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Trial registered on ANZCTR


Registration number
ACTRN12613001376730
Ethics application status
Not yet submitted
Date submitted
11/12/2013
Date registered
16/12/2013
Date last updated
16/12/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating a new approach to re-starting Warfarin after Surgery
Scientific title
A prospective, randomised comparison in hospitalised patients re-commenced on warfarin post-operatively at the usual maintenance dose versus a loading dose strategy to assess time to a stable therapeutic INR.
Secondary ID [1] 283758 0
Nil known
Universal Trial Number (UTN)
U1111-1151-2779
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Re-commencing post-operative warfarin 290732 0
elective surgery 290733 0
Condition category
Condition code
Surgery 291095 291095 0 0
Other surgery
Blood 291121 291121 0 0
Other blood disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Guidelines uniformly recommend pre-operative cessation/reversal of the anticoagulant warfarin to ensure an INR <1.5 prior to surgery. Warfarin is recommenced orally on the night of surgery at the prior known maintenance dose. The patient has often been discharged prior to achieving a stable therapeutic INR, and is commonly followed by a hospital-based extended care service until this occurs. This requires daily point-of-care INR monitoring and bridging anticoagulation, usually with a low-molecular weight heparin. This study utilises the fact that the response to a warfarin loading dose is proportional to the maintenance dose to explore the utility of a structured loading dose strategy in these patients to shorten the time to re-achieve a stable therapeutic INR. This would decrease the use of bridging anticoagulation and shorten the length-of-stay under extended care services. The oral loading dose strategy uses twice the Standardised Maintenance Dose daily for the first 3 days of re-commencement (commencing on the night of surgery) and returning to the normal maintenance dose on the 4th day, where the Standardised Maintenance Dose is 2.5 x current dose / current INR. The new loading dose strategy will be compared to current guideline recommendations in a non-blinded, randomised study. Medication adherence will not be monitored.
Intervention code [1] 288444 0
Treatment: Drugs
Intervention code [2] 288445 0
Treatment: Surgery
Comparator / control treatment
Patients undergoing surgery who are re-commenced on warfarin at their prior maintenance dose according to current guidelines. Re-commencement will occur on the night of surgery.
Control group
Active

Outcomes
Primary outcome [1] 291078 0
Time to achieve a stable therapeutic INR (range 2-3) where a stable INR is the first INR of two consecutive daily INRs in the therapeutic range or the first INR in the therapeutic range where the previous INR was within 0.5
Timepoint [1] 291078 0
achievement of stable therapeutic INR
Secondary outcome [1] 305977 0
episodes of overanticoagulation (INR>=4) prior to achieving a stable therapeutic INR
Timepoint [1] 305977 0
achievement of a stable therapeutic INR
Secondary outcome [2] 305978 0
Length of stay under Hospital at Home care
Timepoint [2] 305978 0
achievement of a stable therapeutic INR
Secondary outcome [3] 305979 0
Subgroups analysis of patients commenced on drugs known to interact with warfarin that are commenced during the induction period. This will be separated into two groups - interacting drugs known to increase the response to warfarin (elevate the INR) and drugs known to decrease the efficacy of warfarin. All new post-operative drug use during warfarin re-commencement will be recorded.
Timepoint [3] 305979 0
achievement of a stable therapeutic INR
Secondary outcome [4] 305980 0
Sub-group analysis of patients maintained on daily doses (measured as the Standardised Maintenance Dose) of <2mg
Timepoint [4] 305980 0
achievement of a stable therapeutic INR
Secondary outcome [5] 305981 0
Sub-group analysis of patients maintained on daily doses (measured as the Standardised Maintenance Dose) of >7.5mg
Timepoint [5] 305981 0
achievement of a stable therapeutic INR

Eligibility
Key inclusion criteria
> 18 years old, receiving ongoing warfarin therapy, undergoing elective surgery, able to provide written, informed consent, and followed-up by Hospital-at-Home services for INR monitoring
Minimum age
18 Years
Maximum age
100 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unable to provide written, informed consent
Not followed-up by Hospital-at-Home until a stable therapeutic INR is achieved
Undergoing cardiac surgery (note – patients with pre-existing artificial mitral or aortic valves are eligible as long as the surgery is not cardiac)
Surgery expected to grossly prevent normal oral intake in the week post-operatively eg colon resection
Use of more than 2 mg of vitamin K, fresh frozen plasma, or Prothrombinex-VT for INR reversal immediately pre-operatively
Use of any vitamin K, fresh frozen plasma, or Prothrombinex for INR reversal in the week after surgery, prior to a stable therapeutic INR being achieved. Normal blood transfusions are permissible and will be considered as a sub-group.
Commencement of regular therapy with drugs known to interact with warfarin in the period between the most recently measured maintenance INR and the commencement of surgery, excluding routine drugs administered immediately prior to surgery, such as antibiotic prophylaxis. This includes, imidazole antifungals, macrolide antibiotics, fluoroquinolones, amiodarone, omeprazole, metronidazole, cholestyramine, carbamazepine, phenytoin, barbiturates, rifampicin, sulfamethoxizole/trimpethoprim, SSRI’s, thyroxine, NSAIDs.
Lack of reliable INR results with corresponding maintenance dose
Most recent routine maintenance dose INR below 1.5 or above 3.5 for patients with a therapeutic range of 2-3, or above 4.0 for patients with a therapeutic range of 2.5-3.5
Warfarin reversed during warfarin re-commencement period due to unexpected return to theatre

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)
Patients recieving ongoing warfarin management requiring elective surgery will be approached pre-operatively. Consenting patients will be randomised to either normal warfarin re-commencement or a loading dose strategy. The allocation will not be blinded to patient or staff.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A patient allocation chart will be drawn up where the sequence generation will be stratified in blocks of four using the toss of a coin. Patients will be entered into the study as consecutive patients on the allocation chart.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Time to reach a stable INR will be assessed with survival analysis and co-variants analysed using Cox’s F-test. The chi-square test will be used for non-parametric data, Student’s t test for parametric data. P values are considered significant at less than 0.05.
Previous local data from patients who were commenced on doses equivalent to their eventual maintenance dose indicate a median time to stable INR of 6 days (50% of patients in range at 6 days). For the test group we aim to have at least 70% of patients in the therapeutic range by then. This requires 93 patients in each group (at beta=0.8, alpha=0.5). For a safety endpoint, this would also enable us to detect up to an 8% absolute increase in episodes of overanticoagulation (INR>4), assuming there are no episodes of overanticoagulation using the national guideline approach.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2014
Actual
Date of last participant enrolment
Anticipated
1/05/2015
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
186
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 1854 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 1855 0
Repatriation Hospital - Daw Park
Recruitment postcode(s) [1] 7637 0
5042 - Bedford Park
Recruitment postcode(s) [2] 7638 0
5041 - Daw Park

Funding & Sponsors
Funding source category [1] 288424 0
Hospital
Name [1] 288424 0
Flinders Medical Centre
Country [1] 288424 0
Australia
Primary sponsor type
Hospital
Name
Flinders Medical Centre
Address
Flinders Drive
Bedford Park SA 5042
Country
Australia
Secondary sponsor category [1] 287129 0
None
Name [1] 287129 0
Address [1] 287129 0
Country [1] 287129 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 290300 0
Southern Adelaide Combined Human Research Ethics Committee
Ethics committee address [1] 290300 0
Ethics committee country [1] 290300 0
Australia
Date submitted for ethics approval [1] 290300 0
28/11/2013
Approval date [1] 290300 0
Ethics approval number [1] 290300 0
EC00188

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

Contacts
Principal investigator
Name 44946 0
Mr Greg Roberts
Address 44946 0
Pharmacy Department
Flinders Drive
Flinders Medical Centre
Bedford Park SA 5042
Country 44946 0
Australia
Phone 44946 0
61 8 82046655
Fax 44946 0
Email 44946 0
greg.roberts2@health.sa.gov.au
Contact person for public queries
Name 44947 0
Greg Roberts
Address 44947 0
Pharmacy Department
Flinders Medical Centre
Flinders Drive
Bedford Park SA 5042
Country 44947 0
Australia
Phone 44947 0
61 8 82046655
Fax 44947 0
Email 44947 0
greg.roberts2@health.sa.gov.au
Contact person for scientific queries
Name 44948 0
Greg Roberts
Address 44948 0
Pharmacy Department
Flinders Medical Centre
Flinders Drive
Bedford Park SA 5042
Country 44948 0
Australia
Phone 44948 0
61 8 82046655
Fax 44948 0
Email 44948 0
greg.roberts2@health.sa.gov.au

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
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Documents added automatically
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