Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12608000022369
Ethics application status
Approved
Date submitted
11/01/2008
Date registered
16/01/2008
Date last updated
11/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised study of a Nurse-led Intervention for Less Chronic Heart Failure: The NIL-CHF Study
Scientific title
A randomised study of a Nurse-led Intervention in patients with cardiovascular disease states who are at high risk of developing heart failure comparing all-cause mortality during 5-year follow-up.
Secondary ID [1] 253427 0
Nil known
Universal Trial Number (UTN)
Trial acronym
The NIL-CHF Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular disease 2704 0
Condition category
Condition code
Cardiovascular 2824 2824 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Specialist nurse-led multi-disciplinary, home and clinic based intervention involving comprehensive clinical assessment with application of gold-standard pharmacologic and non-pharmacologic therapy, promotion of self-care behaviours and enhanced surveillance & facilitated access to cardiac nurse in order to maximise patients' cardiac, renal and neurological function. The intervention follow-up period for participants will be 3.5 years in total.
Intervention code [1] 2442 0
Treatment: Other
Comparator / control treatment
The control treatment is "usual care" following discharge from hospital which involves follow-up with GP and specialist physicians in out-patients as required.
Control group
Active

Outcomes
Primary outcome [1] 3710 0
Event-free from all cause mortality or chronic heart failure related hospitalisation
Timepoint [1] 3710 0
Interventions will be performed following discharge from hospital (7 to 14 days after discharge) with one and two year annual follow-up clinic assessments and a final assessment at 3 years for all patients. Each visit will be 1 to 1.5 hours duration.
Secondary outcome [1] 6288 0
Quality of life, functional status and satisfaction with overall healthcare using the SF-12, EQ-5D (quality of life tools).
Timepoint [1] 6288 0
After discharge from hospital and one annual assessment for 3 years follow-up.
Secondary outcome [2] 6289 0
Cognitive function (using the Montreal Cognitive Assessment Tool)
Timepoint [2] 6289 0
After discharge from hospital and one annual assessment for 3 years follow-up.
Secondary outcome [3] 6290 0
Mental health status (using the Arrol screening tool for depression and the CES depression scale).
Timepoint [3] 6290 0
After discharge from hospital and one annual assessment for 3 years follow-up.
Secondary outcome [4] 308323 0
Cardiac function as assessed by echocardiography (blinded acquisition and adjudication) according to 5 pre-specified criteria. Change from baseline to 3 years assessed according to: a) no change, b) progressive dysfunction or c) reversal/recovery of cardiac function
Timepoint [4] 308323 0
Baseline and 3 year assessments
Secondary outcome [5] 308324 0
All hospitalisations and related hospital stay including unplanned / emergency admissions and cardiovascular-related admissions.

All hospitalisation data were collected based on standardised data collection (with data linkage to patient medical records including clinical notes and hospital discharge summaries). Self-report data and information from each subject’s GP were also triangulated with this information to ensure capture of hospital admissions to interstate or private hospitals.
Timepoint [5] 308324 0
Entire study follow-up (41 - 66 months)

Eligibility
Key inclusion criteria
All elective and emergency patients admitted to the Alfred Hospital, Melbourne. Eligible for study if (i) discharged to home (ii) have a diagnosis of one of the common forms of cardiovascular disease or being actively treated for either of the 2 most common heart failure antecedents other than coronary heart disease (eg diabetes, metabolic syndrome or hypertension)
Minimum age
45 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Diagnosed with congenital condition, have surgically repairable or significant valvular disease, have a terminal malignancy, live beyond a 45km radius from the hospital or have an acute coronary event (eg acute myocardial infarction) within previous 30 days.
Further exclusion of those randomised subjects who experience a HF-related hospitalisation prior to the 30-35 day advanced clinical assessment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A blinded, randomisation protocol (using SPSS 14.0) at the Preventative Cardiology Unit at the Baker, will allocate eligible patients to the study intervention or usual care group (on a 1:1 basis). The allocation will be performed centrally by phone. To minimise a potentially critical imbalance between groups in respect to future risk of developing symptomatic CHF, sequence generation randomisation will ensure that the two study groups contain equal numbers of patients prospectively classified into the 5 groups based on the results of their echocardiogram.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified allocation. Patients will be allocated depending on the results of their echocardiograms (hence, stratified).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Study hypothesis

The NIL-CHF Study will test the hypothesis that relative to usual post-discharge hospital and primary care, a nurse-led, multidisciplinary management program for hospitalized patients aged greater than or equal to 45 years with pre-existing CVD (but not CHF) and/or common antecedents of CHF, that implements gold-standard pharmacological and non-pharmacological therapy directed by advanced risk assessment and monitoring to achieve optimal cardiac, renal and neurological protection, will reduce the incidence of admission for CHF or all-cause mortality (composite end-point) by a clinically significant amount (40% relative difference) during 3 to 5 years follow-up.

Study Follow-up & Data Acquisition

Recruitment for the NIL-CHF Study commenced in 1st June 2008 – the first randomised subject being discharged from their index admission on 13th June 2008. The last subject was discharged from hospital on 21st July 2010 (a 25 month recruitment window).

Two structured visits were applied (wherever possible and in a dedicated trial clinic) to the entire study cohort for the purpose of assessing definitive study eligibility and for determining the major secondary endpoint relating to extent of cardiac dysfunction in the medium-to-longer term. The first visit occurred within a window of 30-35 days post index hospital discharge and the second at 3 years post-index hospital discharge (close as possible to calendar date). Personnel blinded to study allocation acquired study data.

With censoring of all study endpoints relating to mortality and hospitalisation on the 30th December 2013, maximum and minimum possible study follow-up was 2026 days (66 months/5.5 years) and 1259 days (41 months), respectively.

All subjects were followed-up directly or via their nominated next of kin or primary care physician to determine their survival status and to cross-check all and any hospital events occurring during study follow-up. The latter were determined via clinical notes and electronic records documenting the precipitating factors, procedures and diagnoses (primary and secondary).

All data were collected on standardised case-report forms, definitive study status and study endpoint data acquisition will occur in the 3 months (to the 31st March 2014) following the census date.

Definition of Major Study End-points

The primary endpoint (all-cause mortality or de novo heart failure hospitalisation) will predominantly rely on adjudication of hospital episodes. Initially, these will be classified as follows:

1. Day hospitalisation (not including an overnight stay) adjudicated on the following basis:
a. Minor/day surgery procedure undertaken on an elective basis
b. Emergency/unplanned admission
2. Overnight hospitalisation (minimum one night and counted as 2 days) adjudicated on the following basis:
a. Elective/pre-arranged admission (typically for surgery or minor procedure)
b. Emergency admission

Based on standardised data collection (including clinical notes and hospital discharge summary), blinded adjudication will further classify hospital episodes as follows:

* Cardiovascular-related versus non-cardiovascular related hospitalisation

If a cardiovascular-related overnight hospitalisation, each episode will be classified (blinded adjudication) as follows:

* Heart failure-related (as per contemporary Australian guidelines)
* Acute coronary syndrome-related and, specifically, acute myocardial infarction (ST-segment and non-ST elevated AMI) according to ESC guidelines
* Stroke-related (ischaemic versus haemorrhagic) according to ESC guidelines

All recorded hospital events will be further coded using the MedDRA dictionary (Version 12.0).

All echocardiographic data were obtained by a highly experienced sonographer who undertook blinded 2D echocardiography assessments (with further blinded review by a consultant cardiologist and his team) of all NIL-CHF subjects who attended a dedicated clinic at baseline (30-35 days post index admission) and at 3 years (an additional clinic visit was performed at 18 months for intervention subjects).

We will evaluate changes in each subject’s cardiac function according to five prospectively defined criteria:

1) no evidence of a cardiac abnormality, 2) systolic dysfunction as defined by left ventricular ejection fraction (LVEF) less than or equal to 45% (asymptomatic at baseline), 3) diastolic dysfunction as defined by any moderate diastolic dysfunction (with pseudonormalization pattern) and above or mild diastolic dysfunction with elevated filling pressure (E/E prime ratio greater than or equal to 15) - also asymptomatic at baseline, 4) combination of systolic and diastolic dysfunction (2 & 3), and 5) other cardiac abnormality (other than 2 & 3) including at least mild-moderate cardiac abnormalities OR presence of left ventricular hypertrophy (LVH) defined by 2D LV Interventricular Septal thickness at diastole (IVSd) of >1.1 cm and 2D LV Posterior Wall Dimension end diastolic (PWDd) of >1.1 cm and/or presence of septal hypertrophy.

Given differential patterns of cardiac function at baseline (e.g. significantly more subjects in the intervention group displayed asymptomatic LVSD) we will examine the Echocardiographic status of subjects on the following basis from baseline to 3 years:

1. Status quo – no change in classification according to the key criteria outlined above; particularly in respect to reversal of systolic and diastolic dysfunction and presence of LVH.
2. Progressive dysfunction – those subjects who had normal cardiac function at baseline but demonstrated dysfunction at 3 years.
3. Reversal/Recovery – those subjects who had any form of dysfunction (e.g. LVSD and/or LVH) at baseline but this was absent at 3 years (including those who now show normal cardiac function).

Standardised tools and procedures will be used to assess baseline to 3-year changes in the following parameters:

* Health-related quality of life measured via the SF-12 and EQ-5D
* Functional capacity: six-minute walk test and self-reported exercise measured via the IPAQ
* Depressive symptoms measured via the Arrol tool
* Cognitive function measured via the Montreal Cognitive Assessment tool

In order of priority, study endpoints will be analysed and reported on the following-basis:

1. Primary endpoint of freedom from death or de novo heart failure-related hospitalisation during the entire period of study follow-up
2. Secondary endpoints relating to hospital events and stay (cardiovascular versus non-cardiovascular and occurring on an unplanned basis)
3. Comparison of cardiac function (based on echocardiographic comparisons) at 3 years
4. Clinical and functional parameters measured at 3 years.

Pre-specified sub-group analysis

Whilst acknowledging the negative implications for study power and post-hoc nature of such analyses, the following sub-groups will be of particular interest to determine potentially important differences in the impact of the study intervention:
* Men versus women
* Baseline CAD versus rest
* Asymptomatic systolic and/or diastolic dysfunction at baseline

Study Power

We previously used outcome data from our previous research to conservatively estimate that the composite primary end-point would occur in > 20% of UC patients (15% incident CHF admission and 5% death without prior CHF admission) over a median of 4.5 years.

Original recruitment projections called for >900 subjects to adequately address the study hypothesis. As per the index study report a revised target of 750 subjects was established following initial recruitment patterns. Ultimately, a total of 624 of eligible subjects were recruited into this study. On this basis, we retrospectively calculated that with a minimum of 300 patients in each group (approximately 600 in total) has > 80% power to detect a 40% variation or > 85% power to detect a 35% variation in clinically significant difference in the primary endpoint between the two groups while allowing for patient drop-out, intention-to-treat analyses and power to compare secondary endpoints.

Statistical Analyses

Efficacy analyses will be performed using the intent-to-treat population (ITT), which will consist of all subjects randomized to a study intervention arm and were not readmitted within 35 days with a heart-failure related hospitalisation. Analysis will be based on the treatment the subject is randomized to.

The primary endpoint will be treated as a binary variable.

Hospitalisation data will be treated as a binary variable (yes or no to different types of hospitalisation) and consistent with our previously reported trials, the rate of hospital episodes (events per patient per month of follow-up) and related hospital stay (days per patient per month of follow-up) will be calculated to adjust for individual study follow-up.

If appropriate, a combination of survival and hospitalisation data will be used to calculate days alive and event-free from all unplanned and cardiovascular-related hospitalisation.

Where appropriate, comparison of baseline and end-point data will involve Chi-square analysis (with calculation of OR and 95% CI) for discrete variables, Student’s t test for normally distributed continuous variables and Mann-Whitney test (or Wilcoxon signed rank test where appropriate) for non-normally distributed variables. If event rates are highly skewed, differences between event rates per month by group (including the primary end point) will be assessed using generalized linear models. Effect sizes will be reported.

Kaplan-Meier survival curves will also be constructed using time-dependent, all-cause survival and event-free survival data for all patients on an intention-to-treat basis. Survival data will be further analysed with both the log-rank test and the Breslow test to determine any difference between groups in respect to the number and/or timing of events.

To examine the various interactions between risk factors, treatment mode and other potential correlates (i.e. study centre) of event-free survival and all-cause mortality during study follow-up, we will construct Cox-Proportional Hazards Models with calculation of HR and 95% CI.

Health Economic Analysis

Depending on study outcomes, a cost-effectiveness analysis will calculate the incremental costs per QALY gained as well as other natural outcomes (e.g. hospitalisation averted). Prospectively collated health care costs for each group will be summed and divided to calculate cost per patient-month (and patient-year). The scoring algorithms for the EQ-5D and the SF-12 (i.e. the SF-6D) will be used to convert patient scores into (Australian-specific) utility weights and, hence, to calculate QALYs. The evaluation will adhere to the recommendations of the Washington Panel on Cost-effectiveness in Health and Medicine.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/02/2008
Actual
12/06/2008
Date of last participant enrolment
Anticipated
Actual
12/07/2010
Date of last data collection
Anticipated
Actual
Sample size
Target
624
Accrual to date
Final
624
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 545 0
3004

Funding & Sponsors
Funding source category [1] 2956 0
Government body
Name [1] 2956 0
NHMRC
Country [1] 2956 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Baker IDI Heart and Diabetes Institute
Address
Preventive Cardiology,
75 Commercial Road,
Melbourne 3004
Country
Australia
Secondary sponsor category [1] 2669 0
Charities/Societies/Foundations
Name [1] 2669 0
NHMRC
Address [1] 2669 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 2669 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 4897 0
Bayside Health Human Ethics Committee
Ethics committee address [1] 4897 0
Ethics committee country [1] 4897 0
Australia
Date submitted for ethics approval [1] 4897 0
01/12/2007
Approval date [1] 4897 0
03/03/2008
Ethics approval number [1] 4897 0
262/07

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 28291 0
Prof Simon Stewart
Address 28291 0
Mary MacKillop Institute for Health Research, Australian Catholic University
Level 5, 215 Spring St, Melbourne, VIC 3000
Country 28291 0
Australia
Phone 28291 0
+61399533677
Fax 28291 0
+61396635726
Email 28291 0
[email protected]
Contact person for public queries
Name 11448 0
Melinda Carrington
Address 11448 0
Mary MacKillop Institute for Health Research, Australian Catholic University
Level 5, 215 Spring St, Melbourne, VIC 3000
Country 11448 0
Australia
Phone 11448 0
+61399533688
Fax 11448 0
+61396635726
Email 11448 0
[email protected]
Contact person for scientific queries
Name 2376 0
Melinda Carrington
Address 2376 0
Mary MacKillop Institute for Health Research, Australian Catholic University
Level 5, 215 Spring St, Melbourne, VIC 3000
Country 2376 0
Australia
Phone 2376 0
+61399533688
Fax 2376 0
+61396635726
Email 2376 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseImpact of a nurse-led home and clinic-based secondary prevention programme to prevent progressive cardiac dysfunction in high-risk individuals: The Nurse-led Intervention for Less Chronic Heart Failure (NIL-CHF) randomized controlled study.2015https://dx.doi.org/10.1002/ejhf.272
N.B. These documents automatically identified may not have been verified by the study sponsor.