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Trial registered on ANZCTR


Registration number
ACTRN12610000221055
Ethics application status
Approved
Date submitted
12/03/2010
Date registered
17/03/2010
Date last updated
11/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Standard vs Atrial Fibrillation spEcific managemenT studY
Scientific title
Patients with atrial fibrillation undergoing a disease-specific patient management intervention programme compared to standard care for the optimisation of health and well-being
Secondary ID [1] 1502 0
None
Universal Trial Number (UTN)
Trial acronym
SAFETY
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation 256890 0
Condition category
Condition code
Cardiovascular 257038 257038 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Atrial fibrillation-specific disease management programme involving improved understanding and delineation of a patient's underlying risk of thrombo-embolic events, progressive cardiac dysfunction and poorly controlled clinical status. This will be done via evaluation of haemodynamic and embolic risk and the optimisation of a patient's psychosocial adaptation to the requirements of pharmacotherapy for atrial fibrillation involving home visitation.
The approximately 2 hour home visit will be performed by a cardiac research nurse and will occur 7-14 days post-hospital discharge. The nurse will identify and address any areas that require improvement for the improvement of the patient's health status and well-being and reduction of cardiovascular risk factors (e.g. suggestion of a weight-loss intervention if the patient is overweight).
In addition, due to the heart rate focussed nature of atrial fibrillation, the nurse will visit the patient for approximately 30 minutes at 1 month, 3 months and 6 months to make sure that they are within their target heart rate that has been set by their physician. If not, the nurse will instigate action required to rectify this via lifestyle or pharmacological means.
At 12 months and 24 months, patients will have an approximately 2 hour, one-on-one clinic visit with a member of the research team to undergo and compare with baseline measurements, the following: their physical health, any medical issues that have arisen in the follow-up period, the electrical activity of the heart (using an electrocardiogram - ECG), how the heart is pumping (via echocardiography), their general clinical status (via pathology testing), the clinical status of their atrial fibrillation, their cognitive and functional capacity, and their mental health and well-being. A 24 hour continuous recording of the electrical activity of the heart that will be taken at baseline and 12 months via a Holter Monitor (which will be fitted by the cardiac nurse) will also be performed. In summary, these patients will be followed-up for a period of 24 months and the above measurements will be taken.
Intervention code [1] 256085 0
Treatment: Other
Intervention code [2] 256086 0
Lifestyle
Comparator / control treatment
Usual care involving the usual care that the patient's physician provides for the medical management of their atrial fibrillation. This will include management by the patient's general practicioner and a cardiologist. We will put no restrictions and make no suggestions as to these patients' management. Management of atrial fibrillation usually involves assessment on a case-by-case basis according to what is required to maintain a patient's health and well-being.
Control group
Active

Outcomes
Primary outcome [1] 257942 0
All-cause mortality or unplanned readmission. This will be assessed by accessing data from the National Death Index at the conclusion of the trial (for all-cause mortality) and medical records data (for unplanned readmission).
Timepoint [1] 257942 0
At baseline and 24 months post-randomisation
Secondary outcome [1] 263465 0
Cardiovascular-related morbidity and mortality (with a particular focus on events relating to stroke, heart failure and falls), duration and rate of hospital stay. Again, this will be assessed by accessing data from the National Death Index at the conclusion of the trial (for cardiovascular-related mortality) and Medicare and medical records data (for cardiovascular-related morbidity).
Timepoint [1] 263465 0
At baseline and 24 months post-randomisation
Secondary outcome [2] 263466 0
All-cause hospital stay rates which will be assessed by accessing medical records data.
Timepoint [2] 263466 0
At baseline and 24 months post-randomisation
Secondary outcome [3] 263467 0
Change in the cost of health care (health economic analysis) in both cohorts. This will be performed by accessing Medicare data for each patient for the life of the trial.
Timepoint [3] 263467 0
At baseline and 24 months post-randomisation
Secondary outcome [4] 263468 0
Change in health-related quality of life and function. Quality of life will be measured using the validated questionnaires Short Form-12 (SF-12) and EuroQol-5 Dimensions (EQ-5D). Cognitive function will be measured using the Montreal Cognitive Assessment tool (MOCA) and physical function will be measured using the 6-minute walk test.
Timepoint [4] 263468 0
At baseline and at 12 months and 24 months post-randomisation
Secondary outcome [5] 263469 0
Changes in left ventricular systolic and diastolic function. This will be measured using echocardiographic medical equipment operated by an echocardiographer.
Timepoint [5] 263469 0
At baseline and 24 months post-randomisation
Secondary outcome [6] 263470 0
Failure rate of treatment targets. Failure of heart rate target will be monitored by using a single channel ECG machine. Failure of pharmacological treatments will be measured simply as "is the medication controlling what it has been prescribed for?" - this will be "yes" or "no" and will be able to be determined in each follow-up visit by understanding that patient's health status.
Timepoint [6] 263470 0
Throughout study follow-up period

Eligibility
Key inclusion criteria
1. Documented diagnosis of sustained form of non-valvular atrial fibrillation
2. A minimum of one hospitalisation (including index admission) related, at least in part, to atrial fibrillation
3. Are living independently in the community or their own home post-hospitalisation
4. Are able and willing to provide written informed consent to participate in the trial
Minimum age
45 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Aged below 45 years
2. Have a diagnosis of valvular atrial fibrillation
3. Are scheduled for a catheter ablation for treatment of atrial fibrillation
4. Have evidence of pre-existing New York Heart Association (NYHA) Class III-IV with a documented left ventricular ejection fraction less than 45%
5. Have alcohol-induced atrial fibrillation
6. Have transient forms of atrial fibrillation associated with acute myocardial infarction and/or pericarditis
7. Have a terminal condition or malignancy requiring palliative care
8. Cannot adequately provide written informed consent to participate
9. Have any other medical condition that results in the belief that it is not appropriate for the patient to embark on participation within this study

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)
Central randomisation by telephone
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation with physician designated rate versus rhythm control (with accompanying heart rate target in both groups) used for stratification
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A detailed statistical analysis plan can be found at www.cre2rihd.org.au.

As per the pre-determined statistical analysis plan, the primary endpoint (unplanned hospitalisation or death – both all cause) will be treated as both a timed dichotomous variable (event-free versus event) and a continuous variable of days alive out-of-hospital. The latter will be calculated as a proportion of maximal follow-up (assuming no days lost to hospitalisation or death).

Sample size calculation were based on the assumption that 60% of subjects randomised to the standard care arm of the SAFETY Trial would experience a recurrent hospitalisation or fatal event during the 24 month follow-up (dichotomous primary endpoint of event versus event-free). Assuming an alpha (a) of 0.05, we calculated that a total of 320 patients (n = 160 in each group) would have 85% power (beta of 0.15) to detect a 25% relative difference in the primary endpoint (45% in the SAFETY intervention group) and >90% power (beta of 0.10) to detect a 30% difference (42% in the SAFETY intervention group). Ultimately, a total of 335 subjects were recruited into this study which allows for patient withdrawal, intention-to-treat analyses and sufficient power to compare days alive out-of-hospital and secondary endpoints relating to recurrent hospitalisation and stay.

Data for all participating sites will be pooled and summarised with respect to demographic and baseline characteristics. Exploratory data analyses will be performed using descriptive statistics. Data will be presented for the complete intent-to-treat (ITT) population. Efficacy analyses will be performed using the ITT population and analysis will be based on the treatment group that the subject is randomised to (i.e. SAFETY intervention or Standard Care). Statistical analysis and endpoint adjudication will be undertaken in a blinded manner by the Study Statistician.

Where appropriate, comparison of baseline and endpoint data will involve chi-square analysis (with calculation of odds ratio [OR] and 95 % confidence interval [CI]) for discrete variables, Student’s t-test for normally distributed continuous variables and Mann-Whitney U 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 endpoint) will be assessed using generalised linear models. Effect sizes will be reported. Kaplan-Meier survival curves will be constructed using time-dependent, all-cause survival and event-free survival data for all patients on an ITT basis. Survival data will be further analysed with both the log-rank test and the Breslow test to determine differences between groups with respect to the number and/or timing of events. Multivariate analyses will also be undertaken to examine the independent determinants of study endpoints.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,SA,VIC
Recruitment hospital [1] 2065 0
Western Hospital - Footscray
Recruitment hospital [2] 2066 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [3] 2067 0
The Canberra Hospital - Garran
Recruitment postcode(s) [1] 7764 0
2605 - Garran
Recruitment postcode(s) [2] 7762 0
3011 - Footscray
Recruitment postcode(s) [3] 7763 0
5011 - Woodville
Recruitment postcode(s) [4] 2617 0
Adelaide, Melbourne, Canberra

Funding & Sponsors
Funding source category [1] 256593 0
Government body
Name [1] 256593 0
NHMRC Program Grant
Address [1] 256593 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 256593 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Baker IDI Heart & Diabetes Institute
Address
75 Commercial Road
Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 255888 0
Hospital
Name [1] 255888 0
The Queen Elizabeth Hospital
Address [1] 255888 0
28 Woodville Road
Woodville South SA 5011
Country [1] 255888 0
Australia
Secondary sponsor category [2] 255889 0
University
Name [2] 255889 0
University of Queensland- School of Medicine
Address [2] 255889 0
Princess Alexandra Hospital
Ipswich Road
Woolloongabba QLD 4102
Country [2] 255889 0
Australia
Secondary sponsor category [3] 284361 0
Hospital
Name [3] 284361 0
The Western Hospital
Address [3] 284361 0
Gordon Street Footscray VIC 3011
Country [3] 284361 0
Australia
Secondary sponsor category [4] 284362 0
Hospital
Name [4] 284362 0
Canberra Hospital
Address [4] 284362 0
Clinical Trials Unit
Level 2, Building 1 Canberra Hospital
Yamba Drive Garran ACT 2605
Country [4] 284362 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258622 0
Central Northern Adelaide Health Service Ethics of Human Research Committee (The Queen Elizabeth Hospital [TQEH] & Lyell McEwin Hospital [LMH])
Ethics committee address [1] 258622 0
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South SA 5011
Ethics committee country [1] 258622 0
Australia
Date submitted for ethics approval [1] 258622 0
Approval date [1] 258622 0
05/03/2010
Ethics approval number [1] 258622 0
2010008
Ethics committee name [2] 258623 0
Metro South Health Service District Human Research Ethics Committee
Ethics committee address [2] 258623 0
Princess Alexandra Hospital
Ipswich Road
Woolloongabba QLD 4102
Ethics committee country [2] 258623 0
Australia
Date submitted for ethics approval [2] 258623 0
11/02/2010
Approval date [2] 258623 0
Ethics approval number [2] 258623 0
Ethics committee name [3] 287538 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [3] 287538 0
PO Royal Melbourne Hospital Parkville VIC 3050
Ethics committee country [3] 287538 0
Australia
Date submitted for ethics approval [3] 287538 0
01/01/2011
Approval date [3] 287538 0
16/02/2011
Ethics approval number [3] 287538 0
2010.268
Ethics committee name [4] 287539 0
ACT Government Health Directoralte Human Research Ethics Committee
Ethics committee address [4] 287539 0
Building 10, Level 6
The Canberra Hospital
PO Box 11 Woden ACT 2601
Ethics committee country [4] 287539 0
Australia
Date submitted for ethics approval [4] 287539 0
01/11/2011
Approval date [4] 287539 0
15/12/2011
Ethics approval number [4] 287539 0
ETHLR.12.014

Summary
Brief summary
The purpose of this trial is to understand the differences between a disease management program incorporating better risk identification and management, and atrial fibrillation-specific components of treatment designed to specifically improve health outcomes in patients with chronic, non-valvular forms of atrial fibrillation. Given that this represents an increasing patient population subject to complex treatment, it has the potential to deliver significant clinical benefits from an individual to a health care system perspective.
Therefore, SAFETY will test the hypothesis that in patients with chronic, non-valvular forms of atrial fibrillation, a specific program of enhanced risk identification and management (above conventional risk profiling) combined with an atrial fibrillation-specific form of chronic disease management will significantly reduce all-cause death and/or unplanned hospital readmission relative to standard medical care during a follow-up of 24 months.
Trial website
www.cre2rihd.org.au
Trial related presentations / publications
Publications:
Stewart S, Ball J, Horowitz JD, Marwick TH, Mahadevan G, Wong C, Abhayaratna WP, Chan YK, Esterman A, Thompson DR, Scuffham PA, Carrington MJ. Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial. Lancet 2015;385(9970):775-784.

Ball J, Thompson DR, Ski CF, Carrington MJ, Gerber T, Stewart S. Estimating the current and future prevalence of atrial fibrillation in the Australian adult population. Med J Aust 2014; accepted for publication.

Ball J, Carrington MJ, Thompson DR, Horowitz JD, Stewart S on behalf of the SAFETY Investigators. Post-discharge ECG Holter monitoring in recently hospitalised individuals with chronic atrial fibrillation to enhance therapeutic monitoring and identify potentially predictive phenotypes. Eur J Cardiovasc Nurs 2014; published online 14 August, 2014.

Ball J, Carrington MJ, McMurray JJV, Stewart S. Atrial fibrillation: Profile and burden of an evolving epidemic in the 21st century. Int J Cardiol 2013; 167:1807-24.

Ball J, Carrington MJ, Stewart S. Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart 2013; 99:542-7.

Ball J, Carrington MJ, Stewart S. Reply: diagnosing vascular mild cognitive impairment with atrial fibrillation remains a challenge. Heart 2013; 99:819-20.

Ball J, Carrington MJ, Wood KA, Stewart S. Women versus men with chronic atrial fibrillation: insights from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). PLoS ONE 2013; 8:e65795.

Ball J, Carrington MJ, Stewart S. A new or old solution to an old problem? Eur Heart J 2013; E-letter: published online 11 April, 2013.

Carrington MJ, Ball J, Horowitz JD, Marwick TH, Mahadevan G, Wong C, Abhayaratna WP, Haluska B, Thompson DR, Scuffham PA, Stewart S. Navigating the fine line between benefit and risk in chronic atrial fibrillation: Rationale and design of the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). Int J Cardiol 2013; 166:359-65.

World Congress of Cardiology, Melbourne - May 2014:
Ball J, Carrington MJ, Thompson DR, Horowitz JD, Stewart S. Post-discharge ECG Holter monitoring in recently hospitalised individuals with chronic atrial fibrillation to enhance therapeutic monitoring and identify potentially high risk phenotypes. Glob Heart 2014; 9(1S):e44-5 (Abstract O163).

Procter NEK, Ball J, Ngo D, Chirkov YY, Isenberg JS, Hylek EM, Stewart S, Horowitz JD. Is there a biochemical basis for differential thromboembolic risk in atrial fibrillation? Studies with platelet nitric oxide signalling. Glob Heart 2014; 9(1S):e240-1 (Abstract PT365).

European Society of Cardiology Congress, Munich - August 2012:
Ball J, Carrington MJ, Stewart S. Sub-optimal heart rate and rhythm control post-hospitalisation in high risk patients with chronic atrial fibrillation: the value of therapeutic ECG Holter monitoring. Eur Heart J 2012; 33(suppl_1):66 (Abstract P608).

Ball J, Carrington MJ, Stewart S. Impact of cognitive impairment on the management of patients with atrial fibrillation. Eur Heart J 2012; 33(suppl_1):183 (Abstract 1175).

Ball J, Carrington MJ, Stewart S. Optimising the management of high risk patients with atrial fibrillation: Promising signs from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). Eur Heart J 2012; 33(suppl_1):450 (Abstract P2638).

Ball J, Carrington MJ, Stewart S. Do clinical trial cohorts reflect the complexities of real-world patients with chronic atrial fibrillation? Eur Heart J 2012; 33(suppl_1):955 (Abstract 5234).

Procter NEK, Ball J, Carrington MJ, Nguyen TH, Ngo D, Chirkov YY, Stewart S, Horowitz JD. Determinants of platelet response to nitric oxide in association with atrial fibrillation: evidence for an acute suppression of response. Eur Heart J 2012; 33(suppl_1):376-7 (Abstract P2352).

Cardiac Society of Australia and New Zealand Annual Scientific Meeting 2012:
Ball J, Carrington MJ, Stewart S. Sub-optimal heart rate and rhythm control post-hospitalisation in high risk patients with chronic atrial fibrillation: the value of therapeutic ECG Holter monitoring. Heart Lung Circ 2012; 21(suppl_1):S133 (Abstract 326).

Ball J, Carrington MJ, Stewart S. Impact of cognitive impairment on the management of patients with atrial fibrillation. Heart Lung Circ 2012; 21(suppl_1):S304-5 (Abstract 739).

Ball J, Carrington MJ, Stewart S. Optimising the management of high risk patients with atrial fibrillation: Promising signs from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). Heart Lung Circ 2012; 21(suppl_1):S286-7 (Abstract 691).

Ball J, Carrington MJ, Stewart S. Do clinical trial cohorts reflect the complexities of real-world patients with chronic atrial fibrillation? Heart Lung Circ 2012(suppl_1): S248 (Abstract 597).

Procter NEK, Ball J, Carrington MJ, Nguyen H, Ngo D, Chirkov YY, Stewart S, Horowitz JD. Determinants of platelet response to nitric oxide in association with atrial fibrillation: evidence for an acute suppression of response. Heart Lung Circ 2012; 21(suppl_1):S247 (Abstract 596).

Australasian Cardiovascular Nursing College Annual Conference 2012:
Waite L, Ball J. Optimising the management of high risk patients with atrial fibrillation: Promising signs from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). Accepted for oral presentation.


American Heart Association (AHA) Scientific Sessions 2014
late-breaking Clinical Science Special Report - Results of the SAFETY Trial 17th November, 2014.

American Heart Association Annual Congress 2011:
Stewart S, Ball J, Carrington M. Optimizing the management of high risk patients with atrial fibrillation: Promising signs from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). Circulation 2011; 124(21 suppl_1):A11541
Public notes

Contacts
Principal investigator
Name 30883 0
Prof Simon Stewart
Address 30883 0
Mary MacKillop Institute for Health Research, Australian Catholic University
Level 5, 215 Spring St, Melbourne, VIC 3000
Country 30883 0
Australia
Phone 30883 0
+61399533677
Fax 30883 0
Email 30883 0
simon.stewart@acu.edu.au
Contact person for public queries
Name 14130 0
A/Prof Melinda Carrington
Address 14130 0
Mary MacKillop Institute for Health Research, Australian Catholic University
Level 5, 215 Spring St, Melbourne, VIC 3000
Country 14130 0
Australia
Phone 14130 0
+61399533688
Fax 14130 0
+61396635726
Email 14130 0
melinda.carrington@acu.edu.au
Contact person for scientific queries
Name 5058 0
Prof Simon Stewart
Address 5058 0
Mary MacKillop Institute for Health Research, Australian Catholic University
Level 5, 215 Spring St, Melbourne, VIC 3000
Country 5058 0
Australia
Phone 5058 0
+61399533677
Fax 5058 0
+61396635726
Email 5058 0
simon.stewart@acu.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary