Evaluation of heart failure treatment guided by N-terminal pro b-type natriuretic peptide (NTproBNP) vs clinical symptoms and signs alone

Study identifier:D2452L00010

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A randomised, single blind, multicentre, 9-month, phase IV study, comparing treatment guided by clinical symptoms and signs and NT-proBNP vs treatment guided by clinical symptoms and signs alone, in patients with heart failure (HF) and left ventricular systolic dysfunction

Medical condition

heart failure

Phase

Phase 4

Healthy volunteers

Study drug

Captopril, Enalapril, Lisinopril, Ramipril, Trandolapril, Bisoprolol, Carvedilol, Metoprolol succinate, Candesartan, Valsartan, Eplerenone, Spironolactone, Diuretics, HF treatment according to Swedish guidelines

Sex

All

Actual Enrollment

252

Study type

Interventional

Age

18 Years +

Date

Study Start Date: 01 Oct 2006

Primary Completion Date: 01 Jan 2009

Study Completion Date: 01 Jan 2009

Study design

Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind
Primary Purpose: Treatment

Verification:

Verified 01 Jun 2012 by AstraZeneca Pharmaceuticals

Collaborators

Inclusion and exclusion criteria

Location

Research Site

UMEA, Sweden

Location

Research Site

UPPSALA, Sweden

Location

Research Site

VASTERAS, Sweden

Location

Research Site

ALVESTA, Sweden

Location

Research Site

ARVIKA, Sweden

Location

Research Site

BJUV, Sweden

Location

Research Site

BORENSBERG, Sweden

Location

Research Site

BROMMA, Sweden

Arms	Assigned Interventions
Other: Guided by NT-proBNP Treatment guided by clinical symptoms and signs + NTproBNP	-
Other: Not Guided by NT-proBNP Treatment guided by clinical symptoms and signs	-

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This was a randomised, parallel group, single blind, multicentre, 9-month study in chronic heart failure in patients with New York Heart Association classification of heart failure (NYHA) class II-IV, left ventricular systolic dysfunction and elevated NT-proBNP levels in the primary care setting.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
At visit 1 was the NT-proBNP value measured at this value should be above 800 (females) or 1000 (males) before randomisation at visit 2. One patient from each group are excluded from the full analysis set (FAS) due to “total unavailability of efficacy data after randomisation”.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Participant Flow: Overall Study

	Guided by NT-proBNP	Not guided by NT-proBNP
STARTED	127^[1]	125^[2]
COMPLETED	119^[3]	118^[4]
NOT COMPLETED	8	7
Adverse Event	4	1
Did not meet the required elig. crit	2	2
Withdrawal by Subject	2	3
Developed study specific DC criteria	0	1

[1]	Of the 127 randomised patients 8 were discontinued
[2]	Of th 125 randomised patients 7 were discontinued
[3]	119 completed patients includes 4 CV related deaths
[4]	118 completed patients includes 5 CV related deaths

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Baseline Measures

	Guided by NT-proBNP	Not guided by NT-proBNP	Total
Number of Participants [units: Participants]	127	125	252
Age Continuous [units: Years] Mean ( Full Range )	78 (57 to 92)	77 (51 to 94)	77 (51 to 94)
Gender, Male/Female [units: Participants]
Female	30	42	72
Male	97	83	180
Electrocardiogram (ECG), Abnormal/Normal [units: Participants]
Abnormal ECG	115	113	228
Normal ECG	12	12	24
Diastolic blood pressure [units: mmHg] Mean ± Standard Deviation	73 ± 11	75 ± 12	74 ± 11
Pulse [units: Beats/minute] Mean ± Standard Deviation	71 ± 14	72 ± 14	72 ± 14
Systolic blood pressure [units: mmHg] Mean ± Standard Deviation	133 ± 21	135 ± 22	134 ± 21

Outcome Measures

1. Primary Outcome Measure: Composite value of 3 variables after 9 months: Cardiovascular death (days alive), Cardiovascular hospitalization (days out of hospital), Heart failure symptoms (symptom score subset of the Kansas City Cardiomyopathy Questionnaire - questions 3,5,7,9) [ Time Frame: 9 months ]

Measure Type	Primary
Measure Name	Composite value of 3 variables after 9 months: Cardiovascular death (days alive), Cardiovascular hospitalization (days out of hospital), Heart failure symptoms (symptom score subset of the Kansas City Cardiomyopathy Questionnaire - questions 3,5,7,9)
Measure Description	The non-parametric scale is constructed from 3 variables, modified after Cleland. Each patient receives a rank score from 1 to 246 (246-number of patients in the study). The lowest score receive patients who die (due to CV event), next patients still alive at end-of-study with the worst composite score, the best alive patients with 0 days in hospital and the largest improvement in the KCCQ (self-administered by patient symptom score, where the higher score reflect better health status). Scores will be summarized using non-parametric calculations. The mean of non-parametric scores is presented
Time Frame	9 months
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	123	123
Composite value of 3 variables after 9 months: Cardiovascular death (days alive), Cardiovascular hospitalization (days out of hospital), Heart failure symptoms (symptom score subset of the Kansas City Cardiomyopathy Questionnaire - questions 3,5,7,9) [units: Scores on a scale] Mean (Standard Deviation)	118.6 (558)	128.4 (558)

No statistical analysis provided for Composite value of 3 variables after 9 months: Cardiovascular death (days alive), Cardiovascular hospitalization (days out of hospital), Heart failure symptoms (symptom score subset of the Kansas City Cardiomyopathy Questionnaire - questions 3,5,7,9)

2. Secondary Outcome Measure: Number of CV deaths [ Time Frame: 9 months ]

Measure Type	Secondary
Measure Name	Number of CV deaths
Measure Description	Number of deaths
Time Frame	9 months
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	123	123
Number of CV deaths [units: Participants]	4	5

No statistical analysis provided for Number of CV deaths

3. Secondary Outcome Measure: Number of days in hospital for CV reason [ Time Frame: 9 months ]

Measure Type	Secondary
Measure Name	Number of days in hospital for CV reason
Measure Description	Each overnight stay is counted as one day. The lower the better
Time Frame	9 months
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	123	123
Number of days in hospital for CV reason [units: Days in hospital] Mean (Standard Deviation)	5.79 (6.63)	5.94 (6.32)

No statistical analysis provided for Number of days in hospital for CV reason

4. Secondary Outcome Measure: Changes in heart failure symptoms [ Time Frame: 9 months and baseline ]

Measure Type	Secondary
Measure Name	Changes in heart failure symptoms
Measure Description	Changes from baseline in the symptom score subset (question 3, 5, 7 and 9) of KCCQ (swelling, fatigue, shortness of breath, shortness of breath night time). KCCQ is a self-administered by patient symptom score, where higher score reflect better health status. Scale scores are transformed to a 0 to 100 range by subtracting the lowest possible scale score, dividing by the range of the scale and multiplying by 100. This mean that the KCCQ scale is from 0 to 100 with the higher value showing a better health status.
Time Frame	9 months and baseline
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	123	123
Changes in heart failure symptoms [units: Categorial scale] Mean (Standard Deviation)	3.67 (20.02)	6.11 (21.00)

No statistical analysis provided for Changes in heart failure symptoms

5. Secondary Outcome Measure: Changes in NT-proBNP values over time in all patients [ Time Frame: 9 months and baseline ]

Measure Type	Secondary
Measure Name	Changes in NT-proBNP values over time in all patients
Measure Description	The 95% confidential interval (CI) is given as measure of dispersion
Time Frame	9 months and baseline
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	123	123
Changes in NT-proBNP values over time in all patients [units: ng/L] Geometric Mean (95% Confidence Interval)	2332.1 (1986.1 to 2738.4)	2063 (1743.2 to 2442.7)

No statistical analysis provided for Changes in NT-proBNP values over time in all patients

6. Secondary Outcome Measure: Changes in health-related quality of life [ Time Frame: 9 months and baseline ]

Measure Type	Secondary
Measure Name	Changes in health-related quality of life
Measure Description	Change range –100 to 100. The higher the better.
Time Frame	9 months and baseline
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	123	123
Changes in health-related quality of life [units: KCCQ overall score] Mean (Standard Error)	1.739 (1.39)	3.172 (1.39)

No statistical analysis provided for Changes in health-related quality of life

7. Secondary Outcome Measure: Total Number of Titration steps in Prescribed Heart Failure Treatment [ Time Frame: 9 months ]

Measure Type	Secondary
Measure Name	Total Number of Titration steps in Prescribed Heart Failure Treatment
Measure Description	Each titration step in prescribed medication is counted as one step, either up or down. One step up indicates an increase of dose in prescribed medication and one step down indicates a decrease of dose in prescribed medication. The sum of steps is given as a score. Score is given for each arm as a total number of titration steps for all patients in arm.
Time Frame	9 months
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	123	123
Total Number of Titration steps in Prescribed Heart Failure Treatment [units: Titration steps]	517	485

No statistical analysis provided for Total Number of Titration steps in Prescribed Heart Failure Treatment

8. Secondary Outcome Measure: Discontinuations [ Time Frame: 9 months ]

Measure Type	Secondary
Measure Name	Discontinuations
Measure Description	Number of patients discontinued due to adverse events’
Time Frame	9 months
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
In the above analysis regarding The number of participants analyzed the ‘last observation carried forward’ principle is used, as pre-specified in the protocol.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs

Measured Values

	Guided by NT-proBNP	Not guided by NT-proBNP
Number of Participants Analyzed [units:participants]	127	125
Discontinuations [units: Participants]	8	6

No statistical analysis provided for Discontinuations

Serious Adverse Events

Time Frame	No text entered.
Additional Description	Only Serious Adverse Event were to be reported. Other Adverse Events (Non-Serious Adverse Events) were to be reported by investigators directly to MPA (Medical Product Agency) in accordance to local legislation.

Reporting Groups

	Description
Guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms, signs and NT-proBNP
Not guided by NT-proBNP	Chronic heart failure treatment guided by clinical symptoms and signs