Clinical Trials in Degenerative Diseases

RESEARCH ARTICLE
Year
: 2018  |  Volume : 3  |  Issue : 4  |  Page : 119--122

Sacubitril/valsartan improves ejection fraction in heart failure with reduced ejection fraction: A retrospective study


Walid Ibrahim1, Ahmed S Yassin1, Ahmed Subahi1, Hassan Mohamed2, Ayman Khaddam2, Muhammad Bajwa3, Ashraf Abugroun4, Amir Kaki5, Mahir Elder5, Tamam Mohamad5,  
1 Department of Internal Medicine, Wayne State University, Detroit Medical Center, Detroit, MI, USA
2 Hearts and Vascular Institute, Detroit Medical Center, Detroit, MI, USA
3 University of Oklahoma Health Science Center, Oklahoma City, OK, USA
4 Department of Medicine, Advocate Illinois Masonic Medical Center, Chicago, IL, USA
5 Department of Cardiovascular Medicine-CCU, Wayne State University, Detroit Medical Center, Detroit, MI, USA

Correspondence Address:
Walid Ibrahim
Department of Internal Medicine, Wayne State University, Detroit Medical Center, Detroit, MI
USA

Abstract

Background and objectives: The discovery and introduction of Neprilysin inhibitor in treating chronic heart failure (New York Heart Association class II–IV) with reduced ejection fraction (HFrEF) is a remarkable landmark in therapy. The clinical outcome of reducing the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure was demonstrated at the large randomized, double blind, “Angiotensin-Neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF trial).” We studied a total of 228 patients with HFrEF who was recently started on sacubitril/valsartan (EntrestoTM; previously known as LCZ696) testing the hypothesis of improving ejection fraction with sacubitril/valsartan, defined as an increase of ejection fraction from the baseline before treatment by 10–15%. Methods: This is a single-center, retrospective, descriptive study. The data was collected from the charts of patients followed up for a mean of 4.7 weeks after initiation of treatment with sacubitril/valsartan. A total of 228 patients with heart failure were prescribed 200 mg of sacubitril/valsartan twice daily, an improvement in ejection fraction by 10–15% was considered a successful response. Results: Out of the 228 patients, 51.3% showed a successful response. Most of the patients 97.9% and 58.0% were taking beta-blockers and aspirin respectively. The absolute number of black patients who improved was higher than others ethnic groups. However, the higher percentage of ejection fraction improvement 71% was reported among other ethnicities (not blacks or Caucasians). Patients without episodes of hospitalization showed better improvement than those with one or more episodes. Conclusion: In a predominantly black population with HFrEF, sacubitril/valsartan has shown improvement in ejection fraction effect. This finding was independent of other risk factors and concomitant heart failure treatment; however, further studies are recommended to validate this result. Ethics: Ethical approval of this study was obtained from the Research Committee, DMC/Wayne State University (IRB# 015618MP4X) on February 14, 2018.



How to cite this article:
Ibrahim W, Yassin AS, Subahi A, Mohamed H, Khaddam A, Bajwa M, Abugroun A, Kaki A, Elder M, Mohamad T. Sacubitril/valsartan improves ejection fraction in heart failure with reduced ejection fraction: A retrospective study.Clin Trials Degener Dis 2018;3:119-122


How to cite this URL:
Ibrahim W, Yassin AS, Subahi A, Mohamed H, Khaddam A, Bajwa M, Abugroun A, Kaki A, Elder M, Mohamad T. Sacubitril/valsartan improves ejection fraction in heart failure with reduced ejection fraction: A retrospective study. Clin Trials Degener Dis [serial online] 2018 [cited 2019 Mar 25 ];3:119-122
Available from: http://www.clinicaltdd.com/text.asp?2018/3/4/119/248010


Full Text

 Introduction



The management of heart failure with reduced ejection fraction (HFrEF) had progressed significantly over the last two decades. Improving the quality of life and decreasing overall mortality were the main accomplishments. Since the introduction of angiotensin-converting enzyme inhibitors (ACEIs) in 1987 vivid reduction in death was shown earlier by randomized controlled studies; The CONSENSUS (Enalapril in severe heart failure [HF]) and The 1991 Studies of Left Ventricular Dysfunction SOLVD Investigators.[1],[2] The overall mortality had dropped to 30% with optimal medical therapy with the addition of beta-blockers, and mineralocorticoid-receptor antagonists to ACEIs.[3],[4],[5],[6] A further benefit has proven after the landmark study in heart failure management (PARADIGM trial), which favored the use of angiotensin receptor-neprilysin inhibitors over ACEIs. This conclusion based on the reported 20% reduction in the composite endpoint of cardiovascular death or HF hospitalization, and entitled the integration of the outcome into the 2016 American College of Cardiology/American Heart Association/Heart Failure Society of America Guidelines.[7],[8] We studied a total of 228 patients with hHFrEF who recently started on sacubitril/valsartan and proposed the hypothesis of improving ejection fraction (EF) after treatment with sacubitril/valsartan.

 Subjects/Methods



Study design

This single-center, retrospective, descriptive study was performed at the Outpatient Heart Failure Clinic in Heart and Vascular Institute, Detroit, Michigan/Wayne State University. Data were collected retrospectively from the charts of diagnosed patients with HFrEF, defined as EF less than 40%. EF was calculated based on quantitative measurement of left ventricular systolic function by the Modified Simpson’s Method. The patients enrolled attended the clinic during the period from January 2017 to December 2017. The cohort was followed up for a mean of 4.7 weeks after initiation of treatment. Patients who met the criteria mentioned earlier for HFrEF and started on sacubitril/valsartan (LCZ696; EntrestoTM, Novartis, Switzerland) 200 mg twice daily, were followed by another echocardiography to estimate the EF using the same method. An increase of EF from the baseline before treatment by 10–15% is considered an appropriate response. Ethical approval of this study was obtained from the Research Committee, DMC/Wayne State University (IRB# 015618MP4X) (Additional file 1 [SUPPORTING:1]) on February 14, 2018 for the analysis and publication of this study.

Statistical analysis

Data presented as a mean and standard deviation for quantitative variables and frequencies, percentages used to summarize qualitative variables. Percentage improvement according to different risk factors was compared using the chi-square test or Fisher’s exact test as appropriate. A P-value less than 0.05 was considered statistically significant. SPSS version 22 (IBM, Armonk, NY, USA) was used to analyze the data.

 Results



Demographic data

The cohort has a mean age of 59.2 ± 11.7 years, and mean EF before treatment of 15–20% with the New York Heart Association class (NYHA) II to IV. 145 (63.6%) were males. 77.6% of them were blacks, 10.1% white Caucasians, and 12.3% other ethnic groups [Table 1].{Table 1}

Data on the cohort comorbid conditions and heart failure treatment

The highest percentage of the co-morbidities in the examined sample was hypertension (94.7%). However, the prevalence of diabetes, coronary artery disease, vascular heart disease, arrhythmias, and alcoholism were 43.4%, 35.5%, 19.3%, 11.4%, respectively [Table 2].{Table 2}

Concerning the heart failure treatment, the majority of patients were on beta-blockers and aspirin 96.9% and 86.4%, respectively. Except those who could not tolerate the medicines, 29.8% were on spironolactone, only ~1.3% was on digoxin. Furosemide users were 56.6% and 36.4% wearing a defibrillator [Table 3]. There is no statistically significant link between the improvement in EF and other comorbid conditions or heart failure treatment. More than 2/3 (177 out of 228) of the participants were blacks. However, the higher percentage of improvement (71%) was shown among non-blacks or non-Caucasians). Patients without a history of hospitalization showed better post-treatment EF improvement than those with one or more hospital admission [Table 4].{Table 3}{Table 4}

 Discussion



Congestive heart failure affects around 2% of population aged > 18 years in the developed countries, approximately five million in the US alone.[1],[2],[3] Chronic heart failure is associated with high morbidity and mortality.[9],[10],[11] In the United States alone, 5-year mortality rate is 50%, and heart failure is the reason for more than one million hospitalizations each year, with high re-admissions rate.[1],[12] For a long time, ACEIs, β-adrenergic receptor antagonists and mineralocorticoid/aldosterone receptor antagonists have been the backbone of therapy for HFrEF, because of their benefits on morbidity and mortality.[3] However, the introduction of sacubitril/valsartan is a new era with even more reduction in mortality, morbidity, and hospitalization among heart failure patients with reduced EF.[4],[5]

Sacubitril is a neprilysin inhibitor, and valsartan is an angiotensin receptor blocker. The combination of sacubitril and valsartan inhibits neprilysin (neutral endopeptidase) via LBQ657, the active metabolite of the pro-drug sacubitril, and blocks the angiotensin II type-1 receptor via valsartan.[13],[14] Through a multi-mechanism action and at different receptor levels, sacubitril combined with valsartan enhances the neurohormonal response of the myocardium, in the same time blocking the renin-angiotensin-aldosterone devastating effect and halting the remodeling process.[15]

Our study highlighted the effect of the sacubitril/valsartan in the real EF value, demonstrating a calculated value to judge the efficacy of this drug. Improvement in EF was found to be associated with lower mortality in HFrEF patients. Kramer et al.[16] conducted a meta-analysis of over 69,000 patients and reported that improvement in left ventricular ejection fraction (LVEF) was associated with lower rates of mortality among patients with HFrEF. Of interest, there are only a few studies in the literature studying the direct effect of sacubitril/valsartan on EF, although sacubitril/valsartan effect on enhancing the mortality in HFrEF is always the reported outcome in most of the previous studies. Our study aims to document the effect of this new novel medication in the EF narrative value, and it is clinically implication. Out of the 228 of our study patients, 117 patients (51.3%) showed an objective improvement, which was defined by our study as a 10–15% increase in the baseline EF.

PARADIGM-HF trial[7] is the largest RCT to assess sacubitril/valsartan efficacy in comparison to the standard treatment. Patients enrolled in the trial were adults (age ≥ 18 years) with NYHA class II–IV symptoms, an EF of ≤ 40% and a plasma B-type natriuretic peptide level of ≥ 150 pg/mL (or N-terminal B-type natriuretic peptide level ≥ 600 pg/mL) or a B-type natriuretic peptide ≥ 100 pg/mL (or N-terminal B-type natriuretic peptide ≥ 400 pg/mL) if hospitalized for heart failure in the previous year to the study. However, the trial was terminated prematurely (after 1251 deaths from cardiovascular causes) because of a statistically compelling benefit with sacubitril/valsartan compared with enalapril alone for the primary endpoint (cardiovascular death or hospitalization for HF exacerbation). The PARADIGM-HF 7 concluded significantly fewer patients on sacubitril/valsartan either died from cardiovascular causes or were hospitalized for worsening heart failure (primary endpoint) than patients on enalapril, representing a 20 % reduction in the risk of the primary endpoint (21.8 vs. 26.5 %; hazard ratio: 0.80; 95% CI, 0.73–0.87, P < 0.001). However, this trial is not without criticism, especially in regards to the trial population, who were predominantly white (66%), male (78%), and NYHA functional class II HF (70%). Only 60 patients (< 1%) had NYHA functional class IV HF at baseline, and only 5% of the study population was black patients. These factors might reduce the external validity and generalizability of the data from this trial.

Around 78% of our study population is black patients, this group of patients are essential to include, so to generate data in the future might be a backbone for more significant meta-analysis studies that will consist of all population variation and produce results with high external validity and generalization. Another point to rising is that PARADIGM-HF trial population was mainly middle-aged with a mean age of 64 years. Our study includes more age groups with a mean age of 59.2 ± 11.7 years, giving the fact that HF patients are usually older. However, our study is just a descriptive study to report a noticeable EF improvement before and after sacubitril/valsartan treatment.

In the study of Almufleh et al.,[17] 48 patients with HFrEF were treated with sacubitril/valsartan, there was an increase in the mean EF of 5.09 ± 1.36% in the medium/high sacubitril/valsartan dose cohort, and 4.03 ± 3.17% in low dose cohort, respectively. They concluded that sacubitril/valsartan was found to improve LVEF above and beyond the effect of pre-existing optimal medical therapy. It was the first study to describe improvements in LVEF after treatment with sacubitril/valsartan. Our study agrees with the study of Almufleh et al.[17] showing EF improvement following sacubitril/valsartan treatment. Our results regarding improved EF also go in line with the study of Suematsu et al.,[18] their mice-based study showed that statistically significant improvement in LVEF after sacubitril/valsartan treatment.

Our study has some limitations. First, the use of a database to quantify and compare EF before/after sacubitril/valsartan administration is prone to reporting and coding errors. Disparities in reporting and coding practice have been shown to significantly impact the reported incidence and outcome of conditions based on a database.[19] However, different database-based data have been used in a wide variety of medical subspecialties and considered a validated tool. Second, our study used a single center data, so the external validity of our results might not be enough to be generalized,[20] therefore more multicenter studies should be conducted to strengthen our study findings. Finally, most of our patients (77%) were blacks, so the results of our research should be managed with caution before applying for the general population.

In conclusion, sacubitril/valsartan has an exceptional therapeutic role in reducing mortality and rate of hospitalizations in heart failure with reduced EF patients. Our study analysis showed improvement of EF in one out of every two patients with HFrEF treated with sacubitril/valsartan, this result is independent of other risk factor and concomitant heart failure treatment. Further studies with more significant patient samples and a more diverse population are warranted to explore this subject and address our study question.

Additional file

Additional file 1: Ethical approval documentation.

References

1Group CTS. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435.
2Investigators S, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.
3Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651-1658.
4Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007.
5The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
6Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709-717.
7McMurray JJ, Packer M, Desai AS, et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16:817-825.
8Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147-239.
9O’Connor CM, Whellan DJ, Wojdyla D, et al. Factors related to morbidity and mortality in patients with chronic heart failure with systolic dysfunction: the HF-ACTION predictive risk score model. Circ Heart Fail. 2012;5:63-71.
10Angermann CE, Stork S, Gelbrich G, et al. Mode of action and effects of standardized collaborative disease management on mortality and morbidity in patients with systolic heart failure: the Interdisciplinary Network for Heart Failure (INH) study. Circ Heart Fail. 2012;5:25-35.
11Nassar AI, Hasaneen AG, Alshikha MA, Enany BE. Three months morbidity and mortality of newly diagnosed systolic heart failure patients after their first admission. J Clin Exp Cardiol. 2012;3:183.
12Ziaeian B, Fonarow GC. The prevention of hospital readmissions in heart failure. Prog Cardiovasc Dis. 2016;58:379-385.
13Entresto (sacubitril and valsartan) tablets [prescribing information]. East Hanover, NJ: Novartis; 2015.
14Fala L. Entresto (Sacubitril/Valsartan): First-in-class angiotensin receptor neprilysin inhibitor FDA approved for patients with heart failure. Am Health Drug Benefits. 2015;8:330-334.
15Langenickel TH, Dole WP. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discov Toda y.2014;9:e131-139.
16Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. 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: a meta-analytic approach. J Am Coll Cardiol. 2010;56:392-406
17Almufleh 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. 2017;7:108-113.
18Suematsu Y, Miura S, Goto M, et al. LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice. Eur J Heart Fail. 2016;18:386-393.
19Lindenauer PK, Lagu T, Shieh MS, Pekow PS, Rothberg MB. Association of diagnostic coding with trends in hospitalizations and mortality of patients with pneumonia, 2003–2009. JAMA. 2012;307:1405-1413.
20Khorsan R, Crawford C. How to assess the external validity and model validity of therapeutic trials: a conceptual approach to systematic review methodology. Evid Based Complement Alternat Med. 2014;2014:694804.