Comparative Efficacy of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) vs. ACE Inhibitors in Heart Failure - Systemic Review and Meta Analysis

Ghazala S. Virk¹, Babar Hameed², Zara Baloch³, Arhum Mahmood⁴, Hafsa Zubair⁵, Dinesh Aravind Rongali⁶, Abanoub Soliman⁷, Kerolos E. Naguib⁸,  Zubair Ahmed⁹, Muhammad Sohail S. Mirza^10*

¹MD, Avalon University School of Medicine, Willemstad, Curacao, USA

²MBBS. Akhtar saeed medical college, lahore, Pakistan

³MBBS. Shaheed Zulfiqar Ali Bhutto Medical University Islamabad, Pakistan

⁴MD, Henry Ford Health System, Detroit, USA

⁵Medical student. king edward medical university, Lahore, Pakistan

⁶MBBS. Rush university medical center, Illinois, USA

⁷MD. Cairo University,Cairo, Egypt

⁸MD.  Cairo university, Cairo, Egypt

⁹MD, Richmond university medical center, Staten Island, NY, Chandka Medical College Larkana, Sindh, Pakistan

¹⁰Shandong University School of Medicine, Jinan, China

^*Corresponding author: Muhammad Sohail S. Mirza, Shandong University School of Medicine, Jinan, China.

Received: 10 May 2025; Accepted: 20 May 2025; Published: 29 May 2025

1. Introduction

Heart failure (HF), which has a high morbidity and mortality rate, is often caused by ventricular and atrial remodeling, a not-unusual feature of many cardiovascular illnesses that commonly results from aberrant neurohumoral regulation [1,2]. Coronary heart failure is generally divided into two classes [3]: heart failure with reduced ejection fraction (HFrEF; LVEF <40%) and coronary heart failure with preserved ejection fraction (HFpEF; LVEF ≥50%) [4]. Improvements in the volume, size, and shape of the ventricle or atrium are called cardiac opposite reworking (CRR) [5-7].  In patients with HFrEF, earlier studies have shown that renin-angiotensin-aldosterone system (RAAS) inhibition can enhance LVEF [8-10].  The outcomes of RAAS inhibition in HFpEF sufferers are nonetheless uncertain and up for discussion.

Sacubitril/valsartan seems to be more effective than valsartan or a neprilysin inhibitor by itself due to the fact that it is able to boost systemic exposure to valsartan with the aid of 40% [11,12] which amplifies its antiremodeling results [13,14]. Sacubitril/valsartan has shown promise in treating cardiac remodeling (CRR) as compared to angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) [15-21]. Several studies, which include PRIME, highlight its superior consequences on parameters like left ventricular end-diastolic volume (EDV), although inconsistencies remain, with a few trials reporting constrained benefits on unique indices [22-26]. A dose-based effect has been cited, with higher doses yielding more improvements in CRR; however, no longer all research corroborates this. Additionally, the length of the remedy plays an essential role; longer-term remedies have been related to improved LVEF even as short-term influences are more variable [27-31]. These mixed findings underscore the need for further studies to determine the premier dosing, duration, and patient populations that could benefit most from ARNI therapy.

Rationale: Residual dangers of cardiovascular loss of life and hospitalization persist, prompting the improvement of angiotensin receptor-neprilysin inhibitors (ARNIs), which provide twin neurohormonal modulation by combining neprilysin inhibition with angiotensin receptor blockade. The landmark PARADIGM-HF trial verified the prevalence of sacubitril/valsartan over enalapril in decreasing cardiovascular mortality and HF hospitalizations in HFrEF sufferers, but uncertainties remain regarding its comparative efficacy in numerous HF populations, effects on cardiac remodeling, and effects on lengthy-time period outcomes. This evaluation aims to comprehensively synthesize evidence on the efficacy and safety of ARNIs in comparison to ACEIs in HF, imparting essential insights to optimize treatment strategies and enhance clinical outcomes.

Objectives: Heart failure (HF) remains a major cause of morbidity and mortality the world over, regardless of advances in pharmacological healing procedures, inclusive of angiotensin-converting enzyme inhibitors (ACEIs), which have been foundational in improving outcomes. However, residual dangers of cardiovascular loss of existence and hospitalization persist, prompting the improvement of angiotensin receptor-neprilysin inhibitors (ARNIs), which offer dual neurohormonal modulation through combining neprilysin inhibition with angiotensin receptor blockade. The landmark PARADIGM-HF trial demonstrated the superiority of sacubitril/valsartan over enalapril in lowering cardiovascular mortality and HF hospitalizations in HFrEF patients, but uncertainties remain concerning its comparative efficacy in severe HF populations, effects on cardiac remodeling, and outcomes in the prolonged-time period. This assessment (SRMA) objectives to comprehensively synthesize evidence on the efficacy and protection of ARNIs in comparison to ACEIs in HF, presenting essential insights to optimize remedy strategies and enhance scientific outcomes.

2. Methodology

This study pursuits to assess the comparative efficacy of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) versus Angiotensin-Converting Enzyme Inhibitors (ACEIs) in heart failure sufferers. The method follows the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A complete search was performed in more than one digital database to discover research evaluating the effectiveness of ARNIs and ACEIs in coronary heart failure.

2.1 Protocols and Registration

No registration or ethical approval was required for this systematic review and meta-analysis, as it is based on previously published studies.

2.2 Eligibility Criteria

The Population, Intervention, Comparison, Outcome, and Study Design (PICOS) framework served as the basis for the eligibility requirements for this systematic review and meta-analysis. The following were the requirements for inclusion: (1) Only full-text original articles were included; (2) only studies that compared the effectiveness of ACEIs and ARBs in heart failure patients were eligible; (3) only human subjects studies were included; (4) only English-language studies were included; (5) there were no limitations on the time period for publication; (6) both male and female participants were included, with no discrimination based on gender or ethnicity; (7) the preferred study design was randomized controlled trials (RCTs). (1) Full-text articles were excluded; (2) observational studies, non-randomized trials, and studies not directly related to the intervention were excluded; (3) animal studies were not taken into consideration; (4) publications published in languages other than English were excluded; (5) studies with insufficient data to assess the relative effectiveness of ARNIs and ACEIs were excluded.

Table 1: PICOS framework.

2.3 Information Sources:  A complete search for studies on the efficacy of ARNIs versus ACEIs in coronary heart failure was conducted across more than one digital database, consisting of PubMed, Google Scholar, ScienceDirect, and Cochrane Library. Independent journals and other scholarly guides have also been covered. The seek method adhered to PRISMA tips to ensure comprehensive coverage.

2.4 Search Strategy: The search method concerned the use of Boolean operators (AND/OR) to combine phrases related to ARNIs, ACEIs, coronary heart failure, and applicable results. Databases had been searched for the usage of terms which include “sacubitril/valsartan,” “heart failure,” “ejection fraction,” “mortality,” and “hospitalization.” Filters have been applied to attention in randomized controlled trials and human research. The search yielded twelve studies (n=12) that met the inclusion criteria.

2.5 Selection Process: The article selection was accomplished in stages. First, titles and abstracts had been screened for relevance. In the second level, the full texts of the selected articles were reviewed to verify eligibility. Data on the primary creator, year of guide, observation layout, use of a sample size, results, and methods were extracted using a standardized records extraction tool.

2.6 Data Items: For every study, information on the sample size, study layout, effects, and statistical measures (means, standard deviations) was extracted. The outcome measures protected cardiovascular mortality, hospitalizations, and functional results related to heart failure. Data were synthesized and analyzed the usage of RevMan software for meta-analysis.

2.7 Study Risk of Bias Assessment: The Cochrane Risk-of-Bias (version 2) tool was used to evaluate the threat of bias throughout seven domains: random series era, allocation concealment, blinding, incomplete outcome records, selective reporting, and other biases. The risk of bias for every look was assessed as low, unclear, or excessive.

2.8 Statistical Analysis: Meta-analysis changed into completed the usage of Review Manager (RevMan) software (version 5.4). For dichotomous results (e.g., mortality, hospitalization), risk ratios had been computed. A random-consequences model was used due to predicted heterogeneity throughout the research. Heterogeneity was assessed the usage of the I² statistic, and meta-regression turned into performed where applicable.

2.9 Reporting Bias Assessment: Potential reporting biases have been minimized by means of selecting high-quality studies and undertaking a thorough search for all relevant publications. Funnel plots have been used to visually check for ebook bias.

3 Results

3.1 Study Selection and Screening

The initial search of the database yielded 969 papers. After the removal of duplicates and applying the inclusion criteria total of 28 studies for selected for full-text analysis.  Based on the methodological quality assessment and inclusion and exclusion criteria, a total of 12 articles finally met the criteria to be included in this systematic review and meta-analysis. Figure 1 presents the detailed PRISMA flowchart diagram of the selection process of the included studies.

Figure 1: PRISMA Flow diagram of included studies [7].

3.2 Study Characteristics: Study Characteristics of all the included studies are given in Table 2.

Table 2: Study Characteristics of the included studies.

3.3 Risk of Bias: Risk of Bias [44] of the included studies was calculated using the Cochrane ROB 2 tool [45] since all of the included studies are Randomised Controlled Trials.

Figure 2: Risk of Bias of the included studies.

3.4 Meta-Analysis: RevMan was used to perform the meta-analysis for this study. 4 Forest plots were made, each one for dichotomous data, i.e, Cardiovascular death, renal adverse outcomes, hospitalisation due to HF, and angioedema as a side effect.

(i) Renal Adverse Effects: A overall of six studies comprising 5,418 patients (2,705 in the ARNI group and 2,713 in the ACE inhibitor group) have been covered in the meta-evaluation comparing the incidence of renal adverse effects. The pooled analysis verified a trend in the direction of reduced odds of renal negative activities within the ARNI institution compared to ACE inhibitors, although the result changed into marginally non-substantial (Odds Ratio [OR] 0.76, 95% Confidence Interval [CI] 0.58 to 1.00; p = 0.05). There turned into low to slight heterogeneity in some of the studies (I² = 31%, p = 0.21), suggesting a quite regular impact throughout studies. Notably, 3 research (Butt et al., Mentz et al., and Morrow et al.) suggested statistically sizable discounts in renal destructive effects with ARNI remedy, while the others showed no vast distinction. These findings advocate a renal protection advantage of ARNI over ACE inhibitors, warranting further investigation in large-scale randomized trials.

Figure 3: Forest Plot of Renal Adverse Effects [32-35,38,42].

(ii) Cardiovascular Death: Five studies, including a total of 3,066 patients (1,533 in every institution), assessed the impact of ARNI as opposed to ACE inhibitors on cardiovascular (CV) mortality. The meta-analysis found that the remedy with ARNI considerably reduced the chances of CV dying as compared to ACE inhibitors (Odds Ratio [OR] 0.71, 95% Confidence Interval [CI] 0.57 to 0.89; p = 0.002). Heterogeneity in a few of the included studies turned into negligible (I² = 0%, p = 0.58), indicating consistency of findings across one-of-a-kind populations and observational designs. The majority of research, which includes the ones with the aid of Mentz et al., Tanaka et al., and Morrow et al., preferred ARNI with statistically significant discounts in CV demise. These findings support the superior efficacy of ARNI in lowering cardiovascular mortality as compared to ACE inhibitors, reinforcing its function in coronary heart failure control.

Figure 4: Forest Plot of Cardiovascular Death [33,34,38,39,42].

(iii) Hospitalisation due to HF: Five studies with a total of 3,066 patients (1,533 in each group) were included within the analysis of hospitalization charges. The pooled consequences confirmed a statistically significant discount in the odds of hospitalization amongst patients receiving ARNI as compared to the ones on ACE inhibitors (Odds Ratio [OR] 0.78, ninety five% Confidence Interval [CI] zero.64 to 0.95; p = 0.01). There was no observed heterogeneity across the included studies (I² = 0%, p = 0.48), indicating sturdy consistency in the observed impact. Notably, the research through Mentz et al., Morrow et al., and Tanaka et al. Showed a clean benefit of ARNI, while others did not reach statistical significance individually. These findings propose that ARNI remedy is related to a meaningful reduction in hospitalizations as compared to ACE inhibitors, similarly helping its scientific software in managing patients vulnerable to heart failure–related activities.

Figure 5: Forest Plot of Hospitalisation due to HF [33,34,38,39,42].

(iv) Angioedema: The meta-evaluation comparing angioedema as an aspect impact of angiotensin receptor-neprilysin inhibitors (ARNIs) versus ACE inhibitors covered two studies with a mixed group of 906 individuals within the ARNI group and 907 in the other group. The pooled odds ratio (OR) turned into 0.62 (95% confidence interval [CI]: 0.08 to 5.08), suggesting a decreased chance of angioedema with ARNIs as compared to ACE inhibitors. However, this end result became now not statistically significant (P = 0.66), because the self-assurance interval crosses 1. Heterogeneity a number of the covered studies becomes minimal, with an I² value of 0% and a chi-squared P-value of 0.61, indicating consistency within the findings throughout the research. Despite the apparent trend favoring ARNIs, the low event charge and wide self-assurance durations limit the precision of the estimate, making it tough to draw definitive conclusions.

Figure 6: Forest Plot of Angioedema [33,34].

3.5 Publication Bias: The funnel plot [46] displays the standard error (SE) of the log odds ratio (log[OR]) at the vertical axis against the odds ratio (OR) on the horizontal axis for research comparing ARNI versus ACE inhibitors. The distribution of studies seems asymmetrical, in particular with studies displaying larger standard errors (smaller pattern sizes) tending to favor one side of the plot. This asymmetry may additionally advocate potential publication bias or heterogeneity within the protected research.

4. Discussion

This meta-analysis blanketed a total of 12 studies comparing the clinical efficacy and safety of sacubitril/valsartan in various heart failure populations. The findings revealed that sacubitril/valsartan validated a greater discount within the primary endpoint as frailty improved as compared to valsartan, even though this distinction became no longer statistically significant while analyzing the usage of the Frailty Index (FI) as a variable [32]. In hemodynamically stabilized sufferers with acute decompensated coronary heart failure (ADHF), sacubitril/valsartan exhibited efficacy and safety that were consistent throughout numerous dose levels. Moreover, the treatment was associated with an extra boom in left atrial extent index and improvements in cardiovascular risk factors as compared to valsartan [34]. Early initiation of sacubitril/valsartan therapy in put-up-STEMI sufferers confirmed capacity advantages in myocardial remodeling and clinical consequences [42]. Additionally, in-health center initiation of sacubitril/valsartan, along with cutting-edge endorsed remedies, led to a greater sizable discount in NT-proBNP levels in Japanese patients hospitalized for acute heart failure (AHF).

This meta-analysis tested the comparative safety and efficacy of angiotensin receptor-neprilysin inhibitors (ARNIs) and ACE inhibitors across four medical consequences. For renal unfavourable results, six studies involving five,418 sufferers showed a fashion favoring ARNIs with decreased odds of renal destructive activities as compared to ACE inhibitors, even though this result turned into marginally non-widespread with low-to-slight heterogeneity (I² = 31%). Cardiovascular demise became assessed in 5 studies, inclusive of 3,066 patients, revealing a widespread discount in CV mortality with ARNIs in comparison to ACE inhibitors (OR 0.71, 95% CI 0.57–0.89, p=0.002) and no heterogeneity (I² = 0%). Similarly, hospitalization due to heart failure (HF) turned into substantially lower in ARNI-handled sufferers (OR 0.78, 95% CI 0.64–0.95, p = zero.01) with regular findings across research (I² = 0%). These findings suggest that ARNIs might also offer benefits over ACE inhibitors, especially in reducing CV mortality and HF-associated hospitalizations, with a potential trend in the direction of renal protection and decreased angioedema threat, warranting similar research.

Previous meta-analyses, by and large, tested ARNI on blood pressure and the mixed outcome of mortality and coronary heart failure hospitalization. Studies have proven reductions in left ventricular mass index (LVMI) in patients with coronary heart failure with reduced ejection fraction (HFrEF) and those with essential high blood pressure, highlighting ARNI's ability to address cardiac hypertrophy [47,48]. While a few studies have diagnosed sturdy institutions among mortality in sufferers handled with ACEIs or ARBs, not all medicines that induce short-term cardiac remodeling (CRR) have shown improvements in long-term outcomes [49,50]. Further research is required to clarify the link between CRR and reduced mortality following ARNI therapy.

Another observe tested that ARNIs considerably improved left ventricular size and hypertrophy in patients with coronary heart failure with reduced ejection fraction (HFrEF), even within a short-term period comply with-up period. Patients showed more advantages in terms of cardiac reverse remodelling (CRR) whilst treated with ARNIs as early as possible and for a minimum length of three months [51].

This meta-analysis has several obstacles that warrant consideration. While heterogeneity changed into typically low to mild, variations in study designs, patient populations, and treatment protocols may have influenced the results. The brief follow-up intervals of many included research constrained the potential to evaluate long-term outcomes and protection of ARNI therapy. Some vital results, together with quality of lifestyles and cost-effectiveness, had been underrepresented or not assessed. Additionally, the low occurrence of charges for rare negative consequences, consisting of angioedema, decreased the statistical strength to draw definitive conclusions. Although no widespread guide bias changed into detected, the capacity for unpublished poor consequences can't be excluded.

5. Conclusion

In the end, this meta-evaluation highlights the clinical benefits of angiotensin receptor-neprilysin inhibitors (ARNIs) in patients with heart failure with decreased ejection fraction (HFrEF). ARNI remedy turned into associated with tremendous discounts in cardiovascular mortality, heart failure hospitalizations, and renal negative consequences, along with improvements in left ventricular remodeling and functional effects. Despite a few barriers, along with the variety in take a look at designs and underrepresentation of certain outcomes, these findings strengthen the efficacy and protection of ARNIs in the control of heart failure. Future research with extended follow-up, numerous affected person populations, and a broader assessment of effects, along with pleasant of lifestyles and cost-effectiveness, is warranted to similarly establish the function of ARNIs in coronary heart failure control. This evidence helps the recommendation for early and sustained ARNI initiation as a cornerstone in coronary heart failure treatment to improve patient outcomes.

6. References

1. Braunwald E. The war against heart failure: the Lancet lecture. The Lancet 385 (2014): 812-284.
2. Bhatt AS, Ambrosy AP, Velazquez EJ: Adverse remodeling and reverse remodeling after myocardial infarction. Current Cardiology Reports 19 (2017).
3. Ponikowski P, Voors AA, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal 37 (2016): 2129-2200.
4. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 76 (1987): 44-51.
5. Ambrosy AP, Mentz RJ, Fiuzat M. The role of angiotensin receptor–neprilysin inhibitors in cardiovascular disease—existing evidence, knowledge gaps, and future directions. European Journal of Heart Failure 20 (2018): 963-972.
6. Greenberg B, Quinones MA, Koilpillai C, Limacher M, Shindler D, et al. Effects of long-term Enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Circulation 91 (1995): 2573-2581.
7. Haddaway NR, Page MJ, Pritchard CC, McGuinness LA. PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Systematic Reviews 18 (2022).
8. Effects of Enalapril on mortality in severe congestive heart failure. New England Journal of Medicine 316 (1987): 1429-1435.
9. Pfeffer MA, Swedberg K, Granger CB. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. The Lancet 362 (2003): 759-766.
10. Zhang Q, Chen Y, Liu Q, Shan Q. Effects of renin–angiotensin–aldosterone system inhibitors on mortality, hospitalization, and diastolic function in patients with HFpEF. Herz 41 (2015): 76-86.
11. McMurray JJ, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371 (2014): 993-1004.
12. Yancy CW, Jessup M, Bozkurt B. 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. Circulation 134 (2016): e282–e293.
13. Von Lueder T, Wang B, Kompa A. Angiotensin receptor neprilysin inhibition (ARNI) attenuates adverse cardiac remodeling in vitro and in vivo. Heart Lung Circ 22 (2013): S71.
14. Suematsu Y, Miura S, Goto M. LCZ696, the angiotensin-receptor neprilysin inhibitor, attenuates cardiac fibrosis and improves its function in the heart failure model of diabetes mellitus in mice. Eur Heart J 36 (2015): 661.
15. Schmieder RE, Wagner F, Mayr M, et al.: The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodeling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study. Eur Heart J 38 (2017): 3308-3317.
16. Solomon SD, Zile M, Pieske B, et al.: The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet 380 (2012): 1387-1395.
17. Almufleh A, Marbach J, Chih S, et al. Ejection fraction improvement and reverse remodeling achieved with sacubitril/valsartan in heart failure with reduced ejection fraction patients. Am J Cardiovasc Dis 7 (2017): 108-113.
18. De Diego C, González-Torres L, Nuñez JM, et al. Angiotensin-neprilysin inhibition further reverses cardiac remodeling as compared to angiotensin inhibition in reduced heart failure patients. Europace 20 (2018): i139.
19. Kang DH, Park SJ, Shin SH, et al.: Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation 139 (2019): 1354-1365.
20. Nazzari H, Yeung M, Marceau A, et al. Left ventricular function improves in heart failure patients treated with sacubitril-valsartan. Can J Cardiol 33 (2017): S163.
21. Barrett MJ, Hammond M, Zhou S, et al. Effect of sacubitril/valsartan therapy on risk stratification biomarkers in a real-world heart failure population. Eur J Heart Fail 19 (2018): 585-586.
22. Murray G, Barrett M, Earls S, et al. The use of sacubitril/valsartan: a real-world experience in a high-volume specialist heart failure service. Heart 103 (2017): A8-A9.
23. Maurin V, Canu A, Bernard A, et al.: Early reverse remodeling and improvement of echo parameters after introduction of sacubitril/valsartan in 80 stable and well-treated HFrEF patients. Eur J Heart Fail 19 (2017): 296.
24. Canu A, Hebert M, Gachet A, et al.: Results of a single-center experience on 110 consecutive patients treated with Entresto (sacubitril/valsartan). Arch Cardiovasc Dis Suppl 9 (2017): 33.
25. Martens P, Beliën H, Dupont M, et al. The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction. Cardiovasc Ther 36 (2018): e12435.
26. Groba-Marco M, Singh M, Galvan Ruiz M, et al. Early left ventricular reverse remodeling after sacubitril/valsartan treatment in clinical practice. Eur J Heart Fail 20 (2018): 225.
27. Kalantari S, Medvedofsky DM, Grinstein JG, et al. Remodel: demonstration of reverse remodeling effects of sacubitril/valsartan. Eur J Heart Fail 20 (2018): 36-37.
28. Mercedes Faraudo M, Beltran P, Freixa R, et al. How does sacubitril/valsartan improve submaximal functional capacity measured through six-minute walk test? Eur J Heart Fail 19 (2017): 307.
29. Rafael Bravo Marques R, Torres Calvo F, Lopez Tejero S, et al. Initial experience using LCZ696 in real life: tolerability and clinical evolution in a short term. Eur J Heart Fail 19 (2017): 290-291.
30. Hlavata K, Hoskova L, Franekova J, et al. Transition from angiotensin-converting enzyme inhibitor/angiotensin-II-receptor-blocker to sacubitril/valsartan in chronic heart failure patients: initial experiences in clinical practice. Cor Vasa 60 (2018): e209-e214.
31. Beltrán P, Palau P, Domínguez E, et al. Sacubitril/valsartan and short-term changes in the 6-minute walk test: a pilot study. Int J Cardiol 252 (2018): 136-139.
32. Butt JH, Dewan P, Jhund PS, et al. Sacubitril/Valsartan and frailty in patients with heart failure and preserved ejection fraction. Journal of the American College of Cardiology 80 (2022): 1130-1143.
33. Morrow DA, Velazquez EJ, Desai AS, et al. Sacubitril/Valsartan in patients hospitalized with decompensated heart failure. Journal of the American College of Cardiology 83 (2024): 1123-1132.
34. Mentz RJ, Ward JH, Hernandez AF, et al. Angiotensin-Neprilysin inhibition in patients with mildly reduced or preserved ejection fraction and worsening heart failure. Journal of the American College of Cardiology 82 (2023): 1-12.
35. Berg DD, Braunwald E, DeVore AD, et al.: Efficacy and safety of Sacubitril/Valsartan by dose level achieved in the PIONEER-HF trial. JACC Heart Failure 8 (2020): 834-843.
36. Ledwidge M, Dodd JD, Ryan F, et al. Effect of Sacubitril/Valsartan vs Valsartan on Left Atrial Volume in Patients with Pre–Heart Failure With Preserved Ejection Fraction. JAMA Cardiology 8 (2023): 366.
37. Rezq A, Saad M, Nozahi ME. Comparison of the Efficacy and Safety of Sacubitril/Valsartan versus Ramipril in Patients With ST-Segment Elevation Myocardial Infarction. The American Journal of Cardiology 143 (2021): 7-13.
38. Tanaka A, Kida K, Matsue Y, et al. In-hospital initiation of angiotensin receptor–neprilysin inhibition in acute heart failure: the PREMIER trial. European Heart Journal.
39. Tsutsui H, Momomura SI, Saito Y, et al. Efficacy and safety of Sacubitril/Valsartan in Japanese patients with chronic heart failure and reduced ejection fraction-results from the PARALLEL-HF study-. Circulation Journal 85 (2021): 584-594.
40. Du H, Li X, Zhao W, Jiang N. The Difference between Sacubitril Valsartan and Valsartan on Vascular Endothelial Function, APN, MMP-9, and BNP Levels in Patients with Hypertension and Chronic Heart Failure. Journal of Healthcare Engineering 2022 (2022): 1-8.
41. Mogensen UM, Gong J, Jhund PS, et al. Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). European Journal of Heart Failure 20 (2018): 760-768.
42. Jain AR, Aggarwal RK, Rao NS, Billa G, Kumar S. Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study. Indian Heart Journal 72 (2020): 535-540.
43. Fraile RR, Malafarina V, López GT Sacubitril–valsartan in heart failure and multimorbidity patients. ESC Heart Failure 5 (2018): 956-959.
44. Ma LL, Wang YY, Yang ZH, Huang D, Weng H, Zeng XT. Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better? Military Medical Research 7 (2020).
45. Sterne Ja C, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ (2019) l4898.
46. Page MJ, Sterne Ja C, Higgins JPT, Egger M. Investigating and dealing with publication bias and other reporting biases in meta-analyses of health research: A review. Research Synthesis Methods 12 (2020): 248-259.
47. Solomon SD, Claggett B, McMurray JJV, Hernandez AF, Fonarow GC: Combined neprilysin and renin–angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis. European Journal of Heart Failure 18 (2016): 1238-1243.
48. Ye L, Wang J, Chen Q, Yang X. LCZ696, a promising novel agent in treating hypertension (a meta-analysis of randomized controlled trials). Oncotarget 8 (2017): 107991-108005.
49. Zhao Y, Yu H, Zhao X, Ma R, Li N, Yu J. The effects of LCZ696 in patients with hypertension compared with angiotensin receptor blockers. Journal of Cardiovascular Pharmacology and Therapeutics 22 (2017): 447-457.
50. Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction. Journal of the American College of Cardiology 56 (2010): 392-406.
51. Wang Y, Zhou R, Lu C, Chen Q, Xu T, et al. Effects of the Angiotensin-Receptor neprilysin inhibitor on cardiac reverse remodeling: Meta-Analysis. Journal of the American Heart Association 8 (2019).