Optimizing Therapy In Heart Failure

Dr Devendra Khandke MD
Head- Medical Services
Alembic Pharmaceuticals Ltd

Epidemiology of HF in Indian
Population

Prevalence: 1.8 crores

Incidence: 15.7 lakhs per year

Common Causes:
Rheumatic Heart Disease: 52.8%
Ischemic Heart disease & Hypertension:
27.2%

Pathogenesis and Sequel of Heart Failure

Arrhythmia

Coronary artery
disease

Hypertension
Cardiomyopathy

Left
ventricular
dysfunction

Remodeling

Low
ejection
fraction

Pump
failure

Valvular
disease
Neurohormonal
stimulation
Endothelial
dysfunction
Vasoconstriction
Renal sodium
retention

Death

Noncardiac
factors

Symptoms:
Dyspnea
Fatigue
Edema

Chronic
heart
failure

Adapted from Cohn J. N Engl J Med. 1996;335:490-498.

Ventricular Remodeling in CHF

Jessup, NEJM 2003

20% Lifetime risk for HF after age 40

Framingham Heart Study
Men

Cumulative
risk (%)

25

25

20

20

15

15

10

10

40

50

60

70

80

90

Women

40

50

60

70

80

90

Attained age (years)

Lifetime risk for HF for given index age
is cumulative through age 94 years

Lloyd-Jones DM et al. Circulation. 2002;106:3068-72.

Hypertension is the No. 1 risk factor for HF

Framingham Heart 60
Study
40
Populationattributable
risk (%)

20

0
Hazard ratio

HTN

MI

Angina

VHD

LVH

Diabetes

2.1

6.3

1.4

2.5

2.2

1.8

3.3

6.0

1.7

2.1

2.8

3.7

Men
VHD = valvular heart disease

Women
Levy D at al. JAMA. 1996;275:1557-62.

Prognosis in Heart Failure

In people diagnosed with heart failure, sudden

death occurs at 6 - 9 times the rate of the general
population

In- patient mortality rate 1st year post diagnosis: 5-20%

Out-patient mortality rate 1st year post diagnosis: 20%
5-year mortality rate is 50%
Each re-hospitalization increases mortality by 20-30%
American Heart Association.

Diagnosis of HF

History: cardiomyopathy, Valvular heart disease,

alcohol use, hypertension, Prior MI, Angina
S/S: Exertional dysnea, orthopnea, PND, fatigue,
palpitations, nocturia, pulmonary rales, HT,
hepatojugular reflex, edema, S3 gallop
Investigations: CBC, Electrolytes, Renal function
test, Hepatic function test, B-type natriuretic
peptides, Doppler and 2-D ecocardiography, ECG,
Cardiac MRI, Angiography, Heart catheterization,
Right ventricular endomyocardial biopsy

Biomarkers in HF

Most commonly biomarkers for diagnosis of

suspected HF are natriuretic peptides
Synthesized as pro-BNP cleaved by corin into
inactive N-terminal proBNP (NT-proBNP) and
biologically active BNP
BNP produced by vascular myocardium released in
response to pressure and volume stress
Active BNP causes vasodilation, natriuresis and
antagonism of RAAS

Assessment & Treatment of Chronic HF

Assess LV Function (echo, gated RNA)
EF < 40%-systolic dysfunction
EF 40-55%-systolic/diastolic dysfunction
EF >55%-diastolic dysfunction

Assess Volume Status

Signs and Symptoms of

Fluid Retention
Loop Diuretic
+/- Thiazide
(titrate to euvolemic state)

Add Digoxin for

symptom control

No Signs and Symptoms

of Fluid Retention

ACE inhibitor/ARB if ACE intolerant

Combination Rx if HF, hospitalization or -blocker intolerant

-blocker (NYHA II-IV)

Spironolactone/ Eplerenone
(NYHA Class III-IV CHF/EF<35%/Cr<200/K<5)

HFSA 2010 Practice Guideline

HF Risk Factor Treatment Goals

Risk Factor
Hypertension

Goal
Generally < 130/80

Diabetes

See ADA guidelines1

Hyperlipidemia

See NCEP guidelines2

Inactivity
Obesity

20-30 min. aerobic 3-5 x wk.

Weight reduction < 30 BMI

Alcohol

Men 2 drinks/day, women 1

Smoking

Cessation

Dietary Sodium

Maximum 2-3 g/day

Diabetes Care 2006; 29: S4-S42

JAMA 2001; 285:2486-97
1

Pharmacological Therapies for HF

Diuretics
ACE inhibitors
ARB
Beta Blockers
K sparing diuretic agents
Triamterene, Amiloride, Spironolactone
Aldosterone inhibitors
Eplerenone
Digitalis
Vasodilators
Hydralazine, Nitroprusside
Positive ionotropic agents
dopamine, dobutamine, milrinone, imamrinone
Recombinant form of human brain natriuretic peptide: Nesiritide
Potent vasodilator that reduces ventricular filling pressures
and improves cardiac output
Anti-arrhythmic agents

Beta Blockers in HF- A Paradigm Shift

The single most significant addition to the

pharmacological management of heart
failure since the publication of previous
guidelines [ACC/AHA] involves the use of
beta-receptor antagonists.
-Heart Failure Society of America (1999)

Heart Failure Society of America (HFSA) Practice Guidelines. J Cardiac Fail. 1999;5:357-382.

Effect of Beta Blockade on Outcome

in Patients With HF and Post-MI LVD
HF
Severity

Target
Dose (mg)

Outcome

Study

Drug

US Carvedilol1

carvedilol

mild/
moderate

6.2525 BID

48% disease progression

(p= .007)

CIBIS-II2

bisoprolol

moderate/
severe

10 QD

34% mortality (p <.0001)

MERIT-HF3

metoprolol
succinate

mild/
moderate

200 QD

34% mortality (p = .0062)

COPERNICUS4

carvedilol

severe

25 BID

35% mortality (p = .0014)

CAPRICORN5

carvedilol

post-MI
LVD

25 BID

23% mortality (p =.031)

4. Packer M et al. N Engl J Med 2001;3441651-8.

1. Colucci WS et al. Circulation 1196;94:2800-6.
5. The CAPRICORN Investigators. Lancet 2001;357:1385-90.
2. CIBIS II Investigators. Lancet 1999;353:9-13.
3. MERIT-HF Study Group. Lancet 1999;353:2001-7.

Effects of Adding -Blockers vs Increasing

ACE Inhibitor Dose in HF
Symptoms

Morbidity

Mortality

Increase dose
of ACE inhibitor1

No
effect

10-15%

NS

Add -blockade2

20-35%

35%

No evidence for the need to maximize ACE-I

doses before starting -blocker therapy
(BB + ACE-I better than high dose ACE alone)
Packer M et al. Circulation. 1999;100:23122318.
Lechat P et al. Circulation. 1998;98:11841191.

1
2

Metoprolol CR/XL Randomized

Intervention Trial in Congestive Heart
Failure (MERIT-HF)
M ortality

CV deaths

0%
M o

rta

lity

C V

d e

th s

Sudden death
S

u d d

d e

th

Death due to
worsening HF
D e

th d

to

w o

rse

in

H F

Risk reduction (%)

-10%
-20%
-30%
-40%
-50%
-60%

34%

38%

Mild to moderate HF; LVEF < 40%

41%

N = 3991 t = 1 year

49%

Metoprolol CR/XL (200 mg od) vs placebo

Lancet 1999; 353: 2001-2007

MERIT-HF: Mortality benefit

of -blockade in the elderly
Sudden death

12

Risk reduction
43%

Risk reduction
37%

Placebo

15

P = 0.0032

Metoprolol succinate CR/XL

%
Patients 6

All-cause mortality

20

P = 0.0008

Metoprolol
succinate
CR/XL

%
Patients 10

Placebo

HF mortality

0
0

9 12 15 18

Months

Placebo

Risk
reduction
61%

P = 0.0005

%
Patients

9 12 15 18

Months

Metoprolol succinate CR/XL

0
0

N = 1982 age 65 years

9 12 15 18

Months
Deedwania PC et al. Eur Heart J. 2004;25:1300-9.

Randomized Evaluation of Strategies for

left ventricular Dysfunction Pilot Study
(RESOLVD)
9

No. of deaths (%)

8
7

8.1

Reduces total mortality by 54.3%

6
5
4

3.7

3
2
1
0

ACE Inhibitor + diuretic + digitalis

ACE inhibitor + diuretic + digitalis +
Metoprolol extended release

Circulation 2000; 101: 378-384

Mortality Reductions with ACE - I

Relative Risk Reduction (%)

30
25
20
15
10
5
0

CONSENSUS
n = 253

SOLVD
n = 4228

SAVE
n = 2231

AIRE
n = 1986

HOPE
n = 3577

CONSENSUS: NEJM 1987;316:1429-435, SOLVD: NEJM 1991;325:293-302, SAVE: NEJM 1992;327:669-677

AIRE: Lancet 1993;342:821-828, HOPE: Lancet 2000;355:253-259

Telmisartan is the Most Studied Amongst

ARBs in Mortality and Morbidity Endpoint
Trials
Number of patients

51,878
44,264

19,335
12,565
1,405
Eprosartan
MOSES1

4,449
Olmesartan
ROADMAP2

6,405

Irbesartan

Candesartan

Losartan

Valsartan

Telmisartan

IRMA II3

SCOPE6

RENAAL8

Val-HeFT12

TRANSCEND16

IDNT4

CHARM7

ELITE II9

NAVIGATOR13

PRoFESS16

OPTIMAAL10

VALIANT14

ONTARGET16

LIFE11

VALUE15

I-Preserve5

1. Schrader et al. Stroke. 2005;36:12181226; 2. http://www.roadmapstudy.org/resident.aspx; 3. Parving et al. N Engl J Med. 2001;345:870878; 4. Lewis et al. N Engl J Med. 2001;345:851860; 5.
Carson et al. J Card Fail. 2005;11:576585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:11751180; 7. www.atacand.com; 8. Brenner et al. N Engl J Med. 2001;345:861869; 9. Pitt et al.
Lancet. 2000;355:15821587; 10. Dickstein et al. Lancet. 2002;360:752760; 11. Dahlof et al. Lancet. 2002;359:9551003; 12. Cohn et al. N Engl J Med. 2001;345:16671675; 13.
www.novartis.com; 14. Pfeffer et al. N Engl J Med. 2003;349:18931906; 15. Julius et al. Lancet. 2004;363:20222031; 15. www.ontarget-micardis.com.

Telmisartan has a Unique Pharmacology

Profile in its Class (ARB)

Epro- LoVal- Cande- Olme- Irbe- Telmisartan sartan sartan sartan sartan sartan sartan

Losartan

Valsartan

Candesartan

Olmesartan

Telmisartan

500

Most lipophilic
(high tissue penetration)

Highest selective PPAR activation

Active metabolite of losartan

PPARy fold activation

Volume of distribution (L)

500

Highest receptor affinity

Receptor dissociation
half-life (min)

Plasma half-life (h)

Longest plasma half-life

Cande- Epro- Val- Olme- LoIrbe- Telmisartan sartan sartan sartan sartan sartan sartan

Epro- Olme- EXP Cande- ValIrbe- Telmisartan sartan 3174 sartan sartan sartan sartan

Burnier, Brunner. Lancet. 2000;355:637645; Brunner. J Hum Hypertens. 2002;16(Suppl 2):S13S16; Kakuta et al. Int J Clin Pharmacol Res. 2005;25:
4146; Wienen et al. Br J Pharmacol. 1993;110:245252; Song, White. Formulary. 2001;36:487499; Asmar. Int J Clin Pract.
2006;60:315320; Israili. J Hum Hypertens. 2000;14(Suppl 1):S73S86; Benson et al. Hypertension. 2004;43:9931002.

ONTARGET
Trial

Methods
Patients underwent double-blind randomization
8576 assigned to 10 mg of ramipril per day
8542 assigned to 80 mg of telmisartan per day
8502 assigned to both drugs (combination
therapy)
Primary composite outcome
death from cardiovascular causes
myocardial infarction
Stroke
hospitalization for heart failure.

ONTARGET
Conclusion:

Telmisartan was equivalent to ramipril in patients

with vascular disease or highrisk diabetes and
was associated with less angioedema.

N Engl J Med 2008;358:1547-59

Combination of ARB and Beta Blockers

in Heart Failure

HFSA2006
2010 Practice
Practice Guideline
HFSA
Guideline(7.14-7.15)
(7.14-7.15)

Pharmacologic Therapy:
Aldosterone Antagonists
An aldosterone antagonist is recommended for
patients on standard therapy, including diuretics,
who have:

NYHA class IV HF (or class III, previously class IV)

due to LV systolic dysfunction (LVEF 35%)

One should be considered in patients post-MI

with clinical HF or diabetes and an LVEF < 40%
who are on standard therapy, including an ACE
inhibitor or an ARB.
Strength of Evidence = A
Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive
Heart Failure Guideline. J Card Fail 2006;12:e1-e122.

Aldosterone Antagonists in HF

Probability of Survival

RALES (Advanced HF)

EPHESUS (Post-MI)

1.00

1.00

0.90

0.90

0.80

Spironolactone

0.70

0.80

Placebo
0.70

0.60
0.50

Epleronone

Placebo

0.60
0.50

RR = 0.70
P < 0.001

0.40

RR = 0.85
P < 0.008

0.40
0 3 6 9 12 15 18 21 24 27 30 33 36

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Months
Pitt B. N Engl J Med 1999;341:709-17.
Pitt B. N Engl J Med 2003;348:1309-21.

HFSA 2010 Practice Guideline (7.2)

HFSA 2010 Practice Guideline (7.2)

Pharmacologic Therapy: Substitutes

for ACEI

It is recommended that other therapy be substituted for ACE

inhibitors in the following circumstances:
In patients who cannot tolerate ACE inhibitors due to
cough, ARBs are recommended. Strength of Evidence = A
The combination of hydralazine and an oral nitrate
may be considered in such patients not tolerating ARBs.
Strength of Evidence = C

A combination of hydralazine and isosorbide dinitrate may be

considered in patients with HF and reduced LVEF who remain
symptomatic despite optimized standard therapy.
Strength of Evidence = C

A-HeFT All-Cause Mortality

43% Decrease in Mortality

100

Survival %

Fixed Dose ISDN/HDZN

95

90

Placebo
P = 0.01

85
0

100

200

300

400

500

600

Days Since Baseline Visit

Taylor AL et al. N Engl J Med 2004;351:2049-57.

HFSA
2006
Practice
(7.24)
HFSA
2010
Practice Guideline
Guideline (7.24)

Pharmacologic Therapy: Diuretics

Restoration of normal volume status may require multiple
adjustments.
Once a diuretic effect is achieved with short-acting loop
diuretics, increase frequency to 2-3 times a day if necessary,
rather than increasing a single dose.
Strength of Evidence = B
Oral torsemide may be considered in patients exhibiting poor
absorption of oral medication or erratic diuretic effect.
Strength of Evidence = C

IV administration of diuretics may be necessary .

Strength of Evidence = A

Diuretic refractoriness may represent patient noncompliance,

a direct effect of diuretic use on the kidney, or progression of
underlying dysfunction.
Adapted from: Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive
Heart Failure Guideline. J Card Fail 2006;12:e1-e122.

HFSA2006
2010 Practice
Practice Guideline
HFSA
Guideline
Digoxin
Recommendation 7.29

Digoxin should be considered for patients with LV

systolic dysfunction (LVEF ?< 40) who have signs
or symptoms of HF while receiving standard
therapy, including ACE inhibitors and beta
blockers:
NYHA class II-III

Strength of Evidence = A

NYHA class IV

Strength of Evidence = B

Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive

Heart Failure Guideline. J Card Fail 2006;12:e1-e122.

HFSA 2010 Practice Guideline

Digoxin

Digoxin should be considered for achieving

adequate control of the ventricular response to
atrial fibrillation in patients with HF.
Strength of Evidence = B

High doses of digoxin (maintenance dose >

0.25 mg daily) for the purpose of rate control
are not recommended.
Strength of Evidence = C

HFSA 2010 Practice Guideline

Prophylactic ICD Placement
Prophylactic ICD placement should be considered in patients with an
LVEF 35% and mild to moderate HF symptoms:
Ischemic etiology
Non-ischemic etiology

In patients who are undergoing implantation of a biventricular pacing

device, ICD should be considered

ICD implantation is recommended for survivors of cardiac arrest from

ventricular fibrillation or hemodynamically unstable sustained VT that is
not due to a transient, potentially reversible cause, such as acute MI

ICD placement is not recommended in chronic, severe refractory HF

when life expectancy of less than 1 year

MADIT II: Prophylactic ICD in

Ischemic LVD (LVEF 30%)
Probability of Survival

1.0
.9

.7

Conventional
Therapy

.6
0

Number at Risk
Defibrillator
Conventional

Defibrillator

.8

110 (.78)
65 (.69)

9
3

Year
742
490

503 (.91)
329 (.90)

274 (.84)
170 (.78)

Moss AJ et al. N Engl J Med 2002;346:877-83.

ICD Therapy in the SCD-HeFT Trial:

Mortality by Intention-to-Treat
.4

Mortality

.3

HR

97.5% Cl

P Value

Amiodarone vs
Placebo

1.06

.86-1.30

.53

ICD vs Placebo

.77

.62-.96

.007

22%
.2

17%
.1

Amiodarone
ICD Therapy
Placebo

0
0

12

18

24
30
36
Months of Follow-Up

42

48

54

60

Bardy GH et al. N Engl J Med 2005;352:225-37

HFSA 2010 Practice Guideline

Biventricular Pacing

Biventricular pacing therapy is recommended for patients with all of the

following:
Sinus rhythm or AF
A widened QRS interval (120 ms)
Severe LV systolic dysfunction (LVEF < 35%)
Persistent, moderate to severe HF (NYHA III) despite optimal medical
therapy

Biventricular pacing therapy should be considered in patients with reduced

LVEF and QRS 150 ms who have NYHA I-II HF symptoms.

CRT Improves Quality of Life and

NYHA Functional Class

(%)

*P<.05

Abraham WT et al. Circulation 2003;108:2596-603

CRT in Patients with Advanced HF and

a Prolonged QRS Interval:
COMPANION
Primary End Point: All-Cause Mortality
Death or Hospitalization Due to HF

Risk of all-cause mortality reduced by 19%

in group with CRT and ICD (p =.014)
Risk of death or hospitalization from HF
reduced by 34% in ICD group and by 40% in
ICD-CRT group (p < .001)
Bristow MR et al. N Engl J Med 2004;350:2140-50

HFSA 2010 Practice Guideline

Warfarin

Warfarin (goal INR 2.0-3.0) is recommended for all patients:

With HF and chronic or documented paroxysmal,
persistent, or long-standing atrial fibrillation
Strength of Evidence =
A
Or a history of systemic or pulmonary emboli, including
stroke or transient ischemic attack, unless contraindicated
Strength of Evidence =
C

Patients with symptomatic or asymptomatic ischemic

cardiomyopathy and documented recent large anterior MI or
recent MI with documented LV thrombus be treated with
warfarin (goal INR 2.0-3.0) for the initial 3 months post-MI,
unless contraindicated.
Strength of
Evidence = B

HFSA 2010 Practice Guideline

Long-Term Antithrombotic Therapy

Long-term aspirin (75-81 mg), recommended for patients

with HF due to ischemic cardiomyopathy, whether or not
they are receiving ACE inhibitors
Strength of Evidence = B
Warfarin (goal INR 2.0-3.0) and clopidogrel (75 mg) also
have prevented vascular events in post-MI patients and
may be considered as alternatives to aspirin
Strength of Evidence = B
Routine use of aspirin is not recommended in patients
with HF without atherosclerotic vascular disease
Strength of Evidence = C

HFSA 2010 Practice Guideline

Anti-arrhythmic

Anti-arrhythmic agents, including amiodarone- not

recommended for the primary prevention of sudden death
in patients with HF
Strength of Evidence = A
In patients with HF and an ICD, amiodarone may be
considered to reduce the frequency of recurrent
symptomatic arrhythmias causing ICD shocks
Strength of Evidence = C
Routine use of amiodarone therapy for asymptomatic
arrhythmias that are not felt to contribute to HF or
ventricular dysfunction is not recommended
Strength of Evidence = B

Ventricular Assist Devices

VADs commonly used

Bridge the acutely failing heart to eventual heart transplantation
Not transplant candidates, who otherwise would die

Abiomed BVS 5000 circulatory support system (Abiomed, Inc,

Danvers, Mass), which is typically used for short-term support

Abiomed AB5000 circulatory support system (Abiomed, Inc)

Centrimag or Levitronix system (Thoratec, Pleasanton, Calif)

Thoratec paracorporeal and intracorporeal LVAD and RVAD

(Thoratec)

Novacor LVAD (World Heart Inc, Oakland, Calif)

HeartMate I LVAD (Thoratec)

HFSA 2010 Practice Guideline (8.1)

Heart Failure Patient Education
It is recommended that patients with HF and their
family members or caregivers receive
individualized education and counseling that
emphasizes self-care.
This education and counseling should be delivered
by providers using a team approach.
Teaching should include skill building and target
behaviors.
Strength of Evidence = B
Adapted from: