Reverse cardiac remodeling response and its effect on quality of life after initiation of sacubitril/valsartan in heart failure with reduced ejection fraction

Mohamed Said Darwish, Mohammed Ahmed Hamouda, Hesham Mohamed Aboul-Enein, Mohamed Ahmed Metwally, Ahmed Emad Eldin Mohamed. Reverse Cardiac Remodeling Response and Its Effect on Quality of Life After initiation of Sacubitril/valsartan in Heart Failure with Reduced Ejection Fraction. Cardiometry; Special issue No. 25; December 2022; p. 60-66; DOI: 10.18137/cardiometry.2022.25.6066; Available from:

Heart failure (HF) is not a single pathological diagnosis, but a clinical syndrome consisting of cardinal symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure (JVP), pulmonary crackles, and peripheral oedema). It is due to a structural and/ or functional abnormality of the heart that results in elevated intra-cardiac pressures and/or inadequate cardiac output at rest and/or during exercise [1].

Echocardiography plays a central role in the diagnosis and management of patients with HF. It is the primary method for assessment of left ventricular ejection fraction (LVEF). Echocardiography can also help to distinguish among the different types and the potential etiologies of HF. Moreover, dilatation of the heart itself results in functional mitral regurgitation, which is both a marker of HF severity and may itself be amenable to therapeutic intervention. In addition, right ventricular (RV) function and left atrial (LA) size have incremental prognostic value in HF and assessing these chambers has become crucial to the assessment of the HF patient [2].

Health-related quality of life (HRQL) is a key target of therapy in the management of patients with chronic HF [3]. The HRQL of HF patients is more impaired than age matched patients without chronic illnesses and those with other comorbidities, and HRQL perceptions are predictive of future risk for morbidity and mortality [4].

Several medication classes including beta blockers, angiotensin converting enzyme inhibitors (ACEI), and aldosterone receptor antagonists have been shown to reduce mortality in HFrEF. The most recent therapy to demonstrate a mortality benefit in HFrEF is sacubitril–valsartan, an angiotensin receptor block-er-neprilysin inhibitor (ARNI) which is currently recommended as a replacement for an ACEI or ARBs in patients with New York Heart Association (NYHA) Class II or III symptoms [5].

Sacubitril/valsartan, a novel complex of the ARB: valsartan with an inhibitor of neprilysin: sacubitril, was superior to enalapril in reducing the risks of death and of hospitalization for HF in symptomatic patients with a reduced ejection fraction [6] , and was recently approved as a replacement for ACE inhibitors or ARBs in these patients [7]. As the neprilysin inhibitor has vasodilating effects and facilitates sodium excretion [8] , combined inhibition of the renin-angiotensin system and neprilysin has greater hemodynamic and neuro-hormonal effects than ACEI or ARB alone. However, the effect of therapy with sacubitril/valsar-tan on cardiac function and its effect on quality of life remains uncertain [9].

Therefore, aim of this study was to evaluate if switching therapy from an ACEI or ARB to sacubitril/ valsartan induces incremental LV reverse remodeling and the effect of switching on quality of life in HFrEF.

Methodology

The study was done after being approved by the institutional ethical committee, and informed consent was obtained from all participants included.

A total of 100 patients with HFrEF were evaluated. Inclusion criteria were: symptomatic HF defined as NYHA class II-IV, LVEF below 35% measured by echocardiography and pretreatment with an individual optimal dose of ACEI or ARB for at least 4 weeks.

Exclusion criteria were: concomitant initiation of a therapy known to induce reverse remodeling (e.g., Cardiac Resynchronization therapy [CRT] ) during study follow-up or in the previous 6 months, insufficient echocardiographic image quality to allow reliable offline assessment, symptomatic hypotension, a SBP of less than 100 mmHg, glomerular filtration rate (GFR) below 30 mL/min per 1.73 m2, a serum potas- sium level of more than 5.0 mmol/L, or a history of angioedema, patients had any evidence of structural mitral valve disease, percutaneous coronary intervention within 3 months and substantial myocardial ischemia requiring coronary revascularization, an indication for cardiac resynchronization therapy, a plan of coronary revascularization, mitral valve intervention, or heart transplantation during the trial.

The patients were subdivided into two equal groups: Group one included patients who were switched to sacubitril/valsartan and group two included patients continued on ACEIs or ARBs as control group.

The following data were collected: Patients characteristics: All of these data were assessed at day zero and after 3 months of treatment. Full medical history included age, gender, cardiovascular risk factors e.g., hypertension (HTN), DM, smoking, dyslipidemia, chronic kidney disease (CKD), symptoms suggestive of cardiac disease and current medications. Full clinical examination included assessment of body weight, height, body mass index (BMI) and vital signs including blood pressure, pulse and respiratory rate.

Heart failure related data: Etiology of the disease either ischemic or dilated and duration of HF before starting Sacubitril/valsartan therapy, the NYHA Functional Classification which places patients in one of four categories based on how much they are limited during physical activity (Class I means no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation or dyspnea, Class II means slight limitation of physical activity but ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath), Class III means marked limitation of physical activity, less than ordinary activity causes fatigue, palpitation, or dyspnea and Class IV means unable to carry on any physical activity without discomfort moreover, symptoms of HF at rest), dose of oral diuretics, hospitalization with HF manifestations and clinical features of volume overload (Pulmonary rale, elevated JVP > 6 cm, lower limb edema and ascites) were also recorded.

Blood samples and chemistry: Complete blood count (CBC), serum creatinine, blood urea and glomerular filtration rate (GFR) and Potassium (K) level.

Transthoracic Echocardiography (TTE): Comprehensive transthoracic echocardiographic examinations were performed using a Philips, Epic 7C machine, with the 5.5 X transducer S5-1 probe with simultaneous ECG signal. Patients were examined in the left lateral decubitus position. All echocardiographic examinations were obtained and recorded offline.

The following was evaluated: LV end-diastolic and end-systolic volumes were used to calculate LVEF using modified biplane Simpson’s method in the apical four chamber and apical two chamber views ^[10]. Evaluation of LVEDVI and LVESVI. Evaluation LAVI. Assessment of MR severity using effective regurgitant orifice area (EROA) determined by dividing the regurgitant flow rate, calculated as 2πr2 × aliasing velocity, where r is the proximal isovelocity surface area (PISA) radius, by peak MR velocity ^[11].

Quality of life assessment: Patient’s functional capacity & quality of life was measured through the score change in the the Kansas City Cardiomyopathy Questionnaire–12 (KCCQ) which is a HF disease-specific questionnaire consisting of 12 questions. It is divided into several domains including physical and social limitations, symptoms, self-efficacy and QOL, each transformed to score range between 0 and 70. The clinical summary score combines measures of symptoms and social factors, while the overall summary score brings together all the domains. A higher score is representative of a better health status.

Statistical analysis

Analysis of data was performed using software MedCalc v. 20.110. Description of variables was presented as follows: Description of quantitative variables was in the form of mean, standard deviation (SD), minimum and maximum. Description of qualitative variables was in the form of numbers (No.) and percent (%). Data were explored for normality using Kolmogorov-Smirnov test of normality. The results of Kolmogorov-Smirnov test indicated that most of data were normally distributed (parametric data) so parametric tests were used for most of the comparisons. Comparison between quantitative variables was carried out by One way analysis of variance (ANOVA) which was used to test the difference between the means of several subgroups of a variable. Comparison between qualitative variables was carried out by Chi-square test, which was used to test the statistical significance of differences in a classification system (one-way classification) or the relationship between two classification systems (two-way classification). A two tailed P-value less than 0.05 was considered statically significant.

Results

The demographic and clinical history between the studied groups are illustrated in Table 1.

Table 1

Demographic and clinical history between studied groups

Demographic &clinical history			Group 1 (n=50)	Group 2 (n=50)	P-value
Males Females		N (%) N (%)	46 (92%) 4 (8%)	47 (94%) 3 (6%)	0.6966
Age (y)		Mean ± SD Range	64.4±9.3 41-83	63.3±8.6 41-82	0.541
Weight (kg)	Initial	Mean ± SD Range	84.9±16.5 54-138	84.9±13.9 .58-138	0.990
	Follow up (3 months)	Mean ± SD Range	84.6±15.9 55-132	85.3±13.4 64-132	0.817
BSA	Initial	Mean ± SD Range	1.9±0.2 1.2-2.5	1.9±0.1 1.6-2.5	0.715
	Follow up (3 months)	Mean ± SD Range	1.9±0.2 1.2-2.4	1.9-0.1 1.6-2.5	0.595
DM		N (%)	22 (44%)	18 (36%)	0.4166
HTN		N (%)	29 (58%)	30 (60%)	0.8397
Dyslipidaemia		N (%)	18 (36%)	27 (54%)	0.0719
COPD		N (%)	4 (8%)	6 (12%)	0.5071
CKD		N (%)	10 (20%)	6 (12%)	0.2776
IHD		N (%)	32 (64%)	32 (64%)	1

Regarding initial laboratory results and the follow up laboratory results, there was no significant difference of urea, creatinine, GFR and K levels between group 1 and group 2 (P >0.05). Table 2

Regarding initial echocardiographic measurements: for group 1: the mean LVEF was 25.06% ± 6%, the mean LVEDVI was 89.14 ± 24.77, the mean LVESV was 66.76 ± 19.2 and the mean LAVI was 35.81 ± 14.67. For group 2: the mean LVEF was 25.82% ± 5.99%, the mean LVEDVI was 84.65 ± 26.33, the mean LVESV was 63.77 ± 20,41 and the mean LAVI was 35.81 ± 14.67. There was no significant difference of EF, LVEDVI, LVESVI and LAVI between group 1 and group 2 (P.>0.05). Regarding follow up echocardiographic measurements at 3 months, there was significant increase of EF in group 1, in comparison to group 2 (P.≤0.05). No significant difference of LVED-VI, LVESVI and LAVI between group 1 and group 2 (P.>0.05). Table 3

Regarding initial mitral regurgitation grades, there was no significant difference in mitral regurgitation grades between group 1 and group 2 (P.>0.05). At follow up, group 1 was significantly associated with no MR (12%) and less severe grade (2%) than group 2 (2%, 16% respectively) (P.≤0.05). Table 4

Comparing echocardiographic measurements between initial and follow up in group 1: Within group 1, at follow up, there was significant increase of EF and significant decrease of LVEDVI, LVESVI and LAVI, in comparison to initial measurements (P.≤0.05). Table 5

Table 2

Comparing initial laboratory results and follow up laboratory results between two groups

Initial laboratory	Group 1 (n=50)		Group 2 (n=50)		P-value
	Mean	SD	Mean	SD
Urea	36.03	10.20	37.06	9.96	0.612
Creatinine	1.20	0.32	1.22	0.30	0.759
GFR	77.38	27.97	74.58	24.57	0.596
K	4.01	0.45	4.11	0.36	0.224
Follow up laboratory (3 months)
Urea	40.10	11.43	38.56	11.09	0.496
Creatinine	1.25	0.37	1.27	0.36	0.761
GFR	75.60	26.98	75.46	27.28	0.979
K	4.26	0.59	4.23	0.59	0.840

Table 3

Comparing initial and follow up echocardiographic measurements between two groups

Initial Echocardiography	Group 1 (n=50)		Group 2 (n=50)		P-value
	Mean	SD	Mean	SD
EF	25.06	6.09	25.82	5.99	0.531
LVEDVI	89.14	24.77	84.65	26.33	0.382
LVESVI	66.76	19.20	63.77	20.41	0.453
LAVI	35.81	14.67	44.91	44.71	0.175
Follow up Echocardiography
EF	32.10	6.63	27.08	6.12	0.001*
LVEDVI	81.44	20.70	82.23	25.21	0.864
LVESVI	58.50	16.02	61.01	18.61	0.472
LAVI	33.07	14.43	37.17	15.82	0.179

Table 4

Comparing initial and follow up mitral valve regurgitation grades (MRG) between two groups

Initial MRG	Group 1 (n=50)		Group 2 (n=50)
	N	%	N	%
Trivial	7	14	6	12
Mild	17	34	20	40
Moderate	16	32	12	24
Severe	5	10	11	22
No MR	5	10	1	2
Chi square	5.808
P-value	0.2139
Follow up MRG
Trivial	20	40	12	24
Mild	14	28	17	34
Moderate	9	18	12	24
Severe	1	2	8	16
No MR	6	12	1	2
Chi square	11.735
P-value	0.0194*

Table 5

Comparing echocardiographic measurements between initial and follow up in group 1

Echocardiography (Group 1)	Initial		Follow up		P-value
	Mean	SD	Mean	SD
EF	25.06	6.09	32.10	6.63	< 0.0001*
LVEDVI	89.14	24.77	81.44	20.70	< 0.0001*
LVESVI	66.76	19.20	58.50	16.02	< 0.0001*
LAVI	35.81	14.67	33.07	14.43	< 0.0001*

*P ≤ 0.05 is considered significant

Within group 2, at follow up, there was no significant difference of EF, LVEDVI, LVESVI, and LAVI between initial and follow up measurements (P.>0.05). Table 6

Table 6

Comparing echocardiographic measurements between initial and follow up in group 2

Echocardiography (Group 2)	Initial		Follow up		P-value
	Mean	SD	Mean	SD
EF	25.82	5.99	26.03	4.12	0.0702
LVEDVI	84.65	26.33	83.13	24.21	0.0811
LVESVI	63.77	20.41	62.15	17.61	0.0612
LAVI	44.91	44.71	37.17	15.82	0.2024

Within group 1, at follow up, moderate (18%) and severe MR (2%) were significantly lower in comparison to initial MR (32%, 10% respectively) (P.≤0.05). Table 7

Table 7

Comparing mitral valve regurgitation grades (MRG) between initial and follow up in group 1

MRG (Group1)	Initial		Follow up
	N	%	N	%
Trivial	7	14	20	40
Mild	17	34	14	28
Moderate	16	32	9	18
Severe	5	10	1	2
No MR	5	10	6	12
Chi square	11.267
P-value	0.0237*

*P ≤ 0.05 is considered significant

Within group 2, at follow up, no significant difference of MR grades in comparison to initial MR grade (P.>0.05). Table 8

Table 8

Comparing mitral valve regurgitation grades (MRG) between initial and follow up in group 2

MRG (Group 2)	Initial		Follow up
	N	%	N	%
Trivial	6	12	12	24
Mild	20	40	17	34
Moderate	12	24	12	24
Severe	11	22	8	16
No MR	1	2	1	2
Chi square	2.717
P-value	0.6063

KCCQ was significantly higher at follow up in group 1 in comparison to initial KCCQ (P.≤0.05), while in group 2 there was no significant difference of KCCQ between initial and follow up (P.> 0.05). Table 9

Table 9

Comparing between initial and follow up KCCQ

KCCQ	Initial		Follow up		P-value
	Mean	SD	Mean	SD
Group 1	26.36	6.42	41.10	7.10	<0.0001*
Group 2	28.52	7.37	29.11	4.20	0.073

*P ≤ 0.05 is considered significant

Discussion

Recently the MI survival rates increased resulted in an increase in the incidence of HF, which is an economic burden due to the decrease of the functioning capacity and high treatment costs. HF is the leading cause of inpatient admissions in the US for adults aged over 65 years and accounts for more than $17 billion in medicare expenditures annually. Optimization of medical therapy will have a great impact on the economy and will improve the functional capacity of population.

In the current study, LVEDVI, LVESVI and LAVI were significantly reduced after treatment with significant improvement in LVEF. Quality of life was significantly improved which was calculated by modified KCCQ score.

In the same aspect, the PRIME (Pharmacological Reduction of Functional, Ischemic Mitral Regurgitation) prospective randomized study by Kang et al. [12] has demonstrated that an angiotensin receptor nepri-lysin inhibitor is more effective in improving functional mitral regurgitation associated with HF than an angiotensin receptor blocker. The authors found that in comparison with valsartan, sacubitril/valsartan further reduces the ERO, LVEDVI, LAVI, and the ratio of mitral in- flow velocity to mitral annular relaxation velocity (E/E´).

However, Schmieder et al. [13] showed that no benefit was observed in LVEF but the authors excluded the more severe patients with LVEF ≤ 25% and only patients with significant mitral regurgitation. This inconsistency may affect the judgment of ARNI effects. Furthermore, the results in terms of different doses and follow-up periods remain inconclusive.

On the other hand, Vecchis et al. [14] a retrospective cohort study demonstrated that the use of sacubitril/ valsartan for HFrEF patients, extended for a mean duration of 14 months, yields a significant improvement in the echocardiographic parameters of systolic function along the transverse (LVEF) and longitudinal (GLS) axis.

This comes in harmony with results of Bayard et al. [15] prospective study on 41 patients using PARA-DIGM-HF criteria: Class II, III, or IV HF; ejection fraction (EF) of 40% or less; hospitalized for HF within the previous 12 months, TTE Echo evaluation was performed before initiating sacubitril/valsartan and 3 months after optimal dose adjustment. (Based on previous studies, patients with (absolute) improvement in LVEF ≥ 5% were considered significant sacubitril/ valsartan responders.

Similarly, Chang et al. [16] study on chronic HF patients with LVEF less than 40% who received sacubi-tril/valsartan and results showed that approximately one third of patients would have LVEF improved at least 10% points from baseline, and a total of 17.6% patients achieved complete restoration of their LVEF to 50% or greater after sacubitril / valsartan treatment within one year.

This finding was consistent with Chang et al. [16] who showed that after 1 year therapy with sacubitril/ valsartan there was a significant decrease in LA diameter, end diastolic volume, end systolic volume. Bayard et al. [15] showed a significant decrease in left ventricular end diastolic volume after treatment with sacu-bitril/valsartan than before, although the end systolic volume change was of no significance.

In contrast, Mazzetti et al. [17] results showed that there were non-significant differences in the size of the left atrium, RV function, and pulmonary pressures were found at 6 months.

Similar concepts were presented in published manuscripts of percutaneous mitral-valve repair for HFrEF patients with secondary mitral regurgitation. In Obadia et al. [18] trial, percutaneous mitral-valve repair therapy failed to show any survival benefit over medical therapy during the one-year follow-up.

However, in Stone et al. [19] trial, patients receiving the percutaneous mitral-valve repair had 47% lower risk of HF hospitalization and 38% lower risk of allcause mortality than patients receiving medical therapy alone within 2 years of follow-up.

The current study results, there was a marked reduction of PISA and ERO area after 3 months with P value 0.02.

This was in accordance with Bayard et al. [15] who reported that sacubitril/valsartan responders had less significant mitral regurgitation compared to non-re-sponders, Sacubitril/valsartan responders displayed less severe LV remodeling and less significant mitral regurgitation, Accordingly, sacubitril/valsartan could be used at an earlier time in HFrEF patients in order to further limit LV remodeling. Prior studies on sacu-bitril/valsartan remodeling properties showed an improvement of LV volumes and mass as Almufleh et al. [20] and Liu et al. [21] studies.

Conclusion

In HFrEF patients, sacubitril/valsartan significantly improves LV function; furthermore, it induces incremental LV reverse remodeling as well as improves quality of life in HF patients. Moreover MR severity significantly decreased.

Acknowledgements

Nothing to be acknowledged

Conflicts of interest

No conflict of interest