ACE Inhibitors and ARBs

in Heart Failure

In the United States:

• HF incidence increases with age

• >650,000 new HF cases diagnosed annually

• >1 million hospitalizations annually

• Absolute mortality rates for HF: 50% within 5 years of diagnosis

structural or functional impairments that leads to alteration of ventricular filling or contraction

inadequate cardiac output to maintain metabolic requirements

Myocardial injury

Cardiac function

Activation of SNS, RAAS, endothelin,

AVP, inflammatory cytokines,

oxidative stress

Acute

(adaptive) Hypertrophy,

remodeling,

apoptosis

Neurohormonal model

1980s-2000s

Hemodynamic model

1950s-1980s

Reduced contractility

Pump dysfunction

Treatment:

Positive inotropic drugs

Vasodilators

Conventional drugs

Diuretics

Digitalis

Progressive remodeling &

impaired myocard function

Treatment:

Neurohormone blockers:

ACE inhibitors, ARBs

β-blockers

Conventional drugs

Diuretics

Digitalis

Jessup, M. et al. N Engl J Med 2003;348:2007-2018

Weber K. N Engl J Med 2001;345:1689-1697

GFR

Proteinuria

Aldosterone release

Glomerular sclerosis

Atherosclerosis

Vasoconstriction

Vascular hypertrophy

Endothelial dysfunction

LV hypertrophy

Fibrosis

Remodeling

Apoptosis

Stroke

DEATH

Hypertension

Heart failure

MI

Renal failure

AT1 receptors

Angiotensinogen

Angiotensin I

Angiotensin II

AT1R AT2R

Renin

ACE Non-ACE pathways ACE

inhibitor

AT1

receptor

blocker

Bradykinin

Nitric oxide

Inactive

peptides

CV protection Vasodilatation Anti fibrosis Anti growth

Vasoconstriction Proatherosclerosis Proinflammation Prothrombosis

ACE

inhibitors

Vasodilatory

effects

Plaque

stabilization

Regression of

LV hypertrophy

Regression of VSMC

proliferation

↓ Formation of

superoxide anions

Ris

k C

ontinuum

CONSENSUS

SOLVD Rx

V-HeFT II

SAVE, AIRE, TRACE

SOLVD Prevention

Class IV cardiac failure, low EF

Class II-III cardiac failure, EF <35%

Cardiac failure post-infarct ± cardiac failure,

EF<35-40%

Class I, EF <35%

Size of Population Affected

Smoking, Dyslipidemia, Hypertension, Diabetes CV Risk Factors

Vascular disease, LVEF >40% TIA Stroke

CAB

GC

PAD

Diabetes

+ 1 CV

risk

factor

Angina PCI CABG MI

EUROPA

HOPE

SOLVD Investigators N Engl J Med 1991;325:293-302

0

10

20

30

40

50

0 6 12 18 24 30 36 42 48

Placebo

Enalapril

Follow-up (months)

Mortality (%)

Risk reduction 16%

p=0.0036

Mortality 26%

Readmission for CHF 27%

Reinfarction 20%

Yancy CW, et al. Circulation 2013;128:000-000.

• Randomized large (>1000 patients), long term (1 year) trials

• ACE inhibitors vs placebo

• 12,763 patients in 4 trials

Randomized comparison of low dose (2.5-5mg/d) and

high dose lisinopril (32.5-35mg/d)

8% lower risk of death (p= 0.01)

15% lower risk of death or hospitalization for heart

failure (p=0.001)

greater risk of hypotension, renal insufficiency and

hyperkalemia with high dose

Packer et al. Circulation. 1999;100:2312-2318.

The Assessment of Treatment with

Lisinopril and Survival (ATLAS)

Yancy CW, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure : A Report of the American College of

Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:000-000.

McMurray JJV, et al. ESC Guidelines for

the diagnosis and treatment of acute and

chronic heart failure 2012. The Task Force

for the Diagnosis and Treatment of Acute

and Chronic Heart Failure 2012 of the

European Society of Cardiology. European

heart Journal 2012; 33:1787-1847

Adverse effects :

• Hypotension

• Hyperkalemia

• Renal dysfunction

• Dry cough

• Angioedema

ACE

inhibitors

Initial doses Target doses

Captopril

Ramipril

Trandolapril

Enalapril

Fosinopril

Lisinopril

Quinapril

Perindopril

6,25 mg t.i.d

2,5 mg o.d.

1 mg o.d.

2,5 mg b.i.d.

10 mg o.d.

2,5-5 mg o.d.

5 mg b.i.d.

2 mg o.d.

50 mg t.i.d.

10 mg o.d.

4 mg o.d.

10-20 mg

b.i.d.

40 mg o.d.

20-40 mg o.d.

20 mg b.i.d.

8-16 mg o.d.

ACE Inhibitor intolerant?

Angiotensin Receptor

Blockers (ARBs)

Alternative agents

Additional therapy

More complete inhibition of RAAS

Retard bradykinine degradation

• ELITE II

• OPTIMAAL

• RESOLVD

• VALHEFT

• VALIANT

• CHARM

0 100 200 300 400 500 600 700

Days of Follow-up

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bili

ty o

f S

urv

iva

l

Losartan (N=1578) 280 Events

Captopril (N=1574) 250 Events

Captopril/Losartan Hazard Ratio (95% C.I.):

0.88 (0.75, 1.05) P=0.16

Primary Endpoint:

All-Cause Mortality

McKelvie RS et al. Circulation. 1999;100:1056-1064.

35

30

25

20

15

10

5

0

-5

17 Weeks 43 Weeks 0 Weeks

**

End Diastolic

Volume

(mL)

Candesartan

Candesartan + enalapril

Enalapril

*

*

* P <0.01 compared with 0 weeks.

**P <0.05 compared with enalapril.

Captopril

0

0.05

0.1

0.15

0.2

0.25

0.3

0 6 12 18 24 30 36

Pro

bab

ilit

y o

f E

ven

t

Mortality by treatment

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726

Valsartan

Valsartan + Captopril

CHARM Added

CHARM Preserved

3 component trials comparing candesartan to placebo in patients with symptomatic heart failure

CHARM Alternative

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 death

Primary outcome for each trial: CV death or CHF hospitalisation

0 1 2 3 years 0

10

20

30

40

50

Placebo

Candesartan

%

HR 0.77 (95% CI 0.67-0.89), p=0.0004

Adjusted HR 0.70, p<0.0001

3.5

406 (40.0%)

334 (33.0%)

CV mortality HR 0.85 (95% CI 0.71-1.02 Adjusted HR 0.80 (95% CI 0.66-0.97) p=0.02

MI HR 1.52 (95% CI 1.06-2.18)

Primary Outcome:

CV death or CHF hospitalization

0 1 2 3 years 0

10

20

30

40

50

Placebo

Candesartan

3.5

HR 0.85 (95% CI 0.75-0.96), p=0.011

Adjusted HR 0.85, p=0.010

483 (37.9%)

538 (42.3%)

%

CV mortality : HR 0.84 (95% CI 0.72-0.98) p=0.02 Covariate Adjusted HR p=0.021

MI : Not reported

Primary Outcome:

CV death or CHF hospitalization

0 1 2 3 years Number 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=0.118

Adjusted HR 0.86, p=0.051

%

366 (24.3%)

333 (22.0%)

Primary Outcome:

CV death or CHF hospitalization

Yancy CW, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure : A Report of the American College of

Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:000-000.

McMurray JJV, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis

and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. European heart Journal 2012; 33:1787-1847

Yancy CW, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure : A Report of the American College of

Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128:000-000.

McMurray JJV, et al. ESC Guidelines

for the diagnosis and treatment of

acute and chronic heart failure 2012.

The Task Force for the Diagnosis

and Treatment of Acute and Chronic

Heart Failure 2012 of the European

Society of Cardiology.

European heart Journal 2012;

33:1787-1847

ARBs Initial doses Target doses

Candesartan

Irbesartan

Losartan

Valsartan

Telmisartan

4 mg o.d.

75-150 mg o.d.

12,5-50 mg o.d.

20-40 mg b.i.d.

40 mg o.d.

32 mg o.d.

300 mg o.d.

150 mg o.d.

160 mg b.i.d.

80 mg o.d.

Adverse effects:

• Hypotension

• Hyperkalemia

• Renal dysfunction

• More AE when

combined to

ACEIs

One strategy to manage heart failure is RAS blockade with ACE inhibitors or ARBS.

ACE inhibitors are beneficial in all stages of heart failure and remain to be the first-line therapy

ARBs are alternative agents for heart failure in patients who are ACE inhibitors intolerant.

Combination therapy of ACE inhibitors and ARBs reduce morbidity in heart failure patients, with more adverse effects.

CHARM Added

CHARM Preserved

3 component trials comparing candesartan to placebo in patients with symptomatic heart failure

CHARM Alternative

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 death

Primary outcome for each trial: CV death or CHF hospitalisation

Trial Agent Target

Doses

Population Findings

CONSENSUS I

(n: 253)

Enalapril

(vs. placebo)

20 mg bid NYHA class

IV

•40% RRR of all-cause

mortality at 6 months

•50% RRR of deaths from

progressive heart failure

SOLVD Treatment

Trial

(n: 2569)

Enalapril

(vs. placebo)

10 mg bid NYHA

classes II-IV,

EF ≤35%

•16% decrease in 3.5-year

mortality

•26% decrease in death or

hospitalization for CHF

SOLVD

Prevention Trial

(n: 4228)

Enalapril

(vs. placebo)

10 mg bid NYHA class I,

EF ≤35%

•20% decrease in death or

hospitalization for CHF

•Non significant mortality

trend favoring enalapril

ATLAS

(n: 3164)

Lisinopril low dose

(2,5-5 mg)

vs. high

dose (32,5-

35 mg)

NYHA III-IV

or class II

with

exacerbation

in prior 6

months

•8% mortality reduction in

high-dose group

•24% RRR of

hospitalization for HF

ACEIs ARBs

• RESOLVD

• ELITE II

• CHARM-Programme

• VALHEFT

• OPTIMAAL

Telmisartan 80mg added to ramipril 10mg: as effective as ramipril alone

Composite CV risk = cardiovascular mortality + non-fatal myocardial infarction + hospitalisation for congestive heart failure + non-fatal stroke

Reduction in composite CV risk

The ONTARGET Investigators. N Engl J Med 2008;358:1547–1559

ACE Inhibitors Β-blockers

ARBs

RESOLVD : Neurohormones

McKelvie RS et al. Circulation. 1999;100:1056-1064.

10

17 Weeks 43 Weeks

BNP

(pmol/mL)

0 Weeks

*† * †

Candesartan

Candesartan + enalapril

Enalapril

5

0

-5

-10

*P <0.01 compared with 0 weeks. †P <0.01 compared with enalapril.

RESOLVD : Ventricular Function

McKelvie RS et al. Circulation. 1999;100:1056-1064.

35

30

25

20

15

10

5

0

-5

17 Weeks 43 Weeks 0 Weeks

**

End Diastolic

Volume

(mL)

Candesartan

Candesartan + enalapril

Enalapril

*

*

* P <0.01 compared with 0 weeks.

**P <0.05 compared with enalapril.