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Heart Center, Cheng Hsin General Hospital, Taipei, TaiwanNational Defense Medical Center, Taipei, TaiwanInstitute of Emergency and Critical Care Medicine, National Yang Ming University, Taipei, Taiwan
Recovery of left ventricular ejection fraction (LVEF) within 1 year was noted in 18% patients taking sacubitril/valsartan.
•
Non-ischemic etiology of heart failure and smaller LV size could predict LVEF recovery.
•
Tapering sacubitril/valsartan in these patients was associated with worse prognosis.
Abstract
Background
Literature describing recovery of left ventricular (LV) function post sacubitril/valsartan treatment and the optimal management of heart failure (HF) patients receiving sacubitril/valsartan remain sparse.
Methods
We recruited 437 consecutive chronic HF patients with baseline left ventricular ejection fraction (LVEF) less than 40%, who were treated with sacubitril/valsartan. All patients underwent routine echocardiographic measurement.
Results
During treatment period, recovery of LVEF to 50% or greater was observed in 77 (17.6%) patients. After multivariate analysis, recovery of LV dysfunction was associated with non-ischemic etiology of HF, smaller baseline LV end-diastolic diameter (LVEDD), and higher initial dosage of sacubitril/valsartan. Compared to those without recovery of LV dysfunction, death from cardiovascular causes or first unplanned hospitalization for HF (CVD/HFH) were significantly lower in patients with LVEF recovery [11.7% vs. 24.4%, hazard ratio (HR) 0.42, p = 0.014]. Among patients with recovery of LVEF, 51 patients continued to receive the same dosage of sacubitril/valsartan had higher LVEF and were less likely to have deterioration of LVEF than the other 26 patients who received either tapering dose of sacubitril/valsartan or switching from sacubitril/valsartan to renin-angiotensin-system blockers (LVEF 56.4 ± 5.3% vs. 45.0 ± 12.8%, p < 0.001; ΔLVEF 1.2 ± 5.1% vs. −9.3 ± 12.0%, p < 0.001). CVD/HFH occurred more frequently in the taper group than the maintenance group (23.1% vs. 5.9%, HR 0.22, p = 0.035).
Conclusions
Non-ischemic etiology of HF, smaller baseline LVEDD, and higher initial dosage of sacubitril/valsartan could predict better recovery of LV function. Among patients with functional recovery, tapering sacubitril/valsartan dose was associated with deterioration of recovered heart function and had less favorable prognosis during follow-up.
Chronic heart failure (HF) is a major public health problem and global burden. It is associated with high mortality rates, frequent re-hospitalizations, and poor quality of life [
]. In HF patients with reduced ejection fraction (HFrEF), recovery of left ventricular (LV) function is one of the primary goals of treatment. Pharmacological therapy, including angiotensin-converting enzyme inhibitors (ACEIs) [
Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)..
Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.
Improvement of left ventricular ejection fraction, heart failure symptoms and prognosis after revascularization in patients with chronic coronary artery disease and viable myocardium detected by dobutamine stress echocardiography.
] are all used in the modern era to achieve this objective.
Recently, a new therapeutic class of agents acting on the renin-angiotensin system (RAS) and the neutral endopeptidase system has been developed. This angiotensin receptor neprilysin inhibitor (ARNI) combines the moieties of valsartan and sacubitril in a single pill. Valsartan blocks angiotensin receptor and reduces vasoconstriction, sodium, and water retention and myocardial hypertrophy. Sacubitril inhibits neprilysin and substantially increases circulating natriuretic peptide and results in natriuresis, myocardial relaxation, and anti-remodeling. The PARADIGM-HF study showed that a combination of sacubitril and valsartan reduced cardiovascular mortality by 20% and all-cause mortality by 16%, as compared with enalapril [
]. Thereafter, updated guidelines for HF treatment gave class I, level of evidence B recommendation to replace RAS blockers with sacubitril/valsartan in patients with chronic symptomatic HFrEF despite optimal treatment [
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the american college of Cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America.
However, the study design of PARADIGM-HF did not include patients with echocardiographic follow-up. To date, minimal data were available about the recovery of LV function after sacubitril/valsartan treatment. Almufleh demonstrated a 5% increase in left ventricular ejection fraction (LVEF) after sacubitril/valsartan treatment, but the study sample size was small and the median duration of treatment was short - only 3 months [
]. The aim of our current study is to identify the characteristics of patients who had significant recovery of LV function after sacubitril/valsartan treatment and to investigate the clinical outcomes of these patients.
Methods
Study design and study population
The study protocol was approved by the Institutional Review Board. This study retrospectively and consecutively examined 511 chronic HF patients who were treated with sacubitril/valsartan between 2016 and 2017 from Cheng Hsin General Hospital, a referral center for HF and cardiac transplant in Taiwan. Patients’ clinical data were retrospectively reviewed without patients’ written consent.
After exclusion patients who did not fulfil the diagnosis of HFrEF, patients lost to follow-up, patients without routine echocardiographic follow-up, and patients deceased within 6 months, the study included 437 HFrEF patients for data analysis (Fig. 1). All patients’ LVEF had to be documented as less than 40% before initiation of sacubitril/valsartan. Baseline characteristics, vital signs, concomitant HF treatment, dosage, and condition of sacubitril/valsartan at initiation and follow-up were collected.
Echocardiographic images were acquired at baseline, routinely every 6 months in the first year of sacubitril/valsartan treatment, and whenever need by physicians’ clinical decision. LVEF was calculated using the biplane Simpson’s method on apical 4-chamber and 2-chamber views. Left ventricular end-diastolic diameter (LVEDD) was measured at end-diastole, and left ventricular end-systolic diameter (LVESD) and left atrial (LA) anteroposterior dimension were measured at end-systole on parasternal views. Continuous wave Doppler of the tricuspid regurgitation trace is used to measure and estimate pulmonary artery systolic pressure (PASP).
Recovery of LVEF was defined as improvement of LVEF to 50% or greater by biplane Simpson’s method on echocardiography after sacubitril/valsartan treatment at 6-month and 12-month follow-up. Echocardiographic follow-up for patients with recovery of LVEF were routinely performed 6 months after documentation of LVEF recovery and/or whenever need by physicians’ decision. ARNI responder was defined as an improvement in LVEF 20% or greater from baseline by biplane Simpson’s method on echocardiography after sacubitril/valsartan treatment. Parameters of ventricular and atrial remodeling, including delta improvement in LVEF, changes in LVEDD, LVESD, LA diameter, PASP, severities of valvular regurgitation from baseline were also collected.
Treatment strategies after recovery of LVEF
Among those patients with recovery of LVEF who received outpatient department follow-up, we defined two treatment strategies as below: (1) continue sacubitril/valsartan with same dosage (maintenance group), and (2) decrease dosage of sacubitril/valsartan or switch sacubitril/valsartan to ACEI or ARB (taper group). The treatment strategies were decided by physicians according to clinical condition, patient’s tolerability, and cost of treatment. There were no specific protocols for adjustment of medication.
Statistical analysis
Quantitative data were expressed as mean ± standard deviation or as median and interquartile range, and categorical variables were presented as percentages. Descriptive summaries were presented for different groups of patients. The Student’s t-test or the Mann–Whitney U test was used for comparisons between continuous data, and a chi-square test was used for comparisons between categorical data. Multivariate logistic regression analysis with forward selection was performed to assess the predictability of variables on the recovery of LVEF presented as odds ratios (ORs) and 95% confidence intervals (CIs) using p < 0.1 in univariate analyses for inclusion. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of the variables to predict the recovery of LVEF. A Kaplan–Meier survival analysis was used to plot the survival curves. A p-value of <0.05 was considered to be statistically significant. All tests were two-sided. All the statistical analyses were performed using the SPSS Statistics 17.0 software (Chicago, IL, USA).
Results
General information and HF management
This study consisted of 437 patients (age 61.2 ± 14.5 years, 74.6% male) who were treated with sacubitril/valsartan between 2016 and 2017. All patients’ LVEF were documented less than 40% at baseline. Baseline characteristics of enrolled patients are shown in Table 1.
Table 1Baseline characteristics of enrolled patients.
Overall (n = 437)
Recovery of LVEF ≥ 50% (n = 77)
Follow-up LVEF < 50% (n = 360)
p-value
Age (years)
61.2 ± 14.5
60.5 ± 15.8
61.4 ± 14.2
0.632
Male gender, n (%)
326 (74.6)
52 (67.5)
274 (76.1)
0.117
Body mass index (kilogram/m2)
25.9 ± 4.7
26.0 ± 5.2
25.9 ± 4.6
0.900
Systolic BP (mmHg)
121.2 ± 18.9
126.0 ± 20.7
120.2 ± 18.3
0.015
Heart rate (bpm)
80.8 ± 15.0
82.0 ± 17.0
80.5 ± 14.5
0.436
Medical history, n (%)
Non-ischemic cardiomyopathy
260 (59.5)
60 (77.9)
200 (55.6)
<0.001
Diabetes mellitus
162 (37.1)
21 (27.3)
141 (39.2)
0.050
Hypertension
194 (44.4)
38 (49.4)
156 (43.3)
0.335
Old myocardial infarction
128 (29.3)
11 (14.3)
117 (32.5)
0.001
Stroke/TIA
48 (11.0)
11 (14.3)
37 (10.3)
0.307
Atrial fibrillation
162 (37.1)
37 (48.1)
125 (34.7)
0.028
Previous HF Hospitalization
282 (64.5)
48 (62.3)
234 (65.0)
0.658
Previous valvular surgery
48 (11.0)
4 (5.2)
44 (12.2)
0.073
Hyperlipidemia
227 (51.9)
39 (50.6)
188 (52.4)
0.784
COPD/asthma
34 (7.8)
9 (11.7)
25 (6.9)
0.158
Chronic kidney disease
107 (24.5)
16 (20.8)
91 (25.3)
0.405
GFR (ml/min/1.73 m2)
68.1 ± 25.9
70.2 ± 26.4
67.7 ± 25.8
0.443
Echocardiographic parameters
LVEF (%)
27.0 ± 6.8
29.3 ± 8.0
26.5 ± 6.4
0.004
LA diameter (mm)
49.4 ± 8.8
48.8 ± 9.6
49.5 ± 8.7
0.537
LVEDD (mm)
59.3 ± 8.8
55.1 ± 6.8
60.2 ± 8.9
<0.001
LVESD (mm)
49.0 ± 10.2
44.2 ± 8.4
50.0 ± 10.3
<0.001
PASP (mmHg)
38.3 ± 15.9
39.1 ± 15.3
38.1 ± 16.0
0.604
Severe mitral regurgitation, n (%)
94 (21.5)
18 (23.4)
76 (21.1)
0.661
Severe tricuspid regurgitation, n (%)
60 (13.7)
15 (19.5)
45 (12.5)
0.106
Characteristics when ARNI was initiated
NYHA Fc III or IV, n (%)
92 (21.1)
9 (11.7)
83 (23.1)
0.026
ACEI/ARB naïve, n (%)
116 (26.5)
22 (28.6)
94 (26.1)
0.657
During HF hospitalization, n (%)
54 (12.4)
9 (11.7)
45 (12.5)
0.844
Daily dosage (mg)
93.4 ± 41.4
106.5 ± 41.4
90.6 ± 40.9
0.002
ARNI, angiotensin receptor neprilysin inhibitor; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BP, blood pressure; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; HF, heart failure; LA, left atrial; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; NYHA Fc, New York Heart Association functional classification; PASP, pulmonary artery systolic pressure; TIA, transient ischemic attack.
Before the prescription of sacubitril/valsartan, RAS blockers were prescribed in 321 patients (73.5%). In addition to sacubitril/valsartan, prescription rates of beta-blocker, MRA, ivabradine, and digoxin at baseline were 83.8%, 70.9%, 10.1%, and 26.3%, respectively. A total of 46 (10.5%) patients received implantation of CRT and/or implantable cardioverter-defibrillator. At follow-up, the prescription rates of beta-blocker, MRA, ivabradine, and digoxin did not change significantly. Table 2 shows the summarized HF medications and devices at baseline and follow-up in the study.
Table 2Anti-heart failure medications and devices at baseline and follow-up.
Echocardiographic parameters comparison between baseline and follow-up
All patients had routine echocardiographic follow-up after initiation of sacubitril/valsartan. Table 3 shows paired analysis of the echocardiographic parameters at baseline and during follow-up. Baseline LVEF was 26.9 ± 6.6%, LA diameter was 49.4 ± 8.8 mm, LVEDD was 59.3 ± 8.8 mm, LVESD was 49.0 ± 10.2 mm, and PASP was 38.3 ± 15.9 mmHg. These parameters significantly improved during follow-up, and mean ΔLVEF was 7.7 ± 11.1%. At baseline, 60 patients (13.7%) had severe LV systolic dysfunction (LVEF less than 20%), 234 patients (53.5%) had moderate LV systolic dysfunction (LVEF 20% to 29%), and 143 patients (32.7%) had mild LV systolic dysfunction (LVEF 30% to 39%). During follow-up, the percentages of severe, moderate, and mild LV systolic dysfunction decreased to 6.9%, 31.6%, and 32.3%, respectively. Improvement in LVEF more than 10% from baseline was observed in 149 patients (34.1%). ARNI responder, defined as improvement in LVEF more than 20% from baseline was observed in 70 patients (16.0%). The severities of mitral regurgitation and tricuspid regurgitation also decreased significantly during follow-up.
Table 3Baseline and follow-up echocardiographic parameters.
Fig. 2 shows the distribution of LVEF in this study population over time. All patients received echocardiographic follow-up at 6 months. Twenty-three patients died or received heart transplantation after 6 months and did not receive echocardiographic follow-up at 12 months. There was progressively an increase in patient numbers with LVEF 40–49% and 50% or greater, and decrease in patient numbers with LVEF less than 20% and 20–29%, respectively. Additional echocardiography was performed in 161 patients at 3 months by physician’s decision. Improvement in LVEF was noted in 16 patients with LVEF improved to 40–49% and 19 patients improved to 50% or greater at 3 months.
Fig. 2The distribution of left ventricular ejection fraction (LVEF) over time after sacubitril/valsartan treatment.
Characteristics and predictors of patients with LVEF recovery and ARNI responders
In addition to 75 patients with LVEF recovery at 12 months, recovery of LVEF to 50% or greater was noted in another 2 patients at 6 months (but deteriorated to less than 50% at 12 months). In these 77 patients (17.6%), mean sacubitril/valsartan treatment duration for documented LVEF recovery was 6.9 ± 3.3 months (median 6 months). Mean daily sacubitril/valsartan dose at the time of documented LVEF recovery was 144.5 ± 57.2 mg (median 100 mg). Table 1 shows the baseline characteristics between patients with and without evidence of LVEF recovery after sacubitril/valsartan treatment. In patients with LVEF recovery, baseline systolic blood pressures were higher (126.5 ± 20.7 mmHg vs. 120.2 ± 18.3 mmHg, p = 0.015), LVEFs were higher (29.3 ± 8.0% vs. 26.5 ± 6.4%, p = 0.004), LV diameters were smaller, and initial dosage of sacubitril/valsartan was higher (106.5 ± 41.4 mg vs. 90.6 ± 40.9 mg, p = 0.002) than those without LVEF recovery. Moreover, patients with LVEF recovery were more likely to have non-ischemic cardiomyopathy (77.9% vs. 55.6%, p < 0.001), and atrial fibrillation (48.1% vs. 34.7%, p = 0.028), but less likely to have history of myocardial infarction (14.3% vs. 32.5%, p = 0.001) and New York Heart Association functional class III/IV (11.7% vs. 23.1%, p = 0.026) compared with patients without LVEF recovery.
After adjusting for baseline characteristics and echocardiographic parameters, multivariate analysis showed that the recovery of LV dysfunction after sacubitril/valsartan treatment was associated with non-ischemic etiology of HF, smaller baseline LVEDD, and higher initial dosage of sacubitril/valsartan (Table 4). ROC curve showed that optimal cut-off value to predict the LVEF recovery was baseline LVEDD less than or equal to 62 mm (sensitivity 90.9%, specificity 37.5%, positive predictive value 23.7%, negative predictive value 95.1%).
Table 4Multivariate analysis for factors associated with recovery of LVEF.
Univariate analysis
Multivariate analysis
Recovery of LVEF ≥ 50% (n = 77)
Follow-up LVEF < 50% (n = 360)
p-value
HR (95% CI)
p-value
Past history, n (%)
Non-ischemic cardiomyopathy
61 (79.2)
200 (55.6)
<0.001
3.80 (2.06–7.00)
<0.001
Diabetes mellitus
21 (27.3)
141 (39.2)
0.050
–
NS
Old myocardial infarction
11 (14.3)
117 (32.5)
0.001
–
NS
Previous valvular surgery
4 (5.2)
44 (12.2)
0.073
–
NS
Atrial fibrillation
37 (48.1)
125 (34.7)
0.028
–
NS
Baseline Systolic BP (mmHg)
126.0 ± 20.7
120.2 ± 18.3
0.015
–
NS
Baseline LVEF (%)
29.3 ± 8.0
26.5 ± 6.4
0.004
–
NS
Baseline LVEDD (mm)
55.1 ± 6.8
60.2 ± 8.9
<0.001
0.91 (0.88–0.94)
<0.001
NYHA Fc III or IV
9 (11.7)
83 (23.1)
0.026
–
NS
ARNI initial daily dosage (mg)
106.5 ± 41.4
90.6 ± 40.9
0.002
1.01 (1.00–1.02)
0.001
ARNI, angiotensin receptor neprilysin inhibitor; BP, blood pressure; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA Fc, New York Heart Association functional classification.
Among 70 ARNI responders, 58 patients had their LVEF improved more than 20% from baseline and recovered to the level of 50% or greater (82.9%) and the other 12 patients had not recovered totally (17.1%). Multivariate analysis again showed that the ARNI responders were associated with mainly non-ischemic etiology of HF, smaller baseline LVEDD and higher initial dosage of sacubitril/valsartan (Supplement Table 1).
Managements in patients with recovery of LVEF and their influence on heart function
Among 77 patients with recovery of LVEF, 51 patients continued to receive the same dosage of sacubitril/valsartan (maintenance group), whereas 26 patients received either tapering dose of sacubitril/valsartan or switched from sacubitril/valsartan to RAS blockers alone (taper group). Among these 26 patients, the respective causes of tapering off medication included high cost and health insurance regulation in 18 (69%), renal dysfunction in 1 (4%), dizziness and/or hypotension in 4 (15%), and unknown in 3 (12%). The starting timelines of tapering sacubitril/valsartan in these patients were from 213 ± 136 days since the initiation of sacubitril/valsartan, 70 ± 93 days since the documentation of LVEF recovery by echocardiography. Serial echocardiographic follow-up results and medications are shown in Table 5. Fig. 3 demonstrates the change in LVEF of the two groups. Patients in the maintenance group kept the same dosage of sacubitril/valsartan throughout the treatment period, had higher follow-up LVEF, and were less likely to have deterioration of LVEF than those in the taper group (LVEF 56.4 ± 5.3% vs. 45.0 ± 12.8%, p < 0.001; ΔLVEF 1.2 ± 5.1% vs. −9.3 ± 12.0%, p < 0.001). There were trends of numerical increase in LVEDD, LVESD, and LA diameter in patients in the taper group than those in the maintenance group, although not statistically significant.
Table 5Comparisons between patients with evidence of LVEF recovery after sacubitril/valsartan treatment with different managements.
Fig. 3Change in left ventricular ejection fraction in patients with different treatment strategies before and after recovery of left ventricular systolic function.
During a mean follow-up period of 557 ± 136 days, death from cardiovascular causes or first unplanned hospitalization for HF occurred in 88 patients without recovery of LVEF (24.4%) and 9 patients with recovery of LVEF [11.7%, hazard ratio compared to those without LVEF recovery, 0.42; 95% confidence interval (CI), 0.21 to 0.84; p = 0.014; Fig. 4A].
Fig. 4Kaplan-Meier curves of death from cardiovascular causes or first unplanned hospitalization for heart failure (HF) in patients with and without recovery of left ventricular ejection fraction (LVEF) (A) and in patients with different treatment strategies (B).
Among patients with recovery of LVEF, death from cardiovascular causes or first unplanned hospitalization for HF occurred in 6 patients in the taper group (23.1%) and 3 patients in the maintenance group (5.9%, hazard ratio compared to taper group, 0.22; 95% CI, 0.06 to 0.90; p = 0.035; Fig. 4B). In the taper group, one cardiovascular death happened 31 days after switching sacubitril/valsartan to valsartan alone, and 5 unplanned hospitalizations for HF occurred 165 ± 164 days (median 99 days) after either tapering sacubitril/valsartan dosage or switching sacubitril/valsartan to RAS blockers alone.
Discussion
Reverse remodeling response after sacubitril/valsartan treatment
LV remodeling is a major underlying mechanism for HF progression [
Echocardiographic variables as prognostic indicators and therapeutic monitors in chronic congestive heart failure. Veterans Affairs cooperative studies V-HeFT I and II. V-HeFT VA Cooperative Studies Group.
Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging.
], have demonstrated significant effects on reverse remodeling and improvement in LVEF in previous studies. In the current study, 437 chronic HFrEF patients were treated with sacubitril/valsartan, and serial echocardiographic follow-up showed that the improvement in heart function was significant and may occur as soon as 3 months after initiation of treatment. The improvement in heart function involved not only reduction in size of LV and enhancement of LVEF, but also reverse remodeling of LA size, downgrading of severities of mitral and tricuspid regurgitation, and lowering pressure of pulmonary artery.
Previous studies evaluating LV reverse remodeling used different assessments, such as LVEF increase 10% or more, or LVEDD decrease to 55 mm or smaller, had demonstrated that LV reverse remodeling is a dynamic process and could take many years to achieve [
Time course of left ventricular reverse remodeling in response to pharmacotherapy: clinical implication for heart failure prognosis in patients with idiopathic dilated cardiomyopathy.
]. In the current study, 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.
Although PARADIGM-HF demonstrated that sacubitril/valsartan reduced mortality and decreased hospitalizations as compared with enalapril, the study design of PARADIGM-HF did not include echocardiographic follow-up. Currently, only a few papers reported the reverse remodeling response after sacubitril/valsartan treatment. In a single-center study, Martens et al. reported that in 125 HFrEF patients, treatment with sacubitril/valsartan improved LVEF from 29.6% to 34.8% over a median follow-up of 118 days [
]. A multi-center Spanish registry showed that administration of sacubitril/valsartan in 378 patients resulted in the improvement of LVEF from 29.1% to 32.3% during a follow-up period of 6 months [
]. In the current study including 437 HFrEF patients, we showed the improvement of LVEF from 26.9% to 34.6% after one year of sacubitril/valsartan treatment, and the degree of improvement appeared to be consistent with the results in previous reports.
Factors associated with reverse remodeling response
Recovery of LV function is an important treatment goal for HFrEF. In a meta-analysis, improvement in LVEF, and LV volume was associated with lower rates of mortality among patients with HFrEF [
Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach.
]. The current study echoed this finding which confirmed that after sacubitril/valsartan treatment, the prognosis of patients presented with LVEF recovery was more favorable than those without recovery.
Martens et al. clearly demonstrated the impact of sacubitril/valsartan dosage on reverse remodeling response. In patients treated with low dose of sacubitril/valsartan (50 mg), there was no improvement in LVEF and LV end-systolic volume during follow-up; while in patients treated with medium dose (100 mg) and high dose (200 mg) of sacubitril/valsartan, there was a dose-dependent impact on LVEF improvement and LV end-systolic volume reduction [
]. In the current study, we sought the factors associated with recovery of LVEF to 50% or greater. Similar to the observation of Martens, we also noted that higher initial dose of sacubitril/valsartan was associated with LVEF recovery. Non-ischemic cardiomyopathy was reported as a factor associated with positive response after CRT [
], and in the current study non-ischemic cardiomyopathy was also independently correlated with LVEF recovery after ARNI treatment.
An increased LVEDD suggested a long and severe remodeling process of the LV, which is difficult to be reversed. Similar concepts were presented in recently published manuscripts of percutaneous mitral-valve repair for HFrEF patients with secondary mitral regurgitation. In MITRA-FR trial, percutaneous mitral-valve repair therapy failed to show any survival benefit over medical therapy during the one year follow-up [
]. However, in the COAPT trial, patients receiving the percutaneous mitral-valve repair had 47% lower risk of HF hospitalization and 38% lower risk of all-cause mortality than patients receiving medical therapy alone within 2 years of follow-up [
]. These differences might be partially explained by different degrees of HF disease progression, as the indexed left-ventricular end-diastolic volume was higher in the MITRA-FR trial (135 ± 37 ml/m2) and lower in the COAPT trial (101 ± 34 ml/m2). In the current study, ROC curve results suggested that sacubitril/valsartan should be prescribed in a timely fashion, especially before LVEDD increment to larger than 62 mm, otherwise patients might become too sick and it is too late to gain full benefit from ARNI treatment.
Managements in patients with recovery of LVEF
Current HF treatment guidelines suggested an add-on strategy of drugs and devices for patients with HF symptoms and persistent low ejection fraction [
ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the american college of Cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America.
]. However, it is not well-known how to manage patients with recovery of LVEF, particularly after sacubitril/valsartan treatment. In the current study, even in patients with LVEF recovering to 50% or greater after sacubitril/valsartan, decreasing dosage of sacubitril/valsartan or switching from sacubitril/valsartan to RAS blockers alone were associated with re-deterioration of heart function and substantially worse prognosis.
The recently published TRED-HF trial showed that in patients with previous dilated cardiomyopathy whose LVEF had improved to 50% or greater, complete withdrawal of HF guideline-recommended therapy led 44% of patients meeting the criteria for HF to relapse within 6 months, compared with none of the comparable patients assigned to maintenance treatment [
Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.
]. In the current study, although sacubitril/valsartan was de-escalated or switched to RAS blockers alone in taper group patients, other guideline-recommended medical treatments, namely beta-blocker, MRA, and ivabradine had not been changed during the study period. Even though, re-deterioration of LV function, death from cardiovascular causes, and unplanned hospitalization for HF occurred more frequently in the taper group patients compared with patients maintained on the same sacubitril/valsartan dose. This finding suggests that improvement in LV function following sacubitril/valsartan treatment might be remission rather than completely recovery in some patients. Moreover, this remission seems to be potentially associated with natriuretic peptides, and withdrawal of sacubitril rather than RAS blockers resulted in clinical deterioration.
However, there were still a proportion of patients with LV recovery not suffering from adverse outcomes despite tapering sacubitril/valsartan. From the viewpoint of cost-effectiveness, further research could be designed to identify parameters that differentiate remission from permanent recovery of LV function in patients receiving sacubitril/valsartan treatment.
Study limitations
Several limitations should be addressed in the current study. First, we documented that tapering sacubitril/valsartan dose was associated with deterioration of recovered heart function. Caution should be taken because of the relatively small patient numbers (26 patients). More extensive studies are needed to clarify the risks and adverse effects of tapering sacubitril/valsartan treatment in HFrEF patients. Second, socio-economic status is a well-known and important factor of HF outcomes, but it was not measured in this survey. In the current study, high cost and health insurance regulations are major reasons for tapering sacubitril/valsartan. Although sacubitril/valsartan treatment was covered by our national health insurance, it was claimable only if LVEF remained less than 35% despite adequate treatment of RAS blockers and beta-blockers. In that perspective, the relationship between taper group and low socio-economic status may not have a close association. The dosage of expensive medicine could be tapered by physicians due to the policy of global budget payment and daily pharmacological price limitation. To date, no solid evidence could be shown whether sacubitril/valsartan should be continuously prescribed in HFrEF patients with LV function recovery. Our study findings could be referred to future health policy amendments.
Conclusions
In our study, sacubitril/valsartan treatment was associated with significant reverse remodeling response in serial echocardiographic follow-up. Non-ischemic etiology of HF, smaller baseline LV end-diastolic diameter, and higher initial dosage of sacubitril/valsartan could predict 50% or greater LVEF recovery. In the LVEF recovered patients, decreasing dosage of sacubitril/valsartan or switching from sacubitril/valsartan to RAS blockers were associated with re-deterioration of heart function, and hence poorer clinical outcome.
Funding
This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
All the authors declare no conflict of interest.
Acknowledgments
We are grateful to Dr Wei-Tsung Lai, Dr Chao-Wen Hsueh, Ms I-Ching Liu, and Ms Wei-Ting Huang for their effort of data collection.
Appendix A. Supplementary data
The following is Supplementary data to this article:
Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)..
Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.
Improvement of left ventricular ejection fraction, heart failure symptoms and prognosis after revascularization in patients with chronic coronary artery disease and viable myocardium detected by dobutamine stress echocardiography.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the american college of Cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America.
Echocardiographic variables as prognostic indicators and therapeutic monitors in chronic congestive heart failure. Veterans Affairs cooperative studies V-HeFT I and II. V-HeFT VA Cooperative Studies Group.
Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging.
Time course of left ventricular reverse remodeling in response to pharmacotherapy: clinical implication for heart failure prognosis in patients with idiopathic dilated cardiomyopathy.
Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach.
Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.
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