ACEIs versus ARBs in Heart Failure : Current evidence

1. ACE Inhibitor and ARBs in Heart Failure
– What does the evidence say ?
Syed Raza
Awali Hospital

2. 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)

3. 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

4. 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

5. RAAS System

6. 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.

7. 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

8. Drugs Commonly Used for HFrEF
Drug
Initial Daily
Dose(s)
Maximum
Doses(s)
Mean Doses Achieved in
Clinical Trials
ACE Inhibitors
Captopril 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 ---------
ARBs
Candesartan 4 to 8 mg once 32 mg once 24 mg/d (419)
Losartan 25 to 50 mg once
50 to 150 mg
once
129 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)

9. Beta
blocker
Mineralocorticoid
receptor
antagonist
Drugs That Reduce Mortality in Heart
Failure With Reduced Ejection Fraction
ACE
inhibitor
Angiotensin
receptor
blocker
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%
%DecreaseinMortality

10. 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

11. 253 pts NYHA cl 4

12. 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

14. SOLVD Treatment TrialSOLVD Treatment Trial
CV 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
Events%
Placebo
Enalapril
N Engl J Med 1991;325:293-302N Engl J Med 1991;325:293-302
26% Risk Reduction26% Risk Reduction
p<0.0001p<0.0001

15. -27% RR

16. 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

18. Val-HeFT : Study Overview
5010 patients
≥18 years; EF <40%; NYHA II-IV; LVIDd >2.9 cm/m2
ACE inhibitors, diuretics,
digoxin, β-blockers
Valsartan
40 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.

19. Effect of Valsartan on Combined
Morbidity/Mortality Endpoint*
Months
3 6 9 12 15 18 21 24 27
0
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
Valsartan
Placebo
P = 0.009
13.2% Risk Reduction

20. HF = heart failure.
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
3 6 9 12 15 18 21 24 27
0
65
70
75
80
85
90
95
100
Months
Event-Free
Probability
P < 0.001
27.5% Risk Reduction
0
Valsartan
Placebo
HF-Related Hospitalizations*
30

21. CHARM Programme
n=3025
LVEF >40%
ACE inhibitor
treated/not treated
CHARM
Added
CHARM
Preserved
3 component trials comparing
7,601 patients with heart failure
Follow up min 2 years
Candesartan (4 or 8 mg/day, titrated to target dose of 32 mg) to placebo
CHARM
Alternative
n=2028
LVEF ≤40%
ACE inhibitor
intolerant
n=2548
LVEF ≤40%
ACE inhibitor
treated
Primary outcome:
CV death or CHF hosp

22. CHARM Overall Program
23.3%
24.9%
0%
10%
20%
30%
Candesartan Placebo
All-cause mortality
HR 0.91
95% CI 0.83-1.00
p=0.055
30.2%
34.5%
0%
10%
20%
30%
40%
Candesartan Placebo
European Society of Cardiology 20
CV Mortality or
CHF Hospitalization
HR 0.84
p<0.0001

23. CHARM-Alternative: Primary outcome
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
Number at risk
Candesartan 1013 929 831 434 122
Placebo 1015 887 798 427 126
3.5
406 (40.0%)
334 (33.0%)

24. CHARM Alternative Trial
33.0%
40.0%
0%
10%
20%
30%
40%
50%
Candesartan Placebo
CHF hospitalization
HR 0.77
p=0.0004
21.6%
24.8%
0%
10%
20%
30%
Candesartan Placebo
European Society of Cardiology 20
CV Mortality
HR 0.85
p=0.072

25. CHARM Added Trial
37.9%
42.3%
0%
10%
20%
30%
40%
50%
Candesartan Placebo
CHF hospitalization
HR 0.85
p=0.011
23.7%
27.3%
0%
10%
20%
30%
Candesartan Placebo
European Society of Cardiology 20
CV Mortality
HR 0.84
p=0.02

26. 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 with
starting 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 in
CHF
Equivalent Yes N/a No N/a N/a N/a
Efficacy to ACEi
post MI
Evidence for Various ARBs

28. Study Design
- Age ≥ 65 years
- LVEF ≥ 40%
- Absence of
exclusion criteria
SCREENING
after 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

29. Remodelling
Incidence of remodelling (mean ± SD) defined as an increase ≥ 8%
of the LVEDV
p < 0.001
%incidence(+/-95%CI)
0.0
20.0
40.0
60.0
51.2%
Perindopril
(N = 455)
Placebo
(N = 441)
27.7%
RRR=46%

30. 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

31. Perindopril 10 mg added to aspirin, β-blocker, and statin
-35-35
-15-15
-20-20
-10-10
-5-5
00
CV death, MI, or
cardiac arrest
Nonfatal MI
Stable CAD patientsStable CAD patients
Hospitalization
for 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 21812 218
stable CAD patientsstable CAD patients
without heart failurewithout heart failure
12 21812 218
stable CAD patientsstable CAD patients
without heart failurewithout heart failure
Active cardiovascular risk reductions
P=0.002
P=0.001

36. Mortality benefit in preserved EF
HFpEF HFrEF
Aldosterone antagonists
ACE inhibitors
ARBs
β-blockers
Vasodilators??

37. 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

38. 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

39. 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.

40. 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.

41. 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.

42. CHARM Preserved Trial
22.0%
24.3%
0%
10%
20%
30%
Candesartan Placebo
CHF hospitalization
HR 0.89
p=0.118
11.2% 11.3%
0%
5%
10%
15%
Candesartan Placebo
European Society of Cardiology 20
CV Mortality
HR 0.99
p=0.918

43. 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.

44. 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

45. Thank
you…