European Journal of Cardiovascular Medicine

Heart failure with reduced ejection fraction (HFrEF) is a chronic and progressive clinical syndrome characterized by a weakened left ventricle (LV), which fails to pump blood efficiently and results in reduced ejection fraction (EF)(1,2). As per European Society of cardiology (ESC) heart failure (HF) guidelines, HF has been categorized into three main HF conditions centered on the measurement of left ventricular ejection fraction (LVEF). The HF with preserved EF (HFpEF) has a LVEF of 50% or higher, the HF with midrange EF (HFmrEF) has a LVEF of 41-49% whereas HFrEF has a LVEF of 40% or lower (3,4). The ESC guidelines suggest patients with HFrEF to be treated by quadruple therapy, i.e. Angiotensin receptor blocker/neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose co-transporter 2 inhibitors (SGLT2i), making them the first-line therapy (4,5). Sacubitril/Valsartan, an ARNI, has been approved by the Food and Drug Administration (FDA) in 2015 for the treatment of patients with HF and has since then notably altered the clinical course of patients with HFrEF (6). Several clinical studies have established that sacubitril/valsartan improves myocardial function in HFrEF patients significantly increasing the LVEF(7,8).

LVEF is the most commonly used measure of myocardial function indicating the percentage of blood ejected from the LV per cardiac cycle. LVEF is measured via two-dimensional (2D) electrocardiography and  is a volumetric parameter that is affected by the ventricular loading and falls short in detecting early myocardial dysfunction (9). 2D-speckle tracking echocardiography (STE) is a novel technique used to evaluate the myocardial function and contractility using global longitudinal strain (GLS)(10,11). GLS is considered as a more sensitive and reliable measure of LV systolic dysfunction than LVEF because it is independent of the ventricular loading, can detect early myocardial impairment and identify subclinical myocardial dysfunction in a high-risk population of HFrEF (12). In a recent study, the myocardial function of HFrEF patients at baseline, 3 months, and 6 months post-treatment of sacubitril/valsartan using LVEF and GLS was evaluated. While LVEF displayed significant improvement only at 6 months, GLS revealed a progressive improvement as early as 3 months, with continued augmentation at 6 months (13). This ascertained the superiority of GLS evaluation over LVEF in detecting early contractile improvements and LV remodeling, rendering it a sensitive tool for observing the early benefits of ARNI therapy in HFrEF patients.

The sacubitril/valsartan combination was originally developed by Novartis and marketed in India by JB Chemicals under the brand name Azmarda. Azmarda utilizes a patented polymorphic co-crystal technology, which has been recognised for its unique pharmaceutical properties. This cocrystal formulation is the one that has been tried and proven effective in RCTs. In contract, generic manufacturers of sacubitril/valsartan cannot utilize the patented co-crystal technology and therefore, cannot imitate the associated formulation advantages. Consequently, several pharmaceutical companies have adopted alternative strategies to formulate sacubitril/valsartan, including the use of fixed-dose combinations (FDCs) through different manufacturing processes. A recently published article demonstrated that the co-crystal formulation of Azmarda exhibits superior physicochemical properties compared to various generic formulations, particularly in terms of dissolution profile, thermal stability, optimized sodium content and distinctive crystal lattice structure. These attributes may influence the clinical efficacy and safety of sacubitril/valsartan-containing formulations in patients with heart failure with reduced ejection fraction (HFrEF) (14).

While, the advantage of co-crystal technology of Azmarda has been well established in in-vitro settings and clinical studies, the efficacy and safety of generic formulations in human subjects needs to be evaluated. Therefore, the current study is the first of its kind to evaluate the efficacy and safety of Azmarda (innovator sacubitril/valsartan) compared to generic sacubitril/valsartan in patients with HFrEF using GLS as a key assessment parameter

Study Design

The present investigator-initiated clinical study was designed as a prospective, randomized, crossover, single-center, and active-controlled study aimed to evaluate the efficacy and safety of Azmarda (innovator Sacubitril /Valsartan) in comparison with generic Sacubitril/ Valsartan in patients with HFrEF. The study has been registered in the Clinical Trials Registry - India (CTRI) under the registration number CTRI/2024/09/074204.

Patient Population

A total of 12 patients with HFrEF were enrolled in the present pilot study. Patients with a confirmed diagnosis of HFrEF (LVEF) ≤40%) and HFrEF patients having a GLS Score of >- 15, and those who are on stable doses of beta blockers, mineralocorticoids, and/or SGLT2 inhibitors since the last 4 weeks of either sex aged between 18-75 years without previously been treated with Sacubitril/Valsartan were included in the study. Patients were excluded for any of the following reasons: moderate renal impairment (eGFR <60 mL/min/1.73 m²), significant liver disease (Child-Pugh B or C), uncontrolled hypertension (BP>160/100 mmHg), usage of Sacubitril/Valsartan within the last 4 weeks, current usage of other concomitant medications known to interfere with Sacubitril/Valsartan or medication prohibited as per protocol, hypersensitive or allergic to Sacubitril/Valsartan, pregnant or lactating females, participation in another clinical study within last 30 days before screening.

Study flow, Screening, and Randomization. 

In the present study, patients with a known diagnosis/symptoms of HFrEF, those who were on stable doses of beta blockers, mineralocorticoids and / or SGLT2 inhibitors and eligible for ARNI therapy were screened on visit 1. A 2D STE was performed to assess the left ventricular GLS score and LVEF to evaluate cardiac function and determine eligibility for study participation. On the same visit, the eligible participants were then randomly allocated into the following 2 study groups, according to the centralized computer-generated randomization plan in an approximately 1:1 ratio. Azmarda (innovator sacubitril/valsartan) and Generic sacubitril/valsartan group. As the study was designed to follow a crossover design, after randomization, each patient received one formulation for the first 8 weeks and then switched to the alternate formulation for the remaining 8 weeks. All the patients in the Azmarda (innovator sacubitril/valsartan) and Generic sacubitril/valsartan groups were instructed to take assigned medication twice daily (BID) (one in the morning and one in the evening) by the oral route as per the approved package insert of the product. Patients were followed up on an outpatient basis with scheduled visits at the end of Week 4 (Visit 2 - Follow-up), Week 8 (Visit 3 - Crossover), Week 12 (Visit 4 - Follow-up), and Week 16 (Visit 5 - End of Study). At every visit, all the patients underwent a thorough clinical evaluation including recording of vital signs, BP, pulse rate, respiratory rate, oxygen saturation, and systemic examination, along with a comprehensive 2D-STE analysis to evaluate left ventricular function and measure the GLS score at each visit throughout the study. The urine pregnancy test was performed in females of childbearing potential on visit 1. Any Adverse events (AEs) occurring during the follow-up period were documented (Figure 1).

Figure 1. Study Flow

Study Assessment

Assessment of Efficacy

GLS score is calculated to detect subtle myocardial deformation, providing earlier and more accurate detection of systolic dysfunction. Moreover, Average Time to Peak (TTP) is calculated to assess the time taken for myocardial segments to reach the peak strain during ventricular systole reflecting myocardial contractility and efficiency. The clinical efficacy was evaluated by measuring the GLS score and TTP values at the end of Week 4, Week 8, Week 12, and Week 16 from baseline in the two groups. Change in the GLS score and TTP value of both the groups, recorded at weeks 4 and 8 was compared to baseline, and that recorded at week 12 and 16 was compared to the GLS score recorded at week 8.

Assessment of Safety

The safety of the study medication was assessed by recording the adverse events that occurred during the study. All abnormalities found in the physical examination (including vitals) were dealt with as adverse events.

Statistical Analysis

The data is presented as mean ± SD/SE or number (percentage). Change in GLS parameters was compared in the two groups using an unpaired T-test. A p-value of <0.05 was considered statistically significant.

Ethical Considerations

The study protocol was approved by the Institutional Ethics Committee (IEC). Written informed consent was obtained from all participants before screening, and the confidentiality of patient data was maintained throughout the study. The study adhered to the principles of the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines.

Between September 2024 and October 2024, a total of 12 patients were enrolled in the study and assessed for their eligibility for randomization according to the inclusion and exclusion criteria of the study, the 12 eligible patients were randomly allocated to either Azmarda the Innovator group (N=6) or the Generic group (N=6). Patients of both groups received the assigned medication twice daily (BID) for the treatment duration of 16 weeks.

Baseline Demographics

The demographic and mean baseline characteristics of the enrolled patients are shown in Table 1. The mean age of the patient population (N=12) was 54.7 ± 6.5 years. The proportion of men was considerably higher than that of women, >75%. The basal metabolic index (BMI) values were 27.6 ±2.5. The concomitant medial history data revealed that all the patients had hypertension. Additionally, 58.3% had coronary artery disease (CAD), 41.7% had diabetes mellitus (DM) and 33.3% had dyslipidemia. The baseline background information revealed that beta blockers, ARB, and Diuretics were taken by all the enrolled patients. Further, SGLT2i, Aspirin, other antidiabetic medications and anti-hyperlipidemia medication were taken by 66.7%, 58.3%, 41.7 %, and 33.3 % respectively of the total population (Table 1).

Table 1: Demographic and baseline characteristics of the enrolled patients.

Effects of Study Drugs on left ventricular systolic function

The GLS scores as well along with TTP of all the patients in the study were recorded at every visit.  

The GLS score of both the arms

The mean GLS score at visits 1 (Baseline), 4, 8, 12, and 16 are shown in Figure 2 The mean GLS scores of the patients in the Azmarda (Innovator) and Generic groups were analyzed from baseline to every follow-up week (4,8,12, and 16). As shown in Figure 2, the mean GLS score of patients at baseline (visit 1) was -12.8 ± 1.7% in the Azmarda group and -13.1 ± 1.4% in the Generic group. As evident from Figure 2, Azmarda   group demonstrated better improvement in the mean GLS values compared to Generic group which showed a comparatively slower improvement over the course of treatment.

Further, the change in GLS score from baseline to weeks 4 and 8, and the change in GLS score from weeks 8 to 12 and 16 were estimated and presented in Table 2.  As shown in Table 2, the change in mean GLS score (from baseline to week 4) in the Azmarda group (-0.9±0.1%) was significantly higher than that recorded in the Generic group (-0.2±0.2%; P=<0.05). When the Change in GLS score was calculated from baseline to week 8, a significantly higher change of -1.7 ± 0.3% was observed in the Azmarda group as compared to that of the Generic group [-0.5 ± 0.1% (p<0.05)]. Further, the change in the GLS score of the patients from week 8 to weeks 12 and 16 was calculated. The change in the GLS score of patients in the Azmarda and Generic group was (-0.7 ± 0.2% vs. -0.2 ± 0.2%) at week 12 and (-1.4 ± 0.2% vs. -0.4 ± 0.1%) at week 16 (Table 2). The difference observed in the change in GLS score between the Azmarda and the Generic group at weeks 12 and 16 (P =<0.05) was statistically significant. These findings suggest that patients treated with the Azmarda showed greater improvement in the GLS values indicating enhanced myocardial function, compared to those treated with Generic sacubitril/valsartan.

Figure 2. Mean GLS score and change in GLS score: The mean GLS score of patients in the Azmarda group (N=6) and Generic (sacubitril/valsartan) group (N=6) at baseline, and week 4,8,12 and 16.

Table 2. The change in GLS score from baseline to weeks 4 and 8 and change from week 8 to weeks 12 and 16.

Change in the TTP score of both arms

The mean TTP values were analyzed from baseline to weeks 4 and 8 and from week 8 to weeks 12 and 16 in both study groups (Table 2). At baseline, the mean TTP score of patients in the Azmarda group (373.7 ± 102.3 ms) was higher than that of the Generic group (330.0 ± 44.1 ms, p=0.42). By week 4, both the groups displayed a reduction in the mean TTP scores with Azmarda group exhibiting a greater change in TTP score from baseline. At week 8, a further reduction in the mean TTP score was observed in the Azmarda group than in the Generic group with Azmarda group exhibiting a greater change in the TTP score. Following the crossover at week 8, the mean TTP score in the Azmarda group exhibited a significantly greater reduction (297.0 ± 13.7 ms) in contrast to an increased TTP score in the Generic group 347.6 ± 20.9 ms (p=<0.05) at week 12. The mean change in TTP score from weeks 8 to 12 suggested a significant declining trend in the Azmarda group (-20.6 ± 28.4 ms) in contrast to the increasing trend in the Generic group (+24.4 ± 25.7 ms, p=<0.05). By week 16 the mean TTP score continued to be significantly reduced in the Azmarda group (283.4 ± 16.7 ms) compared to an increase in the Generic group (352.2 ± 24.0 ms, p<0.05), with a change in mean TTP score of -34.2 ± 36.7 ms for Azmarda and +29.0 ± 25.3 ms for Generic (p<0.05).

Table 3: Change in the Average Time to Peak (TTP) score of both arms

Safety Assessments of both the arms.

During the study duration of 16 weeks, therapy with sacubitril/valsartan was well-tolerated and no serious adverse effects (AEs) occurred throughout the study in either of the arms.

In all the landmark studies to date, the innovator ARNI with its unique cocrystal formulation has been used and proven effective in patients with HFrEF. Therefore, the present prospective clinical study aimed to evaluate the efficacy of the Azmarda drug (innovator formulation of Sacubitril and Valsartan 24/26 mg) compared to the Generic sacubitril/valsartan in patients with HFrEF focusing on the impact on left ventricular systolic function using GLS score along with the TTP. Patients with HFrEF demonstrate impaired myocardial function that is often reflected by the remodeling of the left ventricle (LV) chamber. Given the clinical significance of the LV and its role in myocardial function, reverse remodeling of LV can be considered as a valuable strategy for estimating treatment response in patients with HFrEF.

In this study, the assessment of GLS score was selected as a predictor of global myocardial deformation, because it’s a more sensitive marker and makes a more precise prediction of myocardial dysfunction. Patients receiving sacubitril/valsartan exhibited measurable improvements in GLS, signifying enhanced LV contractile function. These findings are consistent with previous studies where the effect of Sacubitril/Valsartan on GLS has been extensively evaluated in patients with HFrEF displaying significant improvement in the myocardial function over different treatment periods. Bras et al. showed that sacubitril/valsartan therapy in HFrEF patients was associated with improved cardiac performance as indicated by a GLS improvement of -1.9 ± 0.2% after 6 months(15). Similarly, Moon et al. and Monosilio et al. observed a significantly pronounced improvement in GLS scores to ≥13% within 6 months of sacubitril/valsartan treatment leading to the left heart reverse remodeling (LHRR) involving improved myocardial contractility(16,17). Other teams of researchers, like Dattilo et al. and Elshafey et al., evaluated the long-term impact of Sacubitril/Valsartan on the cardiac performance, especially focused on the LV function and found the therapy to significantly improve the GLS score and hence myocardial functionality and efficiency (18,19).

Moreover, this study revealed that the patients treated with Azmarda displayed significant improvement in the left ventricular systolic function in patients with HFrEF compared to the patients treated with the Generic sacubitril/valsartan. This is indicated by the sustained and significant improvement in the GLS score that provides a global assessment of myocardial function in the patients of the Azmarda. Additionally, TTP values that epitomize the interval from the beginning of myocardial contraction to the point of maximum strain or the timing of peak myocardial deformation were also significantly reduced after cross-over in the Azmarda group compared to that of the Generic group. These improvements were more pronounced after the patients were transitioned from the Generic group to the Azmarda group, establishing the superiority of the Azmarda formulation. These findings are well supported with the literature, which shows a difference in the molecular structure between generic formulation and Azmarda (innovator formulation) of sacubitril/valsartan. The presence of the unique co-crystal lattice in Azmarda has been associated with the enhanced bioavailability, Optimal Sodium & Moisture content, superior thermal stability, and improved drug release profile and hence explain its superiority over generic formulation observed in this study and is associated with significantly improved myocardial contractile efficiency in the treated patients.

Collectively, the findings of this study indicate that the patients in the Azmarda group displayed significant improvements in LV function and cardiac performance. However, there is need for larger cohort studies with long-term follow up to validate these results and assess long-term clinical outcomes.

This randomized, crossover pilot study demonstrated that Azmarda, led to significantly greater improvements in GLS compared to the generic formulation in patients with HFrEF. This study establishes the superiority of Azmarda manufactured by unique co-crystal technology over generic formulation while displaying enhanced LV reverse remodeling in HFrEF patients and further highlight the value of GLS as a sensitive and reliable parameter for early detection of left ventricular systolic dysfunction.

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