Clinical trial NCT02788656
Conditions: Congestive Heart Failure
Keywords: heart failure neprilysin implantable hemodynamic monitor angiotensin-receptor blocker angiotensin-converting enzyme inhibitor
Sponsor: Brigham and Women's Hospital
Start date: 2016-09-01; Completion date: 2018-11-09
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Group A will receive sacubitril/valsartan + placebo for weeks 1-12. and then sacubitril/valsartan only for weeks 13-32. All subjects in Group A will also receive longitudinal pulmonary artery pressure monitoring using a previously placed implantable hemodynamic monitor (CardioMEMS device). arm 2: Group B will receive an Angiotensin-Converting Enzyme Inhibitor (ACEi) or Angiotensin II Type 1 Receptor Blocker (ARB) + placebo for weeks 1-6 (depending on previous background therapy) and then switch to sacubitril/valsartan + placebo for weeks 7-12.

Group B will then receive sacubitril/valsartan only for weeks 13-32. All subjects in Group B will also receive longitudinal pulmonary artery pressure monitoring using a previously placed implantable hemodynamic monitor (CardioMEMS device).
Interventions: intervention 1: Implantable Hemodynamic Monitor intervention 2: Angiotensin-Converting Enzyme Inhibitor intervention 3: Angiotensin II Type 1 Receptor Blocker intervention 4: sacubitril/valsartan
Intervention descriptions: intervention 1: 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. intervention 2: Conventional, guideline-directed therapy for heart failure and reduced ejection fraction intervention 3: Conventional, guideline-directed therapy for heart failure and reduced ejection fraction in ACE-inhibitor intolerant patients intervention 4: 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

Protocol documents:
Prot_SAP_000.pdf: 
05.31.2017 
 
1 
 
PARENT Trial Pilot 
Pulmonary Artery Pressure Reduction with ENTresto (sacubitril/valsartan) 
 
Detailed Protocol  
Version 4.2 
This pilot study will compare the hemodynamic impact of approved drugs for heart failure (HF) 
on the elevated pulmonary artery pressures measured by an implanted monitoring device that is 
also approved for such patients.  Both the medications and the monitoring device will be used 
according to approved indications. The only aspects of the study that are not standard care will 
be the increased frequency of pressure measurement and clinical assessment schedule.  
I. 
BACKGROUND AND STUDY RATIONALE 
a. Background 
Almost 25 years ago, the CONSENSUS and SOLVD trails demonstrated a decrease in the 
mortality rate of patients with heart failure with reduced ejection fraction (HFrEF) on 
angiotensin-converting enzyme inhibitors (ACEi).1, 2 Since then, ACEi have been a cornerstone 
HFrEF treatment. They are included in every major set of guidelines for HFrEF management.3, 4 
Angiotensin receptor blockers (ARB’s, such as valsartan) have similarly been shown to decrease 
the mortality rate of patients with HFrEF for patients who could not tolerate ACEi therapy. 5, 6  
The Medication: 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 neprolysin inhibitor), combining the approved 
angiotensin receptor blocker valsartan with sacubitril, an inhibitor of neprilysin, which is a 
neutral endopeptidase that degrades endogenous vasoactive peptides.7 ,8,9,10 Sacubitril increases 
circulating natriuretic peptides, which have been shown to facilitate natriuresis and vasodilation.  
Entresto reduces fluid retention and vasoconstriction that contribute to heart failure symptoms, 
and is also thought to decrease apoptosis and remodeling that lead to disease progression.11  
The Monitoring Device: 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 arteriole, 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.   


05.31.2017 
 
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b. Previous Pre-Clinical or Clinical Studies  
The Medication: Entresto (sacubitril/valsartan) was first tested in hypertensive patients in 2010, 
compared to valsartan (an ARB) alone.12 In a study of over 1300 patients, Entresto reduced 
blood pressure more than the valsartan alone..12 In the PARADIGM-HF trial of  8442 patients, 
Entresto was shown to be superior to the ACEi enalapril, reducing the risk of death and 
hospitalization among patients with heart failure with reduced ejection fraction (HFrEF).13 The 
study was stopped early for overwhelming benefit after a median follow-up of 27 months, at 
which time  the hazard ratio for the primary outcome of death/HF hospitalization was 0.80 (95% 
CI 0.73-0.87) for patients randomized to Entresto, as compared to enalapril. The hazard ratio for 
reducing all cause mortality was 0.84.  These impressive results lead the FDA to grant priority 
review and full approval in August 2015. Entresto is now being used increasingly in the care of 
patients with HFrEF.  
The Monitoring Device: The CardioMEMS HF System, a wireless hemodynamic monitoring 
system has been shown to measure pulmonary artery pressures reliably over years.  The device 
was implanted in all patients in the randomized single-blind CHAMPION trial, which compared  
the management strategy using these pressures together with clinical information to guide 
therapy, compared to management based only on weight and symptoms in patients whose care 
team were not able to see the pressure information.  The device was associated with a 37% 
reduction in HF hospitalizations and a reduction in total hospitalizations, and the freedom from 
device-related complications was 98.6%.  As of May 2014 it was approved by the FDA for the 
management of HF in patients who had at least one hospitalization during the previous year for 
heart failure.14 Subsequent information published this year in Lancet demonstrated  a 48% 
reduction in hospitalization rate in the real-world setting  when the control patients crossed over 
to pressure management strategy.15 
c. Study Rationale 
The clinical benefits of Entresto are widely accepted, but there are many pathways through 
which these benefits may be derived.  The increase in circulating natriuretic peptides are 
considered to decrease myocardial apoptosis and ventricular remodeling and to oppose other 
systemic effects of adverse activation of the renin-angiotensin and sympathetic nervous systems.  
The natriuretic peptides also have direct hemodynamic effects on sodium and water excretion 
and on vascular tone.  These effects could lead to reduction in elevated pulmonary artery 
pressures, which are associated with many of the symptoms of HF and with the development of 
pulmonary hypertension which impairs right heart function and contributes to development of 
secondary right heart failure.   
This pilot study takes advantage of the availability of the home monitoring device for HF 
management, and will include only patients in whom this device has already been implanted for 
management according to clinical indications.  It will test the primary hypothesis that the 


05.31.2017 
 
3 
 
replacing ACEI/ARB therapy with Entresto will lower pulmonary artery pressure at 6 weeks 
compared to continuation of ACE inhibitor/ARB therapy and that that improvement will be 
sustained over the course of 20 additional weeks of therapy. In addition, the immediate first-dose 
response will be assessed on the first day of administration, with the hypothesis that the first dose 
will lead to immediate reduction in pulmonary artery pressures.  The durability of the effect will 
be assessed over the next 20 weeks during the longitudinal phase, with the hypothesis that early 
reductions in pulmonary artery pressure will be sustained.   
 
II. 
OBJECTIVES AND ENDPOINTS 
 
a. Specific Objectives and Hypotheses to Test in the Research Project  
Co-Primary Objectives:  
 
Intensive Phase:  
• Determine the difference between mean change in PAPm after 6 weeks on Entresto 
compared to 6 weeks on continued ACEi/ARB  
Acute First-Day Response  
• Determine the change in PAPm between baseline and first 3 hours after the first 
dose of Entresto  
Secondary Objectives:  
• Determine the mean change in PAPm in both groups on Entresto from week 12 to 
week 32 in longitudinal study 
• Determine the difference between mean change in PAPm from baseline on  
ACEI/ARB to 6 weeks on Entresto (Groups A and B) 
• *Determine the change in distance walked during and the change in exercise recovery 
PAPm after a standard 6 minute walk test 
• *Determine the impact of therapy over time on double Master’s Step test16, 
assessing changes in PAPm during recovery after test. 
• *Determine the impact of therapy over time on Handgrip  Test17, assessing changes 
in PAPm, blood pressure and heart rate during isometric exercise and recovery after 
test. 
• *Determine the impact of therapy over time on Stroop Color Test18, assessing 
changes in PAPm, blood pressure and heart rate during mental stress challenge and 
recovery after test. 
• *Determine the change in  NT-proBNP and the BNP/NT-proBNP ratio  


05.31.2017 
 
4 
 
Tertiary Objectives (Exploratory):  
• 
Examine the relationship of change in PAPm to change in the questions in the Kansas 
City Cardiomyopathy Questionnaire (KCCQ) 3, 7,8,9 which describe the severity of 
symptoms of congestion 
• 
Determine the mean change in total daily diuretic dose while on Entresto 
*Will be 3 comparisons:  
1)  6 weeks of Entresto vs 6 weeks of continued ACEI/ARB (Group A compared to B at 6 weeks) 
2) Baseline on ACEI/ARB compared to 6 weeks on Entresto (Groups A and B combined) 
3) 12 weeks on Entresto compared to 32 weeks on Entresto in longitudinal study (all pts)\ 
 
II. STUDY DESIGN 
The study is a randomized, active comparator study of the hemodynamic effects of Entresto vs. 
ACEi/ARB as measured by an implantable hemodynamic monitor. Formal blinding is not 
possible due to the lack of placebos available to match all potential ACE inhibitors and ARBs, 
but every effort will be made to mask the specific drug assignment from the patients to limit bias. 
For safety reasons, physicians will not be blinded to study drug assignment.  
 
III. 
PATIENT POPULATION 
 
a. Inclusion/Exclusion Criteria 
Inclusion Criteria 
Key inclusion criteria: The disease to be studied is HF with reduced ejection fraction (HFrEF).  
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. Currently treated with an ACEi or ARB  
6. CardioMEMS HF System implanted for NYHA Class III HF. Patient transmitting 
information regularly and system functioning appropriately. 
7. NT-proBNP > 500 pg/ml within 90 days of CardioMEMS implantation. 
8. Average PAPm >20mm Hg during the 7 days prior to enrollment, including at least 4 daily 
measurements.   
Women of childbearing age must be practicing a highly effective method of contraception 
Acceptable methods of “high effective contraception” include abstinence, prior 
sterilization, contraceptive implants, intrauterine device, injectable contraception, 
contraception pills, contraception patches, and contraceptive rings. 


05.31.2017 
 
5 
 
 
 
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 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  
17. Participation in another study with investigational drug/device within the past 30 days 
 
b. Source of Subjects 
Research staff will identify potential patients by reviewing the panel of patients at Brigham 
and Women’s Hospital (BWH) and Massachusetts General Hospital (MGH) with 
CardioMEMS devices. Patients must carry a diagnosis of HFrEF and have a documented 
ejection fraction ≤35% within the past year so that they have an indication for Entresto 
Patients must also have a previously placed CardioMEMS device to allow measurement of 
pulmonary pressures during the study. This study is open to individuals of both genders and 
all racial/ethnic backgrounds who are over the age of 18. Only adult patients will be 
considered for enrollment because Entresto has only been studied and FDA approved for 
adults.  
 


05.31.2017 
 
6 
 
 
IV. 
SUBJECT ENROLLMENT  
 
a. Identification of Patients and Consent 
The investigators and study staff will screen the outpatient cardiology clinic rosters to identify 
eligible subjects. If a subject is eligible, the investigator and/or study staff member will follow 
Partners Human Research Committee (PHRC) guidelines on recruitment. Permission to approach 
a potential subject will be obtained from the attending physician who will gain permission from 
the potential subject before a study staff member proceeds to introduce the study.  
A licensed physician investigator will obtain written informed consent from subjects after all 
aspects of the study have been discussed and the potential subject has agreed to participate in the 
study. Sufficient time will be allowed for the potential subject to review the consent form. All 
questions will be answered by the investigator before the consent form is signed. Contact 
information will be given to the potential subject so that he or she may contact the study 
physician or staff with any questions or concerns. 
When a potential subject is the investigator’s own patient, every effort will be made to have an 
investigator other than the patient’s physician obtain informed consent. It will be made clear to 
the potential subject that participation in the study is entirely voluntary and that their decision 
will not affect their care now or in the future.  
 
b. Treatment Assignment and Randomization 
Randomized codes designating treatment group assignment will be generated for each patient. 
After informed consent is obtained, study personnel will obtain assigned to treatment group A or 
B based on the relevant randomization code.     
Three study drugs will be utilized during the study: 
 
Study Drug A = Masked Placebo, dosed twice daily 
 
Study Drug B = Masked Active Entresto 
 
Study Drug C = Masked Active Entresto 
Group A will receive Study Drug A + Study Drug B for weeks 1-6 , Study drug A + Study Drug 
C for weeks 6-12,  and then open-label Entresto only for weeks 13-32.  
Group B will receive Study drug A + their previous ACEi/ARB for weeks 1-6,  and then, after a 
2 day (minimum 36 hours as per FDA labelling) washout period, switch to Study Drug A + 
Study Drug C for weeks 7-12. This group will then receive open-label Entresto only for weeks 
13-32 (as with Group A).  


05.31.2017 
 
7 
 
 
V. 
STUDY PROCEDURES 
 
a. Visit Schedule and Assessments 
Over the course of the study, patients will come in for a total of 10 clinic visits (baseline visit, 6 
during the intensive phase and 3 during the longitudinal phase) during which the following 
parameters will be measured:  
 
 
Intensive Phase 
Longitudinal Phase 
Visit 
Enroll/ 
Baseline 
Assmnt. 
 
Week 2  
Visit 
Week 4  
Visit 
Week 6 
Clinic 
Visit 
Week 8 
Visit 
Week 10  
Visit 
Week 12 
Clinic Visit 
Week 18 
Clinic 
Visit 
Week 24 
Clinic 
Visit 
Week 32 
Clinic 
Visit 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom and 
Side Effect 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PAP Recording 
CardioMEMS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6 Minute Walk 
Test 
X 
 
 
X 
 
 
X 
 
 
X 
NT-ProBNP &  
BNP/NT-
ProBNP 
X 
 
 
X 
 
 
X 
 
 
X 
*Safety Labs 
 
 
X  
(Group A) 
 
 
X  
(Group B) 
 
 
 
 
 
Urine 
Pregnancy Test 
for Women of 
Childbearing 
Age 
X 
 
 
 
 
 
 
 
 
 
Quality of Life 
(KCCQ) 
X 
 
 
X 
 
 
X 
 
 
X 
Double Master’s 
step test 
X 
 
 
X 
 
 
X 
 
 
X 
Handrip test 
X 
 
 
X 
 
 
X 
 
 
X 
Stroop color test 
X 
 
 
X 
 
 
X 
 
 
X 
*Safety labs (potassium and creatinine) will also be drawn within 2 weeks any dose change of 
either Entresto or ACEi/ARB 
b. Drug Administration and Drug Dosing Guidelines 


05.31.2017 
 
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Entresto dosing 
Entresto (valsartan/sacubitril) will be given to patients during the study. This FDA approved 
drug is currently available in three doses: 24/26 mg, 49/51 mg, and 97/103 mg (equivalent to 50 
mg, 100 mg, and 200 mg of LCZ696). Entresto is dosed twice a day. Patients will initially be 
transitioned to a dose of Entresto that is based on their previous ACEi/ARB dose using the 
dosing conversion algorithm19 provided by the manufacter (see table below): 
 Patients on ACEi 
Prior ACEi Dose 
Initial Starting Dose of Entresto 
Patients receiving a total daily 
dose of >10 mg of enalapril or 
therapeutically equivalent doses of another ACEi  
Examples: 
• 
Lisinopril >10mg  
• 
Ramipril >5mg 
Start Entresto 49/51mg BID (100 mg 
LCZ696 BID) 
Patients receiving a total daily 
dose of ≤10 mg of enalapril or 
therapeutically equivalent doses 
of another ACEi 
Examples: 
• 
Lisinopril ≤10 mg 
• 
Ramipril ≤5 mg 
Start Entresto 24/26mg BID (50 mg 
LCZ696 BID) 
Patients on ARB 
Prior ARB Dose 
Initial Starting Dose of Entresto 
Patients receiving a total daily dose of >160 mg 
of valsartan or therapeutically equivalent doses of 
another ARB 
Examples:  
• 
Losartan >50 mg  
• 
Olmesartan >10 mg 
Start Entresto at 49/51 mg BID (100 mg 
LCZ696 BID) 
Patients receiving a total daily dose of ≤160 mg 
of valsartan or therapeutically equivalent doses of 
another ARB 
Examples:  
• 
Losartan ≤50 mg  
• 
Olmesartan ≤10 mg 
Start Entresto at a dose of 24/26 mg BID 
(50mg of LCZ696 BID) 
 
Dosage of Entresto will be titrated at the 2 and 4 week visits towards the maximum dose of 
97/103 mg bid as tolerated. 
ACEi/ARB Dosing 


05.31.2017 
 
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Following randomization atients assigned to group B will restart their previously prescribed 
ACEi/ARB at the previously prescribed dose. This dose will be further titrated towards the target 
dose as directed by guidelines at the 2 and 4 week visits as tolerated. 
 
Placebo Dosing 
 
Group A 
Group B 
Weeks 1-6  
Placebo 1 pill BID 
Placebo 1 pill BID 
Weeks 7-12  
Placebo 1 pill BID 
Placebo 1 pill BID 
Weeks 13-32  
No placebo 
No placebo 
 
Method  
Entresto is only available orally.  
Schedule of Administration 
Entresto is administered twice a day. On day 5 and day 47, patients will be instructed to hold 
their other morning medications and take only their first dose of Entresto and placebo or 
ACEi/ARB and placebo. They will then be asked to measure their PA pressures using their home 
CardioMEMS device 1, 2, and 3 hours after their first dose of Entresto or ACEi/ARB.  
Both groups will do this on day 5 and day 47. On day 5, Group A will be measuring the first 
dose effect of Entresto and Group B will be measuring the first dose effect of ACEi/ARB after 
the washout period. On day 47, Group A will be measuring the acute effects of Entresto after 6 
weeks of therapy and Group B will be measuring the first dose effects of Entresto.  
Patients will also be asked to complete this “acute PA pressure measurement” schedule, i.e. 
holding morning medications, measuring PA pressure before and at hours 1, 2, 3 after their 
morning dose of Entresto or ACEi/ARB, after any dosing change.  
On all other days, patients will take their morning dose of Entresto or ACEi/ARNB and placebo 
with their other morning medications. The evening dose of Entresto or ACEi/ARB and placebo 
can be taken with other evening medications as well.  
Dose Modifications 
At each clinic visit, if clinically indicated, the dose of Entresto and/or ACEi/ARB will be 
uptitrated if possible, per standard clinical protocol depending on blood pressure and tolerability. 
The goal dose of Entresto for all patients will be 97/103 mg BID (dose studied in the trials). 
ACE-inhibitors and ARBs will be titrated to the effective target doses prescribed by clinical 
guidelines. fter each medication dose change (of either Entresto or ACEi/ARB) the patients will 


05.31.2017 
 
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be asked to measure “acute PA pressures” at home (see above regimen) and have safety labs will 
be checked within 2 weeks of the dosing change. Patients will be called by a study nurse 2-3 
days after any dosing changes to assess for any side effects. 
 Toxicities  
In this study, we will be supplying patients Entresto, a chronic heart failure medication which 
has been proven efficacious in large, randomized clinical research trials. After any dosing 
changes, of either Entresto or ACEi/ARB, for the first administration of the new dose, patients 
will hold their other medications, measure their PA pressures before medication administration 
and then every hour for 3 hours after the new dose. Patients will be called by a study nurse 2-3 
days after any dosing changes to assess for any side effects.  
During the ACEi/ARB “washout periods,” all patients will have 24/7 access to study staff and/or 
study physicians to report any new symptoms or ask questions.  
Similar to ACEi therapy, Entresto has a small risk of angioedema (0.2% in the Entresto group 
compared to 0.1% in the ACEi group in the PARADIGM trial, with no incidence of upper 
airway obstruction).  To eliminate any increased risk of angioedema from prior ACEi or ARB 
exposure in this study, all patients will undergo a mandatory 2 day (minimum 36 hours as per 
FDA labelling)  washout period between any administration of these medications and  Entresto 
administration.  This is consistent with prior clinical trials and the standard of care as would be 
practiced for any patient switching from ACEi to Entresto, regardless of whether or not they 
were enrolled in this study. 
c. Devices to be Used  
Only HF patients with previously implanted CardioMEMS devices will be eligible for 
enrollment. The CardioMEMS device has been studied extensively in previously clinical trials 
and shown to be both effective and safe, decreasing HF hospitalization by 37%, with freedom 
from device-related or system-related complication rate of 98.6%.14  The FDA approved the 
CardioMEMS device on May 28, 2014 for patients with NYHA III heart failure who have been 
hospitalized for heart failure within the previous year. Once the device is implanted, patients are 
set up with a home monitoring system and instructed to transmit their PA pressures daily. They 
record and transmit their pulmonary artery pressures non-invasively by laying on a special pillow 
connected to a home recording and transmission consol. Each recording requires that the patient 
lay still for approximately 18 seconds. The PA pressure measurement is automatically and 
electronically transmitted to a trained HF nurse who checks the recording for accuracy and 
reliability. If the recording is not acceptable, the monitoring nurse will call the patient and ask 
that the recording be repeated. The recording and transmission process is quick and completely 
painless. The PA pressure measurement and waveforms are visible to the monitoring nurse and 
the clinical team, but not to the patients.  


05.31.2017 
 
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Each CardioMEMS recording provides a PA systolic (PAPs), diastolic (PAPd) and mean 
(PAPm) pressure as well as the tracings. These measurements and their trend over time are 
reviewed by the patient’s heart failure team. Medications and other therapies are adjusted based 
on these trends. Patients are called every few days to review their trends and discuss medication 
changes. If a patient has an acute change in their measurements, they are called as part of 
standard clinical care the next business day to assess their clinical status and potential changes in 
therapy.   
Patients will continue their regular, daily monitoring schedule just as before the trial. The only 
change will be additional PA pressure measurements will be “acute PAP measurements” before 
and at hours 1,2,3 after Entresto/ACEi/ARB on day 5 and 47. Patients will also be asked to 
measure their PA pressure on day 5 and 47 in the evening, before they take their evening dose of 
Entresto/ACEi/ARB.  
“Acute PA pressure measurements” will also be obtained on the first day of any new dosing 
regimen (after any dosing changes) for safety.   
PA pressure measurements before and at 5 minute intervals for 30 minutes after the 6 minute 
walk test will be performed by the study staff in the clinic setting.   
PA pressure measurements before and at 5 minute intervals for 30 minutes after the double 
Master’s Step test will be performed by the study staff in the clinic setting.   
PA pressure and blood pressure measurements before, during the Handgrip test (with 30 seconds 
intervals during the 2-minute test) and at 5 minutes intervals for 15 minutes of recovery will be 
performed by the study staff in the clinic setting. Heart rate is going to be recorded throughout 
test and recovery. 
PA pressure and blood pressure measurements before, during the Stroop Color test (with 30 
seconds intervals during the 3-minute test) and at 5 minutes intervals for 15 minutes of recovery 
will be performed by the study staff in the clinic setting. Heart rate is going to be recorded 
throughout test and recovery. 
d. Procedures/Surgical Interventions  
There will be no procedures or surgical interventions undertaken during this study.  
e. Data to be Collected 
Baseline Clinic Visit, Variables to be Collected: 
• Demographics and HF History (first visit only) 
• Age 
• Sex (male/female)  
• Race (white, black, other) 


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• Ethnicity (Hispanic, non-Hispanic)  
• Type of Insurance (Medicare, Medicaid, commercial, other)  
• Etiology of heart failure (ischemic, nonischemic)  
• NYHA (I-IV) in clinic   
• Number of previous hospitalizations for heart failure in the past year  
• Time since diagnosis of heart failure (years)  
• Time since placement of CardioMEMS (months 
• Time of most recent echo (< 1 month,  1-5 months, 6-12 months, > 1 year 
o LVEF    
o LVDD  mm  
o MR (0,trace,mild/mod/mod-sev/severe) 
o  TR (0,trace,mild/mod/mod-sev/severe) 
 
• Medication Data 
o Beta blocker total daily dose (metoprolol equivalents, mg/d), has there been a 
dose change   
o ACEi no/yes (if yes, total daily dose in captopril equivalents, mg/d), has there 
been a dose change   
o  ARB no/yes (if yes, total daily dose in valsartan equivalents, mg/d), has there 
been a dose change   
o Nitrate no/yes (if yes total daily dose mg), has there been a dose change   
o Hydralazine no/yes (if yes total daily dose mg), has there been a dose change   
o Diuretic total daily dose (furosemide equivalents, mg/d), has there been a dose 
change   
o Use of thiazide diuretic in past 14 days (no/yes) if yes, # days, has there been a 
dose change   
• Clinical Assessment   
o History:   
▪ Orthopnea or paroxysmal nocturnal dyspnea within last 14 days (no/yes) If 
yes, # days  
▪ Bendopnea within last 14 days (no/yes) If yes, # days  
▪ Dizziness or lightheadedness on standing (no/yes)  
• If yes, rare / 1-2 x weekly /  only if stand quickly / often  
▪ Symptoms limiting bathing and dressing (no/yes) If yes, #days 
o Examination  
▪ HR sitting  
▪ Rhythm (from EKG) regular (SR/paced/ 
▪ SBP/ DBP  mmHg sitting  and standing 
▪ Jugular venous pressure (estimated cmH20)  
▪ S3 yes/ no 


05.31.2017 
 
13 
 
▪ Systolic murmur  (0,1,2,3,4) 
▪ Rales (absent/bases/one-quarter/one third up) 
▪ Hepatomegaly  no/yes if yes,  1-3, 4-6, > 6 cm) 
▪ Peripheral edema (none/trace/1+/2+/3+/4+)  
• PA pressure measurements baseline in clinic (recorded by staff) 
o PA systolic/ diastolic/ mean pressures at rest (in clinic, mmHg) 
• Planned Medication Changes after this Visit  
o Do you plan to uptitrate Entresto or ACEi/ARB?  
o If not, why not? (postural hypotension, resting hypotension, renal dysfunction, 
fatigue) 
o Did you consider decreasing diuretics instead?  
o If not, why not? (PAP not low, signs of fluid retention ________, symptoms of 
fluid retention _______)  
 
• 6 Minute Walk Test  
o Distance walked (meters)   # stops if any  
o PA systolic/diastolic, and mean pressure immediately before 6 minute walk  
Then repeat X 7: Immediately after walk, 5, 10, 15, 20, 25, 30 minutes  
• Double Master’s step test 
o PA systolic/diastolic, and mean pressure immediately before double Master’s step 
test .  
Then repeat X 7: Immediately after walk, 5, 10, 15, 20, 25, 30 minutes 
• Handgrip test 
o Maximal handgrip effort  
o PA systolic/diastolic, and mean pressure  
▪ Immediately before 
▪ Each 30 seconds during the test (total= 4 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
 
o Blood pressure 
▪ Immediately before 
▪ Each 30 seconds during the test (total= 4 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
o Heart rate 
▪ Continuously recorded during the test and recovery 
 
• Stroop Color test 
o PA systolic/diastolic, and mean pressure  
▪ Immediately before 


05.31.2017 
 
14 
 
▪ Each 30 seconds during the test (total= 6 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
 
o Blood pressure 
▪ Immediately before 
▪ Each 30 seconds during the test (total= 6 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
o Heart rate 
▪ Continuously recorded during the test and recovery 
o Level of difficulty of the test 
• Quality of Life KCCQ Questionnaire 
o Total score and specifically questions 3,7,8,9 which relate to symptoms of 
congestion  
•  Laboratory Data 
o Serum sodium (in clinic, mEq/L) 
o Serum potassium (in clinic, mEq/L) 
o Blood urea nitrogen (in clinic, mEq/L) 
o Serum creatinine (in clinic, mEq/L) 
o NT-proBNP (in clinic, ng/L)  
o Urine pregnancy test for women of childbearing age  
PA pressure measurements done by the patient at home   
“Acute PAP Measurement”  (Done on Days 5 and 47 and done on the first day of any 
dosing change  ) 
o Baseline Time 1 (time before taking medication) – 1st PA pressure measurement  
o Time of measurement 1 (1 hour post dose) – 2nd PA pressure measurement  
o Time of measurement 2 (2 hours post dose) – 3rd PA pressure measurement 
o Time of measurement 3 (3 hours post dose) – 4th PA pressure measurement  
o Heart rate 
o PA pressures   
o Any instructions required to optimize tracing  
(e.g. breath-hold, turn on pillow, reposition wand) 
o Any comments on PA tracing morphology 
 
Routine Daily Pulmonary Pressure Data   
Transmitted routinely in the morning before meds, emphasis on Mon and Thurs  
o Time of measurement 
o Morning medications taken? No/if yes, how long previously 
o Heart rate 
o PA pressures  (measured at end-expiration if variable) 
o Any comments on PA tracing morphology 
 
 


05.31.2017 
 
15 
 
ALL CLINIC VISITS AFTER RANDOMIZATION:  
 
• Hospitalization or ED visit since last visit?  No / Yes, if yes, When 
• If so, cause: 
o HF/Syncope or Heart rhythm/ Other cardiac / Renal / Pulmonary 
o Other non-cardiac  
• Medication Data 
o Beta blocker total daily dose (metoprolol equivalents, mg/d), any change since the 
last visit?  
o ACEi no/yes (if yes, total daily dose in captopril equivalents, mg/d) , any change 
since the last visit? 
o  ARB no/yes (if yes, total daily dose in valsartan equivalents, mg/d), any change 
since the last visit?    
o Nitrate no/yes (if yes, total daily dose mg), any change since the last visit? 
o Hydralazine no/yes (if yes,  total daily dose mg), any change since the last visit? 
o Diuretic total daily dose (furosemide equivalents, mg/d) , any change since the 
last visit? 
o Use of thiazide diuretic in past 14 days (no/yes) if yes, # days, any change since 
the last visit? 
o Study drug # tablets / day 
• Side Effect Assessment  
o Swelling/respiratory distress/angioedema/anaphylaxis (yes/no) 
o Decreased urinary output (yes/no) 
o Palpitations (yes/no) 
o New/changed difficulty breathing (yes/no) 
o  New/changed orthopnea, paroxysmal nocturnal dyspnea, peripheral edema 
(yes/no) 
• Clinical Assessment   
o History:   
▪ Orthopnea within last 14 days (no/yes) If yes, # days  
▪ Bendopnea within last 14 days (no/yes) If yes, # days  
▪ Dizziness or lightheadedness on standing (no/yes)  
• If yes, rare / 1-2 x weekly /  only if stand quickly / often  
▪ Symptoms limiting bathing and dressing (no/yes) If yes, #days 
o Examination  
▪ HR sitting  
▪ Rhythm (from EKG) regular (SR/paced/ 
▪ SBP/ DBP  mmHg sitting   ///  SBP/DBP mmHg standing 
▪ Jugular venous pressure (estimated cmH20)  
▪ S3 yes/ no 
▪ Systolic murmur  (0,1,2,3,4) 


05.31.2017 
 
16 
 
▪ Rales (absent/bases/one-quarter/one third up) 
▪ Hepatomegaly  no/yes if yes,  1-3, 4-6, > 6 cm) 
▪ Peripheral edema (none/trace/1+/2+/3+/4+)  
o Laboratory Data 
▪ Urine pregnancy test for women of childbearing age 
o PA systolic/ diastolic/ mean pressures at rest (in clinic, mmHg) 
 
Additional Data Obtained At Endpoints As Below:  
 
+ Week 6, Week 12, (Week 24) Week 32, for study endpoints : 
• 6 Minute Walk Test  
o Distance walked (meters)    # stops if any  
o PA pressures after 6 minute walk  
▪ PA systolic/diastolic/mean   
▪ Repeat X 7:  Immediately after peak exercise 5, 10, 15, 20, 25, 30 minutes  
• Double Master’s step test 
o PA pressures after step test  
▪ PA systolic/diastolic/mean   
▪ Repeat X 7:  Immediately after peak exercise 5, 10, 15, 20, 25, 30 minutes  
• Handgrip test 
o Maximal handgrip effort  
o PA systolic/ diastolic/ mean  
▪ Immediately before 
▪ Each 30 seconds during the test (total= 4 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
 
o Blood pressure 
▪ Immediately before 
▪ Each 30 seconds during the test (total= 4 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
o Heart rate 
▪ Continuously recorded during the test and recovery 
 
• Stroop Color test 
o PA systolic/diastolic/ mean   
▪ Immediately before 
▪ Each 30 seconds during the test (total= 6 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
 
o Blood pressure 


05.31.2017 
 
17 
 
▪ Immediately before 
▪ Each 30 seconds during the test (total= 6 measurements) 
▪ Then repeat X 3: 5, 10, 15 minutes after test 
o Heart rate 
▪ Continuously recorded during the test and recovery 
o Level of difficulty of the test 
 
• Quality of Life KCCQ questionnaire, total score and specifically questions 3,7,8,9  
• Natriuretic peptides 
o NT proBNP 
o BNP 
 
+ Week 2, Week 6, Week 8, Week 12,  Week 24,  Week 32 and after any adjustment of 
study medication or if otherwise clinically indicated for standard care 
o Serum sodium (in clinic, mEq/L) 
o Serum potassium (in clinic, mEq/L) 
o Blood urea nitrogen (in clinic, mEq/L) 
o Serum creatinine (in clinic, mEq/L) 
 
Pulmonary pressure monitoring transmitted from home: 
Patients will transmit pressures every morning before taking medications.  Specific case report 
data entry in addition to the clinic measurements and first dose time points at home will include 
PA pressures every Monday and Thursday and daily for 5 days following any change in study 
drug or in other heart failure medications.  All transmitted pressure information remains 
available on the CardioMEMS website so can be retrieved at any time if other questions arise 
about trends from pressure transmitted on other days.  
 
 
 
 
 
 


05.31.2017 
 
18 
 
VI. 
STATISTICAL METHODS AND DATA ANALYSIS 
 
f. Specific Data Variables being Collected for the Study (e.g. Data Collection Sheet)  
Baseline Visit Data Collection Sheet  
Demographic Data 
 
Age 
___________ (years) 
 
Sex 
____Male                    ____Female 
 
Race 
____ White      ____Black     ____Other 
 
Ethnicity 
____ Non-Hispanic     ____Hispanic    
 
Type of Insurance 
____ Medicare     ____Medicaid     ____Commercial  
 
____ Other 
 
Etiology of Heart Failure 
____Male                    ____Non-Ischemic 
 
Ejection Fraction 
___________ (%) 
 
NYHA 
____ I           ____ II            ____ III            ____IV 
 
Number of Previous HF 
Hospitalizations within the 
Past Year 
___________ (hospitalizations) 
Time since diagnosis of heart 
failure 
___________ (years)  
Time Since Placement of 
CardioMEMS 
___________ (months) 
Time Since Most Recent Echo _____< 1 month 
 
_____ 1-5 months 
 
_____  6-12 months 
 
_____ > 1 year 
 
Most Recent Echo Results 
LVEF   _______% 


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19 
 
 
LVDD  _________ mm  
 
MR ___ none   ___ trace   ___ mild   ___mod   ___ 
mod/severe     
         
        ___ severe 
 
TR ___ none   ___ trace   ___ mild   ___mod  ___ mod/severe  
         
        ___ severe 
 
Medication Data 
 
Beta Blocker Total Daily 
Dose 
____________ (metoprolol equivalents, mg/d) 
 
______ Not on a beta blocker  
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
ACEi Total Daily Dose 
____________ (captopril equivalents, mg/d)   
 
______ Not on an ACEi 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 


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20 
 
ARB Total Daily Dose 
____________ (valsartan equivalents, mg/d)   
 
______ Not on an ARB 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
Nitrates 
____________ (total daily dose equivalents, mg/d)   
 
______ Not on nitrates 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 
Hydralazine 
____________ (total daily dose equivalents, mg/d)   
 
______ Not on hydralazine 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 


05.31.2017 
 
21 
 
 
Diuretic Total Daily Dose  
____________ (furosemide equivalents, mg/d)   
 
______ Not on diuretics 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 
Use of thiazide diuretic in past 
14 days 
_____ Yes 
 
If yes, how many days ago?______ days 
 
_____ No 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
Clinical Assessment 
Orthopnea or paroxysmal 
nocturnal dyspnea within last 
14 days  
_____ Yes 
 
If yes, how many days______  
_____ No 
Bendopnea within last 14 
days 
_____ Yes         _______ No 
 
 If yes, how many days? ________ days 
 
Dizziness or lightheadedness 
on standing 
_____ Yes     _____ No dizziness or lightheadedness standing 
 
If yes, how often? 
  


05.31.2017 
 
22 
 
_____ Rare 
 
_____ 1-2x/week 
 
_____ Only if Stand Quickly  
 
_____ Often  
 
 
Symptoms limiting bathing 
and dressing 
_____ Yes           _____ No 
 
If yes, how many days has this happened?______ days 
 
Examination  
 
Heart Rate (sitting)  
___________ (bpm) 
 
Rhythm (from EKG)  
_____ NSR  
 
______ Irregular  
 
______ Paced  
 
Systolic Blood Pressure  
__________ (mmHg) 
 
Diastolic Blood Pressure 
__________ (mmHg) 
 
Systolic Blood Pressure 
(sitting)  
__________ (mmHg) 
 
Diastolic Blood Pressure 
(sitting)  
__________ (mmHg) 
 
Systolic Blood Pressure 
(standing)  
__________ (mmHg) 
 
Diastolic Blood Pressure 
(standing)   
__________ (mmHg) 
 
Jugular Venous Pressure 
___________ (cmH20) 
 
S3 present  
____Yes                    ____No 
 
Systolic Murmur   
____Yes                    ____No 
 
If yes, how severe? _____1/6, ______2/6, ______ 3/6, 
_____4/6, ______5/6, ______6/6  


05.31.2017 
 
23 
 
Rales  
____Yes                    ____No 
 
If yes, how severe? _____ bases, _____1/4, _____ 1/3, 
_____>1/2 or more of the way up  
Hepatomegaly 
____Yes                    ____No 
 
If yes, how severe? _____1-3cm below costal margin,  
_____4-6cm below costal margin, ___ >6cm below costal 
margin 
 
Peripheral Edema 
____None     ____ Trace      ____1+      _____2+ 
 
CardioMEMS Measurements (recorded by staff)  
 
PA Systolic Pressure (at rest)  
___________ (mmHg) 
 
PA Diastolic Pressure (at rest) 
___________ (mmHg) 
 
PA Mean Pressure (at rest)  
___________ (mmHg) 
 
Planned Medications Changes after this Visit  
Do you plan to uptitrate 
Entresto or ACEi/ARB? 
_____ Yes          _____ No  
 
If not, why not?  
_____ Postural hypotension  
 
_____ Resting hypotension  
 
_____ Renal dysfunction  
 
_____ Fatigue  
 
_____ Other (if “other,” describe: 
______________________) 
 
If not, did you consider 
decreasing diuretics instead? 
______ Yes      ______ No  
 
If no, why not?  
 
_____ PAP not low  
 
_____ Signs of fluid retention 
If so, what: ___________________________________ 


05.31.2017 
 
24 
 
 
_____ Symptoms of fluid retention 
If so, what: ___________________________________ 
 
6 Minute Walk Test 
 
Distance Walked 
___________ (meters) 
 
_______ # of stops (if any)  
Stopped Early (before six 
minutes) 
_____ Yes          _____ No  
 
IF “YES” ONLY: (indicating that the patient stopped walking 
before 6 minutes had elapsed)  
 
_______ Time Walked (minutes)  
 
_______ Distance Walked (meters)  
 
REASON FOR STOPPING EARLY (check only 1 as the 
“primary reason”)  
_____ Orthopedic/Joint Pain 
_____ Chest Pain  
_____ Shortness of Breath 
_____ Fatigue 
_____ Leg Pain/Fatigue (not joint related)  
_____ Dizziness 
_____ Other  
 
PA pressures immediately 
after walk 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 5 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 


05.31.2017 
 
25 
 
PA pressures 10 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 15 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 20 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 25 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 30 minutes after 
stopping exercise  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
Quality of Life 
 
KCCQ Score (total)  
___________ (points 
 
Score on Questions 3,7,8,9 
which relate to symptoms of 
congestion 
___________ (points) 
Double Master’s Step test 
 


05.31.2017 
 
26 
 
Stopped Early (before three 
minutes) 
_____ Yes          _____ No  
 
IF “YES” ONLY: (indicating that the patient stopped 
climbing before three minutes had elapsed)  
 
_______ Time stepping (minutes)  
 
_______ Number of trips  
 
REASON FOR STOPPING EARLY (check only 1 as the 
“primary reason”)  
_____ Orthopedic/Joint Pain 
_____ Chest Pain  
_____ Shortness of Breath 
_____ Fatigue 
_____ Leg Pain/Fatigue (not joint related)  
_____ Dizziness 
_____ Other  
 
PA pressures immediately 
after test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 


05.31.2017 
 
27 
 
PA pressures 5 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 10 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 15 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 20 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 


05.31.2017 
 
28 
 
PA pressures 25 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 30 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
Handgrip test 
 
Maximal handrip effort 
Max handgrip________(Pounds Force) 
PA pressures immediately 
before test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure immediately 
before test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate immediately before 
test 
HR _______________(bmp) 


05.31.2017 
 
29 
 
PA pressures at 30s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 30s of 
Handrip 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 30s of Handrip 
HR _______________(bmp) 
PA pressures at 60s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 60s of 
Handrip 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 60s of Handrip 
HR _______________(bmp) 
PA pressures at 90s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 90s of 
Handrip 
BP systolic ___________ (mmHg) 


05.31.2017 
 
30 
 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 90s of Handrip 
HR _______________(bmp) 
PA pressures at 120s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 120s of 
Handrip 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 120s of Handrip 
HR _______________(bmp) 
PA pressures 5 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 5 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 5 minutes after 
stopping the test 
HR _______________(bmp) 
PA pressures 10 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 


05.31.2017 
 
31 
 
 
PA mean ___________ (mmHg) 
Blood pressure 10 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 10 minutes after 
stopping the test 
HR _______________(bmp) 
PA pressures 15 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 15 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 15 minutes after 
stopping the test 
HR _______________(bmp) 
Stroop Color test 
 
PA pressures immediately 
before test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure immediately 
before test 
BP systolic ___________ (mmHg) 


05.31.2017 
 
32 
 
 
BP diastolic___________ (mmHg) 
 
Heart rate immediately before 
test 
HR _______________(bmp) 
PA pressures at 30s of  Stroop 
Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 30s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 30s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 60s of  Stroop 
Color test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 60s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 60s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 90s of  Stroop 
Color test 
PA systolic ___________ (mmHg) 
 


05.31.2017 
 
33 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 90s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 90s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 120s of  
Stroop Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 120s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 120s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 150s of  
Stroop Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 150s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 


05.31.2017 
 
34 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 150s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 180s of  
Stroop Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 180s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 180s of  Stroop 
Color test 
HR _______________(bmp) 
Level of difficulty 
(   ) non-stressful 
(   ) slightly stressful 
(   ) moderately stressful 
(   ) very stressful  
(   ) extremely stressful. 
PA pressures 5 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 5 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 5 minutes after 
stopping the test 
HR _______________(bmp) 


05.31.2017 
 
35 
 
PA pressures 10 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 10 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 10 minutes after 
stopping the test 
HR _______________(bmp) 
PA pressures 15 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 15 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 15 minutes after 
stopping the test 
HR _______________(bmp) 
Laboratory Data 
 
Serum Sodium 
___________ (in clinic, mEq/L) 
 
Serum Potassium 
___________ (in clinic, mEq/L) 
 
Blood Urea Nitrogen 
___________ (in clinic, mEq/L) 
 
Serum Creatinine 
___________ (in clinic, mEq/L) 


05.31.2017 
 
36 
 
 
NT-proBNP 
___________ (ng/L) 
 
Urine Pregnancy Test  
(for women of childbearing 
age)  
_________ (Not Pregnant) 
 
_________ (Pregnant) 
* If pregnant, must discontinue Entresto or ACEi/ARB 
immediately  
  
 
PA Pressure Measurements Done By Patient At Home Collection Sheet  
Acute PAP Measurement (Days 5 and 47 and after any dose change)  
Times recorded by patient  
PAP measurements added by study staff   
Baseline Time  
(time before medications 
taken)  
______:______ AM/PM 
(record time) 
 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
Time medication taken  
______:______ AM/PM 
(record time) 
 
Measurement #1 
(1 hours after dose)  
______:______ AM/PM 
(record time) 
 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
Measurement #2 
(2 hours after dose)  
______:______ AM/PM 
(record time) 
 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 


05.31.2017 
 
37 
 
PA mean ___________ (mmHg) 
 
Measurement #3 
(3 hours after dose)  
______:______ AM/PM 
(record time) 
 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
Heart Rate  
_____ beats/minutes 
 
To be completed by study staff  
Any instructions required to 
optimize tracing 
_____ Yes  
 
If so, what? _________________________________ 
 
_____ No  
 
Any comments on PA tracing 
morphology 
 
 
Routine Daily PA Pressure Data   
Times recorded by patient  
PAP measurements added by study staff   
Time of PAP Measurement   
______:______ AM/PM 
(record time) 
Morning Medications Taken?  
_____ Yes  
 
If yes, when? ______:______ AM/PM 
                         (record time) 
 
_____ No  
 
Heart Rate  
________ beats/minute 
 
Measurement (study staff)  
 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 


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38 
 
 
Data Collection Form for ALL Clinic Visits After Randomization 
Hospitalization or Emergency Room Visits 
Any hospitalizations or ER 
visits since your last study visit?  
_____ Yes          _____ No  
 
If yes, for what?  
 
_____ Heart Failure  
_____ Syncope  
_____ Heart Rhythm  
_____ Other cardiac  
_____ Kidney/Renal issue 
_____ Pulmonary/Lung issue  
_____ Other, non-cardiac reason  
 
Medication Data 
 
Beta Blocker Total Daily Dose 
____________ (metoprolol equivalents, mg/d) 
 
______ Not on a beta blocker  
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 
ACEi Total Daily Dose 
____________ (captopril equivalents, mg/d)   
 
______ Not on an ACEi 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 


05.31.2017 
 
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_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
ARB Total Daily Dose 
____________ (valsartan equivalents, mg/d)   
 
______ Not on an ARB 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
Nitrates 
____________ (total daily dose equivalents, mg/d)   
 
______ Not on nitrates 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 


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40 
 
Hydralazine 
____________ (total daily dose equivalents, mg/d)   
 
______ Not on hydralazine 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 
Diuretic Total Daily Dose  
____________ (furosemide equivalents, mg/d)   
 
______ Not on diuretics 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 
Use of thiazide diuretic in past 
14 days 
_____ Yes 
 
If yes, how many days ago?______ days 
 
_____ No 
 
Any dose change since most recent clinic visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 


05.31.2017 
 
41 
 
Dose change: From __________mg/d to _________ mg/d.  
 
 
Study Drug # tablets/day  
_____ Tablets/day  
 
Was your Study Drug dose 
changed since your last clinic 
visit?  
______ Yes               _______No 
 
If there has been a recent dose change, describe:  
 
_______ Increased Dose        ________ Decrease Dose  
 
Dose change: From __________mg/d to _________ mg/d.  
 
 
Side Effect Assessment  
(within the last 14 days, does the patient report any of the following symptoms that are 
new or different/worsened) 
Swelling/respiratory 
distress/angioedema/anaphylaxis 
 
_____ Yes          _____ No  
 
If yes, quantify severity (check most severe symptom) 
 
_____ Swelling (least severe)   
 
_____ Respiratory Distress 
 
_____ Angioedema 
 
_____ Anaphylaxis (most severe)  
 
Palpitations 
_____ Yes          _____ No 
 
Difficulty Breathing/Shortness 
of Breath 
_____ Yes          _____ No 
 
Orthopnea 
 
_____ Yes          _____ No 
Paroxysmal Nocturnal Dyspnea 
_____ Yes          _____ No 
 
Peripheral Edema 
_____ Yes          _____ No 
 
Clinical Assessment 


05.31.2017 
 
42 
 
Orthopnea or paroxysmal 
nocturnal dyspnea within last 
14 days  
_____ Yes 
 
If yes, how many days? _____days 
 
_____ No 
 
Bendopnea within last 14 days 
_____ Yes 
 
If yes, how many days? ______ days  
 
_____ No 
 
Dizziness or lightheadedness 
on standing 
_____ Yes     _____ No dizziness or lightheadedness 
standing 
 
If yes, how often?  
_____ Rare 
 
_____ 1-2x/week 
 
_____ Only if Stand Quickly  
 
_____ Often  
 
 
Symptoms limiting bathing and 
dressing 
_____ Yes 
 
If yes, how many days?______ days  
 
_____ No 
 
Examination  
 
Heart Rate (sitting)  
___________ (bpm) 
 
Rhythm (from EKG)  
_____ NSR  
 
______ Irregular  
 
______ Paced  
 
Systolic Blood Pressure 
(sitting)  
__________ (mmHg) 
 
Diastolic Blood Pressure 
(sitting)  
__________ (mmHg) 
 


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43 
 
Systolic Blood Pressure 
(standing)  
__________ (mmHg) 
 
Diastolic Blood Pressure 
(standing)   
__________ (mmHg) 
 
Jugular Venous Pressure 
___________ (cmH20) 
 
S3 present  
____Yes                    ____No 
 
Systolic Murmur   
____Yes                    ____No 
 
If yes, how severe? _____1/6, ______2/6, ______ 3/6, 
_____4/6, ______5/6, ______6/6  
 
Rales  
____Yes                    ____No 
 
If yes, how severe? _____ bases, _____1/4, _____ 1/3, 
_____>1/2 or more of the way up  
Hepatomegaly 
____Yes                    ____No 
 
If yes, how severe? _____1-3cm below costal margin,  
_____4-6cm below costal margin, ___ >6cm below costal 
margin 
 
Peripheral Edema 
____None     ____ Trace      ____1+      _____2+ 
 
Laboratory Data 
 
Urine Pregnancy Test  
(for women of childbearing 
age)  
_________ (Not Pregnant) 
 
_________ (Pregnant) 
* If pregnant, must discontinue Entresto or ACEi/ARB 
immediately  
  
CardioMEMS Measurements (recorded by staff in clinic)  
 
PA Systolic Pressure (at rest)  
___________ (mmHg) 
 
PA Diastolic Pressure (at rest) 
___________ (mmHg) 
 
PA Mean Pressure (at rest)  
___________ (mmHg) 
 
 


05.31.2017 
 
44 
 
Additional Data Obtained at Endpoint Visits 
(In addition to the data collection sheet above for ALL visits, this additional data collection sheet 
will be used on weeks 6, 12, 24, 32  only)   
6 Minute Walk Test 
 
Distance Walked 
___________ (meters) 
 
_______ # of stops (if any)  
Stopped Early (before six 
minutes) 
_____ Yes          _____ No  
 
IF “YES” ONLY: (indicating that the patient stopped walking 
before 6 minutes had elapsed)  
 
_______ Time Walked (minutes)  
 
_______ Distance Walked (meters)  
 
REASON FOR STOPPING EARLY (check only 1 as the 
“primary reason”)  
_____ Orthopedic/Joint Pain 
_____ Chest Pain  
_____ Shortness of Breath 
_____ Fatigue 
_____ Leg Pain/Fatigue (not joint related)  
_____ Dizziness 
_____ Other  
 
PA pressures immediately 
after stopping walk 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 5 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 


05.31.2017 
 
45 
 
PA pressures 10 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 15 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 20 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 25 minutes after 
stopping exercise 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 30 minutes after 
stopping exercise  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
Quality of Life 
 
KCCQ Score (total)  
___________ (points 
 
Score on Questions 3,7,8,9 
which relate to symptoms of 
congestion 
___________ (points) 
Double Master’s Step test 
 


05.31.2017 
 
46 
 
Stopped Early (before three 
minutes) 
_____ Yes          _____ No  
 
IF “YES” ONLY: (indicating that the patient stopped 
climbing before three minutes had elapsed)  
 
_______ Time stepping (minutes)  
 
_______ Number of trips  
 
REASON FOR STOPPING EARLY (check only 1 as the 
“primary reason”)  
_____ Orthopedic/Joint Pain 
_____ Chest Pain  
_____ Shortness of Breath 
_____ Fatigue 
_____ Leg Pain/Fatigue (not joint related)  
_____ Dizziness 
_____ Other  
 
PA pressures immediately 
after test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 5 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 10 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 15 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 


05.31.2017 
 
47 
 
 
PA mean ___________ (mmHg) 
 
PA pressures 20 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 25 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
PA pressures 30 minutes after 
stopping test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
 
Handgrip test 
 
Maximal handrip effort 
Max handgrip________(Pounds Force) 
PA pressures immediately 
before test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure immediately 
before test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 


05.31.2017 
 
48 
 
Heart rate immediately before 
test 
HR _______________(bmp) 
PA pressures at 30s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 30s of 
Handrip 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 30s of Handrip 
HR _______________(bmp) 
PA pressures at 60s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 60s of 
Handrip 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 60s of Handrip 
HR _______________(bmp) 
PA pressures at 90s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 


05.31.2017 
 
49 
 
Blood pressure at 90s of 
Handrip 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 90s of Handrip 
HR _______________(bmp) 
PA pressures at 120s of  
Handrip  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 120s of 
Handrip 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 120s of Handrip 
HR _______________(bmp) 
PA pressures 5 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 5 minutes after 
stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 5 minutes after 
stopping the test 
HR _______________(bmp) 
PA pressures 10 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 


05.31.2017 
 
50 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 10 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 10 minutes after 
stopping the test 
HR _______________(bmp) 
PA pressures 15 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 15 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 15 minutes after 
stopping the test 
HR _______________(bmp) 
Stroop Color test 
 
PA pressures immediately 
before test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 


05.31.2017 
 
51 
 
Blood pressure immediately 
before test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate immediately before 
test 
HR _______________(bmp) 
PA pressures at 30s of  Stroop 
Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 30s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 30s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 60s of  Stroop 
Color test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 60s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 60s of  Stroop 
Color test 
HR _______________(bmp) 


05.31.2017 
 
52 
 
PA pressures at 90s of  Stroop 
Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 90s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 90s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 120s of  
Stroop Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 120s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 120s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 150s of  
Stroop Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 


05.31.2017 
 
53 
 
Blood pressure at 150s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 150s of  Stroop 
Color test 
HR _______________(bmp) 
PA pressures at 180s of  
Stroop Color test 
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure at 180s of  
Stroop Color test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate at 180s of  Stroop 
Color test 
HR _______________(bmp) 
Level of difficulty 
(   ) non-stressful 
(   ) slightly stressful 
(   ) moderately stressful 
(   ) very stressful  
(   ) extremely stressful. 
PA pressures 5 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 5 minutes after 
stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 


05.31.2017 
 
54 
 
 
Heart rate 5 minutes after 
stopping the test 
HR _______________(bmp) 
PA pressures 10 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 10 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 10 minutes after 
stopping the test 
HR _______________(bmp) 
PA pressures 15 minutes after 
stopping the test  
PA systolic ___________ (mmHg) 
 
PA diastolic___________ (mmHg) 
 
PA mean ___________ (mmHg) 
Blood pressure 15 minutes 
after stopping the test 
BP systolic ___________ (mmHg) 
 
BP diastolic___________ (mmHg) 
 
Heart rate 15 minutes after 
stopping the test 
HR _______________(bmp) 
Laboratory Data (natriuretic peptides)  
 
NT-proBNP 
___________ (ng/L) 
 
 
Additional Lab Data  


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55 
 
(Collected on Weeks 2, 6, 8, 12, 24, 32 or after ANY adjustment of study medication or if 
otherwise indicated for standard care) 
Laboratory Data 
 
Serum Sodium 
___________ (in clinic, mEq/L) 
 
Serum Potassium 
___________ (in clinic, mEq/L) 
 
Blood Urea Nitrogen 
___________ (in clinic, mEq/L) 
 
Serum Creatinine 
___________ (in clinic, mEq/L) 
 
 
 
 


05.31.2017 
 
56 
 
Study Endpoints  
 
Co-Primary Endpoints:  
 
Intensive Phase:  
• Difference between mean change in PAPm after 6 weeks on Entresto compared to 6 
weeks on continued ACEI/ARB  
Acute First-Day Response  
• Change in PAPm between baseline and first 3 hours after the first dose of Entresto  
Secondary Endpoints:  
• The mean change in PAPm in both groups on Entresto from week 12 to week 32 in 
longitudinal study 
• Difference between mean change in PAPm from baseline on  ACEI/ARB to 6 weeks on 
Entresto (groups A and B) 
• *Change in exercise recovery PAPm  
• *Change PAPm, blood pressure and heart rate during isometric exercise and recovery 
after isometric exercise. 
• Change PAPm, blood pressure and heart rate during isometric exercise and recovery 
after mental stress chalenge. 
• *Change in  NT-proBNP and the BNP/NT-proBNP ratio  
Tertiary Endpoints (Exploratory):  
• 
Relationship of change in PAPm to change in the questions in the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) 3, 7,8,9 which describe the severity of 
symptoms of congestion 
• 
Mean change in total daily diuretic dose while on Entresto 
Other Endpoints:  
• Death  
• All-cause re-hospitalization  
• Need to progress to advanced therapies (i.e. start home inotropes, place a ventricular 
assist device or list for cardiac transplantation)  
• Unscheduled visits for IV loop diuretics  
• Other interventions (i.e. nutrition referrals)  
 
*Will be 3 comparisons:  


05.31.2017 
 
57 
 
1)  6 weeks of Entresto vs 6 weeks of continued ACEI/ARB (Group A compared to B at 6 weeks) 
2) Baseline on ACEI/ARB compared to 6 weeks on Entresto (Groups A and B combined) 
3) 12 weeks on Entresto compared to 32 weeks on Entresto in longitudinal study (all pts) 
 
Statistical Analysis  
Co-Primary Endpoints:  
Intensive Phase:  
• Determine the difference between mean change in mean pulmonary artery pressure 
(PAPm) after 6 weeks on Entresto compared to 6 weeks on continued ACEi/ARB  
o Statistical Plan: These changes from baseline to 6 weeks constitute continuous 
data. Therefore, the distribution of average changes in PAPm from baseline to 6 
weeks will be assessed in Group A and Group B. If both distributions are normal, 
t-testing will be performed to compare the mean changes between groups. If the 
distributions are not normal, Wilcoxon testing will be used. P <0.05 will be 
significant. 
 
Acute First-Day Response  
• Determine the change in PAPm between baseline and first 3 hours after the first dose of 
Entresto  
o Statistical Plan: These changes in PAPm from baseline to 2 hours after Entresto 
constitute a distribution of continuous data. The distribution of change in PAPm 
from the morning baseline visit (before Entresto) to 2 hours after the first dose of 
Entresto will be assessed in both groups. The distribution of changes will be 
assessed for normality. If the distributions are normal, the results will be 
presented as means with standard errors. If the distributions are not normal, the 
results will be presented as medians with interquartile ranges.  
 
Secondary Endpoints:  
• Determine the mean change in PAPm in both groups on Entresto from week 12 to week 
32 in longitudinal study 
o Statistical Plan: The changes in PAPm from week 12 to week 32 constitute 
continuous data. The distribution of average change in PAPm from week 8 to 
week 32 will be assessed in both group A and B. The distribution of changes in 


05.31.2017 
 
58 
 
PAPm will be assessed for normality. If the distributions are normal, the results 
will be presented as means with standard errors. If the distributions are not 
normal, the results will be presented as medians with interquartile ranges.  
 
• Determine the difference between mean change in PAPm from baseline on  ACEI/ARB to 
6 weeks on Entresto (Groups A and B) 
o Statistical Plan: The distribution of the average change in PAPm from baseline to 
6 weeks will be assessed in Group A and combined with the distribution of 
change in PAPm from week 6 to week 12 in Group B. The combined distributions 
will be assessed for normality. If the combined distribution of changes in PAPm is 
normal, the results will be presented as means with standard errors. If the 
distributions are not normal, the results will be presented as medians with 
interquartile ranges.  
 
• Determine the impact of therapy over time on standard 6 minute walk test, assessing  
distance walked and changes in PAPm during recovery after the walk.  
o Statistical Plan: These changes in distance walked from baseline to 6 weeks 
constitute continuous data. Therefore, the distribution of average changes in 
PAPm from baseline to 6 weeks will be assessed in Group A and Group B. If both 
distributions are normal, t-testing will be performed to compare the mean changes 
between groups. If the distributions are not normal, Wilcoxon testing will be used. 
P <0.05 will be significant. 
o Statistical Plan (Intensive Phase, patients in both groups as their own control 
after 6 weeks of Entresto- Group A: week 6 minus baseline; Group B: week 12 
minus week 6): The change in PAPm from pre to peak exercise at baseline and at 
5 minute intervals for 30 minutes of recovery will be compared to the change in 
PAPm from pre to peak exercise and at 5 minute intervals for 30 minutes of 
recovery at 6 weeks in Group A.  If the distributions are normal, the results will 
be presented as means with standard errors. If the distributions are not normal, the 
results will be presented as medians with interquartile ranges. The change in 
PAPm from pre to peak exercise at 6 weeks and at 5 minute intervals for 30 
minutes of recovery will be compared to the change in PAPm from pre to peak 
exercise and at 5 minute intervals for 30 minutes of recovery at week 12 in Group 
B.  If the distributions are normal, the results will be presented as means with 
standard errors. If the distributions are not normal, the results will be presented as 
medians with interquartile ranges. 


05.31.2017 
 
59 
 
o Statistical Plan (Intensive Phase, patients on the Entresto Group A: week 6 minus 
baseline) compared to patients on continued ACEi/ARB therapy; Group B: week 
6 minus baseline): The change in PAPm from pre to peak exercise and at 5 
minute intervals for 30 minutes of recovery at 6 weeks in Group A will be 
compared to the change in PAPm from pre to peak exercise and at 5 minute 
intervals for 30 minutes of recovery at 6 weeks in Group B.  If both distributions 
are normal, t-testing will be performed to compare the mean changes between 
groups. If the distributions are not normal, Wilcoxon testing will be used. P <0.05 
will be significant. 
o Statistical Plan (Longitudinal Phase, Patients in both groups - week 32 minus 
week 12): The change in PAPm from pre to peak exercise and at 5 minute 
intervals for 30 minutes of recovery at 32 weeks will be compared to the change 
in PAPm from pre to peak exercise and at 5 minute intervals for 30 minutes of 
recovery at 12 weeks in both groups. If the distributions are normal, the results 
will be presented as means with standard errors. If the distributions are not 
normal, the results will be presented as medians with interquartile ranges. 
• Determine the impact of therapy over time on standard double Master’s step test, 
assessing changes in PAPm during recovery after the test.  
o Statistical Plan (Intensive Phase, patients in both groups as their own control 
after 6 weeks of Entresto- Group A: week 6 minus baseline; Group B: week 12 
minus week 6): The change in PAPm from pre to peak exercise at baseline and at 
5 minute intervals for 30 minutes of recovery will be compared to the change in 
PAPm from pre to peak exercise and at 5 minute intervals for 30 minutes of 
recovery at 6 weeks in Group A.  If the distributions are normal, the results will 
be presented as means with standard errors. If the distributions are not normal, the 
results will be presented as medians with interquartile ranges. The change in 
PAPm from pre to peak exercise at 6 weeks and at 5 minute intervals for 30 
minutes of recovery will be compared to the change in PAPm from pre to peak 
exercise and at 5 minute intervals for 30 minutes of recovery at week 12 in Group 
B.  If the distributions are normal, the results will be presented as means with 
standard errors. If the distributions are not normal, the results will be presented as 
medians with interquartile ranges. 
o Statistical Plan (Intensive Phase, patients on the Entresto Group A: week 6 minus 
baseline) compared to patients on continued ACEi/ARB therapy; Group B: week 
6 minus baseline): The change in PAPm from pre to peak exercise and at 5 
minute intervals for 30 minutes of recovery at 6 weeks in Group A will be 
compared to the change in PAPm from pre to peak exercise and at 5 minute 
intervals for 30 minutes of recovery at 6 weeks in Group B.  If both distributions 
are normal, t-testing will be performed to compare the mean changes between 


05.31.2017 
 
60 
 
groups. If the distributions are not normal, Wilcoxon testing will be used. P <0.05 
will be significant. 
o Statistical Plan (Longitudinal Phase, Patients in both groups - week 32 minus 
week 12): The change in PAPm from pre to peak exercise and at 5 minute 
intervals for 30 minutes of recovery at 32 weeks will be compared to the change 
in PAPm from pre to peak exercise and at 5 minute intervals for 30 minutes of 
recovery at 12 weeks in both groups. If the distributions are normal, the results 
will be presented as means with standard errors. If the distributions are not 
normal, the results will be presented as medians with interquartile ranges. 
• Determine the impact of therapy over time on standard Handgrip test, assessing changes 
in PAPm, blood pressure and heart rate during test and recovery.  
o Statistical Plan (Intensive Phase, patients in both groups as their own control 
after 6 weeks of Entresto- Group A: week 6 minus baseline; Group B: week 12 
minus week 6): The change in PAPm, blood pressure and heart rate from pre to 
peak isometric exercise at baseline and at 5 minute intervals for 15 minutes of 
recovery will be compared to the changes in PAPm, blood pressure and heart rate 
from pre to peak isometric exercise and at 5 minute intervals for 15 minutes of 
recovery at 6 weeks in Group A.  If the distributions are normal, the results will 
be presented as means with standard errors. If the distributions are not normal, the 
results will be presented as medians with interquartile ranges. The change in 
PAPm, blood pressure and heart rate from pre to peak isometric exercise at 6 
weeks and at 5 minute intervals for 15 minutes of recovery will be compared to 
the change in PAPm, blood pressure and heart rate from pre to peak isometric 
exercise and at 5 minute intervals for 15 minutes of recovery at week 12 in Group 
B.  If the distributions are normal, the results will be presented as means with 
standard errors. If the distributions are not normal, the results will be presented as 
medians with interquartile ranges. 
o Statistical Plan (Intensive Phase, patients on the Entresto Group A: week 6 minus 
baseline) compared to patients on continued ACEi/ARB therapy; Group B: week 
6 minus baseline): The change in PAPm, blood pressure and heart rate from pre to 
peak isometric exercise and at 5 minute intervals for 15 minutes of recovery at 6 
weeks in Group A will be compared to the change in PAPm, blood pressure and 
heart rate from pre to peak isometric exercise and at 5 minute intervals for 15 
minutes of recovery at 6 weeks in Group B.  If both distributions are normal, t-
testing will be performed to compare the mean changes between groups. If the 
distributions are not normal, Wilcoxon testing will be used. P <0.05 will be 
significant. 
o Statistical Plan (Longitudinal Phase, Patients in both groups - week 32 minus 
week 12): The change in PAPm, blood pressure and heart rate from pre to peak 


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isometric exercise and at 5 minute intervals for 15 minutes of recovery at 32 
weeks will be compared to the change in PAPm, blood pressure and heart rate 
from pre to peak isometric exercise and at 5 minute intervals for 15 minutes of 
recovery at 12 weeks in both groups. If the distributions are normal, the results 
will be presented as means with standard errors. If the distributions are not 
normal, the results will be presented as medians with interquartile ranges. 
• Determine the impact of therapy over time on standard Stroop Color test, assessing 
changes in PAPm, blood pressure and heart rate during test and recovery.  
o Statistical Plan (Intensive Phase, patients in both groups as their own control 
after 6 weeks of Entresto- Group A: week 6 minus baseline; Group B: week 12 
minus week 6): The change in PAPm, blood pressure and heart rate during Stroop 
Color test at baseline and at 5 minute intervals for 15 minutes of recovery will be 
compared to the changes in PAPm, blood pressure and heart rate during Stroop 
Color test and at 5 minute intervals for 15 minutes of recovery at 6 weeks in 
Group A.  If the distributions are normal, the results will be presented as means 
with standard errors. If the distributions are not normal, the results will be 
presented as medians with interquartile ranges. The change in PAPm, blood 
pressure and heart rate during Stroop Color test at 6 weeks and at 5 minute 
intervals for 15 minutes of recovery will be compared to the change in PAPm, 
blood pressure and heart rate during Stroop Color test and at 5 minute intervals 
for 15 minutes of recovery at week 12 in Group B.  If the distributions are normal, 
the results will be presented as means with standard errors. If the distributions are 
not normal, the results will be presented as medians with interquartile ranges. 
o Statistical Plan (Intensive Phase, patients on the Entresto Group A: week 6 minus 
baseline) compared to patients on continued ACEi/ARB therapy; Group B: week 
6 minus baseline): The change in PAPm, blood pressure and heart rate during 
Stroop Color test and at 5 minute intervals for 15 minutes of recovery at 6 weeks 
in Group A will be compared to the change in PAPm, blood pressure and heart 
rate during Stroop Color test and at 5 minute intervals for 15 minutes of recovery 
at 6 weeks in Group B.  If both distributions are normal, t-testing will be 
performed to compare the mean changes between groups. If the distributions are 
not normal, Wilcoxon testing will be used. P <0.05 will be significant. 
o Statistical Plan (Longitudinal Phase, Patients in both groups - week 32 minus 
week 12): The change in PAPm, blood pressure and heart rate during Stroop 
Color test and at 5 minute intervals for 15 minutes of recovery at 32 weeks will be 
compared to the change in PAPm, blood pressure and heart rate during Stroop 
Color test and at 5 minute intervals for 15 minutes of recovery at 12 weeks in both 
groups. If the distributions are normal, the results will be presented as means with 


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standard errors. If the distributions are not normal, the results will be presented as 
medians with interquartile ranges. 
 
• Determine the change in  NT-proBNP and the BNP/NT-proBNP ratio  
o Statistical Plan (Intensive Phase, patients in both groups as their own control - 
Group A: week 4 minus baseline; Group B: week 8 minus week 4)  The change in 
NT-proBNP from baseline to week 6 will be assessed in Group A and combined 
with the change in NT-proBNP levels from week 6 to week 12  in Group B. These 
distributions will be continuous distributions. If the distributions are normal, the 
results will be presented as means with standard errors. If the distributions are not 
normal, the results will be presented as medians with interquartile ranges. 
o Statistical (Intensive Phase, patients on the Entresto Group A: week 6 minus 
baseline) compared to patients on continued ACEi/ARB therapy; Group B: week 
6 minus baseline): The change in NT-proBNP levels will be assessed from 
baseline to week 6 in Group A and Group B. If both distributions are normal, t-
testing will be performed to compare the mean changes between groups. If the 
distributions are not normal, Wilcoxon testing will be used. P <0.05 will be 
significant. 
o Statistical Plan (Longitudinal Phase, Patients in both groups - week 32 minus 
week 8): The change in NT-proBNP levels from week 12 to week 32 will be 
assessed in both groups. If the distributions are normal, the results will be 
presented as means with standard errors. If the distributions are not normal, the 
results will be presented as medians with interquartile ranges. 
 
Tertiary Endpoints (Exploratory):  
• 
Relationship of change in PAPm to change in the questions in the Kansas City 
Cardiomypathy Questionnaire (KCCQ)  3, 7,8,9 which describe the severity of 
symptoms of congestion 
o Statistical Plan (Intensive Phase, patients in both groups as their own control - 
Group A: week 6 minus baseline; Group B: week 12 minus week 6): The change 
in KCCQ questions #3, 7, 8 & 9 will be assessed from baseline to week 6 in 
Group A and from week 6 to week 12 in Group B. The change in “score” for 
these four questions will be a continuous distribution when the groups are 
combined. If the combined distribution is normal, the results will be presented as 
means with standard errors. If the distributions are not normal, the results will be 
presented as medians with interquartile ranges. 


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63 
 
o Statistical Plan (Intensive Phase, patients on the Entresto Group A: week 6 minus 
baseline) compared to patients on continued ACEi/ARB therapy; Group B: week 
6 minus baseline): The change in KCCQ questions #3, 7, 8 & 9 from baseline to 
week 4 will be assessed in Group A and Group B. The change in  “score” for 
these four questions will be a continuous distribution for both groups. If both 
distributions are normal, t-testing will be performed to compare the mean changes 
between groups. If the distributions are not normal, Wilcoxon testing will be used. 
P <0.05 will be significant. 
o Statistical Plan (Longitudinal Phase, Patients in both groups - week 32 minus 
week 12): The change in KCCQ questions #3, 7, 8 & 9 from week 12 to week 32 
will be assessed in both groups. The change in “score” for these four questions 
will be a continuous distribution when the groups are combined.  If the 
distribution is normal, the results will be presented as means with standard errors. 
If the distributions are not normal, the results will be presented as medians with 
interquartile ranges. 
 
• 
Mean change in total daily diuretic dose while on Entresto 
o Statistical Plan (Intensive Phase, patients in both groups as their own control 
- Group A: week 6 minus baseline; Group B: week 12 minus week 6): The 
change in total daily diuretic dose from baseline to week 6 in Group A and 
from week 6 to week 12 in Group B will be assessed. If the distributions are 
normal, the results will be presented as means with standard errors. If the 
distributions are not normal, the results will be presented as medians with 
interquartile ranges. 
o Statistical Plan (Intensive Phase, patients on the Entresto Group A: week 6 
minus baseline) compared to patients on continued ACEi/ARB therapy; Group 
B: week 6 minus baseline):  The change in total daily diuretic dose score from 
baseline to week 6 in Group A and Group B will be assessed. If both 
distributions are normal, t-testing will be performed to compare the mean 
changes between groups. If the distributions are not normal, Wilcoxon testing 
will be used. P <0.05 will be significant. 
o Statistical Plan Plan (Longitudinal Phase, Patients in both groups - week 32 
minus week 12): The change in total daily diuretic dose from week 12 to week 
32 will be assessed in both groups. If the distributions are normal, the results 
will be presented as means with standard errors. If the distributions are not 
normal, the results will be presented as medians with interquartile ranges. 
 
 
Power Analysis 
There will be 20 patients total, 10 in each group.  


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64 
 
Between group comparison: This sample size will provide 90% power with 2-sided alpha of 0.05 
to detect a 20% difference between the 2 groups (Entresto and ACEI/ARB) in the PAPm change 
at 6 weeks, based on an assumed baseline PAPm of 25 mm, using a t-test with a standard 
deviation in the mean change of as high as 3.4. We do not yet have data on which to estimate the 
standard deviation of this change, but we have found a standard deviation of 3-4 mm Hg of 
PAPm pressures during 5 day periods in stable patients followed on Cardiomems devices at 
Brigham and Women’s Hospital (unpublished data).  
All patients after 6 weeks of Entresto compared to chronic ACEI/ARB at baseline: There is 
additional power for this highest secondary endpoint.  Assuming the PAPm baseline on 
ACEI/ARB mean of 25mm,  a sample size of 20 patients will provide 90% power with two-sided 
alpha of 0.05 paired t-test to detect a 20% decrease (to PAPm of 20 mm) after 6 weeks of 
Entresto, with a standard deviation for the change as high as 6.8.   
 
VII. 
RISKS AND DISCOMFORTS 
 
Complications from Surgical and Non-Surgical Procedures : Not applicable to this study. There 
are no surgical and non-surgical procedures.  
 
a. Although all patients are eligible for open-label Entresto at randomization, those randomized 
to group B  will  be initiated 6 weeks later than those in group A. This may delay access to 
the potential incremental benefits of Entresto; however, there is currently a wide variation of 
practice in initiation of Entresto.  This is partly relatd to cost and partly to concern for how 
best to titrate this agent in the setting of diuretics and beta blocking agents that the patient 
will continue to take.   
 
b. Drug Side Effects and Toxicities 
Subjects are not exposed to any risks other than those occurring during standard  approved care 
for HFrEF, which includes both the medication Entresto and the CardioMEMS monitoring 
device. The only way in which their enrollment in the study differs from standard of care is that 
they will undergo more frequent monitoring, which increases the safety of drug titration to avoid  
lowering of filling pressures to levels that might be associated with postural hypotension when  
Entresto is added to their previous HF regimen.  
It is unlikely that there will be any adverse effects of holding ACEI/ARB for 2 days (minimum 
36 hours as per FDA labelling) at the beginning of the study. For the A group, this would occur 
anyway for safety, as a washout period of at least 2 days (minimum 36 hours as per FDA 
labelling) is required before initiation of Entresto.  For the B group who will resume ACEI/ARB 
after 2 days (minimum 36 hours as per FDA labelling), such pauses in one component of therapy 


05.31.2017 
 
65 
 
are common around the time of surgery and are not anticipated to lead to any symptoms, as the 
other medications will be continued as usual.    
Common: Based on Novartis’ published prescribing guidelines for Entresto and previous clinical 
trials, the major side effects are similar to ACEi/ARB therapy: hypotension, hyperkalemia and 
renal dysfunction. All of these potential side effects will all be monitored for by study staff with 
frequent lab work, as is standard of care. In addition, due to their enrollment in this trial, 
hemodynamic assessment (including blood pressure) will be checked at each visit and PA 
pressures will be monitored daily by patient and reviewed by the study staff. This will increase 
the patient’s level of safety as compared to standard clinical practice. Any dose changes will be 
followed by “acute PAP measurements” the next day and safety lab work as clinically indicated.  
Uncommon: Similar to ACEi therapy, Entresto has a small risk of angioedema (0.2% in the 
Entresto group compared to 0.1% in the Enalapril group in the PARADIGM trial). These events 
have to date not been known to cause airway compromise.  
To eliminate any increased risk of angioedema from prior ACEi exposure in this study, all 
patients will undergo a mandatory 2 day (minimum 36 hours as per FDA labelling) washout 
period between any ACEi administration and any Entresto administration. This is consistent with 
prior clinical trials as well as the standard of care and for any patient switching from ACEi to 
Entresto, regardless of whether or not they were enrolled in this study.  
If a patient has an adverse reaction to any drug in the study (ACEi, ARB or Entresto) that cannot 
be ameliorated with dose reduction or adjustment, the medication will be stopped. No patients 
will be “removed” from the study. Even if a patient experiences symptoms that require cessation 
of the medication, we will continue to monitor them for the duration of the study. 
 
c. Device Complications/Malfunctions 
Subjects are not exposed to any risks from their monitoring device other than those consistent 
with the standard of care for HFrEF. All of the patients enrolled in this study already have 
CardioMEMS devices in place for clinical indications. Therefore, they incur no additional risk 
from the CardioMEMS device by enrolling in this study. There is essentially no risk from 
making pressure measurements and transmitting them to a central server.  
d. Psychological (Non-Medical) Risks    
Common: There are no expected, common psychological risks to the patients in this study. 
Patients undergoing pulmonary pressure monitoring at home generally feel reassured by regular 
transmission of data to a health care team. Monitoring in this study will be even more frequent 
and intensive than normal care, which may be even more reassuring to the patient.  Uncommon: 
There are no expected, uncommon psychological risks to the patient from participation in this 


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study. If a patient experiences any new psychological symptoms during the course of this study, 
he/she will be referred, as per standard care, to the appropriate psychological and/or psychiatric 
resources.  
e. Radiation Risks  
This is not applicable to this study since patients are not exposed to radiation during this study. 
No statement from the Radiation Safety Committee is necessary.  
 
VIII. POTENTIAL BENEFITS 
 
a. Potential Benefits to Participating Individuals  
The subjects enrolled in this study will receive Entresto at no cost. This medication decreases 
both HFrEF mortality and hospital readmission rates.. Patients enrolled in this study will be 
provided with Entresto for the duration of the study (Group A 32 weeks, Group B 26 weeks).  At 
the conclusion of the trial, subjects can discuss receiving Entresto as part of their heart failure 
medical therapy with their physician. It is likely that the information gained from monitoring 
PAP will allow earlier identification of a need for adjustment in a concomitant medication. This 
could lead to lower incidence of reversible side effects such as hypotension and renal 
dysfunction. As compensation for patient time and effort, the study will provide $25/visit for 
each of the 8 required clinic visits during this study. This will cover both the cost of parking ($10 
for up to 4 hours in the BWH patient parking lot) and the cost of a meal at the hospital. 
 
 
b. Potential Benefits to Society  
It is hoped that this study will help the medical community to better understand what effect, if 
any, Entresto has on pulmonary pressures. It is hoped that this information will allow physicians 
to better select the right doses and to adjust other medications with Entresto for greater benefit  
and safety.  If, as anticipated,  Entresto is shown to cause a sustained decrease in PA pressures, a 
further trial can be designed to determine if and how it could delay or prevent the development 
of secondary right-sided heart failure, which often heralds irreversible decompensation for 
patients with reduced left ventricular ejection fraction. 
 
 
IX. 
SAFETY MONITORING AND REPORTING 
 
a. Independent Monitoring of Source Data 


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Trained research assistants will be responsible for inputting the data into the locked study 
database. The study’s project coordinator will then be responsible for verifying key baseline data 
within one week of enrollment for each patient enrolled. The project coordinator will also review 
the study data on a monthly basis thereafter for accuracy. The study database will be checked 
monthly using random audits of ~10% of subjects for data for missing, out-of-range, or 
inconsistent values.   
 
b. Safety Monitoring 
Due to the fact that we are using an FDA approved drug for its FDA approved indication and a 
previously-placed FDA approved device for its FDA approved indication, we will not have a 
formal Data Safety Monitoring Board. Nevertheless, we will take all necessary steps to ensure 
the safety of our patients and the validity of the results.  
All of the study data will be stored on a Partners desktop computer housed in a locked office in 
the Advanced Heart Failure section of Building A at BWH. A dedicated and trained data entry 
research assistant will enter all initial demographic data within 2 days of a patient’s enrollment in 
the study into a secure, password protected database. A study coordinator will verify the 
accuracy of the information on a regular basis to check for accuracy.  
Subsequent clinical information obtained during the course of the study, will be entered into the 
password-protected database by a trained research assistant per standard protocol and a study 
coordinator will review the accuracy of this information as well. The investigators will review all 
safety and data management policies and procedures with new staff and annually with current 
staff. 
This study will have an independent reviewer (licensed cardiologist who practices outside of the 
Partners System and has no involvement with or relation to the study) to review, in a de-
identified fashion, any/all potential adverse events and determining if they are appropriate to 
report to Novartis and the Partners IRB.  
c. Outcome Monitoring 
This study will have an independent reviewer (licensed cardiologist who practices outside of the 
Partners System and has no involvement with or relation to the study) to review both results of 
the study. The independent reviewer for this study will be:  
 
Robb D. Kociol, MD 
Beth Israel Deaconess Medical Center.  
Director of the Ventricular Assist Device Program 
Associate Director of Advanced Heart Failure 
 
Dr. Kociol is a heart failure specialist outside the Partners system who is experienced in both the 
clinical care of heart failure patients and in clinical investigation, having participated in clinical 


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68 
 
events adjudication, patient recruitment, and Data Safety Monitoring Committee roles for a 
number of cardiovascular device and pharmaceutical trials. He is an active clinical member of 
the Cardiovascular Division and the Associate Director of the Advanced Heart Failure Program 
at Beth Israel Deaconess Medical Center. In addition, he is currently a member of the Clinical 
Events Committee for the Harvard Clinical Research Institute in Boston, MA as well as a 
member of the Data Safety Monitoring Committee for a clinical trial of esmolol in severe sepsis.  
 
Specifically, Dr. Kociol will review all endpoint data including PA pressures (daily trends, 
acute/first dose/dose change PA pressures, exercise recovery PA pressures) hemodynamic and 
side effect information obtained in clinic, 6-minute walk test, double Master’s step test, Handgrip 
test, Stroop Color test, laboratory work, KCCQ scores and medication dose changes. He will be 
blinded to the study group assignment and will  review this data in a de-identified fashion. He 
will also be responsible for reviewing any/all potential adverse events and determining if they are 
appropriate to report to Novartis and the Partners IRB. He will review all clinical and safety data 
after every 5 patients have been enrolled. Potential adverse events will be reviewed as soon as 
possible if/when they occur. The study will have a pre-specified stopping guideline of p<0.01 for 
harm on any safety outcomes. 
 
d. Adverse Event Reporting Guidelines 
All of the following events will be collected for review by the independent reviewer and reported 
to Novartis Pharmaceuticals (along with the relevant randomization codes): All serious adverse 
events (SAE), all reports of drug exposure during pregnancy, all non-serious adverse events, all 
reports of misuse and abuse of the study drug, other medication errors, and uses outside what is 
foreseen in the protocol (irrespective of  whether a clinical event has occurred). Any member of 
the study team can report a potential adverse event. Since Entresto is an FDA approved drug and 
it will be using it for its FDA approved indication, any adverse events thought to be related to 
Entresto will be reported FDA’s MedWatch program, in keeping with standard practice. Given 
the mechanism of action of the drug, angioedema is an event of special interest, and all 
angioedema-like events will be submitted for independent review. Any adverse events that are 
deemed “significant” by the independent reviewer will also be reported to the Partners IRB.  
 
An SAE is defined as any adverse event (appearance of or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria: 
• 
is fatal or life-threatening 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 


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• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• 
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• 
social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• 
is medically significant, i.e. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 
 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.  
 
 
 
X. 
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