Bleeding Clinical Trial
Official title:
A Multicentre Study of Low Dose Oral Vitamin K for INR Control in Patients Receiving Warfarin
Warfarin is highly effective for the prevention of both first and recurrent thrombotic events, however even minor excursions outside the reference INR range of 2.0 to 3.0 are associated with bleeding or thrombotic complications. The importance of maintaining the INR within the desired interval has led to the concept of "time in therapeutic range (TTR)" - the total proportion of time that the INR is between 2.0 and 3.0. The investigators propose a multicentre, double blind, randomized trial which will determine if 0.150 mg of oral vitamin K increases time in the therapeutic range for patients receiving warfarin.
What is/are the principal research objective(s) and question(s) to be addressed? Research
Objectives: Our broad objective is to improve the quality of anticoagulant care for patients
receiving warfarin. Our specific objective is to determine if we can improve the TTR with
LDVK, a non-toxic, inexpensive and easily administered medication.
Hypothesis: We hypothesize that patients receiving vitamin K will have a higher TTR than
those receiving placebo. In a mechanistic study we proposed that VKORC1 and CYP2C9 genotype
will modulate the impact of vitamin K on INR control.
Research questions:
Efficacy (primary): When compared with placebo does the addition of 150 micrograms of daily
vitamin K to "usual warfarin therapy" improve anticoagulant control as measured by "time in
the therapeutic range"? Safety (Secondary): Does LDVK increase the frequency of adverse
clinical events, including thromboembolism? Does LDVK reduce the risk of major and/or all
bleeding? Mechanistic (Hypothesis generating): Do VKORC1 and CYP2C9 genotypes modulate the
effect vitamin K on INR stability?
Study design:
The proposed pilot study is a multi-centre, placebo controlled, randomized trial with an
additional pilot mechanistic study (Figure 1 provides a broad outline of the study).
Study interventions:
Patients will receive a daily dose of 150 micrograms of vitamin K or a matching placebo
medication for a total of 7 months - a one month "run in period" and a 6 month period of
follow-up. They will continue to receive warfarin under the supervision of their
anticoagulant clinic - other than one study mandated INR within 7 days of enrolment no
changes in patient care will be made as a result of participation in this study.
All patients will be enrolled in a mechanistic study. Patients will have blood drawn at the
time they provide consent to have their VKORC1 and CYP2C9 genotypes determined.
Allocation of patients into study groups:
Randomization will be achieved using a computer generated random number table. Patients will
be stratified based on clinical centre. Practically, a random number table will be produced
at the coordinating centre for each clinical centre. The study coordinating centre will
package a six week supply of drug and placebo into sequentially numbered, identical drug
containers based on the randomization sequence for each site. The drug packages will then be
shipped to each centre. After consent is obtained, and the coordinating centre is notified,
patients will be allocated to treatment by dispensing sequential drug containers in numeric
sequence. Additional supplies (for a total of seven months of therapy for each patient) will
be dispensed by the anticoagulant clinic in blocks of 6 weeks. This method of allocation
ensures research subjects and study staff are masked to allocation as drug and placebo are
identical. Masked allocation will be further protected by not providing an unblinding
schedule for centres as we can foresee no circumstance in which immediate unblinding would
be required.
Frequency and duration of trial follow-up:
Patients will have their INR checked at a minimum of 1 week after initiation of study drug
and then will be followed as per their anticoagulant clinic routine. We will not mandate any
particular frequency of INR testing as changing clinic routines will induce unwanted changes
in INR control is a co-intervention that could influence TTR and that is not attributable to
the study intervention. Clinical events will be reviewed, as per current clinic routine, at
each INR check. If clinical events are reported source documentation will be sought for the
purposes of adjudication. Our research group has extensive prior experience with collection
and interpretation of INR values, and of the ascertainment, collection and reporting of
clinical events in anticoagulated patients.
Primary and secondary outcome measures:
The primary outcome is a simple comparison of mean TTRs in the LDVK and placebo patients. As
noted, calculation of the TTR will begin at the first INR obtained a minimum of 4 weeks
after randomization and will end 7 months after enrolment. The TTR will be calculated using
a previously validated computer algorithm, based on the method of Rosendaal et al (7).
Secondary outcome measures will include (a) all significant INR excursion (INR < 1.5 or >
4.5), (b) number of INR determinations and (c) bleeding and thrombotic events of sufficient
severity to require a medical intervention - where possible source documents from hospital
admissions will be obtained to allow characterization of these events. Major bleeding will
be defined as bleeding consistent with the 8th ACCP guidelines (36). All bleeding and
thrombotic events will be independently adjudicated by a panel of experts based on submitted
source documentation.
Plan for ascertaining outcome measures at follow-up:
INR values are obtained routinely as part of warfarin care. All INR determinations will be
performed in clinical laboratories that participate in provincially mandated external
quality assessment exercises to ensure quality. INR values and current warfarin dose will be
reported to the coordinating centre using the online data entry and reporting system.
Clinical events will be measured as per the "Primary and secondary outcome measures"
section.
Will health services research issues be addressed within this trial? As a pilot study we do
not feel that a valid health services research question can be posed in the context of this
study. We do propose a simple cost effectiveness analysis which will examine the estimated
total costs of participation in the study - for this analysis we will compare the number and
type of medical interventions (and their costs) in the two arms of the study. Costs will be
determined from validated Ontario costing data for INR tests, clinical visits and monitoring
costs as well as any estimated costs attributable to clinic events, should these occur.
Funding for this analysis will be sought from different sources, however we will ensure that
the data required to complete this analysis will be collected within the context of this
study.
Trial sample size and justification for the assumptions underlying the power calculations:
As a pilot study of a novel intervention we do not have estimates of the improvement of the
TTR we expect to see with LDVK. As such the proposed sample size of 400 patients (200 per
arm) is one of convenience however the study is powered to detect probable changes in TTR.
Thus, we have an 85% likelihood of detecting a 15% increase in TTR assuming a TTR of 55% in
the placebo arm (two sided alpha = 0.05, comparison of proportions, Fleiss correction) (37).
A table of conditional powers is presented in Table 2. In subsequent studies (if justified,
based on the results of this study) we will power based on the rates of clinical events. One
prior paper has examined increases in TTR with vitamin K administration; the increase in TTR
in this study was 28%, thus we are reassured by our ability to reliably detect a 15%
difference in TTR (17).
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT03678168 -
A Comparison Between Conventional Throat Packs and Pharyngeal Placement of Tampons in Rhinology Surgeries
|
N/A | |
Completed |
NCT04058223 -
Comparison of the Short-term Outcomes of Using DST and PPH Staplers in the Treatment of Grade III and IV Hemorrhoids
|
||
Completed |
NCT05669313 -
The Effects of Hypothermia and Acidosis on Coagulation During Treatment With Rivaroxaban Measured With ROTEM
|
||
Completed |
NCT04590898 -
Peri-device Leakage Closure After LAAO
|
||
Active, not recruiting |
NCT05563883 -
Atrial Fibrillation and Cancer: a Nationwide French Cohort Study
|
||
Not yet recruiting |
NCT04537533 -
Tranexamic Acid Infusion in Low Dose Versus in High Dose for Reducing Blood Loss in Radical Cystectomy Operations
|
Phase 4 | |
Withdrawn |
NCT02851940 -
Pain and Bleeding Following Hypertonic Saline Sclerotherapy Compared to Brand Ligation for Symptomatic Hemorrhoids
|
N/A | |
Completed |
NCT02722720 -
Carotid Arteries Stenting Complications: Transradial Approach Versus Transfemoral
|
N/A | |
Recruiting |
NCT02279186 -
Effectiveness of Intravenous Tranexamic Acid in Reducing Blood Loss During and After Cesarean Section
|
Phase 4 | |
Active, not recruiting |
NCT02244853 -
Heart Rate and Cardiovascular Diseases Prognosis in People With Stable Coronary Artery Disease
|
N/A | |
Completed |
NCT02980497 -
Antiplaque/Antigingivitis Efficacy of Essential Oil Mouthrinses in Six-Month Study
|
N/A | |
Completed |
NCT02245854 -
Efficacy and Safety of a New Polypectomy Snare for Cold-polypectomy for Small Colorectal Polyps
|
N/A | |
Completed |
NCT02092415 -
Assessment of Limb Perfusion During Junctional Tourniquet
|
N/A | |
Not yet recruiting |
NCT01438736 -
Is Cerazette Use Before Nexplanon Insertion Predictive for Bleeding Pattern?
|
Phase 4 | |
Completed |
NCT00515541 -
Lovaza's Effect on the Activation of Platelets
|
Phase 2 | |
Completed |
NCT00143715 -
Oral Vitamin K for Warfarin Associated Coagulopathy
|
Phase 3 | |
Terminated |
NCT03954314 -
DEPOSITION - Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery
|
Phase 3 | |
Recruiting |
NCT05945680 -
Tranexamic Acid in Breast Esthetic Surgery.
|
Phase 4 | |
Recruiting |
NCT03783182 -
Betamethasone (Betapred®) as Premedication for Reducing Postoperative Vomiting and Pain After Tonsillectomy
|
Phase 4 | |
Not yet recruiting |
NCT05464394 -
Peroperative Administration of Tranexamic Acid in Roux-en-Y Gastric Bypass and One-anastomosis Gastric Bypass
|
Phase 3 |