Beneficial Effect of Left Ventricular Remodeling After Early Change of Sacubitril/Valsartan in Patients with Nonischemic Dilated Cardiomyopathy

Design

Retrospective chart review

N= 296

Objective

To investigate whether early changes to sacubitril/valsartan could improve outcomes in patients with nonischemic dilated cardiomyopathy (DCM) in real-world practice

Study Groups

Group A: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB; n= 150)

Group S/E: Early change to sacubitril/valsartan (n= 59)

Group S/L: Late change to sacubitril/valsartan (n= 87)

Inclusion Criteria

Consecutive patients with heart failure with reduced ejection fraction (HFrEF), continuously prescribed ACEI/ARB or prescription switched to sacubitril/valsartan from ACEI/ARB, underwent coronary angiography or coronary computed tomography, HF due to nonischemic DCM, did not meet Felker criteria of ischemic cardiomyopathy

Exclusion Criteria

Age < 18 years, combined significant valvular disease, undergone cardiac resynchronization therapy

Methods

Data was compiled via analysis of patient medical records. Patients in the sacubitril/valsartan group were split between those who had medication switched to the sacubitril/valsartan group early (within 60 days) or late change. Echocardiographic (ECG) examinations were performed at the time of initial diagnosis and at the last follow-up. 

Duration

Patients were diagnosed with nonischemic DCM between January 2009 and November 2019

Patients were followed-up until February 2020

Outcome Measures

Primary: difference in left ventricular ejection fraction (LVEF) from the initial diagnosis to the last follow-up, degree of LV reverse modeling (LV end-diastolic [EDD] and end-systolic dimension [ESD]) between initial ECG and final ECG

Secondary: HF hospitalization, cardiac death

Baseline Characteristics

ACEI/ARB

(Group A, n= 150)

Early change to sacubitril/valsartan

(Group S/E, n= 59)

Late change to sacubitril/valsartan

(Group S/L, n= 87)

Age, years

Male

Sacubitril/valsartan

Initiation at an outpatient clinic

Starting dose, mg/day

Last maintenance dose, mg/day

Achievement of target dose

-

-

-

- 

93.2%

126.3

184.8

16.9% 

90.8%

133.9

193.1

18.4% 

Other medications

ACEI/ARB

Beta blocker

Spironolactone

Ivabradine

94.7%

90.0%

75.3%

8.7% 

100.0%

98.3%

81.4%

8.5% 

98.9%

95.4%

74.7%

14.9%

Patients in the sacubitril/valsartan group had greater LV EDD (Group A vs. sacubitril/valsartan, 61.7 ± 7.4 vs. 66.5 ± 8.0, p< 0.001) and lower LVEF (28.9 ± 8.2% vs. 23.9 ± 7.5%, p< 0.001) compared to group A at initial diagnosis.

Results

Endpoint

ACEI/ARB

(Group A, n= 150)

Early change to sacubitril/valsartan

(Group S/E, n= 59)

Late change to sacubitril/valsartan

(Group S/L, n= 87)

p-Value 

(Group A vs. S/E)

p-value

(Group S/E vs. S/L)

Change in LVEF

Change in LVEDD

Change in LVESD

In patients who switched to sacubitril/valsartan, those with an earlier change showed a significant correlation with greater LVEF improvement (r= −0.367, p< 0.001) and LV reverse remodeling (r= 0.277, p< 0.001). 

No significant differences in cardiac events were observed between groups over the follow-up period. 

Adverse Events

Study Author Conclusions

An earlier switch to sacubitril/valsartan was significantly associated with a greater improvement in LV function in patients with nonischemic DCM. Early switch to sacubitril/valsartan might be helpful in improving the outcomes of patients with HFrEF.

InpharmD Researcher Critique

This single-center, retrospective study was performed in Korea. The use of sacubitril/valsartan was not randomized, and patients who switched to sacubitril/valsartan had a more severe disease as well as more types of HF medications. 

The Effect of Sacubitril/Valsartan on Device Detected Arrhythmias and Electrical Parameters among Dilated Cardiomyopathy Patients with Reduced Ejection Fraction and Implantable Cardioverter Defibrillator

Design

Single-center, prospective, observational cohort study

N= 167

Objective

To evaluate the incidence of device-detected tachyarrhythmia events, both atrial and ventricular, and the change in measured implantable cardioverter defibrillator (ICD) electrical parameters among dilated cardiomyopathy (DCM) patients with ICD on sacubitril/valsartan treatment 

Study Groups

All subjects (n= 167)

Inclusion Criteria

ICD recipients with DCM, left ventricular ejection fraction (LVEF) ≤40%, functional New York Heart Association (NYHA) class II, in need of sacubitril/valsartan therapy

Exclusion Criteria

Patients with permanent atrial fibrillation, pacemaker dependency, subcutaneous ICD, cardiac resynchronization therapy device, single chamber ICD, dual chamber ICD-less than one year), and prosthetic heart valves 

Methods

Eligible patients underwent medical history examination, physical examination, laboratory evaluation, 12-lead surface electrocardiogram (ECG), 2-dimensional color Doppler echocardiography, and device interrogation. These assessments were performed at enrollment, prior to administration of sacubitril/valsartan, and at six- and 12 months follow-up. 

Sacubitril/valsartan was administered at a recommended starting dose of 49/51 mg BID, and the goal dose was 97/103 mg BID. For patients with severe renal impairment or for those who were taking low doses of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), the starting dose was 24/26 mg twice daily.

Duration

Follow-up: 12 months 

Outcome Measures

Baseline Characteristics

All subjects (n=167) 

Age, years

Male

Body mass index, kg/m²

Ischaemic DCM

Non-ischaemic DCM

Ejection Fraction, %

Co-morbidities

Smoking

Hypertension

Diabetes

Dyslipidemia

Previous stroke

COPD

Peripheral artery disease

60%

68%

41%

56%

4%

27%

38%

Other medications

ACE-I or ARB

Beta-blocker

Ivabradin

Calcium Antagonist

Amiodarone

Sotalol

Aldosterone antagonist

Loop diuretic

Thiazide diuretic

100%

98%

10%

4%

10%

5%

90%

95%

15%

The ICD was implanted 757 ± 152 days before enrollment in the present study. The study population received ACEi or ARB for at least six months before ICD implantation (1137 ± 267 days).

DCM: dilated cardiomyopathy; COPD: chronic obstructive pulmonary disease; ACE-I: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ICD: implantable cardioverter defibrillator. 

Results

Endpoint

Baseline

6 Months

12 Months

p-value*

NYHA Class I

NYHA Class II

NYHA Class III

0

67

33

15

75

10

18

71

10

0.01

0.4

0.04

6-MWT distance, meters

257 ± 122

343 ± 134

338 ± 142

0.001

NT-proBNP, pg/mL

427.3 ± 69.3

380.1 ± 56.3

376.5 ± 62.3

0.02

p *: refers to six months follow-up. The results remain with the same significance level over time.

NYHA: New York Heart Association; 6-MWT: six-minute walking test; NT-proBNP: N-terminal pro b-type natriuretic peptide; CP: copeptin; LVEDV: left ventricular end-diastolic volume; VT: ventricular tachycardia; VF: ventricular fibrillation; ATP: anti-tachycardia pacing; AT: atrial tachycardia; AF: atrial fibrillation.

Adverse Events

Not disclosed. 

Study Author Conclusions

Dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillators on sacubitril/valsartan treatment experienced a reduction in both atrial and ventricular arrhythmias incidence and an improvement in ICD atrial electrical parameters. The findings might be explained by the electro-mechanical cardiac reverse remodeling on sacubitril/valsartan therapy.

InpharmD Researcher Critique

The study is subject to limitations and biases inherent to its small sample size, single-center, observational design, lack of a comparator group, and limited follow-up time.

Study of endothelial function and vascular stiffness in patients affected by dilated cardiomyopathy on treatment with sacubitril/valsartan

Design

Longitudinal prospective cohort study 

N= 15

Objective

To evaluate the possible therapeutic effects of sacubitril/valsartan on endothelial function and arterial stiffness

Study Groups

All participants (N= 15)

Inclusion Criteria

Caucasian ethnicity, aged ≥ 18 years, dilated cardiomyopathy with left ventricular ejection fraction (LVEF) < 40%, absence of recent acute coronary syndrome (6 months)

Exclusion Criteria

Congenital cardiomyopathy, rheumatological or orthopedics diseases of the upper limbs that could somehow affect the use of EndoPAT® for peripheral arterial tonometry

Methods

Eligible patients who initiated sacubitril/valsartan were assessed for endothelial function, aortic stiffness, and parameters of cardiac function via transthoracic echocardiography at study entry and 6 months after the beginning of the medication. 

Duration

Outcome Measures

Change in endothelial function (Reactive Hyperemia Index [RHI] ≤ 1.67 as dysfunction), arterial stiffness (Augmentation Index normalized for 75 bpm and calculated with peripheral arterial tonometry [Aix-75 PAT], a parameter for reduction of vascular resistance), blood pressure, LVEF

Baseline Characteristics

Age, years

Male 

Risk factors

Cardiac resynchronization therapy

Hypertension

Cardiovascular familiarity

Coronary artery disease

60%

53.3%

53.3%

46.7%

Medications

Beta-blockers

Mineralocorticoid receptor antagonists

Statins

Loop diuretics

93.3%

73.3%

73.3%

66.7%

Clinical data before treatment with sacubitril/valsartan

Systolic arterial pressure, mmHg

Diastolic arterial pressure, mmHg

Aix-75 PAT, %

RHI

EF, %

121.69 ± 14.8

73 ± 8.5

2.50 ± 27

1.516 ± 0.47

32.21 ± 5.7

Diastolic dysfunction before treatment with sacubitril/valsartan

Degree I

Degree II

Degree III

Degree IV

4 (28.6%)

3 (21.4%)

7 (50%)

0

Results

Endpoint

All participants (N= 15) 

p-value

Clinical data after treatment with sacubitril/valsartan

Systolic arterial pressure, mmHg

Diastolic arterial pressure, mmHg

Aix-75 PAT, %

RHI

EF, %

123.46 ± 16.8

73.85 ± 10.5

-21.50 ± 25

2.679 ± 1.13

38.43 ± 8.4 

0.528

0.687

0.006

0.001

0.010

Diastolic dysfunction after treatment with sacubitril/valsartan

Degree I

Degree II

Degree III

Degree IV

11 (73.3%)

3 (20%)

1 (6.7%)

0

Study Author Conclusions

Even though in a study with a limited number of patients, sacubitril/valsartan improved endothelial function, left ventricular function, and diastolic function significantly in patients with dilated cardiomyopathy and reduced LVEF. It showed no effects on vascular stiffness.

InpharmD Researcher Critique

The study is limited by its small sample size and single-center experience. Dosing regimens of sacubitril/valsartan were not detailed to explore a dose-dependent response on cardiovascular remodeling. 

Recovery of complete left bundle branch block in a dilated cardiomyopathy patient after treatment with sacubitril/valsartan: A case report

Design

Case presentation

A 38-year-old male patient presenting with exacerbated dyspnea symptoms at night, accompanied by cough and sputum with no accompanying abdominal pain was admitted to the hospital for 20 days. His electrocardiogram was suggestive of tachycardia and complete left bundle branch block (CLBBB). Laboratory tests revealed the patient had an elevated B-type natriuretic peptide and troponin. Coronary angiography did not indicate coronary stenosis or collateral circulation. Based on these findings, the patient was diagnosed with dilated cardiomyopathy with CLBBB and was classified into the New York Heart Association (NYHA) functional class III.

Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), was initiated along with antiventricular remodeling inhibitors and diuretics. Following a 7-day treatment duration, the patient was discharged with improved symptoms. The ARNI was initiated at a dose of 50 mg twice daily at first, gradually increasing to the target dose of 200 mg twice daily in the following 9 months. Concomitant metoprolol 25 mg once daily, diuretics 20 mg once daily, and aldosterone 20 mg once daily were also initiated and continued outpatient.

After 2 months of therapy, CLBBB was no longer evident on his electrocardiogram with no trace found after 4 months post-discharge. The patient's left ventricular diastolic diameter gradually decreased from 71 to 59 mm, ejection fraction increased from 23% to 47%, left atrial internal diameter decreased from 54 to 37 mm, right ventricular internal diameter decreased from 34 to 24 mm, and his condition was categorized as NYHA class I after 9 months. 

Study Author Conclusions

In conclusion, it was demonstrated that sacubitril/valsartan could improve dilated cardiomyopathy prognosis, reverse ventricular remodeling, improve uneven electrical conduction, and improve CLBBB. Of note, the patient's cardiac magnetic resonance imaging was performed too late to develop a strong baseline

Clinical Experience of Use of Sacubitril/Valsartan in a Patient with Dilated Cardiomyopathy, Chronic Heart Failure with Reduced Ejection Fraction and Ventricular Arrhythmias

Design

Case presentation

A 61-year-old male patient was admitted presenting with dyspnea on exertion, reduced exercise tolerance, palpitations, and ankle swelling. He had a past medical history of vasospastic angina, hypertension, and ventricular ectopy. The patient had noted clinical deterioration the previous two weeks before hospitalization. His current medications included metoprolol 25 mg BID, ramipril 5 mg QID, spironolactone 50 mg QID, aspirin 75 mg PO QID, and atorvastatin 10 mg QID.

Upon initial presentation, the patient had a respiratory rate of 22 breaths/min, heart rate of 82 beats/min, blood pressure of 160/100 mm Hg, and 97% oxygen saturation on ambient air. Cardiac auscultation revealed an audible S3 sound and moderate systolic murmur, indicative of mitral regurgitation. The patient also was noted to have edema in his feet and ankles. Electrocardiogram revealed sinus rhythm with left atrial enlargement and left ventricular (LV) hypertrophy with secondary ST-T wave changes. His baseline echocardiogram showed dilation of all heart chambers, pulmonary trunk and its branches, significant decrease in systolic function of the LV myocardium with severe global hypokinesis. His LV ejection fraction (LVEF) was 23%. The patient also had moderate mitral and tricuspid regurgitation (grade II), atherosclerotic lesions of the aorta and aortic valve, dilation of ascending aorta (42 mm), moderate aortic regurgitation (grade II) and pulmonary hypertension (49 mm Hg). The patient also had an elevated pro-brain natriuretic peptide level of 3,203 pg/mL. Taking into account his dyspnea on exertion and reduced exercise tolerance, the patient underwent coronary angiography, which revealed 75% proximal stenosis of the diagonal branch (D1) of his left anterior descending artery (LAD). 

The patient was diagnosed with dilated cardiomyopathy, probably secondary to myocarditis, and was initiated on carvedilol 6.25 mg BID, spironolactone 50 mg BID, furosemide 40 mg QID, ringer's solution, aspirin 75 mg QID, atorvastatin 10 mg QID and amiodarone 200 mg BID. Due to the patient fitting inclusion criteria for the PARADIGM-HF trial, the patient's ramipril was switched to sacubitril/valsartan at an initial dose of 24/26 mg BID after the recommended period of 36 hours for discontinuing ACE-inhibitor therapy. At the time, the patient was noted to be in New York Heart Association (NYHA) class III.

After 7 days of treatment, the patient noted dyspnea reduction on exertion, absence of dyspnea at rest, and a slight reduction in palpitations. Lab tests, however, demonstrated no change in natriuretic peptide levels. The patient was discharged on the 14th day with sacubitril/valsartan 24/26 mg BID, carvedilol 6.25 mg BID, eplerenone 50 mg BID, aspirin 75 mg QID, rosuvastatin 10 mg QID and amiodarone 200 mg QID. Sacubitril/valsartan dosage was meant to be titrated slowly and doubled every 3–4 weeks to the maintenance dose of one tablet of 97/103 mg BID if tolerated by the patient.

At a follow-up a few months following his hospitalization, the patient reported a significant improvement in quality of life. Two months later (6 months of treatment with sacubitril/valsartan), the patient's natriuretic peptide levels decreased to 317 pg/mL. His electrocardiogram revealed sinus rhythm with LV hypertrophy with secondary ST-T wave changes. However, there were visible improvements in systolic function (LVEF= 52%), a reduction in the size of both ventricles and atria, and absence of hypokinesis of the left ventricle. He subsequently reported improved exercise tolerance and quality of life. His clinical condition has improved to NYHA class II, and he reportedly continues his optimal medical therapy, including sacubitril/valsartan 49/51 mg BID.

Study Author Conclusions

Sacubitril/valsartan therapy did not only improve left ventricular systolic function but also reduced the frequency of ventricular rhythm disturbances. In this case, sacubitril/valsartan therapy allowed to avoid or delay cardioverter defibrillator implantation for the primary prevention of sudden cardiac death (Class I). After the achievement of clinical and functional improvement, sacubitril/valsartan therapy should be continued and requires constant intake.

A case series about the favorable effects of sacubitril/valsartan on anthracycline cardiomyopathy

Design

Case presentation 1

A 55-year-old woman with stage 2 Hodgkin lymphoma was treated with three ABVD cycles (adriamycin, doxorubicin, bleomycin, vinblastine, and dacarbazine). Eight months after the final cycle, the patient presented with hypertension and New York Heart Association (NYHA) Class II chronic heart failure. Based on echocardiography and invasive measurements of hemodynamic function, the patient was diagnosed with anthracycline-related dilated cardiomyopathy.

Initial treatment consisted of carvedilol 25 mg BID, enalapril 10 mg once daily, canrenone 50 mg once daily, and furosemide 40 mg daily, depending on symptoms. Yet despite maxing doses to tolerated levels, NT-proBMP levels continued to rise while the left ventricular ejection fraction remained at 22%. The patient has switched from enalapril 20 mg to sacubitril/valsartan 50 mg BID, then increased to 100 mg BID two weeks later. Two weeks later, cardiac signs and symptoms improved, and the patient was on sacubitril/valsartan 100 mg BID plus carvedilol 25 mg BID.

Case presentation 2

A 65-year-old woman with a history of invasive ductal carcinoma of the right breast and esophageal metastasis treated with TAC therapy (docetaxel, doxorubicin, and cyclophosphamide) presented with NYHA class II symptoms at 5-month follow-up. 

Initial treatment consisted of carvedilol 12.5 mg BID, canrenone 25 mg daily, and furosemide 25 mg as demanded by patient's status. However, the patient was hospitalized 6 months later for worsening dyspnea and bilateral ankle edema. Congestive heart failure with reduced left ventricular ejection fraction (HFrEF) was diagnosed, and the carvedilol and ramipril doses were increased. Canrenone was switched to eplerenone 25 mg daily while furosemide continued. However, the patient's cardiac status continued to decline 3 months later, and she was switched from ramipril to sacubitril/valsartan 50 mg BID with eventual up-titration to 100 mg BID. The patient's status continued to improve without heart failure-related hospitalization in 24 months.

Study Author Conclusions

Sacubitril/valsartan would seem to be able to antagonize the unfavorable remodeling of the left ventricle induced by anthracyclines. Further studies would be warranted for better evaluating the potential role of sacubitril/valsartan as a novel therapeutic tool against anthracycline cardiotoxicity.

Case of a patient with heart failure, dilated cardiomyopathy, and atrial fibrillation treated with sacubitril/valsartan

Design

Case presentation

A 29-year-old male patient was diagnosed with heart failure with reduced ejection fraction, dilated cardiomyopathy possibly related to myocarditis, and atrial fibrillation. After two years of standard treatment, sacubitril/valsartan at a dosage of 24/26 mg BID was added to the therapy with furosemide 25 mg/day, metoprolol 50 mg BID, canreonate 25 mg/day, allopurinol 150 mg/day, and warfarin. Therapy with sacubitril/valsartan led to an improvement of several clinical parameters, including persistence in sinus rhythm and progressive recovery of ejection fraction. A marked reduction in chamber dimensions and cardiac volumes was also observed. In his last visit prior to the publication of this case report, his left ventricular ejection fraction was 49% (improved from 35%), and the left ventricle volume TD was 57 mm. His tests revealed a blood pressure of 120/80 mmHg, heart rate of 69 bpm, New York Heart Association class II, NT-pro BNP 44 pg/ml, plasma creatinine 0.92 mg/dL, and K 4.6 mEq/L. Sacubitril/valsartan was well tolerated, no hospitalization for heart failure was reported, and the patient remained in good condition and has suspended the diuretic therapy.  

Study Author Conclusions

Early initiation of sacubitril/valsartan might remarkably influence the patient clinical course and might reduce the number and frequency of HF hospitalizations. The authors believe that their case report, from field-practice experience, on the novel combination of sacubitril/valsartan might provide clinicians with a useful tool in the management of challenging patients with several cardiac morbidities. 

Sacubitril/valsartan treatment improved the clinical outcome and reduced the hospitalization rate in three patients with chronic heart failure: a case series

Design

Case presentation

A 70-year-old Caucasian male, with HF functional class NYHA II-III, a family history of cardiovascular disease, with a risk of hypertension and diabetes got admitted to the intensive care unit, followed by acute pulmonary edema and cardiorespiratory arrest. Echocardiography showed a low left ventricular ejection fraction (28%) and moderate mitral insufficiency. In addition to regular heart failure management, the patient underwent percutaneous transluminal coronary angioplasty with drug-eluting stent (DES) insertion in the 3 arteries and was discharged on ramipril, bisoprolol, spironolactone, and furosemide for heart failure. 

Unfortunately, 12 days after discharge, the patient was admitted to the emergency room again due to acute pulmonary edema with a hypertensive crisis. Further check-ups revealed severe mitral insufficiency and ischemic-hypertensive cardiomyopathy in dilating phase (LVEDD = 72 mm) with heart failure with reduced ejection fraction (30%). While mitral insufficiency was reduced, HF was class NYHA II, and arterial pressure was stabilized with optimization of heart failure medications, LVEF was still too low (< 35%). Given the high pill burden, ramipril therapy was suspended, and 36 h later, a therapy with sacubitril/valsartan 49/51 mg BID was initiated, and gradually titrated to 94/103 mg BID while decreasing other antihypertensive agents. 

The patient maintained stable and good conditions in all the follow-up visits. At echocardiography of control, dilatation of the left ventricle was reduced (LVEDD = 64 mm), and the LVEF increased to 40%, with normal mitral pattern and mild mitral insufficiency.

Study Author Conclusions

In conclusion, the real-life case series reported here demonstrates that sacubitril/valsartan therapy was beneficial for performance even in elderly patients with HFeEF. Angiotensin receptor/neprilysin inhibitors (ARNIs) may play a crucial role in optimizing treatment and in reducing the need for surgical interventions or insertion of implantable devices and hospitalization events in HFrEF patients with different characteristics and comorbidities.