Sacubitril/Valsartan Treatment in Heart Failure Increases The Left Ventricular Ejection Fraction: A Bayesian Analysis
1Department of Cardiology, Atatürk University Faculty of Medicine, Erzurum, Türkiye
2Clinic of Cardiology, Hisar Intercontinental Hospital, İstanbul, Türkiye
3Clinic of Cardiology, Kırıkkale Yüksek İhtisas Hospital, Kırıkkale, Türkiye
4Clinic of Cardiology, Erzurum City Hospital, Erzurum, Türkiye
Keywords: ARNI; bayesian; ejection fraction
Introduction: Heart failure is an important leading cause of mortality and morbidity despite optimal medical treatment and device therapy. Sacubitril/valsartan, a first-generation drug, was approved to use heart failure treatment recently. There are limited studies on the relationship between sacubitril/valsartan and left ventricular contraction. In our study, we aimed to evaluate the changes in left ventricular ejection fraction (LVEF) after sacubitril/valsartan treatment.
Patients and Methods: Fifty-two patients with heart failure and reduced ejection fraction (HFrEF) were enrolled in this study. The baseline demographic, clinical, and echocardiographic characteristics of 52 patients were compared using the Bayesian method.
Results: Fifty-two patients with heart failure and reduced ejection fraction (HFrEF) were included in the final analysis (66.2 ± 9.3 years, 69.2% male). Sacubitril/valsartan initial dose was low in 44.2% of patients, and intermediate in 55.8%. In the low initial dose population, the increase in absolute LVEF was 3.87 (95% HDI 1.53-6.20) and in the intermediate initial dose population, the increase in absolute LVEF was 5.89 (95% HDI 4.18-7.61). In the female population, the increase in absolute LVEF was 5.56 (95% HDI 3.49-7.63) and in the male population 4.75 (95% HDI 2.91-6.58) respectively.
Conclusion: In this study, we demonstrated that sacubitril/valsartan is associated with increased LVEF regardless of baseline clinical characteristics.
Mortality in patients with heart failure and reduced ejection fraction (HFrEF) has improved over time because of the stepwise introduction of a variety of pharmacological treatments. For years, recommended treatments for patients with HFrEF included the combination of an angiotensin-converting enzyme inhibitor [ACEI; or an angiotensin II receptor blocker (ARB) if an ACEI is not tolerated], a β-blocker (BB), and a mineralocorticoid receptor antagonist (MRA). Despite these recommended treatments being evidence-based, the mortality rate for patients with HFrEF remains high(1-3).
Sacubitril/valsartan, a first-in-class angiotensin receptor– neprilysin inhibitor (ARNI), was recommended as a new treatment option for patients with HFrEF. These recommendations were based on the results of the PARADIGMHF trial (Prospective Comparison of ARNI With ACE to Determine Impact on Global Mortality and Morbidity in Heart Failure), in which sacubitril/valsartan 20% reduction in the risk of cardiovascular death, 21% reduction in the risk of hospitalization for heart failure and 16% reduction in the risk of all-cause mortality comparing to the patients on enalapril treatment(4). Recent studies have demonstrated that sacubitril/ valsartan treatment has favorable effects on the left ventricular ejection fraction (LVEF)(5-8). In our study, we aimed to investigate by using Bayesian analysis the effect of sacubitril/ valsartan treatment on the ejection fraction in HFrEF patients in the cardiology practice in Türkiye.
Patients and Methods
The study consisted of 56 patients who were diagnosed with HFrEF in three different centers. After the administration of sacubitril/valsartan therapy, we evaluated them with a follow-up phone call. Four patients were lost to follow-up because they could not be reached. The baseline characteristics of the remaining 52 patients were examined and recorded from their hospital files. In addition, clinical characteristics, echocardiographic findings, and drug doses were recorded at the mean follow-up of six weeks. The same transthoracic echocardiography machines [Vivid 3, GE, Norway (in two hospitals) and Vivid 7, GE, Norway (in one hospital)] as previously used were preferred for each patient for follow-up evaluation. The LVEF (%) was determined by using a modified Simpson’s method.
In this study, we used Bayesian inferential analyses. Continuous variables were demonstrated with mean ± standard deviation (SD), and categorical variables were demonstrated with percent (%). Assuming “p” as the probability of an increase in LVEF after sacubitril/valsartan treatment; null hypothesis (Ho): p= 0 (absence of effect) and alternative hypothesis (H1): p≠ 0 (presence of effect). The prior probability of Ho and H1 were shown as Pr (Ho) and Pr (H1). After combining current data (D) and prior belief, the posterior probability of H0 and H1 were Pr (Ho/D) ve Pr (H1/D). The Bayes factor (BF10) was Pr (H1/D)/Pr (Ho/D). The BF10 is a statistical index that quantifies the evidence for a hypothesis, compared to an alternative hypothesis (i.e., BF10 equals 10, the data are 10 times more likely under H1 than under H0 or BF10 equals 0.2 the data are five times more likely under H0 than under H1). The interpretation of BF10 was demonstrated in Table 1. LVEF, mean credible value (±SD) of the actual difference and 95% highest density interval (HDI) as the range were the actual differences before-after sacubitril/valsartan is demonstrated with 95% credibility. We used the Bayesian paired t-test to compare LVEF values before and after sacubitril/valsartan treatment and the Bayesian independent test to compare LVEF changes between male/female and baseline low/intermediate sacubitril/valsartan doses. Inferential analyses were calculated utilizing a Bayesian paradigm by using Markov Chain Monte Carlo (MCMC) methods to evaluate posterior distributions and probabilities and to measure the probability for a coefficient to be positive. The MCMC methods are based upon simulations under specific assumptions, and empirical posterior distributions and probabilities are evaluated for the conclusion. Statistical analyses were done using JASP (0.8.4) and R (3.4.2) packages.
We included 52 patients with systolic heart failure (LVEF ranged from 19 to 40%) (66.2 ± 9.3 years, 69.2% male). Overall, 82.7% (n= 43) of the patients had HF with ischemic etiology, and 67.3% (n= 35) had been hospitalized for HF at least once in the last six months. The frequency of patients using ACEI was 75%, the frequency of patients using BB was 80.8%, and the frequency of patients using MRA was 42.3%. Other baseline clinical features are summarized in Table 2.
Low doses of sacubitril/valsartan were administrated to 44.2% of patients and intermediate doses to 55.8%. After adjusting the dose according to blood pressure, creatinine, and potassium levels at follow-up, 7.7% of patients had received low, 36.5% intermediate and 55.8% target doses of sacubitril/ valsartan at the end of the study. From April 2017 to November 2017, eight patients using sacubitril/valsartan were re-hospitalized. Of these, five were hospitalized for pneumonia/exacerbation of COPD and urinary infection, and three for decompensated heart failure (one of them had not used sacubitril/valsartan for one month).
The LVEF was 30.8 ± 5.6 (95% HDI 29.1-32.3) before starting sacubitril/valsartan, and 35.8 ± 7.3 (95% HDI 34.0- 37.7) 1-3 months after starting sacubitril/valsartan (Figure 1). After initiation of sacubitril/valsartan, patients had a marked increase in LVEF. The Bayesian posterior probability of any increment in LVEF (>0%) after sacubitril/valsartan was 100% and the posterior probability of any decrement in LVEF (<0%) was 0.02% (Figure 2). The absolute increase in LVEF was -5.0% with 95% HDI -7.4, -2.6 (the median effect size was -1.4, 95% HDI -1.80, -0.95, and the BF> 1000) (Figure 3a). The Bayesian sequential analysis in Figure 3b revealed that after about 20 observations, the BF equals 10 and after 30 observations, the BF equals 100. These results indicate that there was extreme evidence against Ho hypothesis when we used different types of prior distribution even in a low sample size.
The increase in absolute LVEF was 3.87 (95% HDI 1.53- 6.20) in low initial sacubitril/valsartan doses and 5.89 (95% HDI 4.18- 7.61) in intermediate initial sacubitril/valsartan doses (the BF was 0.681 and posterior probability was 92%) (Figure 4a) Similarly, increase in absolute LVEF was 5.56 (95% HDI 3.49-7.63) in women and 4.75 (95% HDI 2.91-6.58) in men (the BF was 0.334 and posterior probability was 72%) (Figure 4b). There was no significant Bayesian correlation between absolute change in LVEF and age (Pearson r= -0.02, 95% HDI -0.28, 0.25, the BF= 0.175, and posterior probability was 22%).
The main findings of this study are, i) sacubitril/valsartan increased the LVEF by approximately 5.0%, ii) improvement in LVEF is independent from sacubitril/valsartan doses, sex, and age in the Bayesian analyses.
Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin(9-11). Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling(12,13). Combined inhibition of the renin-angiotensin system and neprilysin had effects that were superior to those of either approach alone in experimental studies(4).
Sacubitril/valsartan (LCZ696) offers new hope to patients with HFrEF. The drug secured a high position in the 2016 guidelines on heart failure of the European Society of Cardiology and the American College of Cardiology/American Heart Association(14,15). These recommendations were based on the findings of the PARADIGM-HF trial (Prospective Comparison of ARNI With ACE to Determine Impact on Global Mortality and Morbidity in Heart Failure), which found that sacubitril/ valsartan reduced the risk of cardiovascular death by 20%, hospitalization for heart failure by 21%, and all-cause mortality by 16% in the LCZ696 group compared to the enalapril group(4). Furthermore, the secondary outcomes were the time to death from any cause and the change in clinical summary score from baseline to eight months on the Kansas City Cardiomyopathy Questionnaire (KCCQ)(16). (On a scale from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with heart failure).
Several different effects of sacubitril/valsartan treatment on biochemical and clinical outcomes have been demonstrated. Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycemic control in patients with diabetes and HfrEF(13). In another study, sacubitril/ valsartan treatment was more effective than olmesartan in terms of reducing LV mass index. It has been hypothesized that the vasodilatory and antiproliferative effects of the neprilysin inhibitor moiety of sacubitril/valsartan may provide additional benefits to those of the RAS-inhibitor component, further reducing the risks associated with LV remodeling(12) Furthermore, sacubitril/valsartan reduced cardiac remodeling and dysfunction after experimental MI and inhibited cardiac fibrosis and hypertrophy in vivo and in vitro, which was greater than that achieved by ARB alone(17). This data may offer novel mechanistic insight into the benefits observed with LCZ696 in clinical studies.
In a study of 77 HFrEF patients, LV functions were assessed using standard and advanced echocardiographic examination. Sacubitril/valsartan was shown to have beneficial effects on LVEF(18). In addition, in several studies performed with similar patient numbers, it was demonstrated that sacubitril/valsartan treatment significantly improved LV systolic and diastolic functions(5,6). In a retrospective study examining 501 HFrEF patients with end-stage renal disease, sacubitril/valsartan was demonstrated to significantly increase LVEF(7). Similarly, in the ARNi-TR study conducted in Türkiye, in which approximately 800 patients were evaluated retrospectively, it was demonstrated that sacubitril/valsartan treatment improved LVEF (34308869). In line with the results of these studies, our study showed that there was an improvement in LVEF with sacubitril/valsartan treatment, and these findings may be associated with positive changes in cardiac remodeling. In addition, these results were defined irrespective of gender, doses of sacubitril/valsartan, and age with Bayesian analysis.
The use of sacubitril/valsartan in patients with HFrEF improves left ventricular ejection fraction. This improvement is independent from baseline clinical characteristics.
Limitations of the Study
It was a retrospective study. The analyzed sample size was small, and patients were not treated according to the established protocol. More research and clinical experience are required. Lastly, due to the small number of patients, the Bayesian analysis method, which allows for more flexibility, was preferred.
Cite this article as: Birdal O, Saygı M, Demir Gündoğmuş P, Aksakal E, Özkalaycı F. Sacubitril/valsartan treatment in heart failure increases the left ventricular ejection fraction: A bayesian analysis. Koşuyolu Heart J 2022;25(3):250-256.
The approval for this study was obtained from Erzurum Regional Training and Research Hospital Clinical Research Ethics Committee 'Decision no: 2022/06-59, Date: 16.05.2022).
This is retrospective study, we could not obtain written informed consent from the participants.
Concept/Design - OB, MS; Analysis/Interpre- tation - PDG, FÖ; Data Collection - OB, PDG, MS; Writing - OB, MS, EA; Critical Revision - EA; Final Approval - All of authors; Statistical Analysis - FÖ; Overall Responsibility - OB.
The authors have no conflicts of interest to declare.
The authors declare that this study has received no financial support.
- McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association 'HFA) of the ESC. Eur J Heart Fail 2012;14'8):803-69.
- Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Executive summary: Heart disease and stroke statistics-2010 update: A report from the American Heart Association. Circulation 2010;121'7):948-54. [Crossref]
- Burnett H, Earley A, Voors AA, Senni M, McMurray JJ, Deschaseaux C, et al. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction: A network meta-analysis. Circ Heart Fail 2017;10'1):003529. [Crossref]
- McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371'11):993-1004. [Crossref]
- Elshafey WEH, Al Khoufi EA, Elmelegy EK. Effects of sacubitril/valsartan treatment on left ventricular myocardial torsion mechanics in patients with heart failure reduced ejection fraction 2D speckle tracking echocardiography. J Cardiovasc Echogr 2021;31'2):59-67. [Crossref]
- Pericas P, Mas-Llado C, Ramis-Barcelo MF, Valadron I, Noris Mora M, Pasamar Marquez L, et al. Impact of sacubitril-valsartan treatment on diastolic function in patients with heart failure and reduced ejection fraction. High Blood Press Cardiovasc Prev 2021;28'2):167-75. [Crossref]
- Lee S, Oh J, Kim H, Ha J, Chun KH, Lee CJ, et al. Sacubitril/valsartan in patients with heart failure with reduced ejection fraction with end-stage of renal disease. ESC Heart Fail 2020;7'3):1125-29. [Crossref]
- Ekici B, Yaman M, Kucuk M, Dereli S, Yenercag M, Yigit Z, et al. Angiotensin receptor neprilysin inhibitor for patients with heart failure and reduced ejection fraction: Real-world experience from Turkey 'ARNi-TR). Turk Kardiyol Dern Ars 2021;49'5):357-67. [Crossref]
- Cruden NL, Fox KA, Ludlam CA, Johnston NR, Newby DE. Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. Hypertension 2004;44f6):913-8. [Crossref]
- Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T. Neutral endopeptidase inhibition: Augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. Clin Sci 'Lond) 1996;91'3):283-91. [Crossref]
- Wilkinson IB, McEniery CM, Bongaerts KH, MacCallum H, Webb DJ, Cockcroft JR. Adrenomedullin 'ADM) in the human forearm vascular bed: Effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide 'PAMP). Br J Clin Pharmacol 2001;52'2):159-64. [Crossref]
- Schmieder RE, Wagner F, Mayr M, Delles C, Ott C, Keicher C, et al. The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: The results of a randomized, double-blind, active-controlled study. Eur Heart J 2017;38(44):3308-17. [Crossref]
- Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: A post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2017;5(5):333-40. [Crossref]
- Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr., Colvin MM, 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(13):282- 93. [Crossref]
- Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37(27):2129-200. [Crossref]
- Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: A new health status measure for heart failure. J Am Coll Cardiol 2000;35(5):1245-55. [Crossref]
- King JB, Shah RU, Bress AP, Nelson RE, Bellows BK. Cost-effectiveness of sacubitril-valsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction. JACC Heart Fail 2016;4(5):392-402. [Crossref]
- Castrichini M, Manca P, Nuzzi V, Barbati G, De Luca A, Korcova R, et al. Sacubitril/valsartan induces global cardiac reverse remodeling in longlasting heart failure with reduced ejection fraction: Standard and advanced echocardiographic evidences. J Clin Med 2020;9(4):906. [Crossref]