Heart Failure
Conditions
Keywords
LCZ696, sacubitril/valsartan, Heart Failure, Heart failure with reduced ejection fraction, HFrEF, Ventricular arrhythmias, Implanted Device, Healthcare resource utilization
Brief summary
The purpose of this study was to generate effectiveness data of Angiotensin receptor neprilysin inhibitor (ARNI), in the Chinese Heart failure with reduced ejection fraction (HFrEF) patients with implantable cardioverted defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D).
Detailed description
The rationale of this study was to compare the effect of angiotensin-converting enzyme inhibitor (ACEI) / Angiotensin receptor blockers (ARB) with the effect of ARNI on ventricular arrhythmia (VA) events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional, open-label, and prospective single-arm study was considered. ACEI/ARB was given to the patient for 6 months. After 6 months, patients using ACEI needed to undergo a 36-hr washout period (36-hr washout period was not needed for patients using ARB at month 6). Patients then received ARNI (sponsored by Novartis only for this study).
Interventions
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: 1. Male or female patients ≥18 and ≤80 years of age 2. Implanted with an ICD or CRT-D within 2 weeks 3. NYHA functional class II - IV 4. LVEF ≤40% (measured by echocardiography) 5. Signed informed consent must be obtained prior to participation in the study. Key
Exclusion criteria
1. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes. 2. Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the 6-week period prior to study enrollment. 3. Participation in other clinical studies 3 months prior to participating study. 4. Advanced cancer or other significant comorbidities with life expectancy of \<1 year. 5. Previous history of angioedema associated with ACEI/ARB treatment, hereditary or idiopathic angioedema. 6. Patients with renal artery stenosis history. 7. Current stage D HF patients requiring vasoactive drugs. 8. Symptomatic hypotension \< 100/60 mmHg at visit 1 (screening) or Symptomatic hypotension \< 90/60 mmHg in anti-hypertension drug treatment at visit 1 (screening). 9. Serum potassium \>5.4 mmol/L at visit 1 (screening). 10. Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m2 as measured at visit 1 (screening). 11. Pregnant or nursing (lactating) women. 12. Other exclusion depend on investigator's discretion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events | Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment) | VA events were measured through devices to determine sustained ventricular tachycardia (SVT), non-sustained ventricular tachycardia (NSVT) and premature ventricular contraction (PVC). SVT was defined as tachycardia lasting for ≥30 seconds or with hemodynamic disorder as determined by Holter and/or device. NSVT was defined as recorded by Holter and/or device. PVC was defined as an early ventricular depolarization as determined by the device, and/or detected by Holter. PVC data were not available for patients with single -lumen implantation type |
| Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event | Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment) | Once VA events were detected, implantable cardioverter defibrillator (ICD) could treat with high-energy shocks or Anti-tachycardia pacing (ATP). ATP consists of one or more trains of pacing stimuli, expressed as a percentage of the tachycardia cycle length for a given RR interval, from the onset of the preceding R wave. Patients with sustained VA events would receive ICD or cardiac resynchronization therapy-defibrillator (CRT-D) shock therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| New York Heart Association Classification | Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment) | To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments. NYHA classification is a subjective physician's assessment of heart failure patient's functional capacity and symptomatic status. Class I - No limitation of physical activity. Class II - Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III - Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV - Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. |
| Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment) | To assess the number of occurrences of Ventricular arrhythmia (VA) events and Implantable cardioverter defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D) shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment. PVC data were not available for patients with single-lumen implantation type |
| Number of Hospitalizations for Arrhythmia or HF Related Hospitalizations | Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment) | To compare the healthcare resource utilization of Heart Failure (HF) patients during ACEI/ARB and ARNI treatments |
| N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Level | Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment) | To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments. NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. |
| Left Ventricular Ejection Fraction | Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment) | To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments. LVEF is a measurement expressed as a percentage of how much blood in the left ventricle is pumped out with each contraction of the heart. |
Countries
China
Participant flow
Recruitment details
Participants took part in 23 investigative sites in China
Pre-assignment details
All patients provided written informed consent prior to the start of any study-related activities.
Participants by arm
| Arm | Count |
|---|---|
| ACEI/ARB Followed by ARNI Patients received angiotensin-converting enzyme inhibitor/angiotensin receptor blockers treatment the first 6 months. The following 6 months patients received angiotensin receptor neprilysin inhibitor treatment. | 201 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 3 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Patient/guardian's decision | 1 |
| Overall Study | Patient withdraw informed consent | 9 |
| Overall Study | Physician Decision | 45 |
| Overall Study | sponsor terminated the study early | 16 |
Baseline characteristics
| Characteristic | ACEI/ARB Followed by ARNI |
|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 10.32 |
| Race/Ethnicity, Customized Asian | 201 Participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 160 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 201 | 0 / 140 |
| other Total, other adverse events | 99 / 201 | 58 / 140 |
| serious Total, serious adverse events | 38 / 201 | 19 / 140 |
Outcome results
Primary
Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event
Once VA events were detected, implantable cardioverter defibrillator (ICD) could treat with high-energy shocks or Anti-tachycardia pacing (ATP). ATP consists of one or more trains of pacing stimuli, expressed as a percentage of the tachycardia cycle length for a given RR interval, from the onset of the preceding R wave. Patients with sustained VA events would receive ICD or cardiac resynchronization therapy-defibrillator (CRT-D) shock therapy.
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Population: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI. Only subjects who had this measurement index successfully paired (ACEI/ARB treatment and ARNI treatment) were included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ACEI/ARB | Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event | Occurrence of at least one ICD or CRT-D shock | 3 Participants |
| ACEI/ARB | Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event | Occurrence of at least one ATP event | 15 Participants |
| ARNI | Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event | Occurrence of at least one ICD or CRT-D shock | 2 Participants |
| ARNI | Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event | Occurrence of at least one ATP event | 8 Participants |
Comparison: Occurrence of at least one shockp-value: >0.9999McNemar
Comparison: Occurrence of at least one ATP eventp-value: 0.0654McNemar
Primary
Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events
VA events were measured through devices to determine sustained ventricular tachycardia (SVT), non-sustained ventricular tachycardia (NSVT) and premature ventricular contraction (PVC). SVT was defined as tachycardia lasting for ≥30 seconds or with hemodynamic disorder as determined by Holter and/or device. NSVT was defined as recorded by Holter and/or device. PVC was defined as an early ventricular depolarization as determined by the device, and/or detected by Holter. PVC data were not available for patients with single -lumen implantation type
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Population: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI. Only subjects who had this measurement index successfully paired (ACEI/ARB treatment and ARNI treatment) were included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ACEI/ARB | Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events | At least one SVT occurred | 13 Participants |
| ACEI/ARB | Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events | At least one NSVT occurred | 23 Participants |
| ACEI/ARB | Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events | At least one PVC occurred | 40 Participants |
| ARNI | Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events | At least one PVC occurred | 38 Participants |
| ARNI | Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events | At least one SVT occurred | 12 Participants |
| ARNI | Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events | At least one NSVT occurred | 21 Participants |
Comparison: At least one SVT occurredp-value: >0.9999McNemar
Comparison: At least one NSVT occurredp-value: 0.7905McNemar
Comparison: At least one PVC occurredp-value: 0.625McNemar
Secondary
Left Ventricular Ejection Fraction
To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments. LVEF is a measurement expressed as a percentage of how much blood in the left ventricle is pumped out with each contraction of the heart.
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Population: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI. Only participants with assessment of LVEF at 6 months of ACEI/ARB treatment and 6 months of ARNI treatment are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACEI/ARB | Left Ventricular Ejection Fraction | 38.84 percentage of ejected blood | Standard Deviation 9.923 |
| ARNI | Left Ventricular Ejection Fraction | 41.24 percentage of ejected blood | Standard Deviation 10.021 |
p-value: 0.000895% CI: [1.11, 3.7]Wilcoxon signed-rank
Secondary
New York Heart Association Classification
To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments. NYHA classification is a subjective physician's assessment of heart failure patient's functional capacity and symptomatic status. Class I - No limitation of physical activity. Class II - Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III - Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV - Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Population: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI. Only participants with assessment of NYHA at 6 months of ACEI/ARB treatment and 6 months of ARNI treatment are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACEI/ARB | New York Heart Association Classification | 2.03 score on a scale | Standard Deviation 0.499 |
| ARNI | New York Heart Association Classification | 2.00 score on a scale | Standard Deviation 0.509 |
p-value: 0.573395% CI: [-0.07, 0.04]Ridit analysis
Secondary
N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Level
To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments. NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure.
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Population: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI. Only participants with assessment of NT-proBNP at 6 months of ACEI/ARB treatment and 6 months of ARNI treatment are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACEI/ARB | N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Level | 1233.79 pg/mL | Standard Deviation 1974.401 |
| ARNI | N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Level | 1002.33 pg/mL | Standard Deviation 1738.4 |
p-value: 0.000695% CI: [-415.9, -47.02]Wilcoxon signed rank test
Secondary
Number of Hospitalizations for Arrhythmia or HF Related Hospitalizations
To compare the healthcare resource utilization of Heart Failure (HF) patients during ACEI/ARB and ARNI treatments
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Population: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ACEI/ARB | Number of Hospitalizations for Arrhythmia or HF Related Hospitalizations | Number of hospitalizations | 25 number of hospitalizations |
| ACEI/ARB | Number of Hospitalizations for Arrhythmia or HF Related Hospitalizations | Number of hospitalizations for heart failure | 13 number of hospitalizations |
| ARNI | Number of Hospitalizations for Arrhythmia or HF Related Hospitalizations | Number of hospitalizations | 16 number of hospitalizations |
| ARNI | Number of Hospitalizations for Arrhythmia or HF Related Hospitalizations | Number of hospitalizations for heart failure | 3 number of hospitalizations |
Secondary
Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients
To assess the number of occurrences of Ventricular arrhythmia (VA) events and Implantable cardioverter defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D) shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment. PVC data were not available for patients with single-lumen implantation type
Time frame: Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Population: Efficacy analysis set (EAS): Patients in the safety set who received at least one dose of ARNI and completed 12 months of complete treatment and follow-up or withdrew early after receiving at least one dose of ARNI. Only subjects who had this measurement index successfully paired (ACEI/ARB treatment and ARNI treatment) were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ACEI/ARB | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | NSVT | 5353 number of events |
| ACEI/ARB | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | ICD or CRT-D shock | 6 number of events |
| ACEI/ARB | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | PVC | 9676979 number of events |
| ACEI/ARB | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | ATP | 217 number of events |
| ACEI/ARB | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | SVT | 170 number of events |
| ARNI | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | ATP | 156 number of events |
| ARNI | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | SVT | 117 number of events |
| ARNI | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | NSVT | 1648 number of events |
| ARNI | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | PVC | 17482398 number of events |
| ARNI | Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events Experienced by Patients | ICD or CRT-D shock | 5 number of events |