Angiotensin Receptor Blocker -Neprilysin Inhibitor is now first line drug in Heart Failure with reduced ejection fraction.

1. ARNI- revisiting
evidence and
guideline
Dr Syed Raza
MD, MRCP, FRCP, CCT(UK), FESC, FACC, FAECVI
Consultant Cardiologist
Awali Hospital
Bahrain

2. Case
56 M
HPN, Dyslipidemia. Not Diabetic. Heavy Smoker
5 weeks ago admitted with acute SOB , diagnosed and treated as
HFrEF. Currently no SOB , orthopnea, PND or leg swelling,.
HR 78/mt, Reg, BP -122/70 mmHg
NT-Pro BNP = 400 ( 3000 )pg/ml e-GFR = 76 ml/mt/1.73m2
ECG – QRS : 136 ms. No signs of ischemia.
Echo – Global LV systolic dysfunction . LVEF = 35 %
Med. Perindopril 5 mg, Bisoprolol 2.5 mg , Furosemide 40 mg OD,
Eplerenone 12.5 mg OD

3. As per new
2021 ESC
guideline ,
what should
be your next
action ?
Add Add Ivabradine
Add Add ARNI
Replace Replace Perindopril with ARNI
Start Start SGLT2 Inhibitor
Put on Put on list for CRT
Reduce Reduce Furosemide dose

4. Objectives
1. Current recommendations for choice of anti HF medications
2. PARADIGM –HF
3. My personal experience with ARNI

5. Bringing Science to Practice
Evidence Based Medicine and Guidelines Medication Efficacy and Safety

10. Prospective comparison of ARNI with ACEI to Determine
Impact on Global Mortality and morbidity in Heart Failure

11. ARNI –mechanism of action

12. PARADIGM-HF – Key inclusion and
exclusion criteria
• Chronic HF NYHA FC II–IV with LVEF
≤40%*
• BNP (or NT-proBNP) levels as
follows:
• ≥150 (or ≥600 pg/mL), or
• ≥100 (or ≥400 pg/mL) and a
hospitalization for HFrEF within the
last 12 months
• ≥4 weeks’ stable treatment with an
ACEI or an ARB, and a β-blocker
• Aldosterone antagonist should be
considered for all patients (with
treatment with a stable dose for ≥4
weeks, if given)
*The ejection fraction entry criteria was lowered to ≤35% in a protocol amendment.
ACE=angiotensin-converting enzyme; ACEI=ACE inhibitor; ARB=angiotensin-receptor-blocker; BNP=B-type natriuretic peptide; CV=cardiovascular;
eGFR=estimate glomerular filtration rate; HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association; NT-proBNP=N-terminal
pro-brain natriuretic peptide; PCI=percutaneous coronary intervention; SBP=systolic blood pressure
McMurray et al. Eur J Heart Fail 2013;15:1062–73
• History of angioedema
• eGFR <30 mL/min/1.73 m2
• Serum potassium >5.2 mmol/L at screening OR
>5.4 mmol/L at the end of the enalapril run-in or
end of the sacubitril/valsartan run-in
• Requirement for treatment with both ACEI and
ARBs
• Symptomatic hypotension, SBP <100 mmHg at
screening, OR SBP <95 mmHg at end of enalapril
run-in or at randomization
• Current acute decompensated HF
• History of severe pulmonary disease
• Acute coronary syndrome, stroke, transient
ischemic attack, cardiac, carotid, or other major CV
surgery, PCI, or carotid angioplasty within the 3
months prior to screening
Key exclusion criteria
Key inclusion criteria
12

13. 2 weeks 1–2 weeks 2–4 weeks Median of 27 months’ follow-up
Sacubitril/valsartan200 mg BID
(N=4,209)
Enalapril* 10 mg BID
(N=4,233)
1:1 RANDOMIZATION
Double-blind
treatment period
Single-blind active
run-in period
Sacubitril/
valsartan
100 mg BID
Sacubitril/
valsartan
200 mg BID
ACE-inhibitor*
10 mg BID
*Enalapril 5 mg BID (10 mg TDD) for 1–2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated with
ARBs or with a low dose of ACEI
ACE=angiotensin-converting enzyme; ARB=angiotensin-receptor-blocker; BID=twice daily; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association;
TDD=total daily dose
1. McMurray et al. Eur J Heart Fail 2014;16:817–25; 2. McMurray et al. N Engl J Med 2014;371:993–1004;
3. Sacubitril/valsartan Core Data Sheet, version 1.2. Novartis Pharmaceuticals, July 2017
PARADIGM-HF
Over 8400 patients with chronic heart failure with systolic dysfunction (LVEF ≤40%)
in NYHA classes II–IV2,3
13

14. *Compared with enalapril, as assessed via time until cardiovascular death or first hospitalization for HF.1 ‡Enalapril 10 mg 2x daily as comparator vs
sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy). §27 months since randomization (median)
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection
fraction; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004
Cumulative
probability
0.4 Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
6
Months since randomization
0.3
0.2
0.1
0
p<0.0001
HR: 0.80
(95 % CI: 0.73–0.87)
ARR: 4.7 %
12 18 24 30 36 42
RELATIVE RISK REDUCTION
OF PRIMARY ENDPOINT
Sacubitril/valsartan significantly reduced death from
CV causes or first hospitalization for HF*
4,187 3,922 3,663 3,018 2,257 1,544 896 249
4,212 3,883 3,579 2,922 2,123 1,488 853 236
No. at risk
Sacubitril/
valsartan
Enalapril
Composite primary endpoint
14

15. *Compared with enalapril, as assessed via time to first hospitalization for HF (single component of primary endpoint). ‡Enalapril 10 mg 2x daily as
comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy). §27 months since randomization (median)
ACE=angiotensin-converting enzyme; ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HFrEF=heart failure with reduced ejection
fraction; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004g
Cumulative
probability
Months since randomization
0.3
0.2
0.1
RELATIVE RISK REDUCTION OF
FIRST HOSPITALIZATION FOR HF
Sacubitril/valsartan significantly reduces the risk of first HF
hospitalization, keeping HFrEF patients out of the hospital*
4,187 3,922 3,663 3,018 2,257 1,544 896 249
4,212 3,883 3,579 2,922 2,123 1,488 853 236
No. at risk
Sacubitril/
valsartan
Enalapril
6
0
12 18 24 30 36 42
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
p<0.001
HR: 0.79
(95 % CI: 0.71–0.89)
ARR: 2.8 %
Primary endpoint
15

16. *Time to all-cause death. ‡Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard
therapy).
§27 months since randomization (median)
ARR=absolute risk reduction; CI=confidence interval; HF=heart failure; HR=hazard ratio; NNT=number needed to treat
McMurray et al. N Engl J Med 2014;371:993–1004
Cumulative
probability
6
Months since randomization
12 18 24 30 36 42
RELATIVE RISK REDUCTION
OF ALL-CAUSE MORTALITY
Sacubitril/valsartan significantly reduced all-cause mortality*
4,187 4,056 3,891 3,282 2,478 1,716 1,005 280
4,212 4,051 3,860 3,231 2,410 1,726 994 279
No. at risk
Sacubitril/
valsartan
Enalapril
0.3
0.2
0.1
0
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
p<0.01
HR: 0.84
(95 % CI: 0.76–0.93)
ARR: 2.8 %
16

17. *Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy). §27 months since randomization (median)
ARR=absolute risk reduction; CI=confidence interval; HR=Hazard Ratio; NNT=number needed to treat
1. Desai et al. Eur Heart J 2015;36:1990–7
Cumulative
probability
6
Months since randomization
12 18 24 30 36 42
RELATIVE RISK REDUCTION
OF SUDDEN DEATH
Sacubitril/valsartan significantly reduced the risk of sudden death1
4,187 3,891 2,478 1,005
4,212 3,860 2,410 994
No. at risk
Sacubitril/
valsartan
Enalapril
0.10
0.06
0.02
0
Enalapril‡ (N=4,212)
Sacubitril/valsartan (N=4,187)
p=0.008
HR: 0.80
(95 % CI: 0.68–0.94)
ARR: 1.4 %
0.08
0.04
17

18. Secondary outcomes – summary
Outcome, n %
Sacubitril/
valsartan
(n=4,187)
Enalapril
(n=4,212)
Hazard ratio*
(95% CI) p value‡
Death from any cause, n (%) 711 (17.0) 835 (19.8)
0.84
(0.76–0.93)
<0.001
Change in KCCQ clinical summary
score§ at 8 months, mean ± SD
–2.99 ± 0.36 –4.63 ± 0.36
1.64
(0.63–2.65)
0.001
New onset atrial fibrillation¶,
n (%)
84 (3.1) 83 (3.1)
0.97
(0.72–1.31)
0.83
Decline in renal function#,
n (%)
94 (2.2) 108 (2.6)
0.86
(0.65–1.13)
0.28
*Calculated with the use of stratified cox proportional-hazard models; ‡Two-sided p values calculated by means of a stratified log-rank test without adjustment for
multiple comparisons; §KCCQ scores range from 0 to 100 – higher scores indicate fewer symptoms and physical limitations associated with HF; ¶2,670 patients in the
sacubitril/valsartan and 2,638 in the enalapril group who did not have atrial fibrillation at randomization were evaluated; #Defined as: (a) ≥50% decline in eGFR from
randomization; (b) >30 mL/min/1.73 m2 decline in eGFR from randomization or to a value of <60 mL/min/1.73 m2, or (c) progression to end-stage renal disease.
CI=confidence interval; eGFR=estimated glomerular filtration rate; HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire; SD=standard deviation
McMurray et al. N Engl J Med 2014;371:993–1004
18

19. *In surviving patients
HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire
Treatment with sacubitril/valsartan provides sustainable
improvement of patients’ quality of life*
• Treatment with sacubitril/valsartan improves patients’ quality of life*, including HF symptoms and physical
limitations (as measured based on the KCCQ)
• The effect of sacubitril/valsartan on quality of life is sustained for up to 36 months; over the same treatment
period, patients treated with enalapril experience a quality of life decline
• Sacubitril/valsartan had similar improvements as were seen with cardiac
resynchronization therapy
Lewis et al. Circ Heart Fail 2017;10:e003430
-2
-1
0
1
2
Randomization
Month 4 Month 8 Month 12 Month 24 Month 36
Entresto
Enalapril
Change in KCCQ-Overall Summary Scores vs. baseline
KCCQ-OS
Time from
randomization
Sacubitril/valsarta
n
Enalapril
19

20. Lower proportion of sacubitril/valsartan-treated patients
required intravenous positive inotropic support , CRT , LVAD
compared with enalapril
Event
Sacubitril/
valsartan§
n (%)
Enalapril¶
n (%)
Rate ratio
(95% CI) p value
Relative risk
reduction¶
Patients receiving i.v.
positive inotropic drugs
161 (3.9) 229 (5.4)
0.69
(0.57–0.85)
<0.001 31%
Patients requiring
cardiac
resynchronization,
ventricular assist device
implantation or cardiac
transplantation*
94 (2.3) 119 (2.8)
0.78
(0.60–1.02)
0.07
22%
(non-
significant)
*Number of patients who received a left ventricular assist device or underwent cardiac transplantation was 23 in the enalapril group and 13 in the sacubitril/valsartan group; ‡With
sacubitril/valsartan, compared with enalapril; §N=4,187; ¶N=4,212.
CI=confidence interval; HFrEF=heart failure with reduced ejection fraction; HR=hazard ratio; i.v.=intravenous
Packer et al. Circulation 2015;131:54–61
20

21. Sacubitril/valsartan had fewer adverse events leading to
permanent study drug discontinuation
76% of patients remained on the target dose of sacubitril/valsartan (200 mg 2x daily) until
the end of the study2
*Enalapril 10 mg 2x daily as comparator vs sacubitril/valsartan 200 mg 2x daily in the PARADIGM-HF study (in addition of standard therapy)
1. McMurray et al. N Engl J Med 2014;371:993–1004; 2. Packer et al. Circulation 2015;131:54–61
15
Therapy
discontinuation
(%)
10
5
0
10.7
p=0.03
Any adverse event Hypotension Renal impairment Hyperkalemia
12.3
0.9 0.7 0.3 0.4
p=0.56
0.7 1.4
p=0.002
p=0.38
Sacubitril/valsartan (N=4,187)
Enalapril* (N=4,212)
21

22. The majority of patients achieved and maintained the target
dose of sacubitril/valsartan throughout PARADIGM-HF
OF PATIENTS REMAINED AT THE TARGET DOSE OF
SACUBITRIL/VALSARTAN 97 MG/103 MG* TWICE DAILY AT
THE END OF THE STUDY1
76%
• There were fewer discontinuations due to
adverse events with sacubitril/valsartan vs
enalapril (mean daily dose of 375 mg and 18.9
mg, respectively)2
*In PARADIGM-HF, sacubitril/valsartan 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.
1. Sacubitril/valsartan Core Data Sheet, version 1.2. Novartis Pharmaceuticals, July 2017;
2. McMurray et al. N Engl J Med 2014;371:993–1004
22

23. Conclusions
• HEART FAILURE remains a chronic disease with unmet needs despite current available
treatment.
• In the PARADIGM-HF trial, the superiority of
sacubitril/valsartan vs enalapril was demonstrated
as follows:2*
• 20% reduction‡ in CV mortality or first HF hospitalization
(primary composite endpoint)
• 20% reduction‡ in CV mortality
• 20% reduction in risk of sudden cardiac death
• 21% reduction‡ in first HF hospitalization
• 16% reduction‡ in all-cause mortality (secondary endpoint)
• The superiority of sacubitril/valsartan over enalapril was
not accompanied by important safety concerns
• Implications for clinical practice
#For the full safety profile of sacubitril/valsartan please see
actual approved label; *Enalapril 10 mg 2x daily as comparator
vs sacubitril/valsartan 200 mg 2x daily in
the *PARADIGM-HF study (in addition of standard therapy);
‡Relative risk reduction
CV=cardiovascular; HF=heart failure
1. Langenickel and Dole. Drug Discov Today: Ther Strateg
2012;9:e131–9; 2. McMurray et al. N Engl J Med 2014;371:993–
1004.
23

26. Back to the case
At 9 months follow up
Patient has no symptoms and signs of HF .Repeat Echo shows
LVEF of 50% On ARNI 200 mg BID . BP – 114/70 e-GFR = 70
What is the best approach with ARNI ?
• 1. Reduce ARNI dose to 100mg BID
• 2. Stop ARNI
• 3. Continue ARNI same dose
• 4. Change ARNI back to Perindopril

27. ARNI

28. Summary
1. ARNI is now first line medication in HFrEF
- Class I recommendation LOE =B ( ESC-HF
2021 )
2. PARADIGM –HF trial has demonstrated a
clear benefit in favor of ARNI when compared
with ACEI.
3. ARNI is well tolerated
4. Stopping ARNI once patient stable is not
desirable