This document discusses the 2016 ESC Guidelines for the diagnosis and treatment of heart failure. It focuses on the PARADIGM-HF trial which compared the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (LCZ696) to enalapril in patients with heart failure with reduced ejection fraction. The trial found LCZ696 reduced the risks of cardiovascular death or heart failure hospitalization and all-cause mortality compared to enalapril. LCZ696 was also better tolerated with less cough, hyperkalemia, and renal impairment reported compared to enalapril.

1. By
Waseem Omar
A. Lecturer of cardiology

2. 2016 ESC Guidelines for the
diagnosis and treatment of heart
failure

3. Definition
Clinical syndrome characterized by typical symptoms
with or without signs caused by a structural and/or
functional cardiac abnormality, resulting in a reduced
cardiac output and/or elevated intracardiac pressures
at rest or during stress.

4. Classification

5. ARNI
Angiotensin Receptor-Neprilysin Inhibitors
sacubitril/valsartan(LCZ696)

7. the largest clinical trial ever
conducted in heart failure (8442
patients over 47 countries).
Stopped early due to compelling
efficacy: risk of CV death was
significantly reduced.

8. PARADIGM-HF trial
Prospective Comparison of ARNI with
ACE-I to Determine Impact on Global
Mortality and Morbidity in Heart
Failure

9. Background
LCZ696
LCZ696

10. Randomized double-blinded trial compare efficacy
of LCZ696 to high dose enalipril
Selected inclusion criteria:
 ≥18 years old
 NYHA class II, III, or IV symptoms
 Systolic dysfunction (left ventricular ejection fraction
≤40%)
 Plasma B-type natriuretic peptide (BNP) level of ≥150
pg/mL.
 For ≥4 weeks before screening, patients were required to
take a stable, maximally tolerated dose of a beta-blocker
and an ACE inhibitor or ARB equivalent to ≥10 mg of
enalapril daily.

11.  Selected exclusion criteria:
 Symptomatic hypotension
 Systolic blood pressure <100 mm Hg.
 Estimated glomerular filtration rate (eGFR) <30
mL/min/1.73 m2.
 Serum potassium level >5.2 mmol/L.
 History of angioedema
 History of unacceptable side effects while on treatment
with an ACE inhibitor or ARB

12. 2 weeks 1-2 weeks 2-4 weeks
Single-blind run-in period Double-blind period
(1:1 randomization)
Enalapril
10 mg
BID
100 mg
BID
200 mg
BID
Enalapril 10 mg BID
LCZ696 200 mg BID
PARADIGM-HF: Study Design
Randomization
LCZ696

13. Primary end point:
Cardiovascular death or heart
failure hospitalization
Secondary end point: all cause
mortality.

14. 0
16
32
40
24
8
Enalapril
(n=4212)
360 720 10800 180 540 900 1260
Days After Randomization
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236
LCZ696
Enalapril
Patients at Risk
1117
Kaplan-MeierEstimateof
CumulativeRates(%)
914
LCZ696
(n=4187)
HR = 0.80 (0.73-0.87)
P = 0.0000002
Number needed to treat = 21
PARADIGM-HF: Cardiovascular Death or Heart
Failure Hospitalization (Primary Endpoint)

15. PARADIGM-HF: All-Cause Mortality
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
1005
994
280
279
LCZ696
Enalapril
Enalapril
(n=4212)
LCZ696
(n=4187)
HR = 0.84 (0.76-0.93)
P<0.0001
Kaplan-MeierEstimateof
CumulativeRates(%)
Days After Randomization
Patients at Risk
360 720 10800 180 540 900 1260
0
16
32
24
8
835
711

16. LCZ696
(n=4187)
Enalapril
(n=4212)
P
Value
Prospectively identified adverse events
Symptomatic hypotension 588 388 < 0.001
Serum potassium > 6.0 mmol/l 181 236 0.007
Serum creatinine ≥ 2.5 mg/dl 139 188 0.007
Cough 474 601 < 0.001
Discontinuation for adverse event 449 516 0.02
Discontinuation for hypotension 36 29 NS
Discontinuation for hyperkalemia 11 15 NS
Discontinuation for renal impairment 29 59 0.001
Angioedema (adjudicated)
Medications, no hospitalization 16 9 NS
Hospitalized; no airway compromise 3 1 NS
Airway compromise 0 0 ----
PARADIGM-HF: Adverse Events

17. In heart failure with reduced ejection fraction,
when compared with recommended doses of
enalapril:
LCZ696 was more effective than enalapril in . . .
•Reducing the risk of CV death and HF
hospitalization
•Reducing the risk of CV death by incremental 20%
•Reducing the risk of HF hospitalization by
incremental 21%
•Reducing all-cause mortality by incremental 16%
•Incrementally improving symptoms and physical
limitations
PARADIGM-HF: Summary of Findings

18. LCZ696 was better tolerated than
enalapril . . .
• Less likely to cause cough, hyperkalemia or
renal impairment
• Less likely to be discontinued due to an adverse
event
• More hypotension, but no increase in
discontinuations
• Not more likely to cause serious angioedema

19. 10%
Angiotensin Neprilysin Inhibition With LCZ696 Doubles
Effect on Cardiovascular Death of Current Inhibitors of the
Renin-Angiotensin System
20%
30%
40%
ACE
inhibitor
Angiotensin
receptor
blocker
0%
%DecreaseinMortality
18%
20%
Effect of ARB vs placebo derived from CHARM-Alternative trial
Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial
Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial
Angiotensin
neprilysin
inhibition
15%

22. What should I know
about ARNI????

23. Trade name:

24. Dosing & Uses
 Recommended starting dose: 49 mg/51 mg PO BID
 Target maintenance dose: After 2-4 weeks, double the
dose to the target maintenance dose of 97 mg/103 mg
PO BID as tolerated.
 Patients not taking an ACE inhibitor or other ARB:
Reduce starting dose to 24 mg/26 mg BID.

25. Renal impairment
 Mild-to-moderate (eGFR ≥30 mL/min/1.73
m²): No starting dose adjustment required
 Severe (eGFR <30 mL/min/1.73 m²): Reduce
starting dose to 24 mg/26 mg BID; double the
dose every 2-4 weeks to target maintenance
dose of 97 mg/103 mg BID as tolerated

26. Hepatic impairment
 Mild (Child-Pugh A): No starting dose adjustment
required
 Moderate (Child-Pugh B): Reduce starting dose to 24
mg/26 mg BID; double the dose every 2-4 weeks to
target maintenance dose of 97 mg/103 mg BID as
tolerated
 Severe (Child-Pugh C): Not recommended

27. Adverse Effects
 >10%: Hypotension (18%), Hyperkalemia (12%)
 1-10%: Cough (9%), Dizziness (6%), Orthostasis (2.1%)
 <1%: Angioedema,

28. Black Box Warnings
 Discontinue as soon as possible when pregnancy is
detected
 Drug affects renin-angiotensin system, causing
oligohydramnios, which may result in fetal injury or death

29. Contraindications
 Hypersensitivity to any component
 History of angioedema related to previous ACE inhibitor
or ARB therapy
 Should not be administered concomitantly with ACE
inhibitors or within 36 hours of the last dose of ACE
inhibitor
 Concomitant use with aliskiren in patients with diabetes

30. Cautions
 Observe for signs and symptoms of angioedema
 Sacubitril/valsartan lowers blood pressure and may
cause symptomatic hypotension especially in
patients who are volume-depleted or salt-depleted.
 Monitor renal function and potassium levels.

31. This is a step closer
to taking the failure
out of heart failure

32. Thanks