ACE Inhibitor and ARBs in Heart Failure – What does the evidence say ?

Syed Raza

Awali Hospital

Objectives

1.Management issues in Heart Failure.

2.Role of ACEI and ARBs.

3.Landmark trials in Heart Failure using ACEIs and ARBs.

4.Comparative data (based on evidence)

Heart Failure : Complex Issues

• High Mortality• High re-admission rates• On-going symptoms• Reduced Quality of Life• Poor understanding of disease• Poor Rx adherence• Dose Adjustments in the Elderly

Rational for Medications(Why does my doctor have me on so many pills??)

• Improve Symptoms– Diuretics (water pills)– Digoxin– Ivabradine

• Improve Survival– Beta-blockers– Ivabradine– ACE-inhibitors– Angiotensin receptor

blockers (ARB’s– Aldosterone blockers

RAAS System

ACEI and ARB : Mechanism of Action in HF

• Vasodilatation : reduce cardiac preload and after load and thereby improve systolic function and increase cardiac output.

• Facilitate salt and water excretion by complex effects on the kidney (attenuation of Aldosterone effect.)

• ACE inhibitors and ARBs reduce LVH , myocardial fibrosis and stiffness.

Pharmacological Therapy for Management of Stage C HFrEF

Recommendations COR LOE

Diuretics

Diuretics are recommended in patients with HFrEF with fluid retention I C

ACE Inhibitors

ACE inhibitors are recommended for all patients with HFrEF I A

ARBs

ARBs are recommended in patients with HFrEF who are ACE inhibitor intolerant I A

ARBs are reasonable as alternatives to ACE inhibitor as first line therapy in HFrEF IIa A

The addition of an ARB may be considered in persistently symptomatic patients with HFrEF on GDMT

IIb A

Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful III: Harm C

Drugs Commonly Used for HFrEF Drug

Initial Daily Dose(s)

Maximum Doses(s)

Mean Doses Achieved in Clinical Trials

ACE InhibitorsCaptopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/d (421)Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/d (412)Fosinopril 5 to 10 mg once 40 mg once ---------Lisinopril 2.5 to 5 mg once 20 to 40 mg once 32.5 to 35.0 mg/d (444)Perindopril 2 mg once 8 to 16 mg once ---------Quinapril 5 mg twice 20 mg twice ---------

Ramipril 1.25 to 2.5 mg BD 5 mg BD ---------

Trandolapril 1 mg once 4 mg once ---------ARBsCandesartan 4 to 8 mg once 32 mg once 24 mg/d (419)

Losartan 25 to 50 mg once50 to 150 mg

once129 mg/d (420)

Valsartan 20 to 40 mg twice 160 mg twice 254 mg/d (109)Aldosterone Antagonists

Spironolactone 12.5 to 25 mg once

25 mg once or twice

26 mg/d (424)

Eplerenone 25 mg once 50 mg once 42.6 mg/d (445)

Betablocker

Mineralocorticoidreceptor

antagonist

Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction

ACEinhibitor

Angiotensinreceptorblocker

Drugs that inhibit the renin-angiotensin system have modest effects on

survival

Based on results of SOLVD-Treatment, CHARM-Alternative,COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

10%

20%

30%

40%

0%

% D

ec

rea

se in

Mo

rtal

ity

ACE Inhibitors are the Cornerstone of Rx in CHF

CCS 2003 Consensus HF Update (draft)

• ACE I Rx ASAP post MI– Continue indefinitely if EF < 40% or clinical HF– Rx for all asymptomatic patients with LVEF ≤ 35%– Rx for all symptomatic patients with LVEF ≤ 35%– Target dose use in clinical trials or max tolerated

dose

253 pts NYHA cl 4

SOLVD(Studies of Left Ventricular

Dysfunction)• Enalapril vs placebo in 4228 patients• Ejection fraction < 35%• End points include:

– Delaying the progression of heart failure

– Improving signs and symptoms

– Reducing mortality

• Treatment arm - 2,111 (Enalapril 2.5 -40 mg)• Placebo - 2117

• FU : av 37.4 months

N Engl J Med 1991:325:293-302N Engl J Med 1991:325:293-302

SOLVD Treatment TrialSOLVD Treatment TrialCV Mortality or Hospitalization for CHFCV Mortality or Hospitalization for CHF

0

10

20

30

40

50

60

70

0 6 12 18 24 30 36 42 48

Months

Eve

nts

%

Placebo

Enalapril

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

26% Risk Reduction26% Risk Reductionp<0.0001p<0.0001

-27% RR

ARB(angiotensin 2 antagonist)ELITE (evaluation of losartan in elderly)

•ELITE 1 (Lancet 1997) – •Losartan showed less morbidity & mortality than captopril. •Death & hospitalisation for heart failure 9.4% (losa.) Vs 13.2% (capt) NNT 26

Elite 2 (lancet 2000)•No significant diff in mortality and hospitalization.•Insufficient data to recommend ARB as 1st line Rx

Val-HeFT : Study Overview

5010 patients ≥18 years; EF <40%; NYHA II-IV; LVIDd >2.9 cm/m2

ACE inhibitors, diuretics,digoxin, β-blockers

Valsartan40 mg bid titrated to

160 mg bid

Randomized to

Receiving background therapy

Placebo

Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.

Effect of Valsartan on Combined Morbidity/Mortality Endpoint*

Months

3 6 9 12 15 18 21 24 270

65

70

75

80

85

90

95

100

Probability of Event-Free

Survival

0

*All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators.

Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

30

ValsartanPlacebo

P = 0.00913.2% Risk Reduction

HF = heart failure. Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

3 6 9 12 15 18 21 24 270

65

70

75

80

85

90

95

100

Months

Event-Free Probability

P < 0.001

27.5% Risk Reduction

0

ValsartanPlacebo

HF-Related Hospitalizations*

30

CHARM Programme

n=3025

LVEF >40% ACE inhibitor

treated/not treated

CHARM Added

CHARMPreserved

3 component trials comparing7,601 patients with heart failure

Follow up min 2 yearsCandesartan (4 or 8 mg/day, titrated to target dose of 32 mg) to placebo

CHARMAlternative

n=2028

LVEF ≤40%ACE inhibitor

intolerant

n=2548

LVEF ≤40%ACE inhibitor

treated

Primary outcome:CV death or CHF hosp

CHARM Overall Program

23.3%24.9%

0%

10%

20%

30%

Candesartan Placebo

All-cause mortalityHR 0.91

95% CI 0.83-1.00p=0.055

30.2%

34.5%

0%

10%

20%

30%

40%

Candesartan Placebo

European Society of Cardiology 2003

CV Mortality orCHF Hospitalization

HR 0.84p<0.0001

CHARM-Alternative: Primary outcome CV death or CHF hospitalisation

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

%

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

Number at risk

Candesartan 1013 929 831 434 122

Placebo 1015 887 798 427 126

3.5

406 (40.0%)

334 (33.0%)

CHARM Alternative Trial

33.0%

40.0%

0%

10%

20%

30%

40%

50%

Candesartan Placebo

CHF hospitalizationHR 0.77p=0.0004

21.6%

24.8%

0%

10%

20%

30%

Candesartan Placebo

European Society of Cardiology 2003

CV MortalityHR 0.85p=0.072

CHARM Added Trial

37.9%

42.3%

0%

10%

20%

30%

40%

50%

Candesartan Placebo

CHF hospitalizationHR 0.85p=0.011

23.7%

27.3%

0%

10%

20%

30%

Candesartan Placebo

European Society of Cardiology 2003

CV MortalityHR 0.84p=0.02

Diovan Avapro Cozaar Atacand Micardis Teveten(valsartan) (irbesartan) (losartan) (candesartan (telmisartan) (eprosartan)

cilexetil)

Reduction in -45% -6% -35% -30% N/a N/a microalbumin-uria withstarting dose

Heart failure -27.5% N/a -8.1% -17% N/a N/a hospitaliza- (ValHeFT) (ELITE II) (CHARM) tions

CV outcome in -13.3% N/a +7% -15% N/a N/a CHF-treated (ValHeFT) (ELITE II) (CHARM) patients

Positive CV Yes N/a No Yes N/a N/a outcomes inCHF

Equivalent Yes N/a No N/a N/a N/a Efficacy to ACEipost MI

Evidence for Various ARBs

Study Design

- Age ≥ 65 years

- LVEF ≥ 40%

- Absence of exclusion criteria

SCREENINGafter AMI

Perindopril or placebo RANDOMISATION(within 20 days from AMI and after at least 24 hours of ACE-I wash-out)

FOLLOW-UP Month 1

Month 3

Month 6: ECHO

Month 9

Month 12: ECHO

8 mg

4 mg

RemodellingIncidence of remodelling (mean ± SD) defined as an increase ≥ 8% of the LVEDV

p < 0.001

% in

cid

ence

(+

/-95

% C

I)

0.0

20.0

40.0

60.051.2%

Perindopril(N = 455)

Placebo(N = 441)

27.7%

RRR=46%

Perindopril significantly reduces death-hospitalisation

for heart failure-cardiac remodelling by 38%

Coversyl better Placebo better RRR (%)

Total mortality 0

Hospitalisation for HF

Remodelling

27

46

Death and HF 38

P

0.90

0.24

<0.001

<0.001

0.0 1.0 2.0

Primary end point

Perindopril 10 mg added to aspirin, β-blocker, and statin

-35-35

-15-15

-20-20

-10-10

-5-5

00

CV death, MI, orcardiac arrest

Nonfatal MI

Stable CAD patientsStable CAD patients

Hospitalizationfor heart failure

-25-25

-30-30

-40-40

-20%P=0.0003 -22%

-39%

Fox K; EUROPA Investigators. The EUROPA study. Fox K; EUROPA Investigators. The EUROPA study. LancetLancet. 2003;362:782-788. . 2003;362:782-788.

12 218 12 218

stable CAD patients stable CAD patients

without heart failurewithout heart failure

12 218 12 218

stable CAD patients stable CAD patients

without heart failurewithout heart failure

Active cardiovascular risk reductions

P=0.002

P=0.001

Mortality benefit in preserved EF

HFpEF HFrEF

Aldosterone antagonists

ACE inhibitors

ARBs

β-blockers

Vasodilators??

Assessment Question #1• Which treatments have been shown to

decrease mortality in patients with HFpEF?

A. ACE inhibitors/ARBs

B. β-blockers

C. Aldosterone antagonists

D. All of the above

E. None of the above

Assessment Question #1• Which treatments have been shown to

decrease mortality in patients with HFpEF?

A. ACE inhibitors/ARBs

B. β-blockers

C. Aldosterone antagonists

D. All of the above

E. None of the above

ACE inhibitors/ARBs in HFpEF

• No mortality benefit in HFpEF from prospective trials

• ACEI and ARBs decrease symptoms and hospitalization.

• Heart failure guidelines

– First line medication for hypertension management in HFpEF

- Utilize in presence of co-morbidities (diabetes, CAD, CKD)

Eur Heart J 2012;33:1787-1847.Circulation 2013;128:e240-327.

PEP-CHF Trial – Perindopril compared to placebo in 850

symptomatic HFpEF patients (EF > 40%)– Non-significant difference in mortality or HF

hospitalizations with perindopril (23.6% vs 25.1%)

– Perindopril significantly improved symptoms and exercise capacity

– Conclusion: ACE inhibitor improved HFpEF symptoms but had no reduction in mortality or HF hospitalizations

Eur Heart J 2006;27:2338-45.

CHARM-preserved• Candesartan compared to placebo in 3,023

symptomatic HFpEF patients (EF > 40%)

• Significant decrease in HF hospitalizations with ARB (15% vs. 18%)

• No difference in mortality (11% for each treatment)

• Conclusion: No mortality benefit with use of an ARB in HFpEF but mild impact in preventing HF hospitalizationLancet 2003;362:777-81.

CHARM Preserved Trial

22.0%24.3%

0%

10%

20%

30%

Candesartan Placebo

CHF hospitalizationHR 0.89p=0.118

11.2% 11.3%

0%

5%

10%

15%

Candesartan Placebo

European Society of Cardiology 2003

CV MortalityHR 0.99p=0.918

I-preserve

• Symptomatic HFpEF patients (EF > 45%) who were > 60 years were randomized to Irbesartan or placebo (N = 4,128)

• No difference in composite primary endpoint of death or cardiovascular hospitalization between groups (36% vs. 37%)

• Conclusion: No benefit in terms of mortality and hospitalization.

N Engl J Med 2008;359:2456-67.

Summary

• ACE inhibitors form the corner stone of management of HF with reduced EF.

• Most guidelines recommend use of ARBs in patients who are intolerant to ACEIs.

• ARBs are generally shown to be better tolerated.• ACE inhibitors after an MI improve survival, rates of

hospitalization, symptoms, cardiac output and promote reverse remodeling.

• Not certain whether any difference among the many different ACE inhibitors out there today

Thank you…