Asian nations have a 1.3–6.6% prevalence of heart failure (HF), which rises with increasing age [1]. The use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers (ACEIs/ARBs) for heart failure (HF) has been demonstrated in several trials to reduce overall mortality by 16–40% [2-4]. For this reason, ACEIs and ARBs constitute an essential part of medical therapy for HF that is guided by guidelines and diagnosed with symptoms [5, 6]. The PARADIGM-HF research found that sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, reduced ejection fraction (HFrEF) and decreased hospitalization and mortality risks for HF patients [7]. Consequently, the 2022 AHA/ACC/HFSA guideline suggests that patients with New York heart association (NYHA) class II or III symptoms and chronic symptomatic HFrEF should be switched to sacubitril/valsartan if they tolerate an ACEI or ARB due to improvements in echocardiographic parameters, morbidity, and mortality [8, 9].

Patients with heart failure often have renal impairment, which is linked to unfavorable results [10]. The term "cardiorenal syndrome" (CRS) refers to a group of conditions that affect the heart and kidneys. Acute or chronic dysfunction in one organ can lead to acute or chronic dysfunction in the other organ. The Acute Dialysis Quality Initiative consensus conference divided CRS into five categories: acute CRS, chronic CRS, acute renocardiac syndrome, chronic renocardiac syndrome, and secondary CRS [11, 12].

HF continues to be a major cause of morbidity and death even with a number of neurohumoral blocking medications. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved Sacubitril/Valsartan, a novel combination medication that contains an angiotensin receptor blocker (ARB) (Valsartan) and a neprilysin inhibitor (Sacubitril) angiotensin receptor/neprilysin inhibitor (ARNI), for the treatment of patients with heart failure (HFrEF) with reduced ejection fraction [7-9]. There was another paradigm shift in HF therapy after the publication of the PARADIGM-HF research in 2014 [10]. The use of ARNI reduced cardiovascular mortality by 20% and all-cause mortality by 16% when compared to enalapril.

This study found that the evidence-based guidelines for the management of heart failure (HF) were recently amended by the European Society of Cardiology (ESC), the American College of Cardiology (ACC), and the American Heart Association (AHA) [7-9]. Sacubitril/Valsartan was indicated as a class I indication in both clinical practice recommendations for patients who had decreased ejection fraction (HFrEF) and persistent HF symptoms while receiving optimal treatment.

MATERIALS AND METHODS The current open label non-randomized clinical trial was carried out at the Cardiology department Loralai Medical College by including a total of 101 patients.. Sacubitril and Valsartan were prescribed to patients with HF/HFrEF, and they were monitored for 06 months to determine the impact of this combination on patient heart failure. In compliance with the Declaration of Helsinki, a clinical trial was conducted. The study commenced following approval from ethical review committee. Written informed consent was obtained from all patients regarding their participation in the study and the publication of data, with confidentiality and anonymity guaranteed. For this study, the necessary number of consecutive patients who satisfied the inclusion criteria were included. The patient's demographic information and baseline clinical features were acquired upon the receipt of signed informed permission. The study's inclusion requirements are any gender, age range of 18 to 80 years, diagnosis of HF/HFrEF with left ventricular ejection fraction (LVEF) < 40%, and New York Heart Association (NYHA) class II–IV. Patients who were stable on any dosage of beta blockers, ACEI, or ARB before enrolling in the trial satisfied the pre-inclusion safety criterion. Individuals who declined to partake in the investigation, as well as those with hyperkalemia (baseline potassium  > 5.2 mmol/L), hypotension (baseline systolic blood pressure (SBP)  < 90 mmHg), renal impairment (baseline estimated glomerular filtration rate (eGFR)  < 30 mL/min), anemia (baseline hemoglobin level: < 13.5 g/dL in men and < 11.0 g/dL in women), and a history of hypersensitivity to the study's active ingredients, Sacubitril/Valsartan, or any excipients or medications of comparable chemical classes. Patients with a history of previous heart failure hospitalization, anticoagulant use, receiving sodium/glucose cotransporter-2 inhibitors (SGLT2i) therapy, or having an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) device met the pre-recruitment initial screen criteria. These patients were excluded from the research due to their possible confounding influence. Sacubitril/Valsartan was prescribed to all enrolled patients at a beginning dose of 50 (24/26) mg BID. Over the course of the first six weeks, the dose was up-titrated to the maximum tolerated level of 200 (97/103) mg BID, and the patients were then monitored for an additional twelve weeks. A weekly phone follow-up was conducted to evaluate the patient's degree of medication compliance and any untoward incidents. For a duration of 12 weeks, every patient was closely monitored, and the safety and tolerability of the results were evaluated. The analysis of the collected data was done with SPSS version-24. For the quantitative (continuous) variables, such hemodynamic parameters, laboratory parameters, and echocardiographic parameters, as well as paired samples, mean ± standard deviation (SD) was calculated. A t-test was used to compare assessments from the baseline and the 12th week. Using the Chi-square test, the NYHA classification was compared at the beginning and completion of the 12-week therapy period. For categorical variables like tolerability and safety precautions, frequency and percentages were computed. The Chi-square test and Fisher's exact test were used to compare the findings for different patient baseline characteristics.

Baseline Demographics

The trial included 101 patients in all who met the eligibility requirements and had a successful 12-week follow-up. The research patients had a mean age of 53.12 ± 10 years, and 75 out of the 101 patients were male. In contrast, the study population's comorbidities included 45.5% (46) hypertension, 56.4% (57) diabetes mellitus, and 66.3% (67) coronary artery disease (table 1).

Table 1: baseline demographic characteristics

Clinical Characteristics

Together with a considerable increase in systolic dimensions, a significant improvement in left ventricular EF was also noted, rising from 25.60 ± 6.55% at baseline to 34.11 ± 9.96% following a 12-week course of treatment. Additionally, a comparison of laboratory and hemodynamic data was provided in (Table 2)

Table 2: Comparison of parameters related to HF at baseline and after 12 weeks

After 12 weeks of therapy, there was a substantial improvement (p = 0.011) in the NYHA function class; at baseline, the majority of patients (75.2%; 76) were in class I, whereas at 12 weeks, the majority (70.2%; 71) were in class II (Table 3).

Table 3: comparison of NYHA functional classes at baseline and after 12^th week

Even though HFrEF treatment has greatly improved recently, it is still the leading cause of morbidity and death for cardiac patients. Sacubitril/Valsartan is a class I indication in patients with HFrEF [7-9] due to the positive outcomes of several clinical studies [10–12]. However, because of its two modes of action, it can be a useful combination for the treatment of heart failure. Since the advantages of sacubitril/valsartan did not approach statistical significance in the Asian sub-group of the PARADIGM-HF study, there is still debate on the drug's effectiveness in Asian HF patients [13]. Thus, the purpose of the current study was to investigate the impact of the combination of sacubitril and valsartan on mortality in Pakistani patients suffering from heart failure. A markedly better functional class was also observed after 12 weeks of observation, with 75.2% of patients in class I, 23.8% in class II, and only one patient (0.99%) in class III at the conclusion of the 12-week period. The most common safety issue among South Asian HF patients receiving Sacubitril/Valsartan in the PARADIGM-HF research was hypotension, which occurred in 10.5% of cases, followed by hyperkalaemia in 8.9% and angioedema in 0.3% [13]. Because of the higher corresponding incidence rates in our research compared to PARADIGM-HF, which may be due to physical variations in the Asian population, such as smaller stature and lower body weight, lower medication dosages are recommended for them [14, 15]. When compared to enalapril, the PARALLEL-HF research found that Sacubitril/Valsartan was safe and well-tolerated in Japanese patients with HFrEF [16–17]. The tolerability of sacubitril/valsartan in certain patients can be improved by a systematic titration based on patient physical and laboratory examination and close monitoring. Among these patients, we observed an increase in vertigo complaints, as well as symptomatic elevations in creatinine and potassium levels. Sacubitril/Valsartan tolerability in real-world clinical settings can be influenced by a number of patient- and system-related variables, including race, age, and co-morbid diseases, as well as by the availability or accessibility of the healthcare system. The PREDICT-HF model was found to be a helpful clinical model for risk assessment of patients with HFrEF in a research by Hsu et al. [18]. A number of recent studies have shown that Sacubitril/Valsartan is safe and effective when used in real-world patient trials with HFrEF. In a study by Armentaro et al. [19], it was found that during a 2-year follow-up of 60 patients, Sacubitril/Valsartan therapy improved the NYHA functional class with improvements in renal function, NT-proBNP levels, and several hemodynamic, clinical, and echocardiographic parameters. Armentaro et al. [20] documented a possible therapeutic function for Sacubitril/Valsartan treatment in patients with HFrEF who also had metabolic co-morbidities in another trial. Over the course of the 12-month follow-up period, a consistent metabolic improvement has been noted in addition to functional and echocardiographic improvements [20]. The primary limitations of our investigation were the prospective clinical study in the Pakistani population, the experience of a single facility, the absence of a control group, and the small sample size. The little follow-up period continued to be a significant drawback given the chronic nature of the illnesses. More extensive multicenter randomized trials with extended follow-up periods are required to clarify the effect of sacubitril/valsartan in Pakistani patients with HFrEF.

In conclusion, Pakistani population heart failure patients receiving sacubitril/valsartan medication showed stable hemodynamic parameters, a marked improvement in left ventricular function, and a considerable improvement in NYHA function class. Therefore, it reduces the cause of HF-related morbidity and mortality and can be utilized as the first line of treatment for individuals having risk of HF.

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