Oral Vitamin K for Warfarin Associated Coagulopathy
Oral Vitamin K for Warfarin Associated Coagulopathy
Excessive prolongation of the international normalized ratio (INR) occurs frequently in
 patients taking warfarin; in fact, about one in six INR values is above the desired range.
 Excessive prolongation of the INR is clinically important because the risk of bleeding
 approximately doubles for each one point increase in the INR beyond the usual therapeutic
 range. Thus, treatment strategies which rapidly and reliably lower an excessively prolonged
 INR into the desired range have the potential to reduce bleeding. When taken by patients with
 INR values between 4.5 and 10, a small dose of oral vitamin K (1 mg to 2.5mg) reduces the INR
 into the desired INR range in about 75% of cases within 24 hours of its administration. If
 warfarin is simply withheld, and no vitamin K is given, about 25% of patients will have an
 INR in the desired range at 24 hours. However, vitamin K is rarely given to such patients. In
 a recent survey carried out by our group, less than 20% of such patients would have been
 given low dose oral vitamin K by a group of physicians who regularly supervise warfarin
 therapy.

 The most common treatment for excessive prolongation of the INR is to simply withhold
 warfarin and allow the INR to fall into the therapeutic range. Although this strategy is
 effective its safety has never been adequately examined. In fact, recent evidence suggests
 that patients with INR values of more than 6.0 who are treated with simple warfarin
 withdrawal have a risk of major bleeding of 4% in the two weeks after they develop their
 prolonged INR.

 When asked why they did not give oral vitamin K to a non-bleeding patient who has an
 excessively prolonged INR, physicians generally give one of three reasons: (1)They are not
 convinced that oral vitamin K reduces bleeding. (2) They are concerned that oral vitamin K
 may cause thrombosis. (3) In contrast with simply withholding warfarin, giving oral vitamin K
 requires a patient to visit the physician, and the physician must have a supply of vitamin K.

 The investigators hypothesize that the routine practice of not administering oral vitamin K
 to patients with excessively prolonged INR values is causing patients to have major,
 life-threatening and fatal bleeds. To convince physicians that oral vitamin K should be
 administered to all non-bleeding patients with INR values of more than 4.5, the investigators
 propose a study which the investigators anticipate will demonstrate that oral vitamin K
 reduces bleeding, does not cause thrombosis, and can be administered at home without direct
 physician supervision.

 To accomplish these goals, the investigators propose a multinational, double-blind,
 placebo-controlled trial. The investigators will randomize patients with INR values between
 4.5 and 10.0 to receive 1.25 mg of oral vitamin K or placebo and follow them for bleeding and
 thrombosis. Patients with INR values of more than 10.0 will receive a single 1.25 mg dose of
 oral vitamin K.

 Successful completion of this study will establish a treatment standard supported by clinical
 data which will, in turn, change the way that patients taking warfarin who present with an
 excessively prolonged INR are treated.
What is the problem to be addressed ? Although warfarin is a highly effective anticoagulant,
 it causes bleeding. The risk of bleeding in an individual is increased by a number of
 factors, including age, gender and previous hemorrhage. However, the single strongest
 predictor of hemorrhage is excessive prolongation of the international normalized ratio
 (INR). We have shown that low-dose oral vitamin K reliably reduces an excessively prolonged
 INR; we hypothesize this treatment will also reduce the risk of hemorrhage without increasing
 the risk of thrombosis. The objective of this study is to demonstrate that low dose oral
 vitamin K improves the safety of oral anticoagulant therapy, by reducing the risk of bleeding
 without causing thrombosis, in patients presenting with INR values of more than 4.5.

 Background and rationale for the study (Efficacy and toxicity of warfarin): Warfarin reduces
 the risk of first or recurrent venous thrombosis by 80 to 90 percent, and reduces the risk of
 first or recurrent arterial thrombosis by 50 to 65 percent (1;2). In North America more than
 1 million patients receive warfarin on a daily basis and in Ontario more than 300,000
 prescriptions for warfarin are filled annually. The major toxicity of warfarin is bleeding,
 which may be fatal. Although bleeding may occur when the international normalized ratio (INR)
 is in the "therapeutic range" (2.0 to 3.0 for most indications), many patients who bleed have
 supratherapeutic INR values. Indeed, large studies suggest patients spend 10 to 20 percent of
 their time with excessively prolonged INR values and one anticoagulation clinic has reported
 that out of 7,279 patients managed over a 5 year interval, 1,995 had at least one INR greater
 than 6.0 (3). Furthermore, the risk of hemorrhage approximately doubles for each increase in
 the INR of 1.0 unit (4-7).

 Background and rationale for the study (Risks of an excessively prolonged INR) The risk of
 hemorrhage in patients with asymptomatic warfarin-associated coagulopathy has been
 highlighted by Hylek and colleagues (8). In this study, 114 patients who presented with INR
 values of more than 6.0 simply had their warfarin withheld until the INR had declined to the
 desired range. In the two-week follow-up period, 10 of the 114 (8.8%, 95% confidence interval
 (CI) 3.6 to 14.0) patients experienced bleeding including 5 major and two fatal bleeds. Thus
 the risk of major hemorrhage and fatal hemorrhage was 4.4% (95% CI 0.6, 8.1), and 1.7% (95%
 CI 0, 4.2), respectively. Similarly, Oden and colleagues (4) demonstrated the mortality rate
 attributable to bleeding per 100 patient years of follow-up was 22 fold higher in patients
 with INR values between 6.0 and 6.9, compared with patients with an INR between 2.0 and 2.4.
 The observation that excessive elevation of the INR is associated with bleeding suggests that
 identifying an effective technique to lower the INR will reduce bleeding.

 Background and Rationale (Treatment of warfarin associated coagulopathy) Other than simply
 withholding warfarin and allowing the INR to fall to the desired range, two "active"
 approaches are used to lower the INR in excessively anticoagulated patients. Transfusion of
 coagulation factor concentrates replaces missing coagulation factors. Supplemental vitamin K
 antagonizes the effect of warfarin, thus increasing endogenous synthesis of these same
 factors.

 Transfusion with human derived or recombinant clotting factors can rapidly normalize the INR.
 However, this treatment is expensive, inconvenient, associated with infectious or other
 complications such as allergy or thrombosis, and has never been prospectively studied in
 non-bleeding patients (9). Thus, transfusion therapy should not be used to correct an
 excessively prolonged INR value in non-bleeding patients.

 What is this study designed to prove ?

 We anticipate that this study will prove that:

 1. Oral vitamin K reduces the risk of bleeding in patients taking warfarin who present with
 INR values between 4.5 and 10.0.

 2. That oral vitamin K does not increase the risk of thrombosis when given to such
 patients.

 3. That low dose oral vitamin K will reduce the INR to an acceptable range in a high
 proportion of patients presenting with an INR of more than 10.0

 Why is this trial needed now ? This trial is needed now because there is new evidence
 confirming the association between prolonged INR values and the risk of bleeding (4;8),
 because new evidence suggests that oral vitamin K effectively lowers the INR (12-15;17) and
 thus may reduce bleeding (13), and because the risk:benefit ratio of oral vitamin K remains
 unclear.

 Studies which have been previously published by our group suggests that oral vitamin K
 effectively reduces the INR value. However, despite their rigour, and their publication in
 high-impact journals, our studies have not yet influenced clinical practice. A recent US
 survey confirmed that most clinicians faced with an excessively anticoagulated, non-bleeding
 patient would simply withhold warfarin and not give oral vitamin K (18). The lack of use of
 vitamin K is attributable to at least four factors; first, no study has unequivocally shown
 that oral vitamin K reduces the risk of hemorrhage. Although our first randomized trial (13)
 did find less bleeding in patients who received vitamin K, the bleeding in the placebo group
 occurred more than one week after randomization, making it possible that this observation was
 attributable to the play of chance. Second, there is concern that, irrespective of its route
 of administration, vitamin K may place patients at risk of thrombosis by "over-correcting"
 the INR. Although our two randomized trials showed no evidence that low dose vitamin K causes
 either warfarin resistance or thrombosis, at least one other publication has suggested this
 might occur (19). Third, the "passive" strategy of merely withholding warfarin is simple,
 inexpensive and easily applied. Finally, access to a convenient form of vitamin K is a major
 barrier as there is no convenient and easily administered form of oral vitamin K in many
 jurisdictions.

 Study design and implementation

 Trial design: This study is a randomized, double-blind, placebo-controlled, multicentre
 clinical trial with a concurrent cohort study (Appendix 1 - Study Flow Diagram). The
 randomized trial will enrol patients with INR values of 4.5 to 10.0. The cohort study will
 enrol patients with INR values of more than 10.0.

 Study interventions:

 RANDOMIZED TRIAL (INR 4.5 to 10.0): Eligible, consenting patients will temporarily
 discontinue warfarin and will be randomized to receive a single capsule containing either
 1.25 mg of oral vitamin K or no active drug.() COHORT STUDY (INR more than 10.0): All
 eligible consenting patients will receive 2.5 mg of vitamin K.

 Allocation to study groups:

 Three types of anticoagulant clinics exist. In the first type, patients present to the clinic
 for blood-drawing, and wait for their INR. Their dose of warfarin is then prescribed based on
 these results. Within this type of clinic, patients will be identified at the time that their
 INR prolongation is discovered. Consent for the study will be obtained, and the patient will
 be provided with the next numbered study kit, from which a single capsule containing either
 vitamin K or placebo will be administered. In clinics in which a point-of-care device is used
 for INR determinations the INR will be confirmed with a venous sample before the patient is
 enrolled. For the purposes of this study, such centres will be called "group 1" sites.

 The more common anticoagulant clinic is one within which patients have their INR determined
 by an outside laboratory, with the results called to a clinic physician, nurse or pharmacist.
 Within such a clinic, it is impractical to require patients to present to the hospital for
 assessment and randomization on the day that their INR is prolonged. For clinics using this
 model, we propose that when patients are found to have an INR of more than 4.5 they be
 assessed over the telephone for inclusion and exclusion criteria for the study. Patients
 meeting inclusion criteria, with no exclusion criteria, will be asked to provide consent over
 the telephone for the study. Once consent is obtained, and study forms are completed using
 information obtained over the telephone, the study centre will arrange to have the next
 numbered study drug allocated to the patient. The study drug will then be shipped to the
 patient using taxi cabs or a dedicated courier service. Receipt and consumption of the drug
 will then be confirmed at the time of the mandatory in centre assessment the following day.

 For the purposes of this study, all centres using this form of allocation to study drug will
 be called "group 2" centres.

 In both group 1 and group 2 centres patients with INR values of more than 10.0 will be given
 two capsules each containing 1.25 mg of oral vitamin K. A supply of such capsules will be
 provided to all participating centres in a clearly marked container. This drug will be
 provided to the patient in the same fashion as drug is provided to patients in the cohort
 study.

 Timely return of INR values is a problem when INR values are obtained outside the hospital.
 In some cases, for example, the INR may not be available until late in the evening or the day
 following the blood draw. If more than 24 hours has elapsed since the blood draw and the time
 at which a patient would be eligible for randomization the patient will be deemed ineligible
 for the study. In such cases however, the INR can be repeated (for example at the hospital or
 clinic laboratory) and if the INR remains above 4.5, the patient can then be enrolled.

 Patients who self-administer study drug will be asked to bring their unused capsule to the
 clinic on the day following randomization. This will ensure that they took the correct
 capsule.

 The least frequently used mechanism for monitoring warfarin therapy is patient
 self-monitoring using a point of care testing (POCT) device. Patients monitored with POCT are
 responsible for determining their INR and adjusting their warfarin dose based on their INR
 result. Patients who self-monitor using point of care testing and who find themselves to have
 an INR of more than 4.5 will be asked to contact their clinic staff. Prior to being
 approached for consent to enter this study the patient's INR will be confirmed on a venous
 blood sample organized by their host anticoagulant clinic. Given that patients in this group
 will be randomized while at the study centre, for the purposes of this study such patients
 will be considered to be in group 1.

 Group 1 and group 2 defines arbitrary groups. Clinics may have a mixture of group 1 and group
 2 patients; such clinics will have some patients who have signed consents and who will be
 randomized "at home" (group 2 patient) and others who are randomized and receive study drug
 "in centre". Irrespective of where patients are at the time of randomization they will be
 allocated the next available study drug supply at the time of randomization.

 Procedure for dealing with patients who are eligible for the study on more than one occasion:
 Patients can only be enrolled in either the randomized trial or the cohort study once.
 However, a patient previously enrolled in the cohort study who presented on a later occasion
 with an INR of 4.5 to 10 would be eligible for the randomized trial. Similarly, patients
 previously enrolled in the randomized trial are eligible for the cohort study. To ensure that
 the results of the randomized trial are not confounded by participation in the cohort study,
 a minimum of one month must pass between the time a patient is enrolled in the cohort study
 and their subsequent enrollment in the randomized clinical trial.

 Method of randomization: Randomization will be performed using a computer-generated
 randomization sequence. This sequence will guide drug packaging. Study drug supply will be
 packaged and dispensed to each study centre in lots of sequentially numbered appropriately
 labeled pill bottles. An additional, clearly labeled, supply of capsules containing 1.25 mg
 of oral vitamin K will be dispensed to each participating centre. Patients will be randomized
 by allocating the next, sequentially numbered pill bottle.

 What is the frequency of study follow-up ? Patients will be seen at each participating
 clinical centre by study staff on days 1 and 14 (+/- 2 days) after randomization. All
 patients will be contacted by telephone on days 3, 7, 28 and 90. Additional contact and INR
 sampling necessary to manage the patient's anticoagulant therapy will be made as required.

 What are the study outcome measures ? The primary outcome measure is "all clinically overt
 bleeding". Secondary outcome measures are "all adjudication-confirmed major hemorrhage", "all
 adjudication-confirmed thrombotic events", "changes in INR values" and "cost effectiveness"

 Why include all bleeding, and how is this endpoint defined ? Previous studies of both
 antithrombotic treatment and the treatment of warfarin-associated coagulopathy have used only
 major hemorrhage as the measure of bleeding. In those studies, "major hemorrhage" has been
 chosen as the primary measure because it is both detected and independently adjudicated more
 easily than "all hemorrhage". In addition, in most such studies of antithrombotic therapy,
 patients with acute thrombosis (or those at high risk of acute thrombosis) are enrolled. In
 the setting of acute thrombosis it is likely that physicians and patients are willing to
 tolerate minor bleeding as one of the "unavoidable" complications of antithrombotic therapy.
 Neither patients nor physicians would be willing to stop an effective treatment for acute,
 life threatening thrombosis because of minor bleeding. In the setting of warfarin maintenance
 therapy, however, minor bleeding such as unanticipated bruising, epistaxis or excessive
 menstrual blood loss in the setting of an excessively prolonged INR value is disconcerting,
 disruptive, costly if patients seek medical attention and likely to reduce compliance. Since
 we believe that reducing all bleeding complications (major and minor) is necessary to
 maximize the utility of warfarin therapy, we have chosen to measure all bleeding as our
 primary outcome measure of efficacy. We feel this is appropriate since the study intervention
 is masked; thus although minor bleeding is subjective, patients should be unaware of their
 treatment allocation and thus the treatment they receive will not influence their reporting
 of clinical events.

 Secondary outcome measures:

 Major Hemorrhage: Since we anticipate that many clinicians will wish to know the impact of
 vitamin K on "major bleeding", we will also compare the rates of all adjudication-confirmed
 major bleeds between groups. All bleeding events will be submitted to the central
 adjudication committee and major bleeding will be confirmed by standardized, masked central
 adjudication (see appendix 2).

 Thrombotic Events: At each clinic visit and telephone follow-up signs and symptoms of
 thrombotic events will be sought. If a thrombotic event is suspected, appropriate objective
 documentation will be obtained and will be forwarded to the Central Adjudication Committee.
 The committee will adjudicate these thrombotic events using validated, pre-specified criteria
 (see appendix 2).

 Cost-effectiveness: Details on the number and frequency of interventions, outcomes and their
 associated morbidity will be collected. This material will form the basis for a subsequent
 cost-effectiveness study. Given that vitamin K is very inexpensive (oral vitamin K costs less
 than 5$ Canadian per dose in most jurisdictions) and the expense of bleeding is high
 (previous cost effectiveness studies have estimated that an episode of major bleeding costs
 more than 5000 $ Canadian per event (20)) it is very likely that the use of oral vitamin K
 will be highly cost-effective.

 Plan for ascertaining outcome events: Signs or symptoms of all (major and minor) bleeding and
 thrombosis will be sought at each clinic visit or telephone call. If bleeding or thrombosis
 is reported, all available objective documentation such as hospital records, transfusion
 records or results of diagnostic or therapeutic investigations (such as endoscopy) will be
 obtained. Minor bleeding will frequently not have led to medical evaluation; in cases where
 minor bleeding is reported the specific setting, nature, duration and required actions will
 be sought for each event reported by the patient.

 Determination of the sample size (INR 4.5 to 10.0): The estimated rate of all bleeding in
 patients who present with excessive, warfarin-associated prolongation of the INR, treated
 with simple warfarin withdrawal, is 8% over the ensuing 30 days (8). We believe that
 clinicians would be willing to treat a minimum of 20 patients with oral vitamin K to prevent
 one episode of bleeding, thus the "minimally clinically important difference" that we wish to
 reliably detect is 5% (21;22). This reduction in the risk of bleeding (from 8% in those who
 receive placebo to 3% in those who receive vitamin K) represents about a 60% risk reduction.
 It is reasonable to expect that 1.25 mg of oral vitamin K will produce at least a 60%
 reduction in the risk of bleeding based on the following assumptions: (a) The INR in the
 placebo arm is likely to decline by about one INR point over the first 24 hours while the INR
 in the vitamin K group is likely to decline by about 3.9 INR points. These declines are based
 on the results achieved in our 3 published studies of oral vitamin K (10;12;13). (b) A 2.9
 point reduction in the INR should be associated with a 6 fold reduction in the risk of
 hemorrhage (based on the assumption that a 1 point increase in the INR doubles the risk of
 bleeding (4-7)). (c) The 60 percent risk reduction is a conservative interpretation of the
 effect of a 6 fold decrease in the risk of hemorrhage.

 To accomplish our goal of reliably detecting a 5% reduction in the risk of hemorrhage we will
 need to enrol 330 patients into each arm of the study to have 80% power with a two sided
 alpha of 0.05. This sample size calculation is based on the following assumptions:

 Figure 4: Sample size calculation

 2N = 4(Zα + Z)2 * (1-p)/(pc-pi)2 where Zα = 1.96, Z = 0.84

 pc is the proportion with success in the control group (no bleed) and is equal to 0.92 pi is
 the proportion with success in the intervention group (no bleed) and is equal to 0.97

 and p = (pi + pc)/2

 thus the total sample size is 652

 To accommodate for anticipated losses to follow up (which have been minimal in our previous
 studies) we will increase the sample size by 5% (to 690 patients)

 Sample size determination (cohort study): The sample size for the cohort study is entirely
 one of convenience; since there is no good quality data on the efficacy of oral vitamin K in
 patients with INR values of more than 10.0 we will simply enrol and follow such patients as
 they become available. Data derived from this cohort might then be used as the basis for
 future investigations.

 Study administration:

 Accounting for non-compliance: The sample size has not been adjusted to reflect
 non-compliance. It is unlikely that patients will be non-compliant with a single dose of
 study drug administered at the time of randomization. For example, in our previous studies
 none of the 134 patients receiving oral vitamin K have been non-compliant or lost to
 follow-up.

 Accounting for "loss to follow-up": We have not previously had patients lost to follow-up in
 our vitamin K studies, and we anticipate the rate in this study will be negligible (i.e. less
 than 5%). The low rate of loss to follow-up is due, in large part, to the fact that (a)
 patients will have only 2 clinic visits over the course of the study (day 1 and 14) and (b)
 all other follow-up will be performed over the telephone, Further, patients receiving
 warfarin are aware of the need for monitoring of their warfarin and thus accept the need for
 periodic medical and laboratory re-assessments. This increases the likelihood that they will
 be willing and able to participate in study follow-up.

 Coordination of the study: The study will be coordinated by the Thromboembolism Research Unit
 at St Joseph's Hospital in Hamilton, Ontario. Data submission to the coordinating centre will
 occur over a secure, web-based database system, which will be supplemented by paper copies of
 the case report forms which will be maintained at each clinical centre. Details of the
 web-based data-entry system are currently being determined; a revised study manual with full
 data entry details will be included in the subsequent versions of this study manual.

 The study will be coordinated by a professional data coordinator, who is based at St Joseph's
 hospital. Data integrity will be ensured by manually reviewing the electronic database for 5%
 of submitted records, and comparing these with copies of the paper CRFs from the relevant
 centres.

 The randomization sequence for all patients will be generated at the coordinating centre; the
 coordinator will remain masked to treatment allocation at all times.

 Provision of study drug: There is no oral form of vitamin K currently marketed in Canada,
 thus our previous investigations have used the intravenous formulation administered by mouth.
 Demonstration that a tablet form is effective would further simplify (and encourage) the use
 of oral vitamin K. A 5 mg vitamin K tablet is available in both Canada and the United States
 (in Canada the drug is available only after Health Canada approval). For this study, a supply
 of the 5 mg vitamin K tablets will be obtained from Merck Frosst Incorporated. Study
 pharmacies will compound this drug to produce matching capsules containing either lactose or
 lactose and 1.25 mg of vitamin K. This pharmacy will also provide drug packaging and will be
 responsible for preparing study drug kits which consist of sequentially numbered drug
 supplies for each clinical centre (following a randomization list provided by the study
 coordinating centre) and a supply of labeled 1.25 mg capsules (for the cohort study). These
 supplies will then be distributed, by the coordinating centre to each participating clinical
 centre.

 Role of the participating investigators: Dr Mark Crowther is the principal applicant and will
 be primarily responsible for all aspects of the study. Drs Ageno and Garcia, in addition to
 fulfilling the roles of co-investigators, will coordinate recruitment and management of
 centres in Italy, and the United States, respectively. Drs Crowther, Ageno and Garcia will
 comprise the executive steering committee which will meet by teleconference at least monthly
 to discuss specific trial implementation and management issues. The steering committee will
 consist of the members of the executive steering committee, as well as the Canadian
 participating investigators (Drs Blostein, Anderson, Wells, Kahn, Ginsberg, Kovacs, Kearon
 and Selby) and Dr Witt from the United States. Telephone Steering Committee meetings will
 occur six monthly, or more frequently as determined by the Principal Investigator. The
 Steering Committee is responsible for the overall conduct of the study, and will act on the
 recommendations of the study's subcommittees.

 Participating centres represented by letters of support on this grant include; Duke
 University (Dr Ortel); University of Washington (Dr Wittkowsky); University of Massachusetts
 (Dr Becker); IRCCS Maggiore Hospital of Milano (Dr Moia); Centro Emostasi e Trombosi Reggio
 Emilia (Dr Silingardi); Instituti Ospitalieri di Cremona (Dr Testa and Alatri); Dr. Siragusa
 (Policlinico Palermo)

 Adjudication committee: An Adjudication Committee of three thromboembolism experts not
 otherwise involved in this study will be convened.All reported hemorrhagic and thrombotic
 events will be reviewed by this committee, which will use all available source documentation
 to adjudicate clinical events. This committee will be convened when complete data are
 available on the first 20 bleeds or clots, and subsequently with each multiple of 20 events.
 To ensure uniformity, all episodes of hemorrhage will be adjudicated according to
 pre-specified criteria. The committee will report the results of their adjudication to the
 Coordinating Centre for inclusion in the study database. Although adjudication of all events
 may seem excessive it is possible that adjudication could "upgrade" events deemed minor by
 the site investigator, highlighting the need for central review of all bleeding events.

 DSMB: An independent Data Safety Monitoring Board (DSMB) will be constituted. The committee
 will consist of 2 experts who are not otherwise involved in the study. Proposed members are
 Dr Martin O'Donnell (Thromboembolism expert, Henderson Hospital, Hamilton, Ontario) and Dr
 William Geerts (Thromboembolism expert, Sunnybrook Hospital, Toronto, Ontario). The number of
 outcome events will be recorded for the cohort study and the randomized trial separately. The
 DSMB will be convened when a total of 20 (or multiples thereof) adjudication-confirmed major
 bleeds or thrombi have occurred in either of the randomized trial or the cohort study. While
 remaining masked to treatment allocation, the DSMB will review the source material describing
 the events. If the DSMB is concerned about the type or number of events, they will have the
 right to ask the steering committee to allow them to contact the study statistician and have
 an unblinded, unplanned, interim analysis for safety performed. Only experienced
 thromboembolism experts have been invited onto this committee, to ensure that such an interim
 analysis is not performed in response to less significant observations. If the interim
 analysis suggests that there is a significant safety concern (for example, if there is
 evidence of excess major bleeding or thrombotic events, as indicated by a P value of less
 than 0.05) the DSMB will have the right to recommend to the Steering Committee that the study
 be closed.

 Analysis plan:

 Primary analysis (Randomized trial): The primary analysis will be a simple comparison of the
 proportion of patients in the placebo and vitamin K arm with adjudication-confirmed bleeding.
 The proportion in each group will be compared using a Chi square or Fisher's exact test, as
 dictated by the number of events.

 Secondary analysis: The proportion of patients in each group with major hemorrhage,
 thrombosis and a composite of all adverse outcomes (thromboembolism, death and major
 hemorrhage) will be performed using a Chi square or Fisher's exact technique, as indicated. A
 regression analysis will be performed to determine if baseline variables including the
 receipt of drug or placebo, demographic characteristics, degree of prolongation of the
 international normalized ratio or other baseline variables predict adverse events. Finally,
 the mean INR values in the two groups will be compared using ANOVA.

 Primary analysis (cohort study): The change in the INR, and the number of bleeds and clots
 will be presented graphically.

 Frequency of analyses (Randomized trial): Three interim analyses are planned. The first will
 occur after 200 patients have been enrolled. In this analysis, the statistician will not be
 aware of treatment allocation; the overall rate of bleeding for the entire population will be
 computed. Assuming balanced allocation, we anticipate the event rate will be 5.7 percent. If
 the observed rate of hemorrhage is more than 2.5 percent above or below 5.7 percent, a
 revised sample size will be calculated. If the revised sample size suggests an unfeasibly
 large study (defined by the need for more than 500 patients per arm), the statistician will
 determine whether limiting enrollment to patients with INR values of more than 6.0 will
 enrich the event rate sufficiently to allow completion of the study with less than 500
 patients per arm. In these analyses, blinding to treatment allocation will be maintained and
 the sample size will be revised assuming a 60 percent reduction in the risk of bleeding in
 the vitamin K arm.

 Second and third interim analyses will be performed after 350 and 500 patients have been
 enrolled. If the sample size is adjusted at the first interim analysis, the second and third
 analyses will be performed after 60% and 75%, respectively, of the required sample size is
 enrolled. For these analyses, the study statistician will be unblinded to treatment
 allocation and the proportion of patients suffering adjudication confirmed major hemorrhage
 will be compared between the two groups. If there is a treatment advantage as measured by a
 two-tailed Chi-square or Fisher's exact test with a P value of less than 0.001 the
 statistician will recommend to the study Steering Committee that the study be stopped. Any
 other result will result in a recommendation to continue this study.

 Frequency of analyses (Cohort study): No interim analyses are planned. The Data Safety
 Monitoring Board (DSMB, see below) will be instructed to monitor the frequency of hemorrhage
 in this group. If the upper limit of the 95% CI about the risk of hemorrhage exceeds 5% after
 a minimum of 20 patients have completed the 90 day outcome ascertainment, the DSMB will
 notify the Steering Committee that the risk of hemorrhage in the cohort study is excessive.
 The steering committee will then decide whether this arm of the study should be discontinued
 or the intervention modified.

 Planned subgroup analyses The response to vitamin K or placebo is measured in two ways in
 this study. The first way is by observing the number of clinical events (thrombosis and
 hemorrhage) and the second is by observing changes in the INR values between the day of study
 drug and the next day. The number of clinical events in the study is likely to be relatively
 low, reducing the power of subgroup analyses to determine if baseline variables such as the
 degree of prolongation of the INR influence the response to oral vitamin K. However, since
 changes in the INR value will occur in all patients and since the INR is a continuous
 variable, a subgroup analysis which examines the influence of baseline variables (such as the
 degree of prolongation of the INR) on the response to vitamin K will have more power if
 performed with the change in the INR value as the dependant variable. This analysis will
 include: baseline demographic variables (such as gender, weight, presence of cancer, and
 age), the degree of prolongation of the INR, baseline maintenance warfarin dose and the
 indication for warfarin therapy. The ability of these variables to predict changes in the INR
 in both the vitamin K and placebo groups will be calculated. The ultimate goal of this line
 of investigations is to generate hypotheses about those factors (if any) that influence the
 response to vitamin K. These hypotheses could be tested in future studies within which the
 dose of vitamin K is modified based on the presence or absence of these risk factors.
Inclusion Criteria:

 -  Currently receiving warfarin with a target INR of 2.0 to 3.5

 -  INR value > 4.49 and drawn within last 24 hrs

 Exclusion Criteria:

 -  Elective discontinuation of warfarin

 -  Age < 18 years

 -  Life expectancy of less than 10 days

 -  Indication for the acute normalization of INR i.e. active major bleeding (bleeding
 into central nervous system, retroperitoneum or other critical area or any bleeding
 requiring transfusion), need for surgery, major non-orthopedic surgery within the last
 seven days, invasive diagnostic procedure, head injury or termination of warfarin

 -  Known Severe liver disease AST or ALT > 5 x normal, bilirubin > 50 umol/litre, known
 coagulopathy due to liver disease

 -  Recent (<1 month) history of major bleeding episode i.e. Hemorrhagic stroke,
 gastrointestinal bleed or other bleed requiring transfusion or admission to hospital

 -  Known bleeding disorder or thrombolytic therapy within 48 Hrs i.e. Hemophilia,
 disseminated intravascular coagulation

 -  Known allergy to vitamin K

 -  Inability to take oral medications

 -  Known significant thrombocytopenia i.e. Platelet count of < 50 x 10 9/litre

 -  Geographic inaccessibility/inability to have serial INR's performed

 -  Failure to obtain informed consent