GUIDE-IT: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment

• Sponsor: Duke University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01685840
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 894
• Locations: 46
• Arms: 2
• Duration (Months): 45.6
• Patients Per Site: 19.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The primary objective is to determine the efficacy of a strategy of biomarker-guided therapy compared with usual care in high risk patients with left ventricular systolic dysfunction.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Other: Usual Care; Device: Biomarker-guided care NT-proBNP	N/A

Detailed Description

Heart failure is a common disorder in which the heart cannot pump enough blood to meet the needs of the rest of the body. Common symptoms of heart failure include shortness of breath, swelling, and fatigue. Standard treatment for heart failure include diuretics to control fluid, as well as drugs called "neurohormonal antagonists" (such as beta-blockers and ACE-inhibitors) that help the heart work more efficiently and prevent worsening of heart function. Typically, doctors adjust these medicines based on their clinical judgment about what doses and combination will work best for you. We are testing whether the use of a blood test called NT-proBNP (which measures a hormone released by the heart) can help doctors do a better job of adjusting these heart failure medicines over time than clinical judgment alone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 894 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Sep 20, 2016
• Actual Study Completion Date: Sep 20, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Usual Care Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure.	Other: Usual Care; Usual Care
Experimental: Biomarker-Guided Care Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses.	Device: Biomarker-guided care NT-proBNP; Device: NT-proBNP

Outcome Measures

Primary Outcome Measures

1. CV Death or Heart Failure Hospitalization [24 Months]

   Composite of First Heart Failure Hospitalization or Cardiovascular Mortality

Secondary Outcome Measures

1. All-cause Mortality [24 months]

   All-cause mortality by treatment arm

2. Cumulative Morbidity [24 months]

   Days alive and not hospitalized for CV reasons

3. CV Death [24 months]

   CV death by treatment arm

4. Number of Hospitalizations for First Heart Failure [24 months]

   First Heart Failure Hospitalization

5. Number of Hospitalizations for Recurrent Heart Failure [24 months]

   Recurrent Heart Failure Hospitalization

6. Percentage of Patients With Moderate to Severe Depression [Baseline, 3,6, 12 and 24 months]

   Percentage of patients with moderate to severe depression as measured by the Center for Epidemiologic Studies Depression Scale (CES-D). CES-D is a 20-item scale measuring general depression. Scores range from 0-60, with higher scores indicating greater general depression. Moderate to severe depression is indicated by a score of 11 or higher.

7. Duke Activity Status Index (DASI) [Baseline, 3, 6, 12 and 24 months]

   The DASI is a self-administered questionnaire that measures a patient's functional capacity. It can be used to get a rough estimate of a patient's peak oxygen uptake. The maximum score for the DASI is 58.2 (better functional ability/capacity) and the minimum score is 0 (worse functional ability/capacity).

8. EQ-5D Health Index [Baseline, 3, 6, 12 and 24 months]

   The EQ-5D measures the subjects health status in 5 categories (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and totals them into 1 score, from -0.59 (worst) to 1 (best).

9. EQ-5D Visual Analog Scale [Baseline, 3, 6, 12 and 24 months]

   The EQ-5D VAS records participants self-rated health status on a vertical (0-100) scale with higher scores indicating higher Health-Related Quality of Life, where 0 = worst imaginable health state and 100 = best imaginable health state.

10. Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Score [Baseline, 3, 6,12 and 24 months]

    This KCCQ overall score represents the mean of the following 4 scores: Physical Limitation, Total Symptom, Quality of Life, and Social Limitation. Mean scores are transformed to a 0-100 scale with high scores representing better outcomes.

11. Short Form-36 (SF-36) General Health Subscale [Baseline, 3, 6, 12 and 24 months]

    SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.

12. Short Form-36 (SF-36) Mental Health Subscale [Baseline, 3, 6, 12 and 24 months]

    SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.

13. Short Form-36 (SF-36) Social Functioning Subscale [Baseline, 3, 6, 12 and 24 months]

    SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.

14. Short Form-36 (SF-36) Physiological Functioning Subscale [Baseline, 3, 6, 12 and 24 months]

    SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.

15. Short Form-36 (SF-36) Vitality Subscale [Baseline, 3, 6, 12 and 24 months]

    SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.

16. Resource Utilization [24 months]

    Observed Resource Use

17. Resource Utilization Cost [24 months]

    Observed Hospital-Based Cost.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18 years or older

• Most recent LVEF to be ≤ 40% by any method within 12 months of randomization.

• High risk heart failure as defined by the following criteria:

A Heart Failure Event in the prior 12 months, defined as any one of the following:

• HF Hospitalization

• Treatment in the Emergency Department (or equivalent) for Heart Failure

• Outpatient treatment for heart failure with intravenous diuretics

AND

• NT-proBNP greater than 2000 pg/mL or BNP greater than 400 pg/mL at any time during the 30 days prior to randomization

• Willing to provide informed consent

Exclusion Criteria:

• Acute coronary syndrome (clinical diagnosis) or cardiac revascularization procedure within 30 days

• Cardiac resynchronization therapy (CRT) within prior 3 months or current plan to implant CRT device

• Active myocarditis, Hypertrophic obstructive cardiomyopathy, pericarditis, or restrictive cardiomyopathy

• Severe stenotic valvular disease

• Anticipated heart transplantation or ventricular assist device within 12 months

• Chronic inotropic therapy

• Complex congenital heart disease

• End stage renal disease with renal replacement therapy

• Non cardiac terminal illness with expected survival less than 12 months

• Women who are pregnant or planning to become pregnant

• Inability to comply with planned study procedures

• Enrollment or planned enrollment in another clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Heart Center PC	Huntsville	Alabama	United States	35801
2	Sutter Memorial Hospital	Sacramento	California	United States	95819
3	University of California San Diego Medical Center	San Diego	California	United States	92037
4	Yale University School of Medicine	New Haven	Connecticut	United States	06510
5	Holy Cross Medical Group	Coral Springs	Florida	United States	33065
6	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
7	Emory University	Atlanta	Georgia	United States	30322
8	University Cardiology Associates, LLC	Augusta	Georgia	United States	30901
9	Fox Valley Clinical Research Center, LLC	Aurora	Illinois	United States	60504
10	Krannert Institute of Cardiology	Indianapolis	Indiana	United States	46202
11	University of Maryland	Baltimore	Maryland	United States	21201
12	Metropolitan Cardiovascular Consultants	Beltsville	Maryland	United States	20705
13	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
14	Beth Israel Medical Center	Boston	Massachusetts	United States	02215
15	Pentucket Medical Associates	Haverhill	Massachusetts	United States	01830
16	Mayo Clinic	Rochester	Minnesota	United States	55905
17	Washington University School of Medicine	San Luis	Missouri	United States	63112
18	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
19	Cardiovascular Associates of the Delaware Valley	Cherry Hill	New Jersey	United States	08034
20	Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
21	Cardiovascular Associates of the Delaware Valley	Sewell	New Jersey	United States	08080
22	Bronx-Lebanon Hospital Center	Bronx	New York	United States	10457
23	Jacobi Medical Center	Bronx	New York	United States	10461
24	Albert Einstein University Hospital	Bronx	New York	United States	10467
25	New York Methodist Hospital	Brooklyn	New York	United States	11215
26	Saratoga Cardiology Associates	Saratoga Springs	New York	United States	12866
27	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
28	Novant Health Heart and Vascular Institute	Charlotte	North Carolina	United States	28204
29	Duke University Medical Center	Durham	North Carolina	United States	27710
30	LeBauer Cardiovascular Research Foundation	Greensboro	North Carolina	United States	27401
31	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45267
32	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
33	Capitol Area Research, LLC	Camp Hill	Pennsylvania	United States	17011
34	Drexel University College of Medicine	Philadelphia	Pennsylvania	United States	19102
35	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
36	Allegheny-Singer Research Institute	Pittsburg	Pennsylvania	United States	15212
37	AnMed Health Medical Center	Anderson	South Carolina	United States	29621
38	University of Texas Southwestern Medical Center Dallas	Dallas	Texas	United States	75390
39	Intermountain Medical Center	Murray	Utah	United States	84157
40	Cardiovascular Associates, Ltd.	Chesapeake	Virginia	United States	23320
41	Foothills Medical Centre	Calgary	Alberta	Canada	T2N 4Z6
42	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
43	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
44	Saint Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
45	Hamilton Health Sciences	Hamilton	Ontario	Canada	L8L 2X2
46	St. Michaels Hospital	Toronto	Ontario	Canada	M5B 1W8

Sponsors and Collaborators

• Duke University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Michael Felker, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT01685840
• Other Study ID Numbers: Pro00033097
• First Posted: Sep 14, 2012
• Last Update Posted: Dec 12, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Duke University: Heart Failure
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Pre-assignment Detail	894 participants were randomized

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Period Title: Overall Study
STARTED	448	446
COMPLETED	119	114
NOT COMPLETED	329	332

Baseline Characteristics

Arm/Group Title	Usual Care	Biomarker-Guided Care	Total
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP	Total of all reporting groups
Overall Participants	448	446	894
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (13.4)	60.4 (14.3)	61.5 (13.9)
Sex: Female, Male (Count of Participants)
Female	147 32.8%	139 31.2%	286 32%
Male	301 67.2%	307 68.8%	608 68%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	28 6.3%	30 6.7%	58 6.5%
Not Hispanic or Latino	420 93.8%	416 93.3%	836 93.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.2%	2 0.4%	3 0.3%
Asian	11 2.5%	16 3.6%	27 3%
Native Hawaiian or Other Pacific Islander	3 0.7%	4 0.9%	7 0.8%
Black or African American	155 34.6%	167 37.4%	322 36%
White	257 57.4%	228 51.1%	485 54.3%
More than one race	14 3.1%	13 2.9%	27 3%
Unknown or Not Reported	7 1.6%	16 3.6%	23 2.6%

Outcome Measures

1. Primary Outcome

Title	CV Death or Heart Failure Hospitalization
Description	Composite of First Heart Failure Hospitalization or Cardiovascular Mortality
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	448	446
Number [events]	164	164

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	A sample size of 1100 patients was expected to provide approximately 90% power to detect a difference in the primary endpoint with an assumed type I error rate of 0.05, 2-sided. Analysis was adjusted for age, sex, ejection fraction, NT-proBNP and DM.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	All-cause Mortality
Description	All-cause mortality by treatment arm
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	448	446
Number [deaths]	77	66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Cumulative Morbidity
Description	Days alive and not hospitalized for CV reasons
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	448	446
Mean (95% Confidence Interval) [days]	616	626

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Bang-Tsiatis Partitioned Estimator
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	9
	Confidence Interval	(2-Sided) 95%; -20 to 39
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	CV Death
Description	CV death by treatment arm
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	448	446
Number [deaths]	57	53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Hospitalizations for First Heart Failure
Description	First Heart Failure Hospitalization
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	448	446
Number [hospitalizations]	141	147

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Hospitalizations for Recurrent Heart Failure
Description	Recurrent Heart Failure Hospitalization
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	448	446
Number [hospitalizations]	277	350

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Anderson-Gill Intensity Model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Patients With Moderate to Severe Depression
Description	Percentage of patients with moderate to severe depression as measured by the Center for Epidemiologic Studies Depression Scale (CES-D). CES-D is a 20-item scale measuring general depression. Scores range from 0-60, with higher scores indicating greater general depression. Moderate to severe depression is indicated by a score of 11 or higher.
Time Frame	Baseline, 3,6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	439	437
Baseline	34.6 7.7%	36.2 8.1%
3 month	26.2 5.8%	27.8 6.2%
6 month	25.6 5.7%	27.6 6.2%
12 month	25.9 5.8%	27.6 6.2%
24 month	25.4 5.7%	25.8 5.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	Baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.636
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.628
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.586
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.669
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.949
	Comments
	Method	Mixed Models Analysis
	Comments

8. Secondary Outcome

Title	Duke Activity Status Index (DASI)
Description	The DASI is a self-administered questionnaire that measures a patient's functional capacity. It can be used to get a rough estimate of a patient's peak oxygen uptake. The maximum score for the DASI is 58.2 (better functional ability/capacity) and the minimum score is 0 (worse functional ability/capacity).
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	443	435
Baseline	11.1 (12.6)	12.6 (13.5)
3 month	16.9 (14.2)	17.7 (14.9)
6 month	17.9 (15.8)	19.7 (16.6)
12 month	17.4 (16.1)	19.3 (17.0)
24 month	19.6 (17.8)	18.2 (17.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.404
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.880
	Confidence Interval	(2-Sided) 95%; -1.188 to 2.947
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.219
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.478
	Confidence Interval	(2-Sided) 95%; -0.881 to 3.836
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.104
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.099
	Confidence Interval	(2-Sided) 95%; -0.433 to 4.630
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.228
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.999
	Confidence Interval	(2-Sided) 95%; -1.253 to 5.250
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	EQ-5D Health Index
Description	The EQ-5D measures the subjects health status in 5 categories (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and totals them into 1 score, from -0.59 (worst) to 1 (best).
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	439	431
Baseline	0.7 (0.3)	0.7 (0.3)
3 month	0.7 (0.3)	0.7 (0.3)
6 month	0.7 (0.3)	0.7 (0.3)
12 month	0.7 (0.3)	0.7 (0.3)
24 month	0.7 (0.3)	0.7 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.421
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; -0.025 to 0.060
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.028
	Confidence Interval	(2-Sided) 95%; -0.018 to 0.074
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.402
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.021
	Confidence Interval	(2-Sided) 95%; -0.028 to 0.070
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.780
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.009
	Confidence Interval	(2-Sided) 95%; -0.057 to 0.076
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	EQ-5D Visual Analog Scale
Description	The EQ-5D VAS records participants self-rated health status on a vertical (0-100) scale with higher scores indicating higher Health-Related Quality of Life, where 0 = worst imaginable health state and 100 = best imaginable health state.
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	446	445
Baseline	60.2 (37.6)	59.2 (22.6)
3 month	62.3 (25.9)	60.2 (27.8)
6 month	60.5 (26.5)	61.5 (25.8)
12 month	63.7 (25.8)	62.1 (24.9)
24 month	65.9 (24.0)	60.8 (24.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.268
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.131
	Confidence Interval	(2-Sided) 95%; -5.902 to 1.640
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.599
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.069
	Confidence Interval	(2-Sided) 95%; -2.921 to 5.058
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.852
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.389
	Confidence Interval	(2-Sided) 95%; -4.486 to 3.707
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.221
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.343
	Confidence Interval	(2-Sided) 95%; -8.708 to 2.022
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Score
Description	This KCCQ overall score represents the mean of the following 4 scores: Physical Limitation, Total Symptom, Quality of Life, and Social Limitation. Mean scores are transformed to a 0-100 scale with high scores representing better outcomes.
Time Frame	Baseline, 3, 6,12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	444	441
Baseline	57.7 (22.4)	57.5 (21.6)
3 month	69.2 (22.8)	68.8 (22.6)
6 month	70.1 (22.2)	70.4 (21.8)
12 month	70.3 (21.9)	68.4 (24.3)
24 month	71.6 (24.4)	70.2 (22.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.615
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.816
	Confidence Interval	(2-Sided) 95%; -3.999 to 2.367
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.878
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.252
	Confidence Interval	(2-Sided) 95%; -2.977 to 3.482
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.441
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.406
	Confidence Interval	(2-Sided) 95%; -4.989 to 2.178
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.653
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.091
	Confidence Interval	(2-Sided) 95%; -3.673 to 5.856
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Short Form-36 (SF-36) General Health Subscale
Description	SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	441	436
Baseline	48.4 (11.1)	48.6 (10.7)
3 month	51.1 (12.6)	50.0 (12.9)
6 month	50.5 (12.7)	49.9 (12.9)
12 month	51.0 (12.2)	50.8 (12.6)
24 month	48.8 (12.8)	50.4 (11.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.199
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.226
	Confidence Interval	(2-Sided) 95%; -3.097 to 0.645
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.465
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.742
	Confidence Interval	(2-Sided) 95%; -2.735 to 1.250
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.943
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.074
	Confidence Interval	(2-Sided) 95%; -2.119 to 1.970
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.294
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.478
	Confidence Interval	(2-Sided) 95%; -1.286 to 4.241
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Short Form-36 (SF-36) Mental Health Subscale
Description	SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	441	438
Baseline	69.7 (20.4)	69.8 (20.9)
3 month	77.6 (19.9)	76.1 (21.5)
6 month	77.7 (20.5)	77.1 (21.3)
12 month	77.5 (20.3)	76.2 (22.2)
24 month	79.6 (17.6)	76.6 (22.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.294
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.579
	Confidence Interval	(2-Sided) 95%; -4.527 to 1.369
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.555
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.946
	Confidence Interval	(2-Sided) 95%; -4.096 to 2.203
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.643
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.798
	Confidence Interval	(2-Sided) 95%; -4.178 to 2.583
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.757
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.647
	Confidence Interval	(2-Sided) 95%; -4.767 to 3.472
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Short Form-36 (SF-36) Social Functioning Subscale
Description	SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	440	437
Baseline	60.2 (32.7)	64.8 (30.1)
3 month	75.4 (30.8)	74.9 (31.8)
6 month	77.0 (32.3)	75.0 (32.1)
12 month	76.4 (30.9)	74.5 (31.5)
24 month	76.7 (30.3)	77.2 (31.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.837
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.484
	Confidence Interval	(2-Sided) 95%; -5.102 to 4.133
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.288
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.693
	Confidence Interval	(2-Sided) 95%; -7.662 to 2.276
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.567
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.539
	Confidence Interval	(2-Sided) 95%; -6.810 to 3.732
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.475
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.512
	Confidence Interval	(2-Sided) 95%; -4.394 to 9.419
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Short Form-36 (SF-36) Physiological Functioning Subscale
Description	SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	442	433
Baseline	30.6 (32.1)	31.5 (31.2)
3 month	43.5 (35.9)	43.3 (37.5)
6 month	43.4 (37.4)	45.6 (37.2)
12 month	41.9 (38.2)	47.4 (37.1)
24 month	47.0 (38.1)	43.2 (38.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.696
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.057
	Confidence Interval	(2-Sided) 95%; -4.250 to 6.364
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 months
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.497
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.966
	Confidence Interval	(2-Sided) 95%; -3.715 to 7.647
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.564
	Confidence Interval	(2-Sided) 95%; 0.456 to 12.673
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.488
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.857
	Confidence Interval	(2-Sided) 95%; -5.247 to 10.961
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Short Form-36 (SF-36) Vitality Subscale
Description	SF-36 measures perceived Quality of Life. The following subscales were used: General Health, Mental Health, Social Functioning, Physiological Functioning, and Vitality Each subscale is scored from 0-100 with 0 indicating lowest quality of life.
Time Frame	Baseline, 3, 6, 12 and 24 months

Outcome Measure Data

Analysis Population Description

"Number of participants analyzed" is the number of participants who completed the questionnaire

Arm/Group Title	Usual Care	Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
Measure Participants	441	438
Baseline	43.9 (22.5)	44.3 (22.3)
3 month	54.5 (23.6)	54.6 (23.6)
6 month	55.1 (24.6)	55.8 (23.9)
12 month	54.4 (23.6)	55.2 (24.3)
24 month	57.9 (24.8)	55.9 (24.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	3 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.992
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.017
	Confidence Interval	(2-Sided) 95%; -3.383 to 3.417
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	6 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.882
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.280
	Confidence Interval	(2-Sided) 95%; -3.409 to 3.969
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	12 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.647
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.904
	Confidence Interval	(2-Sided) 95%; -2.973 to 4.782
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	24 month
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.903
	Comments	Adjusted P-value
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.322
	Confidence Interval	(2-Sided) 95%; -4.894 to 5.538
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Resource Utilization
Description	Observed Resource Use
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

US Patients in Economics Substudy

Arm/Group Title	Biomarker-Guided Care	Usual Care
Arm/Group Description	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care
Measure Participants	373	362
Number of Hospitalizations	1.93 (2.80)	1.83 (2.36)
Number of ER only events	0.57 (1.28)	0.56 (1.29)
Number of Rehab facilities	0.06 (0.35)	0.06 (0.25)
Total admissions	2.56 (3.64)	2.45 (3.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	Hospitalizations
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	ER only events
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	Rehab facilities
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	Total admissions
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

18. Secondary Outcome

Title	Resource Utilization Cost
Description	Observed Hospital-Based Cost.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

US Patients with billing data

Arm/Group Title	Biomarker-Guided Care	Usual Care
Arm/Group Description	Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care
Measure Participants	363	350
Hospital Costs	47,055 (92,270)	34,396 (60,842)
Physician Fees	2,291 (4,128)	1,761 (2,601)
Total Cost	49,346 (96,082)	36,157 (63,110)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	Hospital Costs
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Usual Care, Biomarker-Guided Care
	Comments	Physician Fees
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Usual Care
	Comments	Total Cost
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Randomization through completion of the final study visit at 24 months
Adverse Event Reporting Description	SAEs and AEs of Interest that occur from randomization through completion of the final study visit will be reported.
Arm/Group Title	Usual Care		Biomarker-Guided Care
Arm/Group Description	Usual Care group will receive standard heart failure treatment based on the doctor's best judgment and following the recommendation of current guidelines. This will typically include the use of medicines such as beta-blockers, ACE-inhibitors, and diuretics, all of which are approved, recommended treatments for heart failure. Usual Care: Usual Care		Device: Biomarker-Guided care NT-proBNP The Biomarker Guided Therapy group will receive the standard heart failure treatments. In addition, the doctor will use the results of a blood test called NT-proBNP to help adjust the treatments and drug doses. Biomarker-guided care NT-proBNP: Device: NT-proBNP
All Cause Mortality
	Usual Care		Biomarker-Guided Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/448 (17.2%)		66/446 (14.8%)
Serious Adverse Events
	Usual Care		Biomarker-Guided Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/448 (8%)		51/446 (11.4%)
Blood and lymphatic system disorders
Hyperkalemia	6/448 (1.3%)		11/446 (2.5%)
Cardiac disorders
Symptomatic Hypotension	2/448 (0.4%)		7/446 (1.6%)
Symptomatic Bradycardia	0/448 (0%)		0/446 (0%)
Investigations
Other Adverse Events	19/448 (4.2%)		17/446 (3.8%)
Renal and urinary disorders
Worsening renal function	9/448 (2%)		16/446 (3.6%)
Other (Not Including Serious) Adverse Events
	Usual Care		Biomarker-Guided Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	157/448 (35%)		178/446 (39.9%)
Blood and lymphatic system disorders
Hyperkalemia	22/448 (4.9%)		30/446 (6.7%)
Cardiac disorders
Symptomatic Hypotension	30/448 (6.7%)		37/446 (8.3%)
Symptomatic Bradycardia	3/448 (0.7%)		2/446 (0.4%)
Investigations
Other Adverse Events	19/448 (4.2%)		18/446 (4%)
Renal and urinary disorders
Worsening renal function	83/448 (18.5%)		91/446 (20.4%)

Limitations/Caveats

[Not Specified]

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.