Current & Future Perspectives in the Treatment of Heart Failure.

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


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.


**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


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


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.


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


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


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


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


CHARM – Baseline Medication

0

1020

30

4050

60

70

8090

100

Diuretics Beta-Blockers Digoxin Spironolactone CCBs

CHARM Alternative CHARM Added CHARM Preserved

%


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%)


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



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


Cough

Placebo

Candesartan

Increasedpotassium

0

2.6

(1/39)

Angioedema



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



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%)

%


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


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


treated

Primary outcome:CV death or CHF hosp


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


%

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.


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)



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

%


945 (24.9%)

886 (23.3%)


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


p=0.45

3.5Number at risk

Candesartan 3803 3563 3271 2215 761

Placebo 3796 3464 3170 2157 743



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%)



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


Increasedpotassium

AE/ lab. abnorm.

16.7

1.73.0

0.6

21.0

3.5

6.2

2.2



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:



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


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


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.

Current & Future Perspectives in the Treatment of Heart Failure.

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Transcript of Current & Future Perspectives in the Treatment of Heart Failure.