A Prospective Evaluation of Natriuretic Peptide Based Referral of CHF Patients in Primary Care
Phase: NA
Conditions: Chronic Heart Failure (CHF)
Sponsor: Novartis Pharmaceuticals

 
Global Clinical Development - General Medicine 
Clinical Trial Protocol / NCT02807857
a Prospective evaluation of natRiuretic pEptide based 
reFerral of CHF patiEnts in pRimary care - PREFER 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2016-000473-20 
Version number: 
00 (Original Protocol) 
Clinical trial phase: 
Low-interventional study 
Release date: 
15-Feb-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 03 (August 2015) 

 
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Disclaimer: 
This low-interventional research project should be submitted to Ethics Committees and 
regulatory authorities (only if applicable) according to local laws and regulations. 
The study identification is coded for technical reasons as CLCZ696B3402 to allow for 
oversight and tracking in the sponsor’s data bases and systems, even though the project is not 
targeting a specific medicinal product and no study medication is stipulated. 

 
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Table of contents 
Disclaimer: .......................................................................................................................... 2 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 6 
List of figures....................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 8 
Protocol summary ................................................................................................................ 9 
1 
Introduction ....................................................................................................................... 13 
1.1 
Background ............................................................................................................ 13 
1.2 
Purpose .................................................................................................................. 15 
2 
Study objectives and endpoints ......................................................................................... 15 
2.1 
Primary objective(s) ............................................................................................... 15 
2.2 
Secondary objective(s) ........................................................................................... 15 
 
 16 
2.4 
Objectives and related endpoints ........................................................................... 16 
3 
Investigational plan............................................................................................................ 20 
3.1 
Study design ........................................................................................................... 20 
3.2 
Rationale for study design ..................................................................................... 21 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 23 
3.4 
Rationale for choice of comparator ....................................................................... 23 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 23 
3.6 
Risks and benefits .................................................................................................. 23 
4 
Population .......................................................................................................................... 23 
4.1 
Inclusion criteria .................................................................................................... 24 
4.2 
Exclusion criteria ................................................................................................... 24 
5 
Treatment ........................................................................................................................... 25 
5.1 
Study treatment ...................................................................................................... 25 
5.1.1 
Investigational and control drugs .......................................................... 25 
5.1.2 
Additional treatment .............................................................................. 25 
5.2 
Treatment arms ...................................................................................................... 25 
5.3 
Treatment assignment and randomization ............................................................. 25 
5.4 
Treatment blinding ................................................................................................. 25 
5.5 
Treating the patient ................................................................................................ 25 
5.5.1 
Patient numbering ................................................................................. 26 
5.5.2 
Dispensing the study drug ..................................................................... 26 

 
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5.5.3 
Handling of study and additional treatment .......................................... 26 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 26 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ......... 26 
5.5.6 
Rescue medication ................................................................................ 26 
5.5.7 
Concomitant medication ....................................................................... 26 
5.5.8 
Prohibited medication ........................................................................... 26 
5.5.9 
Emergency breaking of assigned treatment code .................................. 27 
5.6 
Study completion and post-study treatment ........................................................... 27 
5.6.1 
Discontinuation of Study Treatment ..................................................... 27 
5.6.2 
Withdrawal of informed consent ........................................................... 27 
5.6.3 
Loss to follow-up .................................................................................. 27 
5.6.4 
Early study termination by the sponsor ................................................. 28 
6 
Visit schedule and assessments ......................................................................................... 28 
6.1 
Information to be collected on screening failures .................................................. 30 
6.2 
Patient demographics/other baseline characteristics.............................................. 30 
6.3 
Treatment exposure and compliance ..................................................................... 30 
6.4 
Efficacy .................................................................................................................. 30 
6.5 
Safety ..................................................................................................................... 31 
6.5.1 
Physical examination ............................................................................ 31 
6.5.2 
Vital signs .............................................................................................. 31 
6.5.3 
Height and weight ................................................................................. 31 
6.5.4 
Laboratory evaluations .......................................................................... 31 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 31 
6.5.6 
Pregnancy and assessments of fertility .................................................. 32 
6.5.7 
Appropriateness of safety measurements .............................................. 32 
6.6 
Other assessments .................................................................................................. 32 
6.6.1 
Clinician Reported Outcomes ............................................................... 32 
6.6.2 
Patient Reported Outcomes (PRO) ....................................................... 32 
 
 33 
6.6.4 
Pharmacokinetics .................................................................................. 33 
6.6.5 
NT-proBNP measurements ................................................................... 33 
6.6.6 
Other biomarkers ................................................................................... 34 
7 
Safety monitoring .............................................................................................................. 34 
7.1 
Adverse events ....................................................................................................... 34 
7.2 
Serious adverse events ........................................................................................... 35 
7.2.1 
Definition of SAE.................................................................................. 35 

 
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7.2.2 
SAE and Adverse drug reactions (ADR) reporting ............................... 36 
7.3 
Liver safety monitoring ......................................................................................... 36 
7.4 
Renal safety monitoring ......................................................................................... 36 
7.5 
Reporting of study treatment errors including misuse/abuse ................................. 36 
7.6 
Pregnancy reporting ............................................................................................... 36 
8 
Data review and database management ............................................................................. 37 
8.1 
Site monitoring ...................................................................................................... 37 
8.2 
Data collection ....................................................................................................... 37 
8.3 
Database management and quality control ............................................................ 37 
8.4 
Data Monitoring Committee .................................................................................. 38 
8.5 
Adjudication Committee ........................................................................................ 38 
9 
Data analysis ...................................................................................................................... 38 
9.1 
Analysis sets .......................................................................................................... 38 
9.2 
Patient demographics and other baseline characteristics ....................................... 38 
9.3 
Treatments ............................................................................................................. 38 
9.4 
Analysis of the primary variable(s) ....................................................................... 39 
9.4.1 
Variable(s) ............................................................................................. 39 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 39 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 40 
9.4.4 
Sensitivity analyses ............................................................................... 40 
9.5 
Analysis of secondary variables ............................................................................ 40 
9.5.1 
Patient reported outcomes ..................................................................... 40 
9.5.2 
Safety variables ..................................................................................... 41 
9.5.3 
Biomarkers ............................................................................................ 41 
 
 41 
9.7 
Interim analyses ..................................................................................................... 41 
9.8 
Sample size calculation .......................................................................................... 41 
10 Ethical considerations ........................................................................................................ 42 
10.1 
Regulatory and ethical compliance ........................................................................ 42 
10.2 
Informed consent procedures ................................................................................. 42 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 43 
10.4 
Publication of study protocol and results ............................................................... 43 
11 Protocol adherence ............................................................................................................ 43 
11.1 
Protocol Amendments............................................................................................ 44 
12 References ......................................................................................................................... 44 

 
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List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 16 
Table 6-1 
Assessment schedule ............................................................................. 29 
 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 21 

 
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  List of abbreviations 
 
ACE 
Angiotensin Converting Enzyme 
AE 
Adverse Event 
AT1R 
Angiotensin Receptor 1 
BNP 
Brain Natriuretic Peptide 
CFR 
US Code of Federal Regulations 
CDS 
Core Data Sheet (for marketed drugs) 
CHF 
Chronic Heart Failure 
CI 
Confidence Interval 
ClinRO 
Clinician Reported Outcome 
COPD 
Chronic Obstructive Pulmonary Disease 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTRD 
Clinical Trial Results Database 
CV 
Cardiovascular 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ER 
Emergency Room 
ESC 
European Society of Cardiology 
eGFR 
Estimated Glomerular Filtration Rate 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LVEF 
Left Ventricular Ejection Fraction 
MAH 
Market Authorization Holder 
MedDRA 
Medical dictionary for regulatory activities 
NP 
Natriuretic Peptide 
NT-proBNP 
N-Terminal prohormone of BNP 
PRO 
Patient Reported Outcome 
QoL 
Quality of Life 
RAAS 
Renin Angiotensin Aldosterone System 
SAE 
Serious Adverse Event 
SR 
Spontaneous Report 
UK 
United Kingdom 
WHO 
World Health Organization 
 

 
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Glossary of terms 
Cohort 
A specific group of patients/subjects fulfilling certain criteria 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol) 
Epoch 
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Medication pack number 
A unique identifier on the label of each investigational drug package 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients/subjects 
with established disease and in those with newly-diagnosed disease. 
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation (TD) 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study 
Withdrawal of consent 
(WoC) 
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
material 

 
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Protocol summary 
Protocol number 
CLCZ696B3402 
Title 
A prospective evaluation of natriuretic peptide based referral of CHF 
patients in primary care 
Brief title 
A prospective evaluation of natriuretic peptide based referral of CHF 
patients in primary care 
Sponsor and Clinical 
Phase 
Novartis 
Investigation type 
other 
Study type 
Low-interventional, observational. 
Purpose and rationale 
In the majority of European countries, the primary management of chronic 
heart failure (CHF) patients is performed by general practitioners in 
collaboration with cardiologists (specialists). Previous studies have shown 
that many patients suffering from CHF do not receive optimal 
pharmacological and/or device treatment for their disease. An increase in 
natriuretic peptides is associated with increased risk of cardiovascular 
events in heart failure patients. The purpose of the present study is to 
assess if a referral of clinically stable CHF patients with reduced ventricular 
ejection fraction (EF≤40%) with NT-proBNP levels ≥ 600 pg/ml to a 
specialist (cardiologist) will lead to treatment optimization, defined as 
adherence to the treatment recommendations according to the ESC 
guidelines. In addition, data obtained in this study will be used to describe 
demographic, clinical (including NT-proBNP levels) and treatment 
characteristics of CHF patients who are managed in the primary care 
setting across Europe. 
Primary Objective(s) 
To assess if NT-proBNP measurement-guided cardiologist-referral of CHF 
patients, who are currently judged by their primary care physician as being 
clinically stable*, leads to optimization of HF treatment, defined as 
adherence# to level I-A treatment recommendations of the current§ ESC 
guidelines for the treatment of HF. 
*Note: Within this study, clinically stable patients are defined as those 
patients, who by the judgement of their primary care physician currently do 
not require and, in the last 3 months prior to the baseline visit have not had, 
any change in their pharmacological or device treatment of HF. 
#Note: Adherence to the recommendations of the ESC guidelines within 
this study is defined as the prescription of all HF specific drugs with level I- 
A recommendation for a given patient’s clinical status at a dose > 50% of 
the recommended daily dose. 
§Note: Current ESC guidelines are those which are in force on the date the 
patient signs the informed consent form. 
Secondary Objectives 
To describe the baseline demographic and clinical characteristics, as well 
as pharmacological and device treatment of CHF patients managed in the 
primary care setting (in the total population of enrolled patients and also 
sub-grouped into different European country and patient characteristics 
clusters). 

 
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To assess in clinically stable patients the impact of patients’ key baseline 
characteristics on the cardiologists’ and primary care physicians’ 
prescription practice for HF treatment and the adherence of these 
treatment choices to the recommendations of the current ESC guidelines. 
To describe the blood levels of NT-proBNP in CHF patients managed in the 
primary care setting. 
To describe the proportion of CHF patients managed in the primary care 
setting considered as being clinically stable according to the above 
definition. 
To describe local prescription practice of cardiologists for the treatment of 
clinically stable CHF patients with NT-proBNP levels ≥ 600 pg/ml. 
To describe local prescription practice and decision making of primary care 
physicians for the treatment of clinically stable CHF patients with NT- 
proBNP levels ≥ 600 pg/ml. 
To characterize how treatment optimization, defined as prescription of 
treatment regimens adherent to the recommendations of the ESC 
guidelines, affects NT-proBNP levels in clinically stable CHF patients with 
baseline NT-proBNP levels ≥ 600 pg/ml. 
To assess the baseline health-related quality of life (QoL) in CHF patients 
and describe the temporal course of QoL after specialist referral in clinically 
stable CHF patients with NT-proBNP ≥ 600 pg/ml, by means of EuroQoL 
EQ-5D and KCCQ questionnaires. 
Study design 
This is a low-interventional, prospective, study enrolling patients with 
chronic heart failure who are managed in the primary care setting across 
Europe. The study comprises three visits over a period of maximum 10 
months. Enrollment is planned to last 24 months. 
At baseline (visit 1) for all consecutive patients, who satisfy the inclusion 
and exclusion criteria, the demographic and clinical characteristics, their 
current therapy regimen for the treatment of HF, any concomitant 
medication and their baseline QoL will be documented (EQ-5D, KCCQ). At 
this visit, after the investigator documents his/her decision whether the 
patient is considered being clinically stable, all patients (clinically stable and 
not stable) will have a blood test for assessing NT-proBNP levels. 
Only patients who are considered being clinically stable by the investigator 
and who show NT-proBNP blood levels ≥ 600 pg/ml will enter the 
prospective period of the study. 
The Patients will be referred to a cardiologist for evaluation of their HF 
treatment. After the referral visit to the specialist’s office, the patient will 
return to the primary care physician for visit 2. During visit 2 the primary 
care physician will evaluate and record the recommendations provided or 
treatment changes introduced by the specialist and will make and record 
his/her decision on the patient’s future HF treatment. In addition, EQ-5D 
and KCCQ questionnaires will be filled out by the patient at this visit. 
The patients in the prospective period will have a final visit (visit 3), where 
they will be asked to fill out two QoL questionnaires (EQ-5D, KCCQ) again, 
will have their vital signs and medication documented and a final NT- 
proBNP measurement will be obtained. 

 
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Population 
The study population will consist of adult (≥ 18 years) male and female 
patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 
40%) who are currently managed in a primary care setting in sites across 
Europe. 
Key Inclusion criteria 
• 
Willing and able to provide written informed consent and accept 
study procedures and time schedule. 
• 
Age ≥ 18 years. 
• 
Patients suffering from chronic heart failure (the heart failure 
diagnosis must have been made or confirmed by a cardiologist 
and/or hospital physician at any time point in the patient’s medical 
history). 
• 
Patients with reduced ejection fraction (LVEF ≤ 40%) as confirmed 
at any time point in the patient’s medical history. 
Key Exclusion criteria 
• 
Use of investigational drugs within 5 half-lives of enrollment, or 
within 30 days /until the expected pharmacodynamic effect has 
returned to baseline, whichever is longer. 
• 
Major surgery in the last 3 months or planned/foreseeable major 
surgery or cardiac intervention during the study. 
• 
Cancer or other significant co-morbidities implying that the 
patient’s condition is unstable. 
• 
Comorbidities that can be associated with elevated natriuretic 
peptide (NP) levels: renal insufficiency, (eGFR < 25 ml/min/1.73 
m² calculated according to MDRD formula), recent (less than 3 
months) cerebral trauma or recent (less than 3 months) 
cerebrovascular incident, novel diagnosis or acute exacerbation of 
COPD within the last 3 months. 
• 
Patients who are primarily managed and regularly followed-up by 
a cardiologist for their HF. 
• 
Highly frail patients whose estimated lifespan due to comorbidities 
is less than 6 months. 
Study treatment 
Not applicable. There is no treatment stipulated by this protocol. 
Efficacy assessments 
Not applicable. There are no efficacy assessments in this study. 
Key safety 
assessments 
Adverse event monitoring, Physical examinations, monitoring of safety lab 
parameters (if available within the investigator’s clinical routine). 
Other assessments 
Assessment of patient reported outcomes (Quality of Life) is planned in this 
study using the EQ-5D and KCCQ questionnaires. 
Patients’ demography, medical history and HF-treatment will be assessed. 
Therapy for HF at baseline and after consultation with a cardiologist, i.e. at 
visit 2 and visit 3, will be documented and assessed. 
 
 
NT-proBNP levels will be measured by means of an on-site device, and will 
be documented and assessed. 
Data analysis 
Analyses of baseline variables will be carried out on all patients who signed 
the study information consent (Enrolled Set). Analyses regarding the 
prospective period of the study will be carried out on all patients who have 
entered the prospective period of the study (Follow-up Set). 

 
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The variables used for the primary analysis are the assessment of the 
patient’s treatment at baseline (A1) and the assessment of the patient’s 
treatment at visit 2 (A2) with respect to the adherence to the current ESC 
guidelines. 
Cross-tabulation between the variables A1 and A2 will be displayed 
showing absolute and relative frequencies. The analysis yielding to the 
primary objective will be performed by estimating the proportion of patients 
who are switched to an ESC guideline recommendation-adherent regimen 
after referral to a cardiologist based on all referred patients whose 
treatment does not adhere to these recommendations. A respective 95%- 
confidence interval (CI) will be provided for this proportion. 
The analysis of the primary endpoint will be performed on all enrolled 
patients entering the prospective period of the study. 
Analysis of secondary variables in the Follow-up Set will be additionally, 
stratified by the assessment of the treatment before and after referral to a 
cardiologist (ESC non-conform/ESC conform, ESC non-conform/ESC non- 
conform, ESC conform/ESC conform, ESC conform/ESC non-conform). 
Key words 
low-interventional observational study, heart failure, primary care, Europe 

 
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1 
Introduction 
1.1 
Background 
Chronic heart failure (CHF) is a common chronically progressive syndrome, with an 
estimated point prevalence of 1-2% that is increasing with age (McMurray, Adamopoulos et 
al. 2012).The syndrome is characterized by a severe prognosis (Hobbs, Doust et al. 2010) and 
is one of the most cost demanding medical conditions in the Western world (Hobbs, Doust et 
al. 2010). Progress made in the past two decades has yielded evidence based strategies 
significantly reducing CHF mortality and morbidity; the effects of targeted multi-drug 
therapies (Parikh and Kadowitz 2013), patient centric outpatient management systems 
(Wakefield, Boren et al. 2013) as well as advances in implantable devices (Kuck, Bordachar 
et al. 2014) are all well proven. 
Natriuretic peptides (NP) are endogenous hormones produced by, amongst other tissues, the 
heart and released in response to myocardial wall stress and/or overload (Del Ry, Cabiati et al. 
2014). The mode of action and the effects of the NP release in CHF are yet to be completely 
elucidated, however numerous studies indicate that the NP release and increase is positively 
correlated with the severity of HF. It is also hypothesized that the increased circulating NP 
during HF may contribute to a compensatory mechanism in the failing heart, counteracting 
many of the detrimental pathophysiological cascades seen in HF by increasing natriuresis, 
diuresis, vasorelaxation and possibly reducing mal-adaptive cardiac remodeling (Del Ry, 
Cabiati et al. 2013) . The use of NP levels as a laboratory parameter, especially BNP and its 
amino-terminal propeptide equivalent (NT-proBNP), is recommended in the European  
Society of Cardiology (ESC) guidelines to “exclude alternative causes of dyspnea (if the level 
of NP is below the exclusion cut-point, HF is very unlikely)” and to “obtain prognostic 
information” (McMurray, Adamopoulos et al. 2012). Some studies in the literature also 
suggest that BNP/NT-proBNP could be used to guide HF treatment, ultimately providing a 
clinical benefit (Troughton, Frampton et al. 2014, Pruett, Lee et al. 2015). Levels of NPs have 
also been shown, in a limited number of studies, to be related to outcome, where elevated 
levels of NT-proBNP significantly increase risks of adverse outcomes (Januzzi, Sakhuja et al. 
2006, Masson, Latini et al. 2008, Flint, Allen et al. 2014). 
The daily follow up of CHF patients in Europe lies mostly within the responsibility of primary 
care physicians. A significant amount of primary care physicians have difficulties with the 
precision of diagnosing HF (Fonseca 2006) due to the unspecific nature of signs and 
symptoms of HF and, due to different reasons, HF patients’ therapy and monitoring  in 
primary care could be optimized (Cleland, Cohen-Solal et al. 2002, Calvert, Shankar et al. 
2009). In 2009, Dahlstrom and colleagues performed an observational multicenter study on 
the treatment of CHF with more than 2000 patients by primary care physicians in more than 
200 centers in Sweden. They showed that only 42% of patients were on treatment with Renin 
Angiotensin Aldosterone System (RAAS) inhibitors and beta blockers and that only 20% of 
patients were receiving doses ≥ 50% of the doses recommended by the ESC guidelines 
(Dahlstrom, Hakansson et al. 2009). 

 
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The beneficial effect of an increased collaboration between primary care physicians and 
specialists has been previously reported (Singh, McGregor et al. 2014). A recent study 
involving chart reviews of HF patients showed that the proportion of patients prescribed 
optimal, evidence based doses of ACE-inhibitor/AT1R-blocker and beta blocker was 69 %,  
33 % and 25 % for patients treated by interdisciplinary physician teams, cardiologists and 
primary care physicians, respectively (p < 0.0167) (Crissinger, Marchionda et al. 2015). 
Additionally, published evidence shows that treatment of CHF in a specialty care setting is 
often more adherent to ESC guideline recommendations. Maggioni et al reviewed the 
treatment of 12.440 patients from the ESC Heart Failure Long-Term Registry from 211 
cardiology centers across Europe, and showed that RAAS inhibitors, beta blockers and 
mineralocorticoid antagonists were prescribed in the vast majority of patients (respectively 92, 
93 and 67% of cases) (Maggioni, Anker et al. 2013). In respectively 29, 24 and 17% of cases 
the dose was on target; in about an additional 30% drugs were being up-titrated and in about 
another 30% a clinical reason for under-dosing was clearly defined (Maggioni, Anker et al. 
2013). 
A study performed in 2009 by a group of investigators in the UK included a systematic review 
of the literature and a meta-analysis of individual patient data set in primary care with the aim 
to determine the potential value of clinical features and diagnostic tests for the diagnosis of 
HF in primary care and to drive referral to a specialist (Mant, Doust et al. 2009). This work 
showed that several clinical symptoms (orthopnea, edema, lung crepitations) are associated 
with a high specificity but low sensitivity and that, conversely, NP measurement is highly 
sensitive. In the absence of symptoms (namely ankle edema), the suggestion of the authors is 
to refer the de novo diagnosed heart failure patient to a cardiologist in the presence of NT- 
proBNP > 620 pg/ml in females and > 390 pg/ml in males. According to the authors, the 
measurement of NT-proBNP is the most sensitive tool to drive referral to a specialist in the 
absence of compelling specific HF symptoms (Mant, Doust et al. 2009). 
Adherence of prescriptions to guideline recommendations is of key importance to ensure 
patients an optimal treatment and it has been used in several trials as a measure of the 
appropriateness of clinical practice (Gustafsson and Arnold 2004, Dahlstrom, Hakansson et al. 
2009, Maggioni, Anker et al. 2013). It has been reported that more than 50% of acute HF 
admissions are preventable and under-treatment is one of the leading factors in this regard 
(Gustafsson and Arnold 2004). In a large, prospective observational survey named MAHLER, 
conducted in six European countries, it was shown that adherence to HF therapy in 
symptomatic HF patients is a strong independent predictor of reduced cardiovascular 
hospitalization rate in daily clinical practice (Komajda, Lapuerta et al. 2005). In addition, 
although not in HF patients, a paper recently published in Circulation with the title “Doing the 
right things and doing them the right way” shows that in patients with an acute coronary 
syndrome there was a significant association between hospitals’ composite guideline 
adherence rates and unadjusted in-hospital mortality. For every 10% increase in composite 
adherence at a center, the patient’s in-hospital mortality odds ratio fell by a corresponding 
39%. Similarly, for every 10% increase in appropriate dosing at a center, the patient’s in- 
hospital mortality odds ratio fell by a corresponding 18% (Mehta, Chen et al. 2015). 
Taken together, all these observations suggest that optimizing HF treatment is impactful for 
patients and that referral of selected CHF patients from primary care physicians to specialists 

 
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might be beneficial to improve adherence of drug treatment to ESC guideline 
recommendations, ultimately leading to a better clinical outcome. 
 
1.2 
Purpose 
The purpose of the present study is to assess if a referral of clinically stable CHF patients with 
reduced ventricular ejection fraction (≤ 40%) with NT-proBNP levels ≥ 600 pg/ml to a 
specialist (cardiologist) will lead to treatment optimization, defined as adherence to the 
treatment recommendations according to the ESC guidelines (McMurray, Adamopoulos et al. 
2012). In addition, data obtained in this study will be used to describe demographic, clinical 
(including NT-proBNP levels) and treatment characteristics of CHF patients who are  
managed in the primary care setting across Europe. A patient will be judged as being 
clinically stable when in the opinion of the primary care physician no change of the patient’s 
pharmacological or device treatment for HF is necessary and no change of HF-treatment has 
been performed within the last 3 months prior to enrollment in the study. 
 
2 
Study objectives and endpoints 
2.1 
Primary objective(s) 
To assess if NT-proBNP measurement-guided cardiologist-referral of CHF patients, who are 
currently judged by their primary care physician as being clinically stable*, leads to 
optimization of HF treatment, defined as adherence# to level I-A treatment recommendations 
of the current§ ESC guidelines for the treatment of HF. 
*Note: Within this study, clinically stable patients are defined as those patients, who by the 
judgement of their primary care physician currently do not require and, in the last 3 months 
prior to the baseline visit have not had, any change in their pharmacological or device 
treatment of HF. 
#Note: Adherence to the recommendations of the ESC guidelines within this study is defined 
as the prescription of all HF specific drugs with level I-A recommendation for a given 
patient’s clinical status at a dose > 50% of the recommended daily dose. 
§Note: Current ESC guidelines are those which are in force on the date the patient signs the 
informed consent form. 
 
2.2 
Secondary objective(s) 
• To describe the baseline demographic and clinical characteristics, as well as 
pharmacological and device treatment of CHF patients managed in the primary care 
setting (in the total population of enrolled patients and also sub-grouped into different 
European country and patient characteristics clusters). 
• To assess in clinically stable patients the impact of patients’ key baseline 
characteristics on the cardiologists’ and primary care physicians’ prescription practice 
for HF treatment and the adherence of these treatment choices to the recommendations 
of the current ESC guidelines. 

 
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• To describe the blood levels of NT-proBNP in CHF patients managed in the primary 
care setting. 
• To describe the proportion of CHF patients managed in the primary care setting 
considered as being clinically stable according to the above definition (Section 2.1). 
• To describe local prescription practice of cardiologists for the treatment of clinically 
stable CHF patients with NT-proBNP levels ≥600 pg/ml. 
• To describe local prescription practice and decision making of primary care physicians 
for the treatment of clinically stable CHF patients with NT-proBNP levels ≥600 pg/ml. 
• To characterize how treatment optimization, defined as prescription of treatment 
regimens adherent to the recommendations of the ESC guidelines affects NT-proBNP 
levels in clinically stable CHF patients with baseline NT-proBNP levels ≥ 600 pg/ml. 
• To assess the baseline health-related quality of life (QoL) in CHF patients and  
describe the temporal course of QoL after specialist referral in clinically stable CHF 
patients with NT-proBNP ≥ 600 pg/ml by means of EuroQol EQ-5D and KCCQ 
questionnaires. 
 
 
2.4 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints 
 
OBJECTIVE 
Endpoint Title, Description and Reporting Time Frame for 
analysis and Unit of Measure 
Stat 
Analysis 
Section 
Primary 
To assess if NT- 
proBNP 
measurement-guided 
cardiologist-referral of 
CHF patients, who are 
currently judged by 
their primary care 
physician as being 
clinically stable, leads 
to optimization of HF 
treatment, defined as 
adherence to level I-A 
treatment 
recommendations of 
the current ESC 
guidelines for the 
treatment of HF. 
Title: Change of the proportion of clinically stable patients 
whose therapy regimen adheres to ESC guideline 
recommendations before and after specialist referral. 
Description: Assessment of patients’ treatment regimen with 
respect to ESC guideline adherence at baseline (Visit 1) and 
after referral to a specialist (visit 2); the change between both 
visits will be calculated to reflect the proportion of patients for 
whom optimization was deemed necessary and implemented. 
For definitions of clinically stable patients and adherence to 
current ESC guidelines see Section 2.1. 
Units of Measure: Bivariate absolute and relative frequency 
distributions including 95%-confidence intervals. 
Time Frame: Baseline, Visit 2 
Section 9.4 

 
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OBJECTIVE 
Endpoint Title, Description and Reporting Time Frame for 
analysis and Unit of Measure 
Stat 
Analysis 
Section 
Secondary 
To describe the 
baseline demographic 
and clinical 
characteristics, as well 
as pharmacological 
and device treatment 
of CHF patients 
managed in the 
primary care setting 
(in the total population 
of enrolled patients 
and also sub-grouped 
into different 
European country and 
patient clusters). 
Title: Demographics 
Description: Age, gender, race, living conditions, employment 
status, smoking status, geographical regions, health insurance 
status, educational level 
Title: Clinical features 
Description: Duration of HF, primary etiology of HF, HF- 
related hospitalizations in the previous 12 months prior to 
baseline and during the study, cardiovascular and non- 
cardiovascular comorbidities 
Title: Pharmacological / device treatment of HF 
Description: previous and concomitant compound, dose and 
frequency of administration, device type, duration of treatment 
Units (for all above, as appropriate/applicable): Absolute and 
relative frequency distributions, descriptive statistics for 
quantitative data. 
Section 9.2 
Section 9.3 
Time frame (for all above): Baseline (Visit 1), Visit 2 and 
Visit 3 
To assess in clinically 
stable patients the 
impact of patients’ key 
baseline 
characteristics on the 
cardiologists’ and 
primary care 
physicians’ 
prescription practice 
for HF treatment and 
the adherence of 
these treatment 
choices to the 
recommendations of 
the current ESC 
guidelines. 
Title: Proportion of clinically stable patients for whom the 
cardiologist and/or primary care physician optimizes treatment 
(i.e. prescribes a treatment regimen adherent to ESC guideline 
recommendations) post referral, stratified according to key 
baseline characteristics 
Description: For patients who enter the prospective period of 
the study the post-referral treatment choice of cardiologists 
and/or primary care physicians will be documented; for 
patients, for whom the cardiologist and/or primary care 
physician chose to prescribe a novel HF treatment, the 
treatment will be assessed, if it fulfills the definition of adherent 
to ESC guideline recommendation. The proportion of patients 
for whom an ESC guideline adherent treatment was de novo 
prescribed will be assessed stratified according to anamnestic 
(e.g. duration of HF, previous treatment of HF, presence of 
cardiovascular/ metabolic/ pulmonary comorbidities), 
demographic (e.g. sex, race, smoking status) and NT-proBNP 
level categories (e.g. 600 -799 pg/ml, 800 – 999 pg/ml, 1000 – 
1200 pg/ml, > 1200 pg/ml). 
Section 9.3 
Units: Absolute and relative frequency distributions. 
Time frame: Visit 2 and Visit 3 
To describe the blood 
levels of NT-proBNP 
in CHF patients 
managed in the 
primary care setting 
Title: NT-proBNP 
Description: NT-proBNP levels (pg/ml) will be measured at 
baseline in all consecutive patients who satisfy the inclusion 
and exclusion criteria. Measurements are performed on-site by 
means of a handheld device provided for the purposes of the 
study. 
Section 
9.5.3 
Units: Descriptive statistics for quantitative data, absolute and 
relative frequency distributions in clinically stable and unstable 
CHF patients 

 
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OBJECTIVE 
Endpoint Title, Description and Reporting Time Frame for 
analysis and Unit of Measure 
Stat 
Analysis 
Section 
Time frame: One measurement in all consecutive patients at 
baseline (Visit 1) 
To describe the 
proportion of CHF 
patients managed in 
the primary care 
setting considered as 
being clinically stable 
according to the 
above definition. 
Title: Proportion of clinically stable patients 
Description: Clinically stable patients in this study are defined 
as those patients for whom the primary care physician does 
not see a necessity (based on signs and symptoms of HF) to 
change the current pharmacological and/or device treatment of 
HF and who have been on stable pharmacological and/or 
device treatment for HF for at least 3 months prior to inclusion. 
Units: Absolute and relative frequency distribution 
Time frame: Baseline (Visit 1) 
Section 9.2 
To describe local 
prescription practice of 
cardiologists for the 
treatment of clinically 
stable CHF patients 
with NT-proBNP levels 
≥600 pg/ml. 
Title: Description of cardiologist prescription practice per 
country/region 
Description: The cardiologists’ suggestions for 
pharmacological and/or device therapy for the treatment of 
clinically stable CHF patients (definition see Section 2.1) will be 
documented and assessed by means of descriptive statistical 
measures stratified by country/region 
Units: Descriptive statistics, absolute and relative frequency 
distribution 
Time frame: Visit 2 
Section 9.4 
To describe local 
prescription practice 
and decision making 
of primary care 
physicians for the 
treatment of clinically 
stable CHF patients 
with NT-proBNP levels 
≥600 pg/ml. 
Title: Description of primary care physicians’ prescription 
practice per country/region 
Description: For clinically stable CHF patients (definition see 
Section 2.1) the primary care physicians’ prescription of 
pharmacological and device treatment for HF will be 
documented prior to (at baseline) and post cardiologist-referral 
(Visit 2 and Visit 3). At the post-referral visit the degree of 
implementation of cardiologist-recommendations and the 
medical decision making (e.g. reasons for non-implementation) 
will be documented. The primary care physicians’ prescriptions 
will be assessed by means of descriptive statistical measures 
stratified by country/region. 
Section 9.4 
Units: Descriptive statistics, absolute and relative frequency 
distribution 
Time frame: Baseline (Visit 1), Visit 2 and Visit 3 
To demonstrate that 
treatment 
optimization, defined 
as prescription of 
treatment regimen 
adherent to the 
recommendations of 
the ESC guidelines 
will lead to clinically 
relevant decrease of 
NT-proBNP levels in 
Title: NT-proBNP levels in clinically stable patients at Visit 3 
Title: Change of NT-proBNP levels in clinically stable CHF 
patients with and without treatment optimization at Visit 2 
Description: At the Visit 3 (end of study) NT-proBNP will again 
be assessed in clinically stable CHF patients with baseline NT- 
proBNP levels ≥ 600 pg/ml. Thus, for those patients two NT- 
proBNP measurements will be available: at baseline and at 
visit 3. The individual change of NT-proBNP between both time 
points will be assessed in accordance to the patients’ 
treatment history during the study, i.e. baseline HF treatment 
and therapeutic decision taken at Visit 2. 
Section 
9.5.3 

 
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OBJECTIVE 
Endpoint Title, Description and Reporting Time Frame for 
analysis and Unit of Measure 
Stat 
Analysis 
Section 
clinically stable CHF 
patients with baseline 
NT-proBNP levels ≥ 
600 pg/ml. 
Units: Descriptive statistics for quantitative data, absolute and 
relative frequency distributions for treatment history subgroups 
Time frame: Baseline (Visit 1) and Visit 3 
To assess the 
baseline health- 
related quality of life 
(QoL) in CHF patients 
and describe the 
temporal course of 
QoL after specialist 
referral in clinically 
stable CHF patients 
with NT-proBNP ≥ 600 
pg/ml 
Title: Change of EQ-5D total and individual sub-scores 
between Visit 3, Visit 2 and baseline 
Title: Change in KCCQ total and individual sub-scores 
between Visit 3, Visit 2 and baseline 
Title: Baseline EQ-5D total and individual sub-scores 
Title: Baseline KCCQ total and individual sub-scores 
Description: At baseline (all patients) and at Visit 2 and Visit 3 
(only patients who have entered the prospective period of the 
study, i.e. clinically stable patients with a NT-proBNP level ≥ 
600 pg/ml) will be asked to fill out the EuroQol 5D (EQ-5D) and 
Kansas City Cardiomyopathy Questionnaire (KCCQ) – two 
quality of life (QoL) questionnaires validated for HF. 
Section 
9.5.1 
Units: Mean scores, Mean change in scores/sub-scores, 
absolute and relative frequency distributions of QoL 
responders (in accordance to the patients’ therapeutic 
regimens at baseline and after specialist referral) 
Time frame: Baseline (Visit 1) and Visit 2 and Visit 3 

 
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3 
Investigational plan 
3.1 
Study design 
This is an international, prospective, low-interventional study enrolling patients with chronic 
heart failure with reduced ejection fraction (LVEF ≤ 40%) who are managed in the primary 
care setting across Europe. The study comprises three visits over a period of maximum 10 
months. Enrollment is planned to last 24 months. 
At baseline (visit 1) for all consecutive patients, who satisfy the inclusion and exclusion 
criteria, the demographic and clinical characteristics, their current therapy regimen for the 
treatment of HF, any concomitant medication and their baseline QoL (EQ-5D and KCCQ 
questionnaires) will be documented. At this visit, after the investigator documents his/her 
decision whether the patient is considered being clinically stable*, all patients (clinically 
stable and not stable) will have a blood test for assessing NT-proBNP levels. 
Only patients who are considered being clinically stable* by the investigator and who show 
NT-proBNP blood levels ≥ 600 pg/ml will enter the prospective period of the study. 
Patients, who do not fulfill these criteria, i.e. are either not meeting the above definition of 
clinical stability or who show NT-proBNP levels < 600 pg/ml will not continue further into 
the study and will have their end-of study documentation at the baseline visit. 
Clinically stable patients with NT-proBNP levels ≥ 600 pg/ml will be referred to a 
cardiologist for evaluation of their HF treatment. After the referral visit to the specialist’s 
office, the patient will return within a suggested time window of up to 4 weeks after the 
cardiologist visit to the primary care physician for visit 2. During visit 2 the primary care 
physician will evaluate and record the recommendations provided or treatment changes 
introduced by the specialist and will make and record his/her decision on the patient’s future 
HF treatment. There is no minimal visit time window for the timing of visit 2, as referral 
policies differ between different European countries and healthcare systems. However, visit 2 
should be performed no later than 6 months after the baseline visit. Within this time frame, the 
exact timing will be managed by the primary care physician according to his/her practice and 
local organizational models. 
The patients in the prospective period will have a final visit (visit 3), that is scheduled  to 
occur at least 3 months but preferably no more than 4 months after visit 2, i.e. maximum 10 
months after the baseline visit. During visit 2 and visit 3, the patients will be asked to fill out 
two QoL questionnaires again (EQ-5D and KCCQ) and a final NT-proBNP measurement will 
be obtained. 
*Note: Within this study, clinically stable patients are defined as those patients, who by the 
judgement of their primary care physician currently do not require and, in the last 3 months 
prior to the baseline visit have not had, any change in their pharmacological or device 
treatment of HF. 

 
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NT-proBNP 
< 600 pg/ml 
NT-proBNP 
≥ 600 pg/ml 
Referral to cardiologist 
NT-proBNP 
measurement 
Document 
decision 
 
Figure 3-1 
Study design 
 
Visit 1 (baseline) 
Visit 2 
Visit 3 
 
Documentation: 
 Specialist’s 
recommendations 
 Implementation of 
recommendations 
and (if any) reasons for 
non-implementations 
 Prescription of 
modified HF treatment 
as per PCP’s discretion 
 Vital signs 
 health status 
 QoL (EQ-5D, KCCQ) 
 
Documentation: 
 
Vital signs 
 
health status 
 
medication 
 
QoL (EQ-5D, KCCQ) 
 
 
 
No 
 
 
 
 
 
 
End of Study (EoS) 
Suggested/preferred time windows: 
Max. 6 months after baseline 
Max. 4 weeks after cardiologist 
visit 
Max. 10 months after baseline 
Min. 3 – Max. 4 months after 
Visit 2 
 
3.2 
Rationale for study design 
This is an international, prospective, low-interventional study which utilizes a biomarker test 
(blood NT-proBNP measurement) as a clinical tool for a referral decision from a primary care 
physician to a cardiologist. A specific treatment does not apply. The primary objective of the 
study is to assess if a cardiologist referral guided by measurements of NT-proBNP in patients 
who, in the judgement of the primary care physician, do not require modifications of their HF 
treatment leads to treatment optimization in these patients, and potentially to better clinical 
outcomes. As a cut off for the identification of clinically stable patients who could benefit 
from treatment optimization, an NT-proBNP level of at least 600 pg/ml was chosen (see 
below). An additional aim is to collect observational data on CHF patients with reduced 
rejection fraction treated in a primary care setting across Europe and physicians’ choices for 
the treatment of these patients. 
Data obtained in Sweden (unpublished, data on file) as well as others (Doust, Pietrzak et al. 
2005, Fonarow, Peacock et al. 2007, Kim and Januzzi 2011) show that elevated NT-proBNP 
is a meaningful predictor of the outcome in HF patients. In fact, elevated NT-proBNP has a 
similar predictive validity on mortality and cardiovascular events as traditional outcome 
predictors in HF (Sachdeva, Horwich et al. 2010). Considering that NT-proBNP elevation is a 
marker reflecting increasing wall stress in the failing heart, and it represents a predictor of 
NT-proBNP 
measurement 
Does the patient meet  the  definition 
of being clinically stable (see Section 2.1) 
Regardless of NT-proBNP level 
NT-proBNP 
measurement 
For all consecutive HFrEF patients 
who satisfy all inclusion/exclusion 
criteria document: 
• Demography 
• HF/non-HF treatment 
• Medical history 
• Vital signs 
• QoL (EQ-5D, KCCQ) 
Yes 

 
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poor outcome and can be assessed easily and objectively in the primary care physician setting, 
we chose NT-proBNP (akin to the primary care physician’s subjective assessment of the 
patients’ clinical stability) as an objective criterion for selecting patients who will be followed 
prospectively. The selection of the cut-off value for NT-proBNP (600 pg/ml) was based on 
data obtained in the primary care setting in Sweden (unpublished, data on file). Thus, this cut- 
off for entering the prospective period of the study, albeit set arbitrarily, should be seen in the 
context of selecting patients, which are rendered stable by their primary care physician and 
thus would otherwise not be considered for HF-therapy optimization, however suffer from at 
least moderate degree of HF-derived cardiac wall stress and therefore bear increased risk of 
poor clinical outcome. 
Supporting this assumption, work by Mant and colleagues suggests that even in the absence of 
clinical symptoms of HF, undiagnosed patients who show NT-proBNP levels higher than 600 
pg/ml could benefit from referral to a cardiologist for further diagnostic evaluation (Mant, 
Doust et al. 2009). 
Based on the literature, no clear guidance could be obtained, if NT-proBNP levels higher or 
lower than the chosen cut-off would be better selection factors when considering also other 
influencing factors, e.g. demographic or clinical/anamnestic factors. For instance, differential 
thresholds regarding gender, country of residence (different healthcare systems) or clinical 
factors (e.g. comorbidities) could be considered, however the impact of these criteria on NT- 
proBNP and the numerical magnitude of respective cut-offs are still a matter of debate in the 
scientific community and indicate the unmet need for further research on this topic. 
Furthermore, the practical implication of such a differential threshold approach would result 
in very high level of complexity and too strong guidance on the investigators, could in turn 
influence the observational nature of the study in an untoward way. 
Thus, under the above considerations, and the fact that major, recent clinical studies in CHF 
have also utilized 600 pg/ml as a selection criterion cut-off for eligible patients (Zannad, 
McMurray et al. 2011, McMurray, Packer et al. 2014) indicates that the here chosen NT- 
proBNP cut-off of 600 pg/ml for all patients offers a plausible and robust benchmark for the 
selection of clinically stable patients who may enter into the prospective period of the study. 
The NT-proBNP measurements in this study will be performed by means of the same 
validated procedure in all sites involved, thus assuring comparability between individuals and 
sites. The chosen cut-off seems to offer the best balance between sensitivity and specificity, 
mitigates risks for errors during the conduct of the study and still allows for assessment of the 
impact of different demographic and clinical factors that can be addressed during the 
statistical analysis of the data. 
To achieve the study objectives, i.e. to understand the CHF treatment practices in a European 
real life setting in clinically stable CHF patients with elevated NT-proBNP levels, data on 
local prescription practices will be observed and assessed by descriptive methods. The 
observational data collection methods mitigate the risks for introducing a selection bias, e.g. 
due to therapeutic, demographic or health-economic factors. Therefore, the chosen design, 
where a diagnostic test and the referral to a cardiologist are the only stipulated procedures and 
patient data and data on local treatment practices are collected in an observational manner is 
best suitable to achieving the study’s objectives. 

 
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Different study protocol package submission pathways and local endorsement processes apply 
for such low-interventional clinical studies with a diagnostic procedure (such as the NT- 
proBNP measurement) depending on country or even investigational site level. Thus, to allow 
for a common standard of robust data collection, reporting and analysis, the framework of 
GCP was chosen as the most stringent and harmonized data handling and documentation 
practice. 
The time-actual version of the ESC guidelines for the treatment of HF will be chosen as 
European reference guideline to which the local prescription practices in the primary care 
setting will be compared. This means, that the version of the ESC guidelines that is in force at 
the time when the patients signs the informed consent for participating in this study will be 
considered as the reference guideline for the analysis of the respective patient’s data. The 
patient population will be described in more detail in the Section 4 below. 
 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
Not applicable. The study protocol does not stipulate any treatment regimen. The primary care 
physician’s choice of treatment at baseline and after cardiologist referral will be observed, 
documented, reported by the primary care physician and analyzed. The primary care 
physicians are advised to follow their local clinical routine, taking the local authorization 
status of any prescribed treatment into account. 
 
3.4 
Rationale for choice of comparator 
Not applicable. 
 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
 
3.6 
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance to the eligibility criteria. 
Blood sampling for NT-proBNP measurements will be performed at the baseline visit and at 
Visit 3 (for patients who enter the prospective period of the study), which bears minimal risks 
for the patient, associated with the sampling procedure (venous puncture). Other study 
procedures are observational, i.e. the investigators should follow and document their local 
clinical routine for the treatment and follow-up of patients with CHF. There is no 
investigational medicinal product and no drug/device treatment that is required by the 
protocol. Therefore the risks associated to this study, besides those associated to the venous 
blood sampling procedure, are comparable to those in a usual primary care setting. 
 
4 
Population 
The study population will consist of adult (≥ 18 years) male and female patients with chronic 
heart failure with reduced ejection fraction (LVEF ≤ 40%) who are currently managed in a 
primary care setting in sites across Europe. Provided the below inclusion and exclusion 

 
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criteria are met, all consecutive CHF patients at a given site will be documented and will be 
subject to NT-proBNP measurement at baseline. Prior to measuring NT-proBNP at baseline, 
the physician must provide his/her judgement, whether the patient is considered as clinically 
stable based on the definition provided in Section 2.1. Patients who do not meet the definition 
of being clinically stable at baseline and/or patients who show NT-proBNP levels < 600 pg/ml 
at baseline will not enter the prospective period of the study, but their baseline information 
will be documented. Patients who enter the prospective period of the study, as defined as 
clinically stable patients with NT-proBNP levels ≥ 600 pg/ml will be referred to a cardiologist 
and will return to the site 2 more times (Visit 2 and Visit 3) for follow-up documentation. 
It is planned to enroll a total of 4,000 CHF patients of which approximately 2,400 are 
estimated to enter the prospective period (are considered clinically stable and show NT- 
proBNP levels ≥ 600 pg/ml). The recruitment will be regarded as completed once 
approximately 2,400 patients have entered the prospective period irrespectively how many 
patients have been enrolled totally. 
 
4.1 
Inclusion criteria 
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. 
Willing and able to provide written informed consent and accept study procedures and 
time schedule. 
2. 
Age ≥ 18 years. 
3. 
Patients suffering from chronic heart failure (the heart failure diagnosis must have been 
made or confirmed by a cardiologist and/or hospital physician at any time in the patient’s 
medical history). 
4. 
Patients with reduced ejection fraction (≤ 40%) as confirmed at any time point in the 
patient’s medical history. 
4.2 
Exclusion criteria 
Patients/subjects fulfilling any of the following criteria are not eligible for inclusion in this 
study. No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients/subjects. 
1. 
Use of investigational drugs either within 5 half-lives of enrollment, or within 30 days, or 
until the expected pharmacodynamic effect has returned to baseline, whichever is longer. 
2. 
Major surgery in the last 3 months prior to baseline or planned major surgery or cardiac 
intervention during the study. 
3. 
Cancer or other significant co-morbidities implying that the patient’s condition is 
unstable. 
4. 
Comorbidities that can be associated with elevated natriuretic peptide (NP) levels: renal 
insufficiency, (eGFR < 25 ml/min/1.73 m² calculated according to MDRD formula), 
recent (less than 3 months) cerebral trauma or recent (less than 3 months) 

 
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cerebrovascular incident, novel diagnosis or acute exacerbation of COPD within the last 
3 months. 
5. 
Patients who are primarily managed and regularly followed-up by a cardiologist for their 
HF 
6. 
Highly frail patients whose estimated lifespan due to comorbidities by the judgement of 
the investigator is less than 6 months. 
 
5 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
Not applicable. No treatment is stipulated by this protocol. 
The patients will receive the treatment that their primary care physician has decided to 
prescribe for their disease. Upon referral to the cardiologist the treatment modification is 
entirely in the discretion of the primary care physician. The protocol also gives no 
recommendations to cardiologists and it is planned to only observe the common medical 
practice. 
 
5.1.2 
Additional treatment 
Not applicable. 
 
5.2 
Treatment arms 
Not applicable. 
 
5.3 
Treatment assignment and randomization 
Not applicable. This is a single arm study without randomization. No treatments are stipulated 
by this protocol – patients’ HF and non-HF treatments will be observed throughout the study. 
The patients’ treatment is entirely in the discretion of the primary care physicians 
(investigators). 
 
5.4 
Treatment blinding 
Not applicable. No blinding of patients or investigators is performed within this study. 
 
5.5 
Treating the patient 
The treatment within this study is not stipulated by the protocol but will be merely 
documented and observed. The patients’ treatment (HF and non-HF therapy) is entirely in the 
discretion of the investigator. The investigator is not obliged to follow the cardiologist’s 
recommendations. 

 
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5.5.1 
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the CRF system. 
 
5.5.2 
Dispensing the study drug 
Not applicable. 
 
5.5.3 
Handling of study and additional treatment 
 
5.5.3.1 
Handling of study treatment 
Not applicable. 
 
5.5.3.2 
Handling of additional treatment 
Not applicable. 
 
5.5.4 
Instructions for prescribing and taking study treatment 
Not applicable. There is no guidance regarding the patients’ treatment (including any dose 
adjustments) stipulated by this protocol. 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Not applicable. 
 
5.5.6 
Rescue medication 
Not applicable. 
 
5.5.7 
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered 12 months before the patient was enrolled into the study, at the time of 
enrollment and during the study must be recorded in the CRF. 
 
5.5.8 
Prohibited medication 
Not applicable. There is no guidance regarding the patients’ treatment (including any dose 
adjustments) stipulated by this protocol. 
The present study aims to observe local treatment routine and does not stipulate a certain 
treatment nor are any treatments prohibited. Physicians are advised to follow their clinical 
routine for the treatment of patients with CHF. 

 
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5.5.9 
Emergency breaking of assigned treatment code 
Not applicable. 
Study Completion and Discontinuation 
 
5.6 
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last performed visit. 
Throughout the study, and beyond completion of the study, the patient’s treatment is entirely 
in the discretion of the investigator, therefore no study and post-study treatments are  
stipulated by this protocol. 
 
5.6.1 
Discontinuation of Study Treatment 
Not applicable. 
 
5.6.2 
Withdrawal of informed consent 
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason 
at any time. Withdrawal of consent from the study is defined as when a patient: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
and 
• Does not allow analysis of already obtained biologic material 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal  should  be  made  as  detailed  in 
Table 6-1. 
 
5.6.3 
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw from the study, the investigator should show "due diligence" by 
contacting the patient, family or family physician as agreed in the informed consent process or 
later in the study and documenting in the source documents steps taken to contact the subject, 
e.g. dates of telephone calls, registered letters, etc.. 

 
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5.6.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to practical issues, or for regulatory or medical reasons (including slow enrolment). 
Should this be necessary, the patient must be seen as soon as possible and treated as a 
prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing the Institutional Review 
Board/Independent Ethics Committee (IRBs/IECs) of the early termination of the trial. 
 
6 
Visit schedule and assessments 
The study comprises 3 visits: baseline (Visit 1), Visit 2 (recommended max. 6 months after 
baseline), Visit 3 (recommended at least 3 months and preferably not later than 4 months after 
Visit 2; max. 10 months after baseline). At baseline (Visit 1) all consecutive CHF patients 
who satisfy all inclusion and exclusion criteria should be documented and should complete  
the QoL questionnaires. At this visit, the investigator will assess whether the patient’s status is 
considered clinically stable (as defined in Section 2.1) and document his/her decision. 
Thereafter all patients will undergo blood-sampling for on-site NT-proBNP measurement. 
Only patients considered clinically stable and with NT-proBNP levels ≥ 600 pg/ml will be 
referred to a cardiologist for evaluation of treatment optimization. After the visit to the 
cardiologist, but no later than 6 months after the baseline visit, the patient should return to the 
investigator’s office for Visit 2. At Visit 2, the patient should complete the QoL 
questionnaires and the cardiologist’s recommendations will be reviewed and documented by 
the investigator; at this visit, the investigator should document, if the cardiologist’s 
recommendations or changes for the patient’s HF-treatment will be followed or continued, 
respectively. The investigator should provide reasons if the recommendations are not followed 
and document the prescribed HF treatment. At Visit 3, maximally 10 months after baseline, 
but no earlier than 3 months after Visit 2, the patient should return for the final visit, where 
clinical and QoL outcomes will be documented and thereafter the patient will undergo blood 
sampling for measurement of NT-proBNP levels. 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients/subjects 
who prematurely discontinue the study for any reason should be scheduled for a visit as soon 
as possible, at which time all of the assessments listed for the final visit will be performed. At 
this final visit, the adverse events and concomitant medications are reconciled on the CRF. 

 
 
 
 
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Table 6-1 
Assessment schedule 
 
Visit number 
Visit 1 
Visit 2 
Visit 3 
Time of Visit and recommended visit windows 
Baseline 
After referral 
(max. 6 months 
after baseline) 
Min. 3 months, 
max 4 months 
after visit 2 
(max. 10 months 
after baseline) 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Demographic and clinical history (incl. diagnostic and therapeutic procedures) 
X 
X 1 
X 1 
Height 
X 
Body weight 
X 
X 1 
Physical examination incl. NYHA-Status and vital signs 
X 
X 1 
X 1 
Observation of ongoing drug/ non-drug treatment for HF 
X 
X 1 
X 1 
Observation of relevant laboratory tests, as available per routine care 
X 
X 1 
X 1 
EQ-5D questionnaire 
X 
X 1 
X 1 
KCCQ questionnaire 
X 
X 1 
X 1 
Assessment and documentation of clinical stability of patient (as per Section 2.1) 
X 
NT-proBNP assessment 
X 
X 1 
Referral to cardiologist 1 
X 1 
Recording of specialist advice/prescription on drug/ non-drug treatment modification 1 
X 1 
Prescription and documentation of revised treatment in the discretion of primary care physician 1 
X 1 
Observation of comorbidities and their changes during the study 
X 
X 1 
X 1 
Adverse events 
X 
X 1 
X 1 
Report adverse drug reactions to any medication and incidents with medical devices as per local 
regulations 
X 
X 1 
X 1 
1 Applies only for patients who enter the prospective period, i.e. clinically stable patients with NT-proBNP ≥ 600 pg/ml 

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6.1 
Information to be collected on screening failures 
Not applicable. 
 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients/subjects 
include: year of birth, age, sex, race, living conditions, employment status, education level  
and smoking status, HF etiology, medical history/current medical conditions that were present 
before signing informed consent where possible, diagnoses and not symptoms will be 
recorded. Furthermore, where allowed by local laws and regulations, information on health 
insurance status will be collected. In addition, HF-hospitalization history and emergency room 
(ER) admissions due to HF over the last 12 months prior to baseline will be recorded. 
The investigator will document for all patients their current HF treatment, including drug- and 
non-drug treatments, as well as any concomitant medication for non-HF indications. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
At baseline all patients will be asked to complete two QoL questionnaires (EQ-5D and 
KCCQ). 
Thereafter the investigator will document if he/she sees the patient as being clinically stable, 
i.e. the patient currently does not require and, in the last 3 months prior to the baseline visit 
has not had, any change in his/her pharmacological or device treatment of HF. 
All patients will have a venous blood sample taken for on-site measurement of NT-proBNP; 
please note that this measurement should only be performed after the decision regarding the 
clinical stability of the patient’s status is made and documented. 
Only patients considered clinically stable as per above definition by the investigator and with 
NT-proBNP levels ≥ 600 pg/ml will be referred to a cardiologist for evaluation for treatment 
optimization. 
Patients, who are considered not clinically stable according to the above definition or show 
NT-proBNP levels < 600 pg/ml will not continue in the prospective period of the study – i.e. 
only baseline information will be documented for these patients. 
 
6.3 
Treatment exposure and compliance 
Not applicable. No treatment is stipulated by the protocol. 
 
6.4 
Efficacy 
Not applicable. There are no efficacy endpoints within the objectives of this study. 

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6.5 
Safety 
There are no safety endpoints within the objectives of this study and no study medication.  
Any adverse event will be recorded in the CRF after the patient has provided his/her informed 
consent, including adverse events that are related to study procedures (e.g. NT-proBNP 
assessments). In addition, the below variables, if available, will be documented at baseline  
and Visit 2 and Visit 3 (as applicable) to describe the clinical features of the patients. Adverse 
drug reactions (ADR) shall be reported to the authorities following local laws and regulations 
(Section 7). 
 
6.5.1 
Physical examination 
The physical examination is to be performed as per the local routine of the primary care 
physician. At baseline and at each visit (for patients in the prospective period), the patients’ 
NYHA status as well as signs and symptoms of HF and their severity should be documented. 
 
6.5.2 
Vital signs 
Vital signs include blood pressure and heart rate measurements. Although the examination is 
to be performed according to local clinical routine, the following process is recommended: 
After the patient has been sitting for five minutes, with back supported and both feet placed  
on the floor, systolic and diastolic blood pressure will be measured in sitting position three 
times at 1-2 minute intervals. It is further recommended that a validated automated device or 
sphygmomanometer with an appropriately sized cuff is used and the measurements are 
obtained on the non-dominant arm. Individual measurements should be recorded in the 
patient’s file and the mean of the three measurements will be recorded in the eCRF. 
 
6.5.3 
Height and weight 
Body height shall be documented at baseline; body weight will be documented at baseline and 
at visit 3. Although the examination is to be performed according to local clinical routine, it is 
advised that body weight be documented to the nearest 0.1 kg in indoor clothing, but without 
shoes. 
 
6.5.4 
Laboratory evaluations 
No central laboratory will be used in this study. The investigator will be asked to document 
relevant laboratory parameters (hemoglobin, creatinine, potassium, as available within the 
sites’ clinical routine) at each visit, however these assessments are not mandatory or stipulated 
by the protocol. 
The on-site measurement of NT-proBNP will be performed by means of a handheld device 
using measuring strips. This measurement is described in greater detail in Section 6.6.5. 
 
6.5.5 
Electrocardiogram (ECG) 
Not applicable. No ECG assessment is requested by the protocol. Sites shall follow their 
clinical routine for the care of patients with CHF. 

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6.5.6 
Pregnancy and assessments of fertility 
Not applicable. 
 
6.5.7 
Appropriateness of safety measurements 
The study has no safety endpoints. The described assessments (Section 6.5) are common in 
daily clinical routine in the treatment of patients with CHF and should only be documented if 
they are available. No treatment is stipulated by the study protocol. However all drug and non-
drug therapy should be documented in the eCRF and the investigators should follow local 
regulations for the spontaneous reporting of adverse drug reactions (ADR, events with causal 
relationship to any treatment the patient may have, see Section 7). 
 
6.6 
Other assessments 
6.6.1 
Clinician Reported Outcomes 
The investigator should document the patients’ current NYHA status, as well as any change in 
the severity of any of the patients’ concomitant diseases. This will allow for a standardized 
evaluation of the patients’ health status in patients who enter the prospective period of the 
study. 
 
6.6.2 
Patient Reported Outcomes (PRO) 
The impact of the disease per se (in all patients) and of CHF treatment optimization (in 
patients in the prospective period) on health related quality of life (QoL) will be assessed by 
the following measures: 
• EuroQol EQ-5D (EQ-5D-5L) 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Both questionnaires are available as validated translations in local language. 
The patient should be given sufficient instruction, space, time and privacy to complete the 
questionnaire. The study coordinator should check the responses to the questionnaire for 
completeness and encourage the patient to complete any missing responses. 
As treatment optimization can affect all derived scores and subscales of both questionnaires, 
the change from baseline for all measures and scales derived from both questionnaires will be 
analyzed for patients who enter the prospective period of the study. 
For patients who are not clinically stable or show NT-proBNP levels < 600 pg/ml only the 
baseline QoL will be documented. 
The patients’ responses shall be entered into the CRF by the investigator. The original 
questionnaire will be kept with the patient’s file as the source document. 
Completed questionnaires will be reviewed and examined by the investigator, before the 
clinical examination, for responses that may indicate potential adverse events (AEs) or serious 
adverse events (SAEs). The investigator should review not only the responses to the questions 
in the questionnaires but also for any unsolicited comments written by the patient. If AEs or 

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SAEs are confirmed, then the physician must record the events as per instructions given in 
Section 7.1 and Section 7.2 of the protocol. 
 
6.6.2.1 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The KCCQ is a self-administered questionnaire that requires 4-6 minutes to complete. It 
contains 23 items, covering physical function, clinical symptoms, social function, self- 
efficacy and knowledge, and Quality of Life (QoL). 
 
6.6.2.2 
EuroQol EQ-5D 
The EuroQol EQ-5D-5L instrument assesses the current health status of patients. It consists of 
five domains and one visual analogue scale. This instrument assesses morbidity, self-care, 
usual activity, pain, and anxiety and depression of patients. The questionnaire requires 3-4 
minutes to complete. 
 
 
6.6.4 
Pharmacokinetics 
Not applicable. 
 
6.6.5 
NT-proBNP measurements 
At the baseline visit, all CHF patients will undergo on-site NT-proBNP measurement. This 
measurement should be obtained after the investigator has made and documented his/her 
judgement of the patient’s clinical stability (as per definition provided in Section 2.1). 
The NT-proBNP measurement is a prerequisite for deciding if a patient is eligible to continue 
in the prospective period of the study; this will only be allowed for clinically stable patients 
with NT-proBNP levels ≥ 600 pg/ml. Only these patients should be referred to a cardiologist 
and will return for Visits 2 and Visit 3. At Visit 3, patients who have entered the prospective 
period will undergo NT-proBNP measurement once again. 
The sample must be venous whole blood collected in a container including heparin as a 
preservative. Other anticoagulants such as EDTA or citrate cannot be used. Once the sample 
has been collected, it must be tested within 8 hours, without prior cooling or freezing. 
The test is performed on-site by means of a portable handheld device that will be provided to 
the sites by Novartis. The device utilizes disposable test strips for testing NT-proBNP levels. 
For one measurement at least 150 µl whole blood is required. 

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Device manuals will be provided with detailed information on sample collection, handling, 
and performing the measurements. The results will be documented in the eCRF by the study 
site. 
 
6.6.6 
Other biomarkers 
Not applicable. 
 
7 
Safety monitoring 
7.1 
Adverse events 
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign, 
including abnormal laboratory findings, symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study 
until the end of the final visit of the study (Visit 3). Therefore, an AE may or may not be 
temporally or causally associated with the study procedures. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory tests, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease. Investigators have the responsibility of managing the safety of 
individual patients and identifying adverse events. The investigators should follow their local 
clinical routine and use their laboratory facilities as per their discretion. No safety laboratory 
assessments are stipulated by this protocol. 
All adverse events, including events related to the study procedures (e.g. the blood sampling 
procedure for the NT-proBNP measurements) should be recorded in the Adverse Events CRF 
under the signs, symptoms or diagnosis associated with them accompanied by the following 
information: 
• the severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• its relationship to the study procedures 

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• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
• whether it constitutes an SAE 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); concomitant medication given; non- 
drug therapy given. The action taken to treat the adverse event should be recorded on the 
Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is  
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study procedures, the 
interventions required to treat it, and the outcome. 
The Sponsor may request additional information on specific adverse events of interest and 
may make requests to perform additional diagnostic tests to further assess the event. Such 
information may include diagnostic procedure reports, discharge summaries, autopsy reports, 
and other relevant information that may help in assessing the reported adverse event. All 
additional information will be de-identified prior to collection by Novartis or its agents. 
Adverse events with a causal relationship to any of the patient’s drug or non-drug therapies  
for any disease shall be reported by the investigator to local authorities as per local regulations. 
 
 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is any adverse event with the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the patient’s 
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• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.2 
 
7.2.2 
SAE and Adverse drug reactions (ADR) reporting 
Every SAE, regardless of suspected relationship to the study procedures, occurring after the 
patient has provided informed consent and until the end of the final study visit (Visit 3) should 
be recorded in the Adverse Events CRF within 24 hours of awareness. 
An SAE occurring at a different time interval or otherwise considered completely unrelated to 
a previously reported one must be reported separately as a new event. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that 
event regardless of when it occurs. 
If the investigator becomes aware of any untoward event for which a causal relationship with 
any of the patient’s medication (and/or medical device) cannot be excluded, the investigator 
should notify local health authorities and the Marketing Authorization Holder (MAH) of the 
suspect drug (and/or the manufacturer of the device) by means of a spontaneous report (e.g. 
Adverse Drug Reaction). 
An untoward medical occurrence or Adverse Event suspected by the investigator to have a 
relationship to any Novartis drug (Adverse Drug Reaction) must be reported to the local 
Novartis Drug Safety and Epidemiology desk following local processes and regulations. 
Contact details of the local Novartis Drug Safety and Epidemiology desk such as the 
telephone and fax number or access to an internet reporting tool are listed in the Investigator 
Folder provided to each site. When reporting incidents to Novartis the study code 
(CLCZ696B3402) should be provided to allow event traceability (even so no study 
medication is under investigation for this project and any applicable Novartis medication 
should be reported). 
 
7.3 
Liver safety monitoring 
Not applicable. 
 
7.4 
Renal safety monitoring 
Not applicable. 
 
7.5 
Reporting of study treatment errors including misuse/abuse 
Not applicable as no study treatment is provided. In cases of drug/device misuse and abuse 
local regulations, processes and legislation on reporting should be followed. 
 
7.6 
Pregnancy reporting 
Not applicable. Local laws and regulations for reporting adverse drug reactions should be 
followed. 

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8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a study center initiation visit or at an Investigator’s meeting, a 
Novartis representative will review the protocol and eCRFs with the Investigators and their 
staff. During the study, the field monitor will visit the study center regularly to check the 
completeness of patient records, the accuracy of entries in the eCRFs, the adherence to the 
protocol and to GCP and the progress of enrollment. Key study personnel must be available to 
support the field monitor during these visits. 
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the patient’s file. The Investigator 
must also keep the original ICF signed by the patient (a signed copy is given to the patient). 
The Investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the patients will be disclosed. 
 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21 Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. During data entry, data is checked for completeness and 
correctness via automatic plausibility checks. In case of data discrepancies an appropriate 
error message will be shown asking the Investigator to confirm or correct data. The 
Investigator must certify by electronic signature that the data entered into the Electronic Case 
Report Forms are complete and accurate. After database lock, the investigator will receive 
copies of the patient data for archiving at the investigational site. 
 
8.3 
Database management and quality control 
The CRO data management working on behalf of Novartis or Novartis staff will review the 
data entered into the eCRFs by investigational staff for completeness and accuracy and 
instruct the site personnel to make any required corrections or additions. Queries are sent to 
the investigational site using an electronic data query. Designated investigator site staff is 
required to respond to the query and confirm or correct the data. Concomitant medications  
and procedures and non-drug therapies entered into the database will be coded using the  
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history and adverse events will be coded using the Medical 

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dictionary for regulatory activities (MedDRA) terminology. Local laboratory data regarding 
hemoglobin, creatinine and/or potassium will be entered into the eCRF if available within the 
sites’ clinical routine. The occurrence of relevant protocol deviations will be determined. 
After these actions have been completed and the database has been declared to be complete 
and accurate, it will be locked and made available for data analysis. Any changes to the 
database after that time can only be made after written agreement by Novartis Development 
management. 
 
8.4 
Data Monitoring Committee 
Not required. 
 
8.5 
Adjudication Committee 
Not required. 
 
9 
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. 
Details of the planned statistical analysis will be described in detail in a separate statistical 
analysis plan. 
 
9.1 
Analysis sets 
Analysis of baseline variables will be carried out on all patients who signed the study 
information consent (Enrolled Set). 
Analysis regarding the prospective period of the study will be carried out on all patients 
entering into this study period – the respective patient set will be labeled Follow-up Set. 
 
9.2 
Patient demographics and other baseline characteristics 
Summary statistics will be provided for demographics and other baseline characteristics 
described in Section 6.2. Additionally, age groups (< 65, ≥ 65 to < 75, ≥ 75 to < 85, ≥ 85 
years) and BMI calculated as weight (kg) / (height (m))2 will be displayed. Classification of 
patients as “clinically stable” will be provided. 
Continuous variables will be summarized using n, mean, median, standard deviation, 
minimum, maximum, and categorical variables will be summarized using frequency and 
percentage. 
Baseline characteristics will be displayed for all patients in the Enrolled Set, stratified by the 
variable “inclusion into the prospective period of the study”. 
 
9.3 
Treatments 
No study treatment will be provided in this trial. 

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Prior and concomitant medication will be presented separately for medications due to HF and 
other medication. Concomitant medications are defined as any medications administered at or 
after the enrollment date into the study, otherwise the medication is defined as prior. 
The assessment of the patient’s treatment at every visit with respect to the adherence to the 
time-actual ESC guidelines will be provided (definition see Section 2.1). 
Separate summaries will be provided for all treatment changes advised by the cardiologist and 
the implementation of these changes to the actual treatment of the patient by the primary care 
physician. 
Additionally, statistical models might be considered for analyzing associations between ESC 
guideline adherence of treatment regimens and possible covariates. Such models will be 
described in detail in the Statistical Analysis Plan. 
The analysis of the patients’ treatment will be performed for all patients in the Enrolled Set 
(where applicable) in the Follow-up Set. All treatment analyses will additionally be performed 
stratified by country/region. 
 
9.4 
Analysis of the primary variable(s) 
The primary objective in this study is to assess if NT-proBNP measurement-guided 
cardiologist-referral of CHF patients, who are currently judged by their primary care 
physician as being clinically stable, leads to optimization of HF treatment, defined as 
adherence to level I-A treatment recommendations of the current ESC guidelines for the 
treatment of HF. Therefore the aim of the primary analysis is to estimate the proportion of 
patients switching from a non-ESC guideline recommendations-adherent HF treatment at 
baseline to a guideline-adherent treatment after referral to a cardiologist. 
 
9.4.1 
Variable(s) 
The variables used for the primary analysis are the assessment of the patient’s treatment at 
baseline (A1) and the assessment of the patient’s treatment at visit 2 (A2) with respect to the 
adherence to the current ESC guidelines. 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The analysis yielding to the primary objective will be performed by estimating the proportion 
of patients who are switched to an ESC guideline recommendation-adherent regimen after 
referral to a cardiologist based on all referred patients whose treatment does not adhere to 
these recommendations. A respective 95%- confidence interval (CI) will be provided for this 
proportion. 
Cross-tabulation between the variables A1 and A2 will be displayed showing further absolute 
and relative frequencies, including the proportion of patients being treated in accordance to 
the ESC guideline recommendations already at baseline (i.e. before referral), the proportion of 
patients receiving ESC guideline-adherent treatment after the referral to the cardiologist and 
the rate of patients who remain on a therapy regimen that does not adhere to ESC guideline- 
recommendations after referral over all patients without ESC guideline-adherent treatment. 
Respective 95%-CIs will be provided for the estimates. 

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The analysis of the primary endpoint will be performed in the Follow-up Set. 
 
9.4.3 
Handling of missing values/censoring/discontinuations 
No imputation of missing values will be performed. The analysis of the primary variable will 
be based on all available cases, i.e. on all patients for whom assessments of treatment before 
and after cardiologist referral are available. Additionally, proportions based on all patients 
including missing values for the treatment after referral will be presented. 
 
9.4.4 
Sensitivity analyses 
In order to detect possible country effects or effects of further subgroups and allow for a site 
and patient profiling, stratified analyses of the primary endpoint will be performed at least for 
the following subgroups: 
• Country/region cluster information for site 
• Sex 
• Age groups 
• NT-proBNP levels 
Please refer for details to the Statistical Analysis Plan. 
 
9.5 
Analysis of secondary variables 
Analysis of secondary variables will be performed in the Follow-up Set and additionally 
stratified by the assessment of the treatment before and after referral to a cardiologist (ESC 
non-conform/ESC conform, ESC non-conform/ESC non-conform, ESC conform/ESC conform, 
ESC conform/ESC non-conform). 
 
9.5.1 
Patient reported outcomes 
Health related quality of life as measured by the patient reported outcomes EQ-5D-5L and 
KCCQ. 
The KCCQ instrument includes several domains. Only the domains that address HF 
symptoms and physical limitations will be analyzed. The clinical summary score of KCCQ is 
computed as the mean of the following available domain scores: 
• 
Physical limitation score 
• 
Total HF symptom score 
Minimal clinical improvement according to the KCCQ will defined for each of the two 
domain scores as an improvement of at least 5 points compared to baseline (Flynn, Lin et al. 
2012). 
The EQ-5D-5L consists of five domains and one visual analogue scale. This instrument 
assesses morbidity, self-care, usual activity, pain, and anxiety and depression of patients on a 
five-point rating scale ranging from 1=no problems to 5=extreme problems. A continuous 
utility index will be derived from these dimensions. 

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Quantitative outcomes such as KCCQ sub-domains, EQ-5D visual analogue scale and EQ-5D 
utility index will be displayed in terms of descriptive statistical parameters such as valid n, 
mean, SD, minimum, median and maximum at each visit. 
Furthermore, for visit 2 the change from baseline and for visit 3 the change from baseline and 
from visit 2 will be calculated and displayed. 
In case of ordinal or dichotomous measures such as EQ-5D dimensions and KCCQ response 
distributions in terms of absolute and relative frequencies will be provided for the single visits. 
 
9.5.2 
Safety variables 
Adverse events (AEs) will be coded by means of the Medical Dictionary for Regulatory 
Activities (MedDRA). Incidence rates of AEs and Serious Adverse Events (SAEs) due to 
study related procedures based on “preferred terms” and “system organ class” will be 
displayed. Additionally, all AEs will be individually listed. 
 
9.5.3 
Biomarkers 
NT-proBNP will be collected in all patients at baseline and visit 3 (only for patients who have 
entered the prospective period). Summary statistics for quantitative and qualitative data will 
be provided for each visit. The change in NT-proBNP level from baseline to visit 3 will be 
calculated and presented describing the amount of quantitative change and the number of 
patients with increase/decrease of NT-proBNP blood level. 
 
9.7 
Interim analyses 
An interim analysis describing baseline characteristics and data collected at Visit 1 can be 
performed. Details are described in the Statistical Analysis Plan. 
 
9.8 
Sample size calculation 
The study is powered to estimate the proportion of patients switching from a non-ESC 
guideline 
recommendations-adherent 
treatment 
to 
regimen 
adhering 
to 
 
these 
recommendations after referral to a cardiologist based on all patients who at baseline are 
judged by their primary care physician to be clinically stable and show NT-proBNP levels ≥ 
600 pg/ml. 
Based on the data from Dahlstrom et al (Dahlstrom, Hakansson et al. 2009), showing that only 
20% of patients followed by primary care physician receive both Renin-Angiotensin System 
inhibitors and beta-blockers at a dose ≥50% of the recommended, we conservatively assume 
20% as the percentage of CHF patients that will be treated in accordance to the ESC 
guidelines (i.e. prescription of any drugs with level I-A recommendation for a given patient’s 

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clinical status at a dose of > 50% of the recommended daily dose) at baseline (Visit 1). In 
addition, we assume that after referral to a specialist (Visit 2), the proportion will increase to 
30% (Maggioni, Anker et al. 2013). Although there are no data in the literature measuring the 
clinical impact of increasing guideline-adherence of treatment in HF, it has been clearly 
demonstrated that a 10% increase in acute coronary syndrome is clinically highly significant. 
In fact, for every 10% increase in guideline-adherence at a hospital center, the in-patient’s 
mortality odds ratio falls by a corresponding 39%. Similarly, for every 10% increase in 
appropriate dosing, the patient’s mortality odds ratio falls by a corresponding 18% (Mehta, 
Chen et al. 2015). 
We further assume that around 25% of patients without ESC guideline recommendations- 
adherent treatment at baseline (i.e. prior to referral to a cardiologist) will receive optimization 
(i.e. ESC guideline adherent treatment) of their HF treatment post referral to the cardiologist. 
This proportion can be estimated with a precision of ± 2% using a 95%-CI by including 1,728 
patients into the analysis; for subgroup analyses (e.g. on country level) the range of a 95%-CI 
increases, however it is still possible to estimate the proportion with a precision of ± 5% for 
subgroups of 300 patients. 
Considering of the above assumptions, a number of 2,160 patients who enter the prospective 
period of the study (i.e. referral to a cardiologist) is required. It is further assumed, based on 
unpublished data from chronic heart failure registries (data on file), that at least around 60% 
of patients treated by primary care physicians will have NT-proBNP levels ≥600 pg/ml at 
baseline. This in turn leads to the calculation that, in order to obtain 2.160 patients in the 
prospective period of the study, 3,600 consecutive patients will need to be enrolled for visit 1 
(baseline). 
Assuming an expected drop-out rate of 10% of patients, 4,000 patients will be enrolled of 
whom 2,400 will enter into the prospective period. 
The sample size calculation was performed with nQuery Advisor version 7.0 ‘using Table 
POC0-1. 
 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki. 
 
10.2 
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 

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about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects as per local law and regulations. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request has 
been made. 
 
10.4 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report  
the results of this trial will be submitted for publication and/or posted in a publicly accessible 
database of clinical trial results (as applicable). 
 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected  
on study participants. Additional assessments required to ensure safety of patients/subjects 
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 

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11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/subjects may be implemented immediately provided the health authorities 
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 
 
12 
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