Fiix-prothrombin Time for Monitoring Warfarin
Fiix-prothrombin Time for Monitoring Warfarin
Experiments suggest that during treatment with vitamin K antagonists (VKA) the activity of
 coagulation factors (F) II and X better reflect anticoagulation than does FVII. Based on this
 a new prothrombin time based monitoring test (Fiix-PT) has been invented which is only
 sensitive to FII and FX. The Fiix-PT can be converted to INR ("Fiix-INR").

 The investigators hypothesize that the Fiix-PT may reflect anticoagulation and the
 antithrombotic effect of VKA as accurately or better than the current PT based tests do (INR
 based on PT or P&P). The protocol describes a prospective randomized double-blind trial that
 will be conducted at the Landspitali Anticoagulation Management Center (AMC).

 The objective of the protocol is to evaluate the efficacy and safety of Fiix-INR as a
 monitoring test compared to the current PT based assays (INR) used to monitor patients
 treated with VKA to prevent thromboembolism. The investigators will randomize 1200 clients of
 the AMC into two identically sized monitoring groups, Fiix-INR (test group) and INR (control
 group).

 The clinical endpoints to be studied include efficacy (arterial and venous thromboembolic
 event rate) and safety (bleeding events). Additionally, surrogate convenience endpoints will
 be studied such as test frequency and time within target range.
Clinical outcome during warfarin anticoagulation to prevent thromboembolism monitored with
 "Fiix-INR" compared to standard monitoring with INR.

 A prospective randomized double-blinded trial. Study protocol Abbreviated Version Jan 25 2012
 Corresponding author: Pall T. Onundarson, M.D., Department of Laboratory Hematology and
 Hemostasis Center, K-building, Landspitali Hringbraut, 101 Reykjavik, Iceland, Phone: +354
 543 1000/5010, Fax +354 543 5539, email: pallt@landspitali.is.

 1. STUDY SYNOPSIS Experiments suggest that during treatment with vitamin K antagonists
 (VKA) the activity of coagulation factors (F) II and X better reflect anticoagulation
 than does FVII. Based on this a new monitoring prothrombin time base test (Fiix-PT) has
 been invented which is only sensitive to FII and FX. The Fiix-PT can be converted to INR
 ("Fiix-INR").We hypothesize that the Fiix-PT may reflect anticoagulation and the
 antithrombotic effect of VKA as accurately or better than the current PT based tests do
 (INR based on PT or P&P). The protocol describes a prospective randomized double-blind
 trial that will be conducted at the Landspitali Anticoagulation Management Center (AMC).
 The objective of the protocol is to evaluate the efficacy and safety of Fiix-INR as a
 monitoring test compared to the current PT based assays (INR) used to monitor patients
 treated with VKA in order to prevent thromboembolism. We will randomize 1200 clients of
 the AMC into two identically sized monitoring groups, Fiix-INR (test group) and INR
 (control group). Each individual will be assessed monthly for up to 24 months (an
 expected average of 18 months) until a total of 600 patients years of observation has
 been reached in each group. The clinical endpoints to be studied include efficacy
 (arterial and venous thromboembolic event rate) and safety (bleeding events). Also,
 surrogate convenience endpoints will be studied such as test frequency and time within
 target range.

 2. INTRODUCTION AND RATIONALE 2.1 Background Vitamin K antagonists (VKA, coumarins) are
 orally active anticoagulants that prevent normal gamma carboxylation of the vitamin K
 dependent coagulation factors (FII, FVII, FIX, FX). The consequence is a reduction in
 the clotability of the blood, ie an anticoagulant effect that can be used
 therapeutically for the purpose of preventing thromboembolism. In order to assure
 efficacy and safety, the dose of VKA needs to be adjusted to maintain the normalized
 prothrombin time ratio (international normalized ratio, INR) within a safe therapeutic
 range (most often with INR target 2.5, range 2.0-3.0). The clotting times obtained with
 PT based tests have in practice for over 50 years been presumed to directly reflect the
 antithrombotic effect of VKA in patients (Loeliger 1984). The PT (or P&P-test) are used
 all over the world for the purpose of monitoring anticoagulation and to make
 dose-adjustments in patients taking VKA. Their results have been standardized by
 calculating the International Normalized Ratio (INR) which takes into account the
 sensitivity (strength) of the thromboplastin used by different reagents.

 However, inherent problems exist with the PT. Due to the VKD factors´ significantly
 different half-lifes (above), the PT clotting time obtained early after initiation or
 dose change may mainly reflect the concentration of factor VII since FVII has the
 notably shortest half-life (about 4-8 hours). If the concentration of factor VII has
 little influence on the antithrombotic effect of VKA (see below), it is possible that
 unnecessary and too frequent dose adjustments are made based on the use of the PT. This,
 could potentially be harmful to the patient.

 Prior studies by others have indicated that the thrombin generation(Xi, Beguin et al.
 1989; Brummel, Paradis et al. 2001) and antithrombotic influence of factor VII in
 rabbits (Zivelin, Rao et al. 1993) may be less important than that of prothrombin or
 factor X. Based on those observations, it is possible that monitoring VKA and their
 safety could be improved by measuring either coagulation factor II or coagulation factor
 X. Measuring and monitoring coagulation factor II alone (native prothrombin antigen) has
 been shown to be very successful and more accurate than PT in clinical studies (Furie,
 Liebman et al. 1984; Xi, Beguin et al. 1989; Furie, Diuguid et al. 1990; Kornberg,
 Francis et al. 1993). The native prothrombin antigen assay, however, is not as
 convenient for laboratories as the PT or P&P. Monitoring coagulation factor X alone has
 not been tested in patients to our knowledge.

 We have investigated (Thrombosis Research 2012, in press.) the influence of each of the
 VKD factors on coagulation induced by dilute (trace amount) thromboplastin using
 rotational thromboelastometry (ROTEM). The dilute thromboplastin is by some scientists
 considered to reflect physiological clotting better than the 17,000 fold stronger
 thromboplastin used in the current PT assays. ROTEM measures coagulation in more detail
 than the traditional clotting times, i.e. initiation phase (clotting time), propagation
 phase (bulk clot formation) and stabilization phase. Taken together, these experiments
 using ROTEM show that the ROTEM clotting time (CT, initiation phase), ROTEM maximum
 velocity of clot formation (Max Vel, propagation phase) and the ROTEM MCF (stabilization
 phase) were affected much more by mildly and moderately low concentrations of factors II
 or X (at activity levels that are present during ideal anticoagulation) than by
 identical FVII or factor IX activity levels. Factors VII and IX mainly influenced the
 ROTEM parameters at very low concentrations (< 5%) which only occur during marked over
 anticoagulation. We conclude from these experiments that when coagulation is initiated
 with trace amount thromboplastin (physiological coagulation), reduction in concentration
 of coagulation factors II or X has much more effect on the development of a clot than do
 the concentrations of factors VII or IX except at extremely low activity levels of the
 latter two factors. Our experimental results may indicate that in patients
 anticoagulated with warfarin, the factor VII activity is a confounding source of
 variation in INR (PT) results. Hence, measuring the influence of factor II or X or both
 II and X simultaneously on fibrin formation might reduce INR fluctuation. Possibly, this
 could better predict the antithrombotic effect than the current tests do. Thus,
 measuring II or X or both simultaneously could possibly improve monitoring and dosing
 during VKA therapy. This has led to our invention of a new test, "Fiix-PT" (or
 Stuart-Prothrombin time) , which measures the combined action of factor II and factor X
 activity on clotting induced by tissue thromboplastin in PPP. We are not aware of any
 other scientists investigating this method and a local patent has been granted with
 international patent applications in process (March 2012). The Fiix-PT is not affected
 by reduced activity of any other coagulation factors. In comparison, the traditional
 test method (Quick PT or Owren´s PT) measures the combined effect of factors II, VII and
 X on fibrin formation in patients taking VKA.

 2.2 Hypothesis: Based on our experimental results as well as the results of others(Xi,
 Beguin et al. 1989; Zivelin, Rao et al. 1993; Brummel, Paradis et al. 2001), we
 hypothesize that the Fiix-PT may reflect anticoagulation and the antithrombotic effect
 of VKA at least as accurately as than the current PT based tests do (PT, P&P).

 3. STUDY OBJECTIVE The objective of the study is to evaluate the efficacy and safety of
 Fiix-INR as a monitoring test compared to the current PT based assays used to monitor
 patients treated with VKA to prevent thromboembolism.

 4. STUDY OVERVIEW This is a prospective, single-center, randomized, double-blinded,
 non-inferiority study(D'Agostino, Massaro et al. 2003; Scott 2009) for the efficacy and
 safety of Fiix-PT as a monitoring method in VKA treated patients involving 1200 patient
 years of observation.

 4.1 Participants: All ambulatory patients 18 years or older currently on or starting on
 warfarin to treat and prevent thromboembolism during the study period at the
 anticoagulation management center (AMC) at the Landspitali University Hospital in
 Reykjavik, Iceland with a treatment goal of INR 2-3 will be eligible for participation
 and randomization irrespective of indication for anticoagulation, age or concurrent
 medication use. Thus, the study population will have various (or mixed) indications for
 OA but the majority likely will have atrial fibrillation. Both current patients and new
 patients will be randomized over a 3-6 month period until adequate number of patients
 have entered the study. After patients sign informed consent they will be randomized
 (see METHOD of randomization in chapter 7) to either Fiix-PT (test method, Fiix INR) or
 PT (PT-INR based on Quick PT method as a control method). We will measure the PT- INR as
 well as the Fiix - INR in the test group for the sake of safety.

 4.2 Randomization standard (PT-INR) vs. new test (Fiix-INR). The aim is to randomize
 1200 clients of the AMC into two identically sized monitoring groups, Fiix-INR (test
 group) and INR (control group). Each individual will be assessed monthly for up to 24
 months (an expected average of 18 months) until a total of 600 patients years of
 observation has been reached in each group.

 4.3 Time frame: The clinical observation period for each participant will be 18 months
 on average.

 4.4 Endpoints to be recorded: see Chapter 7 for details A.Clinical endpoints. Rate of
 all TE or major bleeding. The major efficacy endpoint is symptomatic diagnosed TE events
 or death from TE and the major safety endpoint, is major bleeding, including death from
 major bleeding (Palareti 1996; Abdelhafiz and Wheeldon 2004). TE and major bleeding as a
 combined endpoint. Death and causes of death from natural causes. All bleeding (major
 and any other reported bleeding) B. Convenience/surrogate endpoints, eg. time within
 target range, number of tests within target range, number of tests during study period,
 number of tests needed to achieve stable anticoagulation.

 4.5 Study management: The study will be managed from day to day by an Executive
 Committee (EXC) . All clinical diagnoses will be reviewed by a blinded Independent
 Adjudication Committee (IAC) and Data Safety Monitoring Board (DSMB). The IAC and DSMB
 will be blinded to which test group the patient with event for review belongs. All
 suspected recurrent TEs, deaths, as well as all episodes of bleeding and other possible
 vascular events will be evaluated by the IAC. The patent holders (PTÖ, BRG) will not be
 on the IAC due to potential bias. Only adjudicated results will be the basis for the
 final analyses. The DSMB will also monitor the study progress and patients' safety
 during the study and give recommendations to the EXC.

 Every time a patient has a contact (eg INR measurement or dosing instructions), the
 dosing staff or study nurse will ask questions by exactly following the case review form
 (CRF, 14.2). If the questions are answered with a "yes", the study nurse will without
 delay contact that particular patient for more detailed information (i.e. HCRU form see:
 Event report form / Health Care resource utilization (HCRU)), and, as appropriate, will
 also collect necessary case record documents for the IAC.

 5. STUDY POPULATION, RANDOMIZATION AND BLINDING

 5.1 Planned number of patients. See 11.3.1 5.2 Inclusion criteria

 1. Current or new patients 18 years or older currently on or starting VKA with INR
 treatment target of 2-3

 2. Willingness to participate as volunteers and to signing an informed consent 5.3
 Exclusion criteria

 1. Age under 18 years 2. Patients unable to sign informed consent

 5.4 Randomization and blinding 5.4.1 Random allocation to experimental testing (Fiix-PT,
 Fiix-INR) group and standard testing (PT, PT-INR) group will be done by the study nurse or
 coagulation laboratory staff member in the outpatient phlebotomy ward when patients come for
 scheduled visits or in hospital inpatient wards;

 1. In current stable patients: at time of signing informed consent. Stable patients have
 had at least two INR´s within the target range.

 2. In new patients: no later than on the 4th day of warfarin administration, i.e. prior to
 the first dose adjustment as above.

 Note that the first dose change/first dose adjustment decision of warfarin must be based on
 post-randomization Fiix-PT or PT result.

 5.4.2 Randomization After patients sign informed consent they will be randomized to either
 Fiix-PT (test method, Fiix INR) or PT (PT-INR based on Quick PT method as a control method).
 Randomization will be done manually at time of signing the informed consent, ie the
 participants will draw a labeled color card with an assigned study number (CRF number) which
 will randomize them to either the test group or the control group. The coagulation laboratory
 (supervised by BRG) will maintain a list of study participants during the study. They will be
 responsible for randomization (color assignment) following the signing of informed consent.
 Following randomization, each patient will be assigned a study participant number. The
 laboratory will based on this participant number and color code as appropriate direct each
 patient´s sample to test A (Fiix-INR) or test B (PT-INR) which will be measured in the
 Landspitali coagulation laboratory using the STA-R instrument (Stago).

 5.4.3 Blinding. The study will be double-blinded, i.e. all assessors of clinical effect and
 dosing staff as well as patients will be blinded to the monitoring test-method. Blinded test
 results (INR) will be administered by the coagulation laboratory staff which cannot be
 blinded since they do the laboratory testing. The coagulation laboratory will measure INR
 (PT) on one STA-R instrument and Fiix-INR (Fiix-PT) on another STA-R instrument. All results,
 however will be reported out as "INR". The patients will not be informed on which test is
 used to monitor their anticoagulation and only a value ("INR") will be reported to patients.
 The test results will also be reported electronically as "INR" to the dosing staff (nurses,
 biomedical scientists, physicians) and study nurse who will not have knowledge on which test
 is used to monitor each patient. The data will be managed by the study nurse who will not
 have access to monitoring test allocation. All formal assessors of clinical events and
 secondary endpoints will also be blinded to test allocation. The dosing staff will dose
 patients based on INR, i.e. using the DAWN anticoagulation management software (Onundarson,
 Einarsdottir et al. 2008).

 5.5 Prior and concomitant anticoagulant medication 5.5.1 Anticoagulant medication prior to
 randomization Therapeutic dosages of (LMW)heparin/fondaparinux are allowed concomitantly with
 warfarin in new patients or during bridging therapy in association with procedures.

 6 STUDY TESTS 6.1 INR and Fiix-INR Current patients on stable warfarin therapy (see 5.4.1)
 can be included. In new patients, no later than after the first dose of warfarin should the
 dosing be managed by the AMC staff at Landspitali. The VKA dosage will be adjusted to
 maintain the Fiix-INR or the INR (PT-INR) with the therapeutic target of 2.5 (range 2.0-3.0).

 6.1.1 PT-INR The INR is calculated by the following formula: INR= (Patient PT/mean normal
 PT)ISI .

 6.1.2 Fiix-INR Fiix-PT will be measured using Neoplastin CI plus® and Fiix depleted plasma as
 described in patent application P8151IS00, March, 8th 2011. Fiix-INR will be calculated in
 the same manner as the PT-INR is calculated. ISI is calculated from DEKS calibrators as in
 6.1.1.

 6.2 Packaging, labeling, and storage The test reagents will be stored according to their
 package inserts and the Fiix deficient plasma will be stored in aliquots at -70°C.

 6.3 Accountability and study compliance All testing, dosing and follow-up must be done in
 accordance with the protocol and group assignment. During emergency testing both tests should
 be measured on all patients. When the laboratory is not sure both tests should be measured.
 All samples drawn during weekend and holidays should be kept until coagulation laboratory
 staff has decided that they can be discarded.

 6.3.1 VKA treatment monitoring The INR and Fiix-INR should initially be measured every 2 to 4
 days and when stable (at least two consecutive tests within target range) no less that every
 8 weeks.

 7 STUDY PROCEDURES 7.1 Study period This is the period between randomization (first testing
 with assigned test = Day 1) and final assessment of each individual. Data will be retrieved
 continuously as described above. After 3, 6, 9 and 12 months "interim" (safety, efficacy)
 analyzes will be performed (see Chapter 11). We will randomize 1200 clients of the AMC into
 two identically sized monitoring groups, Fiix-INR (test group) and INR (control group). Each
 individual will be assessed monthly for up to 24 months (an expected average of 18 months)
 until a total of 600 patients years of observation has been reached in each group. The study
 may also be stopped by the recommendation of the DSMB if a clinically significant difference
 in outcome becomes evident at an earlier time-point indicating inferiority of the new method.

 7.1.1 Patient written information Prior to enrollment potential study participants will
 receive an introductory information letter as well as informed consent form detailing the
 study and symptoms suggestive of new or recurrent thromboembolism or major bleeding.

 7.1.2 Patient contacts Data will be retrieved continuously and each patient will be contacted
 on a monthly basis. As described in detail in the protocol, in the case of suspected bleeding
 or thrombotic events or death data will be retrieved from case records, hospital summaries,
 autopsy reports or other records from physicians. When suspected serious events occur, the
 patients will be immediately referred to appropriate level care in the hospital.

 7.1.2.1 Initial CRF form (see: Initial Case Report Form (Initial CRF) form) When the patient
 has signed an informed consent, an initial CRF form (ICRF) will be filled in.

 7.1.2.2 Follow-up CRF form (see: Follow-up Contact Case report (review) form (Follow-up CRF))
 Every time a patient has a contact with the AMC (e.g. INR measurement or dosing
 instructions), the dosing staff or study nurse will ask questions by exactly following the
 case review form (CRF, 14.2). If the questions are answered with a "yes", the study nurse
 will without delay contact that particular patient for more detailed information (ie HCRU
 form, see: Event report form / Health Care resource utilization (HCRU)). The study nurse will
 then, as appropriate, collect necessary documents for the independent adjudication committee
 (IAC), see chapter 9.3.3. During each patient event, the following will be systematically
 checked by interviewing patients and reviewing the hospital chart for thromboembolism,
 bleeding events, concomitant medication, in particular antiplatelet agents such as aspirin or
 clopidogrel and NSAID use and compliance with monitoring 7.1.2.3 Observational period All
 patients will have a 5 day observational period after discontinuing from study.

 7.2 Efficacy and safety outcome criteria for the IAC 7.2.1 Assessment of clinical outcomes
 All suspected clinical outcomes i.e. recurrent TE, bleeding, death and vascular events, will
 be notified expedited to the IAC in a manner blinded to which test was applied. Blinded
 review of the event by the IAC should be completed within 2-4 weeks after occurrence of the
 event. The primary efficacy outcome is symptomatic or fatal recurrent arterial or venous TE
 event during the study period. The primary safety outcome is bleeding. Prespecified criteria
 for these events are excluded from this abbreviated protocol version.

 7.3 Surrogate endpoints/Convenience endpoints

 1. During initiation of VKA therapy: i. Number of tests needed to reach stable INR, i.e.
 until the first of two consecutive INR values are obtained within the target range. ii.
 Time until stable INR within target range

 2. During stable phase: i. Total number of tests per treatment year ii. Dose adjustment
 frequency (interval or number of dose adjustments during observation period) iii.
 Percent tests within treatment range over observation period iv. Percent time within
 target range (TTR) over observation period

 7.4 Measures to minimize bias A series of measures will be implemented to minimize the
 potential for bias in this study as detailed in the full protocol.

 7.5 Approach to the bleeding patient If a patient has a serious bleed during study, the
 following routine measures should be considered.

 Refer the patient immediately to the emergency department Delay or discontinue the next
 anticoagulant dose and consider vitamin K administration and usual treatment for bleeding,
 including blood transfusion, prothrombin complex concentrate administration, recombinant
 factor VIIa (NovoSeven and fresh frozen plasma

 8 PREMATURE DISCONTINUATION OR TEMPORARY DISRUPTION

 Subjects may be withdrawn from the study for the following reasons:

 At their own request or at the request of their legally acceptable guardian. If, in the
 investigator's opinion, continuation on anticoagulation would be detrimental to the subject's
 well-being.

 This is further detailed in the full protocol 9 DATA QUALITY ASSURANCE 9.1 Data quality The
 monitoring and auditing procedures defined below will be followed.

 9.2 Documentation Entries made in the CRF must be either verifiable against source documents,
 or have been directly entered into the CRF, in which case the entry in the CRF will be
 considered as the source data. The source data parameter to be verified and the
 identification of the source document must be documented. The study file and all source data
 will be retained for 5 years following final publication of study results when source data
 can be destroyed. No published result will be traceable to particular persons.

 9.3 Study administration/committees 9.3.1 Executive committee (EXC) The EXC has the overall
 scientific responsibility of the study. Its tasks and responsibilities are to create and
 approve the final protocol, co-author protocol amendments whenever necessary, ensure a
 scientifically sound and safe conduct of the study, including by abiding to DSMB
 recommendations, decide on the DSMB recommendations, review and approve the statistical
 analysis plan, guarantee the integrity of data collection and analyses and to decide on the
 publication- and presentation policy of the final results and ancillary studies 9.3.2 Study
 management and coordination committee (SMCC) The SMCC has the overall clinical responsibility
 of the study. Its tasks and responsibilities are to review the protocol, review the CRF,
 support the EXC by advice, monitor progress of study enrollment, address/resolve study
 management problems and participate in the analysis and presentation of the results.

 Member (author group):

 The Independent adjudication committee (IAC) has the following roles: A. Blinded review of
 clinical events (IAC- function), i.e. all suspected recurrent thromboembolic events, bleeding
 of any kind, any vascular events and all deaths during the study period and the observational
 period will be evaluated by IAC .The study nurse will provide the IAC with all relevant
 documentation related to the events but the IAC will be blinded as to the monitoring method
 of each patient while evaluating events. Adjudication results will be the basis for the final
 analyses. and B. Data safety and monitoring (DSMB-function), i.e. this committee also has the
 responsibility to provide the EXC with recommendations related to the protection of the
 patients' safety, including stopping recruitment and stopping the study. For this purpose,
 the DSMB will review all incidences of recurrent thromboembolism and bleeding every 3 months,
 see Chapter 11.

 9.3.4 External monitoring of study Adherence to study protocol will be monitored by an
 external agency. 10 ETHICAL AND LEGAL ASPECTS 10.1 Ethical committees (EC) The study will we
 conducted in accordance with the Helsinki declaration. Documented approval from appropriate
 ethical committees (EC) (applications will be sent to National Bioethics Committee (NBC)
 ("Vísindasiðanefnd"), The Data Protection Authority ("Persónuvernd") and from the Landspitali
 Medical Director will be obtained prior to the start of the study, according to good clinical
 practice (GCP), local laws, regulations and organizations. Regulatory authority
 approvals/authorizations notifications will be in place and fully documented prior to study
 start.

 10.2 Ethical conduct of the study The procedures set out in this protocol, pertaining to the
 conduct, evaluation, and documentation of this study, are designed to ensure that the
 investigators abide by GCP Guidelines and under the guiding principles detailed in the
 declaration of Helsinki. The study will also be carried out in keeping with applicable local
 law(s) and regulation(s). This may include an inspection by regulatory authority
 representatives at any time, including allowing direct access of source documents to the
 regulatory authority.

 10.3 Subject information and consent A core information and informed consent form will be
 provided. Written informed consent must be obtained before any study specific procedure takes
 place. Participation in the study and date of informed consent given by the subject should be
 documented appropriately in the subject's files.

 10.4 Insurance All subjects participating in the study will be covered by the Landspitali
 Hospital patient insurance in line with applicable laws and/or regulations.

 10.5 Confidentiality All records identifying the subject will be kept confidential and, to
 the extent permitted by the applicable laws and/or regulations, will not be made publicly
 available. Only the subject number will be recorded in the CRF. A list with names and
 subjects numbers will be kept separately by the EXC and its employees. If the results of the
 study are published, the subject's identity will remain totally confidential. The
 investigator will, however, maintain a list to enable subjects' records to be identified.

 10.6 Archiving of data The investigator will arrange for the retention of the study
 documentation file for 5 years. All data and documents should be made available if requested
 11 STATISTICAL AND ANALYTICAL METHODS 11.1 Statistical analysis plan (SAP) The plan is
 described in the following sections. However, the SAPs will allow protocol amendments or
 unexpected issues in study execution or data that affect planned analyses.

 11.2 Analysis populations The intention-to-monitor ("ITM") population will consist of all
 patients who have been randomized, i.e., when the patient number and allocated monitoring
 method are recorded in study-data base.

 Patients will be analyzed by the monitoring method assigned. Patients will contribute to
 patient years during the time they are in the study For patient year analysis the following
 patients will be censored at the last day the patient had a complete assessment for study
 outcomes within the intended treatment duration. Patients who did not have a thromboembolic
 or bleeding event during the time of the predefined randomized test duration, patients lost
 to follow-up patients who died because of other reasons than thromboembolic events patients
 who withdrew informed consent before the end of the predefined treatment duration and who did
 not have an efficacy or safety outcome. The per-protocol-population (PPP) will consist of all
 randomized patients without any major deviation from the protocol. The following deviations
 will lead to exclusion from the PP population: Patients not tested according to allocation or
 no VKA treatment received at all 11.3 Study population/sample size and power/ demographics
 and patient characteristics Baseline characteristics: Demographic characteristics (including
 age, sex, indications for anticoagulation, concomitant drug use) will be summarized by
 treatment group using descriptive statistics and the groups will be compared with regard to
 baseline characteristics using traditional statistical methods. As, all major clinical events
 are likely to be admitted to Landspitali, the only acute care hospital in the Reykjavik area,
 loss to follow-up is expected to be negligible. Therefore, no adjustment of sample size is
 considered necessary. Patients excluded from the analysis population in the per protocol
 analysis will be listed by test method and reason for exclusion. The number and percentage of
 randomized patients who discontinued from the study prematurely will be tabulated by main
 reason for discontinuation and treatment group.

 11.3.1 Non-inferiority margin estimation This study is powered for analysis of successful
 anticoagulation treatment and monitoring. For this calculation we have used data from studies
 on the clinical outcome of patients with mixed indications for anticoagulation, monitored and
 dosed by anticoagulation management centers (Palareti, Leali et al. 1996; Wilson, Wells et
 al. 2003; Abdelhafiz and Wheeldon 2004; Menendez-Jandula, Souto et al. 2005). In these
 studies the combined endpoints of major bleeding and thromboembolic events ranged from 2.7 to
 7.3 per 100 patients years and event rate for thromboembolic events was 0.9 to 5.4 per 100
 patient years (0.9-5.4%) with the lower margin of the 95% CI ranging form 2.9 to 8.2%. The
 largest observational study (Palareti, Leali et al. 1996; Wilson, Wells et al. 2003;
 Abdelhafiz and Wheeldon 2004; Menendez-Jandula, Souto et al. 2005) and the only randomized
 study (Palareti, Leali et al. 1996; Wilson, Wells et al. 2003; Abdelhafiz and Wheeldon 2004;
 Menendez-Jandula, Souto et al. 2005) had an TE event rate of 3.5 and 5.4% respectively. We
 therefore chose to use 3% TE-event rate as our expected TE-event rate (97% success rate) and
 the non-inferiority of 5.5% (94.5% success rate for efficacy). We consider this 2.5%
 difference one that is clinically significant, yet within the 95% CI for event rate in some
 prior studies. Based on these considerations, the appropriate number of participants needed
 to demonstrate statistical non-inferiority of clinically important events for the test method
 with an 80% certainty after one year of observation are about 600 (576) patients in each
 group, i.e. 600 (576) patient years in each group.

 11.4 Major event analysis (Efficacy and safety analysis) Major events analyses, primarily the
 TE event rate (efficacy) but also the secondary end points of the rate of bleeding and major
 bleeding (safety) as well as the combined endpoint of TE events and major bleeding events
 will be based on the ITT population. For the primary and secondary endpoints, event free
 survival will be compared in the two groups using Kaplan-Meier curves. Optionally, the time
 to the first events will be analyzed using Cox's proportional hazard models.

 11.5 Interim analysis 11.5.1 Study monitoring The study progress will be monitored
 continuously. Interim analysis for safety purposes is planned at 3, 6, 9 and 12 months. Based
 on this, risk-benefit will be evaluated by the DSMB.

 11.6 Surrogate endpoint analysis Median time within target range, time until stable INR as
 well as other surrogate parameters will be evaluated using the Mann-Whitney test for numeric
 rows or other appropriate statistical tests.
Inclusion Criteria:

 -  age 18 or over,

 -  INR treatment goal of 2-3,

 -  ability to sign informed consent

 Exclusion Criteria:

 -  nursing home patients