Patient SELF-management With HemodynamIc Monitoring: Virtual Heart Failure Clinic and Outcomes (the SELFIe-HF Trial): Program
Phase: NA
Conditions: Chronic Heart Failure
Sponsor: Montreal Heart Institute

 
Page 1 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
SELFIe-HF 
 
PATIENT SELF-MANAGEMENT WITH HEMODYNAMIC 
MONITORING:  
VIRTUAL HEART FAILURE CLINIC AND OUTCOMES 
 
A preliminary study in high risk patients 
Protocol Number: MHICC-2018-001 
 
Principal Investigator 
 
Co-Investigators 
Anique Ducharme, M.D., M.Sc. 
 
Jean L. Rouleau, M.D. 
Montreal Heart Institute 
 
Anita Asgar, M.D., M.Sc. 
5000 Belanger Street (S-2700) 
 
Jocelyn Dupuis, M.D., Ph.D. 
Montreal, Quebec, H1T 1C8 
 
Simon de Denus, B. Pharm, PhD 
Phone: (514) 376-3330 ext. 3947 
Montreal Heart Institute 
Fax: (514) 593-2575 
 
5000 Belanger Street 
 
Montreal, Quebec, H1T 1C8 
 
 
Phone : (514) 593-7431 
 
 
 
 
Coordinating Center 
Project Leader 
 
 
Hélène Brown, RN, B.Sc. CCRP 
Montreal Health Innovations Coordinating Center 
Montreal Heart Institute  
4100 Molson Street, Suite 400 
 
Phone: (514) 376-3330 ext. 3931 
Montreal (Quebec), H1Y 3N1 
 
Fax: (514) 593-2575 
 
 
 
 
An investigator initiated study 
Montreal Heart Institute 
 
 
This protocol contains information that is confidential and proprietary of  
Dr. Anique Ducharme and the Montreal Heart Institute 
 
 

 
Page 2 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
DATE OF PROTOCOL:  01-JUN-2020 
 
 
Signature Approval Page 
 
By signing below, I indicate that I have reviewed the Clinical Protocol in its entirety and approve 
its contents. 
 
Signature:   
 
 Date:   
 
 
Dr. Anique Ducharme, MD 
 
Principal Investigator 
MHI 
 
Signature:   
 
 Date:   
 
 
Marie-Claude Guertin, PhD 
 
Lead Biostatistics 
 
MHICC 
 
Signature:   
 
 Date:   
 
 
Ourida Mehenni Hadjeres, MD 
 
Lead Medical and Safety 
                     MHICC  
Signature:   
 
 Date:   
 
Andreas Orfanos, MBBCh, FFPM, MBA 
 
Director 
 
MHICC 
 
 
 
 
 
 
 
 
 
 
 

 
Page 3 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
INVESTIGATOR’S STATEMENT AND SIGNATURE 
 
Protocol Title: Patient SELF-management with hemodynamIc monitoring: Virtual Heart Failure 
Clinic and Outcomes. A preliminary study in high risk patients 
 
Protocol Number: Version 10 
 
Version Date: 01-JUNE-2020 
 
I have read the protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol, with applicable laws and regulations and in accordance with the ethical principles 
outlined in the Declaration of Helsinki.  
 
By signing below, I hereby declare that I am not debarred, disqualified, or otherwise restricted by 
any agency from conducting any research studies. 
 
Site Principal Investigator:  
 
Signature: ___________________________ 
   Date:  
 
 
 
 
 
 
Printed Name: Anique Ducharme 
 
Site Name: Montreal Heart Institute  
 
 

 
Page 4 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Synopsis 
Title 
Patient’ SELF-management with HemodynamIc monitoring: virtual Heart 
Failure clinic and outcomes (the SELFIe-HF trial): program. 
Investigator 
Device 
CardioMEMS™ HF System 
Study objectives To demonstrate that a virtual Heart Failure Clinic (HFC) based on patient 
self-management using Pulmonary Artery Pressure (PAP) monitoring  is 
superior to usual care of HFC, leads to decreased: hospital admissions  for 
heart failure (HF), emergency department consultation and/or unplanned 
intravenous heart failure therapy and  cardiovascular death, compared to a 
regular HFC, has low device-related complications and is cost-effective, in 
New York Heart Association (NYHA) class III and II (requiring diuretics) 
patients. 
Study design 
This will be a single center, prospective, randomized, open-label blinded-
endpoint (PROBE) trial in which the treatment group will be implanted 
with a CardioMEMS HF sensor and managed using remote access to 
hemodynamics compared to a non-implanted control group. Patients with at 
least one hospitalization for HF (≥1) in the previous year (12 months) will 
be randomized into two groups, regardless of LVEF: 
 Usual care with the specialized multidisciplinary HF clinic team (Non-
implanted Control) or 
 Hemodynamic monitoring, less intense HF clinic follow-up, and 
remote follow-up by a nurse clinician and patient empowerment with 
access to the PAP data (CardioMEMS group). 
Primary and secondary endpoints will be compared between groups after 12 
months of follow-up and within groups comparing baseline parameters with 
12 month follow-up measurements.  
Key Inclusion 
criteria 
1. Male or female  ≥ 18 years old 
2. Symptomatic HF (NYHA III) with recent heart failure admission in the 
previous year (12 months). 
or  
3. Patient with at least one ER visit or unplanned HF clinic requiring iv 
diuretics within 12 months will be eligible if they have in addition a N-
terminal pro-BNP (NT-proBNP) level > 800pg/ml at screening AND 
NYHA Class II on diuretics (furosemide ≥ 40mg qd), III or ambulatory 
IV.  
4. HF with reduced or preserved EF of at least 3 months duration. 
5. Minimum technological knowledge either with a smartphone or iPAD 
for use of the self-management application, including access to internet. 

 
Page 5 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
6. Anatomical criteria  
a. PA branch diameter between 7 mm – 15 mm 
b. For BMI >35, distance from patient’s back to the target PA<10 cm. 
Key exclusion 
criteria 
1. Recent cardiovascular events: Acute coronary syndrome, percutaneous 
coronary intervention (PCI), new cardiac rhythm management (CRM) 
device (pacemaker, implantable cardioverter defibrillator (ICD) and 
cardiac resynchronization therapy (CRT)), CRM system revision, lead 
extraction or cardiac or other major surgery or transient ischemic attack 
or stroke within 2 months (3 months for CRT or cardiac surgery). 
2. Scheduled cardiac surgery; 
3. History of pulmonary embolism or recurrent deep vein thrombosis 
4. Persistent NYHA Class IV and American College of Cardiology 
 (ACC)/ American Heart Association (AHA) HF Stage D, patients 
 implanted with a ventricular assist device (VAD), or patients listed 
 for cardiac transplantation and likely to be transplanted within 12 
 months 
5. Coexisting severe obstructive valvular lesions, obstructive 
 
hypertrophic cardiomyopathy, endocarditis, tamponade or large 
 
pericardial effusion 
6. Clinically too unstable to be followed remotely; this includes but is 
 
not limited to: 
a) Resting systolic blood pressure < 80 or > 180 mmHg; 
b) Resting heart rate > 100 bpm; 
c) Stage IV or V chronic kidney disease (Estimated Glomerular 
Filtration Rate (eGFR) that remains < 30mL/min/1.73m2 by MDRD) 
or nonresponsive to diuretic therapy or on chronic renal dialysis;  
7. Severe pulmonary hypertension with systolic pulmonary artery   pressure 
≥  80 mmHg. 
8. Pulmonary hypertension other than group II PH; 
9. Anemia requiring transfusions, iron infusions, or hemoglobin  below 
100;  
10. Coagulopathy 
or 
uninterruptible 
anticoagulation 
therapy 
or 
contraindication to antiplatelet/anticoagulant treatments anticipated in the 
protocol; 
11. Intolerance to aspirin or clopidogrel; 
12. Active infection requiring systemic antibiotics; 
13. Life expectancy <1 year; 
 

 
Page 6 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Primary 
Endpoint 
The primary endpoint is the time to first occurrence of any component of 
the composite event as adjudicated by the Clinical Event Committee 
(CEC). Components of the event are: acute decompensated heart failure 
requiring emergency department consultation and/or unplanned 
intravenous heart failure therapy in an outpatient clinic, or hospital 
admission for heart failure or cardiovascular (CV) death during 12 months 
of follow-up.  
Secondary 
Endpoints 
 Time to the first occurrence of the individual components of the 
primary endpoint 
 Changes from baseline in functional ability: 
o NYHA class 
o Health-related Quality of life, as measured by a HF-specific 
instrument (KCCQ)  
o 6-minute walk distance 
 Cost-effectiveness  
 Device related endpoints 
o Safety: adverse events related to the device  
o Number of successful patient contacts (virtual and clinic) 
o PA pressures: changes, frequency of elevated readings 
o Ease of application utilization. 
Tertiary/ 
Exploratory  
endpoints 
 Goal for best practice 
o % achieved target dose of guidelines derived medical therapy 
(GDMT) (HF with reduced ejection fraction (HFrEF)) 
o Medication changes (mean dose achieved by class) 
o Time (days) to achieve target doses of GDMT (HFrEF) 
 Changes in cardiac remodeling assessed by echocardiography between 
baseline and 12 months:  
o indexed LV End-systolic and end-diastolic volumes (LVESVi, 
LVEDVi), left ventricular ejection fraction (LVEF) 
o Right ventricle (RV) dimensions and function,  
o Left atrium volume 
o mitral and tricuspid regurgitation severity 
 Changes in specific biomarkers for heart failure 
 Arrhythmia burden  
 Patient quality of life and satisfaction regarding both the virtual follow-
up itself & the personalized algorithm using the application. 
 Sample for drug concentrations 
Control Group 
Eligible patients who agreed to participate and provide informed consent 
that are randomly assigned to the control group  will be followed using 
standard clinical management at the Montreal Heart Institute specialized 
HF clinic. 
 

 
Page 7 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
CardioMEMS 
Group 
Eligible patients who provide informed consent and randomized to the 
intervention group will be implanted with the CardioMEMS HF System and 
instructed to use the Patient Electronic System.  In addition, patients will be 
provided the MyCardioMEMS smartphone app, which will include PA 
pressure information and instructions for any changes in therapy. 
Number of 
subjects 
150 patients with 1:1 randomization 
Plan for 
statistical 
analysis 
For   the primary endpoint, the analysis will be an unadjusted comparison of 
time to first event. Event-rate curves will be estimated by the Kaplan-Meier 
product-limit method and the difference between groups will be assessed 
using the log-rank test.  Components of the primary endpoint will be 
analyzed similarly.  
ANCOVA models will be used to compare the secondary endpoints 
expressed as a change from baseline to 12 months between groups. The 
models will include fixed effects for group and baseline value as a 
covariate. Difference between groups in other continuous endpoints will be 
tested by either two-sample t-tests or Wilcoxon rank-sum tests depending 
on the distribution of the data. Chi-square tests will be used for categorical 
endpoints. 
All statistical tests will be two-sided and conducted at the 0.05 significance 
level. Statistical analysis will be done using SAS version 9.4 or higher. 
 
 

 
Page 8 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
List of abbreviations 
ACC 
American College of Cardiology 
ACE 
Angiotensin Converting Enzyme 
ADHF 
Acute Decompensated Heart Failure 
AE 
AF 
Adverse Event 
Atrial Fibrillation 
AHA 
ARO 
American Heart Association 
Academic Research Organization 
BMI 
Body Mass Index 
BPM 
Beat Per Minute 
BNP 
B-type Natriuretic Peptide 
BP 
Blood Pressure 
BSA 
Blood Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CCTN 
Canadian Cardiac Transplantation Network 
CEC 
Clinical Event Committee 
CardioMEMS Heart sensor Allows Monitoring of Pulmonary Pressures  
CHAMPION 
CHF 
Heart Failure Patients Trial 
Chronic Heart Failure 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRM 
Cardiac Rythm Management 
CRT 
CV 
Cardiac Resynchronization Therapy 
Cardiovascular 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
estimated Glomerular Filtration Rate 
ED  
Emergency Department 
EF 
ePAD 
ER 
Ejection Fraction 
estimated Pulmonary Artery Diastolic  
Emergency Room 
ERA 
Endothelin Receptor Antagonist 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDMT 
Guidelines Derived Medical Therapy 
H 
Hour 
HF 
HFC 
Heart Failure 
Heart Failure Clinic 
HfpEF 
Heart Failure with preserved Ejection Fraction 
HfrEF 
HFDMP 
Heart Failure with reduced Ejection Fraction 
Heart Failure Disease Management Program 

 
Page 9 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
HR 
Heart Rate 
hs-CRP 
high-sensitivity C-Reactive Protein 
ICD 
ICER 
Implantable Cardioverter Defibrillator 
Incremental Cost- Effectiveness Ratio 
IEC 
Independent Ethic Committee 
IHM 
Implanted Hemodynamic Monitor 
IRB 
LA 
Institutional Review Board 
Left Atrium 
LAP 
LV 
Left Atrial Pressure 
Left ventricle 
LVEF 
Left Ventricular Ejection Fraction 
LVESi 
Left Ventricular volume indexed to BSA 
MDRD 
Modification of Diet in Renal Disease 
Mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
mmHg 
millimeters of mercury 
Mmol 
MHI 
Millimol 
Montreal Heart Institute  
MHICC 
Montreal Health Innovations Coordinating Center 
MLHF 
MRA 
Minnesota Living With Heart Failure 
Mineralocorticoid Receptor Antagonists 
NT-proBNP 
N-terminal prohormone B-type Natriuretic Peptide 
NYHA 
PA 
PAP 
New York Heart Association 
Pulmonary Artery 
Pulmonary Artery Pressure 
PCI 
Percutaneous Coronary Intevention 
PCWP 
Pulmonary Capillary Wedge Pressure 
PDE5I 
Phosphodiesterase 5 Inhibitors 
PH 
Pulmonary Hypertension 
PIIINP 
Procollagen type III N-terminal Propeptide 
pg/ml 
Picogram per millilter 
PROBE 
Prospective Randomized Open-label Blinded-Endpoint 
PVR 
Pulmonary Vascular Resistance 
QALY 
Quality Adjusted Life Year 
Qd 
quaque die (every day) 
QOL 
Quality Of Life 
RHC 
RV 
Right Heart Catherization 
Right Ventricle 
SAE 
Serious Adverse Event 
SGCS 
Solube guynylate cyclase stimulators 
SID 
Subject identification number 
VAD 
VT/VF 
Ventricular Assist Device 
Ventricular Tachycardia/Ventricular Fibrillation  
WHO 
World Health Organization 

 
Page 10 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Table of Contents 
List of abbreviations ....................................................................................................................................... 8 
Table of Contents ......................................................................................................................................... 10 
1. 
RATIONALE ....................................................................................................................................... 12 
1.1 
Background ...................................................................................................................................... 12 
2. 
Hypothesis: ...................................................................................................................................... 16 
2.1 
Primary Hypothesis .......................................................................................................................... 16 
3. 
STUDY OBJECTIVES ........................................................................................................................... 17 
4.1 
Primary  Endpoint ............................................................................................................................. 17 
4.2 
Secondary  Endpoints ....................................................................................................................... 17 
4.2.1 
Time to the first occurrence of the individual components of the composite endpoint ..................... 17 
4.2.2 
Changes in functional capacity between baseline and 12-months ..................................................... 17 
4.2.3 
Device-related endpoints (for intervention group only) .................................................................... 17 
4.2.4 
Cost-effectiveness ............................................................................................................................ 18 
4.3 
Tertiary/Exploratory  Endpoints ........................................................................................................ 19 
4.3.1 
Goal for best practice ....................................................................................................................... 19 
4.3.2 
Changes in echocardiographic parameters between baseline and 12 months ................................... 19 
4.3.3 
Changes in biomarkers levels between baseline and 12-months ....................................................... 19 
4.3.4 
Arrhythmia Burden ........................................................................................................................... 19 
4.3.5 
Patient quality of life and satisfaction ............................................................................................... 19 
4.3.6 
Drugs concentration ......................................................................................................................... 19 
5. 
STUDY PROTOCOL ............................................................................................................................ 20 
5.1 
Study design ..................................................................................................................................... 20 
5.2 
Inclusion/Exclusion Criteria ............................................................................................................... 21 
5.2.1 
Inclusion Criteria .............................................................................................................................. 21 
5.2.2 
Exclusion Criteria .............................................................................................................................. 22 
5.3 
Subject Attribution Number.............................................................................................................. 23 
6. 
SUBJECT EVALUATION ...................................................................................................................... 24 
6.1 
Informed Consent ............................................................................................................................. 24 
6.2 
Visits 24 
7. 
FLOW CHART .................................................................................................................................... 28 

 
Page 11 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
8.   SAFETY…………………….. ............................................................................................................................. 29 
8.1. 
Definition of Adverse Events, Serious Adverse Events, and procedures for reporting Serious Adverse 
Event…………………………. ................................................................................................................................ 33 
8.1.1. Adverse Event (AE) ........................................................................................................................... 33 
8.1.2. Serious Adverse Event definition(SAE) .............................................................................................. 33 
8.1.6. Procedures for Adverse Event reporting ........................................................................................... 34 
8.1.6.1. Investigator Reporting ...................................................................................................................... 34 
9. 
STATISTICAL ANALYSIS ...................................................................................................................... 35 
9.1. 
Sample size ...................................................................................................................................... 36 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................................................................................... 36 
10.1. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval ............................... 36 
10.2. 
Informed Consent ............................................................................................................................. 37 
10.3. 
Declaration of Helsinki ...................................................................................................................... 37 
10.4. 
Case Report Form ............................................................................................................................. 37 
10.5. 
Confidentiality .................................................................................................................................. 37 
11. 
DATA QUALITY ASSURANCE .............................................................................................................. 38 
11.1. 
Monitoring, Audits and inspections .................................................................................................. 38 
11.2. 
Archiving .......................................................................................................................................... 39 
12. 
DATA MANAGEMENT ....................................................................................................................... 39 
13. 
TRIAL COMMITTEES .......................................................................................................................... 39 
13.1. 
Clinical Events Committee ................................................................................................................ 39 
13.2. 
Data and Safety Monitoring Board (DSMB) ....................................................................................... 40 
Proposed Table 1. Patient Characteristics at Enrollment ............................................................................... 41 
Proposed Table 2. Changes in the main Parameters between baseline and 12-months in Survivors .............. 43 
Proposed Table 3. Pharmacological Profiles and Goal for best practice at 12 months .................................... 44 
Proposed Table 4: Device related endpoints ................................................................................................. 45 
Appendix 1:  Elevated PA Mean Pressure – General Treatment Strategies in Protocol ................................... 53 
Appendix 2: 
Hospital admissions at Montreal Heart Institute with a primary diagnosis of heart failure, 
financial year April 1st 2016 to March 31st 2017 ............................................................................................ 54 
Appendix 3: 
Example of an individualized therapeutic plan ...................................................................... 55 
Appendix 4 
World Medical Association Declaration of Helsinki ................................................................ 56 

 
Page 12 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 
1.0 
RATIONALE 
1.1 Background 
Heart failure (HF) represents a major public health concern and its incidence will continue to rise 
as the population ages. The growing burden of HF on healthcare costs is well documented.1 Despite 
major advances in diagnosis and treatment, HF is associated with high rates of decompensation, 
hospitalization and mortality. Developing new approaches for patients with HF are essential.  In 
the past, major efforts have been directed toward reducing length of stay by the development of 
performance measures, with the intent to improve post-discharge outcomes.2,3 Recently, however, 
the focus has shifted towards 30-day post-discharge readmission rates as a measure of quality of 
care due to important changes in reimbursement patterns in the US.  
Congestion is one of the hallmarks of HF hospitalizations and an increase in body weight seems 
to be associated with HF-related hospitalizations, usually beginning at least one week before 
admission for acutely decompensated heart failure (ADHF).4 Consequently, increased daily weight 
may identify a high risk period during which one can intervene to avert ADHF requiring 
hospitalization.5  
In addition to congestion, the presence of pulmonary hypertension (PH) secondary to heart failure, 
classified as World Health Organization (WHO) Group 2 PH6 is associated with increased 
morbidity and mortality.7 Therefore, in theory, an elevated pulmonary artery pressure (PAP) and 
increased pulmonary vascular resistance (PVR) should represent meaningful triggers for 
therapeutic interventions, and the reduction of decompensated HF an attractive therapeutic target.  
HF management programs which rely on patients’ empowerment through education and careful 
follow-up, as well as pharmacological and device-optimization have been shown to decrease 
hospital admissions, emergency consultations, improve quality of life and probably survival.8  
Unfortunately, due to resource limitations and the increasing number of patients with moderate to 
severe heart failure, the majority of patients that could benefit from follow-up in multidisciplinary 
heart failure clinics (HFC) do not readily have access to them in a timely manner.9 Innovative 
approaches might be crucial to changing the emphasis of the HFC and processes. New transitional 
models for HF care have been developed, such as structured telephone care (or telehealth) with 

 
Page 13 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
symptoms and vital signs monitoring, home visits, use of technology and remote monitoring 
systems to reduce HF-related hospitalizations, but with mixed results.10-12 Recently, the BEAT-
HF trial failed to show a benefit for 30 and 180 days readmission or mortality using a combined 
approach of health coaching telephone calls and telemonitoring with electronic equipment for daily 
information (BP, HR, symptoms and weight);13 likewise, the REM-HF14,15 trial using a similar 
approach was also negative.  
Weight may not be a specific enough marker of ADHF, since it may vary for many reasons. It is 
possible that current markers such as symptoms and weight gain are late and indirect measures of 
decompensation and that earlier detection of congestion could prompt interventions and avert the 
incoming ADHF and hospital admission.15 Monitoring of intrathoracic impedance (Optivol® 
CRT-D), with an imbedded feature in some of the implanted devices (pacemaker or defibrillator) 
showed promise, but the DOT-HF study using intrathoracic impedance with an audible alert did 
not improve outcomes and increased HF admissions,16 while the recent Multisense trial was 
negative.17 Likewise neutral results were observed in stable patients using electronic implanted 
devices from multiple providers.14 
Using more sensitive physiologic markers for the development of acute decompensation, such as 
increased filling pressure, may be beneficial. A variety of implantable hemodynamic monitors 
(IHM) have been developed to provide objective and continuous information on hemodynamic 
status in ambulatory HF patients, which may facilitate the timeliness of interventions and improve 
outcomes.18  Interesting initial results were obtained for a pacemaker-like device with a RV lead 
that contains a sensor near its tip to measure right ventricle (RV) pressures (estimated pulmonary 
artery diastolic (ePAD)) in 274 patients enrolled in the COMPASS HF trial (Chronicle Offers 
Management to Patients with Advanced Signs and Symptoms of HF).19  Safety (8% complications, 
mostly lead dislodgements) and primary efficacy (21% decreased in HF-related events) endpoints 
were met. Unfortunately, the REDUCE-HF trial (REducing Decompensation events Utilizing 
intraCardiac prEssures in patients with cHF) was prematurely terminated due to sensor lead failure 
after 400 patients were enrolled and showed no significant difference in HF events after one year 
of follow-up.19 Another device, the Heart-POD (Abbott Laboratories, Illinois, USA) measures 
directly the left atrial pressure and has shown promising results in a preliminary observational 
study of 40 ambulatory HF patients.20 In order to try to further empower the patients in 

 
Page 14 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
HOMEOSTASIS, they followed a physician-directed therapeutic strategy guided by left atrial 
pressure (LAP), which led to a drop in mean daily LAP, decreased the HF hospitalization rate, and 
resulted in improvements in New York Heart Association (NYHA) class, left ventricular ejection 
fraction (LVEF) and pharmacological profiles.20,21 A larger unblinded study, the LAPTOP-HF 
trial,22,23 was recently stopped early due to excess of procedure related complications after 
enrolment of 486 of the 730 planned patients; the annualized HF hospitalization rates for implanted 
patients was 0.40 versus 0.68 in Control patients, RRR 41%, p=0.005, offering insights into the 
benefits of hemodynamic monitoring and the use of physician directed, patient self-
management.22,23 The patient self-management features have been embedded in a smart phone 
application that will be available commercially before the end of 2019 and that we propose to use 
for this protocol.  
Recently the FDA and Health Canada approved a novel implantable sensor inserted into the right 
pulmonary artery that measures pulmonary artery pressures (PAP) in patients with HF, the 
CardioMEMS™ HF System (Abbott Laboratories, Illinois, USA). The coil and capacitor are 
housed within the sensor to form a miniature electrical circuit that resonates at a specific frequency; 
variation in PAP will alter the baseline resonant frequency emitted by the sensor, which is 
electromagnetically coupled to an external antenna for data transmission. Frequency shifts are 
displayed as pressure waveforms. The data can then be transmitted to the web-based platform for 
clinical analysis.24 The CHAMPION trial evaluated the effect of PAP-guided therapy on HF-
related hospitalizations compared to standard of care in 550 patients with NYHA functional class 
III or IV symptoms. A 28% reduction in HF-related hospitalizations was observed after 6-months 
of follow-up.25 As expected, the presence of PH identified HF patients at risk for adverse outcomes, 
but knowledge of hemodynamic variables allowed for more effective treatment strategies to reduce 
hospitalizations, albeit with no impact on mortality.26 Interestingly, both patients with HF with 
preserved ejection fraction (HFpEF) (using a definition of LVEF≥40%) and HF with reduced 
ejection fraction (HFrEF) derived benefit,27 making the CardioMEMS™ HF System the first 
treatment option to show promise for patients with HFpEF, an increasingly recognized cause of 
group 2 PH.28 Moreover, patients with chronic obstructive pulmonary disease (COPD) 
concomitant with HF also derived benefit from hemodynamic monitoring in CHAMPION.29 An 
example of the proposed treatment algorithm is available at the  

 
Page 15 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Annex 1. 
Further, data from CHAMPION have shown that PH is underestimated by right heart 
catheterization (RHC) in nearly 50% of patients with HF.30 RHC provides a “snapshot” of a 
patient’s hemodynamic profile at a single time point, in a hospital-based setting, which may not 
reflect real life hemodynamics in other settings. These results are consistent with the ESCAPE trial 
in ADHF patients, which found that pulmonary artery (PA) catheter–guided care was not superior 
to traditional clinical assessment of volume in preventing subsequent decompensation.31 However, 
levels of certain hemodynamic parameters such as pulmonary capillary wedge pressure (PCWP) 
and mean PA pressure were predictors of later risk for hospitalization. Full characterization of PH 
status and guidance for medical management may be best accomplished with recurrent assessment 
of pressures provided by an implanted hemodynamic monitor (IHM). In CHAMPION, patients 
with no PH on RHC but PH revealed by the IHM had significantly higher HF hospitalization rates 
than those without this “occult” PH,30 suggesting that IHM can provide additional information on 
the patient’s overall risk of HF hospitalization. Further, the use of an IHM such as the 
CardioMEMS™ HF System provides an unique opportunity to fine-tune patient management with 
its dual capacity of providing daily information on congestion (diastolic PAP) and the severity of 
PH (systolic and mean PAP).   
Lastly, there is increasing evidence that filling pressures may influence the arrhythmia burden; a 
positive relationship has been demonstrated between changes in intra-cardiac pressures and risk 
for ventricular tachycardia/ventricular fibrillation (VT/VF).32 There are several potential 
mechanisms by which an elevated ventricular pressure could influence the development of 
arrhythmias: stimulation of neurohormonal activation,33 increase in sympathetic tone,34 and 
aberrant intracellular calcium cycling. In addition, acute diastolic stretch shortens action potential 
duration and refractoriness, whereas chronic dilatation does not,35 presumably because of 
activation of stretch-activated channels.36 There is an opportunity to evaluate the arrhythmia 
burden in patients with IHM, including atrial fibrillation (AF), VT/VF and implantable 
cardioverter defibrillator (ICD) events. 
The possibility of remote HF monitoring with the CardioMEMS™ HF System opens a new avenue 
for patients with HF, especially the elderly or those living far away from HF clinics. The use of 
such high-intensity remote monitoring carries the potential for successful detection of parameter 

 
Page 16 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
deviations, tailored therapy, more rigorous follow-up and improved outcomes. Moreover, it has 
been shown to be cost-effective not only in CHAMPION36 but also in a real life setting,4 mostly 
because of reduction in hospital readmissions.37  
At the Montreal Heart Institute (MHI), during the financial year 2018-19 there were 900 hospital 
admissions with a primary diagnosis of heart failure in 716 patients. Of those, 34% were readmitted 
within the same financial year and 241 patients had ≥1 readmission (range: 1-9) (see appendix 2). 
Targeting these high-risk patients with technology using pulmonary artery pressure monitoring 
could possibly expand our ability at the HFC to treat a larger number of patients remotely, decrease 
costly hospital readmissions and hence create a virtual heart failure disease management program 
(HFDMP). 
Accordingly, we propose a paradigm shift towards disease co-management, using patient remote 
hemodynamic data, accessed through a smart phone app, and a virtual HF clinic run by a nurse 
clinician specialized in HF with the backup of a HF cardiologist.  
2. HYPOTHESIS: 
2.1 Primary Hypothesis 
Due to the dynamic nature of HF and knowledge that filling pressures can rise rapidly over hours 
to days,20 the capacity of patients to get precise PAP measurements as needed will provide critical 
information in a timely manner. Using a personalized strategy will allow for appropriate 
adjustments of medications based on current PAP values categorized and accessed via a 
smartphone app, which will help curtail increases in left-sided filling pressures and thereby avert 
hospitalizations for ADHF. Also providing the patient and nurse clinician access to the patients’ 
hemodynamic data on a continuous basis could empower patients to take more responsibility in 
the management of their disease through engagement and self-learning concerning dietary 
indiscretion, fluid and salt restriction that may impact PAP measures. Finally, knowledge of their 
PAP may provide reassurance in the event of vague symptoms not directly attributable to HF and 
decrease the number of emergency department visits. It may also help in making non-HF diagnoses 
by eliminating HF as a cause of dyspnea (i.e bronchitis). 

 
Page 17 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
3. STUDY OBJECTIVES  
To demonstrate that a virtual Heart Failure Clinic (HFC) based on patient self-management using 
PAP remote monitoring is superior to usual care of HFC, leads to decreased:  hospital admission 
for HF, emergency department consultation and/or unplanned intravenous heart failure therapy 
and cardiovascular death, compared to a regular HF clinic, has low device-related complications 
and is cost-effective, in NYHA class III and II (requiring diuretics) patients.  
4. STUDY ENDPOINTS 
4.1 Primary  Endpoint 
The primary endpoint is the time to first occurrence of any component of the composite event as 
adjudicated by the Clinical Event Committee (CEC). Components of the event are: acute 
decompensated heart failure that requires emergency department consultation and/or unplanned 
intravenous heart failure therapy in an outpatient clinic, or hospital admission for heart failure, or 
cardiovascular (CV) death during 12 months of follow-up. 
4.2 Secondary  Endpoints 
4.2.1 Time to the first occurrence of the individual components of the composite endpoint 
 Acute decompensated heart failure that requires emergency department consultation 
and/or unplanned intravenous heart failure therapy in an outpatient clinic;  
 Hospital admission for heart failure; 
  CV death 
4.2.2 Changes in functional capacity between baseline and 12-months 
 NYHA functional class;  
 Quality of life (Kansas city cardiomyopathy (KCCQ) questionnaire) ; 
 6 minute walk distance. 
4.2.3 Device-related endpoints (for CardioMEMS group only) 
 Safety: adverse events related to the device;  
 Number of successful patient contacts (virtual and clinic); 
 PA pressures: changes, frequency of elevated readings; 
 Ease of application utilization. 

 
Page 18 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
4.2.4 Cost-effectiveness  
A cost utility analysis will be undertaken as part of the study protocol to evaluate the impact 
of the treatment strategy of remote PAP monitoring compared to usual care. An incremental 
cost-effectiveness ratio (ICER) will be calculated by comparison of calculated costs and 
quality-adjusted life years in both study groups.  This data will then be used to construct an 
economic model to evaluate the cost-effectiveness in a hypothetical cohort of 10,000 
patients.  This data will be used to calculate the incremental cost per Quality-Adjusted Life 
Year (QALY) gained and per life-year gained.  We will perform deterministic sensitivity 
analyses to explore the impact of uncertainty in key parameters on the analysis results and a 
probabilistic sensitivity analysis to further characterize uncertainty in model parameters. 
Detailed resource utilization and costs will be collected prospectively for randomized 
patients, including diagnostic evaluation costs directly incurred as a result of the 
CardioMEMS™ HF System procedure, procedural costs, and inpatient treatment costs at a 
large tertiary care hospital in Montreal (MHI). Individual patient-level costs of heart failure 
hospitalizations, emergency room (ER) visits, and short stay costs for intravenous diuretics 
will be obtained from the Montreal Heart Institute. Follow-up costs will include protocol 
driven visits and tests, and additional unscheduled outpatient treatment visits for heart failure 
or visits to the HFC.  
Evaluation of quality of life will be performed using the KCCQ questionnaire and quality 
adjusted life years (life expectancy adjusted for quality of life of the health state experienced) 
will be calculated for each patient in the alive state using published health utilities, which 
measure quality of life from a 0 (dead) to 1 (perfect health) scale, for heart failure according 
to NYHA Class and results of the KCCQ questionnaire. In the absence of questionnaire data 
for hospitalized patients, utility decrements will be applied for heart failure hospitalizations 
and emergency room visits as per the published literature. A short-term utility decrements 
(i.e. disutility) for the CardioMEMS™ procedure will be approximated using published 
decrements for percutaneous coronary intervention (PCI). 

 
Page 19 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
4.3 Tertiary/Exploratory  Endpoints 
4.3.1 Goal for best practice 
 % achieved target dose of Guidelines-derived medical therapy  (GDMT) (HFrEF); 
 Medication changes (mean dose achieved by class of GDMT) between baseline and 12 
months; 
 Time (days) to achieve target doses of GDMT (HFrEF). 
4.3.2 Changes in echocardiographic parameters between baseline and 12 months 
 Cardiac remodeling including left ventricle (LV) end-systolic and end-diastolic volumes 
indexed to blood surface area (BSA), LVEF, RV dimensions and function including RV-
PA coupling, left atrium (LA) volume, mitral and tricuspid regurgitation severity, with a 
complete echocardiography protocol proposal and Core Laboratory analysis. 
4.3.3 Changes in biomarkers levels between baseline and 12-months 
 Blood samples will be collected for biomarkers analysis: General (Electrolytes, BUN, 
creatinine and CBC), and disease-specific (HS-CRP, NT-proBNP, troponin, Osteopontin, 
Angiotensin-II, aldosterone, ST2, Vasopressin, galectin-3, PIIINP, cystatin C). 
4.3.4 Arrhythmia Burden 
 Episodes of atrial fibrillation requiring medical attention (ED visits or hospitalization);  
 VT/VF events; 
 Anti-tachycardia pacing or appropriate ICD shocks in patients with an ICD 
4.3.5 Patient quality of life and satisfaction 
 Regarding both the virtual follow-up itself and the personalized algorithm using the 
application. Standardized quality of life questionnaires will be used. 
4.3.6 Drug concentrations 
 Blood samples will be collected to measure concentrations of drugs commonly used in HF 
patients at the baseline visit, as well as at visits at week 2, month 2, month 12 and at 
unscheduled visits. 
 

 
Page 20 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
5. STUDY PROTOCOL 
5.1 Study design  
Type of study: A single center prospective randomized open-label blinded-endpoint (PROBE) trial 
is proposed comparing two strategies for patients with HF who had at least one admission for a 
primary diagnosis of HF regardless of LVEF in the previous year i.e., usual care by a specialized 
multidisciplinary HF clinic team versus hemodynamic monitoring and self-empowered remote 
follow-up using the newly developed smart-phone/iPad application, with the back-up of a nurse 
clinician and a HF cardiologist and limited HF clinic visits. 
150 eligible patients who consent to participate will be randomized to the control group or 
intervention group in a 1:1 ratio. Patients randomized to hemodynamic monitoring (CardioMEMS 
group) will have the CardioMEMS™ HF System implanted as an outpatient procedure within a 
week of random assignment. 
Before randomization, patients will need to be stable as judged by the treating HF clinic 
cardiologist. After randomization, all subjects will receive education on HF as per local practice 
as well as recommendations regarding nutrition and exercise, for daily weights, medication 
record, clinical notes and appointments.  
Patients in the control group will be followed as per usual practice by the MHI multidisciplinary 
HF clinic. Patients in the CardioMEMS group will be seen at baseline, week 1 and week 2 after 
implantation, two months and twelve months after randomization and will be in regular contact 
with the lead research nurse with virtual follow-ups at weeks 3, 4, 6, 12, 16, 20, 24, 28, 32, 36, 40, 
44, and 48. The specialized HF clinician nurse and cardiologist will design an individualized pre-
specified therapeutic plan according to CHF guidelines and clinical experience with that individual 
patient (Appendix 3). For HFrEF, GDMT will be implemented in both groups, including ICD and 
CRT referral when indicated. 
For patients in the CardioMEMS group, a blood pressure cuff will be provided and hemodynamic 
data will be taken twice daily by the patient from the moment of randomization in the trial. i-Pad® 
internet communication using Skype/Facetime or telephone calls will be done twice in the first 
month, once in the second month and monthly thereafter, unless a medical problem occurs that 

 
Page 21 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
requires more frequent contact, which will be determined by the study team. The patient will 
implement the individualized therapeutic plan designed by the HF clinician nurse and cardiologist, 
following a pre-specified algorithm (Appendix 1), which includes titration of angiotensin-
converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), angiotensin receptor 
neprilysin inhibitors (ARNI), hydralazine, nitrates, beta-blockers and mineralocorticoid 
antagonists as needed. Initiation of some of these medications may require a visit to the research 
clinic, if judged necessary and will be counted as unscheduled visit. Diuretics and potassium 
supplementation will be adjusted according to individualized target PAP pressures, electrolytes 
and renal function. Blood samples for electrolytes and renal function: sodium, potassium, chloride, 
and bicarbonate will be drawn one week after any changes of medications, or as deemed clinically 
indicated by the treating team. The research team will follow the laboratory results and intervene 
as needed. Objectives for PAP pressures will be similar to the CHAMPION trial, i.e., PAP systolic 
(15–35 mmHg), PAP diastolic (8–20 mmHg), and PAP mean (10–25 mmHg).  PA measurements 
will be transmitted daily for the first two weeks, three times a week thereafter, and more frequently 
as needed. Also, patients will have access to the research nurse coordinator for advices or to signal 
changes in their state (for example a bronchial infection, diarrhea etc.). Further, patients in the 
CardioMEMS™ group will have access to categorized data (very low, low, in range, high or very 
high pressures) using the app and be able to adjust their medication (mostly diuretics) according 
to an individualized algorithm. Furthermore, data reaching thresholds will be reviewed daily 
during working days and patients will be contacted in the event of clinically significant changes, 
as individually defined at the outset. The general aim is to introduce and rapidly up-titrate GDMT 
for patients with HFrEF (ACEi, ARB or ARNI), beta-blockers and mineralocorticoid receptor 
antagonists (MRA), to reduce or eliminate diuretic doses for patients with low or very low PAP, 
and to increase diuretic or vasodilator doses for high or very high PAP. A general algorithm is 
proposed in Appendix 1.  
5.2 Inclusion/Exclusion Criteria 
5.2.1 Inclusion Criteria 
1. Male or female ≥ 18 years old.  
2. Symptomatic HF (NYHA III) with recent heart failure admission in the previous year (12 
months). OR  

 
Page 22 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
3. Patient with at least one ER visit or unplanned HF clinic requiring iv diuretics within 12 
months will be eligible if they have in addition a N-terminal pro-BNP (NT-proBNP) level 
> 800pg/ml at screening AND NYHA Class II on diuretics (furosemide ≥ 40mg qd), III 
or ambulatory IV.  
4. HF with reduced or preserved EF of at least 3 months duration. 
5. Minimum technological knowledge either with a smartphone or iPAD for use of the self-
management application, including access to internet. 
6. Anatomical criteria  
a. PA branch diameter between 7 mm – 15 mm 
b. For BMI >35, distance from patient’s back to target PA<10cm  
5.2.2 Exclusion Criteria 
In order to maximize the generalizability of the results, exclusion criteria will be kept to a 
minimum:  
1. Recent cardiovascular event:  Acute coronary syndrome (STEMI/NSTEMI; a small rise 
in the troponin level would be expected in this population and is not a contraindication for 
enrolment); Percutaneous Coronary Intervention (PCI), new cardiac rhythm management 
(CRM) device (pacemaker, ICD and CRT), CRM system revision, lead extraction or 
cardiac or other major surgery or transient ischemic attack or stroke within 2 months (3 
months of stabilization after CRT or cardiac surgery); 
2.  Scheduled cardiac surgery; 
3.   History of pulmonary embolism or recurrent deep vein thrombosis; 
4. Persistent NYHA Class IV and ACC/AHA HF Stage D,  patients implanted with a 
ventricular assist device (VAD), or patients listed for cardiac transplantation and likely to 
be transplanted within 12 months; 
5. Coexisting severe stenotic valve lesions, endocarditis, obstructive hypertrophic 
cardiomyopathy, acute myocarditis, tamponade, or large pericardial effusion; 
6.  Clinically too unstable to be followed remotely; this includes but is not limited to: 
a. Resting systolic blood pressure < 80 or > 180 mmHg; 
b.  Resting heart rate > 100 bpm; 

 
Page 23 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
c. Stage IV or V chronic kidney disease (Estimated Glomerular Filtration Rate (eGFR) 
that  remains < 30 mL/min/1.73m2 by MDRD) or nonresponsive to diuretic therapy or 
on chronic renal dialysis;  
7.   Severe pulmonary hypertension with systolic pulmonary artery pressure ≥80 mmHg; 
8.   Pulmonary hypertension other than group II PH; 
9.   Anemia requiring transfusions, iron infusions, or hemoglobin below 100;  
10. Coagulopathy or uninterruptible anticoagulation therapy or contraindication to 
antiplatelet/anticoagulant treatments anticipated in the protocol; 
11.  Intolerance to aspirin or clopidogrel; 
12.  Active infection requiring systemic antibiotics; 
13.  Unwillingness to sign informed consent or to attend the outpatient clinic; 
14.  Participation in another research trial with intervention; 
15.  Discharge to a chronic care facility or residence in an outlying area; 
16.  Pregnant or lactating women or women of childbearing potential who are not protected 
from pregnancy by an accepted method of contraception, such as the oral contraceptive 
pill, an intrauterine device or surgical sterilization. If necessary a negative urine or blood  
test will be performed before randomization 
17. Any condition that in the opinion of the investigator would jeopardize the evaluation for 
efficacy or safety or be associated with poor adherence to the protocol, including 
cognitive decline.  
18.  Life expectancy <1 year; 
 
5.3 Subject Attribution Number 
Once informed consent is obtained, each subject will be assigned a unique 3-digit subject 
identification (SID) number (“Subject number”) for unambiguous identification throughout the 
study; it will be constructed as follows: 
3 Digits:  Subject number, unique within the study center starting at 001.   
Sequential numbers will reflect the order in which subjects are recruited.  SID numbers will be 
used in sequence with no number skipped, substituted, or re-used. 

 
Page 24 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
6. SUBJECT EVALUATION 
6.1 Informed Consent 
Before any screening examination takes place, potentially eligible subjects will be given a full 
explanation as to what the study entails. This will be performed verbally and in writing. Subjects 
will be given ample time to consider participation and pose any questions they may have. Subjects 
who are willing to take part in the study will then be asked to sign an informed consent form. 
Screening examinations will only be performed after written informed consent is obtained. 
Subjects who continue to meet enrolment criteria upon completion of the screening process will 
be eligible for randomization.   
 
6.2 Visits 
At Baseline visit the consent form will be signed and inclusion and exclusion criteria will be 
reviewed before randomization.  Only Baseline and Final Visits will be scheduled in the study for 
the Control Group. All other visits will be scheduled according to usual care by the treating HF 
clinic team.   
Baseline visit (Visit 1) 
 
Informed Consent 
 
Allocation of unique SID number 
 
Demographic information: demographic data and other population characteristics including 
sex, race, year of birth, age, smoking history, and alcohol consumption  
 
Medical and surgical cardiovascular history (including cardiovascular risk factors)  
 
NYHA Class 
 
Physical examination by physician  
 
Vital signs in sitting position (blood pressure (BP) and heart rate (HR)) after resting for at 
least 5 min, 2 measurements, 2 minutes apart 
 
Weight, height 
 
Echocardiography 
 
12-lead ECG in supine position, after resting for at least 5 min. 
 
Assessment of eligibility criteria   
 
Randomization to study group 

 
Page 25 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 
Current therapy  and timing  
 
Subject education: nutrition, exercise, education regarding HF  
 
Blood tests 
o BUN, Creatinine, Electrolytes, CBC, NT-proBNP 
o Blood samples for subsequent analysis: Cystatin-C, Angiotensin-II, Aldosterone, 
Vasopressin, hS-CRP, ST2, Galectin-3, Troponin, Osteopontin, PIIINP, drug 
concentrations.  
 
Urine or blood pregnancy test for women of childbearing potential 
 
6-minute walk test  
 
Quality of Life Questionnaire (MLHF)  
 
For patients randomized to CardioMEMS: 
Implantation Visit (visit 2) 
 
CardioMEMS Implantation  
 
Hemodynamic data collection 
 
Assessment of AEs/SAEs 
Week 1 after implantation (Visit 3) 
 
Adjustment of medication  
 
Subject technology training  
 
Assessment of AEs/SAEs 
Week 2 after implantation (Visit 4) 
 
NYHA Class 
 
Physical examination by physician 
 
Vital signs in sitting position (blood pressure (BP) and heart rate (HR)) after resting for at 
least 5 min, 2 measurements, 2 min apart 
 
Weight 
 
Current therapy and timing 
 
Adjustment of medication 
 
Lab Assessment : BUN, Creatinine, Electrolytes, CBC, NT-ProBNP 

 
Page 26 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 
Blood sample for drug concentrations 
 
Assessment of AEs/SAEs  
Month 2 (Visit 5) 
 
NYHA Class 
 
Physical examination by physician 
 
Vital signs in sitting position (blood pressure (BP) and heart rate (HR)) after resting for at 
least 5 min, 2 measurements, 2 min apart 
 
Weight 
 
Current therapy and timing 
 
Adjustment of medication 
 
Lab Assessment:  BUN, Creatinine, Electrolytes, CBC, NT-proBNP  
 
Blood sample for drug concentrations 
 
Assessment of AEs/SAEs 
Virtual Visits   
Virtual visits will be done remotely (patient self-management using PAP monitoring) following 
hospital discharge of the implant: week, 3, 4, 6, 12, 16, 20, 24, 28, ..., 48  
 
Current therapy 
 
Adjustment of medication  
 
Remote evaluation by nurse: HF symptoms 
 
Remote hemodynamic evaluation by nurse 
 
Laboratory assessment (if clinically indicated 1 week after change in medication dosage) 
 
Assessment of AEs/SAEs  
 
For all randomized patients: 
Unscheduled Visit(s) 
 
NYHA Class 
 
Physical examination by physician  
 
Vital signs in sitting position (blood pressure (BP) and heart rate (HR)) after resting for at 
least 5 min, 2 measurements, 2 min apart 

 
Page 27 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 
Weight 
 
12-lead ECG (if indicated). 
 
Current therapy  and timing 
 
Adjustment of medication   
 
Blood tests 
o  BUN, Creatinine, Electrolytes, CBC, NT-proBNP 
 
Blood samples for drug concentrations 
 
Assessment of AEs/SAEs 
Month 12 (Final Visit 6)  
 
NYHA Class 
 
Changes in medical and surgical cardiovascular history  
 
Physical examination by physician 
 
Vital signs in sitting position (blood pressure (BP) and heart rate (HR)) after resting for at 
least 5 min, 2 measurements, 2 min apart 
 
Weight 
 
Echocardiography 
 
12-lead ECG in supine position, after resting for at least 5 min. 
 
Current therapy  and timing 
 
Blood tests: BUN, Creatinine, Electrolytes, CBC, NT-proBNP 
 
Blood samples for subsequent Analysis: Cystatin-C, Angiotensin-II, Aldosterone, 
Vasopressin, hs-CRP, ST2, Galectin-3, Troponin, Osteopontin, PIIINP, drug concentrations. 
 
6 minute walk test 
 
Quality of Life Questionnaire (MLHF) 
 
Assessment of AEs/SAEs  
 
End of study visit: 
Every implanted participant will be followed at the Heart Failure Clinic at the end of the 
trail within one month of study termination.  

 
Page 28 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
7. FLOW CHART 
 
CardioMEMS and CONTROL GROUPS 
Group 
Both Groups 
CardioMEMS Group Only 
Both Groups 
Visit (V) 
Baseline 
Randomization 
Visit 1 
Implantation 
Visit 2 
Week 1 
post implantation 
Visit 3 
Week 2 
post implantation 
Visit 4 
Month 2 (5) 
Visit 5 
Virtual (5) 
Week 3, 4, 6,12, 16 
20,24,28,….,48 
Unscheduled 
Month 12 (5) 
Final visit 
Visit 6 
Visit Windows (days) 
0 
≤7 
±4 
±4 
±14 
±4 
 
±14 
Informed Consent Form 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical & Surgical CV History 
X 
 
 
 
 
 
 
X6 
NYHA Class 
X 
 
 
X 
X 
 
X 
X 
Physical Exam by physician  
X 
 
 
X 
X 
 
X 
X 
Vital Signs 
X 
 
 
X 
X 
 
X 
X 
Weight 
X 
 
 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Echocardiography 
X 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
X (3) 
X 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
Randomization to Study Group 
X 
 
 
 
 
 
 
 
Current Therapy and timing 
X 
 
 
X 
X 
X 
X 
X 
Adjustment of  Medication 
 
 
X 
X 
X 
X 
X 
X 
Subject Education (Nutrition, exercice etc.) 
X 
 
 
 
 
 
 
 
CardioMEMS  Device 
 
X 
 
 
 
 
 
 
Subject Technology Training 
 
 
X 
 
 
 
 
 
Remote evaluation by nurse: HF symptoms 
 
 
 
 
 
X 
 
 
Remote hemodynamic Evaluation by nurse: 
 
 
 
 
 
X 
 
 
Hemodynamic Data Collection 
 
X 
 
 
 
 
 
 
Laboratory Assessment: Electrolytes, 
 Creatinine, CBC, Urea, NT-proBNP 
X 
 
 
X 
X 
 
X 
X 
Laboratory Assessment (Virtual Visit):   
 
 
 
 
 
X (4) 
 
 
Blood sample for subsequent analysis: Cystatin 
C, Angiotensin-II, Aldosterone, Vasopressin, 
HS-CRP, Galectin-3, Troponin. Osteopontin, 
ST2, PIIINP 
X 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test  
X(1) 
 
 
 
 
 
 
 
Drug concentrations 
X 
 
 
X 
X 
 
X 
X 
6 min walk test 
X 
 
 
 
 
 
 
X 
Quality of Life Questionnaire  (KCCQ)2 
X 
 
 
 
 
 
 
X 
Assessment of AEs/SAEs 
 
X 
X 
X 
X 
X 
X 
X 
 
 (1) For women of childbearing potential 
 
(3) If indicated 
  (5) Post baseline visit           (6) Change(s) in Med & Surgical CV History           
 (2) Kansas City Cardiomyopathy Questionnaire  
      (4) No Blood test except by local lab if clinically indicated (1 week after change in medication dosage) 

 
Page 29 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
7. SPECIFIC ASSESSMENTS 
7.1 End point variables 
Blood pressure measurement, biochemistry monitoring and renal function 
Blood pressure will be measured and recorded at each visits according to the recommendations of 
the Canadian Hypertension Education Program.38  Electrolytes, serum creatinine and vital signs 
will be assessed as described in the Study flow chart. In the assessment renal function, eGFR will 
be calculated as previously described using the MDRD equation.39  
Cystatin C 
Moreover, in order to better characterize changes in renal function during the study, cystatin C will 
be measured at baseline and at the end of the study.  Cystatin C is a novel biomarker of renal 
function which appears to be more sensitive than serum creatinine to detect modest changes in 
renal function.40Moreover, in HF, it has been shown to be a powerful prognostic marker.40  
 
N-terminal proB-type natriuretic peptide (NT-proBNP). 
BNP is secreted primarily from the ventricles in both healthy individuals and patients with CHF.41 
The production of BNP in the ventricle increases proportionally with increases in both ventricular 
wall tension and stretch. Both BNP and NT pro-BNP, the inactive portion of pro-BNP, have been 
shown to correlate with LVEF, left ventricular volumes and pressures. While neurohumoral 
blockade decrease the NT-proBNP levels and prognosis, to our knowledge, there has been no study  
showing that effective pressure management significantly reduce concentrations of BNP and NT-
proBNP. NT-proBNP will be measured by Dr. Joel Lavoie using the « Roche proBNP assay » 
(Roche Diagnostics, Mannheim, Germany), on the   Elecsys  2010  analyzer  (Roche  diagnostics). 
Our group has had extensive experience in measuring NT-proBNP in previous studies.42-45  
 
PIIINP 
It is now widely accepted that aldosterone induces deleterious effects on extracellular matrix 
balance, for which type I and III collagen constitute the majority of the collagen.46-48 These 
alterations in collagens type I and III have been proposed to play a key role in myocardial 
stiffness.48 Previous work has demonstrated that PIIINP serum levels were associated with poor 
outcomes in patients with HF.49,50 Because it is expected that pressure management will reduce 

 
Page 30 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
myocardial stress in HF patients,50-52 PIIINP will also be measured. PIIINP will be measured in 
the laboratory at the Montreal Heart Institute directed by Dr Martin G. Sirois using the Orion 
Diagnostica’s UniQ PIIINP assay. The use of this assay has been validated in numerous studies in 
humans. Dr Sirois’s laboratory has measured PIIINP in a study comparing circulating levels of 
various biomarkers between patients with systolic HF and HF-PEF, as well as in a study comparing 
concentrations of biomarkers between patients with HF and anemia and HF patients without 
anemia.53 Together with NT-proBNP, this biomarker will be very important in demonstrating that 
the beneficial effects of pressure management on cardiac remodeling.  
 
Osteopontin (OPN) 
An additional marker of remodeling, osteopontin [OPN]) is a glycoprotein that can be detected in 
plasma and was found to be upregulated in several animal models of cardiac failure54 and may thus 
represent a new biomarker that facilitates risk stratification in patients with heart failure;48 it  has 
been shown to correlate with disease severity and poor prognosis.55,56  OPN seems to have a pivotal 
role in the development of Angiotensin II-induced cardiac fibrosis and remodeling. Moreover, the 
effect of Eplerenone on the prevention of cardiac fibrosis, but not cardiac hypertrophy, might be 
partially mediated through the inhibition of OPN expression.57 Thus, we will also measure 
angiotensin-II and aldosterone, two important steps in the remodeling and fibrosis pathways. 
High sensitivity C-Reactive protein (HS-CRP) 
While heart failure has been shown to be an inflammatory condition,58,59 the impact of pressure 
management on HS-CRP has not been well characterized. We herein propose to measure HS-CRP 
in our patients undergoing hemodynamic monitoring. 
Cardiac Troponin T (cTnT) 
In heart failure, the level of troponin correlates with prognostic independently of the presence of 
ischemic etiology or myocardial stretch assessed by NT-proBNP. This troponin leak varies with 
time and has been shown to be associated with decreased survival. We herein propose to measure 
cTnT in our patients undergoing hemodynamic monitoring. 

 
Page 31 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 
Emerging markers 
Galectin-3 serves important functions in numerous biological activities including cell growth, 
apoptosis, pre-mRNA splicing, differentiation, transformation, angiogenesis, inflammation, 
fibrosis and host defense.60-63 Numerous previous studies have indicated that galectin-3 may be 
used as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and 
cancer.64 Galectin-3 levels are correlated with elevated risk for new HF in healthy people and acute 
myocardial infarction with reduced ejection fraction patients.65 Thus, it is probable that galectin-
3 has a more important role in the beginning stage of HF including early fibrosis and ventricular.66 
Whether hemodynamic management leads to improved levels of the biomarker is unknown at the 
present time.  
ST2 cardiac biomarker is a protein biomarker of cardiac stress encoded by the IL1RL1 gene. 
ST2 signals the presence and severity of adverse cardiac remodeling and tissue fibrosis, which 
occurs in response to myocardial infarction, acute coronary syndrome, or worsening heart 
failure.62,67,68,59 ST2 provides prognostic information that is independent of other cardiac 
biomarkers such as BNP, NT-proBNP, highly sensitive troponin, GDF-15, and galectin-3.[3] One 
study indicated that discrimination is independent of age, body mass index, history of heart 
failure, anemia and impaired renal failure or sex. 
Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, ADH) is a peptide hormone 
formed in the hypothalamus, then transported via axons to the posterior pituitary, which releases 
it into the blood. AVP has two principle sites of action: the kidney and blood vessels.69 The primary 
function of AVP in the body is to regulate extracellular fluid volume by regulating renal handling 
of water, although it is also a vasoconstrictor. AVP acts on renal collecting ducts via V2 receptors 
to increase water permeability (cAMP-dependent mechanism), which leads to decreased urine 
formation (hence, the antidiuretic action of "antidiuretic hormone"). This increases blood volume, 
cardiac output and arterial pressure. Heart failure is associated with what might be viewed as a 
paradoxical increase in AVP. Increased blood volume and atrial pressure associated with heart 
failure should decrease AVP secretion, but it does not. It may be that sympathetic and renin-
angiotensin system activation in heart failure override the volume and low pressure cardiovascular 

 
Page 32 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
receptors (as well as the hypothalamic control of AVP release) and cause an increase in AVP 
secretion.70 Nevertheless, this increase in AVP during heart failure may contribute to the increase 
in systemic vascular resistance as well as the enhanced renal retention of fluid that accompanies 
heart failure. Whether hemodynamic monitoring leads to a decrease in AVP is unknown. 
Drug concentrations 
Concentrations of commonly used drugs in patients with HF will be measured at the baseline visit, 
as well as at visits at week 2, month 2, month 12 and at unscheduled visits. At each of these visits, 
the dose, the time of administration of the last dose of the cardiovascular medications and the time 
of the blood draw will be recorded.   
Currently, very little information is available regarding the pharmacokinetic (PK) or 
concentrations of drugs in HF patients.71 Data from our group and others have suggested marked 
differences in the concentrations or PK of commonly used drugs in HF patients compared to 
healthy individuals such as spironolactone and candesartan (manuscripts submitted). This could 
be attributable to several factors such as decreased renal function.71 Moreover, only very limited 
data are available on the factors influencing the PK of drugs in patients with HF.71 
 
In addition, little information is available on the magnitude of the effects of common dosing 
adjustments of HF drugs in “real-life” HF patients on drug concentrations, or whether patients who 
cannot reach target doses of HF medication actually have lower drug concentrations than those 
who do. Indeed, some patients who do not reach target doses could present comparable drug 
concentrations as patients reaching target doses, if they present clinical factors that predispose to 
increased concentrations, such as renal dysfunction.71 
 
The screening and quantification of drugs or their active metabolites will be performed in plasma 
at the Platform of Biopharmacy of the Faculty of Pharmacy at Université de Montréal using Liquid 
Chromatography coupled to triple quadrupole mass spectrometer (LC-MS/MS) in the selective 
MRM mode72-76 and Liquid Chromatography High-Resolution Mass Spectrometer (LC-HRMS) 
of the type quadrupole time-of-flight (QTof) in the full scan mode.77-82 This group has an extensive 
experience for developing and optimising the bioanalytical techniques needed to measure 

 
Page 33 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
drugs/metabolites.83-97 In addition to comparing drug concentrations between groups and 
concentrations changes, for drugs used in 30 or more patients, we will perform exploratory 
population-pharmacokinetics modelling. Modelling analyses will be performed by the STP2 
Laboratory (Faculty of Pharmacy at Université de Montréal) using the gold standard for population 
pharmacokinetics modelling to estimate parameter and, interindividual and residual variability.98,99 
Population pharmacokinetics modelling will be done using nonlinear mixed effect modeling 
(NONMEM®, version 7.4, ICON Development Solutions). Pharmacokinetics studies in patients 
with special conditions are at the center of the STP2 Laboratory research.100-108 
8.   SAFETY  
All Adverse events and serious adverse events will be reviewed by the investigator or a sub-
investigator. 
8.1. Definition of Adverse Events, Serious Adverse Events, and procedures for reporting 
Serious Adverse Event 
 
8.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, 
whether or not related to the investigational medical device. 
This definition includes events related to the investigational medical device and events 
related to the procedures involved. 
 
8.1.2. Serious Adverse Event definition (SAE) 
A serious adverse event is an AE that fulfills one or more of the following: 
1. Results in death 
2. Led to serious deterioration in heath of the subject, that either resulted in 
 A life-threatening illness or injury, or 
 A permanent impairment of a body structure or a body function, or 
 Requires in-patient hospitalization or prolongation of existing hospitalization 

 
Page 34 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 Medical or surgical intervention to prevent life-threatening illness or injury or 
    permanent impairment to a body structure or a body function 
3. Results to fetal distress, fetal death or a congenital abnormality/birth defect. 
Note: Planned hospitalization for a pre-existing condition or a procedure is not considered 
a serious adverse event. 
 
8.1.3.  Adverse device Effect (ADE)  
Adverse event related to the use of an investigational medical device. 
Notes: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device.  
This definition includes any event resulting from use error or from intentional misuse of 
the investigational medical device. 
 
8.1.4.   Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event 
 
8.1.5.  Unanticipated Serious Adverse Device Effect (USADE)  
 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the CardioMEMS user’s Manual, or 
any other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects 41    
 
8.1.6. Procedures for Adverse Event reporting 
8.1.6.1.   Investigator Reporting 
All AEs considered device related will be recorded in the eCRF for enrolled subjects. 

 
Page 35 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Any Serious Adverse Event that occurs in the course of the study must be reported to 
Montreal Health Innovations Coordinating Center (MHICC) within one day of the 
investigator becoming aware of the SAE. All SAEs will be recorded in the electronic Case 
Report Form (eCRF) as adverse events up to 14 days after final visit. The investigator is 
responsible for informing the Ethics Committee of the SAE as per local requirements.  
9. 
STATISTICAL ANALYSIS 
Descriptive statistics of all study endpoints will be presented overall and broken down by group. 
Number of observations, mean, standard deviation, median, minimum and maximum will be 
presented for continuous variables. Count and proportion will be displayed for categorical 
variables.  
For the primary endpoint, the analysis will consist of an unadjusted comparison of time to first 
event. Event-rate curves will be estimated by the Kaplan-Meier product-limit method and the 
difference between groups will be assessed using the log-rank test. Components of the primary 
endpoint will be analyzed similarly.  
ANCOVA models will be used to compare continuous endpoints expressed as change from 
baseline to 12 months between the standard group and the virtual group. The main model will 
include fixed effects for group with the baseline value as a covariate.  Difference between groups 
in other continuous endpoints will be tested by either two-sample t-tests or Wilcoxon rank-sum 
tests depending on the normality of the data. Difference between groups in categorical endpoints 
will be tested using Chi-square tests. 
Basic assumptions of the proposed analyses will be checked and data transformation or other 
analyses could be done if appropriate. For example, as some endpoints are likely to be skewed (ex. 
hs-CRP), log-transformation might be used, in which case descriptive statistics would also include 
geometric means. Missing values will not be imputed. 
All statistical tests will be two-sided and conducted at the 0.05 significance level. Statistical 
analyses will be done using SAS version 9.4 or higher. 

 
Page 36 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
A statistical analysis plan (SAP) will be written to fully describe the statistical analyses that will 
be done. The SAP will be finalized prior to database lock. 
9.1. Sample size 
It is hypothesized that virtual monitoring will be superior to standard care in reducing the risk of 
the composite primary endpoint of acute decompensated heart failure that requires emergency 
department consultation and/or unplanned intravenous heart failure therapy in an outpatient clinic, 
hospital admission for heart failure, or CV death during 12 months of follow-up. The sample size 
rationale and assumptions are based on the following: 
From the CHAMPION trial, the rate of HF hospitalization at 12 months was 0.52 and 0.75 in the 
treatment and control groups respectively (Phil Adamson personal communication, unpublished 
data), leading to a hazard ratio of 0.53. Similar event rates are expected for the primary endpoint 
in this trial. The mortality rate is expected to be similar between the two groups as in CHAMPION. 
Using a log-rank test, a total of 136 subjects (68 in each group) would provide 80% power with a 
two-sided significance level of α=0.05.  Factoring in a drop-out rate of approximately 10%, a total 
of 150 patients are required. 
10. INVESTIGATOR’S REGULATORY OBLIGATIONS 
10.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval 
The protocol and the informed consent document must have the initial and at least annual (when 
required) approval of an IRB/IEC. The signed IRB/IEC approval letter must identify the 
documents approved (i.e. list the investigator’s name, the protocol number and title, the date of the 
protocol and informed consent document, and the date of approval of the protocol and the informed 
consent document).  Written information to be provided to the subject (i.e. patient cards, patient 
diary, instructional material on nutrition, exercise, and HF) and any advertisement used to recruit 
subjects must also be reviewed by the IRB/IEC. 

 
Page 37 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
10.2. Informed Consent 
Regulatory agencies have issued regulations to provide protection for human subjects in clinical 
investigations and to describe the general requirements for informed consent.  The informed 
consent document shall contain all the elements of informed consent specified in the application 
regulations. Some regulations may require the disclosure of additional information to the subject 
and/or inclusion of additional information in an informed consent document. 
10.3. Declaration of Helsinki 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki (Appendix 5) and that are consistent with good clinical practices (GCP) 
and the applicable requirements. 
10.4. Case Report Form 
All data will be recorded on eCRF provided by the MHICC. 
10.5. Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
 
Subject names will not be supplied. Only the subject number will be recorded in the eCRF, and if 
the subject name appears on any other document (e.g. pathologist report), it must be obliterated 
before a copy of the document is supplied to the sponsor. Study findings stored on a computer will 
be stored in accordance with local data protection laws. As part of the informed consent process, 
the subjects will be informed in writing that representatives of the sponsor, IEC/IRB, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
If the results of the study are published, the subject's identity will remain confidential. 
The investigator will maintain a list to enable subjects to be identified. 

 
Page 38 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
11. DATA QUALITY ASSURANCE 
The principal investigator performs quality control and assurance checks on all clinical studies that 
he/she performs. Before enrolling any subjects in this study, the principal investigator and study 
coordinator review the protocol and the eCRFs, determine the procedure for obtaining informed 
consent, and determine the procedure for reporting AEs and SAEs.  The principal investigator or 
study coordinator reviews the data for accuracy and safety information.  The principal investigator 
or study coordinator reviews the data for legibility, completeness and logical consistency. 
11.1. Monitoring, Audits and inspections 
In accordance with applicable regulations, GCP, and sponsor’s / Academic Contract Research 
Organization’s (ARO) procedures, monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and sponsor's requirements. When reviewing data collection procedures, the 
discussion will also include identification and documentation of source data items. 
The sponsor’s designee will monitor the site activity to verify that the: 
 
Data are authentic, accurate, and complete 
 
Safety and rights of subjects are being protected 
 
Study is conducted in accordance with the currently approved protocol (including study 
procedures in accordance with the protocol) 
 
Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated ARO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator / institution will be informed of the audit outcome.  
In addition, inspections by regulatory health authority representatives and IEC(s) / IRB(s) are 
possible. The investigator should notify the MHICC immediately of any such inspection.  

 
Page 39 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
The investigator / institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his / her time and the time of his / her staff to the auditor / inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study. 
11.2. Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they are 
readily available upon authorities' request. 
Patient (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. Where the 
archiving procedures do not meet the minimum timelines required by the sponsor, alternative 
arrangements must be made to ensure the availability of the source documents for the required 
period. 
The investigator/institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).  
The investigator site file is not to be destroyed without the sponsor’s approval. 
The investigator’s contract will contain all regulations relevant for the study center. 
12. DATA MANAGEMENT 
The MHICC will be the data coordinating center. The data collection tool for this study will be a 
validated electronic system. Subject data necessary for analysis and reporting will be entered into 
database or data system. Clinical data management will be performed in accordance with 
applicable sponsor’s standards and data cleaning procedures. This is applicable for data recorded 
in the eCRF as well as for data from other sources (e.g. laboratory). 
13. TRIAL COMMITTEES 
13.1.   Clinical Events Committee 
An independent Clinical Events Committee (CEC) will be established. The CEC will consist of 
physicians who have no affiliation with the CardioMEMS™ HF System trial, are not employees 

 
Page 40 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
of Abbott Laboratories, or have no significant investment in Abbott Laboratories or their entities. 
This committee will be composed of at least 3 members from which at least two are HF 
cardiologists. Events for adjudication will include primary endpoints and device or procedure 
related adverse events. Criteria for adjudication, procedures, data flow will be described in separate 
CEC charter generated and maintained by the MHICC.  
13.2.    Data and Safety Monitoring Board (DSMB)  
An independent Data and Safety Monitoring Board (DSMB) will be established. The DSMB is 
responsible for safeguarding the interests of study participants, assessing the safety of study 
procedures and for monitoring the overall conduct of the study The DSMB will consist of three 
experienced physicians with expertise in clinical trial conduct. The DSMB will meet by 
teleconference once a year, with additional meetings or conference calls scheduled as needed.  
 
 

 
Page 41 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Proposed Table 1. Patient Characteristics at Enrollment  
 
Standard care 
Virtual clinic 
p value 
Demographics and clinical  
 
 
 
   Age,  
 
 
 
   Gender 
 
 
 
   Weight  
 
 
 
Body Mass Index (BMI) 
 
 
 
   NYHA class, median (range)  
 
 
 
   Heart rate, bpm 
 
 
 
   Systolic blood pressure, mmHg 
 
 
 
   Diastolic blood pressure, mmHg 
 
 
 
Medical History 
 
 
 
   Dyslipidemia, %  
 
 
 
   Diabetes mellitus, % 
 
 
 
   Hypertension, %  
 
 
 
   Aetiology of HF, % ischemic 
 
 
 
   Prior myocardial infarction, %  
 
 
 
   CABG, %   
 
 
 
   Percutaneous coronary intervention, 
% 
 
 
 
   Stroke 
 
 
 
   Atrial fibrillation, % 
 
 
 
   Sustained Ventricular Arrhythmias, % 
 
 
 
   CRT, %  
 
 
 
   ICD, % 
 
 
 
   Pacemaker, % 
 
 
 
Medications 
 
 
 
   ACEi/ARB, % 
 
 
 
   ARNi, % 
 
 
 
   Β-blockers, % 
 
 
 
   MRA, % 
 
 
 
Ivabradine, % 
 
 
 
   Digoxin, % 
 
 
 
   Hydralazine/nitrates, % 
 
 
 
   Loop diuretics, % 
 
 
 
   Other diuretics, % 
 
 
 
Laboratory testing# 
 
 
 
   Sodium, mmol/l 
 
 
 
   NT-proBNP, pg/mL 
 
 
 
   BUN, mmol/L 
 
 
 
   eGFR, mL/min/1.73 m2 (MDRD) 
 
 
 
   Hemoglobin 
 
 
 

 
Page 42 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
   6-Minute walk, m 
 
 
 
Echocardiography# 
 
 
 
   LVEF, % 
 
 
 
 % with HFPEF (LVEF>40%) 
 
 
 
   LVESVI, ml 
 
 
 
   LAVi, ml 
 
 
 
   RV TAPSE 
 
 
 
   ePAPSP 
 
 
 
   PVR, Wood units 
 
 
 
Resting hemodynamics& 
 
 
 
   RAP, mean, mm Hg 
 
 
 
   PAP, systolic, mm Hg  
 
 
 
 
   PAP, diastolic, mm Hg 
 
 
 
   PCWP, mm Hg 
 
 
 
   Cardiac output, L/min 
 
 
 
   Cardiac index, L /min/m2 
 
 
 
   SVRI, dyne/ s/cm/m2 
 
 
 
   PVR, Wood units 
 
 
 
   RVSWI, mL/beat/m2 
 
 
 
# Selected parameters presented here; Data will likely be presented for HFrEF and HFpEF. 
& in implanted patients only. 
NYHA indicates New York Heart Association; CRT, cardiac resynchronization therapy; ICD, implantable cardiac 
defibrillator; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular 
ejection fraction; LVESVI: LV end systolic volume indexed to BSA; LAVi: Left atrial volume indexed to BSA; RV 
TAPSE: RV tricuspid annular plane systolic excursion, using Tissue Doppler imaging; eSPAP: estimated systolic 
PAP; PVR, pulmonary vascular resistance; RAP, right atrial pressure; PAP, pulmonary artery pressure; PCWP, 
pulmonary capillary wedge pressure; SVRI, systemic vascular resistance; and RVSWI, RV stroke work index. 
Data will be summarized as meanSD (range) unless otherwise specified. 
 
 

 
Page 43 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Proposed Table 2. Changes in the main Parameters between baseline and 12-months in 
Survivors  
 
Standard care 
Virtual clinic 
 p value 
Clinical 
 
 
 
   NYHA class, median (range)  
 
 
 
   Heart rate, bpm 
 
 
 
   Systolic blood pressure, mmHg 
 
 
 
 
   6-Minute walk, m 
 
 
 
   MLHFQ 
 
 
 
Laboratory testing# 
 
 
 
   Sodium, mmol/l 
 
 
 
   NT-proBNP, pg/mL 
 
 
 
   BUN, mmol/L 
 
 
 
   eGFR, mL/min/1.73 m2 (MDRD) 
 
 
 
   Hemoglobin  
 
 
 
   Hs-CRP 
 
 
 
   Troponin 
 
 
 
   Osteopontin 
 
 
 
   Angiotensin-2 
 
 
 
   Aldosterone 
 
 
 
   Vasopressin 
 
 
 
   PIIINP 
 
 
 
   Galectin-3 
 
 
 
   ST2 
 
 
 
   Cystatin C 
 
 
 
Echocardiography# 
 
 
 
   LVEF, % 
 
 
 
      % with HFPEF (LVEF>40%) 
 
 
 
   LVESVI, ml 
 
 
 
   LAVi, ml 
 
 
 
   RV TAPSE 
 
 
 
   ePAPSP 
 
 
 
   PVR, Wood units 
 
 
 
*Frailty index using the Fried scale40; # Selected parameters; final table will vary according to findings; & in 
implanted patients only. 
NYHA indicates New York Heart Association; CRT, cardiac resynchronization therapy; ICD, implantable cardiac 
defibrillator; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular 
ejection fraction; LVESVI: LV end systolic volume indexed to BSA; LAVi: Left atrial volume indexed to BSA; RV 
TAPSE: RV tricuspid annular plane systolic excursion, using Tissue Doppler imaging; eSPAP: estimated systolic 
PAP; PVR, pulmonary vascular resistance; RAP, right atrial pressure; PAP, pulmonary artery pressure; PCWP, 
pulmonary capillary wedge pressure; SVRI, systemic vascular resistance; and RVSWI, RV stroke work index. Data 
will be summarized as meanSD (range) unless otherwise specified. p values will be for comparisons across all time 
points.

 
Page 44 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 
Proposed Table 3. Pharmacological Profiles and Goal for best practice at 12 months 
 
Standard care 
Virtual clinic 
p values 
MEDICATION 
All 
HFrEF 
HFpEF 
All 
HFrEF 
HFpEF 
 
ACE or ARB, % and mean dose 
 
 
 
 
 
 
 
% achieved target dose 
 
 
NA 
 
 
NA 
 
ARNi, % and mean dose 
 
 
 
 
 
 
 
% achieved target dose 
 
 
 
 
 
NA 
 
β-blocker, % and mean dose 
 
 
 
 
 
 
 
% achieved target dose 
 
 
NA 
 
 
NA 
 
Mineralocorticoid receptors antagonist, % and mean dose 
 
 
 
 
 
 
 
% achieved target dose 
 
 
 
 
 
 
 
Ivabradine, % and mean dose 
 
 
 
 
 
 
 
% achieved target dose 
 
 
 
 
 
 
 
Loop diuretic, % and mean dose 
 
 
 
 
 
 
 
Thiazide diuretic, % and mean dose 
 
 
 
 
 
 
 
Digoxin, % and mean dose 
 
 
 
 
 
 
 
Long-acting nitrates, % and mean dose 
 
 
 
 
 
 
 
Hydralazine, % and mean dose 
 
 
 
 
 
 
 
MEDICATION CHANGES 
 
 
 
 
 
 
 
Number of medication changes/patient, mean, range 
 
 
 
 
 
 
 
time (days) to achieve target doses of GDMT 
 
 
 
 
 
 
 
 
*P for comparison between baseline and 12 months 

 
Page 45 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Proposed Table 4: Device related endpoints 
 
 Safety: adverse events related to the device;  
 number of successful patient contacts (virtual and clinic); 
 PA pressures: changes, frequency of elevated readings 
 
 
 

 
Page 46 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
REFERENCES 
 
 
1. 
Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and 
framework for future research. Circulation. 2005;112(25):3958-3968. 
2. 
Fonarow GC, Abraham WT, Albert NM, et al. Association between performance measures and 
clinical outcomes for patients hospitalized with heart failure. JAMA. 2007;297(1):61-70. 
3. 
Arnold JM, Howlett JG, Dorian P, et al. Canadian Cardiovascular Society Consensus Conference 
recommendations on heart failure update 2007: Prevention, management during intercurrent 
illness or acute decompensation, and use of biomarkers. Can J Cardiol. 2007;23(1):21-45. 
4. 
Desai AS, Bhimaraj A, Bharmi R, et al. Ambulatory Hemodynamic Monitoring Reduces Heart 
Failure Hospitalizations in "Real-World" Clinical Practice. J Am Coll Cardiol. 2017;69(19):2357-
2365. 
5. 
Adamson PB. Pathophysiology of the transition from chronic compensated and acute 
decompensated heart failure: new insights from continuous monitoring devices. Curr Heart Fail 
Rep. 2009;6(4):287-292. 
6. 
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary 
hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41. 
7. 
Bursi F, McNallan SM, Redfield MM, et al. Pulmonary pressures and death in heart failure: a 
community study. J Am Coll Cardiol. 2012;59(3):222-231. 
8. 
Ducharme A, Doyon O, White M, Rouleau JL, Brophy JM. Impact of care at a multidisciplinary 
congestive heart failure clinic: a randomized trial. CMAJ. 2005;173(1):40-45. 
9. 
Ducharme A. Do Heart Failure Clinics Have to Reinvent Themselves to Remain Germane? Can J 
Cardiol. 2017;33(10):1212-1214. 
10. 
Cleland JG, Louis AA, Rigby AS, Janssens U, Balk AH. Noninvasive home telemonitoring for 
patients with heart failure at high risk of recurrent admission and death: the Trans-European 
Network-Home-Care Management System (TEN-HMS) study. J Am Coll Cardiol. 
2005;45(10):1654-1664. 
11. 
Clark RA, Inglis SC, McAlister FA, Cleland JG, Stewart S. Telemonitoring or structured telephone 
support programmes for patients with chronic heart failure: systematic review and meta-
analysis. BMJ. 2007;334(7600):942. 
12. 
Chaudhry SI, Phillips CO, Stewart SS, et al. Telemonitoring for patients with chronic heart failure: 
a systematic review. J Card Fail. 2007;13(1):56-62. 
13. 
Ong MK, Romano PS, Edgington S, et al. Effectiveness of Remote Patient Monitoring After 
Discharge of Hospitalized Patients With Heart Failure: The Better Effectiveness After Transition -
- Heart Failure (BEAT-HF) Randomized Clinical Trial. JAMA Intern Med. 2016;176(3):310-318. 
14. 
Morgan JM, Kitt S, Gill J, et al. Remote management of heart failure using implantable electronic 
devices. Eur Heart J. 2017. 
15. 
Desai AS, Stevenson LW. Connecting the circle from home to heart-failure disease management. 
N Engl J Med. 2010;363(24):2364-2367. 
16. 
van Veldhuisen DJ, Braunschweig F, Conraads V, et al. Intrathoracic impedance monitoring, 
audible patient alerts, and outcome in patients with heart failure. Circulation. 
2011;124(16):1719-1726. 

 
Page 47 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
17. 
Boehmer JP, Hariharan R, Devecchi FG, et al. A Multisensor Algorithm Predicts Heart Failure 
Events in Patients With Implanted Devices: Results From the MultiSENSE Study. JACC Heart Fail. 
2017;5(3):216-225. 
18. 
Singh B, Russell SD, Cheng A. Update on device technologies for monitoring heart failure. Curr 
Treat Options Cardiovasc Med. 2012;14(5):536-549. 
19. 
Adamson PB, Gold MR, Bennett T, et al. Continuous hemodynamic monitoring in patients with 
mild to moderate heart failure: results of The Reducing Decompensation Events Utilizing 
Intracardiac Pressures in Patients With Chronic Heart Failure (REDUCEhf) trial. Congest Heart 
Fail. 2011;17(5):248-254. 
20. 
Ritzema J, Troughton R, Melton I, et al. Physician-directed patient self-management of left atrial 
pressure in advanced chronic heart failure. Circulation. 2010;121(9):1086-1095. 
21. 
Troughton RW, Ritzema J, Eigler NL, et al. Direct left atrial pressure monitoring in severe heart 
failure: long-term sensor performance. J Cardiovasc Transl Res. 2011;4(1):3-13. 
22. 
Maurer MS, Adamson PB, Costanzo MR, et al. Rationale and Design of the Left Atrial Pressure 
Monitoring to Optimize Heart Failure Therapy Study (LAPTOP-HF). J Card Fail. 2015;21(6):479-
488. 
23. 
William T.Abraham PBA, Maria Rosa Costanzo, Neal Eigler, Michaelold, Marc Klapholz, Mathew 
Maurer, Leslie Saxon, Jagmeet Singh, RichardTroughton. Hemodynamic Monitoring in Advanced 
Heart Failure: Results from the LAPTOP-HF Trial. Journal of Cardiac Failure. 2016;22(11):940. 
24. 
Verdejo HE, Castro PF, Concepcion R, et al. Comparison of a radiofrequency-based wireless 
pressure sensor to swan-ganz catheter and echocardiography for ambulatory assessment of 
pulmonary artery pressure in heart failure. J Am Coll Cardiol. 2007;50(25):2375-2382. 
25. 
Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic 
monitoring in chronic heart failure: a randomised controlled trial. Lancet. 2011;377(9766):658-
666. 
26. 
Benza RL, Raina A, Abraham WT, et al. Pulmonary hypertension related to left heart disease: 
insight from a wireless implantable hemodynamic monitor. J Heart Lung Transplant. 
2015;34(3):329-337. 
27. 
Adamson PB, Abraham WT, Bourge RC, et al. Wireless pulmonary artery pressure monitoring 
guides management to reduce decompensation in heart failure with preserved ejection fraction. 
Circ Heart Fail. 2014;7(6):935-944. 
28. 
Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension 
group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement 
from the Pulmonary Hypertension Council of the International Society for Heart and Lung 
Transplantation. J Heart Lung Transplant. 2012;31(9):913-933. 
29. 
Krahnke JS, Abraham WT, Adamson PB, et al. Heart failure and respiratory hospitalizations are 
reduced in patients with heart failure and chronic obstructive pulmonary disease with the use of 
an implantable pulmonary artery pressure monitoring device. J Card Fail. 2015;21(3):240-249. 
30. 
Raina A, Abraham WT, Adamson PB, Bauman J, Benza RL. Limitations of right heart 
catheterization in the diagnosis and risk stratification of patients with pulmonary hypertension 
related to left heart disease: insights from a wireless pulmonary artery pressure monitoring 
system. J Heart Lung Transplant. 2015;34(3):438-447. 
31. 
Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and 
pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005;294(13):1625-
1633. 

 
Page 48 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
32. 
Reiter MJ, Stromberg KD, Whitman TA, Adamson PB, Benditt DG, Gold MR. Influence of 
intracardiac pressure on spontaneous ventricular arrhythmias in patients with systolic heart 
failure: insights from the REDUCEhf trial. Circ Arrhythm Electrophysiol. 2013;6(2):272-278. 
33. 
Ebinger MW, Krishnan S, Schuger CD. Mechanisms of ventricular arrhythmias in heart failure. 
Curr Heart Fail Rep. 2005;2(3):111-117. 
34. 
Adamson PB, Smith AL, Abraham WT, et al. Continuous autonomic assessment in patients with 
symptomatic heart failure: prognostic value of heart rate variability measured by an implanted 
cardiac resynchronization device. Circulation. 2004;110(16):2389-2394. 
35. 
Reiter MJ. Effects of mechano-electrical feedback: potential arrhythmogenic influence in 
patients with congestive heart failure. Cardiovasc Res. 1996;32(1):44-51. 
36. 
Schmier JK, Ong KL, Fonarow GC. Cost-Effectiveness of Remote Cardiac Monitoring With the 
CardioMEMS Heart Failure System. Clin Cardiol. 2017;40(7):430-436. 
37. 
Adamson PB, Abraham WT, Stevenson LW, et al. Pulmonary Artery Pressure-Guided Heart 
Failure Management Reduces 30-Day Readmissions. Circ Heart Fail. 2016;9(6). 
38. 
Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada's 2018 Guidelines for Diagnosis, 
Risk Assessment, Prevention, and Treatment of Hypertension in Adults and Children. Can J 
Cardiol. 2018;34(5):506-525. 
39. 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate 
glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet 
in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461-470. 
40. 
Iwanaga Y, Miyazaki S. Heart failure, chronic kidney disease, and biomarkers--an integrated 
viewpoint. Circ J.74(7):1274-1282. 
41. 
de Denus S, Pharand C, Williamson DR. Brain natriuretic peptide in the management of heart 
failure: the versatile neurohormone. Chest. 2004;125(2):652-668. 
42. 
Skaf S, Thibault B, Khairy P, et al. Impact of Left Ventricular vs Biventricular Pacing on Reverse 
Remodelling: Insights From the Evaluation of Resynchronization Therapy for Heart Failure 
(EARTH) Trial. Can J Cardiol. 2017;33(10):1274-1282. 
43. 
Thibault B, Ducharme A, Harel F, et al. Left ventricular versus simultaneous biventricular pacing 
in patients with heart failure and a QRS complex >/=120 milliseconds. Circulation. 
2011;124(25):2874-2881. 
44. 
White M, Lepage S, Lavoie J, et al. Effects of combined candesartan and ACE inhibitors on BNP, 
markers of inflammation and oxidative stress, and glucose regulation in patients with 
symptomatic heart failure. J Card Fail. 2007;13(2):86-94. 
45. 
de Denus S, Lavoic J, Ducharme A, et al. Differences in concentrations and correlations amongst 
biomarkers of neurohormonal activation, inflammation and extracellular matrix turnover in 
patients with HF and a reduced or a preserved left ventricular ejection fraction. Journal of 
Cardiac Failure. 2008;14(6):S38-S38. 
46. 
Lopez B, Gonzalez A, Varo N, Laviades C, Querejeta R, Diez J. Biochemical assessment of 
myocardial fibrosis in hypertensive heart disease. Hypertension. 2001;38(5):1222-1226. 
47. 
Nishikawa N, Yamamoto K, Sakata Y, et al. Differential activation of matrix metalloproteinases in 
heart failure with and without ventricular dilatation. Cardiovasc Res. 2003;57(3):766-774. 
48. 
Zannad F, Radauceanu A. Effect of MR blockade on collagen formation and cardiovascular 
disease with a specific emphasis on heart failure. Heart Fail Rev. 2005;10(1):71-78. 

 
Page 49 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
49. 
Cicoira M, Rossi A, Bonapace S, et al. Independent and additional prognostic value of 
aminoterminal propeptide of type III procollagen circulating levels in patients with chronic heart 
failure. J Card Fail. 2004;10(5):403-411. 
50. 
Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover 
may contribute to survival benefit of spironolactone therapy in patients with congestive heart 
failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. 
Circulation. 2000;102(22):2700-2706. 
51. 
Tsutamoto T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic 
peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll 
Cardiol. 2001;37(5):1228-1233. 
52. 
Macdonald JE, Kennedy N, Struthers AD. Effects of spironolactone on endothelial function, 
vascular angiotensin converting enzyme activity, and other prognostic markers in patients with 
mild heart failure already taking optimal treatment. Heart. 2004;90(7):765-770. 
53. 
O'Meara E, Rouleau JL, White M, et al. Heart failure with anemia: novel findings on the roles of 
renal disease, interleukins, and specific left ventricular remodeling processes. Circ Heart Fail. 
2014;7(5):773-781. 
54. 
Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on 
cardiac form and function. Physiol Rev. 2007;87(4):1285-1342. 
55. 
Ashkar S, Glimcher MJ, Saavedra RA. Mouse osteopontin expressed in E. coli exhibits 
autophosphorylating activity of tyrosine residues. Biochem Biophys Res Commun. 
1993;194(1):274-279. 
56. 
Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin): an early component of 
type-1 (cell-mediated) immunity. Science. 2000;287(5454):860-864. 
57. 
Iraqi W, Rossignol P, Angioi M, et al. Extracellular cardiac matrix biomarkers in patients with 
acute myocardial infarction complicated by left ventricular dysfunction and heart failure: 
insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and 
Survival Study (EPHESUS) study. Circulation. 2009;119(18):2471-2479. 
58. 
Ahmad T, Fiuzat M, Neely B, et al. Biomarkers of myocardial stress and fibrosis as predictors of 
mode of death in patients with chronic heart failure. JACC Heart Fail. 2014;2(3):260-268. 
59. 
Chaikijurajai T, Tang WHW. Reappraisal of Inflammatory Biomarkers in Heart Failure. Curr Heart 
Fail Rep. 2020. 
60. 
Meijers WC, Januzzi JL, deFilippi C, et al. Elevated plasma galectin-3 is associated with near-term 
rehospitalization in heart failure: a pooled analysis of 3 clinical trials. Am Heart J. 
2014;167(6):853-860 e854. 
61. 
Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL. Galectin-3, cardiac 
structure and function, and long-term mortality in patients with acutely decompensated heart 
failure. Eur J Heart Fail. 2010;12(8):826-832. 
62. 
Shah RV, Januzzi JL, Jr. Soluble ST2 and galectin-3 in heart failure. Clin Lab Med. 2014;34(1):87-
97, vi-vii. 
63. 
Zilinski JL, Shah RV, Gaggin HK, Gantzer ML, Wang TJ, Januzzi JL. Measurement of multiple 
biomarkers in advanced stage heart failure patients treated with pulmonary artery catheter 
guided therapy. Crit Care. 2012;16(4):R135. 
64. 
Simpson CE, Damico RL, Hassoun PM, et al. Noninvasive prognostic biomarkers for left heart 
failure as predictors of survival in pulmonary arterial hypertension. Chest. 2020. 

 
Page 50 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
65. 
Lubrano V, Balzan S. Role of oxidative stress-related biomarkers in heart failure: galectin 3, 
alpha1-antitrypsin and LOX-1: new therapeutic perspective? Mol Cell Biochem. 2020;464(1-
2):143-152. 
66. 
She G, Hou MC, Zhang Y, et al. Gal-3 (Galectin-3) and KCa3.1 Mediate Heterogeneous Cell 
Coupling and Myocardial Fibrogenesis Driven by betaAR (beta-Adrenoceptor) Activation. 
Hypertension. 2020;75(2):393-404. 
67. 
Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL. Serum levels of the 
interleukin-1 receptor family member ST2, cardiac structure and function, and long-term 
mortality in patients with acute dyspnea. Circ Heart Fail. 2009;2(4):311-319. 
68. 
Shah RV, Januzzi JL, Jr. ST2: a novel remodeling biomarker in acute and chronic heart failure. 
Curr Heart Fail Rep. 2010;7(1):9-14. 
69. 
Iovino M, Iacoviello M, De Pergola G, et al. Vasopressin in Heart Failure. Endocr Metab Immune 
Disord Drug Targets. 2018;18(5):458-465. 
70. 
Chirinos JA, Sardana M, Oldland G, et al. Association of arginine vasopressin with low atrial 
natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without 
heart failure. ESC Heart Fail. 2018;5(5):911-919. 
71. 
Ogawa R, Stachnik JM, Echizen H. Clinical pharmacokinetics of drugs in patients with heart 
failure: an update (part 2, drugs administered orally). Clin Pharmacokinet. 2014;53(12):1083-
1114. 
72. 
Gonzalez O, Alonso RM, Ferreirós N, Weinmann W, Zimmermann R, Dresen S. Development of 
an LC–MS/MS method for the quantitation of 55 compounds prescribed in combined 
cardiovascular therapy. Journal of Chromatography B. 2011;879(3):243-252. 
73. 
Gundersen POM, Helland A, Spigset O, Hegstad S. Quantification of 21 antihypertensive drugs in 
serum using UHPLC-MS/MS. Journal of Chromatography B. 2018;1089:84-93. 
74. 
Dias E, Hachey B, McNaughton C, et al. An LC–MS assay for the screening of cardiovascular 
medications in human samples. Journal of Chromatography B. 2013;937:44-53. 
75. 
Gonzalez O, Iriarte G, Rico E, et al. LC–MS/MS method for the determination of several drugs 
used in combined cardiovascular therapy in human plasma. Journal of Chromatography B. 
2010;878(28):2685-2692. 
76. 
De Nicolò A, Avataneo V, Rabbia F, et al. UHPLC–MS/MS method with protein precipitation 
extraction for the simultaneous quantification of ten antihypertensive drugs in human plasma 
from resistant hypertensive patients. Journal of Pharmaceutical and Biomedical Analysis. 
2016;129:535-541. 
77. 
Joye T, Sidibé J, Déglon J, et al. Liquid chromatography-high resolution mass spectrometry for 
broad-spectrum drug screening of dried blood spot as microsampling procedure. Analytica 
Chimica Acta. 2019;1063:110-116. 
78. 
Rosano TG, Ohouo PY, Wood M. Application of High-Resolution UPLC–MSE/TOF Confirmation in 
Forensic Urine Drug Screening by UPLC–MS/MS. Journal of Analytical Toxicology. 
2019;43(5):353-363. 
79. 
Mollerup CB, Dalsgaard PW, Mardal M, Linnet K. Targeted and non-targeted drug screening in 
whole blood by UHPLC-TOF-MS with data-independent acquisition. Drug Testing and Analysis. 
2017;9(7):1052-1061. 
80. 
Kim EH, Seo HS, Ki NY, et al. Reliable screening and confirmation of 156 multi-class illegal 
adulterants in dietary supplements based on extracted common ion chromatograms by ultra-
high-performance liquid chromatography-quadrupole/time of flight-mass spectrometry. Journal 
of Chromatography A. 2017;1491:43-56. 

 
Page 51 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
81. 
Richter LHJ, Jacobs CM, Mahfoud F, Kindermann I, Böhm M, Meyer MR. Development and 
application of a LC-HRMS/MS method for analyzing antihypertensive drugs in oral fluid for 
monitoring drug adherence. Analytica Chimica Acta. 2019;1070:69-79. 
82. 
Tomková J, Ondra P, Kocianová E, Václavík J. Fast and sensitive analysis of beta blockers by ultra-
high-performance liquid chromatography coupled with ultra-high-resolution TOF mass 
spectrometry. Biomedical Chromatography. 2017;31(7):e3911. 
83. 
Hossain MA, Friciu M, Aubin S, Leclair G. Stability of penicillin G sodium diluted with 0.9% 
sodium chloride injection or 5% dextrose injection and stored in polyvinyl chloride bag 
containers and elastomeric pump containers. Am J Health Syst Pharm. 2014;71(8):669-673. 
84. 
Li M, Coursol C, Leclair G. Stability of cyclosporine diluted with 0.9% sodium chloride injection or 
5% dextrose injection and stored in ethylene-vinyl acetate containers. Am J Health Syst Pharm. 
2013;70(22):1970-1972. 
85. 
Li M, Forest JM, Coursol C, Leclair G. Stability of cyclosporine solutions stored in polypropylene-
polyolefin bags and polypropylene syringes. Am J Health Syst Pharm. 2011;68(17):1646-1650. 
86. 
Friciu M, Chefson A, Leclair G. Stability of Hydrocortisone, Nifedipine, and Nitroglycerine 
Compounded Preparations for the Treatment of Anorectal Conditions. Can J Hosp Pharm. 
2016;69(4):329-333. 
87. 
Friciu M, Zaraa S, Leclair G. Stability of Extemporaneously Prepared Enalapril Maleate 
Suspensions in Glass Bottles and Plastic Syringes. Can J Hosp Pharm. 2016;69(6):505-507. 
88. 
Friciu M, Zaraa S, Leclair G. Stability of Extemporaneously Compounded Amlodipine Besylate 
Oral Suspensions. Can J Hosp Pharm. 2016;69(4):327-329. 
89. 
Friciu M, Zaraa S, Leclair G. Stability of Extemporaneously Compounded Tacrolimus in Glass 
Bottles and Plastic Syringes. Can J Hosp Pharm. 2017;70(1):51-53. 
90. 
Sullivan T, Forest JM, Leclair G. Compatibility of Cloxacillin Sodium with Selected Intravenous 
Drugs During Simulated Y-Site Administration. Hosp Pharm. 2015;50(3):214-220. 
91. 
Friciu M, Plourde K, Leclair G, Danopoulos P, Savji T. Stability of Prednisone in Oral Mix 
Suspending Vehicle. Int J Pharm Compd. 2015;19(4):337-339. 
92. 
Melkoumov A, Goupil M, Louhichi F, Raymond M, de Repentigny L, Leclair G. Nystatin nanosizing 
enhances in vitro and in vivo antifungal activity against Candida albicans. J Antimicrob 
Chemother. 2013;68(9):2099-2105. 
93. 
Friciu M, Roullin VG, Leclair G. Stability of gabapentin in extemporaneously compounded oral 
suspensions. PLoS One. 2017;12(4):e0175208. 
94. 
Friciu M, Zaraa S, Roullin VG, Leclair G. Stability of Diazoxide in Extemporaneously Compounded 
Oral Suspensions. PLoS One. 2016;11(10):e0164577. 
95. 
Korol S, White M, O'Meara E, et al. A comparison of the effects of selective and non-selective 
mineralocorticoid antagonism on glucose homeostasis of heart failure patients with glucose 
intolerance or type II diabetes: A randomized controlled double-blind trial. Am Heart J. 
2018;204:190-195. 
96. 
Collin-Levesque L, El-Ghaddaf Y, Genest M, et al. Infant Exposure to Methylphenidate and 
Duloxetine During Lactation. Breastfeed Med. 2018;13(3):221-225. 
97. 
de Denus S, O'Meara E, Desai AS, et al. Spironolactone Metabolites in TOPCAT - New Insights 
into Regional Variation. N Engl J Med. 2017;376(17):1690-1692. 
98. 
Sheiner LB, Rosenberg B, Melmon KL. Modelling of individual pharmacokinetics for computer-
aided drug dosage. Comput Biomed Res. 1972;5(5):411-459. 
99. 
Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug 
development. CPT Pharmacometrics Syst Pharmacol. 2012;1:e6. 

 
Page 52 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
100. 
Marsot A, Boulamery A, Bruguerolle B, Simon N. Vancomycin: a review of population 
pharmacokinetic analyses. Clin Pharmacokinet. 2012;51(1):1-13. 
101. 
Marsot A, Brevaut-Malaty V, Vialet R, Boulamery A, Bruguerolle B, Simon N. Pharmacokinetics 
and absolute bioavailability of phenobarbital in neonates and young infants, a population 
pharmacokinetic modelling approach. Fundam Clin Pharmacol. 2014;28(4):465-471. 
102. 
Marsot A, Gallais F, Galambrun C, et al. Vancomycin in Pediatric Patients with Solid or 
Hematological Malignant Disease: Predictive Performance of a Population Pharmacokinetic 
Model and New Optimized Dosing Regimens. Paediatr Drugs. 2018;20(4):375-381. 
103. 
Marsot A, Guilhaumou R, Riff C, Blin O. Amikacin in Critically Ill Patients: A Review of Population 
Pharmacokinetic Studies. Clin Pharmacokinet. 2017;56(2):127-138. 
104. 
Marsot A, Imbert B, Alvarez JC, et al. High variability in the exposure of baclofen in alcohol-
dependent patients. Alcohol Clin Exp Res. 2014;38(2):316-321. 
105. 
Marsot A, Menard A, Dupouey J, Muziotti C, Guilhaumou R, Blin O. Population pharmacokinetics 
of rifampicin in adult patients with osteoarticular infections: interaction with fusidic acid. Br J 
Clin Pharmacol. 2017;83(5):1039-1047. 
106. 
Marsot A, Michel F, Chasseloup E, Paut O, Guilhaumou R, Blin O. Phenobarbital in intensive care 
unit pediatric population: predictive performances of population pharmacokinetic model. 
Fundam Clin Pharmacol. 2017;31(5):558-566. 
107. 
Marsot A, Vialet R, Boulamery A, Bruguerolle B, Simon N. Vancomycin: Predictive Performance 
of a Population Pharmacokinetic Model and Optimal Dose in Neonates and Young Infants. Clin 
Pharmacol Drug Dev. 2012;1(4):144-151. 
108. 
Thirion DJG, Pasche V, Marsot A. What is the recommended amikacin dosing for cystic fibrosis 
patients with acute pulmonary exacerbations? Pediatr Pulmonol. 2019;54(11):1652-1653. 
 
 
 

 
Page 53 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Appendix 1:  Elevated PA Mean Pressure – General Treatment Strategies in 
Protocol  
 
 
 
Ultimate treatment decisions to be made by the Investigator 
*Minimum weekly review of PA mean trends 
Elevated PA Mean Pressure / PA mean trending 
above the normal hemodynamic range *
Add or increase vasodilators until at targets
- increase ACE/ARB, 
- then increase  BB
Add or increase MRA until target 
dose reached 
- add or increase nitrate
- add or increase hydralazine
-add or increase loop diuretic
- add thiazide diuretic
Re-evaluate PA pressures 2-3 days 
per week until PA pressures stabilize
If PA Pressures remain elevated evaluate other 
etiologies; i.e. dietary indiscretion, sleep apnea, 
etc.
Oupatient visit and Hospitalization as 
needed  if unresponsive to outpatient 
medical therapy
blood drawn at home 5-7 days 
after each change in medication & 
results faxed to the research nurse

 
Page 54 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Appendix 2: Hospital admissions at Montreal Heart Institute with a primary diagnosis of 
heart failure, financial year April 1st 2016 to March 31st 2017 
 
 
Heart Failure 
APRIL 1st  2018 TO MARCH 31st 2019 
# 
hospitalizations 
# Pts 
Mean age 
men 
women 
# emergency 
department 
consultations  
900 
716 
76 
281 
435 
1393 
39,20% 
60,80% 
Nb Readmission during the 
same financial year * 
# Readmission 
# pts 
0 
475 
1 
135 
2 
65 
3 
32 
4 
5 
5 
2 
6 
1 
7 
0 
8 
0 
9 
1 
716 
* nb of readmission after a first HF episode  
 
Source: Karine Pearson, MHI archives, September  23, 2019

 
Page 55 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
Appendix 3: Example of an individualized therapeutic plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Page 56 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 
Appendix 4 
World Medical Association Declaration of Helsinki 

 
Page 57 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 

 
Page 58 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020 
 

 
Page 59 of 59 
Protocol No: MHICC-2018-001  
Version: FINAL 10 
Protocol Version: June 1ST, 2020