drugs to avoid / stop in heart failure

• Class I antiarrythmics
• calcium channel blockers
• NSAIDs
• steroids

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Sudden cardiac death
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Implantable cardioverter defibrillators (ICDs)
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SCD-HEFT trial
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Cardiac resynchronisation therapy (CRT) whats
the rational?

• Poorly co-ordinated LV systolic contraction
  (Intra-ventricular (LV) dyssynchrony)
• LV segments may contract at different time-points
  during systole (and some may even contract after
  systole has ended)
• Results in less forceful ejection/reduced SV
• Abbreviated LV filling time
• Disruption of MV sub-valvular apparatus,
  late/unco-ordinated papillary muscle contraction
• Results in increased systolic mitral
  regurgitation

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Biventricular pacemaker leads
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The early CRT trials

• MUSTIC-SR (QRS150), MUSTIC-AF (QRS 200)
• MIRACLE (QRS130)
• PATH-CHF (QRS120)
• CONTAK-CD (QRS120)
• PATH CHF (QRS120)
• ?Improved NYHA class, QOL, VO2max, increased EF,
  reduced diuretic requirement, reduced
  hospitalisations
• Approx. 30 non-responder rate using ECG criteria
  alone echo assessment may improve this

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COMPANION trial

• 1520 patients, medical Rx, CRT or CRT-D
• NYHA III-IV, QRS120ms, PR150ms, HF hosp in
  prior 12months
• All cause death or hospitalisation
• RRR of 19 with CRT and 20 with CRT-D p0.014
• 12 month all cause mortality 19 medical, 15
  CRT and 12 CRT-D (p0.059 and p0.03
  respectively)
• Bristow NEJM 2004 3502140-2150

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CARE-HF study

• N813, NYHA III-IV, optimal medical Rx, LVEF
  120ms
• If QRS between 120-149ms then dyssynchrony
  required 2 out of 3 criteria Ao PEI 140ms,
  IVMD 40ms or delayed LV posterolat wall
  contraction (M-mode/Cazeau method)
• Primary endpoint death or first unplanned MACE
  hospitalisation
• Secondary endpoints death, deathunplanned HF
  hospitalisation
• Followed for mean 29 months (min 18/12)

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CARE-HF results

• Death/hosp for MACE (major adverse cardiac
  events) 159 in CRT and 224 in medical (HR 0.63,
  0.51-0.77 p
• Death 82 (20) in CRT and 120 (30) in medical
  (HR 0.64,0.48-0.85)
• Death and HF hosp. 118 (20) in CRT vs 191 (47)
  in medical group (HR 0.54, 0.43-0.68 p
• NYHA class and QOL significantly better with CRT

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Summary

• CRT (biventricular pacing) reduces morbidity and
  mortality in suitable patients with advanced
  heart failure
• Implantable cardioverter defibrillators reduce
  mortality by reduction in sudden death
• The effect is additive to maximal medical therapy

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The last resort - Cardiac Transplantation

• Theoretically excellent treatment for patients
  with end-stage CHF
• Advantages
• Good medium-long-term outlook (up to 70 survival
  at 5years and 50 survival at 10 years)
• Problems
• 15-20 mortality in first year
• Progressively fewer donors
• Long list of disqualifying factors therefore
  few patients suitable
• Complex follow-up, immunosuppressive Rx

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Summary

• Heart failure is a common condition with high
  mortality and morbidity
• Pharmacological therapies are very effective
• Device therapy (ICDs and CRTs) are increasingly
  utilised
• Cardiac transplantation is the last resort
  applicable to only a small number of patients

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Acute Heart Failure

• Top 10 Medical admission
• In patient mortality 20
• 3 year mortality 60

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Acute Heart FailureDifferential Diagnosis

• Respiratory causes of breathlessness
• pneumonia
• PTE
• fibrosis
• COPD
• Mixed picture (NB pneumonia may cause
  exacerbation of chronic heart failure)
• Acidosis - respiratory compensation
• Psychogenic hyperventilation

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Acute Heart FailureKey Indicators

• Prior history of heart failure or AMI?
• Absence of history of respiratory disease
• Look for causative factors
• Evidence of myocardial ischaemia?
• Cardiac arrhythmia?
• Valve disease? (loud systolic murmur or any
  diastolic murmur)
• Heart failure
• Anaemia

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Acute Heart FailureBedside assessment

• ABC with high flow oxygen
• Oxygen saturations
• Respiratory rate
• Heart rate and rhythm
• Blood pressure
• Urine output
• Clinical signs- JVP, hydration status

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Acute Heart FailureKey Investigations

• 12 lead ECG
• Chest X-ray
• Blood gases
• Other
• FBC, UEs
• Troponin
• BNP
• Echocardiogram

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Acute Heart FailureImmediate therapy

• High flow O2
• i.v. loop diuretic - frusemide 50-100 mg IV
• i.v. opiates (small doses) anti-emetic
• BP 100mmHg systolic
• i.v. nitrates (e.g. GTN 0.5 mg/hour titrating up)
• BP
• urgent cardiology opinion
• may need echocardiogram ? PA catheter
• consider inotropes