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Trial registered on ANZCTR


Registration number
ACTRN12618000185268
Ethics application status
Approved
Date submitted
29/01/2018
Date registered
5/02/2018
Date last updated
18/09/2019
Date data sharing statement initially provided
11/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Influence of Non-Anaemic Iron Deficiency on Outcomes Following Cardiac Surgery
Scientific title
A prospective, observational study to determine if non-anaemic iron deficiency increases hospital stay and decreases days alive and at home in patients undergoing elective cardiac surgery.
Secondary ID [1] 293893 0
HREC/Austin/16/308
Universal Trial Number (UTN)
U1111-1208-6520
Trial acronym
IDOCS
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Iron deficiency 306364 0
Cardiac surgical patients 306365 0
Perioperative optimisation of elective surgery patients 306366 0
Condition category
Condition code
Blood 305448 305448 0 0
Other blood disorders
Cardiovascular 305449 305449 0 0
Coronary heart disease
Anaesthesiology 305450 305450 0 0
Other anaesthesiology
Cardiovascular 305487 305487 0 0
Other cardiovascular diseases
Surgery 305488 305488 0 0
Other surgery
Metabolic and Endocrine 305489 305489 0 0
Other metabolic disorders
Diet and Nutrition 305490 305490 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Elective cardiac surgical patients with non-anaemic iron deficiency at time of surgical booking.
Intervention code [1] 300163 0
Diagnosis / Prognosis
Comparator / control treatment
Elective cardiac surgical patients classified as non-anaemic, iron replete at time of surgical booking, with observation up to 90 days postoperatively.
Control group
Active

Outcomes
Primary outcome [1] 304594 0
Days alive and out of hospital at post-operative day 30, assessed by data linkage to the medical record and study specific questionnaire.
Timepoint [1] 304594 0
30 days following induction of anaesthesia for primary surgical procedure.
Secondary outcome [1] 342472 0
Total number of days spent in ICU during the initial inpatient stay, assessed by data linkage to the medical record and study specific questionnaire.
Timepoint [1] 342472 0
Initial inpatient stay hospital discharge.
Secondary outcome [2] 342473 0
Total length of acute hospital stay during study, assessed by data linkage to the medical record and study specific questionnaire.
Timepoint [2] 342473 0
90 days after induction of anaesthesia for the primary surgical procedure.
Secondary outcome [3] 342474 0
Functional status as measured by EQ-5D-5L.
Timepoint [3] 342474 0
Baseline and post-operative day 30.
Secondary outcome [4] 342475 0
Disability status as measured by WHODAS 2.0.
Timepoint [4] 342475 0
Baseline and post-operative day 90.
Secondary outcome [5] 342476 0
Post-operative recovery as measured by QoR-15.
Timepoint [5] 342476 0
Post-operative day 3.
Secondary outcome [6] 342477 0
Mortality.
Timepoint [6] 342477 0
90 days following induction of anaesthesia for the primary surgical procedure.
Secondary outcome [7] 342478 0
Units of allogeneic blood transfused, as assessed by data linkage to the medical record.
Timepoint [7] 342478 0
30 days following induction of anaesthesia for the primary surgical procedure.
Secondary outcome [8] 342479 0
Surgical site infection rate, defined by the Centers for Disease Control and Prevention (CDC) with the National Healthcare safety Network (NHSN) criteria, and assessed using data linkage to the medical record.
Timepoint [8] 342479 0
30 days following induction of anaesthesia for index procedure.
Secondary outcome [9] 342480 0
Days alive and out of hospital at post-operative day 90 as assessed by data linkage to the medical record and study specific questionnaire.
Timepoint [9] 342480 0
90 days following induction of anaesthesia for the primary surgical procedure.

Eligibility
Key inclusion criteria
Patients scheduled to undergo elective cardiac surgery.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Emergency or inpatient surgery.
Pregnancy.
Age < 18 years.
Known or suspected haemoglobinopathy.
Bone marrow disease.
Haemochromatosis.
End stage renal failure requiring dialysis.
Erythropoetin or iron (IV or oral) in the preceding 4 weeks prior to enrolment.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Case control
Timing
Prospective
Statistical methods / analysis
SAMPLE SIZE

Sample size was calculated using data from a pilot study performed by our group (Miles LF, et al. Postoperative outcomes following cardiac surgery in non-anaemic iron-replete and iron-deficient patients - an exploratory study. Anaesthesia, 2017; Epub ahead of print).
The primary endpoint (DAOH) has a left-skewed distribution with a spike at 0, mainly due to deaths in hospital post-surgery. Power was obtained by simulations (B = 20,000). DAOH-looking data were generated by simulating first length of stay (LOS) using a lognormal distribution, truncating it at 28 days (a plausible maximum based on existing data) and finally computing DAOH as 28 minus LOS. Such data are bimodal with a spike at 0 as required. The lognormal distribution was calibrated to generate DAOH with a median of 23 days and 5% zeroes in the control arm. A sample size of n = 480 (240/arm) has respectively 83% power to detect a median increase of 1.25 days using the Wilcoxon sum rank test for the analysis.

STATISTICAL ANALYSIS OF STUDY DATA

Continuous baseline variables will be analysed using Student’s T-test or Wilcoxon rank-sum test depending on normality. The chi-squared test or Fisher's exact test will be used for categorical endpoints.

The primary outcome measure, DAOH-30, will be modelled using median or, more generally, quantile regression. As DAOH-30 is left skewed with a spike at zero, it is more relevant to model the median (or alternatively, the 75th percentile) that is closer to the major distribution mode and directly interpretable. Difference in median DAOH between the two groups (patients with iron deficiency versus those who are iron replete) will be adjusted for potential known confounders (e.g. age, sex, haemoglobin, eGFR, etc.). A propensity score analysis will also be carried out.

A similar strategy will be used for DAOH-90 to assess whether findings are consistent over time. Binary outcomes will be analysed using logistic regression. Results will be expressed as odds ratios and 95% CI. Quality of life (QoL) scores like QoR-15 and EQ-5D-5L at 30 days will be treated like continuous outcomes and analysed using linear regression adjusted for the baseline reading. A repeated measures analysis based on mixed linear models will also be conducted to include QoL at 90 days. Time-to-event (disability free survival) will be analysed using Cox proportional hazard regression. Similar adjustment to the primary outcome will be carried out for all secondary endpoints. Safety endpoints will be tabulated and compared using exact logistic regression as number are like to be small and ideally we would like to adjust for potential confounders (non-randomised comparison).

Recruitment
Recruitment status
Recruiting
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)
VIC
Recruitment hospital [1] 9891 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 9892 0
The Alfred - Prahran
Recruitment postcode(s) [1] 18697 0
3084 - Heidelberg
Recruitment postcode(s) [2] 18698 0
3004 - Prahran

Funding & Sponsors
Funding source category [1] 298516 0
Charities/Societies/Foundations
Name [1] 298516 0
ANZCA Research Foundation
Address [1] 298516 0
PO Box 6095
Melbourne VIC 3004
Country [1] 298516 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
HEIDELBERG VIC 3084
Country
Australia
Secondary sponsor category [1] 297664 0
None
Name [1] 297664 0
Not applicable
Address [1] 297664 0
Not applicable
Country [1] 297664 0
Other collaborator category [1] 279920 0
University
Name [1] 279920 0
Anaesthesia, Perioperative and Pain Medicine Unit, University of Melbourne
Address [1] 279920 0
C/O Melbourne Medical School
The University of Melbourne
Grattan Street
PARKVILLE VIC 3010
Country [1] 279920 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299494 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 299494 0
Office for Research
Level 8, Lance Townsend Building
145 Studley Road
HEIDELBERG VIC 3084
Ethics committee country [1] 299494 0
Australia
Date submitted for ethics approval [1] 299494 0
03/08/2016
Approval date [1] 299494 0
06/10/2016
Ethics approval number [1] 299494 0
HREC/Austin/16/308

Summary
Brief summary
Adequate iron stores are essential for the ability of the body to produce new red blood cells, and the key component of those red blood cells, haemoglobin. A low blood concentration of haemoglobin is referred to as “anaemia”, and is often due to low iron stores, or an inability for the bone marrow to access them. This latter phenomenon is referred to as “iron deficiency”. Iron deficiency and anaemic may exist in a patient separately, or together. A combination of the two is termed “iron deficiency anaemia”, and patients with the condition are said to be “anaemic”.

Iron deficiency anaemia has long been associated with worse outcomes for patients undergoing cardiac surgery. Compared to a normal person, the patient with iron deficiency anaemia has a higher risk of requiring a blood transfusion, sustaining a kidney injury, or dying following their operation.

There is another group that, up until now, has been poorly studied: those patients who are iron deficient, but not anaemic. Whilst these patients may have a normal haemoglobin concentration in their blood prior to surgery, inevitable blood loss during surgery and the inflammation during and afterwards causes the haemoglobin concentration to fall. If the patient has inadequate stores of iron, or is unable to access those stores, these patients will be unable to increase their production of haemoglobin. Hypothetically, these patients are at risk of many of the complications that patients with anaemia prior to their operation will face. However, because this research question is yet to be formally studied, it is not known whether or not this is correct.

Proposed trial and investigators

The IDOCS study has been designed to test this theory. Patients with iron deficiency, but who are not anaemic before their operation will be followed during and after their surgery and compared to a cohort of normal patients (who are iron replete and not anaemic) as a reference point. If the trial hypothesis is correct, patients who are iron deficient but not anaemic will have worse outcomes than those patients who are not anaemic and iron replete.

IDOCS will be undertaken at two major tertiary hospitals in Melbourne: The Alfred and the Austin Hospital.


Significance

If the hypothesis of IDOCS is proven, it will identify a new group of patients who are at risk of poor outcomes following cardiac surgery, opens an exciting new frontier in preparing patients for these procedures, and improving survival and reducing complications from the operation.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2401 2401 0 0
/AnzctrAttachments/374387-IDOCS Ethics Approval.rtf (Ethics approval)

Contacts
Principal investigator
Name 80606 0
Dr Lachlan Miles
Address 80606 0
Department of Anaesthesia, Austin Health
Level 2, Austin Tower
HEIDELBERG VIC 3084
Country 80606 0
Australia
Phone 80606 0
+61394965704
Fax 80606 0
+61394596421
Email 80606 0
Lachlan.MILES@austin.org.au
Contact person for public queries
Name 80607 0
Ms Sarah Baulch
Address 80607 0
Department of Anaesthesia, Austin Health
Level 2, Austin Tower
HEIDELBERG VIC 3084
Country 80607 0
Australia
Phone 80607 0
+61394965704
Fax 80607 0
+61394596421
Email 80607 0
Sarah.BAULCH@austin.org.au
Contact person for scientific queries
Name 80608 0
Dr Lachlan Miles
Address 80608 0
Department of Anaesthesia, Austin Health
Level 2, Austin Tower
HEIDELBERG VIC 3084
Country 80608 0
Australia
Phone 80608 0
+61394965704
Fax 80608 0
+61394596421
Email 80608 0
Lachlan.MILES@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data relating to participant demographics and outcomes. No data that may be used to re-identify participants will be shared.
When will data be available (start and end dates)?
Data will be available after the publication of the primary manuscript resulting from the study (anticipated Dec. 2021). End date of IPD availability will be 7 years after the study concludes.
Available to whom?
Academic authors. Requests from industry unaffiliated with an academic body such as a University will not be considered.
Available for what types of analyses?
Meta-analysis and systematic review.
How or where can data be obtained?
Electronic transfer.
What supporting documents are/will be available?
No other documents available
Summary results
No Results