Current & Future Perspectives in the Treatment of Heart
Failure
Stewart et al. Eur J of Heart Failure 2001, 3(3):pp315-322.
HF – More malignant than cancer?
HF admission rates per annum – 7 countries 1978-1993
McMurray & Stewart, Heart 2000;83:pp596-602.
Change in causal factors for HF Framingham 1950-1987
McMurray & Stewart, Heart 2000;83:pp596-602.
Prevalence of HF by age in Framingham
0
10
20
30
40
50
60
70
80
30-39 40-49 50-59 60-69 70-79 80-89
Men
Women
Lakatta & Levy, Circulation 2003;107:pp139-146
Rate per 1000
Age
HF Epidemiology - Australia
HF prevalence: 1% of patients aged 50-59yrs but >50% for those 85+
Likely to be 300,000 Australians affected by CHF
30,000 new cases annually
Between 1996 and 1997
41,000 hospitalisations for HF as principal diagnosis
CHF accounted for 0.8% of all hospitalisations
(NHF guidelines, MJA 2001;174:pp.459-466)
Chronic Heart Failure in Australian General Practice
0
10
20
30
40
50
60
70
Diuretics ACEI Digoxin BB CCB-DHP CCB-NDHP Aspirin Warfarin Spironolactone Hydralazine AIIRADiuretics ACEI Digoxin BB CCB-DHP CCB-nonDHP Aspirin Warfarin Spironolactone Hydralaz ine AIIRA
70
60
50
40
30
20
10
0
% of patients prescribed each class of drug
Adapted from Krum et al. The Cardiac Awareness Survey & Evaluation (CASE study), MJA 2001; 174:pp.439-444.
Causes of Chronic Heart Failure
Systolic (impaired ventricular contraction)– Common
• Ischaemic heart disease• Hypertension
– Less common• Non-ischaemic idiopathic dilated cardiomyopathy
Diastolic (impaired ventricular relaxation)– Common
• Hypertension• Ischaemic heart disease• Diabetes
– Less common• Valvular disease, especially aortic stenosis
(NHF guidelines, MJA 2001;174:pp.459-466)
Severe symptoms (NYHA Class IV)
Pharmacological TreatmentNon-pharmacological treatment Salt/fluid restriction Exercise/conditioning
program
Add Beta Blocker
Add Beta Blocker (irrespective of NYHA
class*)
Consider heart transplantation if age <65yrs + no major
co-morbidity
Diuretic + ACE inhibitor
ImprovementNo improvement
Add spironolactone
+/- Digoxin
No improvement not tolerated
Improvement
Palliative care if unsuitable for heart
transplantation**
Continue medical treatment
**Palliative care options may include use of multiple diuretics, hydralazine, nitrates and/or short term use of inotropic agents to control intractable heart failure symptoms.
Treatment of systolic HF – (LVEF<40%)
Identify/treat acute precipitant
e.g. acute ischaemia/infarction arrhythmia
non-compliance
*Patients with NYHA Class IV heart failure should be challenged with beta blockers provided they have been rendered euvolaemic and do not have any contra-indication to beta blockade.
(NHF guidelines, MJA 2001;174:pp.459-466)
**With rare exception, patients with diastolic heart failure present with symptoms and signs of fluid overload, either pulmonary or systemic congestion, or both
***Choice of therapy will vary according to clinical circumstances. E.g. thiazide diuretic – elderly, systolic hypertension ACEI – LVH, diabetes, IHD Beta blocker - angina
Management of diastolic heart failure (heart failure with
preserved systolic function)
Is there fluid overload**?
Diuretic Treat cause
Is there an identifiable cause?
HypertensionIschaemic
heart diseaseCardiomyopathy
Anti-Hypertensive therapy***
Investigate suitability for
revascularisation
Pharmacological treatment ACEI
Beta blocker CCB
Pharmacological treatment
Beta blocker CCB
Hypertrophic CM Investigate
family hx
Restrictive CM
Endomyocardial biopsy for infiltrative
diseases e.g. sarcoidosis
amyloidosis
If no specific cause found consider
constrictive pericarditis
Surgical pericardiectomy
Yes No
Management of diastolic HF
(NHF guidelines, MJA 2001;174:pp.459-466)
Drug Use in Symptomatic Chronic Heart Failure
First line agents• ACEI• Diuretics
• Beta Blockers • for systolic heart failure despite appropriate doses of ACEI’s and diuretics/or
for advanced symptoms of CHF • Spironolactone
• for severe HF despite appropriate doses of ACEI
• AIIRAs• (currently) for patients intolerant of ACEI
Second-line agents• Digoxin• Hydralazine and isosorbide dinitrate
– Where no other option exists
AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia
(NHF guidelines, MJA 2001;174:pp.459-466)
Inhibition of the RAAS in HF• Because of the major importance of RAAS activation
in the progression of CHF, blockade of this system has become the cornerstone of successful therapy for systolic ventricular dysfunction.
• ACE inhibitors have been shown to: – prolong survival (compared with placebo) in patients with New York
Heart Association Class II, III and IV CHF;
– improve patient symptom status, exercise tolerance and reduce hospitalisation for worsening CHF (in some but not all studies); and
– increase ejection fraction compared with placebo in many studies.
Krum et al. MJA 2001; 174: 459-466
Angiotensin II
Chymase CAGE
Angiotensinogen
Angiotensin I
Sodium and fluid retention
Vaso- constriction
Sympathetic activation
Cell growth
AT1-receptor
Non-ACE pathways
t-PA
Cathepsin G
Renin
ACE
ACE inhibitor
Angiotensin II is produced both by ACE and non-ACE dependent pathways
Peterson and Dunlap, CHF 2002, 8(5):pp.246-250.
AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia
AT1-Receptor Blockers (AIIRA)Clinical Outcome Studies
HBP
LIFE
SCOPE
VALUE 04?
Vascular
ONTARGET 06
TRANSCEND 06
HF
ELITE II
Val-Heft
CHARM 03
HEAAL 05
I-PRESERVE
Pre Diabetes
NAVIGATOR 06
Diabetes Opht
DIRECT 05
Diabetes Renal
RENAAL
IDNT
MI
OPTIMAAL
VALIANT 03
Stroke
ACCESS
PRoFESS
MOSES
These trials may discuss the use of non approved doses or indications, refer to Australian PI before prescribing
AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia
Val-HeFT Subgroup without ACE-I therapy (n=366)
0.6
Time Since Randomization (Months)
44.0%Risk Reduction
P = 0.002
Eve
nt
Fre
e S
urv
ival
Pro
bab
ility
3 6 9 12 211815 24 270
Valsartan (N = 185) Placebo (N = 181)
Cohn et al. NEJM 2001; 345(23):pp.1667-1675
AIIRA’s Are Not Approved for the Treatment of Heart Failure in Australia
8. Recent Heart Failure Data
CHARMCandesartan in Heart failure Assessment of Reduction in Mortality and morbidity
Presented 31st August 2003 at the European Society of Cardiology (ESC) meeting in Vienna, Austria, Published in the Lancet Sep 7, 2003.
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
CHARM Program3 component trials comparing candesartan
to placebo in patients with symptomatic heart failure
CHARMPreserved
CHARMAdded
CHARMAlternative
n=2028
LVEF 40%ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
n=3025
LVEF >40%ACE inhibitor
treated/not treated
Primary outcome for Overall Programme: All-cause deathPrimary outcome for each trial: CV death or CHF hospitalisation
McMurray et al. Eur J Heart Failure, 2003:pp.261-270
candesartan 4mg/8mg-32mg candesartan 4mg/8mg-32mg candesartan 4mg/8mg-32mg
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
CHARM – Baseline Medication
0
1020
30
4050
60
70
8090
100
Diuretics Beta-Blockers Digoxin Spironolactone CCBs
CHARM Alternative CHARM Added CHARM Preserved
%
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
McMurray et al. Eur J Heart Failure, 2003:pp.261-270
CHARM-Alternative: Primary outcome CV death or CHF hospitalisation
Number at risk
candesartan 1013 929 831 434 122
Placebo 1015 887 798 427 126
Placebo
0 1 2 3 years0
10
20
30
40
50
Candesartan
%
HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001
3.5
406 (40.0%)
334 (33.0%)
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Granger et al. Lancet, 2003;362:pp.772-776
CHARM-Alternative Permanent study drug discontinuations
0
5
10
15
20
25Percent of patients
Placebo
Candesartan19.3
0.92.7
0.3 0.4
21.5
3.7
6.1
1.90.2
Hypo-tension
Increased creatinine
Increasedpotassium
CoughAE/lab. abnorm.
0 0.1
p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69 p=0.50
Angio-edema
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Granger et al. Lancet, 2003;362:pp.772-776
CHARM-Alternative Permanent study drug discontinuations
4.2
12.0
1.0 0.5
9.1
23.1
13.6
0.3
According to prior ACE-I intolerance
Percent of patients
0
5
10
15
20
25
Hypo-tension
Increased creatinine
Cough
Placebo
Candesartan
Increasedpotassium
0
2.6
(1/39)
Angioedema
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Granger et al. Lancet, 2003;362:pp.772-776
CHARM-AlternativeConclusions
• Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan was well tolerated
• In patients with symptomatic chronic heart failure and ACE-inhibitor intolerance, candesartan reduces cardiovascular mortality and morbidity
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Granger et al. Lancet, 2003;362:pp.772-776
CHARM-Added:Primary outcome CV death or CHF hospitalisation
0 1 2 3 years
0
10
20
30
40
50
Placebo
Candesartan
Number at risk
Candesartan 1276 1176 1063 948 457
Placebo 1272 1136 1013 906 422
3.5
HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted HR 0.85, p=0.010
483 (37.9%)
538 (42.3%)
%
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
McMurray et al. Lancet, 2003;362:pp.767-771
CHARM-AddedConclusions
• Addition of candesartan to an ACE inhibitor (and beta-blocker) leads to a further and clinically important reduction in CV mortality and morbidity in patients with CHF
• This benefit is obtained with relatively few adverse effects, although there is an increased risk of hypotension, hyperkalaemia and renal dysfunction
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
McMurray et al. Lancet, 2003;362:pp.767-771
n=3025
LVEF >40%ACE inhibitor
treated/not treated
CHARM Added
CHARMPreserved
CHARM Program3 component trials comparing
candesartan to placebo
CHARMAlternative
n=2028
LVEF 40% ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
Primary outcome:CV death or CHF hosp
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Yusuf et al. Lancet, 2003;362:pp.777-781
CHARM-Preserved: Primary outcome CV death or CHF hospitalisation
0 1 2 3 yearsNumber at risk
Candesartan 1514 1458 1377 833 182
Placebo 1509 1441 1359 824 195
3.5
0
10
20
30
Placebo
Candesartan
5
15
25
HR 0.89 (95% CI 0.77-1.03), p=0.118Adjusted HR 0.86, p=0.051
%
366 (24.3%)
333 (22.0%)
Yusuf et al. Lancet, 2003;362:pp.777-781Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum
approved dosage of 16mg once daily.
Yusuf et al. Lancet, 2003;362:pp.777-781
CHARM-Preserved Development of new diabetes
47 77 0.60 0.005 (0.41-0.86)
Number of cases HR p-value
Candesartan Placebo (CI)
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Yusuf et al. Lancet, 2003;362:pp.777-781
CHARM-Overall All-cause death
0 1 2 3 yearsNumber at risk
Candesartan 3803 3563 3271 2215 761
Placebo 3796 3464 3170 2157 743
3.5
0
10
20
30
Placebo
Candesartan
5
15
25
35
%
HR 0.91 (95% CI 0.83-1.00), p=0.055Adjusted HR 0.90, p=0.032
945 (24.9%)
886 (23.3%)
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Pfeffer et al. Lancet, 2003;362:pp.759-766
CHARM-Overall CV death and non-CV death
0 1 2 3 years
5
10
15
20
25
30
%
0
CV death
Non-CV death
Placebo
Candesartan
Placebo
Candesartan
HR 0.88 (95% CI 0.79-0.97), p=0.012Adjusted HR 0.87, p=0.006
p=0.45
3.5Number at risk
Candesartan 3803 3563 3271 2215 761
Placebo 3796 3464 3170 2157 743
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Pfeffer et al. Lancet, 2003;362:pp.759-766
CHARM-OverallCV death or CHF hosp.
0 1 2 3 years
0
10
20
30
40
50
% Placebo
Candesartan
HR 0.84 (95% CI 0.77-0.91), p<0.0001Adjusted HR 0.82, p<0.0001
3.5Number at risk
Candesartan 3803 3563 3271 2215 761
Placebo 3796 3464 3170 2157 743
1310 (34.5%)
1150 (30.2%)
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Pfeffer et al. Lancet, 2003;362:pp.759-766
CHARM-OverallPermanent study drug discontinuations
Placebo
Candesartan
0
5
10
15
20
25
Percent of patients
p<0.0001 p<0.0001 p<0.0001 p<0.0001
Hypo-tension
Increased creatinine
Increasedpotassium
AE/ lab. abnorm.
16.7
1.73.0
0.6
21.0
3.5
6.2
2.2
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Pfeffer et al. Lancet, 2003;362:pp.759-766
CHARM-OverallImplications
• The addition of the ARB, candesartan, can be considered in all patients with chronic heart failure irrespective of ejection fraction, age and sex
• Benefits were achieved on top of other effective concomitant therapies including ACE inhibitors and beta-blockers
The consistent effects of candesartan across the three CHARM trials suggest that:
Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.
Pfeffer et al. Lancet, 2003;362:pp.759-766
MERIT-HF 33
MERIT-HFMERIT-HFA Double-Blind, Placebo-Controlled Survival Study
With Metoprolol CR/XL in Patients With Decreased Ejection Fraction (0.40)
and Symptoms of Heart Failure (NYHA II–IV)
Metoprolol CR/XL Randomised Intervention Trial
in Congestive Heart Failure
Metoprolol CR/XL Randomised Intervention Trial
in Congestive Heart Failure
The MERIT-HF Study Group: Am J Cardiol 1997;80:54-58JLancet 1999;353:2001-7JAMA 2000;283:1295-302
MORTALITY AND MORBIDITY RESULTS
MERIT-HF 34
Primary Objectives
To determine whether metoprolol CR/XL reduces:
• Total mortality
• The combined end point of all-cause mortality and all-cause hospitalisation (time to first event)
Am J Cardiol 1997;80:54-58J
MERIT-HF 35
Months of follow-up
%
0 3 6 9 12 15 18 21
20
15
10
5
0
Placebo
Metoprolol-XL
P=0.0062 (adjusted)P=0.00009 (nominal)
Risk reduction = 34%
Total MortalityTotal Mortality
Lancet 1999;353:2001-7
MERIT-HF 36
12
9
6
Metoprolol-XL
P=0.0002
Sudden DeathSudden Death
0 3 6 9 12 15 18 21Months of follow-up
%
Placebo
Risk reduction = 41%
3
0 Lancet 1999;353:2001-7
MERIT-HF 37
5
4
3
1
Placebo
Metoprolol-XL
P=0.0023
2
Death From Worsening Heart FailureDeath From Worsening Heart Failure
%
0 3 6 9 12 15 18 21Months of follow-up
0
Risk reduction = 49%
Lancet 1999;353:2001-7
0
5
10
15
20
All-cause-10%
310/279
Adverse events-17%
234/196
Worsening HF-25%85/64
Withdrawal of Study Medicine Withdrawal of Study Medicine
%
No. ofwithdrawals
PlaceboMetoprolol-XL
JAMA 2000;283:1295-302
Improvement in NYHA Functional Class and Quality of Life: Last Visit
Improvement in NYHA Functional Class and Quality of Life: Last Visit
Change in NYHA Class P=0.0028 (n=3952)
Change in QOL (OTE) P=0.0089* (n=741)
* Among the 185 patients in the metoprolol CR/XL group whoreported an improvement, 72% judged this improvement asimportant, very important, or extremely important to carry out daily
activities.
JAMA 2000;283:1295-302
MERIT-HF 40
• Improves survival
• Reduces the need for hospital admission due to worsening heart failure
• Improves symptoms of heart failure
• Increases well-being
ConclusionsConclusions
Treatment with metoprolol CR/XL once daily added to standard heart-failure therapy:
Treatment with metoprolol CR/XL once daily added to standard heart-failure therapy:
Lancet 1999;353:2001-7JAMA 2000;283:1295-302
Interpreting Outcomes of Recent Major
Cardiovascular Trials
KB Swedberg(Göteborg, Sweden)
181800 33 66 99 1122 1515 2121 2424 2727 3030 36363333
MonthsMonths
Pro
bab
ilit
y o
f S
urv
ival
Pro
bab
ilit
y o
f S
urv
ival
PlaceboPlacebo
SpironolactoneSpironolactone
0.300.30
0.500.50
0.700.70
0.800.80
0.900.90
0.400.40
0.600.60
1.001.00
3939
Risk Reduction 30% (- 18 - 40)Risk Reduction 30% (- 18 - 40)P < 0.001P < 0.001
Pitt et al NEJM 1999Pitt et al NEJM 1999
RALES: All-cause Mortality• 1,663 Patients randomised to placebo/spironolactone• 95% background ACEI• 11% background blocker
00 33 66 99 1212 1515 1818 2121 2424 2727MonthsMonths
00
6565
7070
7575
8080
8585
9090
9595
ValsartanValsartan PlaceboPlacebo
100100
RR = 13.3%RR = 13.3%P = 0.009P = 0.009
Ev
ent-
fre
e S
urv
ival
(%
)E
ven
t-fr
ee
Su
rviv
al (
%)
Cohn et al. NEJM 2002Cohn et al. NEJM 2002
Val-HeFT: All-Cause Mortality or Morbidity
• 5,010 patients in NYHA class II (61.7%), III (36.2%) or IV (3.1%) with mean EF 27% and age 63 years
• Background: ACEI 92.3%, blocker 35.5%
Conclusions• Treatment of heart failure has resulted in major survival
benefits during the last 10-15 years
• The challenge facing the medical community remains to ensure that ACE-inhibitors and blockers are used in all appropriate patients
• Inhibition of aldosterone seems to carry further benefits
• Addition of an ARB could be considered in all patients
• To optimise neurohormonal blockade, care delivery structures need to be revisited
HOPE study results – primary endpointsCombined
cardiovascular endpoint
Cardiovascular mortality,
myocardial infarction, stroke
Cardiovascular mortality
Myocardial infarction
Stroke
-22% p<0.001
-26% p<0.001
-20% p<0.001
-32% p<0.001
Ramipril n=4645, Placebo n=4652
The HOPE Study Investigators, 2000
Argentina Finland Netherlands SpainAustralia France Norway SwedenAustria Germany Philippines SwitzerlandBelgium Greece Poland TaiwanBrazil Hungary Portugal TurkeyCanada Ireland Redcliffe SingaporeUK China Italy SlovakiaUnited Arab Emirates Czech RepublicKorea South Africa USADenmark Mexico
Participating countries
Impact of Heart Failure
A prevalent condition
Prevalence of HF (per 1000 population)
Age (years)
50-59
80-89
All ages
Men
8
66
7.4
Women
8
79
7.7
Framingham Heart Study: Ho et al. 1993 J Am Coll Cardiol;22:6-13
A growing burden
0
10000
20000
30000
40000
50000
1979 1985 1991 1997
HF
deat
hs
Vital Statistics of the United States, National Center for Health Statistics
Deaths from HF 1979-1997 (USA)
An economic burden
American Heart Association, 2000 Heart and Stroke Statistical Update
HealthcareprovidersIndirect Costs Home health/Other
medical durablesDrugs
15.5
2.2 1.5 1.1 2.2
Annual cost of HF estimated to be $22.5 billion (USA)
Costs in billions of dollars
Hospital/Nursing home
Results:Neurohormones
Time Since Randomization (months)
Per cent mortality
13.816.523.024.2
NE (pg / mL)
< 274274-394395-572
> 572
< Q1Q1 - < Q2Q2 - < Q3 > = Q3
Surv
ival
Pro
babi
lity
p value (log - rank): < 0.00001
1.000
0.962
0.924
0.887
0.849
0.811
0.773
0.736
0.698
0.660
0 4 8 12 16 20 24 28 32 26
Baseline norepinephrine (NE) levels correlate
with total mortality
Anand et al. AHA Scientific Sessions 2001
CarvedilOl ProspEctive
RaNdomIzed
CumUlative Survival Trial
(COPERNICUS)
COPERNICUS
Study Design
• 2289 patients with symptoms of heart failure at rest or minimal exertion with a LV ejection fraction < 25%, despite diuretics and an ACE inhibitor (+ digitalis).
• Diuretics were optimized to achieve euvolemia. No need for intensive care and no treatment with IV inotropic or IV vasodilator therapy within 4 days.
• Patients were randomized to placebo or carvedilol (1:1) [target dose 25 mg BID] to up to 29 months.
MonthsMonths
100100
8080
6060
4040
202033 9900 66 2121181815151212
% S
urv
ival
% S
urv
ival
CarvedilolCarvedilol
PlaceboPlacebo
All-cause mortalityAll-cause mortality
COPERNICUS
Risk reduction 35%Risk reduction 35%PP=0.00013=0.00013
COPERNICUS
In patients with severe chronic heart failure, carvedilol
• Improved the patient’s overall sense of well-being.
• Was well tolerated.
• Was associated with a lower risk of a serious adverse event, particularly one related to the progression of heart failure.
• Was associated with fewer patients requiring withdrawal oftreatment for an adverse event or for another reason.