Congestive Heart Failure
Conditions
Keywords
heart failure, neprilysin, implantable hemodynamic monitor, angiotensin-receptor blocker, angiotensin-converting enzyme inhibitor
Brief summary
This pilot study will assess the impact of sacubitril/valsartan (trade name Entresto) on the elevated pulmonary artery pressures in patients with heart failure with reduced ejection fraction, measured using a previously implanted hemodynamic monitoring device (CardioMEMS).
Detailed description
Angiotensin-converting enzyme inhibitors (ACEi) have been a cornerstone treatment for patients with heart failure and reduced ejection fraction (HFrEF) for over 25 years. They are included in every major set of guidelines for HFrEF management. Angiotensin receptor blockers (ARB's, such as valsartan) have similarly been shown to decrease the mortality rate of patients with HFrEF for patients who are unable to tolerate ACEi therapy. The newest neurohormonal therapy approved for heart failure (August 2015) is sacubitril/valsartan (trade name Entresto). This medication is the first of a new family of agents (ARNI = angiotensin receptor antagonist with neprilysin inhibitor), combining the approved angiotensin receptor blocker valsartan with sacubitril, an inhibitor of neprilysin, which is a neutral endopeptidase that degrades endogenous vasoactive peptides. Treatment with sacubitril increases circulating levels of natriuretic peptides, which have been shown to facilitate natriuresis and vasodilation. Although the precise mechanisms responsible for benefit in heart failure remain unclear, sacubitril/valsartan may reduce the fluid retention and vasoconstriction that contribute to heart failure symptoms, and may also decrease apoptosis and remodeling that lead to disease progression. There is limited data about the incremental acute and long-term hemodynamic effects of composite neprilysin/angiotensin-receptor inhibitors over enalapril, and these data may provide important mechanistic insights. Progress in HF management outside the hospital has included validation of a strategy of ongoing monitoring of pulmonary artery pressures every day from home via a monitor implanted in a distal pulmonary artery, the CardioMEMS device. The information is transmitted to a website where it is reviewed by the HF team, who can intervene to adjust diuretics and other medications by phone to avert decompensation and re-hospitalization. The device received FDA approval in mid 2014, and is now being implanted in many cardiac catheterization laboratories, including at Brigham and Women's Hospital. The pressure information is reviewed regularly by the HF management team who are in regular contact with the patient to aid in management decisions. In summary, this pilot study will assess the impact of sacubitril/valsartan, an approved drug for heart failure with reduced ejection fraction (HFrEF) on the elevated pulmonary artery pressures measured using an implanted monitoring device that is also approved for such patients. Both the medication and the device will be used according to approved indications.
Interventions
DEVICEImplantable Hemodynamic Monitor
The CardioMEMS device is an implantable pulmonary artery pressure monitor that is FDA-approved for use in patients with symptomatic heart failure and previous heart failure hospitalization. Patients eligible for this study are those with an already implanted CardioMEMS device.
DRUGAngiotensin-Converting Enzyme Inhibitor
Conventional, guideline-directed therapy for heart failure and reduced ejection fraction
DRUGAngiotensin II Type 1 Receptor Blocker
Conventional, guideline-directed therapy for heart failure and reduced ejection fraction in ACE-inhibitor intolerant patients
DRUGsacubitril/valsartan
Angiotensin-neprilysin inhibitor that is now FDA-approved and guideline-directed therapy for patients with symptomatic heart failure and reduced ejection fraction despite treatment with an ACE-inhibitor/Angiotensin-Receptor Blocker
Sponsors
Novartis
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients able to provide written informed consent 2. Patients ≥18 years of age, male or female, in NYHA Class II- III HF, previously hospitalized for HFrEF with LVEF \< 35% (measured within the past year), and who have no subsequent LVEF\>35%. 3. Systolic BP \> 95 mm Hg at most recent clinical assessment. 4. Stable, ambulatory patients without the need for change in diuretics and other HF drugs (RAS blockers, beta blockers or mineralocorticoid receptor blockers) during the past 5 days 5. CardioMEMS HF System implanted for NYHA Class III HF. Patient transmitting information regularly and system functioning appropriately. 6. NT-proBNP \> 500 pg/ml within 90 days of CardioMEMS implantation. 7. Average PAPm \>20mm Hg during the 7 days prior to enrollment, including at least 4 daily measurements. 8. Women of childbearing age must be on highly effective method of contraception
Exclusion criteria
1. Treatment with vasodilators (other than nitrates, hydralazine) and/or IV inotropic drugs. 2. Entresto taken within the past 30 days. 3. History of hypersensitivity, intolerance or angioedema to previous renin-angiotensin system (RAS) blocker, ACE inhibitor, ARB, or Entresto. 4. eGFR \< 30 ml/min/1.73 m2 as measured by the simplified MDRD formula. 5. Serum potassium \> 5.5 mmol/L. 6. Acute coronary syndrome, stroke, transient ischemic attack, cardiovascular surgery, PCI, or carotid angioplasty within the preceding 3 months. 7. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within 3 months after trial entry. 8. Non-cardiac condition(s) as the primary cause of dyspnea. 9. Implantation of a cardiac resynchronization therapy device (CRT/D) within the pr preceding 3 months or intent to implant a CRT/D, which may alter the pressures during the course of the study. 10. History of heart transplantation, placement of an LVAD, listing for Status IA for cardiac transplantation or planned placement of an LVAD within 3 months following randomization. 11. Documented untreated ventricular arrhythmia with syncopal episodes within the prior 3 months. 12. Symptomatic bradycardia or second or third degree heart block without a pacemaker. 13. Hepatic dysfunction, as evidenced by total bilirubin \> 3 mg/dl. 14. Pregnancy 15. Women who are breastfeeding 16. Chronic lithium use
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference Between Mean Change in Mean Pulmonary Artery Pressure (PAPm) With Sacubitril/Valsartan Compared to the Mean Change in PAPm With Continued ACEi/ARB | Baseline, 6 weeks | Change in mean PAP in group A versus group B |
| The Acute Change in PAPm After the First Administration of Sacubitril/Valsartan | Baseline, 3 hours (after first dose of sacubitril/valsartan) | Change in PAPm at 3 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Difference Between Mean Change in PAPm From Baseline on Sacubitril/Valsartan Compared to ACEI/ARB | 6 weeks (week 1-6 of the study for group A, weeks 7-12 for group B) | Change in PAPm on sacubitril/valsartan: Measured from baseline to week 6 (group A) and week 7-week 12 (Group B) |
| Change in NT-proBNP | Baseline | Change in NT-proBNP from baseline to 6 weeks |
| Determine the Change in Distance Walked During a Standard 6 Minute Walk Test From Baseline | Baseline, 6 weeks | Change in 6 minute walk distance in Group A vs. Group B at 6 weeks |
| Mean Change in PAPm in Both Groups on Sacubitril/Valsartan | 20 weeks (weeks 12 to 32 of the study) | Change in PAPm from week 12-32 |
Other
| Measure | Time frame | Description |
|---|---|---|
| The Relationship of Change in PAPm to Change in the Questions in the Kansas City Cardiomypathy Questionnaire (KCCQ) 3,7,8,9 | Baseline, 32 weeks (testing performed at intervals during study) | Correlation between change in PAPm and change in KCCQ at 32 weeks |
| Mean Change in Total Daily Diuretic Dose While on Sacubitril/Valsartan | Baseline, 32 weeks (testing performed at intervals during study) | Mean change in total daily diuretic dose while on sacubitril/valsartan (32 weeks) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A Entresto + Placebo | 2 |
| Group B ACE/ARB + Placebo | 2 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Group A | Group B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Continuous | 57.5 years | 66.5 years | 62 years |
| mean PA Pressure | 24 mm Hg | 28 mm Hg | 26 mm Hg |
| NTproBNP | 634 pg/mL | 750 pg/mL | 692 pg/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 1 / 2 | 0 / 2 |
Outcome results
Primary
Difference Between Mean Change in Mean Pulmonary Artery Pressure (PAPm) With Sacubitril/Valsartan Compared to the Mean Change in PAPm With Continued ACEi/ARB
Change in mean PAP in group A versus group B
Time frame: Baseline, 6 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A | Difference Between Mean Change in Mean Pulmonary Artery Pressure (PAPm) With Sacubitril/Valsartan Compared to the Mean Change in PAPm With Continued ACEi/ARB | 0 mm Hg |
| Group B | Difference Between Mean Change in Mean Pulmonary Artery Pressure (PAPm) With Sacubitril/Valsartan Compared to the Mean Change in PAPm With Continued ACEi/ARB | -2.5 mm Hg |
Primary
The Acute Change in PAPm After the First Administration of Sacubitril/Valsartan
Change in PAPm at 3 hours
Time frame: Baseline, 3 hours (after first dose of sacubitril/valsartan)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A | The Acute Change in PAPm After the First Administration of Sacubitril/Valsartan | -3.5 mm Hg |
| Group B | The Acute Change in PAPm After the First Administration of Sacubitril/Valsartan | -15 mm Hg |
Secondary
Change in NT-proBNP
Change in NT-proBNP from baseline to 6 weeks
Time frame: Baseline
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A | Change in NT-proBNP | -85 pg/mL |
| Group B | Change in NT-proBNP | 250 pg/mL |
Secondary
Determine the Change in Distance Walked During a Standard 6 Minute Walk Test From Baseline
Change in 6 minute walk distance in Group A vs. Group B at 6 weeks
Time frame: Baseline, 6 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A | Determine the Change in Distance Walked During a Standard 6 Minute Walk Test From Baseline | 36 m |
| Group B | Determine the Change in Distance Walked During a Standard 6 Minute Walk Test From Baseline | -5 m |
Secondary
Mean Change in PAPm in Both Groups on Sacubitril/Valsartan
Change in PAPm from week 12-32
Time frame: 20 weeks (weeks 12 to 32 of the study)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A | Mean Change in PAPm in Both Groups on Sacubitril/Valsartan | 6 mm Hg |
| Group B | Mean Change in PAPm in Both Groups on Sacubitril/Valsartan | 2 mm Hg |
Secondary
The Difference Between Mean Change in PAPm From Baseline on Sacubitril/Valsartan Compared to ACEI/ARB
Change in PAPm on sacubitril/valsartan: Measured from baseline to week 6 (group A) and week 7-week 12 (Group B)
Time frame: 6 weeks (week 1-6 of the study for group A, weeks 7-12 for group B)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group A | The Difference Between Mean Change in PAPm From Baseline on Sacubitril/Valsartan Compared to ACEI/ARB | 0 mm Hg |
| Group B | The Difference Between Mean Change in PAPm From Baseline on Sacubitril/Valsartan Compared to ACEI/ARB | 1.5 mm Hg |
Other Pre-specified
Mean Change in Total Daily Diuretic Dose While on Sacubitril/Valsartan
Mean change in total daily diuretic dose while on sacubitril/valsartan (32 weeks)
Time frame: Baseline, 32 weeks (testing performed at intervals during study)
Population: \*\* Data not reported as too few participants were enrolled for meaningful analysis (n=4)
Other Pre-specified
The Relationship of Change in PAPm to Change in the Questions in the Kansas City Cardiomypathy Questionnaire (KCCQ) 3,7,8,9
Correlation between change in PAPm and change in KCCQ at 32 weeks
Time frame: Baseline, 32 weeks (testing performed at intervals during study)
Population: Not reported due to lack of adequate data (too few participants enrolled)