Clinical trial NCT02392104
Conditions: Anticoagulation
Keywords: International Normalized Ratio Warfarin
Sponsor: William S. Middleton Memorial Veterans Hospital
Start date: 2015-03-27; Completion date: 2017-06-25
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the feasibility, safety, and acceptability of implementing an extended interval of INR follow-up in Veterans on a stable dose of warfarin in the Anticoagulation Clinic at the William S. Middleton Memorial Veterans Hospital.

All participants will be provided usual care from the anticoagulation clinic, except for the interval between INRs. If the participant continues to be on a stable dose of warfarin and the INRs are within the goal range of 2-3 (including lab variation), follow-up visits will be scheduled following an extended interval protocol. Patient satisfaction will be evaluated at various points throughout the study. Additionally provider satisfaction, confidence, and knowledge of the extended interval protocol will be analyzed. Bleeding and thromboembolic events will be evaluated to ensure the safety of an extended follow-up interval.

Detailed description:
The purpose of this study is to determine the feasibility, safety, and acceptability of implementing an extended interval of INR follow-up in Veterans on a stable dose of warfarin in the Anticoagulation Clinic at the William S. Middleton Memorial Veterans Hospital.

All participants will be provided usual care from the anticoagulation clinic, except for the interval between INRs. If the participant continues to be on a stable dose of warfarin and the INRs are within the goal range of 2-3 (including lab variation), follow-up visits will be scheduled following an extended interval protocol, from 5-6 weeks, to 7-8 weeks, to 11-12 weeks and then continued with 11-12 week visits if INRs continue to remain in goal range and appropriate for the patient. Patient satisfaction will be evaluated at baseline, 6-, 12-, and 24-months. Additionally provider satisfaction, confidence, and knowledge of the extended interval protocol will be analyzed. Bleeding and thromboembolic events will be evaluated to ensure the safety of an extended follow-up interval.

Arms: arm 1: All patients in the study will be in the intervention arm.
Interventions: intervention 1: Warfarin
Intervention descriptions: intervention 1: If the patient's INRs stay within goal range, their interval of INR follow-up will be extended based on a protocol to a maximum of 12 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Prospective evaluation of an extended interval of INR follow-up in a VA anticoagulation 
service 
 
 
 
 
 
PI:  Carla Staresinic, PharmD, BCACP 
William S. Middleton Memorial Veterans Hospital Pharmacy Department 
 
Co-Investigators:   
Andrea Porter, PharmD 
Amanda Margolis, PharmD, MS, BCACP 
Cheryl Ray, RPh, CACP 
Rebecca Schoen, PharmD 
 
 
NCT02392104 
 
Version 8  
4/18/17 
 
 


Purpose:  
 
The purpose of this study is to determine the feasibility, safety, and acceptability of 
implementing an extended interval of INR follow-up in Veterans on a stable dose of warfarin.   
 
Summary: 
 
Patients will be prescreened for study eligibility.  Patients must have an INR goal of 2-3, be on 
indefinite warfarin therapy, and be on a stable warfarin dose for at least 6 months, except for a 
single, one-time adjustment.  Planned procedures with INR(s) out of range would not exclude a 
patient.  All participants will be provided usual care from the anticoagulation clinic, including a 
thorough INR assessment and plan for warfarin.  The exception to usual care is the duration of 
follow-up.  If the participant continues to be on a stable dose of warfarin and the INRs are within 
the goal range of 2-3 (including lab variation), follow-up visits will be scheduled following the 
extended interval protocol, which includes visits at 5-6 weeks, then 7-8 weeks, and then 11-12 
weeks.  If a situation arises where the extended interval is no longer appropriate (e.g. single INR 
outside of goal range and lab variation, a participant has a procedure requiring interruption of 
warfarin, drug interaction, hospitalization, etc.), the issue will be managed per usual care.  If 
there was a permanent weekly dose adjustment or if the temporary dose change was more than 
1 month, the participant would return to usual clinic care.  They could requalify for the extended 
interval protocol when they have been on the same warfarin dose for at least 6 months, except 
for a single, one-time adjustment.  Planned procedures with INR(s) out of range would not 
exclude a patient.  If there was not a permanent weekly dose adjustment or if the temporary 
dose change was less than or equal to one month, two therapeutic INRs 4 weeks apart will be 
needed prior to starting the participant on the extended interval.  Patient satisfaction will be 
evaluated at baseline, 6, 12, and 24 months.  Additionally provider satisfaction, confidence, and 
knowledge of the extended interval protocol will be evaluated at baseline and at the end of the 
study.  A chart review will be conducted to evaluate adherence to the extended interval protocol 
by study staff, including inadvertent protocol violations.  Bleeding and thromboembolic events 
will be evaluated to ensure the safety of an extended follow-up interval.     
 
 
Specific Aims: 
 
1. To determine the feasibility of implementing an extended interval of INR follow-up in 
Veterans on a stable dose of warfarin. 
 
Goal:  We aim to enroll 75 patients within 3 months. 
 
Goal: The anticoagulation pharmacy staff will be able to accurately follow the extended 
interval protocol. 
 
2. To assess the safety of extending the interval of INR follow-up in patients.   
 
Hypothesis: We hypothesize that there will not be a difference between the bleeding and 
thromboembolic events from baseline (12 months prior to study enrollment) to 
events/year at 6, 12, and 24 months. 
 
Hypothesis: We hypothesize that there will not be a difference in the patient’s time in 
therapeutic range (TTR) from baseline (12 months prior to study enrollment) compared 
to the TTR at 12 and 24 months.   


 
3. To examine patients’ and providers’ acceptance of the intervention (to extend the follow-
up interval of INR monitoring).   
 
Hypothesis: We hypothesize that both patients and providers will favorably view the 
intervention.   
 
 
Background: 
 
Anticoagulation treatment with vitamin K antagonists, such as warfarin, can be complicated by 
many variables, such as drug interactions, diet, health status, other medications, and 
adherence.  Frequent INR monitoring is required to keep patients’ INR values within their target 
therapeutic range to lower the risk of hemorrhagic or thrombotic adverse events.  However, 
some patients remain on the same warfarin dose with INRs within their goal range for extended 
periods of time.  Predictors of very stable INR control for patients on long-term anticoagulation 
with warfarin include age greater than 70 years, male gender, INR target less than 3.0, and 
absence of heart failure, diabetes, or other chronic diseases.1, 2    
 
The most recent American College of Chest Physicians 2012 guidelines recommend an INR 
testing frequency of up to 12 weeks over 4 weeks in patients on warfarin with consistently stable 
INRs (Grade 2B; weak recommendation, moderate-quality evidence).3  The guidelines define 
stable INRs as at least 3 months of INRs that are within therapeutic range, thus not requiring 
changes in warfarin dose.  These guidelines are now more comparable to those from the United 
Kingdom, where the practice of a 12-week INR monitoring interval has been usual practice.4  
Despite the guideline recommendations, many United States anticoagulation providers are 
hesitant to extend the duration of INR follow-up to 12 weeks, as historically, the recommended 
interval and standard clinical practice for INR follow-up was a maximum of 4-6 weeks.   
 
The interval of INR follow-up has not been extensively studied in the literature.  Several 
retrospective studies have evaluated the use of an extended interval between INRs.5-7  Two of 
these studies concluded that the time-in-therapeutic range (TTR) improved as the time between 
INR tests was extended5, 6, whereas one study showed a decrease in TTR.7  Three randomized 
controlled trials have evaluated INR intervals longer than 4 weeks.8-10  Fihn et al. utilized 
computer-generated recommendations for follow-up, with intervals of up to 12 weeks.9  The 
computer program determined a follow-up interval based on lab values and goals, number of 
previous visits, lab value variability, and cost of the visits and possible complications.  Pengo et 
al. compared 4-week to 6-week follow-up intervals in patients with a prosthetic heart valve.8  
They found that extending the follow-up interval to 6 weeks did not increase the risk of bleeding 
or thromboembolic events.  Most recently, Schulman et al. compared an INR assessment every 
4 weeks to every 12 weeks in a noninferiority trial.10  This study defined warfarin stability as 
patients being on the same warfarin dose for at least 6 months or longer, and permitted one 
time dose changes for an INR out of range.  The patients who were randomized to the every 12 
week follow-up continued to have contact with the anticoagulation clinic staff every 4 weeks.  
The authors concluded that extended follow-up intervals of 12 weeks were noninferior and safe 
to follow-up intervals of every 4 weeks.  They also recommended further research without 
patient contact every 4 weeks before implementing the extended 12-week follow-up interval in 
routine practice.  
 
A concern with extending the interval of INR follow-up is bleeding or thromboembolic events.  
Two retrospective, longitudinal cohort studies compared stable patients, defined as all INRs 


within goal INR range for 6 or 12 months, to other patients, defined as one or more INRs outside 
of goal range during a 6 or 12 month period.1, 2 Both studies found that bleeding and 
thromboembolic events were significantly lower with stable patients compared to the other 
patients on warfarin.  Schulman et al. found no difference between the 4-week and 12-week 
groups in regards to major bleeding events, objectively verified thromboembolic events, and 
death.10  Schulman defined bleeding events per previously published criteria.11  Although the 
Schulman et al study demonstrated favorable results, it is unknown if the patient contact every 4 
weeks contributed to the positive outcomes.  Additionally, the anticoagulation population in a VA 
Anticoagulation Clinic may be different (increased age, more comorbidities).  Thus, we propose 
to examine an extended interval of INR follow-up in eligible patients at the William S. Middleton 
Memorial Veterans Hospital.     
 
The Anticoagulation Clinic at the William S. Middleton Memorial Veterans Hospital and its 
associated community-based outpatient clinics is a pharmacist-managed service.  The clinic 
currently follows approximately 1800 unique patients.  The clinic manages the initiation of 
antithrombotic therapy, follows patients on short-term and long-term antithrombotic therapy, 
manages the transition from inpatient to outpatient care, and coordinates warfarin interruptions 
for procedures using low-molecular weight heparin if warranted.  During an initial visit to the 
clinic, patients are oriented to warfarin as well as clinic procedures.  A patient and provider 
responsibilities document is reviewed with all patients.  For subsequent visits and INR 
assessments, patients are either seen in clinic or receive follow-up by telephone. The maximum 
interval between INRs is currently 5-6 weeks.  Pharmacists have prescriptive authority under a 
scope of practice.  This type of clinic is similar to other anticoagulation clinics in the Veteran 
Affairs system nationally and is considered high-quality anticoagulation management.12     
 
 
Methods and Procedures 
 
Design:   
A prospective cohort study is proposed to assess the feasibility, safety, and acceptability of 
extending the interval of INR follow-up to 12 weeks in stable warfarin patients.  All participants 
consenting to study participation will have their INR follow-up interval extended according to the 
study protocol.  If a participant's warfarin dose and INRs continue to be stable, the follow-up 
interval will be extended from 5-6 weeks, to 7-8 weeks, and then to 11-12 weeks.  Participants 
will be surveyed to explore their opinions and satisfaction with the changes to their follow-up 
interval at various points in the study (baseline, 6 months, 12 months, 24 months).  At the end of 
the study, a focus group will be held for a random subset of participants to obtain further 
information related to acceptability of this type of follow-up.  
 
Additionally, we plan to assess anticoagulation clinic provider study staff’s knowledge of the 
study protocol prior to the enrollment of participants for quality improvement and programmatic 
evaluation.  At the end of the study, we also plan to hold a focus group for all anticoagulation 
clinic provider study staff to obtain further information related to the extended INR interval 
follow-up process.   
 
Participants:  We propose to enroll 75 eligible patients on warfarin from the William S. 
Middleton Memorial VA Hospital in Madison, WI and the Madison VA’s associated community-
based outreach clinics.  Patients must also meet the following criteria to be invited to participate:   
 
18 years of age or older 
 
requirement for indefinite warfarin therapy 
 
target INR of 2-3 


 
stable weekly warfarin dose for the past 6 months  
o not more than a single, one-time adjustment (boost/omission) in the past 6 
months 
o planned interruption for a procedure or surgery with INR(s) out of range in the 
past 6 months would not exclude a patient 
 
a patient of the Madison VA anticoagulation clinic for the previous 12 months 
Patients will not be eligible to participate in the study if they meet any of the following criteria:   
 
consistently drink ≥4 alcoholic beverages/day or a documented episode of alcohol 
binging in the past 6 months 
 
diagnosis of cancer and on active chemotherapy/radiotherapy in the past 3 months 
 
life expectancy of < 1 year 
 
enrolled in other investigational drug protocols 
 
only receiving anticoagulation care at the Madison VA for part of the year (e.g. 
snowbirds) 
 
receiving visiting nurse services for INR monitoring 
 
thrombocytopenia (<100K) within past 12 months 
 
history of bleeding or thromboembolism requiring medical intervention within past 6 
months 
 
treatment for active liver disease (e.g. hepatitis) 
 
diagnosis or documentation in EMR suggesting cognitive impairment 
 
activated power of attorney 
 
inability to provide informed consent 
 
non-English speaking 
 
unstable mental health disorder that impairs judgment 
 
history of non-adherence to anticoagulation clinic policies and procedures (i.e. missed 
appointments, self-adjustment of warfarin dose, nonadherence, etc.).   
 
Procedures:   
Patient identification:  A study staff member will review anticoagulation clinic patients’ electronic 
medical records (EMR) for eligibility criteria prior to each appointment day until 75 patients are 
enrolled in the study or 3 months has elapsed.  A list of eligible patients will be provided to study 
staff so they are aware that a patient is eligible prior to interacting with the patient during a 
routine clinic visit.  After the initial group of patients has completed 6 months in the study and 
after a safety review, additional patients may be enrolled if 75 patients were not initially enrolled.       
 
Patients who are eligible will be invited to participated in a research study, either face-to-face or 
over the phone, depending on the type of anticoagulation clinic visit.  If they are interested, they 
will be provided information on the study requirements during that anticoagulation clinic visit.  
Potential participants will have the opportunity to ask questions they have regarding the study 
and the consent process initiated.  Participants will not be paid for participation in the study.  
Subjects who receive phone calls and utilize secure messaging as part of their anticoagulation 
clinic visits will first receive an invitation letter by mail.  At the subsequent anticoagulation clinic 
visit, they will be introduced to the study during a phone call. A separate recruitment call will not 
be made.    
 
Face-to-face visit:  For a face-to-face clinic follow-up visit, the informed consent, participant 
responsibilities agreement, and HIPAA authorization form will be reviewed and the patient will 
be provided with two copies of these documents.  One copy of these documents will be 
collected during the visit and the patient will keep one copy.  Once the documents are reviewed 
and signed, the patient will be considered enrolled in the study.  The extended interval protocol 


could be started during the same anticoagulation visit and the follow-up interval extended.  
During this visit, the participant will also complete the baseline survey. 
 
Telephone visit:  All patients will receive an initial invitation letter after being pre-screened for 
eligibility.  For a telephone clinic follow-up visit, and after verbally stating their interest in the 
study, two copies of the informed consent, participant responsibilities agreement, and HIPAA 
form, and one copy of the baseline survey will be mailed to the patient.  For the documents with 
two copies, one copy will be for the participant to keep for their records and one copy is for the 
study team’s records.  About 7-10 days from the anticoagulation clinic visit, the potential 
participant will be contacted by a study team member by phone to ask if the participant if they 
have any questions about the study and/or the forms and if would like to enroll in the study.  If 
the potential participant is agreeable to enrolling in the study, the study team member will 
conduct the informed consent process over the telephone.  After signing the forms, the patient 
will mail the informed consent, participant responsibilities agreement, HIPAA form, and 
satisfaction survey to the study staff at the Madison VA using a pre-addressed stamped 
envelope. If the patient cannot be reached or the documents are not received after three phone 
calls/phone messages, the patient will be considered not interested in study participation.  Once 
the signed informed consent, HIPAA form, and participant responsibilities agreement are 
received, the participant will be enrolled in the study.  The extended interval protocol will be 
started at the next anticoagulation visit with the patient and the follow-up interval extended.          
Secure messaging:  All patients will receive an initial invitation letter after being pre-screened for 
eligibility.  If a patient usually receives communication from the anticoagulation clinic staff by 
secure messaging, the patient will be contacted by phone instead of by secure message for 
their next anticoagulation visit.  This is usual practice for these patients if their INR is out of 
range or additional information is needed from the patient.  Additionally, secure messaging is 
somewhat new to the clinic and previously, these patients were contacted by phone.  During 
their anticoagulation visit on the phone, patient interest in the study will be determined.  .  If they 
are interested, the same steps detailed above for the telephone visit will apply to these patients. 
 
Intervention:  Participants will be provided usual care from the anticoagulation clinic.  After 
having an INR drawn, the participant will be assessed either face-to-face, over the phone, or 
through secure messaging about health changes and other aspects that are pertinent to their 
anticoagulation.  The participant will be provided with a plan for their warfarin dose and a follow-
up date.  The exceptions to usual care include the duration of follow-up.   
 
Follow-up visits will be scheduled following the extended interval protocol, which includes visits 
at 5-6 weeks (if not already), then 7-8 weeks follow up, and then follow up at 11-12 weeks, if the 
participant continues to be on a stable dose of warfarin and the INRs are within the goal range 
of 2-3 (including lab variation) (figure 1).  If the participant is already at a 5-6 week follow-up, 
which is usual care, their next follow-up interval will be 7-8 weeks.  Follow-up visits will continue 
to be scheduled at 11-12 weeks if those criteria are met.  If a situation arises where the 
extended interval is no longer appropriate (e.g. single INR outside of goal range and lab 
variation, a participant has a procedure requiring interruption of warfarin, drug interaction, 
hospitalization, etc.), the clinical situation will be managed per usual care (figure 2).   If there 
was a permanent weekly dose adjustment or if the temporary dose change was more than 1 
month, the participant would return to usual clinic care.  They could requalify for the extended 
interval protocol when they have been on the same warfarin dose for at least 6 months, except 
for a single, one-time adjustment.  Planned procedures with INR(s) out of range would not 
exclude a patient.  If there was not a permanent weekly dose adjustment or if the temporary 


dose change was less than or equal to one month, two therapeutic INRs 4 weeks apart will be 
needed prior to starting the participant on the extended interval.   
 
If an unexpected INR is drawn, the pharmacist provider will assess the reason why the INR was 
drawn (figure 3).  If it was due to a change in health status, the participant would most likely 
require shorter follow-up which would meet the criteria for the situation described previously.  If 
it was truly a random INR, the next follow-up should be scheduled for the originally intended 
interval (e.g. Scheduled for 8 week follow-up and INR was drawn at 6 weeks.  Next follow-up 
scheduled for 8 weeks).   
   
During follow-up visits, study staff will receive information from the participant in one of three 
ways: directly from the participant (either by phone or in person), from an individual the 
anticoagulation clinic has received permission to speak with and a release of information is on 
file, or by written assessment form (paper or by secure messaging), which is used by the 
anticoagulation clinic as part of usual care.  For the latter two, if clarification is needed about the 
participant’s health status or anticoagulation therapy, study staff will contact the participant by 
phone to discuss further.  Study staff will attempt to call the participant 3 times.  If the participant 
is unable to be reached, a voicemail will be left for the participant (if previously authorized by the 
participant), a standard clinic letter will be sent to the participant, and the participant will be 
rescheduled for follow-up at an interval no longer than 4 weeks (not the extended interval), but 
could be sooner as clinically appropriate.  If the participant returns the call to the anticoagulation 
clinic and it is appropriate, the follow-up interval can be extended to the originally intended 
interval.   
 
As with usual care, if an acute medical problem is identified, the participant will be forwarded to 
telephone triage, the emergency room, or 911.  If a non-acute problem is identified, the 
participant’s primary care provider, nurse case manager, or appropriate provider will be 
contacted. 
 
If a participant has a question or a medical problem related to anticoagulation, the 
anticoagulation clinic is available for participants from 8am-4:30pm, Monday through Friday.  If a 
participant requires medical assistance outside of those hours, there is a 24-hour telephone 
triage phone line available for participants.   
 
Patient satisfaction:  Study participants will receive a survey at baseline and at approximately 6, 
12, and 24 months.  The survey includes the Duke Anticoagulation Satisfaction Scale, a 
validated survey instrument assessing a participant’s satisfaction with their anticoagulation 
therapy and management.13  If the participant has a face-to-face visit, they will fill out a paper 
copy of this survey during a clinic visit.  If the participant has a telephone visit, the survey will be 
mentioned during the phone call and the participant will be mailed a copy of the survey with a 
pre-addressed stamped envelope.  If the participant has a secure messaging visit, the survey 
will be mentioned in the return secure message and the participant will be mailed a copy of the 
survey with a pre-addressed stamped envelope.  If the survey is not received by study staff 
within 2 weeks of the visit, the participant will be called to remind them to mail in the survey.  
Participants will be called up to three times to remind them to mail in the survey.  At the end of 
the study, 10 randomly chosen participants will be asked if they would be interested in attending 
a focus group to explore their opinions further. 
 
Provider satisfaction, confidence, and knowledge:  Pharmacist providers who are study team 
members will be surveyed prior to the enrollment of the first participant about their knowledge of 
and confidence with the extended interval protocol.  At the end of the study, all pharmacist 


providers who are study staff will be invited to attend a focus group to discuss the feasibility of 
incorporating extended INR intervals into the anticoagulation clinic as well as their satisfaction 
and attitudes. 
 
Quality assurance:  A member of the study staff not involved with the participant’s direct 
warfarin management will conduct a chart review. The chart review will be conducted to 
evaluate inadvertent protocol violations by anticoagulation study staff in the management of the 
study participants. Deviations will be categorized and quantified by type and frequency of 
protocol violation.  
Safety:  If at any time a participant reports or clinic staff are alerted to a bleeding event, it will be 
documented in the participant chart, as per standard of care practice.  The following criteria, 
which are currently used in the Anticoagulation Clinic at the Madison VA to collect bleeding and 
thromboembolic events, will be used to differentiate major and serious bleeding: 
Major 
 
Fatal or symptomatic bleed into a critical area or organ 
 
Bleeding leading to hospitalization 
 
Transfusion of 2 units or more packed red blood cells 
Serious 
 
Bleeding leading to ED or UC visit or additional testing 
After a major bleed, the participant will be removed from the extended follow-up interval and will 
not be eligible to qualify for the extended follow-up interval for 6 months after the event.  After a 
serious bleed, the patient will be managed with usual care.  If they did not have a permanent 
weekly dose change or if the temporary dose change was less than or equal to one month in 
duration, they must have 2 therapeutic INRs 4 weeks apart to begin the extended INR interval 
protocol.   
 
If at any time a participant reports or clinic staff are alerted to a thromboembolic event, it will be 
documented in the EMR.  The participant will be removed from the extended follow-up interval 
and not be eligible to qualify for the extended follow-up interval for 6 months after the event. 
 
If at any time, anticoagulation clinic study staff do not feel it is appropriate to continue a 
participant with an extended follow-up interval, the participant can return to usual care.  If at any 
time, the participant does not want to continue with an extended follow-up interval, they can 
return to usual care. 
 
A participant will no longer be eligible for an extended INR interval if they meet any of the 
exclusion criteria at any time during the study, except for a bleeding or thromboembolic event.  If 
a major bleeding or thromboembolic event occurs, they will be eligible to requalify after being on 
a stable warfarin dose for 6 months.  A patient will also no longer be eligible for the extended 
INR interval if their INR goal changes and is no longer 2-3.  A participant will be withdrawn from 
the study and no more data collected from the participant if they withdrawal their consent for the 
study or if death occurs.   
 
A data monitoring committee will review the data collected, including bleeding and 
thromboembolic events for safety, protocol violations, and feasibility data at six months after the 
last patient is enrolled (at 3 months or when the 75th patient is enrolled), and then annually.  If 
the data monitoring committee feels that the study is safe to continue, the study will continue 
until patients have been enrolled in the study for 2 years.   
 


The events rates for 2013 clinic data are listed below, including a 95%CI.  Additionally, ranges 
for event rates over the past 4 years are included. 
 
Major bleed: 1.88% (95%CI 1.3-2.62%); range of 1.8-2% 
 
Serious bleed: 0.5% (95%CI 0.23-0.94%); range of 0-0.5% 
 
Thromboembolism: 0.22% (95%CI 0.06-0.6%); range of 0.2-0.44% 
Stoppage rules for the study: 
1. Stoppage rules for the study (based on event rates from the Schulman, et al. article) are 
included below.  If the study is stopped early, all subjects will be scheduled for an INR 
within 6 weeks of their last INR, which is usual practice for the clinic. 
Data from Schluman study 
Madison VA 
Event 
# from 
Schulman 
study 
Rate 
per 1 
year 
95%CI of 
the 1 year 
rate from 
Schulman 
Approx Count 
Based on 50 
patients 
enrolled using 
upper end of 
95% CI 
Stoppage 
of Study 
TE (includes TE-related 
death) 
4 
1.6% 
0.4-4 
2 
3 
Composite of  
TE, TIA, and major 
bleeding, TE-related death 
12 
4.8% 
2.5-8.2 
4.1 
5 
 
2. If an event occurs: 
a. The PI or one of the Co-PIs will thoroughly evaluate the event to determine if it 
was related to study participation.  .  The following chart will be used to determine 
if the event was related to study participation. 
Bleeding or 
TE event¥ 
On Extended 
Interval at Time 
of Event or within 
6 Weeks of Event 
INR Measure at visit 
following extended 
interval and/OR at 
Time of Event  
Relationship to 
Hemostasis  
(as relates to INR 
direction/ magnitude) 
Level  of Attribution 
Yes 
Yes 
Within target range 
‐ 
Possible 
Yes 
Yes 
Outside target range 
No relationship or 
uncertainty 
Possible 
Yes 
Yes 
Outside target range 
Possible relationship  
Probable 
Yes 
Yes 
Outside target range 
Definite relationship 
Definite* 
*Stopping rules apply to the events with a definite attribution.  (Additional events may apply based on the 
discretion of the DMC and IRB.) 
¥ If the event was due to accident, injury, or other clear cause, attribution may not follow table. 
 


b. If a patient has a major bleeding or thromboembolic event, our protocol states 
that the patient will return to usual care and must be on the same dose for 6 
months until they are able to requalify for the extended INR interval. 
Adverse events (AEs) collected for this study only include bleeding and thromboembolic events.  
Serious adverse events (SAEs) will be documented per VA and IRB definitions.  AEs will be 
entered into OnCore after the retrospective review of the medical record at 6, 12, and 24 
months after participant enrollment in the study.  SAEs are entered into the SAE documentation 
area in OnCore as they occur, which may not align with the time period for the chart review.  
The SAEs that include bleeding or thromboembolism will be entered in real-time to the AE table 
in OnCore.   
Measures:  The outcomes of this study include feasibility, safety, and acceptability of extending 
the interval of INR follow-up to 12 weeks in stable warfarin patients.  We propose to use the 
following measures: 
1. Feasibility:  We will examine the following: 
a. Rates of participant accrual (patient interest in participating and reasons for not 
participating).  Number of withdrawals and reasons for withdrawal from protocol 
or study. 
b. Change in frequency of appointments from baseline  
c. Frequency and type of protocol deviations from both participants and study staff  
d. Frequency of time outside of extended INR interval protocol and why 
e. Knowledge assessment of study staff regarding study protocol 
2. Safety:  We will examine the following: 
a. Participant reported and EMR review of bleeding events.  Study participant 
bleeding events for 12 months prior to enrollment and during the study will be 
compared to the clinic’s bleeding event rate.  The following definitions will be 
used to categorize bleeding: 
i. Major 
1. Fatal or symptomatic bleed into a critical area or organ 
2. Bleeding leading to hospitalization 
3. Transfusion of 2 units or more PRBCs 
ii. Serious 
1. Bleeding leading to ED or UC visit or additional testing 
b. Participant reported and EMR review of thromboembolic events that are 
objectively verified.  Study participant thromboembolic events for 12 months prior 
to study enrollment and during the study will be compared to the clinic’s 
thromboembolic event rate. 
c. Participant reported and EMR review of healthcare utilization: hospitalizations, 
ED visits, urgent office visits, telephone triage related to anticoagulation. 
Utilization for 12 months prior to study enrollment will be compared to utilization 
during study enrollment. 
d. Baseline TTR (12 months prior and 6 months prior) for each patient and during 
study14 
e. Number of extreme INRs (<1.5, ≥4.5) 
3. Acceptability:  We will examine the following: 
a. Participant satisfaction will be gathered at baseline and at 6, 12 and 24 months 
after study enrollment through use of a survey. 
b. Provider attitudes about the protocol will be gathered at baseline and at the end 
of the study. 


c. At the end of the study, a participant focus group will be held to obtain further 
data on opinions.  Participants will be randomly chosen to be invited to attend. 
d. At the end of the study, a provider focus group will also be held to obtain further 
data on opinions.  All providers will be invited to attend. 
 
Data to be collected from the medical records (up to 12 months prior to study enrollment):  
 
Name 
 
Age 
 
Sex 
 
Race/ethnicity 
 
Medical conditions 
 
Warfarin dose and dosing history 
 
Medications 
 
International Normalized Ratios (INRs) and dates 
 
Complete blood count and kidney (serum creatinine, eGFR) and liver function 
 
Alcohol intake (for calculation of HAS-BLED score) 
 
Primary site for lab draws 
 
Home address 
 
Bleeding and clotting events 
 
Use of health care outside of the anticoagulation clinic (emergency room visits, 
hospitalizations, or non-routine primary care visits) 
 
Contact with the anticoagulation clinic 
 
Charlson Comorbidity Index and HAS-BLED scores (for all patients) and CHADS2 and 
CHA2DS2-VASc scores (for atrial fibrillation patients only) will be calculated at baseline.15-18   
 
TTR will be calculated using the Rosendaal method.14   
 
Data will only be shared with appropriate team members.  Removal of access to research study 
data will be accomplished for study personnel when they are no longer part of the research 
team.  The Information Security Officer and Privacy Officer will be notified within one hour of any 
actual or suspected data breach. 
 
 
If a breach of confidentiality takes place, it will be immediately reported to the VA R&D 
department and the VA information security officer for further action.  If there is any emotional 
upset by a participant, the will be asked if they would prefer to discontinue participation in the 
study and will have the opportunity to drop out.  If warranted, participants can be referred to 
Integrated Care clinic regarding emotional upset.  Integrated Care is a walk-in clinic at the 
Madison VA and is part of the Mental Health Department.   
 
 
Sample Size:  As this is a feasibility study, the primary concerns are whether or not this process 
could be incorporated into the normal anticoagulation clinic procedures and workflow.  Results 
from this study can be utilized for calculating sample size and power statistical tests in future 
larger studies.   
 
 
Analysis: 
Accrual rate will be determined by average participants enrolled per week. Dropout rate will be 
determined by the number of participants lost to follow up out of the total number of participants 


enrolled. Descriptive statistics (percentages, means, rates, and standard deviations) will be 
determined for all recorded baseline variables. Differences from baseline and at study 
completion will be compared utilizing McNemar Test for categorical data and paired t-test or 
Wilcoxon Signed-Rank Test for continuous and ordinal data (respectively). Thematic analysis 
will be utilized for to determine themes of satisfaction and/or concerns and barriers regarding 
the extended follow-up protocol from of the focus groups. 
 
 
References 
 
 
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