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McMurray JJV, et al. "Angiotensin-neprilysin inhibition versus enalapril in heart failure". The New England Journal of Medicine. 2014. 371(11):993-1004.
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Clinical Question

Among patients with HFrEF, does treatment with an angiotensin receptor-neprilysin inhibitor reduce CV mortality or HF hospitalizations when compared to ACE inhibitor therapy?

Bottom Line

Among patients with HFrEF, treatment with an angiotensin receptor-neprilysin inhibitor reduces CV mortality or HF hospitalizations when compared to enalapril. It is also associated with a reduction in all-cause mortality.

Major Points

ACE inhibitor therapy reduces mortality in patients with HFrEF and has been the standard of care in this disease since the 1990s following publications of trials like CONSENSUS (1987) and SOLVD (1991), though ARBs may be substituted if ACE inhibitors are poorly tolerated.[1] While beta blockers and aldosterone antagonists have further improved survival, mortality remains high.

Neprilysin is an endopeptidase that breaks down vasoactive peptides (BNP, bradykinin, and adrenomedullin); its inhibition may therefore reduce remodeling, vasoconstriction, and renal sodium retention and improve outcomes in HFrEF. The 2002 OVERTURE trial[2] found that use of omapatrilat (an agent that inhibits ACE, aminopeptidase P, and neprilysin) reduced mortality and hospitalization when compared to ACE-inhibitor use. However, omapatrilat was associated with a higher rate of angioedema. Use of a neprilysin inhibitor plus an ARB (termed ARNI or angiotensin receptor-neprilysin inhibitor) may provide benefit over ACE inhibitor monotherapy in treatment of HFrEF without increasing the rates of angioedema. The experimental ARNI named LCZ696 combines an ARB (valsartan 160 mg) with a neprilysin inhibitor (sacubitril). A clinical trial evaluating its efficacy was lacking.

Published in 2014, the industry-sponsored Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial randomized 8,399 patients with HFrEF (LVEF ≤40% and ≤35% were used at different points in the trial) and NYHA class II-IV symptoms to the ARNI LCZ696 (sacubitril) 200 mg PO BID or enalapril 10 mg PO BID (the goal dose from CONSENSUS and SOLVD). Doses were adjusted for tolerability. With a median follow-up of 27 months, the trial was stopped following a positive interval efficacy analysis. The ARNI group had a reduction in the primary outcome of CV mortality or HF hospitalization (21.8% vs. 26.5%; NNT 21) as well as each of the individual components. Importantly, the ARNI had a significant reduction in all-cause mortality (17.0% vs. 19.8%; NNT 36). The ARNI was generally well tolerated except for a higher rate of symptomatic hypotension, though not to an increased rate of discontinuation of the therapy due to hypotension. There was no difference in the rates of angioedema.

The FDA fast tracked the valsartan/sacubitril combination pill for approval in July 2015.[3]


ACC/AHA/HFSA Guideline for the Management of Heart Failure (2016, adapted)[4]

  • In patients with NYHA Stage II-III HFrEF tolerating ACE-inhibitor or ARB, replacement with ARNI is recommended to improved morbidity and mortality (COR I, LOE B-R)
  • Do not prescribe ARNI therapy concomitantly with ACE-inhibitors or within 36 hours of last dose of an ACE-inhivitor (COR III, LOE B-R)
  • Do not prescribe ARNI therapy to patients with prior angioedema (COR III, LOE C-EO)


  • Multicenter, prospective, randomized, comparative trial
  • N=8,399 (8,000 needed by power calculation)
    • ARNI (n=4,187)
    • Enalapril (n=4,212)
  • Setting: 1,043 centers in 47 countries
  • Enrollment: 2009-2012
  • Median follow-up: 27 months (stopped after 3rd interim analysis)
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality or HF hospitalization


Inclusion Criteria

  • Age ≥18 years
  • NYHA class II-IV symptoms
  • LVEF ≤40% until 2010 at which point this was reduced to ≤35%
  • If no HF hospitalizations in prior year: BNP ≥150 pg/mL or NT proBNP ≥600 pg/mL
  • If a HF hospitalization in prior year: BNP ≥100 pg/mL or NT proBNP ≥400 pg/mL
  • ACE-inhibitor or ARB therapy with stable dose for prior 4 weeks, equivalent to enalapril ≥ 10 mg/day
  • Beta blocker with stable dose for prior 4 weeks

Exclusion Criteria

  • Symptomatic hypotension
  • SBP <100 mmHg at screening or <95 mmHg at randomization
  • eGFR <30 mL/min/1.73 m2
  • Reduction in eGFR >25% from screening to randomization (amended to >35%)
  • Potassium >5.2 mmol/L at screening or >5.4 mmol/L at randomization
  • History of angioedema
  • "Unacceptable side effects" with ACE-inhibitors or ARBs

Baseline Characteristics

From the ARNI group.

  • Demographics: Age 64 years, female 21%,
    • Race or ethnicity: White 66%, Black 5%, Asian 18%, other 11%
    • Region: N. America 7%, Latin America 17%, W. Europe or other 24%, central Europe 33%, Asia-Pacific 18%
  • PMH: HTN 71%, DM 35%, AF 36%, HF hospitalization 62%, MI 43%, stroke 9%
  • HF details: ICM 60%, LVEF 30%, ICD 15%, CRT 7%
    • NYHA class: I 4%, II 72%, III 23%, IV 0.8%, unknown <1%
  • Health data: SBP 122 mmHg, HR 72 BPM, BMI 28 kg/m2
  • Laboratory: Creatinine 1.13 mg/dL, BNP 255 pg/mL, NT proBNP 1,631 pg/mL
  • Medications: ACE inhibitor 78%, ARB 22% (no ACE or ARB 20 patients, ACE+ARB 45 patients), diuretic 80%, digitalis 29%, beta blocker 93%, aldosterone antagonist 52%


  • Single-blind run-in period, patients with significant side effects did not continue on
    • All patients received enalapril 10 mg PO BID for two weeks then held for a day then
    • All patients received the ARNI (LCZ696) at 100 mg PO BID then 200 mg PO BID for 4-6 weeks

The authors note that the ARB component of LCZ696 200 mg is equivalent to valsartan 160 mg

Main trial
  • Randomization to a group with concealed assignments
    • ARNI - LCZ696 (later known as sacubitril/valsartan) 200 mg PO BID
    • Enalapril - Enalapril 10 mg PO BID
  • Follow-up q2-8 weeks in the first 4 months then every 4 months
  • The study medication dosing could be reduced if side effects


Comparisons are ARNI vs. enalapril.

Primary Outcome

CV mortality or HF hospitalization
21.8% vs. 26.5% (HR 0.80; 95% CI 0.73-0.87; P<0.001; NNT 21)

Secondary Outcomes

CV mortality
13.3% vs. 16.5% (HR 0.80; 95% CI 0.71-0.89; P<0.001; NNT 31)
HF hospitalization
12.8% vs. 15.6% (HR 0.79; 95% CI 0.71-0.89 P<0.001; NNT 36)
All-cause mortality
17.0% vs. 19.8% (HR 0.84; 95% CI 0.76-0.93; P<0.001; NNT 36)
Change in KCCQ score at month 8
Out of 100, higher scores indicates fewer HF symptoms and limitations. Deaths were counted as a score of zero.
-2.99 vs. -4.63 (between group difference 1.64; 95% CI 0.63-2.65; P=0.001)
Excluding deaths: Increased score vs. decreasing score (between group difference 0.95; 95% CI 0.31-1.59; P=0.004)
New AF
3.1% vs. 3.1% (HR 0.97; 95% CI 0.72-1.31; P=0.83)
Renal function decline
ESRD, decrease in eGFR ≥50%, or decrease in eGFR≥30 mL/min/1.73 m2 with final eGFR <60 mL/min/1.73 m2
2.2% vs. 2.6% (HR 0.86; 95% CI 0.65-1.13; P=0.28)

Additional Analyses

Discontinuation of study medication
17.8% vs. 19.8% (P=0.02)
Mean daily doses of respective medications
375 mg and 18.9 mg
Lost to follow-up
11 vs. 9 patients
Change in vital signs at month 8
SBP: 3.2 mmHg lower with ARNI (P<0.001)
HR: No difference
Discontinuation during run-in phase

This was before randomization. Percents are of all entering run-in phase.

During enalapril phase: 10.5%
Adverse event: 5.6%
Laboratory abnormality: 0.6%
Consent withdrawn: 1.6%
Deviation of protocol, administrative problem, or lost to follow-up: 1.3%
Death: 0.5%
Other: 0.8%
During ARNI phase: 9.3%
Adverse event: 5.8%
Laboratory abnormality: 0.6%
Consent withdrawn: 1.1%
Deviation of protocol, administrative problem, or lost to follow-up: 1.6%
Death: 0.5%
Other: 0.8%

Subgroup Analysis

For the primary outcome.

NYHA class
I or II: ARNI better
III or IV: No difference
P value for interaction 0.03

There were no significant interactions for other subgroups including age, sex, race, region, eGFR, diabetes, SBP, LVEF, AF, NT-proBNP, HTN, prior use of ACE, prior use of aldosterone antagonist, prior HF hospitalization, or time since HF diagnosis.

Adverse Events

Symptomatic: 14.0% vs. 9.2% (P<0.001; NNH 21)
Symptomatic and SBP <90 mmHg: 2.7% vs. 1.4% (P<0.001; NNH 77)
Resulting in permanent discontinuation: 0.9% vs. 0.7% (P=0.38)
Creatinine elevation
≥2.5 mg/dL: 3.3% vs. 4.5% (P=0.007)
≥3.0 mg/dL: 1.5% vs. 2.0% (P=0.10)
Resulting in permanent discontinuation: 0.7% vs. 1.4% (P=0.002)
Potassium elevation
≥5.5 mmol/L: 16.1% vs. 17.4% (P=0.15)
≥6.0 mmol/L: 4.3% vs. 5.6% (P=0.07)
Resulting in permanent discontinuation: 0.3% vs. 0.4% (P=0.56)
11.3% vs. 14.3% (P<0.001)
No treatment or antihistamines: 0.2% vs. 0.1% (P=0.19)
Use of catecholamines or glucocorticoids: 0.1% vs. 0.1% (P=0.52)
Hospitalization without airway compromise: 0.1% vs. <0.1% (P=0.31)
Airway compromise: No events


  • Enalapril dosing differed from that used in clinical practice.[5]
  • Included patients with NYHA I heart failure in analysis although they did not meet inclusion criteria.
  • Neprilysin also breaks down beta-amyloid, which builds up in the brain in Alzheimer's disease. This study was too short to evaluate for cognitive outcomes.[6]
  • The control arm tested an ACE inhibitor, whereas it may have been more appropriate to study an ARB since the experimental arm tested neprilysin inhibitor plus ARB.


Novartis, the manufacturer of Diovan (the brand name of valsartan) and Entresto (valsartan/sacubitril), collected, managed, and analyzed the data.

Further Reading

  1. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.
  2. Packer M, et al. "Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE)." Circulation. 2002;106(8):920-926.
  3. FDA writers. "FDA news release: FDA approves new drug to treat heart failure." Published 2015-07-07. Accessed 2015-07-08.
  4. Yancy CW et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2016. 134:e282-93.
  5. Jessup M. "Editorial: Neprilysin inhibition - A novel therapy for heart failure." The New England Journal of Medicine. 2014;epublished 2014-08-30. Accessed 2014-08-30.
  6. Foster W. "Online comment: Unintended consequences." On comment section of NEJM's publication of PARADIGM-HF. Published 2014-08-30. Accessed 2014-08-30.