INTRODUCTION

MECHANISM OF THE EFFECT OF ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR ON THE PATHOPHYSIOLOGY OF HEART FAILURE
Neurohormonal activation in the pathophysiology of heart failure
![]() | Figure 1.Three axes of the neurohormonal mechanism in heart failure. RAAS, renin-angiotensin-aldosterone system; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; Rc, receptor; MRA, mineralocorticoid receptor antagonist; LV, left ventricular; ARNI, angiotensin receptor-neprilysin inhibitor; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; SNS, sympathetic nervous system; BB, beta-blocker; HR, heart rate; NPS, natriuretic peptide system. |
The development of angiotensin receptor-neprilysin inihibitor

RESULTS FROM RANDOMIZED CONTROLLED TRIALS OF ANGIOTENSIN RECEPTORNEPRILYSIN INHIBITOR IN PATIENTS WITH HEART FAILURE
Heart failure with reduced ejection fraction
![]() | Figure 2.Patient-centered outcomes in major randomized controlled trials and their sub-analyses of sacubitril/valsartan. CV, cardiovascular; HF, heart failure; PARADIGM-HF, Prospective comparison of Angiotensin Receptor-Neprilysin Inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; HFrEF, heart failure with reduced ejection fraction; PIONEER-HF, Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode; LVAD, left ventricular assist device; HT, heart transplantation; PARAGON-HF, Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction; HFpEF, heart failure with preserved ejection fraction. aPrimary endpoint. bAdjudicated outcome by a blinded clinical event committee. cRate ratio. |
Table 1.
Topic | Study | Year | Author | Patients | Number | Intervention | Comparator | Primary endpoint | F/U duration |
---|---|---|---|---|---|---|---|---|---|
HFrEF | PARADIGM-HF [4] | 2014 | McMurray et al. | LVEF ≤ 40% | 8,399 | Sacubitril/valsartan | Enalapril | CV death or first hospitalization for worsening HF | 27 mon (median) |
NYHA class II–IV | |||||||||
Elevated NP | |||||||||
TITRATION [27] | 2016 | Senni et al. | LVEF ≤ 35% | 498 | Condensed regimen | Conservative regimen | Pre-specified adeverse events (hypotension, renal dysfunction, hyperkalemia, angioedema) | 12 wk | |
NYHA class II–IV | |||||||||
EVALUATE-HF [51] | 2019 | Desai et al. | LVEF ≤ 40% | 464 | Sacubitril/valsartan | Enalapril | Aortic characteristic impedance (Zc) | 12 wk | |
NYHA class I–III | |||||||||
History of hypertension | |||||||||
HFrEF with functional MR | PRIME [49] | 2019 | Kang et al. | LVEF 25%–50% | 118 | Sacubitril/valsartan | Valsartan | Changes in EROA | 12 mon |
NYHA class I–III | |||||||||
Chronic functional MR (EROA > 0.1 cm2 despite 6 mon of RAS blocker and BB) | |||||||||
Acute HF | PIONEER-HF [29] | 2019 | Velazquez et al. | LVEF ≤ 40% | 881 | Sacubitril/valsartan | Enalapril | Time-averaged change of NT-proBNP | 8 wk |
Elevated NP | |||||||||
Hospitalized for ADHF | |||||||||
TRANSITION [34] | 2019 | Wachter et al. | LVEF ≤ 40% | 1,002 | Pre-discharge | Post-discharge | Target sacubitril/valsartan dose of 97/103 mg bid at the end of week 10 | 10 wk | |
NYHA class II–IV | |||||||||
Hospitalized for ADHF | |||||||||
HFpEF | PARAMOUNT [36] | 2012 | Solomon et al. | LVEF ≥ 45% | 301 | Sacubitril/valsartan | Valsartan | Change in NT-proBNP from baseline to 12 wk | 12 wk |
NYHA class II–III | |||||||||
Elevated NP | |||||||||
History of HF | |||||||||
On diuretic therapy | |||||||||
PARAGON-HF [38] | 2019 | Solomon et al. | LVEF ≥ 45% | 4,822 | Sacubitril/valsartan | Valsartan | Total hospitalizations for HF and CV death | 35 mon (median) | |
NYHA class II–III | |||||||||
Elevated NP | |||||||||
Signs and symptoms of HF | |||||||||
Structural heart disease | |||||||||
On diuretic therapy |
FU, follow-up; HFrEF, heart failure with reduced ejection fraction; PARADIGM-HF, Prospective comparison of Angiotensin Receptor-Neprilysin Inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; NP, natriuretic peptide; CV, cardiovascular; HF, heart failure; PRIME, Pharmacological Reduction of Functional, Ischemic Mitral REgurgitation; MR, mitral regurgitation; EROA, effective regurgitant orifice area; RAS, renin-angiotensin system; BB, beta-blocker; PIONEER-HF, Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode; ADHF, acute decompensated heart failure; NT-proBNP, N-terminal-pro B-type NP; HFpEF, heart failure with preserved ejection fraction; PARAMOUNT, Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion; PARAGON-HF, Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction.
Acute heart failure
Table 2.
Topic | Study | Year | Author | Number | Intervention | Comparator | Endpoint | Outcome | p value | FU duration |
---|---|---|---|---|---|---|---|---|---|---|
HFrEF | TITRATION [27] | 2016 | Senni et al. | 498 | Condensed regimen | Conservative regimen | Pre-specified adverse events | 12 wk | ||
- Hypotension | HR, 1.19 (0.66–2.13) | 0.57 | ||||||||
- Renal dysfunction | HR, 1.00 (0.52–1.90) | 0.99 | ||||||||
- Hyperkalemia | HR, 1.82 (0.87–3.82) | 0.11 | ||||||||
- Angioedema | NA | NA | ||||||||
Achieved and maintained a dose of sacubitril/valsartan 200 mg twice daily without any dose interruption or down-titration over 12 wk | OR, 0.65 (0.41–1.05) | 0.078 | ||||||||
Tolerated a dose of sacubitril/valsartan of 200 mg twice daily for at least the final 2 wk | OR, 0.72 (0.43–1.20) | 0.207 | ||||||||
EVALUATE-HF [51] | 2019 | Desai et al. | 464 | Sacubitril/valsartan | Enalapril | Aortic characteristic impedance (Zc)a | Between group difference –2.2 dyne × s/m5 (–17.6 to 13.2) | 0.78 | 12 wk | |
Systolic pressure | Between group difference –4.9 mmHg (–7.6 to –2.1) | 0.001 | ||||||||
LVEF | Between group difference 0.6% (–0.4 to 1.7) | 0.24 | ||||||||
LVEDVI | Between group difference –2.0 mL/m2 (–3.7 to –0.3) | 0.02 | ||||||||
Left atrial volume index | Between group difference –2.8 mL/m2 (–4.0 to –1.6) | < 0.001 | ||||||||
Mitral E/e’ ratio | Between group difference –1.8 (–2.8 to –0.8) | 0.001 | ||||||||
NT-proBNP | Ratio of change 0.67 (0.59–0.76) | < 0.001 | ||||||||
HFrEF + functional MR | PRIME [49] | 2019 | Kang et al. | 118 | Sacubitril/valsartan | Valsartan | Changes in EROAa | Between group difference –0.040 cm2 (–0.076 to –0.094) | 0.032 | 12 mon |
Regurgitant volume | Between group difference –7.3 mL (–12.6 to –1.9) | 0.009 | ||||||||
LVEDVI | Between group difference –7.01 mL/m2 (–13.83 to –0.19) | 0.044 | ||||||||
Acute HF | PIONEER-HF [29] | 2019 | Velazquez et al. | 881 | Sacubitril/valsartan | Enalapril | Time-averaged change of NT-proBNPa | Ratio of change 0.71 (0.63–0.81) | < 0.001 | 8 wk |
Change in high-sensitivity troponin T | Ratio of change 0.85 (0.77–0.94) | NA | ||||||||
TRANSITION [34] | 2019 | Wachter et al. | 1,002 | Pre-discharge | Post-discharge | target sacubitril/valsartan dose of 97/103mg bid at the end of week 10a | RRR, 0.90 (0.79–1.02) | 0.099 | 10 wk | |
Acute HF | Achieved and maintained sacubitril/valsartan dose of 49/51 or 97/103 mg bid for more than 2 wk | RRR, 0.91 (0.83–0.99) | 0.034 | |||||||
Achieved and maintained any sacubitril/valsartan dose for more than 2 wk | RRR, 0.96 (0.92–1.01) | 0.089 | ||||||||
HFpEF | PARAMOUNT [36] | 2012 | Solomon et al. | 301 | Sacubitril/valsartan | Valsartan | Change in NT-proBNP from baseline to 12 wka | Ratio of change 0.77 (0.64–0.92) | 0.005 | 12 wk |
FU, follow-up; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; NA, not available; OR, odds ratio; LVEF, left ventricular ejection fraction; LVEDVI, left ventricular end-diastolic volume index; NT-proBNP, N-terminal-pro B-type NP; MR, mitral regurgitation; PRIME, Pharmacological Reduction of Functional, Ischemic Mitral REgurgitation; EROA, effective regurgitant orifice area; HF, heart failure; PIONEER-HF, Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode; RRR, relative risk ratio; HFpEF, heart failure with preserved ejection fraction; PARAMOUNT, Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fraction.
Heart failure with preserved ejection fraction

THE ADDITIONAL EFFECTS OF ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR
Reverse remodeling of the left ventricle
Functional mitral regurgitation
Aortic stiffness
Protection of renal function and increased albuminuria
Glycemic control

ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR IN RECENT UPDATES OF HEART FAILURE GUIDELINES
Chronic symptomatic heart failure
Acute heart failure

ONGOING RANDOMIZED CONTROLLED TRIALS OF ANGIOTENSIN RECEPTORNEPRILYSIN INHIBITOR FOR HEART FAILURE
Table 3.
Study name | NCT | Patients | Estimated enrollment | Comparator | Primary endpoint | FU duration | Study start date | Estimated study completion date |
---|---|---|---|---|---|---|---|---|
HFN-LIFE | NCT02816736 | Advanced HFrEF patients with LVEF ≤ 35% and NYHA class IV symptom | 400 | Valsartan | Change in NT-proBNP | 24 wk | 2017-05 | 2020-09 |
PARADISE-MI | NCT02924727 | Patients with LVEF ≤ 40% and/or pulmonary congestion after AMI | 5,650 | Ramipril | Composite endpoint of CV death, HF hospitalization, or outpatient HF | 43 mon | 2002-01 | 2021-05 |
PARAGLIDE-HF | NCT03988634 | Patients with LVEF > 40% recently hospitalized due to acute decompensation | 800 | Valsartan | Proportional change in NT-proBNP from baseline to the average of weeks 4 and 8 | 8 wk | 2019-06 | 2021-09 |
PERSPECTIVE | NCT02884206 | Patients with chronic HF (LVEF > 40%) | 593a | Valsartan | Change from baseline in the CogState Global Cognitive Composite Score (GCCS) | 3 yr | 2016-11 | 2022-03 |
NCT, National Clinical Trial; FU, follow-up; HFN-LIFE, EntrestoTM (LCZ696) in Advanced Heart Failure (LIFE Study); HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; NT-proBNP, N-terminal-pro B-type NP; PARADISE-MI, Prospective ARNI vs. ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI; AMI, acute myocardial infarction; CV, cardiovascular; HF, heart failure; PARAGLIDE-HF, Changes in NT-proBNP and Outcomes, Safety, and Tolerability in HFpEF Patients With Acute Decompensated Heart Failure (ADHF) Who Have Been Stabilized During Hospitalization and Initiated In-hospital or Within 30 Days Post-discharge; PERSPECTIVE, Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction.

CONCLUSIONS
