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Trial registered on ANZCTR


Registration number
ACTRN12613000818730
Ethics application status
Not yet submitted
Date submitted
15/07/2013
Date registered
24/07/2013
Date last updated
25/03/2021
Date data sharing statement initially provided
25/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Prospective Study on Warfarin Management Post Heart Valve Replacement or Heart Valve Repair Surgery
Scientific title
A Prospective, Comparative Study of Warfarin Management post Mechanical Heart Valve Replacement Surgery over a 12 week period to determine: time to achieve an initial stable therapeutic INR (defined as the first measured INR within the range of 2-2.5 for mechanical aortic valves and 3-3.5 for mechanical mitral valves; where the previous/subsequent two INRs vary by no more than 0.5); time INR is in therapeutic range post-surgery; length of stay under 'Hospital-At-Home' care; and episodes of over-coagulation (INR > 4).
Secondary ID [1] 282818 0
Nil known
Universal Trial Number (UTN)
U1111-1145-6534
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post Mechanical Heart Valve Surgery 289600 0
Warfarin Management in post mechanical heart valve surgery patients. 289601 0
Condition category
Condition code
Cardiovascular 289937 289937 0 0
Other cardiovascular diseases
Surgery 290016 290016 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For unknown reasons, post mechanical heart valve surgery, patients have an immediate post-operative warfarin sensitivity about 50% highter than normal, taking approximately 12 weeks to normalise post operatively.

Routinely, post-mechanical heart valve surgery, all patients receive an oral tablet of warfarin which is commenced two days post-surgery to protect them from forming blood clots on their new valve. Due to the nature of the action of warfarin and the need to stabilise each patient onto the best therapeutic dose specific to them, all patients routinely have a blood test called an INR (International Normalisation Ratio [INR] measurements) so as to monitor how thin their blood is and thus adjust the warfarin dose up or down so as to achieve and then maintain them within their target INR. While warfarin dosing is regulated to try to find the best therapeutic INR, subjects are routinely given an anticoagulant injection while the doctor adjusts the warfarin dose to get to a therapeutic INR and each patient on just the right dose of warfarin.

We will compare two arms:
- (Arm 1) The current warfarin dosing regimen (using the 'age-adjusted, warfarin management protocol' while in hospital and in Hospital-at-Home care, then empirical dosing once in GP care) over a 12 week period post mechanical heart valve surgery,
- (Arm 2) Warfarin dosing post mechanical heart valve surgery following revised age-adjusted, warfarin management protocols, specifically designed to meet the needs of the post-mechanical aortic (therapeutic INR range of 2.0-2.5) and mitral (therapeutic INR range of 3.0-3.5) heart valve surgery patients.

These investigational protocols, designed to cover the 12 week, post-surgery period, will include a specific first four day instruction for oral tablet warfarin dosing, where we will reduce the warfarin dosing of the currently used 'age-adjusted, warfarin management protocol' by 30% for patients receiving a mechanical aortic valve replacement so as to achieve an INR range of 2.0 to 2.5, and reduce the warfarin dosing by 25% for patients receiving a mechanical mitral valve replacement so as to achieve an INR of 3.0 to 3.5. Then from day 5, if the optimal anticoagulation status or therapeutic INR has reached a relative degree of steady-state or stability, we have added to the protocols the incremental dose adjustment approach described by Meijer et al (1), whereby dosing is adjusted up or down on a percentage basis depending on the INR. For patients not in the therapeutic INR range by day 5, empirical dosing will be recommended until INR steady state is achieved before the incremental dose adjustment approach as defined by Meijer et al (2), is applied.

1. Meijer K, Kim YK, Schulman S. Decreasing warfarin sensitivity during the first three months after heart valve surgery: Implications for dosing. Thromb Res. 2010 Mar;125(3):224-229.
2. Meijer K, Kim YK, Carter D, Schulman S. A prospective study of an aggressive warfarin dosing algorithm to reach and maintain INR 2 to 3 after heart valve surgery. Thromb Haemost. 2011 Feb;105(2):232-238.

To monitor adherence a patient diary will be provided to all patients to collect INR results and warfarin dosing during the 12 week period. Also, INR results for all tests conducted during the 12 week period will be collected by the Principal Investigator. Dosage of oral warfarin will be analysed by intention to treat.
Intervention code [1] 287503 0
Treatment: Drugs
Comparator / control treatment
The comparator for this study will be the current warfarin dosing regimen used by the Flinders Medical Centre; Flinders Private Hospital; Hospital-at-Home carers and general practitioners within a 12 week period post mechanical valve surgery.

The current practice for warfarin administration post mechanical heart valve surgery performed at Flinders Medical Centre/Flinders Private Hospital is as follows:
- two days post-surgery, warfarin dosing commences with the use of the South Australian government-approved 'Warfarin Initiation–Age-Adjusted Protocol CC1.347' to determine the best starting dose of oral warfarin as per the patient's age and INR result.
- NOTE: The target INR is 2.0 to 2.5 for post-mechanical aortic valve surgery patients and 3.0 to 3.5 for post-mechanical mitral valve surgery patients at these institutions.
- Adjustments to warfarin dosing up or down is made using the 'Warfarin Initiation–Age-Adjusted Protocol CC1.347' while in hospital and in the care of 'Hospital-at-Home' practitioners.
- Patients routinely stay in the care of the Hospital-at-Home practitioners until a stable, target INR/therapeutic warfarin dose is reached.
- Patients are then referred to their GP for continuing care where INRs are taken 2-4 weekly and empirical adjustments to warfarin dosing is used if required.

For this study, we are requesting for INRs to be taken at least 2 weekly for the 12 week period.

Patients will be given a diary to record INR results and warfarin doses while in the study which will be collected at the end of the 12 week period.
Control group
Active

Outcomes
Primary outcome [1] 289990 0
Time to achieve an initial stable therapeutic INR in post mechanical aortic and mitral valve replacement surgery patients is defined as the first measured INR within the range of 2-2.5 for mechanical aortic valves and 3-3.5 for mechanical mitral valves; where the previous/subsequent two INRs vary by no more than 0.5. INR tests will be taken by venapuncture or by point-of-care CoaguChek 'Registered Trademark' INR monitor at a maximum of daily, or minimum of two weekly as needed per recommended guidelines. INR results will be collected either directly from pathology laboratory or from patient diary up to a 12 week post-surgery timeline.
Timepoint [1] 289990 0
To be determined by study.
Secondary outcome [1] 303728 0
The Time the INR is within the recommended stable therapeutic range in the first 12 weeks post mechanical aortic and mitral valve surgery, where a stable therapeutic INR is defined as measured INRs within the range of 2-2.5 for mechanical aortic valves and 3-3.5 for mechanical mitral valves. INR tests will be taken by venapuncture or by point-of-care CoaguChek 'Registered Trademark' INR monitor at a maximum of daily, or minimum of two weekly as needed, per recommended guidelines. All INR results will be collected during the 12 week period either directly from pathology laboratory or through a patient diary.
Timepoint [1] 303728 0
12 weeks post mechanical aortic and mitral valve surgery
Secondary outcome [2] 303729 0
Length of stay under Hospital at Home Care post mechanical aortic and mitral valve surgery
Timepoint [2] 303729 0
Timepoint to be determined by study - within 12 week period
Secondary outcome [3] 303730 0
Episodes of over-coagulation (INR>4) post mechanical aortic and mitral valve surgery; where all INR results will be collected during the 12 week period either directly from pathology laboratory or through a patient diary card.
Timepoint [3] 303730 0
Within a 12 week period

Eligibility
Key inclusion criteria
-Male or Female, > 18 years old
-Undergoing elective mechanical heart valve surgery
-Able to provide written informed consent, and follow-up by Hospital-at-Home
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Unable to provide written informed consent
-Current atrial fibrillation
-Advanced malignancy
-Fluctuating thyroid state
-Requires emergent/salvage surgery

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is a prospective study design with two phases comparing a cohort of post mechanical heart valve surgery patients. The first cohort of patients (control group) will be given warfarin according to current standard practice; i.e., empirical warfarin dosing; with the subsequent cohort (test group) receiving warfarin according to the new proposed warfarin dosing protocols. The control and test groups will be further stratified into two groups: patients receiving a mechanical aortic valve replacement (target INR range 2 to 2.5) and patients receiving a mechanical mitral valve replacement (target INR range 3 to 3.5). All data will be collected prospectively.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The plan is to enrol 140 elective patients for participation in the study, with enrolment being conducted during the Cardiac Surgery pre-admission clinic at Flinders Medical Centre. The study will consist of two consecutive phases, with Phase 2 to commence at the completion of Phase 1:
Phase 1 (Control group):
- 35 patients electing to have mechanical AVR (Aortic Valve Replacement) heart surgery, with warfarin doses post-surgery being regulated according to current standard practice (empirical warfarin dosing with the aim to regulate a target INR between 2 to 2.5). Patients will be followed up post-operatively, with all INR results being collected. INRs will be taken as per standard practice until patient reaches a stable therapeutic INR, then at least every two weeks up until 12 weeks, and:
- 35 patients electing to have mechanical MVR (Mitral Valve Replacement) heart surgery, with warfarin doses post-surgery being regulated according to current standard practice (empirical warfarin dosing) with the aim to regulate a target INR between 3 to 3.5) Patients will be followed up post-operatively, with all INR results being collected. INRs will be taken as per standard practice until patient reaches a stable therapeutic INR, then at least every two weeks up until 12 weeks.
Phase 2 (Test group):
- 35 patients electing to have mechanical AVR heart surgery, with warfarin doses post-surgery being regulated as per proposed protocol designed specifically for this patient population to a target INR range of 2-2.5. Patients will be followed up post-operatively, with all INR results being collected. INRs will be taken as per protocol until patient reaches a stable therapeutic INR, then at least every two weeks up until 12 weeks.
- 35 patients electing to have mechanical MVR heart surgery, with warfarin doses post-surgery being regulated as per proposed protocol designed specifically for this patient population to target INR range of 3-3.5. Patients will be followed up post-operatively, with all INR results being collected. INRs will be taken as per protocol until patient reaches a stable therapeutic INR, then at least every two weeks up until 12 weeks.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This is a prospective study design with two consecutive phases comparing a cohort of post mechanical heart valve surgery patients. The first cohort of patients (control group) will be given warfarin according to current standard practice; i.e., empirical warfarin dosing; with the subsequent cohort (test group) receiving warfarin according to the new proposed warfarin dosing protocols. The control and test groups will be further stratified into two groups: patients receiving a mechanical aortic valve replacement (target INR range 2 to 2.5) and patients receiving a mechanical mitral valve replacement (target INR range 3 to 3.5). All data will be collected prospectively.
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Simulated data (assuming median time to stable INR of 4 days for the test group, 6 days for the control group) indicated 28 patients will be required in each group (at beta=0.8, alpha=0.5). Planned N = 35 per group. Time to reach a stable INR will be plotted as a Kaplan-Meier plot and analysed using Cox’s F-test. The chi-square test will be used for other non-parametric data while Student’s t test for parametric data. P values are considered significant at less than 0.05.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
1/08/2013
Actual
Date of last participant enrolment
Anticipated
1/08/2015
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
140
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 1275 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 1276 0
Flinders Private Hospital - Bedford Park
Recruitment postcode(s) [1] 7160 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 287601 0
Self funded/Unfunded
Name [1] 287601 0
Country [1] 287601 0
Primary sponsor type
Hospital
Name
Flinders Medical Centre
Address
Flinders Medical Centre
Flinders Drive
Bedford Park SA 5042
Country
Australia
Secondary sponsor category [1] 286349 0
None
Name [1] 286349 0
Address [1] 286349 0
Country [1] 286349 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 289576 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 289576 0
Flinders Medical Centre
Flinders Drive
Bedford Park SA 5042
Ethics committee country [1] 289576 0
Australia
Date submitted for ethics approval [1] 289576 0
05/07/2013
Approval date [1] 289576 0
Ethics approval number [1] 289576 0
346.13

Summary
Brief summary
Patients undergoing surgery for mechanical heart valve replacement require post-operative anticoagulation with warfarin as they are at a higher risk of thrombosis and clot formation. To monitor for therapeutic or optimal anticoagulation status, the extent of blood-thinning is measured by a blood test called the International Normalised Ratio (INR). Depending on the type of heart valve surgery, there are two distinct recommended therapeutic INR ranges, either from 2 to 2.5 for patients receiving mechanical aortic valve replacement, or 3 to 3.5 for patients receiving mechanical mitral valve replacement.
There are two issues with post-mechanical valve surgery patients that distinguish them with respect to warfarin management:
(1) Their immediate post-operative warfarin sensitivity is about 50% higher than normal;
(2) This increased sensitivity to warfarin returns slowly to normal over the 12 week post-operative period.

Using the current empirical dosing method, that is, dosing by the prescriber using his/her clinical judgement, some patients require up to 3 weeks monitoring, when the average for attaining a stable therapeutic INR in patients other than post heart valve surgery with warfarin is less than 1 week, using the current, proven initiation protocols.
We therefore propose that two revised age-adjusted, warfarin management protocols be used, specifically designed to meet the needs of the post-mechanical aortic and mitral heart valve surgery patients. These protocols, designed to cover the 12 weeks post-surgery period, will include the first four days of warfarin dosing not previously discussed by Meijer, where we will reduce warfarin dosing by 30% for patients receiving a mechanical aortic valve replacement, so as to achieve an INR range of 2 to 2.5, and reduce warfarin dosing by 25% for patients receiving a mechanical mitral valve replacement so as to achieve an INR of 3 to 3.5. Then from day 5, if the optimal anticoagulation status or therapeutic INR has reached a relative degree of steady-state or stability, we have added to the protocols the incremental dose adjustment approach described by Meijer et al., whereby dosing is adjusted up or down on a percentage basis depending on the INR. For patients not in the therapeutic INR range by day 5, empirical dosing will be recommended until INR steady state is achieved before the incremental dose adjustment approach as defined by Meijer et al, is applied.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 41386 0
Dr Stuart McKee
Address 41386 0
Cardiac Surgery Research and Perfusion
Flinders Private Hospital
Level 6, R303
1 Flinders Drive
Bedford Park SA 5042
Country 41386 0
Australia
Phone 41386 0
+61 8 8204 5382
Fax 41386 0
+61 8 8404 2019
Email 41386 0
[email protected]
Contact person for public queries
Name 41387 0
Bronwyn Pesudovs
Address 41387 0
Cardiac Surgery Research and Perfusion
Flinders Private Hospital
Level 6, R303
1 Flinders Drive
Bedford Park SA 5042
Country 41387 0
Australia
Phone 41387 0
+61 8 8204 5382
Fax 41387 0
+61 8 8404 2019
Email 41387 0
[email protected]
Contact person for scientific queries
Name 41388 0
Stuart McKee
Address 41388 0
Cardiac Surgery Research and Perfusion
Flinders Private Hospital
Level 6, R303
1 Flinders Drive
Bedford Park SA 5042
Country 41388 0
Australia
Phone 41388 0
+61 8 8204 5382
Fax 41388 0
+61 8 8404 2019
Email 41388 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
No additional documents have been identified.