Kerala Heart Journal - Abraham

Kerala Heart Journal 2017; 7(1):2  Original Article

New Therapeutic Regimen in Heart Failure: A Post-marketing Study employing Speckle Tracking Echocardiography

1 , Abraham AK, 2 Srinivas T                                  



Head, Department of Cardiology Indira Gandhi Co-operative hospital Kochi, Kerala

2.  Medical Registrar, Department of Cardiology Indira Gandhi Co-operative hospital Kochi, Kerala




There is robust evidence on mortality benefit after initiation of sacubitril/valsartan in patients with HFrEF;however, the effect on LV function is unknown or is yet to be reported. To our knowledge, this is the first study to report the effect of sacubitril/valsartan on LV function assessed by using 2D speckle strain echocardiography.



We assessed LV function in 27 patients with HFrEF before and after initiation of sacubitril/valsartan to their maximum tolerated dose. Myocardial strain was assessed using a 2-dimensional speckle-tracking software. Among these patients, changes in ejection fraction, mitral annular velocity (MAV) were also measured.



Treatment with sacubitril/valsartan improved the Longitudinal Strain (LS) score (mean = -11.929, SD + 2.875) relative to pre-treatment (mean = -10.270, SD + 2.677) (t26 = 2.895, p = 0.008). On the other hand, treatment with sacubitril/valsartan did not lead to a statistically significant change in MAV and  EF. The mean MAV value of 3.96 (pre-treatment) was close to 3.98 (post-treatment)(Z = -0.443, p = 0.658). Similarly, mean EF was 34.07% and 39.86% (Z = -1.411, p = 0.158) for pre-treatment and post-treatment respectively.



 After a 4-week treatment with sacubitril/valsartan, there was a statistically significant change in longitudinal strain which may be an early sign of improvement in LV function in patients with HFrEF. The echocardiographic evaluation had shown an improvement in MAV and EF, though not statistically significant.  Our findings in this study clearly show that sacubitril/valsartan has a direct effect on LV leading to improvement in LV function and thereby reduced mortality and morbidity in patients with HFrEF. 



Heart failure, ARNi, Left Ventricle, Longitudinal Strain, Sacubitril, Valsartan



ARNi -Angiotensin Receptor Neprilysin Inhibitor, EF Ejection Fraction, HFrEF-Heart failure with reduced ejection fraction, LS Longitudinal Strain, MAV - Mitral Annular Velocity


Heart failure (HF) is a major public health problem, with a prevalence of more than 5.8 million in the United States and more than 23 million worldwide. In 1997. HF was singled out as an emerging epidemic1. In the American Heart Association (AHA)/American College of Cardiology guidelines.2,3  HF is defined as "a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood." Despite advances in cardiovascular therapeutics over the past few decades, treatment of heart failure (HF) continues to be a challenge for the practicing cardiologist. The co-existence of hypertension, Type 2 diabetes mellitus, obesity. Chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), further complicates the clinical presentation and treatment of HF. It is well known that medications play a central role in the management of heart failure. During recent times new strategy for heart failure treatment has evolved. The modulation of Renin Angiotensin Aldosterone System (RAAS) undoubtedly has become the cornerstone of heart failure treatment. Left ventricular ejection fraction (LVEF) remains the most commonly utilized metric of cardiac function4 and has been related to outcomes in patients across the spectrum of HF.5  In patients with HF and reduced ejection fraction (EF), LVEF had been shown to be predictive of cardiovascular death. HF hospitalization, and all-cause mortality in a relatively linear fashion with those patients at the lowest end of the EF spectrum at the greatest risk.6,7

Patients with symptomatic heart failure with reduced ejection fraction generally take an angiotensin-converting enzyme (ACE) inhibitor, a beta blocker, and an aldosterone antagonist. If volume overloaded, they may take a diuretic as well. An angiotensin receptor blocker (ARB) is recommended for patients who cannot tolerate an ACE inhibitor.8

The most recent pharmacotherapy to demonstrate a mortality benefit in HFrEF is the dual-acting angiotensin receptor neprilysin inhibitor (ARNi), sacubitril, and valsartan (ARB) combination. Sacubitril is a prodrug and its pharmacologically active metabolite (LBQ657) is an inhibitor of neprilysin, a neutral endopeptidase that degrades some vasoactive peptides like natriuretic peptide, bradykinin and adrenomedullin. Valsartan on the other hand, blocks the angiotensin type- I (AT-1) receptor inhibiting angiotensin II and the release of aldosterone.

In July 2015, sacubitril-valsartan was approved by the Food and Drug administration for use in patients with New York Heart Association (NYHA) functional class II to IV HFrEF, based on the results of the PARADIGM-HF (Prospective Comparison of ARNi with ACE inhibitor, Determine Impact on  Mortality and Morbidity in Heart Failure) trial.9 Sacubitril-valsartan treatment resulted in a significant 20% reduction in the primary outcome of a composite of death of cardiovascular causes or hospitalization for HF. The approval of sacubitril/valsartan marked the first new medication with demonstrated mortality benefit in HFrEF in more than 10 years.9 Sacubitril/valsartan has been shown to reduce morbidity and morbidity in patients with heart failure and reduced ejection fraction compared enalapril in the PARADIGM-HF trial.

The PARADIGM-HF trial showed that sacubitrilvalsartan was superior to enalapril in reducing the rates of death from cardiovascular causes or hospitalization for heart failure (the composite primary end point) and death from any cause among patients with heart failure and a reduced ejection fraction10. The PARADIGM-HF focused on mortality and prevention of rehospitalization, but goals of treatment in the clinic for patients with established HF are to relieve symptoms and signs (e.g. oedema), improve cardiac function (ECHO findings), prevent hospital admission, and increase survival. Despite robust clinical evidence, the true effect of sacubitrilvalsartan on the cardiac function needs to be explored further.

We choose to study speckle tracking for the assessment of LV function because of the unreliability of EF as a marker for LV function. EF is erroneously assumed to be a measure of LV contractility. Pathological hypertrophy and fibrosis, are the hallmark of HF, and are associated with abnormal contractility and relaxation. A relatively new technique, speckle tracking echocardiography offers, not only evaluation of regional deformation, but also global function assessment using the longitudinal strain, which is shown to be a better marker for LV dysfunction.11,12

We report here our post-marketing experience with the novel sacubitril/valsartan therapy in Indian patients with HF (HFrEF) using Speckle tracking echocardiography.


The study is a prospective case series looking into the efficacy of sacubitril/valsartan in the management of patients of heart failure with reduced ejection fraction. Dosage of sacubitril/valsartan was started at a dose of 50 mg BID and was uptitrated to 100 mg BID in those who tolerated the therapy. The follow-up was done 4 weeks after initiation of treatment. All the patients were on standard guideline suggested for the treatment of heart failure with reduced ejection fraction.

Patient population

Twenty seven patients of heart failure with reduced ejection fraction were included for evaluation in this study. The mean baseline demographics is presented in Table 1, The mean age was 63 years with all the patients having a chronic history of left ventricular dysfunction; 56% of the patients has reported a history of myocardial infarction or ACS. Echocardiographic findings indicated a mean ejection fraction of 24% and MAV of 4.02. The mean blood pressure was reported to be 120/76 mm Hg with 60% of the patients having a reported history of diabetes mellitus. The mean levels of blood urea were 34.3 mg/dL and that of serum creatinine, 1.38 mg/dL.


Table 1: Demographics

Mean Age

63 Years (41-79)

Mean EF (%)

34.07% (20-55%)

Mean MAV

3.95  (2.5-6.3)

Blood Pressure


Mean SBP

124 mm Hg

Mean DBP

76 mm Hg

Number of patients with DM

16 (60%)

Number of patients with Hypertension

8 (29%)

Mean Blood Urea

34.3 mg/dL

Mean Serum Creatinine

1.38 mg/dL


Echocardiographic analyses

Offline data analyses were performed at the Department of Cardiology, Indira Gandhi Co-operative Hospital, Kochi, Kerala, India. Acquisitions of images were performed during the same echocardiographic examination and patients remained in the same position, QLAB software versions 10.2 were used for images obtained from Philips iE33. Sector size and depth were adjusted to achieve optimal visualization of all LV segments at the highest possible frame rate.



Statistical comparison of pre- and post treatment values was done by paired t-test and by Wilcoxon signed rank test,  if the two related groups had unequal sample sizes or did not meet the assumptions of a parametric test. For all tests, p < 0.05 was considered to be statistically significant. For each evaluation, the 95%confidence intervals (CIs) were calculated.



The mean age of the patients was 63 years with a mean ejection fraction of 30.6%, and 60% of them had a history of T2DM.  All the patients had complete echocardiographic images in appropriate format and of adequate quality for speckle-tracking analysis

Echocardiographic analysis

Conventional 2-dimensional and Doppler echocardiographic parameters were measured. Analysis by Wilcoxon signed-rank tests showed that treatment with sacubitril/valsartan led to minimal change in MAV relative to pre-treatment; the average MAV at the initial visit was 3.96 and during the follow-up visit 3.98(Z = -0.443, p = 0.658, 95% CI). Of all the patients 12 (46%) patients had improvement in MAV.  This, however, did not reach a level of statistical significance.

The mean Ejection fraction at the baseline was 34.07% and  4-week follow-up showed a non-significant change in ejection fraction to 39.86%(Z = -1.411, p = 0.158, 95% CI).Though the change in EF was not statistically significant there was an improvement in 21 (78%) patients.

Speckle tracking 2D echocardiography

Left ventricular parameters were acquired using standard 2D grayscale LV images. Longitudinal strain (LS) was measured as an average of standard apical 4-chamber (AP4) and 3-chamber (AP3).A paired-samples t-test revealed that treatment with Sacubitril/Valsartan improved the LS (mean = -11.929, SD = 2.875) relative to pre-treatment (mean = -10.270, SD = 2.677) and this was statistically significant (t26 = 2.895, p = 0.008).  The change in LS values are shown in Figure 2. Improvement was seen in 21 patients (78%).This study shows that after the 4-week treatment with sacubitril/valsartan there was an improvement in the left ventricular function in patients of heart failure with reduced ejection fraction. 

Figure 2: Longitudinal Strain (LS) before and after treatment with sacubitril/valsartan


The study results show that after a 4-week treatment with angiotensin receptor neprilysin inhibitor, sacubitril along with valsartan,  there was a favorable change in longitudinal strain (LS) and clinically significant improvement in LV function. Echocardiographic observations also indicated improvement in MAV and ejection fraction, though not statistically significant. The changes were consistent irrespective of age, sex or baseline Blood Pressure. The baseline ejection fraction varied from 20% to 55% among the patient population studied. The improvement in LV function was seen in all patients irrespective of baseline ejection fraction. Thus the results show that sacubitril/valsartan treatment has a direct effect on the heart and alters the underlying pathophysiology, leading to improvement in mortality, morbidity and overall quality of life of patients.

Speckle tracking echocardiography measures and assesses the left ventricular deformation and it describes the percentage change in myocardial strain. While the PARADIGM-HF study failed to assess the LV deformation in HFrEF patients, our study focused on the effect of sacubitril/valsartan on longitudinal strain which is in fact a more robust index of LV function compared to ejection fraction. The present study is the first clinical study demonstrating overall increased strain rate in HFrEF patients.

In day to day cardiology practice, LV function is based on EF by echocardiography using the Simpson biplane model. However, LVEF lacks sensitivity to identify accurately myocardial contractility impairment, which first affects sub-endocardial layers and longitudinal component. In addition, LVEF is influenced by load conditions and depends on the experience of the operator.13 In the present study, we demonstrated that in patients with HFrEF, sacubitril/valsartan has shown consistent improvement in EF, MAV and Longitudinal strain values.

Left ventricular ejection fraction is the most commonly used parameter of systolic function. It is essential for the management of heart failure patients, particularly to guide therapy and for prognostication.  Recently, there has been great interest in development of novel quantitative methods to assess systolic function. One promising technique is two-dimensional speckle tracking which can provide information on the rate of segmental and myocardial deformation. Longitudinal Strain (LS) is defined as the change of length of a tissue normalized to its original length.  LS has proved to be a strong prognosticator of all-cause mortality in patients with HFrEF.  Additionally, LS was superior to LVEF and all other conventional echocardiographic parameters in predicting mortality.14,15 The results of this study also throw light on the mechanism behind the previously reported reduction in death and hospitalization with sacubitril/valsartan in  the PARADIGM-HF study.


After a 4-week treatment with sacubitril/valsartan, there was a statistically significant change in longitudinal strain which may be an early sign of improvement in LV function in patients with HFrEF. The echocardiographic evaluation had shown an improvement in MAV and EF, though not statistically significant.  Our findings in this study clearly show that sacubitril/valsartan has a direct effect on LV leading to improvement in LV function and thereby reduced mortality and morbidity in patients with HFrEF. 



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