ETIFIC: Safety and Effectiveness of Drug up Titration by Nurses Specialized in Heart Failure (HF) Patients

• Sponsor: Hospital Galdakao-Usansolo (Other)
• Overall Status: Completed
• CT.gov ID: NCT02546856
• Collaborator: Carlos III Health Institute (Other), Basque Health Service (Other)
• Enrollment: 320
• Location: 1
• Arms: 2
• Duration (Months): 49
• Patients Per Site Per Month: 6.5

Study Details

Study Description

Brief Summary

Introduction: Heart Failure (HF) generates multiple hospital admissions and mortality, which are reduced with the administration of Beta-Blocker (BB), Angiotensin Converting Enzyme Inhibitor (ACEI), Angiotensin II Receptor Blocker (ARB) and Mineralocorticoid Receptor Antagonist (MRA) drugs (Level of Evidence A). The effect is dose-dependent. Nevertheless, dosages are suboptimal. European Guidelines 2012 recommend close monitoring and up-titration of drugs by HF nurses. Trials are needed to evaluate their effectiveness and safety. Objective: To compare doses achieved by patients of BB, ACEI, ARB II and MRA in 4 months ( % relative to target doses) in the intervention group (HF nurse) and in the control group ( cardiologist), adverse events, Left Ventricular Ejection Fraction (LVEF), New York Heart Association (NYHA), 6 min. walking test, quality of life, Nt-proBNP, readmissions and mortality. Hypothesis: Non-inferiority. Design: Multicenter randomized controlled trial. New ("de novo") HF patients with LVEF ≤ 40%, NYHA II-III, without contraindications to BB of 17 Spanish hospitals will be included. Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. In the control group doses are decided by the cardiologist clinical support and education being provided by nurses. Variables: age, sex, education, psycho-social level, Cardio Vascular Risk Factors (CVRF), NYHA, LVEF, ischemic cardiopathy., N-terminal pro B-type natriuretic peptide (Nt-proBNP), 6min. walking test, Creatinine/Glomerular Filtration Rate (GFR), Potassium (K), haemoglobin, Blood Pressure (BP), Heart Rate (HR), mg./drug, European Heart Failure Self-Care Behaviour Scale (EHFScBS), Minnesota Living with Heart Failure questionnaire (MLHFQ), European Quality of life Scale (EQ-5D). Expected Results: If our hypothesis were confirmed, evidence would be provided on the effectiveness of this healthcare management, that could be economically evaluated in future studies. A qualitative study also will be undertaken to explore barriers and facilitators to implementation

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Other: Heart Failure (HF) nurse up-titration; Other: Heart Failure (HF) cardiologist up-titration	N/A

Detailed Description

No apply

Study Design

• Study Type: Interventional
• Actual Enrollment: 320 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Health Services Research
• Official Title: Safety and Effectiveness of Drug up Titration by Nurses Specialized in Heart Failure (HF) Patients
• Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Oct 1, 2018
• Actual Study Completion Date: Apr 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Heart Failure (HF) cardiologist up-titration Active Comparator:Cardiologist decides dosage with nursing clinical and educational support.	Other: Heart Failure (HF) cardiologist up-titration; Up-titration of Beta-Blocker (BB), Angiotensin Converting Enzyme Inhibitor (ACEI), Angiotensin II Receptor Blocker (ARB) and Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure "De Novo" patients with Left Ventricular Ejection Fraction (LVEF)≤ 40%, following a protocol based on 2012 European Society of Cardiology (ESC) Heart Failure (HF) guidelines. Drugs are prescribed and titrated by the cardiologist.
Experimental: HF nurse up-titration Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration.	Other: Heart Failure (HF) nurse up-titration; Up-titration of Beta-Blocker (BB), Angiotensin Converting Enzyme Inhibitor (ACEI), Angiotensin II Receptor Blocker (ARB) and Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure "De Novo" patients with Left Ventricular Ejection Fraction (LVEF)≤ 40%, following a protocol based on 2012 European Society of Cardiology (ESC) Heart Failure (HF) guidelines with cardiologist prescription and support.

Outcome Measures

Primary Outcome Measures

1. BB % Relative Dose (Mean) With Regard to Target Dose [4 months]

   BB mean Relative dose is the mean dose of betablockers achieved 4 months after starting titration, relative to target dose ( %) , which is the target dose of european heart failure guidelines for BB.

Secondary Outcome Measures

1. Number of Participants With Worsening Renal Function (From Baseline to 4th Month) [4 months]

   Number of participants with worsening renal function during the titration process (from baseline to 4 month) that could be associated to the titration process (Creatinine increase >50% baseline creatinine or creatinine>3mg/dl, or Estimated Glomerular Filtration<25 ml/min/1.73 m2)

2. Number of Participants With Potassium (K) ≥5.5 Meq/l (From Baseline to 4 Month) [4 months]

   Number of participants with Potassium≥ 5.5 meq/l during the titration process (from baseline to 4 month) that could be associated to this titration process

3. Number of Participants With Symptomatic Hypotension (From Baseline to 4 Month) [4 months]

   Description: Number of participants with symptomatic hypotension during the titration process (from baseline to 4 month) that could be associated to this titration process. Symptomatic hypotension defined as symptoms such as dizziness or light headedness, associated to hypotension

4. Number of Participants With Heart Rate (HR) < 50 Beats Per Minute (From Baseline to 4 Month) [4 months]

   Number of participants with Heart Rate (HR) < 50 beats per minute during the titration process (from baseline to 4 month) , which could be associated to the titration process. (with or without symptoms)

5. Number of Patients With Atrio Ventricular (AV) Block Due to Titration [4 months]

   Number of patients with AV Block during the titration process, associated to the BB titration

6. Number of Patients With Worsening of Heart Failure Signs and Symptoms [4 months]

   Number of patients with worsening of heart failure signs and symptoms during the titration process ( from baseline to 4 month) which could be associated to the titration process.

7. Number of Patients With Admissions Due to Titration [4 months]

   Number of patients with admissions due to titration ( not due to other causes)

8. Number of Patients: Mortality Due to Titration [4 months]

   Number of patients: Mortality due to titration ( not due to other causes)

9. Number of Paticipants With Drug Stop (Some Titration Drug Withdrawal Due to Intolerance, no Need or Change to Other Treatment) [4 months]

   number of paticipants with drug Stop ( withdrawal) that occur during the titration process that could be due to an adverse event. ( it can be not only due to an adverse event but because there is no need of this drug or its substitution for another kind of drug)

10. Change in % Left Ventricular Ejection Fraction [6 months]

    Change in % Left Ventricular Ejection Fraction (difference of change from baseline to 6 months between groups) Ejection fraction is a measurement of the percentage of blood leaving the heart each time it contracts.

11. N-terminal Pro-B Type Natriuretic Peptide Improvement (Nt-proBNP) [6 months]

    Nt-proBNP (N-terminal pro-B type natriuretic peptide) Improvement (Decrease) difference of change from baseline to 6 months between groups, mean (SD)

12. 6 Minute Walking Test [6 months]

    6 minute walking test improvement ( change) meters.Improvement (difference of change from baseline to 6 months between groups Six minute walking test. Measurement of exercise capacity is an integral element in assessment of patients with cardiopulmonary disease. It provides information regarding functional capacity, response to therapy and prognosis across a range of chronic cardiopulmonary conditions. The six-minute walk test (6MWT) measures the distance (meters) an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway.

13. Number of Participants n(%) in New York Heart Association Functional Classification I,II,III,IV [6 months]

    Number of participants class I-IV New York Heart Association (NYHA) functional classification, based on severity of symptoms and physical activity: NYHA I (better): No limitation of physical activity; NYHA II: Slight limitation of ordinary physical activity, breathlessness; NYHA III: marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results in undue breathlessness, fatigue or palpitations; NYHA IV ( worse): unable to carry on any physical activity without discomfort.Symptoms at rest can be present. If any physical activity is undertaken discomfort is increased.

14. Quality of Life: MLWHFQ [6 months]

    Quality of Life, measured by Minnesota Living with Heart Failure Questionnaire. Improvement (change) from baseline to 6 months. Minnesota Living With Heart Failure Questionnaire (MLWHFQ). The content of this questionnaire was selected to be representative of the ways heart failure and treatments can affect the key physical, emotional, social and mental dimensions of quality of life of patients with heart failure. It consist of 21-items with score 0-5. Final evaluation moves from 0 (none) to 105 (very much); a lower score means better quality of life.

15. European Quality of Life Scale: EuroQol- 5 Dimension Index [6 months]

    European Quality of Life Scale: EuroQol- 5 Dimension index (Range: 1 full health-0 death). It measures health status self-reported by the patient. It has 5 domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is divided into three levels: 1 no problem; 2 some or moderate problems; 3 extreme problems. The EuroQol Research Foundation converts this information into a single summary index, by applying a formula that attaches specific country values (called weights) to each of the levels in each dimension. The index is calculated by subtracting the mentioned weights from 1, the value for full health. We measured the EuroQol-5D index improvement (change) from baseline to 6 months. More information in: EQ-5D-3L-User-Guide_version-6.0 (1).pdf

16. Number of Patients With Admissions Due to Heart Failure (HF) [6 months]

    Number of patients with hospital admissions due to Heart Failure. From Baseline to 6 months

17. Number of Patients With Deaths [6 months]

    Number of Patients with deaths due to Cardiovascular and non cardiovascular causes

18. ACEI % Relative Dose (Mean) With Regard to Target Dose [4 Months]

    ACEI mean Relative dose is the mean dose of ACEI achieved 4 months after starting titration, relative to target dose (%) described in European guidelines

19. ARB % Relative Dose (Mean) With Regard to Target Dose [4 months]

    ARB, angiotensin II receptor blockers, mean relative dose ( % to target dose). Target dose is described in European guidelines. Measured at 4 months after starting titration.

20. MRA % Relative Dose (Mean) With Regard to Target Dose [4 months]

    MRA % relative dose (mean) is the mean dose achieved 4 months after starting titration with regard to target dose (%) described in european guidelines

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient with "de novo" heart Failure and LVEF <= 40% admitted in hospital, without contraindications for BB prescription with cardiologist up-titration prescription and without having achieved BB target dose previous discharge and signing informed consent.

Exclusion Criteria:

• Contraindications for BB.

• Living in a nursing home.

• Life expectancy < 6 months.

• Unable to self-care or mental disease without caregiver.

• Unable to weight

• Without phone

• Unable to go to clinic visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital de usansolo-Galdakao	Usansolo	Bizkaia	Spain	48960

Sponsors and Collaborators

• Hospital Galdakao-Usansolo
• Carlos III Health Institute
• Basque Health Service

Investigators

• Principal Investigator: Maria Juana Oyanguren, Nurse, Osakidetza-Servicio vasco de Salud

Study Documents (Full-Text)

• Study Protocol - Mar 1, 2015
• Statistical Analysis Plan - Mar 1, 2015

More Information

Publications

• Oyanguren J, García-Garrido L, Nebot Margalef M, Lekuona I, Comin-Colet J, Manito N, Roure J, Ruiz Rodriguez P, Enjuanes C, Latorre P, Torcal Laguna J, García-Gutiérrez S; ETIFIC7 research group. Design of a multicentre randomized controlled trial to assess the safety and efficacy of dose titration by specialized nurses in patients with heart failure. ETIFIC study protocol. ESC Heart Fail. 2017 Nov;4(4):507-519. doi: 10.1002/ehf2.12152. Epub 2017 Apr 3. Review.

• Responsible Party: Maria Juana Oyanguren Artola, Heart Failure Nurse, Hospital Galdakao-Usansolo
• ClinicalTrials.gov Identifier: NCT02546856
• Other Study ID Numbers: PI14/01208
• First Posted: Sep 11, 2015
• Last Update Posted: Dec 16, 2020
• Last Verified: Nov 1, 2020

• Keywords provided by Maria Juana Oyanguren Artola, Heart Failure Nurse, Hospital Galdakao-Usansolo: Up-titration; Nursing or Nurse; Heart Failure
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Arm/Group Title	Heart Failure (HF) Nurse Up-titration	Heart Failure (HF) Cardiologist Up-titration
Arm/Group Description	Intervention:The cardiologist prescribes drugs and the HF-nurse implements the up-titration, driven by protocol based on 2012 ESC HF guidelines, with cardiologist support. Up-titration of Beta-Blocker (BB), Angiotensin Converting Enzyme Inhibitor (ACEI), Angiotensin II Receptor Blocker (ARB) and Mineralocorticoid Receptor Antagonist (MRA) drugs of Heart Failure "De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients	Active Comparator:The cardiologist prescribes and decides dosage following a protocol based on 2012 ESC HF guidelines, with nursing clinical and educational support. Up-titration of Beta-Blocker (BB), Angiotensin Converting Enzyme Inhibitor (ACEI), Angiotensin II Receptor Blocker (ARB) and Mineralocorticoid Receptor Antagonist (MRA) drugs of Heart Failure "De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients
Period Title: 4 Months Evaluation
STARTED	164	156
COMPLETED	144	145
NOT COMPLETED	20	11
Period Title: 4 Months Evaluation
STARTED	144	145
COMPLETED	136	138
NOT COMPLETED	8	7

Baseline Characteristics

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration	Total
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" Left Ventricular Ejection Fraction≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Patients, following a protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients. Protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" Left Ventricular Ejection Fraction ≤ 40% Patients, . Protocol based on 2012 ESC HF guidelines.	Total of all reporting groups
Overall Participants	156	164	320
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.64 (12.25)	61.88 (12.14)	61.28 (12.19)
Sex: Female, Male (Count of Participants)
Female	38 24.4%	45 27.4%	83 25.9%
Male	118 75.6%	119 72.6%	237 74.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	156 100%	164 100%	320 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Spain	156 100%	164 100%	320 100%
betablocker mean relative dose (% to target dose) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% to target dose]	34.80 (20.6)	34.81 (18.16)	34.80 (19.38)
left ventricular ejection fraction % (%of blood leaving the heart /beat) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%of blood leaving the heart /beat]	27.45 (7.25)	27.95 (6.69)	27.71 (6.97)
Nt-proBNP (pg/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/ml]	3001 (4041)	3425 (5256)	3217 (4697)
6 minute walking test (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	370 (108)	361 (102)	366 (105)
Number of participants with New York Heart Association (NYHA) I,II,III,IV (Count of Participants)
NYHA I	0 0%	0 0%	0 0%
NYHA II	128 82.1%	139 84.8%	267 83.4%
NYHA III	28 17.9%	25 15.2%	53 16.6%
NYHA IV	0 0%	0 0%	0 0%
Minnesota living with heart failure questionnaire (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	45.71 (22.21)	50.8 (22.61)	48.31 (22.52)
European Quality of Life Scale: EuroQol- 5 Dimension index (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	0.75 (0.24)	0.73 (0.23)	0.74 (0.23)
ACEI mean relative dose (% to target dose) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% to target dose]	40.13 (25.38)	45.92 (30.06)	43.04 (27.81)
Angiotensin II Receptor Blockers (ARB) mean relative dose (% to target dose) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% to target dose]	43.20 (20.63)	29.15 (14.99)	33.84 (17.95)
MRA mean relative dose (% to target dose) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% to target dose]	63.18 (33.00)	61.4 (33.52)	62.30 (33.21)

Outcome Measures

1. Primary Outcome

Title	BB % Relative Dose (Mean) With Regard to Target Dose
Description	BB mean Relative dose is the mean dose of betablockers achieved 4 months after starting titration, relative to target dose ( %) , which is the target dose of european heart failure guidelines for BB.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" Left Ventricular ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" Left Ventricular ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" Left Ventricular ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" Left Ventricular ejection Fraction ≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" Left Ventricular ejection Fraction (EF) ≤ 40% Patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 ESC HF guidelines.
Measure Participants	145	144
Mean (Standard Deviation) [percentage of target dose]	56.29 (31.3)	71.09 (31.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	For the hypothesis that the relative dose of BBs would reach 52% by the end of the study and using an equivalence margin of 7%, we would need 157 patients per group for an alpha level of significance of 0.05 and a statistical power of 80% (beta of 0.80).
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	14.8
	Confidence Interval	(2-Sided) 95%; 7.5 to 22.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Worsening Renal Function (From Baseline to 4th Month)
Description	Number of participants with worsening renal function during the titration process (from baseline to 4 month) that could be associated to the titration process (Creatinine increase >50% baseline creatinine or creatinine>3mg/dl, or Estimated Glomerular Filtration<25 ml/min/1.73 m2)
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines.
Measure Participants	145	144
Count of Participants [Participants]	6 3.8%	4 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Equivalence
	Comments	equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -3.33 to 6.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Potassium (K) ≥5.5 Meq/l (From Baseline to 4 Month)
Description	Number of participants with Potassium≥ 5.5 meq/l during the titration process (from baseline to 4 month) that could be associated to this titration process
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	145	144
Count of Participants [Participants]	3 1.9%	6 3.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	2.10
	Confidence Interval	(2-Sided) 95%; -1.9 to 6.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Symptomatic Hypotension (From Baseline to 4 Month)
Description	Description: Number of participants with symptomatic hypotension during the titration process (from baseline to 4 month) that could be associated to this titration process. Symptomatic hypotension defined as symptoms such as dizziness or light headedness, associated to hypotension
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	145	144
Count of Participants [Participants]	13 8.3%	12 7.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95%; -7.1 to 5.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With Heart Rate (HR) < 50 Beats Per Minute (From Baseline to 4 Month)
Description	Number of participants with Heart Rate (HR) < 50 beats per minute during the titration process (from baseline to 4 month) , which could be associated to the titration process. (with or without symptoms)
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines with cardiologist prescription and support. HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	145	144
Count of Participants [Participants]	7 4.5%	10 6.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	2.12
	Confidence Interval	(2-Sided) 95%; -3.3 to 7.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Patients With Atrio Ventricular (AV) Block Due to Titration
Description	Number of patients with AV Block during the titration process, associated to the BB titration
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients,. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	145	144
Count of Participants [Participants]	0 0%	0 0%

7. Secondary Outcome

Title	Number of Patients With Worsening of Heart Failure Signs and Symptoms
Description	Number of patients with worsening of heart failure signs and symptoms during the titration process ( from baseline to 4 month) which could be associated to the titration process.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients,. Protocol based on 2012 ESC HF guidelines.
Measure Participants	145	144
Count of Participants [Participants]	1 0.6%	2 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.56
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; -1.6 to 3.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Patients With Admissions Due to Titration
Description	Number of patients with admissions due to titration ( not due to other causes)
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patient. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	145	144
Count of Participants [Participants]	0 0%	0 0%

9. Secondary Outcome

Title	Number of Patients: Mortality Due to Titration
Description	Number of patients: Mortality due to titration ( not due to other causes)
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	145	144
Count of Participants [Participants]	0 0%	0 0%

10. Secondary Outcome

Title	Number of Paticipants With Drug Stop (Some Titration Drug Withdrawal Due to Intolerance, no Need or Change to Other Treatment)
Description	number of paticipants with drug Stop ( withdrawal) that occur during the titration process that could be due to an adverse event. ( it can be not only due to an adverse event but because there is no need of this drug or its substitution for another kind of drug)
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Participants analyzed are only participants with drug withdrawal

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients,. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	12	9
betablocker stop	3 1.9%	1 0.6%
ACEI stop	3 1.9%	0 0%
ARB stop	0 0%	1 0.6%
MRA stop	6 3.8%	7 4.3%

11. Secondary Outcome

Title	Change in % Left Ventricular Ejection Fraction
Description	Change in % Left Ventricular Ejection Fraction (difference of change from baseline to 6 months between groups) Ejection fraction is a measurement of the percentage of blood leaving the heart each time it contracts.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

It has to be taken into account that in outcome mesasures the order of groups and their number of participants is reversed ( first HF cardiologist, second HF nurse) in regard to those in the participant flow. ( first HF nurse, second HF cardiologist)

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	138	136
Mean (Standard Deviation) [percentage of blood expelled/each beat]	15.46 (11.46)	15.63 (13.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -2.69 to 2.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	N-terminal Pro-B Type Natriuretic Peptide Improvement (Nt-proBNP)
Description	Nt-proBNP (N-terminal pro-B type natriuretic peptide) Improvement (Decrease) difference of change from baseline to 6 months between groups, mean (SD)
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

BNP was analysed in 11 patients of both groups, instead of Nt proBNP ( 121/117).

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines with cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	121	117
Mean (Standard Deviation) [pg/ml]	-1577 (3225)	-1593 (2733)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.47
	Confidence Interval	(2-Sided) 95%; -781 to 748
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	6 Minute Walking Test
Description	6 minute walking test improvement ( change) meters.Improvement (difference of change from baseline to 6 months between groups Six minute walking test. Measurement of exercise capacity is an integral element in assessment of patients with cardiopulmonary disease. It provides information regarding functional capacity, response to therapy and prognosis across a range of chronic cardiopulmonary conditions. The six-minute walk test (6MWT) measures the distance (meters) an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is allowed to self-pace and rest as needed as they traverse back and forth along a marked walkway.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	138	136
Mean (Standard Deviation) [meters]	50.49 (74.20)	57.76 (79.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.28
	Confidence Interval	(2-Sided) 95%; -11.27 to 25.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Number of Participants n(%) in New York Heart Association Functional Classification I,II,III,IV
Description	Number of participants class I-IV New York Heart Association (NYHA) functional classification, based on severity of symptoms and physical activity: NYHA I (better): No limitation of physical activity; NYHA II: Slight limitation of ordinary physical activity, breathlessness; NYHA III: marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results in undue breathlessness, fatigue or palpitations; NYHA IV ( worse): unable to carry on any physical activity without discomfort.Symptoms at rest can be present. If any physical activity is undertaken discomfort is increased.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	137	135
NYHA I	47 30.1%	59 36%
NYHA II	86 55.1%	72 43.9%
NYHA III	4 2.6%	4 2.4%
NYHA IV	0 0%	0 0%

15. Secondary Outcome

Title	Quality of Life: MLWHFQ
Description	Quality of Life, measured by Minnesota Living with Heart Failure Questionnaire. Improvement (change) from baseline to 6 months. Minnesota Living With Heart Failure Questionnaire (MLWHFQ). The content of this questionnaire was selected to be representative of the ways heart failure and treatments can affect the key physical, emotional, social and mental dimensions of quality of life of patients with heart failure. It consist of 21-items with score 0-5. Final evaluation moves from 0 (none) to 105 (very much); a lower score means better quality of life.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	138	136
Mean (Standard Deviation) [score on a scale]	-25.01 (23.22)	-26.37 (24.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.91
	Confidence Interval	(2-Sided) 95%; -6.63 to 4.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	European Quality of Life Scale: EuroQol- 5 Dimension Index
Description	European Quality of Life Scale: EuroQol- 5 Dimension index (Range: 1 full health-0 death). It measures health status self-reported by the patient. It has 5 domains: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is divided into three levels: 1 no problem; 2 some or moderate problems; 3 extreme problems. The EuroQol Research Foundation converts this information into a single summary index, by applying a formula that attaches specific country values (called weights) to each of the levels in each dimension. The index is calculated by subtracting the mentioned weights from 1, the value for full health. We measured the EuroQol-5D index improvement (change) from baseline to 6 months. More information in: EQ-5D-3L-User-Guide_version-6.0 (1).pdf
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	138	136
Mean (Standard Deviation) [score on a scale]	0.04 (0.28)	0.08 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Number of Patients With Admissions Due to Heart Failure (HF)
Description	Number of patients with hospital admissions due to Heart Failure. From Baseline to 6 months
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	145	144
Count of Participants [Participants]	9 5.8%	1 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Equivalence
	Comments	equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	-5.5
	Confidence Interval	(2-Sided) 95%; -9.7 to -1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Number of Patients With Deaths
Description	Number of Patients with deaths due to Cardiovascular and non cardiovascular causes
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	4	3
mortality due to cardiovascular causes	2 1.3%	2 1.2%
mortality due to non cardiovascular causes	2 1.3%	1 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 5%
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Chi-squared
	Comments	Equivalence margin of 7%
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95%; -4.2 to 2.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	ACEI % Relative Dose (Mean) With Regard to Target Dose
Description	ACEI mean Relative dose is the mean dose of ACEI achieved 4 months after starting titration, relative to target dose (%) described in European guidelines
Time Frame	4 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	115	115
Mean (Standard Deviation) [percentage of target dose]	56.13 (30.4)	72.61 (29.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 7%
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.5
	Confidence Interval	(2-Sided) 95%; 8.7 to 24.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	ARB % Relative Dose (Mean) With Regard to Target Dose
Description	ARB, angiotensin II receptor blockers, mean relative dose ( % to target dose). Target dose is described in European guidelines. Measured at 4 months after starting titration.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

During the titration process several patients that at baseline did not have ARB prescription were prescribed this drug.

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	20	18
Mean (Standard Deviation) [percentage of target dose]	43.51 (33.7)	44.48 (33.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 7%
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; -15.1 to 17.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	MRA % Relative Dose (Mean) With Regard to Target Dose
Description	MRA % relative dose (mean) is the mean dose achieved 4 months after starting titration with regard to target dose (%) described in european guidelines
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration	HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines	Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
Measure Participants	127	125
Mean (Standard Deviation) [percentage of target dose]	70.47 (29.8)	71.00 (32.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Heart Failure (HF) Cardiologist Up-titration, HF Nurse Up-titration
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Equivalence margin of 7%
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -7.1 to 8.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From Baseline to 6 months
Arm/Group Title	Heart Failure (HF) Cardiologist Up-titration		HF Nurse Up-titration
Arm/Group Description	Active Comparator:Cardiologist decides dosage with nursing clinical and educational support. HF cardiologist up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines HF cardiologist up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% Patients, following a protocol based on 2012 ESC HF guidelines		Intervention: The cardiologist prescribes drugs and, driven by protocol, the HF nurse implements the up-titration. HF nurse up-titration: Up-titration of Beta-Blocker (BB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 European Society of Cardiology (ESC) HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin Converting Enzyme Inhibitor (ACEI) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Angiotensin II Receptor Blocker (ARB) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support HF nurse up-titration: Up-titration of Mineralocorticoid Receptor Antagonist (MRA) in Heart Failure " De Novo" EF≤ 40% patients. Protocol based on 2012 ESC HF guidelines. Cardiologist prescription and support
All Cause Mortality
	Heart Failure (HF) Cardiologist Up-titration		HF Nurse Up-titration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/145 (2.8%)		3/144 (2.1%)
Serious Adverse Events
	Heart Failure (HF) Cardiologist Up-titration		HF Nurse Up-titration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/145 (7.6%)		2/144 (1.4%)
Cardiac disorders
hospitalizations due to cardiovascular cause	11/145 (7.6%)	11	2/144 (1.4%)	2
Other (Not Including Serious) Adverse Events
	Heart Failure (HF) Cardiologist Up-titration		HF Nurse Up-titration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/145 (13.8%)		22/144 (15.3%)
Cardiac disorders
heart rate <50 bpm	7/145 (4.8%)	7	10/144 (6.9%)	10
symptomatic hypotension	13/145 (9%)	13	12/144 (8.3%)	12

Limitations/Caveats

the implementation of ETIFIC in a single country; its recruitment characteristics, inclusion of de novo HF patients exclusively, relatively young patients and the low percentage of women and patients with ischemic heart disease.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.