European Journal of Cardiovascular Medicine

The recent publication by Patel S. (1) in the European Journal of Cardiovascular Medicine presents paradigm-shifting preliminary evidence that fundamentally challenges long-held assumptions about therapeutic equivalence between innovator and generic drugs in heart failure management. Their meticulously designed prospective, randomized, active-controlled crossover study - the first of its kind - compared Azmarda® (the patented cocrystal Innovator formulation of sacubitril/valsartan) with generic sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF), revealing clinically significant differences in myocardial functional improvement as measured by two sophisticated echocardiographic parameters: global longitudinal strain (GLS) and time to peak (TTP) strain.

The study demonstrated that formulation differences translate to measurable variations in myocardial response - with Azmarda showing superior improvements in both GLS (-1.7% vs -0.5% at week 8, p<0.05) compared to the generic group. These improvements were consistent, sustained, and significantly greater in the Azmarda group after the cross-over period (-1.4% vs. -0.4% p<0.05 at week 16), along with TTP (-34.2 ms improvement vs +29.0 ms worsening with generics, p<0.05 at week 16). This carries profound implications that extend across multiple domains.

For clinicians, these results necessitate a reconsideration of automatic generic substitution for this life-saving therapy, particularly in patients where optimal reverse remodeling is crucial. The greater GLS improvement with Azmarda may correlate with better long-term outcomes, given established relationships between GLS improvement and reduced hospitalization risk (2).

This is particularly relevant for complex molecular entities like ARNIs where crystalline structure influences drug release kinetics (3).

For the broader cardiovascular community, this study establishes an important precedent for incorporating sensitive functional parameters like GLS into comparative drug evaluations, moving beyond traditional surrogates like LVEF that may lack sensitivity to detect early treatment differences.

The work of Patel S. suggests that for certain drug classes - particularly those with complex formulations or narrow therapeutic indices - the assumption of interchangeability may require more nuanced examination through both advanced imaging and longer-term clinical outcomes.

Key Findings and Clinical Relevance

The study’s most striking finding was the superior improvement in GLS with Azmarda (−1.7% vs. −0.5% at week 8, p<0.05), which persisted throughout the 16-week trial, with GLS improvements of −1.4% for Azmarda versus −0.4% for the generic at Week 16 (p<0.05). This difference is clinically meaningful because:

1. GLS is recognized as a more sensitive marker of early myocardial dysfunction than LVEF (2)
2. Prior studies show that even 1% improvements in GLS correlate with better outcomes (3)
3. The differences emerged early (by week 4) and were sustained 

The TTP data further supported Azmarda’s advantages, showing significant reductions (−34.2 ms) compared to worsening values (+29.0 ms) with generics (p<0.05) by week 16 . These findings suggest the co-crystal formulation provides more efficient myocardial contraction.

The Science Behind the Difference

Azmarda’s patented co-crystal technology differs fundamentally from generic formulations in:

1. Azmarda Co-crystal Technology Background
2. Key Highlights from the GLS Clinical Study

1. Azmarda Co-crystal Technology Background

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. Unlike generic fixed-dose combinations (FDCs), Azmarda’s co-crystal form has been associated with the enhanced bioavailability, Optimal Sodium & Moisture content, superior thermal stability, and improved drug release profile leading to better therapeutic outcomes in patients with heart failure. The formulation has been used in pivotal RCTs and aligns with global standards including data from PARADIGM-HF and PIONEER trials. (1,5)

2. Key Highlights from the GLS Clinical Study

Patel S. (EJCM, 2025) conducted a prospective, randomized, crossover study in 12 HFrEF patients using GLS and TTP. (1,5)

The clinical results of the GLS study demonstrated a marked difference between the innovator and generic formulations. At week 8, patients treated with Azmarda® showed a significantly greater improvement in Global Longitudinal Strain (GLS), with an average change of −1.7%, compared to only −0.5% in those receiving the generic formulation. This difference was statistically significant (p < 0.05) and indicates superior myocardial functional recovery with the co-crystal formulation (1,5).

Further, the Time to Peak (TTP) strain at week 16 showed continued divergence in outcomes. Azmarda treatment led to a reduction in TTP by 34.2 milliseconds, suggesting more efficient myocardial contraction. In contrast, the generic formulation group experienced a worsening of TTP by +29.0 milliseconds. This too was statistically significant (p < 0.05) and reinforces the clinical relevance of formulation-dependent performance (1,5).

Implications for Clinical Practice

For cardiologists managing HFrEF patients, these findings suggest:

1. Formulation choice matters—the innovator product ensures consistent and reliable therapeutic outcomes (1)
2. GLS as a sensitive and reliable parameter for early detection of left ventricular systolic dysfunction.
3. Patients transitioning to generics should be monitored closely (3)

Limitations and Future Directions

While provocative, the study has limitations (n=12, 16-week duration) (1). Future research should:

1. Examine larger cohorts (1)
2. Assess hard endpoints (hospitalization, mortality) (4

Patel S.’s study provides early clinical evidence that physicochemical formulation differences between innovator and generic sacubitril/valsartan may lead to meaningful disparities in myocardial functional outcomes. While larger trials are warranted to evaluate long-term endpoints such as mortality, these findings underscore that in the era of precision medicine, drug formulation is not merely a pharmaceutical detail—it may be a critical determinant of therapeutic effectiveness.

The patented co-crystal technology of Azmarda stands out not just at a physicochemical level, but in clinical performance, offering faster and sustained cardiac reverse remodeling in HFrEF. It is a compelling example of how advanced pharmaceutical engineering can have direct implications on patient care. As clinicians aim for early and optimal myocardial recovery, particularly in high-risk patients, formulation should be a key consideration—not an afterthought

1. Patel S. Comparative Efficacy and Safety of Azmarda vs. Generic Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction. Eur J Cardiovasc Med.2025;15(4):928-34.
2. Abou R, et al. Global longitudinal strain: clinical use and prognostic implications. 2020;106(18):1438-44.
3. Mazzetti S, et al. Short-term echocardiographic evaluation by GLS in HFrEF treated with sacubitril/valsartan. ESC Heart Fail.2020;7(3):964-72.
4. Moon MG, et al. Reverse Remodeling Assessed by Strain Reflects Sacubitril/Valsartan Response. JACC Cardiovasc Imaging.2022;15(9):1525-41.
5. Nair T, et al. Comparative evaluation of sacubitril/valsartan brands for co-crystallization. Eur J Cardiovasc Med.2024;[In Press].
6. Yancy CW, et al. 2017 ACC/AHA/HFSA Heart Failure Guideline Update. 2017;136(6):e137-61