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ACE Inhibitors and ARBs in Heart Failure

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

inadequate cardiac output to maintain metabolic requirements


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

Myocardial injury

Cardiac function

Acute (adaptive)

Hypertrophy, remodeling, apoptosis

Activation of SNS, RAAS, endothelin, AVP, inflammatory cytokines, oxidative stress

1950s-1980s

1980s-2000s

Hemodynamic model
Reduced contractility Pump dysfunction

Neurohormonal model
Progressive remodeling & impaired myocard function Treatment: Neurohormone blockers: ACE inhibitors, ARBs -blockers Conventional drugs Diuretics Digitalis

Treatment: Positive inotropic drugs Vasodilators 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

Stroke Atherosclerosis Vasoconstriction Vascular hypertrophy Endothelial dysfunction LV hypertrophy Fibrosis Remodeling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis Hypertension

AT1 receptors

Heart failure MI

DEATH

Renal failure

Angiotensinogen
Nitric oxide Renin

Angiotensin I
Bradykinin

ACE inhibitor
Inactive peptides

ACE

Non-ACE pathways

Angiotensin II

AT1 receptor blocker

AT1R
Vasoconstriction Proatherosclerosis Proinflammation Prothrombosis

AT2R
CV protection Vasodilatation Anti fibrosis Anti growth

Vasodilatory effects

Formation of superoxide anions

ACE inhibitors

Plaque stabilization

Regression of VSMC proliferation

Regression of LV hypertrophy

CONSENSUS

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%
Diabetes + 1 CV risk factor

Risk Continuum

SOLVD Rx V-HeFT II

SAVE, AIRE, TRACE


SOLVD Prevention EUROPA
TIA Stroke Angina PCI CABG CAB GC MI PAD

Vascular disease, LVEF >40%

HOPE

Smoking, Dyslipidemia, Hypertension, Diabetes

CV Risk Factors

Size of Population Affected

50 40 Placebo
Mortality (%) 30

20 10 0 0

Enalapril Risk reduction 16% p=0.0036 6 12 18 24 30 36 42 48


Follow-up (months)

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

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

The Assessment of Treatment with Lisinopril and Survival (ATLAS)


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.

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

ACE inhibitors Captopril Ramipril Trandolapril Enalapril Fosinopril Lisinopril Quinapril Perindopril

Initial doses 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.

Target doses 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.

Adverse effects : Hypotension Hyperkalemia Renal dysfunction Dry cough Angioedema

Angiotensin Receptor Blockers (ARBs)

Alternative agents

ACE Inhibitor intolerant?


Additional therapy

More complete inhibition of RAAS

Retard bradykinine degradation

ELITE II

OPTIMAAL
RESOLVD VALHEFT

VALIANT
CHARM

1.0 Probability of Survival


0.8 0.6 0.4 0.2 0.0 0

Primary Endpoint: All-Cause Mortality

Captopril
Losartan

(N=1574) 250 Events


(N=1578) 280 Events

Captopril/Losartan Hazard Ratio (95% C.I.): 0.88 (0.75, 1.05) P=0.16 100 200 300 400 500 600 700

Days of Follow-up

35 30 25 20 15 10 5 0 -5

Candesartan Candesartan + enalapril Enalapril


End Diastolic Volume (mL)

* *

**

0 Weeks

17 Weeks

43 Weeks

* P <0.01 compared with 0 weeks. **P <0.05 compared with enalapril. McKelvie RS et al. Circulation. 1999;100:1056-1064.

0.3 Probability of Event 0.25 0.2 0.15

Captopril Valsartan Valsartan + Captopril

Mortality by treatment

0.1
0.05
0

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


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

Months

12

18

24

30

36

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

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

CHARM Alternative
n=2028
LVEF 40% ACE inhibitor intolerant

CHARM Added
n=2548
LVEF 40% ACE inhibitor treated

CHARM Preserved
n=3025
LVEF >40% ACE inhibitor treated/not treated

Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death

50
40 30 20

Primary Outcome: CV death or CHF hospitalization

Placebo

406 (40.0%) 334 (33.0%)

Candesartan

10
0 0

HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001

3.5 years

CV mortality HR 0.85 (95% CI 0.71-1.02 MI HR 1.52 (95% CI 1.06-2.18)

Adjusted HR 0.80 (95% CI 0.66-0.97) p=0.02

% 50 40

Primary Outcome: CV death or CHF hospitalization

Placebo

538 (42.3%) 483 (37.9%)

30
20 10 0
0 1 2

Candesartan

HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010 3 3.5 years

CV mortality : HR 0.84 (95% CI 0.72-0.98) p=0.02 Covariate Adjusted HR p=0.021 MI : Not reported

% 30

Primary Outcome: CV death or CHF hospitalization

25
20 15 10 5 0 0
Candesartan Placebo

Placebo

366 (24.3%) 333 (22.0%)

Candesartan

HR 0.89 (95% CI 0.77-1.03), p=0.118 Adjusted HR 0.86, p=0.051

3.5 years
833 182 824 195

Number at risk 1514 1458 1377 1509 1441 1359

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 Candesartan Irbesartan Losartan Valsartan Telmisartan

Initial doses 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.

Target doses 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.

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

CHARM Alternative
n=2028
LVEF 40% ACE inhibitor intolerant

CHARM Added
n=2548
LVEF 40% ACE inhibitor treated

CHARM Preserved
n=3025
LVEF >40% ACE inhibitor treated/not treated

Primary outcome for each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death

Trial CONSENSUS I (n: 253)

Agent

Target Doses

Population NYHA class IV

Findings 40% RRR of all-cause mortality at 6 months 50% RRR of deaths from progressive heart failure

Enalapril 20 mg bid (vs. placebo)

SOLVD Treatment Trial (n: 2569)


SOLVD Prevention Trial (n: 4228) ATLAS (n: 3164)

Enalapril 10 mg bid (vs. placebo)

NYHA classes II-IV, EF 35%

16% decrease in 3.5-year mortality 26% decrease in death or hospitalization for CHF

Enalapril 10 mg bid (vs. placebo)

NYHA class I, 20% decrease in death or EF 35% hospitalization for CHF Non significant mortality trend favoring enalapril 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

Lisinopril

low dose (2,5-5 mg) vs. high dose (32,535 mg)

ACEIs
RESOLVD
ELITE II

ARBs

CHARM-Programme
VALHEFT

OPTIMAAL

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


Reduction in composite CV risk

Composite CV risk = cardiovascular mortality + non-fatal myocardial infarction + hospitalisation for congestive heart failure + non-fatal stroke The ONTARGET Investigators. N Engl J Med 2008;358:15471559

ACE Inhibitors

-blockers

ARBs

RESOLVD : Neurohormones
10
Candesartan Candesartan + enalapril Enalapril

5
BNP 0 (pmol/mL) -5 -10
0 Weeks
*P <0.01 compared with 0 weeks. P <0.01 compared with enalapril. McKelvie RS et al. Circulation. 1999;100:1056-1064.

*
17 Weeks

*
43 Weeks

RESOLVD : Ventricular Function


35 30 25 20 15 10 5 0 -5 Candesartan Candesartan + enalapril Enalapril
End Diastolic Volume (mL)

* *

**

0 Weeks

17 Weeks

43 Weeks

* P <0.01 compared with 0 weeks. **P <0.05 compared with enalapril. McKelvie RS et al. Circulation. 1999;100:1056-1064.

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