Abstract
Objective: A meta-analysis of the studies involving Sacubitril/Valsartan in chronic heart failure was performed to compare the efficacy and safety of Sacubitril/Valsartan with traditional drug therapy in chronic heart failure. Methods: We searched databases from PubMed, EMBASE, the Cochrane Library, Web of Science, and clinicaltrials.gov for studies published between 2010 and 2020 that reported efficacy and safety following Sacubitril/Valsartan administration. Results: Ten studies enrolling 1689 patients were included. Sacubitril/Valsartan outperformed traditional medicine (especially the Non-ARNI group) in terms of blood pressure, biomarkers and cardiac reverse remodeling indices, with striking changes in left ventricular ejection fraction, systolic blood pressure. Sacubitril/Valsartan showed significant benefit in renal function in patients with chronic heart failure. Conclusions: Compared with traditional drugs, Sacubitril/Valsartan significantly improved echocardiography, vital signs and biomarkers of patients with chronic heart failure, and reduced the incidence of hyperkalemia, renal dysfunction and other adverse reactions. Further large sample trials are needed in the future to determine the long-term effects of Sacubitril/Valsartan on efficacy and safety in patients with chronic heart failure.
Keywords: Chronic heart failure, Sacubitril/Valsartan, cardiac reverse remodeling, meta-analysis
Introduction
Chronic Heart Failure (CHF) is a complex clinical syndrome in which ventricular filling or ejection function is continuously impaired due to structural or functional abnormality of the heart, which is also the terminal stage of various cardiac disorders. The number of heart failure patients worldwide had reached 23 million and was increasing by 2 million per year, and the 5-year mortality of heart failure was much higher than that of most cancers [1]. In recent decades, heart failure has been considered as a chronic and spontaneous progressive disease, and the activation of different neuroendocrine systems leads to cardiac remodeling, which is a key factor in the development of heart failure (HF) [2,3]. The sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS) and natriuretic peptide system (NPS) are the three predominant neuroendocrine systems, that might play a favorable or unfavorable role in the pathophysiology of heart failure. As the first angiotensin receptor-neprilysin inhibitor (ARNI), Sacubitril/Valsartan can block angiotensin II receptor and inhibit neprilysin enzyme through RAAS and NPS, respectively.
In the leading study (PARADIGM-HF trial), Sacubitril/Valsartan was shown to be superior to enalapril in reducing mortality, hospitalization rates and blood pressure of heart failure patients (LVEF≤40%) [4]. T The recently published PARAGON-HF trial results indicate that Sacubitril/valsartan may benefit patients with LVEF ranging from 45% to 57% (median) [5]. Myocardial fibrosis is an important pathophysiological mechanism underlying the development of HF. Sacubitril/Valsartan significantly decreased some biomarkers (associated with profibrotic signaling), which may contribute to improved outcomes [6]. Compared to enalapril, Sacubitril/Valsartan resulted in an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) [7]. The concentration of NT-proBNP correlated with the extent of reversal of ventricular remodeling [8], and a recent study confirmed the involvement of Sacubitril/Valsartan in the above relationship [9]. In this context, we performed a systematic meta-analysis of the latest studies in the field of Sacubitril/Valsartan to compare the effects of other drugs with ARNI on CHF outcomes.
Methods
Literature retrieval
A systematic literature review was conducted for studies published in the English language from 2000 through to 2020 by searching PubMed, EMBASE, the Cochrane Library, Web of Science, and clinicaltrials.gov databases. The research subjects included “angiotensin receptor-neprilysin inhibitor”, “heart failure”, “chronic heart failure”, “Sacubitril/Valsartan”, “angiotensin receptor antagonists” and “angiotensin-converting enzyme inhibitor” (see the Multimedia Appendix 1).
Inclusion and exclusion criteria
All controlled studies involving the treatment of chronic heart failure with Sacubitril/Valsartan were included. Case reports were excluded. Included studies must meet the following criteria: (1) Adult patients aged 18 years old or over), (2) designed to compare the effects of ACEI/ARB with ARNI in the CHF population, (3) reported at least one of the primary outcomes or secondary outcomes: Vital signs (systolic blood pressure, diastolic blood pressure, heart rate), Echocardiography (left ventricular ejection fraction, left ventricular end-systolic dimension, left ventricular end-diastolic dimension, left atrial dimension, peak e-wave velocity/peak a-wave velocity ratio), Biomarkers (N-terminal pro-brain natriuretic peptide) and Safety (all-cause mortality, death from cardiovascular causes, angioedema, hyperkalemia, symptomatic hypotension, renal dysfunction).
Data extraction and quality evaluation
All the titles and abstracts of the literature were initially screened by two authors (Dai Hengfen and Zheng Caiyun) independently. Then, the two authors analyzed the full text respectively. Any disagreements were resolved by discussion and mutual consensus, or where agreement could not be reached, by arbitration with a third author (Huang Jungao). The researchers used a literature data extraction table to extract the required data, and other researchers confirmed the accuracy and authenticity of the data. The contents extracted included study information (study subject, author, date), baseline characteristics of study subjects (sample size, median age, sex ratio, heart failure type), control group, outcome indicators and adverse reactions after follow-up.
The quality of included randomized controlled trials was assessed using the Cochrane risk bias tool of the Cochrane system [10], and the quality of other studies (including retrospective cohort studies and prospective observational studies) were appraised using the Newcastle-Ottawa quality assessment scale [11].
Sensitivity analyses
Meta-analyses were conducted using Cochrane’s Review Manager (RevMan) version 5.3 (The Cochrane Collaboration, Copenhagen, Denmark) and R programming language, version 3.6.3 (R Foundation for Statistical Computing, Guangzhou, China) with included literatures. Chi-square test was used to assess heterogeneity and I2 was used for quantitative analysis. P≥0.05 and I2≤50% were considered to have no heterogeneity and a fixed-effects model was used. If P<0.05 and I2>50%, the random-effects model was used, and then subgroup analysis was conducted to determine the cause of heterogeneity.
Results
Literature search results and baseline characteristics
Seven hundred and thirty-one articles were retrieved from different databases, along with 69 articles on clinical trial.gov. for a total of 800 articles. After removing the repeated studies, the remaining 703 articles were screened. 37 qualified articles with full text were read, 27 articles were excluded, 10 articles were included. Among the 10 literatures, there were 5 RCTs and 5 cohort studies. A total of 1689 patients were included. The system search results are shown in Figure 1. The baseline characteristics are presented in Table 1.
Figure 1.
Outline of our search methodology.
Table 1.
Basic characteristics of included studies of the meta-analysis
| Study | Study Design | Interventions | Category | Patients (N) | Age (year, Mean ± SD) | Women (%) | Outcomes | Follow-up (months) |
|---|---|---|---|---|---|---|---|---|
| Solomon 2012 [19] | RCT | ARNI | HFpEF | 301 | 71.1±9.1 | 56.5 | ECG, Biomarkers, Safety | 3 and 9 |
| Valsartan | ||||||||
| McMurray 2014 [4] | RCT | ARNI | HFrEF | 8399 | 63.8±11.4 | 21.8 | Safety | 27 |
| Enalapril | ||||||||
| Kang 2018 [20] | RCT | ARNI | HFrEF | 118 | 62.6±11.2 | 39.0 | ECG, Safety | 12 |
| Valsartan | ||||||||
| Gao 2019 [21] | RCT | ARNI | HFrEF | 120 | 70.3±7.3 | 26.7 | ECG, Biomarkers, Safety | 2 |
| Valsartan | ||||||||
| Solomon 2019 [5] | RCT | ARNI | HFpEF | 4796 | 72.7±8.4 | 51.7 | Safety | 35 |
| Valsartan | ||||||||
| Martens 2018 [22] | Prospective Observation | ARNI | HFrEF | 125 | 66.0±10.0 | 19.0 | Vital Signs, ECG | 4.2 |
| Non-ARNI | ||||||||
| Romano 2019 [14] | Prospective Observation | ARNI | HFrEF | 205 | 59.0±10.0 | 15.0 | Vital Signs, ECG, Biomarkers | 10.5 |
| ACEI/ARB | ||||||||
| Bayard 2019 [23] | Prospective Observation | ARNI | HFrEF | 41 | 70.0±10.0 | 24.4 | ECG | 3 |
| Non-ARNI | ||||||||
| EI-Battrawy 2019 [24] | Prospective Observation | ARNI | HFrEF | 59 | 66.8±12.1 | NR | Vital Signs, ECG, Biomarkers | 12 |
| Non-ARNI | ||||||||
| Spannella 2019 [25] | Longitudinal Observational | ARNI | HFrEF | 84 | 65.4±11.3 | 32.1 | Vital Signs, ECG | 6 and 12 |
| Non-ARNI |
Vital Signs: including Systolic Blood Pressure, Diastolic Blood Pressure, Heart rate; ECG: echocardiography indicators including LVEF, LVES, LVED, LA and E/A ratio; Biomarkers: mainly refers to the NT-proBNP; Safety: including All-cause mortality, Death from cardiovascular causes, Angioedema, Hyperkalemia, Symptomatic hypotension, Renal dysfunction.
Quality assessment and publication bias
The quality of included randomized controlled trials was evaluated using the Cochrane systematic evaluation method, and other studies were evaluated using the Newcastle-Ottawa scale (Figure 2 and Table 2). Funnel plots did not show significant publication bias (Figure 3).
Figure 2.
Quality evaluation of RCTs.
Table 2.
Quality evaluation of other types of literature
| Study | Representativeness of the exposed cohort | Selection of the non- exposed cohort | Ascertainment of exposure | Demonstration that outcome of interest was not present at start of study | Comparability of cohorts on the basis of the design or analysis | Assessment of outcome | Was follow-up long enough for outcomes to occur | Adequacy of follow up of cohorts | Total |
|---|---|---|---|---|---|---|---|---|---|
| Martens 2018 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 7 |
| Romano 2019 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 8 |
| Bayard 2019 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 8 |
| EI-Battrawy 2019 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 8 |
| Spannella 2019 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 1 | 7 |
Figure 3.
Funnel plot estimating publication bias. A. Left ventricular ejection fraction (LVEF). B. Safety (all-cause mortality, death from cardiovascular causes, angioedema, hyperkalemia, symptomatic hypotension and renal dysfunction).
Efficacy endpoints
LVEF
Ten studies provided data on LVEF. Meta-analysis was conducted according to different drugs in the control group, and there was no significant difference and high heterogeneity in the Valsartan group, while there was a significant difference in the non-ARNI and ACEI/ARB groups (Valsartan group: mean difference [MD] =2.47, 95% CI -2.57 to 7.50, I2=95%, P=0.34; Non-ARNI group: mean difference [MD] =3.12, 95% CI 1.40 to 4.84, I2=68%, P<.01; ACEI/ARB group: mean difference [MD] =3.00, 95% CI 1.67 to 4.33, P<.01), as shown in Figure 4.
Figure 4.
Forest plots for effect of Sacubitril/Valsartan on LVEF.
Subgroup analysis of gender, age, follow-up time and sample size
Subgroup analysis of gender showed that the difference between the ARNI group and the control group was not related to gender, as shown in Figure 5.
Figure 5.
Subgroup analysis of gender in the improvement of LVEF in chronic heart failure with Sacubitril/Valsartan.
Subgroup analysis of age showed that the difference between the ARNI group and the control group was not related to age, as shown in Figure 6.
Figure 6.
Subgroup analysis of age in the improvement of LVEF in chronic heart failure with Sacubitril/Valsartan.
Subgroup analysis of follow-up time (FU) showed that the difference between the ARNI group and the Valsartan group was not affected by follow-up time. Compared with the Non-ARNI group, the ARNI group had a better outcome in FU≤9 M population, and there was no significant difference in FU>9 M population. (FU≤9 M: mean difference [MD] =3.60, 95% CI 1.54 to 5.67, I2=70%, P<.01; FU>9 M: mean difference [MD] =2.26, 95% CI -0.76 to 5.27, I2=61%, P=0.14), as shown in Figure 7.
Figure 7.
Subgroup analysis of follow-up time in the improvement of LVEF in chronic heart failure with Sacubitril/Valsartan.
Subgroup analysis of sample size showed that the difference between the ARNI group and the control group was not related to sample size, as shown in Figure 8.
Figure 8.
Subgroup analysis of sample size in the improvement of LVEF in chronic heart failure with Sacubitril/Valsartan.
Other echocardiography indices
Other echocardiography indices mainly include LVES(D), left ventricular end-systolic dimension; LVED(D), left ventricular end-diastolic dimension; LA(D), left atrial dimension; E/A ratio. Through the meta-analysis, the ARNI group was superior to the Valsartan group of LA and LVED, and with significant differences. Compared with the Non-ARNI group there was no significant difference, as shown in Figure 9.
Figure 9.
Forest plots for effect of Sacubitril/Valsartan on other echocardiography indices.
Vital signs
For vital signs including SBP, DBP and HR, meta-analysis results showed that the ARNI group was superior to the Non-ARNI group in SBP and HR, and there was no significant difference on DBP, as shown in Figure 10 (SBP: mean difference [MD] =-3.65, 95% CI -6.80 to -0.49, I2=23%, P<0.05; DBP: mean difference [MD] =-2.76, 95% CI -6.81 to -1.30, I2=73%, P=0.18; HR: mean difference [MD] =-4.15, 95% CI -6.67 to -1.63, I2=0%, P<0.01).
Figure 10.
Forest plots for effect of Sacubitril/Valsartan on vital signs.
Safety endpoints
Major adverse reactions
The main safety endpoints include all-cause mortality, death from cardiovascular causes, angioedema, hyperkalemia, symptomatic hypotension, renal dysfunction. The adverse reactions of angioedema and symptomatic hypotension in the control group were less than those in the intervention group; There was a significant difference between the Sacubitril/Valsartan group and the traditional treatment group in renal dysfunction, and no significant difference in all-cause mortality, death from cardiovascular causes and symptomatic hypotension, as shown in Figure 11.
Figure 11.
Forest plot of major adverse reactions.
Other adverse reactions
Other adverse reactions include cerebral infarction, heart failure deterioration and rehospitalization, most of the studies had no significant differences in results, as shown in Figure 12.
Figure 12.
Forest plot of other adverse reactions.
Discussion
This study provided the latest systematic meta-analysis of assessing the effects of Sacubitril/Valsartan on LVEF, echocardiographic index, vital signs, biomarkers, and adverse reactions in patients with chronic heart failure. Compared with ACEIs/ARBs, all indicators of heart failure patients treated with Sacubitril/Valsartan showed significant improvement. Sacubitril/valsartan took effect one month after starting treatment, and the study’s follow-up period ranged from 1 to 35 months. Subgroup analysis was used to address heterogeneity in LVEF and observed that gender, age, and follow-up time may contribute to differences in LVEF benefits. Sacubitril/Valsartan has a significant effect on the echocardiography index of CHF patients, including LVES, LVED. There was no significant difference in LA and E/A ratio. Both ACEIs and ARBs are recognized as essential agents for the treatment of chronic heart failure, with beneficial effects in reversing ventricular remodeling and reducing cardiovascular mortality. Therefore, as a unique combination of neprilysin inhibitor and ARB, Sacubitril/Valsartan has a reasonable effect on reversing ventricular remodeling and lowering blood pressure. Ventricular remodeling is a major underlying mechanism for CHF progression. Previous studies using assessments, of LVEF, LVESD, LVEDD, E/A ratio, or LA, had demonstrated that left ventricular reverse remodeling is a dynamic process and could take many years to achieve [12,13]. Recovery of left ventricular function is an important treatment goal for CHF, especially HFrEF. A prospective observational study of HFrEF patients indicated that the use of Sacubitril/Valsartan may produce “hemodynamic recovery” by reducing left ventricular filling pressure, mitral regurgitation from moderate to severe grade, and pulmonary artery systolic pressure, which associated with a reduction in NT-proBNP may ameliorate functional class capacity [14]. NT-proBNP is an epoch-making and specific marker for the determination of HF, which has been confirmed that the concentration of NT-proBNP was closely associated with left ventricular size and function [4]. And a greater reduction in NT-proBNP was associated with more extensive reverse remodeling and a better prognosis in HFrEF patients [8]. Results of the latest meta-analysis focused on cardiac reverse remodeling showed that patients with NT-proBNP reduction following Sacubitril/Valsartan initiation are more likely to experience reverse cardiac remodeling [15].
In terms of safety, compared with the traditional treatment group (the Non-ANRI group, the Valsartan group and the ACEI group), the number of events related to all-cause mortality and death from cardiovascular causes of Sacubitril/Valsartan group was reduced, but there was no significant difference. On the contrary, there were significant differences in the incidence of renal insufficiency. Serum potassium stability and renal function in patients with heart failure may benefit from Sacubitril/Valsartan. But for angioedema and symptomatic hypotension, the control group was superior to the intervention group. Sacubitril is associated with cardiomyocyte cell death, hypertrophy, and impaired myocardial contractility by a systems biology approach, valsartan mainly blocks the AT1 receptor mechanistically [16]. Improved ventricular remodeling may be one of the mechanisms by which Sacubitril/Valsartan reduces cardiovascular and all-cause mortality, so Sacubitril/Valsartan has an advantage over ACEIs/ARBs in terms of therapeutic safety. Sacubitril/Valsartan sodium tablet is a salt compound crystal formed by the combination of Sacubitril and Valsartan in a ratio of 1:1 molar mass [17]. Because of its special crystal structure, it may be more susceptible to anaphylaxis, known as angioedema. Sacubitril/Valsartan is a precursor drug, which can be metabolized into active enkephalinase inhibitor LBQ657 and valsartan in vivo [18], valsartan mainly blocks the AT1 receptor mechanistically to lower blood pressure.
Study limitations: the current meta-analysis included mainly observational studies, while RCT studies were few. Because randomized controlled trials have strict inclusion criteria, there is an observation phase prior to randomization to ensure patient tolerability. This suggests that randomized controlled trials may include healthier patients than observational studies. In addition, in observational studies, some patients may have received ACEIs/ARBs before receiving Sacubitril/Valsartan, and indicators of cardiac remodeling such as LVEF may have progressed from HFrEF to HFmrEF or HFpEF. Therefore, we need more and better RCTs in the future to focus on the efficacy and safety of Sacubitril/Valsartan. At the same time, some of the observational study may have unpredictable factors, so the interpretation of the results should be cautious. In addition, the sample size of some studies was not statistically controlled, and uneven changes in outcome indicators and follow-up time may have influenced the results.
Conclusions
This meta-analysis confirmed that Sacubitril/Valsartan could improve cardiac remodeling regardless of gender, age, sample size and follow-up time, and improve the patient’s vital signs. For safety, Sacubitril/Valsartan can reduce renal insufficiency, but for angioedema and symptomatic hypotension, it showed no difference with the traditional intervention group.
The results of the current study suggest that if patients are treated with Sacubitril/Valsartan as early as possible, they may benefit more from the reversal of cardiac remodeling. Further studies on the long-term effects of Sacubitril/Valsartan on patients with CHF are needed to clarify the relationship between cardiac remodeling and long-term clinical outcomes, as well as the safety of the drug.
Acknowledgements
This study was supported by the Startup Fund for Scientific Research, Fujian Medical University (Grant number: 2020QH1346) and Fuzhou Health and Family Planning Science and Technology Innovation Platform Construction Project (2018-S-wp1).
Multimedia Appendix 1
Pubmed
#1 Search (((((((LCZ696[Title/Abstract]) OR LCZ-696[Title/Abstract]) OR sacubitril[Title/Abstract]) OR sacubitril-valsartan [Title/Abstract]) OR entresto[Title/Abstract]) OR endopeptidase[Title/Abstract]) OR neutral endopeptidase[Title/Abstract]) OR neprilysin[Title/Abstract] OR Angiotensin receptor neprilysin inhibitor
#2 Search (((“Angiotensin-Converting Enzyme Inhibitors”[Mesh]) OR (((((((((((((((((Angiotensin Converting Enzyme Inhibitors[Title/Abstract]) OR Inhibitors, Kininase II[Title/Abstract]) OR Kininase II Antagonists[Title/Abstract]) OR Kininase II Inhibitors[Title/Abstract]) OR Angiotensin I-Converting Enzyme Inhibitors[Title/Abstract]) OR Angiotensin I Converting Enzyme Inhibitors[Title/Abstract]) OR Antagonists, Angiotensin-Converting Enzyme[Title/Abstract]) OR Antagonists, Angiotensin Converting Enzyme[Title/Abstract]) OR Antagonists, Kininase II[Title/Abstract]) OR Inhibitors, ACE[Title/Abstract]) OR ACE Inhibitors[Title/Abstract]) OR Inhibitors, Angiotensin-Converting Enzyme[Title/Abstract]) OR Enzyme Inhibitors, Angiotensin-Converting[Title/Abstract]) OR Inhibitors, Angiotensin Converting Enzyme[Title/Abstract]) OR Angiotensin-Converting Enzyme Antagonists[Title/Abstract]) OR Angiotensin Converting Enzyme Antagonists[Title/Abstract]) OR Enzyme Antagonists, Angiotensin-Converting[Title/Abstract]))) OR ((“Angiotensin Receptor Antagonists”[Mesh]) OR (((((((Antagonists, Angiotensin Receptor[Title/Abstract]) OR Receptor Antagonists, Angiotensin[Title/Abstract]) OR Angiotensin Receptor Blockers[Title/Abstract]) OR Receptor Blockers, Angiotensin[Title/Abstract]) OR Angiotensin II Receptor Antagonists[Title/Abstract]) OR Angiotensin II Receptor Blockers[Title/Abstract]) OR angiotensin receptor antagonist[Title/Abstract]))
#3 #1 and #2
EMBASE
#1 ‘sacubitril plus valsartan’/exp OR ‘lcz696’:ti,ab OR ‘lcz-696’:ti,ab OR ‘entresto’:ti,ab OR ‘sacubitril-valsartan’:ti,ab OR ‘sacubitril’:ti,ab OR ‘endopeptidase’:ti,ab OR ‘neutral endopeptidase’:ti,ab OR ‘neprilysin inhibitor’:ti,ab
#2 ‘dipeptidyl carboxypeptidase inhibitor’/exp OR ‘angiotensin converting enzyme inhibitors’:ti,ab OR ‘kininase ii inhibitors’:ti,ab OR ‘angiotensin i-converting enzyme inhibitors’:ti,ab OR ‘angiotensin i-converting enzyme inhibitors’:ti,ab OR ‘antagonists, angiotensin-converting enzyme’:ti,ab OR ‘antagonists, angiotensin converting enzyme’:ti,ab OR ‘inhibitors, ace’:ti,ab OR ‘ace inhibitors’:ti,ab OR ‘inhibitors, angiotensin-converting enzyme’:ti,ab OR ‘enzyme inhibitors, angiotensin-converting’:ti,ab OR ‘inhibitors, angiotensin converting enzyme’:ti,ab OR ‘angiotensin-converting enzyme antagonists’:ti,ab OR ‘angiotensin converting enzyme antagonists’:ti,ab OR ‘angiotensin receptor antagonist’/exp OR ‘antagonists, angiotensin receptor’:ti,ab OR ‘receptor antagonists, angiotensin’:ti,ab OR ‘angiotensin receptor blockers’:ti,ab OR ‘receptor blockers, angiotensin’:ti,ab OR ‘angiotensin ii receptor antagonists’:ti,ab OR ‘angiotensin ii receptor blockers’:ti,ab OR ‘angiotensin receptor antagonists’:ti,ab
#3 #1 and #2
The Cochrane Library search strategy
#1 MeSH descriptor: [Heart Failure, Systolic] explode all trees
#2 ((cardi*):ti,ab,kw OR (myocardi*):ti,ab,kw OR (heart):ti,ab,kw) AND ((failure):ti,ab,kw OR (dysfunction):ti,ab,kw)
#3 (“heart failure with reduced ejection fraction”):ti,ab,kw OR #1 OR #2
#4 (LCZ696):ti,ab,kw OR (sacubitril-valsartan):ti,ab,kw OR (sacubitril):ti,ab,kw OR (LCZ-696):ti,ab,kw OR (entresto):ti,ab,kw OR (endopeptidase):ti,ab,kw OR (neutral endopeptidase):ti,ab,kw OR (neprilysin inhibitor):ti,ab,kw
#5 #3 and #4
Web of Science search strategy
#1 (TS=(LCZ696 OR entresto OR “sacubitril-valsartan” OR “neprilysin inhibitor”))
#2 (TS=(heart OR myocardi* OR cardio* OR cardia*))
#3 (TS=(failure OR dysfunction))
#4 #2 AND #3
#5 (TS=(“systolic heart failure” OR “heart failure with reduced ejection fraction” OR “ventricular dysfunction”))
#6 #4 OR #5
#7 #1 AND #6
Disclosure of conflict of interest
None.
References
- 1.Blair JE, Huffman M, Shah SJ. Heart failure in North America. Curr Cardiol Rev. 2013;9:128–146. doi: 10.2174/1573403X11309020006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Moser DK. Pathophysiology of heart failure update: the role of neurohumoral activation in the progression of heart failure. AACN Clin Issues. 1998;9:157–171. doi: 10.1097/00044067-199805000-00002. [DOI] [PubMed] [Google Scholar]
- 3.Volpe M, Carnovali M, Mastromarino V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci (Lond) 2016;130:57–77. doi: 10.1042/CS20150469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. doi: 10.1056/NEJMoa1409077. [DOI] [PubMed] [Google Scholar]
- 5.Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Düngen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381:1609–1620. doi: 10.1056/NEJMoa1908655. [DOI] [PubMed] [Google Scholar]
- 6.Zile MR, O’Meara E, Claggett B, Prescott MF, Solomon SD, Swedberg K, Packer M, McMurray JJV, Shi V, Lefkowitz M, Rouleau J. Effects of Sacubitril/Valsartan on biomarkers of extracellular matrix regulation in patients with HFrEF. J Am Coll Cardiol. 2019;73:795–806. doi: 10.1016/j.jacc.2018.11.042. [DOI] [PubMed] [Google Scholar]
- 7.Packer M, McMurray JJ, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile M, Andersen K, Arango JL, Arnold JM, Bělohlávek J, Böhm M, Boytsov S, Burgess LJ, Cabrera W, Calvo C, Chen CH, Dukat A, Duarte YC, Erglis A, Fu M, Gomez E, Gonzàlez-Medina A, Hagège AA, Huang J, Katova T, Kiatchoosakun S, Kim KS, Kozan Ö, Llamas EB, Martinez F, Merkely B, Mendoza I, Mosterd A, Negrusz-Kawecka M, Peuhkurinen K, Ramires FJ, Refsgaard J, Rosenthal A, Senni M, Sibulo AS Jr, Silva-Cardoso J, Squire IB, Starling RC, Teerlink JR, Vanhaecke J, Vinereanu D, Wong RC PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131:54–61. doi: 10.1161/CIRCULATIONAHA.114.013748. [DOI] [PubMed] [Google Scholar]
- 8.Daubert MA, Adams K, Yow E, Barnhart HX, Douglas PS, Rimmer S, Norris C, Cooper L, Leifer E, Desvigne-Nickens P, Anstrom K, Fiuzat M, Ezekowitz J, Mark DB, O’Connor CM, Januzzi J, Felker GM. NT-proBNP goal achievement is associated with significant reverse remodeling and improved clinical outcomes in HFrEF. JACC Heart Fail. 2019;7:158–168. doi: 10.1016/j.jchf.2018.10.014. [DOI] [PubMed] [Google Scholar]
- 9.Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, Camacho A, Piña IL, Rocha RA, Shah AM, Williamson KM, Solomon SD PROVE-HF Investigators. Association of change in N-terminal Pro-B-type natriuretic peptide following initiation of Sacubitril-Valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA. 2019;322:1085–1095. doi: 10.1001/jama.2019.12821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi: 10.1136/bmj.d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–605. doi: 10.1007/s10654-010-9491-z. [DOI] [PubMed] [Google Scholar]
- 12.Matsumura Y, Hoshikawa-Nagai E, Kubo T, Yamasaki N, Furuno T, Kitaoka H, Takata J, Sugiura T, Doi Y. Left ventricular reverse remodeling in long-term (>12 years) survivors with idiopathic dilated cardiomyopathy. Am J Cardiol. 2013;111:106–110. doi: 10.1016/j.amjcard.2012.08.056. [DOI] [PubMed] [Google Scholar]
- 13.Ikeda Y, Inomata T, Iida Y, Iwamoto-Ishida M, Nabeta T, Ishii S, Sato T, Yanagisawa T, Mizutani T, Naruke T, Koitabashi T, Takeuchi I, Nishii M, Ako J. Time course of left ventricular reverse remodeling in response to pharmacotherapy: clinical implication for heart failure prognosis in patients with idiopathic dilated cardiomyopathy. Heart Vessels. 2016;31:545–554. doi: 10.1007/s00380-015-0648-2. [DOI] [PubMed] [Google Scholar]
- 14.Romano G, Vitale G, Ajello L, Agnese V, Bellavia D, Caccamo G, Corrado E, Di Gesaro G, Falletta C, La Franca E, Minà C, Storniolo SA, Sarullo FM, Clemenza F. The effects of Sacubitril/Valsartan on clinical, biochemical and echocardiographic parameters in patients with heart failure with reduced ejection fraction: the “hemodynamic recovery”. J Clin Med. 2019;8:2165. doi: 10.3390/jcm8122165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Wang Y, Zhou R, Lu C, Chen Q, Xu T, Li D. Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis. J Am Heart Assoc. 2019;8:e012272. doi: 10.1161/JAHA.119.012272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Iborra-Egea O, Gálvez-Montón C, Roura S, Perea-Gil I, Prat-Vidal C, Soler-Botija C, Bayes-Genis A. Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach. NPJ Syst Biol Appl. 2017;3:12. doi: 10.1038/s41540-017-0013-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Havakuk O, Elkayam U. Angiotensin receptor-neprilysin inhibition. J Cardiovasc Pharmacol Ther. 2017;22:356–364. doi: 10.1177/1074248416683049. [DOI] [PubMed] [Google Scholar]
- 18.Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) J Clin Pharmacol. 2010;50:401–414. doi: 10.1177/0091270009343932. [DOI] [PubMed] [Google Scholar]
- 19.Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387–1395. doi: 10.1016/S0140-6736(12)61227-6. [DOI] [PubMed] [Google Scholar]
- 20.Kang DH, Park SJ, Shin SH, Hong GR, Lee S, Kim MS, Yun SC, Song JM, Park SW, Kim JJ. Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation. 2019;139:1354–1365. doi: 10.1161/CIRCULATIONAHA.118.037077. [DOI] [PubMed] [Google Scholar]
- 21.Gao Y, Xing C, Hao W, Zhao H, Wang L, Luan B, Hou A. The impact of sacrubitril/valsartan on clinical treatment and hs-cTnT and NT-ProBNP serum levels and the left ventricular function in patients with chronic heart failure. Int Heart J. 2020;61:1–6. doi: 10.1536/ihj.19-231. [DOI] [PubMed] [Google Scholar]
- 22.Martens P, Beliën H, Dupont M, Vandervoort P, Mullens W. The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction. Cardiovasc Ther. 2018;36:e12435. doi: 10.1111/1755-5922.12435. [DOI] [PubMed] [Google Scholar]
- 23.Bayard G, Da Costa A, Pierrard R, Roméyer-Bouchard C, Guichard JB, Isaaz K. Impact of sacubitril/valsartan on echo parameters in heart failure patients with reduced ejection fraction a prospective evaluation. Int J Cardiol Heart Vasc. 2019;25:100418. doi: 10.1016/j.ijcha.2019.100418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.El-Battrawy I, Pilsinger C, Liebe V, Lang S, Kuschyk J, Zhou X, Borggrefe M, Röger S, Akin I. Impact of Sacubitril/Valsartan on the long-term incidence of ventricular arrhythmias in chronic heart failure patients. J Clin Med. 2019;8:1582. doi: 10.3390/jcm8101582. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Spannella F, Marini M, Giulietti F, Rosettani G, Francioni M, Perna GP, Sarzani R. Renal effects of Sacubitril/Valsartan in heart failure with reduced ejection fraction: a real life 1-year follow-up study. Intern Emerg Med. 2019;14:1287–1297. doi: 10.1007/s11739-019-02111-6. [DOI] [PMC free article] [PubMed] [Google Scholar]