Effect of Angiotensin Receptor-Neprilysin Inhibitor versus Valsartan on Cardiac Status in Patients with Chronic Heart Failure with Reduced Ejection Fraction: A Randomized Clinical Trial in Rangpur Medical College Hospital,

Background: Heart failure with reduced ejection fraction has a significant association with considerable morbidity and mortality, but there is still in-adequacy in appropriate treatment to prevent this condition. We observed the effect of angiotensin receptor neprilysin inhibitor (ARNi) with such disorder compared to valsartan. Methods: In this single-blind trial, the patients were enrolled with chronic HF aged on or above 40 years, symptomatic NYHA class II - IV, an elevated NT-proBNP above 400 pg/ml level and a reduced LVEF of 40% or less. The patients were randomly assigned 1:1 to the treatment arms either ARNi (50 mg titrated to 100 mg twice a day) or valsartan (40 mg titrated to 80 mg twice a day) and followed for a median of 88 days. The primary outcome was mode of cardiovascular death and re-hospitalization for heart failure. Changes in the level of NT-proBNP and rate of ejection fraction were also measured. Results: Cardiovascular deaths occurred 4 (8%) in the ARNi treatment arm, while 11 (22%) in the valsartan treatment arm with significant hazard ratio in the ARNi group [Hazard Ratio = 0.37; 95% CI: 0.34, 0.64; p = 0.042] during a median of 88 days of follow up period and 2 (4%) of the patients from the ARNi treatment arm were hospitalized due to HF, while in the valsartan treatment arm, 95% level of significance (p < 0.05). These effects resulted from somewhat increased in LVEF (30.4% ± 6.7% to 38.8% ± 8.1%) and intensely decreased in NT-proBNP (3066.5 ± 1882.1 pg/ml to 808.2 ± 592.5 pg/ml) in the ARNi group, as compared to valsartan group in LVEF (30.6% ± 6.0% to 35% ± 7.9%) and in NT-proBNP (3488.2 ± 2912.2 pg/ml to 1886.4 ± 1017.8 pg/ml). Conclusion: Chronic treatment with the angiotensin receptor neprilysin inhibitor (ARNi) strongly decreases the NT-proBNP as well as morbidity and mortality and increases LVEF in patients with heart failure compared to valsartan.


Introduction
Heart failure (HF) is generally observed as clinical observation caused by different kinds of cardiac diseases [1]. The prevalence of HF has steadily been increasing in recent years and this trend is expected to continue due to a growing aging population with more cardiovascular risk factors [2] [3]. Heart failure with reduced ejection fraction responsible for 50% of the conditions [4] is complicated by means of considerable morbidity and mortality [5] [6]. Previously, a lot of clinical trials were conducted with the pharmacological treatments including β blockers [7] calcium-channel blockers [8] angiotensin-converting enzyme inhibitors (ACEi) [9] and angiotensin receptor blockers (ARBs) [10]. But it was not able to demonstrate absolute benefit as expected.
For patients with HF with reduced ejection fraction (HFrEF), no therapy has proven to be effective at reducing morbidity and mortality [11]. Consequently, there is an urgent need for new safe therapies to prevent and treat HFrEF. Angiotensin receptor neprilysin inhibitor (ARNi) is the new drug class and unprecedented scientifically which forms one compound with molecular moieties of the neprilysin (neutral endopeptidase 24) [11] inhibitor prodrug AHU377 and the ARB valsartan [12]. Enzymatic cleavage absorbs AHU377 to sacubitril at (LBQ657), the active inhibitor of neprilysin.
Except for biologically inactive NT-proBNP, biologically active natriuretic peptides as well as atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide are degraded by Neprilysin [13]. Assays for BNP and NT-proBNP which are both natriuretic peptide biomarkers, have been used increasingly to establish the presence and severity of HF. proBNP (108 amino acid) cleavage into NT-proBNP (76 amino acid) & BNP (32 amino acid).
Notably, BNP but not NT-proBNP, is a substrate for Neprilysin; therefore, ARNi increases BNP level but not NT pro-BNP level. In two studies with ARNi, NT-proBNP level was reduced. With the reduction of NT-pro-BNP in one study had associated with an improved clinical outcome. New data suggest that natriuretic peptide biomarkers screening and early intervention may prevent heart failure [11] [12] [13].
The Dual inhibition of ACE and neprilysin was connected with serious angioedema [14] [15] [16]. LCZ696 which consists of the neprilysin inhibitor Sacubitril (AHU 377) and the ARB was designed to minimize the risk of serious angioedema and fully additive reduction of blood pressure [17] [18]. There are no head to head comparisons of an ARB versus ARNi for HF. The current study will evaluate whether the short-term effects of ARNi on morbidity and mortality were superior to those of Valsartan in patients with chronic heart failure with reduced ejection fraction.

Study Design and Patient's Selection
We conducted a single-blind randomized controlled trial at the Department of  • Any prior measurement of LVEF < 40%.
• Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months, or urgent percutaneous coronary intervention within 3 months or and elective PCI within 30 days prior to entry. • Any clinical event within the 6 months prior to entry could have reduced the LVEF (e.g., MI, CABG), unless an echo measurement performed after the event confirms a LVEF ≥ 45%.
• Current acute decompensated HF requiring therapy.
• Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor. In this single-blind trial, the patients were enrolled with chronic HF aged on or above 40 years, considering based on NYHA class II -IV and LVEF 40% or less. Moreover, NT-proBNP was required to have 400 pg/ml or larger among the patients. In view of inclusion and exclusion criteria, 100 patients with heart failure were randomly assigned 1:1 to the treatment arms either angiotensin receptor neprilysin inhibitor (ARNi) or valsartan through purposive sampling technique and followed for a median of 88 days. The study was approved by ERC (Ethical Research Committee) and IRB (Institutional Review Board) of Rangpur Medical College authority, Rangpur, Bangladesh. The study was approved in April, 2018. All of the subjects were required to receive written informed consent prior to be included in the study. Each patient was prospectively included in the intention-to-treat analysis and study ended on March 3, 2019. days or at early termination of visits by Getein 1100 immunofluorescence Quantitative Analyzer. Level of blood sugar, serum creatinine, eGFR (estimated glomerular filtration rate) and level of serum electrolytes were also examined at baseline, 30 days and 90 days or at early termination of visit or end of the study [19]. To define the functional capacity, the New York Heart Association (NYHA) functional classification (I, II, III, IV) was used.

Procedures
Based on New York Heart Association (NYHA) Classification: 1) Class I-No symptoms and no limitation in ordinary physical activity, e.g.
shortness of breath when walking, climbing stairs etc.
2) Class II-Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity.
3) Class III-Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20 -100 m). Comfortable only at rest. 4) Class IV-Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 5) No NYHA class listed or unable to determine. The clinical composite assessment was done in accordance with the NYHA functional classification, patient-reported outcomes (PROs) or major adverse clinical events (or both) [20]. The patients were considered as improved based on improvement in NYHA functional classification or patient-reported outcomes (PROs) and no major cardiovascular event was reported. In contrast, at the endpoint of follow up, the patients who did have a major cardiovascular event or deteriorating of their NYHA class or patient-reported outcomes (PROs) during this single-blind treatment were adjudicated to be inferior. The primary outcome was mode of cardiovascular death and rate of hospitalization for heart failure or overall mortality.

Statistical Analysis
A total 100 patients were randomly assigned through system generated block randomization into two comparison treatment arms, considering 80% power and at 5% level of significance, to perceive 25% in the ratio of the NT-proBNP at a median of 88 days over baseline between ARNi and valsartan group, we used a two-sided t-test on the logarithm of this ratio (Table 1).

Patient's Demographic Information and Clinical Profiles
Finally, a total of 100 patients with chronic heart failure were recruited to equally distributed between two groups. The patients were predominantly male (67%).
The majority of patients reclined in the age group of (61 -70) years (32%). The most collective symptom was found to have shortness of breath (83%) followed by chest pain (61%). The trial found tobacco smoking/chewing (30%) as the major risk factor followed by hypertension and diabetes (25% each). The both treatment arms were well-adjusted with reference to patient's baseline characteristics.

Study Outcome
The primary endpoints, occurrence of cardiovascular deaths occurred 4 (8%) in the ARNi treatment arm, while 11 (22%) in the valsartan treatment arm with significant hazard ratio in the ARNi group [Hazard Ratio = 0.37; 95% CI: 0.34, 0.64; p = 0.042] during a median of 88 days of follow up period (Table 2(a) and Figure 2). 2 (4%) of the patients from the ARNi treatment arm were hospitalized due to HF, while in the valsartan treatment arm, 10 (20%) patients were hospitalized due to HF followed by receiving treatment respectively with hazard ratio in the ARNi group [Hazard Ratio = 0.80; 95% CI: 0.57, 0.92; p < 0.037] ( Table  2(a)). The secondary outcomes of the trial were to examine the differences of ejection fraction, NT-proBNP and e-GFR between two groups. A significant effect was found to have in both ejection fraction and NT-proBNP at 95% confidence interval (p < 0.05). These effects resulted from somewhat increased in ejection fraction (30.4% ± 6.7% to 38.8% ± 8.1%) and intensely decreased in NT-proBNP (3066.5 ± 1882.1 pg/ml to 808.2 ± 592.5 pg/ml) in the ARNi group, as compared to valsartan group in LVEF (30.6% ± 6.0% to 35% ± 7.9%) and in NT-proBNP (3488.2 ± 2912.2 pg/ml to 1886.4 ± 1017.8 pg/ml) respectively (Table 2(b)).
But no evidence of differences was found to have between the ARNi and valsartan groups with respect to the other echocardiography measurements (LA Diameter, p-value 0.53; LVIDD. p-value 0.78; LVIDS and p-value 0.50) except ejection fraction at a median of 88 days of follow up (Table 3). Similarly, the ARNi and valsartan groups did not differ with regard to the blood sugar (p-value = 0.38), potassium (K) (p-value = 0.23) and chloride (Cl) (p-value = 0.68) but sodium (Na) (p-value = 0.028) of serum electrolytes demonstrated the significance difference between ARNi and valsartan groups.

Adverse Event during Treatment
In the ARNi group, 2 patients (4%) were re-hospitalized followed by receiving treatment while ratio of re-hospitalized increased to a greater extent in the valsartan group, 10 patients (20%) (p-value = 0.014). No adverse effect was found in the ARNi group 0 (0%) with respect to renal impairment but in the valsartan group 4 patients (10.26%) did have the abnormal (≥2.5 mg/dl) level of serum creatinine (p-value = 0.026) ( Table 5). The number of patients with elevated potassium or elevated blood sugar did not differ between the groups.

Discussion
The study revealed that participated patients with chronic heart failure by means of reduced ejection fraction, the angiotensin receptor neprilysin inhibitor (AR-Ni) was to a greater extent effective in dropping the risk of cardiovascular deaths and re-hospitalization resulting from heart failure than did valsartan followed by a median of 88 days. ARNi was also found as superior in powerfully reducing NT-proBNP and increasing ejection fraction compared to valsartan which was consistent with a few studies previously conducted [21] [22]. The results of these extensive benefits of angiotensin receptor neprilysin inhibitor compared to valsartan were found to have a strong significant effect. In the ARNi group, improvement of NYHA class was significant compared to valsartan. To inhibit deteriorating of clinical condition in patients with heart failure, previously conducted few trials have reported advances in exercise tolerance or functional class or reductions in the risk of hospitalization for heart failure [23] [24]. In accordance with these generated findings, this trial recommends that the patients of heart failure with reduced ejection fraction have a greater chance of having a beneficial effect who receive ARNi. In patients with this disorder, further testing of this composite could be justified. Current treatment of heart failure with reduced ejection fraction is continued through both symptom-based and empiric without acceptance of specific treatment for this indication [25]. Even though ACE inhibitors and ARBs have the evidence improving the symptoms, increasing the functional capacity and reduction of hospitalization in patients with this condition [9] [10]. Existing guidelines announced that to decrease morbidity or mortality, current treatment could not show the credibility [26].
Our study aimed to reveal the credible evidence in management of cardiovascular diseases with ARNi in adding with existing treatment. This study observed a benefit with regard to reduce cardiovascular mortality, was one of our primary endpoints which were met by the study ( Table 4).
The patients who received ARNi did have consistently much lower levels of NT-proBNP (reflecting reduced cardiac wall stress) all over the trial in comparison with valsartan which is consistent with the evidence previously reported [27]. NT-proBNP is an indicator of left ventricular tension and decreases in NT-proBNP were associated with better-quality outcomes in patients with heart failure, which was our secondary outcome and achieved expectedly. ARNi was found sound endurable as a whole and its adverse-effect profile was less frequent in comparison with valsartan in this study. Fewer patients of the study participants underwent the adverse events in the ARNi with respect to re-hospitalization and no adverse event was found in regard to renal impairment while in the valsartan group, significant increase in the level of serum creatinine (≥2.5 mg/dl) and re-hospitalization was more frequent (Table 5). This outcome of ARNi on renal impairment is found consistent in the experimental studies [28] [29]. Biomarkers and substitute endpoints were the major determinants for this result of the study, whether the experimental outcomes will interpret into better clinical consequences need to conduct further prospective testing in an appropriately sampled outcomes study.
Limitation of the Study: The study had a limitation on sample size. Based on geographic consideration and traditional perspective, study sample size was limited.

Conclusion
Chronic treatment with the angiotensin receptor neprilysin inhibitor (ARNi) significantly decreases the progressive NT-proBNP, slightly changes sodium (Na) and e-GFR levels [30]. ARNi also increases ejection fraction including decreasing the risks and rates of a number of indicators of clinical worsening of enduring patients with heart failure compared to valsartan. As a result, ARNi has a greater impact on reducing morbidity and mortality in patients with chronic heart failure than valsartan. Besides the treatment effect of ARNi, it steady the progression of heart failure is likely to have significant effect for quality of life in this disorder.

Sponsor
General Pharmaceuticals Limited, Bangladesh.