Evidence-based Synthesis Program 

Safe and Effective Anticoagulation

in the Outpatient Setting:

A Systematic Review of the Evidence 

Department of Veterans Affairs

Health Services Research & Development Service

February 2011

Investigators:

Principal Investigators: 

Hanna E. Bloomfield, MD, MPH 

Brent C. Taylor, PhD, MPH

Co-Investigators: 

Ange Krause, MD

Preetham Reddy, MD

Research Associates:

Nancy Greer, PhD

Roderick MacDonald, MS

Indulis Rutks, BA

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

VA Evidence-based Synthesis Program (ESP) Center

Center for Chronic Disease Outcomes Research

Minneapolis VA Medical Center

Minneapolis, MN

Timothy J. Wilt, MD, MPH, Director
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the Minneapolis VA Medical Center, Minneapolis, MN funded by 

the Department of Veterans Affairs, Veterans Health Administration, Office of Research 

and Development, Health Services Research and Development. The findings and conclusions in this document are those of the author(s) who are responsible for its contents; 

the findings and conclusions do not necessarily represent the views of the Department 

of Veterans Affairs or the United States government. Therefore, no statement in this 

article should be construed as an official position of the Department of Veterans Affairs. 

No investigators have any affiliations or financial involvement (e.g., employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents 

received or pending, or royalties) that conflict with material presented in the report.

PREFACE

Health Services Research & Development Service’s (HSR&D’s) Evidence-based Synthesis 

Program (ESP) was established to provide timely and accurate syntheses of targeted healthcare 

topics of particular importance to Veterans Affairs (VA) managers and policymakers, as they 

work to improve the health and healthcare of Veterans. The ESP disseminates these reports 

throughout VA.

HSR&D provides funding for four ESP Centers and each Center has an active VA affiliation. The 

ESP Centers generate evidence syntheses on important clinical practice topics, and these reports 

help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient outcomes and to 

support VA clinical practice guidelines and performance measures, and 

• set the direction for future research to address gaps in clinical knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of HSR&D Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of HSR&D field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: Bloomfield HE, Taylor BC, Krause A, Reddy P, Greer N, MacDonald 

R, Rutks, I, Wilt, T. Safe and Effective Anticoagulation in the Outpatient Setting: A Systematic 

Review of the Evidence. VA-ESP Project #09-009; 2011
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

TABLE OF CONTENTS

Executive Summary

Background.................................................................................................................................................... 1

Objectives...................................................................................................................................................... 1

Methods......................................................................................................................................................... 1

Results ........................................................................................................................................................... 2

Introduction

Background and Topic Development ........................................................................................................... 6

Methods

Search Strategy ............................................................................................................................................. 8

Data Extraction ........................................................................................................................................... 13

Quality Assessment .................................................................................................................................... 13

Data Synthesis ............................................................................................................................................ 13

Peer Review ................................................................................................................................................ 14

Results

Key Question #1.......................................................................................................................................... 14

Key Question #2.......................................................................................................................................... 25

Key Question #3.......................................................................................................................................... 43

Discussion and Recommendations

Key Question #1.......................................................................................................................................... 49

Key Question #2.......................................................................................................................................... 50

Key Question #3.......................................................................................................................................... 52

References............................................................................................................................................................ 54

Tables

Table 1. Summary of Study Characteristics for Anticoagulation Clinic vs. Usual Care Studies............. 19

Table 2. Outcomes Reported for Anticoagulation Clinic vs. Usual Care Studies.................................... 20

Table 3. Clinical Outcome Events for Anticoagulation Clinic vs. Usual Care Studies.......................... 21

Table 4. Laboratory Outcomes by Study Group for Anticoagulation Clinic 

vs. Usual Care Studies ............................................................................................................... 22

Table 5. Weighted Means for the Percentage of Time within Therapeutic Range for 

Anticoagulation Clinic vs. Usual Care Studies ........................................................... 23

Table 6. Summary of Study Characteristics for Patient Self Testing/Management 

vs. Usual Care Studies ...................................................................... .................. 30

Table 7. Outcomes Reported in for Patient Self Testing/Management vs. Usual Care Studies............... 31

Table 8. Clinical Outcome Events for Patient Self Testing/Management vs. Usual Care Studies........... 33
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Table 9. Laboratory Outcomes for Patient Self Testing/Management vs. Usual Care Studies................ 35

Table 10. Percentage of Time within Therapeutic Range for Patient Self 

Testing/Management vs. Usual Care Studies ............................................................................. 37

Table 11. Percentage of INR Values within Therapeutic Range for Patient Self Testing/Management 

vs. Usual Care Studies .......................................... ........................................................ 37

Table 12. Risk Factors for Serious Bleeding Reported in the Individual Studies ................ ................ 48

Figures

Figure 1. Analytic Framework ..................................................................................................................... 7

Figure 2. Literature Flow Diagram for Key Question 1 .............................................................. 10

Figure 3. Literature Flow Diagram for Key Question 2 ............................................................. 11

Figure 4. Literature Flow Diagram for Key Question 3 ............................................................. 12

Figure 5. All-cause Mortality, Anticoagulation Clinic vs. Usual Care ...................................................... 24

Figure 6. Methodologic Quality Summary, Patient Self Testing/Management vs. Usual Care 

Studies......................................................................................................................................... 38

Figure 7. All-cause Mortality, Patient Self Testing/Management vs. Usual Care

Studies ......................................................................................................... 39

Figure 8. Major Bleeding Events, Patient Self Testing/Management vs. Usual 

Care Studies................................................................................................................................ 40

Figure 9. Major Thromboembolic Events, Patient Self Testing/Management vs.

Usual Care Studies ............................................................................................. 41

Figure 10.Percent Time in Therapeutic Range, Patient Self Testing/Management vs.

Usual Care Studies ............................................................................................. 42

Figure 11.Percent of INRs within Therapeutic Range, Patient Self Testing/Management vs.

Usual Care Studies ............................................................................................. 42

Appendix A. Peer Review Comments and Responses...................................................................... 62

Appendix B. Evidence Tables

Table 1. Randomized Controlled Trials for Anticoagulation Clinic vs. Usual Care (KQ1) .................... 66

Table 2. Observational Studies for Anticoagulation Clinic vs. Usual Care (KQ1) .................................. 68

Table 3. Overview of Individual Short-term (<12 months) Randomized, Controlled Trials 

Investigating PST/PSM (KQ2).............................................................................. 70

Table 4. Overview of Individual Long-term (≥12 months) Randomized, Controlled Trials 

Investigating PST/PSM (KQ2).............................................................................. 74

Table 5. Overview of Individual Studies – Risk Factors for Serious Bleeding (KQ3) ......... ................ 77
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

EVIDENCE REPORT 

INTRODUCTION

BACKGROUND and TOPIC DEVELOPMENT

Long term anticoagulation with Vitamin K antagonists (e.g. warfarin) has been shown to reduce 

major thromboembolic complications in patients with many common chronic conditions, 

including atrial fibrillation, history of deep vein thrombosis and pulmonary embolism, and 

mechanical heart valves. However, Vitamin K antagonists have a very narrow therapeutic 

window requiring frequent laboratory monitoring to ensure that patients are neither excessively 

anti-coagulated, which increases the risk for bleeding, or under anti-coagulated, which increases 

the risk for thromboembolism. Laboratory monitoring consists of measuring the blood’s tendency 

to clot with a test known as the International Normalized Ratio (INR), usually performed every 

4-6 weeks. Dosage adjustments are then based on these results. 

Since management of long term oral anticoagulation requires frequent testing and dose 

adjustment, anticoagulation clinics (ACC) have been developed to streamline and standardize 

this care.1 Typically run by specially trained nurses or pharmacists, these clinics provide intense 

patient education, provide timely follow-up of INR results, use algorithms for dose adjustments, 

and are easily accessible to patients between visits. More recently, portable devices have become 

available that are able to accurately measure the INR with a drop of capillary blood. This means 

that patients can now test themselves at home and either call in the result to their provider 

who suggests dosage adjustments (known as patient self testing, PST) or adjust their dose of 

medication themselves (known as patient self management, PSM).2

As a leader in safety and quality, the Department of Veterans Affairs (VA) is interested in 

assuring that veterans on long-term anticoagulation receive state-of-the-art care that maximizes 

efficacy and minimizes complications. Towards that end, this review was commissioned by 

the VA’s Evidence-based Synthesis Program, in conjunction with the Office of Quality and 

Performance. Rowena Dolor, MD, MHS; Adam Rose, MD, MSc; and Keith Trettin, RPh, MBA 

agreed to serve on the Technical Expert Panel (TEP) for the project. We conferred with the TEP 

members and other experts inside and outside the VA to select the parameters of the review, 

including patient characteristics, interventions, and outcomes (Figure 1, Analytic Framework). 

The final key questions are:

1. For management of long-term outpatient anticoagulation in adults, are specialized 

anticoagulation clinics (ACC) more effective and safer than care in non-specialized clinics (e.g., 

primary care clinics, physician offices)? 

1a. Which components of a specialized anticoagulation clinic are associated with effectiveness/

safety?

2. Is Patient Self Testing (PST), either alone or in combination with Patient Self Management 

(PSM), more effective and safer than standard care delivered in either ACCs or non-specialized 

clinics? 

3. What are the risk factors for serious bleeding in patients on chronic anticoagulant therapy? 
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tion in the Outpatient Setting Evidence-based Synthesis Program

Interventions

ACCPSTPSM

n for 

est

Intermediate Outcomes• Anticoagulation Control• Outpatient visits, labs

3

1,2

1,2 3

Final Health Outcomes• VTE• Stroke, Peripheral arterial 

embolism

• Major Bleeding• Mortality• Satisfaction• Quality of Life• Hospitalizations• Other Health care utilization 

(ER visits, long term care)

ACC: anticoagulation clinicPST: patient self testingPSM: patient self managementINR: International Normalized RatioVTE: venous thrombo-embolism

 of long term outpatient anitcoagulation in adults, are specialized anticoagulation clinics, (ACC) 

fer than care in non-specialized clinics (e.g., primary care clinics, physician offices)?

ents of a specialized anticoagulation clinic are associated with effectiveness/safety?

testing (PST) and self management (PSM) effective, safe and cost-effective?

k factors for serious bleeding in patients on chronic anticoagulant therapy?

Harms

• Minor and Major Bleeding

• Patient Inconvenience
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

METHODS 

SEARCH STRATEGY

We searched Ovid MEDLINE using the search strategies outlined below. For Key Question 1 

we searched the <1950 to 2010> database, downloaded the results and then excluded pre-1996 

references. For Key Question 2, we searched the <1950 to 2010> database, limited the results to 

references from 2005-2010 in the search string and then downloaded the results for further inclusion/exclusion determination. This search was limited to articles published after 2004 because of 

the availability of a 2007 technology assessment report directly related to this question.2 For Key 

Question 3, we searched the <1996 to 2010> database and then downloaded the results for further 

inclusion/exclusion determination. For all three Key Questions, the initial literature search was 

completed in 2009. All searches were updated in March 2010 using identical search strategies. The 

literature search for Key Question 2 was updated again in October 2010. We also searched the

Cochrane Library and identified additional citations from reference lists of relevant articles. 

Search Strategy – Key Question #1:

1 warfarin.mp. or exp Warfarin/

2 coumadin.mp. 

3 coumarin.mp. or exp Coumarins/

4 exp anticoagulants/ or anticoagul*.mp.

5 or/1-4

6 Ambulatory Care Facilities/

7 Outpatient Clinics, Hospital/

8 6 or 7

9 5 and 8

10 (anticoagul* adj clinic*).mp.

11 9 or 10

Search Strategy – Key Question #2:

1 exp anticoagulants/

2 (warfarin or coumadin or coumarin).mp.

3 (oral adj anticoagul$).mp.

4 or/1-3

5 self administration/

6 drug administration schedule/

7 international normalized ratio/

8 near patient test$.mp.

9 point of care systems/

10 self test$.mp.

11 self manage$.mp.

12 drug monitoring/

13 primary health care/

14 (primary care or general practice or general practitioner$).mp.

15 or/5-14

16 4 and 15

17 limit 16 to yr=”2005 -Current”
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Search Strategy – Key Question #3:

1 (warfarin or coumadin or coumarin).mp.

2 exp HEMORRHAGE/ or hemorrhag*.mp.

3 exp CEREBROVASCULAR ACCIDENT/

4 exp CEREBROVASCULAR TRAUMA/

5 bleed$.mp.

6 stroke.mp.

7 or/2-6

8 1 and 7

9 risk factor*.mp. or exp Risk Factors/

10 predict*.mp. or exp Risk/

11 9 or 10

12 8 and 11

13 cohort stud*.mp. or exp Cohort Studies/

14 prospective stud*.mp. or exp Prospective Studies/

15 random*.mp. or exp Randomized Controlled Trial/

16 or/13-15

17 12 and 16

Trained researchers reviewed the titles and abstracts identified by the literature search to identify 

articles published in the English language, in peer-reviewed journals, and related to one of the 

key questions. For KQ1 and KQ2, we included articles that involved an outpatient, adult population receiving chronic (defined as more than 3 months) anti-coagulation therapy. For KQ3, we 

further limited the inclusion criteria to studies that involved warfarin therapy, reported results 

by risk factor status, and had a study population of at least 25 cases of serious bleeding. For all 

questions, we excluded case series, case reports, qualitative reports, narrative reviews, and editorials or letters. Full-text versions of potentially relevant articles were obtained for further review 

(see Figures 2, 3, and 4) and trained researchers extracted data from articles that met inclusion 

criteria.
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

612 potentially relevant 

articles screened by 

abstract review

78 articles retrieved for 

full-text review

11 studies 

(3 RCTs, 8 Cohort 

Studies)

68 articles excluded:

2 not in English, 

published before 1996 

or not peer-reviewed 

journal

0 not outpatient, adult 

population

0 not chronic 

anticoagulation

24 not RCT or Cohort

42 not related to question

4 duplicate and irrelevant articles 

removed by title search

534 records excluded: 

125 not in English, 

published before 1996 

or not peer-reviewed 

journal

13 not outpatient, adult 

population

4 not chronic 

anticoagulation

338 not related to question

54 case series, case 

report, qualitative 

report, narrative review, 

letter or editorial

1 article obtained by hand 

searching

616 articles identified in 

MEDLINE screened for 

retrieval

Figure 2. Literature Flow Diagram for Key Question 1
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

2129 potentially relevant 

articles screened by 

abstract review

81 articles retrieved for 

full-text review

70 articles excluded:

2 not chronic anticoagulation

34 case report, case series, 

qualitative report, narrative 

review, editorial/letter

34 not related to key question 

98 duplicate and irrelevant articles 

removed by title search

2048 records excluded:

164 not in English, published 

before 1996 or not peerreviewed journal

77 not outpatient, adult 

population

61 not chronic anticoagulation

1368 not related to question

378 case series, case report, 

qualitative report, narrative 

review, letter or editorial

16 articles from HTA 20072

2227 articles identified in 

MEDLINE screened for 

retrieval

27 articles reporting on 

22 randomized controlled 

trials

Figure 3. Literature Flow Diagram for Key Question 2
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

78 articles retrieved for 

full-text review

35 articles

46 articles excluded:

5 less than 25 cases of 

serious bleeding

23 no serious bleeding results 

given by risk factor

4 not outpatient, adult 

population on chronic anticoag therapy

4 not warfarin

10 qualitative report, narrative 

review, letter or editorial

603 articles excluded:

44 less than 25 cases of 

serious bleeding

204 no serious bleeding results 

given by risk factor

104 not outpatient, adult 

population on chronic anticoag therapy

37 not in English 

54 not warfarin

160 qualitative report, narrative 

review, letter or editorial

3 articles identified by handsearching

681 articles identified 

in Medline screened by 

abstract review

Figure 4. Literature Flow Diagram for Key Question 3
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

DATA EXTRACTION

For studies related to Key Questions 1 and 2, we extracted data on study design, country of 

origin, funding source, indications for anticoagulation, sample characteristics, interventions, 

mortality, thromboembolic events, major bleeding events, patient satisfaction, quality of life, 

laboratory measures of anticoagulation quality (i.e., percent time within the therapeutic range, 

percent of INR values within the therapeutic range, and INR variability), hospitalizations, 

outpatient and emergency room utilization, outpatient laboratory utilization, and long-term care 

admissions. 

For Key Question #1a, we extracted data on ratio of staff to patient load; qualifications of staff 

and leadership; organizational structure of clinic; frequency and type (e.g., face-to-face versus 

phone) of contact with patient; frequency and timing of INR checks; use of computer-based 

algorithms to adjust dosing; timeliness of follow-up of abnormal INRs; patient education; 

use of genetic information to tailor therapy; protocols for use of vitamin K; clinic volume; 

hypercoagulation workups (e.g., Factor V Leiden); and use of technologies such as Interactive 

Voice Recording.

For Key Question #3, we extracted data on study characteristics, patient factors (e.g., age, 

gender, level of education); indication for anti-coagulation (atrial fibrillation; deep vein 

thrombosis/pulmonary embolism – either first or recurrent and with or without precipitating 

factors; mechanical heart valve; TIA/stroke; other); indices measuring severity of illness, 

functional status, and co-morbidity; time above therapeutic range; type of anticoagulant used; 

frequency and type of monitoring; concomitant use of anti-platelet agents; concomitant use of 

other medications; and setting within which patient is monitored (specialized anticoagulation 

clinic or not).

QUALITY ASSESSMENT

The quality of the individual randomized studies was assessed by the following: 1) adequate 

allocation concealment, denoted by central allocation, including telephone, web-based and 

pharmacy controlled randomization or use of sequentially numbered, opaque, sealed envelopes; 

2) blinding of key study personnel (i.e., providers and/or study personnel who adjudicated 

outcomes blinded to group assignment); 3) analysis by intention-to-treat (i.e., all subjects 

counted in group to which they were randomized in the outcomes analyses); and 4) reporting of 

number of withdrawals/dropouts by group assignment.

DATA SYNTHESIS

For Key Question #1, analyses using a DerSimonian and Laird random-effects model, which 

assumes that the true treatment effects in the individual trials may vary from each other, were 

conducted in Review Manager Version 5.0.3 A random-effects model is an analytical approach 

that incorporates heterogeneity that cannot be readily accounted for. Statistical heterogeneity 

between trials was assessed using the I2 test. An I2 score of 50 or greater indicates substantial 

heterogeneity.4

For Key Question #2, clinical outcomes data were pooled and analyzed in Review Manager 
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Version 5.0.3 Because of low event rates for several clinical outcomes, we used Peto odds ratios 

(fixed effects model). Weighted mean differences were calculated using a random effects model 

using the Comprehensive Meta-Analysis software© (Biostat, Inc., Englewood, NJ). Statistical 

heterogeneity between trials was assessed using the I2 test; a score of 50% or greater suggests 

moderate to substantial inconsistency among studies.4 In order to explore heterogeneity we 

performed subgroup analyses and tested for interactions. The extent of publication bias was 

evaluated through visual inspection of funnel plot asymmetry and the linear regression–based 

test proposed by Egger.5

PEER REVIEW

A draft version of this report was sent to our Technical Expert Panel members and to three peer 

reviewers. Reviewer comments were addressed and our responses incorporated into the final 

report (Appendix A).
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

RESULTS

KEY QUESTION 1

For management of long-term outpatient anticoagulation in adults, are specialized 

anticoagulation clinics (ACC) more effective and safer than care in non-specialized clinics (e.g., 

primary care clinics, physician offices)? 

Literature Search

Using the search strategy outlined in the Methods section, we searched for both randomized 

clinical trials and cohort studies published after 1996 in peer reviewed journals. We excluded 

non-English articles and studies that dealt with inpatients, pediatric populations, or short-term 

anticoagulation (< 3 months). As shown in Figure 2, we reviewed the abstracts of 612 articles 

of which 78 were selected for more detailed review. Of these, we identified a total of 10 articles. 

One more was obtained through a hand search for a total of 11 articles reporting on 3 randomized 

clinical trials and 8 cohort studies that met all inclusion criteria. 

Randomized Controlled Trials

Overview of Included Studies (Table 1; Appendix B - Table 1)

The 3 trials were conducted in the US, China, and Canada. The Canadian trial randomized 221 

subjects with mixed indications for outpatient anticoagulation (OAC) to either an ACC or usual 

care with a family physician and followed them for 3 months.6 The Chinese trial randomized 138 

subjects with mixed indications for OAC to either a hematologist-led or a pharmacist-led ACC 

and followed them for up to 2 years.7 The US trial randomized practice clusters within 6 sites to 

either access or no access to an ACC; only subjects with atrial fibrillation as their indication for 

OAC were included.8 Although 2 of the studies enrolled inception cohorts (i.e., patients new to 

anticoagulation), neither study was designed to detect differences in outcomes between the early 

and the maintenance anticoagulation phases.6,7 

Subject Characteristics in the RCTs (Table 1)

A total of 722 subjects were enrolled in the 3 RCTs. The mean age of the subjects was 68 (range 

of study means, 59 to 76 years). Fifty one percent of subjects were male (range in studies, 45 

to 58%). In the US study 37% of subjects were non-white;8 in the Chinese study all subjects 

were Asian.7 The Canadian study did not report race/ethnicity.6 There were 359 patients in the 2 

studies that allowed mixed indications for OAC6,7 and 363 in the one study restricted to subjects 

with atrial fibrillation.8

Study Quality

The quality of the included studies was generally low. Only the Canadian study met all 4 of 

the quality indicators (adequate allocation concealment, some attempt at blinding, analyses by 

intention to treat [partially], and adequate description of study withdrawals).6

Interventions in the RCTs

In the US study,8 the intervention consisted of an ACC which had responsibility for 3 core 

functions: management of anticoagulation which involved assigning patients to a medically 
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

qualified mid-level provider; screening administrative files to find eligible patients and offering 

ACC services to these patients’ providers; and educating patients about anticoagulation. 

In the Canadian study,6

 all enrolled patients received standard education regarding importance of 

medication compliance, self monitoring for clinical complications, dietary considerations, and 

possible medication interactions and were monitored by the ACC until they had achieved a stable 

dose of warfarin. They were then randomized to continued care in the ACC or with their primary 

care physician. Details of the procedures employed in the ACC were not included in the report. 

In the Chinese study,7

 the intervention consisted of a pharmacist led clinic. The pharmacist 

received 1 month of training from 2 hematologists and was provided with a management 

protocol. A hematologist saw patients on their first visit to determine target INR range and 

duration of therapy. Patients in this arm received “intense education” during visits, written 

materials, and access to a pharmacist consultation through a telephone hotline.

Outcomes in the RCTs

The outcomes reported in each study are shown in Table 2. As shown in Table 3, there were 

very few major clinical outcome events and rates of all-cause mortality, major thromboembolic 

events, and major bleeding did not differ significantly between the two treatment arms in any 

of the 3 studies. Time within therapeutic range did not differ between intervention and control 

groups in the US and Canadian studies but was significantly higher in the intervention group in 

the Chinese study (64% v. 59%, p<0.05). 

Two of the 3 RCTS evaluated patient satisfaction.6,7 Using the Patient Satisfaction Questionnaire 

Short Form (PSQ-18), overall patient satisfaction was significantly higher in the intervention 

group (pharmacist managed) than in the control group (physician managed) (P <0.001).7 Similar 

significant results were also found for the sub-scores measuring technical quality, interpersonal 

manner, communication, time spent with clinician and accessibility but there were no significant 

differences in the general satisfaction and financial sub-scores. In the second study,6 patient 

satisfaction was measured by a “previously validated questionnaire”, not referenced. Ninety six 

percent of patients in ACC reported being satisfied or very satisfied with their overall warfarin 

care compared with 84% of patients randomized to the family physician group (p=0.001). 

Specifically, patients in the ACC group reported significantly higher satisfaction with teaching, 

helpfulness of staff, availability of staff in an emergency, and time spent with staff than the 

subjects randomized to usual care. 

In the one RCT that reported resource utilization,7

 there were no significant differences in cost 

per patient per month between the intervention and control groups for medication use, emergency 

room utilization, and hospitalizations. 

Pooled Data

In the pooled analysis (Figure 5), there were 5 deaths in the ACC group and 6 in the Usual 

Care (UC) group, all from a single study (RR: 0.81, 95%CI: 0.25 to 2.58);6

 6 major bleeding 

events in the ACC patients and 8 in UC patients (RR: 1.05, 95%CI: 0.36 to 3.12); 11 major 

thromboembolic events in the ACC and 14 in the UC patients (RR: 1.29, 95%CI: 0.59 to 2.81).
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Laboratory Outcomes

Percent time in therapeutic range (TTR) by study group is shown in Table 4. In all 3 trials, 

%TTR was higher for the ACC than the UC group, but in only one was the difference statistically 

significant.7 Overall, the pooled weighted mean of TTR for patients randomized to ACC was 

59.9% (range of means 56-64%), only slightly higher than the 56.3% (range of means 52 to 59%) 

for the patients randomized to usual care, for a weighted mean difference of 3.6 (range of mean 

differences 3.3 to 5) (Table 5). 

Cohort Studies

Overview of Included Studies (Table 1; Appendix B - Table 2)

Five of the 8 cohort studies were conducted in the US,9-13 1 in China,14 1 in Sweden,15 and 1 

in multiple countries.16 Three studies were prospective9,14,15 and 5 were retrospective cohort 

studies.10-13,16 Five studies included subjects with mixed indications for OAC9-12,15 and 3 included 

only subjects with atrial fibrillation.13,14,16 One study enrolled an inception cohort, meaning that 

subjects had been on OAC for < 3 months,10 2 did not,11,13 and in the other 5 it was unclear.9,12,14-16

The one study that enrolled an inception cohort did not stratify outcomes by initiation vs. 

maintenance phases.10 Follow-up was less than 12 months in 2,9,12 12 months in 2,13,16 >12 months 

in 1,15 and not reported in 3 studies.10,11,14 In 4 studies, the intervention was an ACC run by a 

pharmacist,9-12 in one it was an ACC run by a nurse,13 in one it was defined as care provided in a 

systematic way by personnel focusing specifically on AC management,16 and in 2 others the ACC 

was not described.14,15

Subject Characteristics in the Cohort Studies (Table 1)

A total of 12,768 subjects were included in the 8 observational studies. The mean age of subjects 

was 69 (range of study means, 57 to 74). Fifty five percent of subjects were male (range in 

studies 42 to 59%). Race/ethnicity was only reported in 2 studies. There were 9946 subjects 

in the studies that allowed mixed indications for OAC and 2822 in the 3 studies that restricted 

enrollment to atrial fibrillation. 

Outcomes in the Cohort Studies

Reported outcomes are shown in Tables 2 and 3. In the only study in which all-cause mortality 

was reported, there were 3 deaths (0.09%) in the intervention group and 2 (0.06%) in the control 

group (p values not reported).12 Four studies reported major thromboembolic events; in 1 of these 

the incidence was significantly higher in the control group,10 in 1 it was significantly higher in 

the intervention group,14 and in 2 studies p values were not reported.12,13 The incidence of major 

bleeding events was significantly higher in the control group in 1 study,

10 and not significantly 

different between groups in 1 study.14 Significance testing was not included for the 3 other 

studies that reported this outcome.12,13,15 We were unable to pool major clinical outcomes because 

outcomes were reported as number of events in only 2 of the 8 studies;12,14 the other studies 

reported events per patient- or treatment-year. 

Laboratory Outcomes

As shown in Table 4, time within therapeutic range or percent of INR values within the 

therapeutic range was higher in the intervention group in all 6 studies that reported this 
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Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

metric.10-14,16 As shown in Table 5, the weighted mean for percent time within therapeutic range 

for the 4 studies reporting this metric,10,12,13,16 was 63.5% for the intervention groups and 53.5% 

for the control groups, for a difference of 10% (range of mean differences, 4.3 to 26%). 

Other Outcomes

Three observational studies reported hospital admissions and/or emergency department (ED) 

visits.9-11 In one there were no significant differences between UC and ACC groups for ED visits 

or inpatient admissions.11 In the second,10 there were significantly fewer anticoagulation related 

hospitalizations (19 v 5) and ED visits (22 v 6) in the ACC group. For hospitalizations unrelated 

to AC use, there were no differences between the 2 groups but the group randomized to AC had 

significantly fewer ED visits for reasons deemed unrelated to anticoagulation. The third study,9

reported warfarin-related hospital admissions in 10 control group patients vs. 3 ACC patients 

(p<0.01). 

KEY QUESTION 1a

Which components of a specialized anticoagulation clinic are associated with effectiveness/

safety?

None of the included studies reported the association between specific elements of ACC (e.g. 

ratio of staff to patient load; qualifications of staff and leadership; organizational structure 

of clinic; frequency and type of contact with patient; use of computer-based algorithms to 

adjust dosing; patient education) and outcomes. In one RCT, patients in both arms received 

algorithm driven dose adjustments,7 and in the other 2 studies only patients in the intervention 

arm were managed with dosing algorithms.6,7 Among the 8 observational studies, 4 commented 

on possible processes of care that might have accounted for observed differences in outcomes. 

These included use of both face-to face and telephone interactions with patients,13 use of a 

computerized patient monitoring system that identified patients who were delinquent in returning 

for timely INR determinations;12 the specialized expertise of the ACC staff;12 more consistency 

in ACCs in obtaining regular INRs;11 and frequency of face-to-face consultations, methods of 

dosage adjustment, and provision of written dosage instructions.16

SUMMARY – KEY QUESTION 1

The evidence suggests that care provided within ACC may lead to better quality anticoagulation 

control as measured by time in therapeutic range but there is insufficient evidence to conclude 

that ACC care leads to fewer deaths, thromboembolic events, or major bleeding events than care 

provided in usual care settings such as primary care clinics. Patients were reported to like the 

convenience and enhanced service provided by these clinics. 
19

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Table 1. Summary of Study Characteristics for Anticoagulation Clinic versus Usual Care Studies 

(KQ1) 

 Randomized controlled 

trials (N=3)

Observational studies 

(N=8)

Characteristic

Range or

Mean %

# studies

reporting

Range or

Mean %

# studies

reporting

Overall: number of subjects per study 138 to 363

(722 total) 3 116 to 6645(12,768 total) 8

Study dropouts/withdrawals, overall: 

mean % (range) 1 (0.7 to 1) 2 NA NA

Age of subjects: mean years (range) 68 (59 to 76) 3 69 (57 to 74) 6

Gender, male: mean % (range) 51 (45 to 58) 3 55 (42 to 59) 8

Race/ethnicity, white: mean % (range) 45 (0 to 63) 2 73 (0 to 86) 2

Race/ethnicity, non-white: mean % 

(range)

55

(37 to 100*) 2 23(14 to 100*) 2

Indication for anticoagulation, mixed 

indications:** number of subjects per 

study

138 to 221

(359 total) 2 116 to 6645(9946 total) 5

Indication for anticoagulation, atrial 

fibrillation: number of subjects per study 363 1 204 to 1511(2822 total) 3

Non-pharmacy, mixed (RN, NP, PA, 

PharmD, MD), or unclear managed 

anticoagulation clinic studies: number of 

subjects per study

221 to 363 

(584 total) 2 204 to 2731(5553 total) 4

Pharmacy-managed anticoagulation 

clinic studies: number of subjects per 

study

138 2 116 to 6645

(7215 total) 4†

Studies conducted in the United States: 

number of subjects per study 363 1 116 to 6645(8322 total) 5

Prospective cohort studies: number of 

subjects per study NA

136 to 2731

(3071 total) 3

Retrospective cohort studies: number of 

subjects per study

116 to 6645

(9697 total) 5

* 1 trial exclusively Asian

** Generally venous thromboembolism; CVA/stroke; heart valve replacement, atrial fibrillation, pulmonary 

embolus, myocardial infarction, cardiomyopathy or prophylaxis;

† All studies conducted in the United States
20

tion in the Outpatient Setting Evidence-based Synthesis Program

or Anticoagulation Clinic versus Usual Care Studies (KQ1) 

tality Thromboembolic 

events

Major 

bleeding 

events

Quality of 

life/patient 

satisfaction

% Time 

within 

therapeutic 

range

% INR 

values within 

therapeutic 

range

Emergency 

Room visits

Hospitalizations

√ √ √

√ √ √ √ √ √√ √ √ √ √ √ √

√

√ √ √ √ √ √

√ √ √

√ √ √ √

√ √ √

√ √

√

√ √ √

3 7 8 2 7 4 3 5
21

tion in the Outpatient Setting Evidence-based Synthesis Program

ents for Anticoagulation Clinic versus Usual Care Studies (KQ1) 

# All-cause deaths # Thromboembolic events # Major bleeding events

ention Control Intervention Control Intervention Control

9/173

(5.2%)†

11/317

(3.5%)

3/173

(1.7%)†

5/317

(1.6%)

12

%)†

6/109

(5.5%)

1/112

(0.9%)†

2/109

(1.8%)

2/112

(1.8%)†

1/109

(0.9%)

69† 0/69 1/68

(1.5%) †

1/69

(1.4%)

1/68

(1.5%) †

2/69

(2.9%)

3.3%

per pt-yr*

11.8%

per pt-yr

9.7%

per pt-yr*

39.2%

per pt-yr*

323

9%)‡

2/3322

(0.06%)

17/3323

(0.5%)‡

41/3322

1.2%)

29/3323

(0.9%)‡

31/3322

(0.9%)

19/138

(13.8%)*

2/66

(3.0%)

8/138

(5.8%)†

2/66

(3.0%)

13/2292 tx-yrs‡ 21/2752 tx-yrs

1.9% per pt-yr‡ 3.7% per pt-yr 2.3% per pt-yr‡ 6.3% per pt-yr

ersus control
22

tion in the Outpatient Setting Evidence-based Synthesis Program

 by Study Group for Anticoagulation Clinic versus Usual Care Studies

 Time within 

apeutic range

% INR values within 

therapeutic range 

% Time above 

therapeutic range

% Time below therapeutic 

range

ntion Control Intervention Control Intervention Control Intervention Control

%† 52.3%

 † 59%

%* 59%

%* 41.4% 36.6%* 31.3%

50.2%‡ 45.8%

%* 55.2% 11.8%* 14.5% 24.7%* 30.3%*

63.6%* 23.3%

57.9% 59.1%‡ 52% 13% 17% 20% 25%

%* 42.1% 11.3% 9.4% 20.6% 48.5%

ersus control
23

tion in the Outpatient Setting Evidence-based Synthesis Program

he Percentage of Time within Therapeutic Range for Anticoagulation Clinic versus Usual Care Studies

 n

AC, % time

within range UC n

UC, % time 

within range

Mean

difference

4 55.6%* 118 52.3% 3.3%

2 63%* 106 59% 4%

8 64%** 69 59% 5%

59.9% 56.3%

Weighted mean 

difference = 3.6% 

(range of means 3.3 to 5)

6 45.7%** 142 41.4% 4.3%

23 63.5%** 3322 55.2% 8.3%

5 67%† 1116 57.9% 9.1%1 68.1%** 756 42.1% 26%

63.5% 53.5%

Weighted mean

difference = 10%

(range of means 4.3 to 26)

ersus Usual Care
24

tion in the Outpatient Setting Evidence-based Synthesis Program

Anticoagulation Clinic versus Usual Care

coagulation Clinic Usual Care Risk Ratio Risk Ratio

vents Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI

0 69 0 69 Not estimable5 112 6 109 100.0% 081 [0.25, 2.58]

181 178 100.0% 0.81 [0.25, 2.58]

5 6

P = 0.72) Favors AC Favors UC
25

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

KEY QUESTION 2

Is Patient Self Testing (PST), either alone or in combination with Patient Self Management 

(PSM), more effective and safer than standard care delivered in either ACCs or non-specialized 

clinics? 

Literature Search

Using the search strategy shown in the Methods section, we looked for randomized clinical 

trials published after 1996 in peer reviewed journals. We excluded non-English articles as 

well as studies that dealt with inpatients, pediatric populations, or short-term anticoagulation 

(<3 months). As shown in Figure 3, we screened 2129 abstracts and selected 81 for full article 

review. Of these, we identified a total of 27 articles reporting on 22 distinct randomized clinical 

trials.

Overview of Included Studies

An overview of the 22 included studies is shown in Appendix B, Tables 3 and 4. Two studies 

were conducted in the US,17,18 1 in Canada,19 and 19 in Europe.20-45 Duration of follow-up was 

less than 12 months in 13 studies and 12 or more months in 9. A total of 8413 subjects were 

included in the 22 trials, with individual trial sample sizes ranging from 50 to 2922 (Table 6). 

Fourteen studies included patients with a variety of indications for anticoagulation17-24,26,28-30,32,39-43

and 8 only included patients with mechanical heart valves (6)31,33-38,44,45 or atrial fibrillation 

(2).25,27 Three trials enrolled inception cohorts (i.e., limited enrollment to patients on OAC for < 

3 months);18,35-37,45 11 trials did not enroll inception cohorts;17,21-26,28-30,32,39,40,42,43 and in 8 studies 

the populations were either mixed or it was unclear.19,20,27,31,33,34,38,41,44 Among the 3 with inception 

cohorts, outcomes were not analyzed by whether they had occurred in the anticoagulation 

initiation or maintenance phase. 

Assessments of Quality and Bias

Measures of trial quality are shown in Figure 6 and reported in Appendix B, Tables 3 and 4. 

Allocation concealment was adequate in 9 trials, some attempt at blinding of endpoint assessors 

was made in 6, an intention to treat analysis was reported in 8, and number of drop-outs was 

reported in 18. Five trials met all 4 of these quality indicators.17,20,24,41-43 Only six trials noted they 

received no funding from industry.17,18,28,29,32,39 Egger’s test suggested little evidence that small 

study effects influenced the findings for thromboembolic events (P = 0.513). 

Subject Selection

The percentage of patients screened who met preliminary eligibility criteria, successfully completed 

the training, and agreed to be randomized was less than 20% in 4 studies,22,23,30,45 between 20 and 

50% in 7 studies,24,25,28,32,39,41,43 and greater than 50% in 3 studies.19,20 Eight studies did not report 

data; THINRS data is presented below. It is difficult to determine how many refusals were due to 

discomfort being in a trial vs. discomfort with self testing and/or self management of anticoagulation. 

Among patients who were randomized, the percentage who continued with the intervention 

throughout the study period ranged from 64-98%. 

Subject Characteristics

The mean age of the subjects was 65 years (range of study means 42 to 75 years) (Table 6). 

Three studies specifically focused on elderly patients, enrolling only patients over the age of 
26

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

6518,25 or 60 years of age.43 Seventy five percent of subjects were male (range in studies, 43 to 

98%). Race/ethnicity was reported only in the 2 US studies, in one of those 8%17 and in the other 

33%18 of the subjects were non-white. A total of 2911 subjects were enrolled in the 12 studies in 

which there were multiple indications for anticoagulation; 2074 were enrolled in the 6 studies 

restricted to a mechanical heart valve indication; 327 in the 2 studies limited to atrial fibrillation; 

and 3101 in the 2 trials that limited enrollment to mechanical heart valve or atrial fibrillation. 

Interventions

Evaluated interventions included patient self testing only (i.e., dose adjustment made by the 

clinic, n=5)17,18,25,32 and patient self-management (i.e. testing and dose adjustment made by 

patient, n=14).19-22,25-28,30,31,35,36,38,39,41,43-45 In one study it was unclear if the intervention was PST 

or PSM.34 In one study there were 4 arms (PST, PSM, routine care with or without education).23

In one study there were 3 groups: routine care alone, routine care with education and PSM with 

education.25 In one study PSM was compared to PST with no control group.26,30 In 11 studies 

warfarin was used in all subjects,17-19,22,25,26,30,32,38,39,44 other oral anticoagulants (phenprocoumon, 

acenocoumarol, fluindione) were used in 7,20,21,23,31,35,36,41,43 in 3 studies the type of oral 

anticoagulant was not reported,27,34,45 and in 1 study both warfarin and phenprocoumon were 

used.28

Details of PST/PSM Intervention:

The patient self testing/self management intervention usually included 2-4 small group training 

sessions of 1-3 hours over several weeks. The sessions, which were led by a nurse, pharmacist 

or physician, were followed by home practice and a test to ensure competency in all procedures. 

Training sessions typically included general information on anticoagulation, possible interactions 

with foods/medicines, how to use the INR testing machine (including demonstrating ability 

to use the machine correctly and to perform quality control checks), how to dose (usually by 

algorithm), how often to check INR, and when to call for help. Patients often had access to a 24 

hour telephone help line. Two studies had much more intensive training. One of the US studies 

included one-on-one daily training by a lay educator while patients were still in the hospital 

followed by a home visit within 3 days of discharge.18 The second study included a 24 week 

training program in which responsibility for dosing was gradually transferred from physician 

to patient,28,29 A recent study from Ireland32 employed an internet-based direct to patient expert 

system in which patients receive advice on dosing from the system after entering their INRs and 

relevant clinical information (e.g. intercurrent illnesses, dietary changes). 

Control Intervention:

The control group received anticoagulation management in an ACC in 11 of the 

trials,17,21-23,25,32,39,41,45 in a primary care or other physician office in 7 trials.18-20,27,31,34-36,44 and in 

multiple settings in 3 trials.28,38,42 The other trial compared PST to PSM without another control 

group.26,30

Outcomes

Reported outcomes are tabulated in Table 7 with details in Tables 8 and 9. All-cause mortality 

was reported in 16 studies, thromboembolic events in 20, major bleeding episodes in 20, and 

patient satisfaction and/or quality of life in 11. All studies reported one or more laboratory 
27

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

measure of quality of anticoagulation, the most common being a measure of time in therapeutic 

range in 18 studies. 

Clinical Outcomes (Figures 7, 8, and 9)

There were 298 deaths in subjects randomized to PST/PSM intervention compared to 369 deaths 

in the control subjects (Peto OR: 0.74, 95%CI: 0.63 to 0.87, P=0.000), I2=51%). The intervention 

group had 283 major bleeding events compared with 300 in the control group (Peto OR: 0.89, 

95%CI: 0.75 to 1.05, P=0.169, I2=2%). There were 99 major thromboembolic events in the 

intervention group compared with 149 in the control group (Peto OR 0.58, 95%CI: 0.45 to 0.75, 

P<0.000, I2=27%). 

Sensitivity Analyses:

There was evidence of inconsistency among the studies, especially for the mortality outcome. 

In order to explore sources of heterogeneity we conducted subgroup analyses for all 3 clinical 

outcomes stratifying by the following variables: duration of study (<12 vs. ≥12 months), 

indication for anticoagulation (mechanical heart valve vs. all other), active intervention (PST vs. 

PSM), control intervention (ACC vs. physician office), study quality (met all 4 quality domains 

cited above), and funding source (industry vs. not reported vs. non-industry). Although in the 

initial analyses there were several significant interactions (i.e., for mortality: indication for 

anticoagulation, active intervention, control intervention, study quality, and funding source; for 

bleeding: study duration; and for thromboembolism: active intervention and funding source), 

only one remained marginally significant after we removed the VA trial, suggesting that the 

VA trial was a major contributing factor to the observed heterogeneity (see below for further 

discussion). The marginally significant interaction was for major bleeding by study duration 

(study duration: > 12 months: Peto OR 1.04 95% CI 0.76 to 1.42; <12 months, Peto OR: 0.44, 

0.22 to 0.85, P for interaction=0.02). 

Effect of Patient Education on Outcomes:

Subjects enrolled in the PSM or PST arms of a trial receive more extensive training and 

education than patients assigned to usual care which might explain the difference in outcomes 

between the 2 groups. In the 2 studies that were designed to explore the independent effect of 

patient education, one found no effect of patient education on time in therapeutic range.23,24 The 

other did find a significant effect on time in therapeutic range using a before-after within group 

comparison, rather than the more robust between group comparison.25

Outcome Differences between PST and PSM:

Two studies23,30 compared PSM to PST. In neither study (Gadisseur23 N=99 for this comparison; 

Gardiner30 N =104) was there a significant difference in TTR between the 2 groups.

Percent Time in Therapeutic Range (TTR) by Study Group (Tables 9 and 10):

Overall, the pooled weighted mean of TTR for patients randomized to PST/PSM interventions 

was 66.1% (range of means 56-76.5%), only slightly higher than the 61.9% (range of means 

32 to 77%) for the patients randomized to usual care (Table 10). As shown in Figure 10, for the 

studies we were able to include in a meta-analysis the weighted mean difference of 1.50% was 

not statistically significant (95% CI: -0.63 to 3.63%, I2=45%, 9 studies, P=0.168).
28

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Percent of INRs within Therapeutic Range:

As shown in Tables 9 and 11, 11 studies reported mean values for this outcome. The pooled 

weighted mean was 70.5% (range of means 43 to 87%) in the PST/PSM group and 59.3% in 

the usual care group (range of means 22 to 78%). For the studies we were able to include in the 

meta-analysis, the weighted mean difference of 5.9% was not statistically significant (Figure 11) 

with a high level of heterogeneity (95%CI: -0.18 to 12.0%, I2=83%, 6 studies, P=0.057). 

Patient Satisfaction and Quality of Life:

There is little uniformity in the measurement or definition of these constructs within the 11 

studies that reported them.17,19-,22,24-26,32,39,45 Three studies that used an instrument developed by 

Sawicki et al.20 all found significant differences between the PST/PSM and the UC groups. 

Specifically, in the German study20 patients randomized to PSM had significantly higher general 

treatment satisfaction and self efficacy, and significantly less distress and daily hassles than those 

in UC. In the cross-over study from the Netherlands,21 patients in the self management group 

reported significantly more self-efficacy and general treatment satisfaction, and significantly 

less distress, social issues and daily worries than those in UC. In the third study, also from the 

Netherlands,24 patients were randomized to usual care, PST only, and PSM. This study showed 

that patients in both intervention arms had significant reductions in daily hassles, distress, and 

strains in social network and increase in self efficacy and general satisfaction compared to the 

UC group. There were no statistically significant differences between the 2 intervention arms. 

In 3 additional studies, one found that all of the patients who had been randomized to PSM 

wanted to continue the program after the study ended,19 in the second, 77% indicated at the 

end of the study that they preferred self-testing to the hospital clinic,26 and in the third, 98% 

expressed a preference for PST.32 Three studies found no significant difference in patient 

satisfaction or quality of life between groups.22,25,40 Patient satisfaction in the VA trial17 is 

described below. 

THINRS

This trial17 is of particular interest since it was conducted in VA and is the largest trial to date 

comparing patient self-testing with usual care. The trial recruited 3,745 subjects in 28 VAMCs 

who required long term oral anticoagulation for either atrial fibrillation or a mechanical heart 

valve. Forty two of these subjects did not meet all entry criteria, 60 did not complete training, 

586 did not undergo competency testing, 112 did not pass competency testing, and 23 passed 

the competency assessment but subsequently withdrew. Thus 78% of screened subjects were 

enrolled in the trial (N=2922). Subjects were randomized to high quality anticoagulation clinic 

management or patient self testing. Randomization was centralized and stratified by length of 

anticoagulation (< 3 months vs. > 3 months) and indication. The primary endpoint was time 

to first event: stroke, major bleed, or death. Although the investigators and subjects were not 

blinded to treatment allocation, outcomes were assessed by independent adjudicators. An 

intention to treat analysis was performed. In both groups, loss to follow up was 1% in and 

warfarin discontinuation was 7%.

Ninety eight percent of the patients were male with a mean age of 67 (range of 33 to 99). Ninety 

two percent were white. Eighty three percent had atrial fibrillation and 24% had a mechanical 

heart valve. The primary endpoint was time to first event: stroke, major bleed, or death. The time 
29

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

to event curves did not differ significantly between intervention groups for either the primary 

endpoint or any of its three individual components. Time in target range and patient satisfaction 

were significantly higher in the PST group. 

As indicated above, our results for major thromboembolism and bleeding appear to be robust 

with negligible heterogeneity, and similar findings have been reported in other reviews.2,46,47

For mortality, however, there was evidence of inconsistency among studies that was likely 

attributable to the VA study. There are several possible reasons why the VA results differed from 

the other studies. First, this trial had substantially longer follow-up than any of the other studies 

and it may be that over time people assigned to PST stop testing as frequently leading to a 

lessening of the difference between those who are seen every month in the anticoagulation clinic 

and those who self test at home. Second, if the VA PST intervention was of lower quality than in 

other trials, this could explain its lower efficacy. However, this did not appear to be the case as 

the PST intervention included a rigorous patient education program and ongoing quality control 

which resulted in high percent time within therapeutic range. Finally, if the VA anticoagulation 

clinic was of higher quality than in the other trials, there would be less of an observed difference 

in outcomes between the 2 arms than in studies in which PSM/PST was compared to a lower 

quality control intervention. This likely was the case as the VA trial employed rigorous criteria to 

ensure that care in the anticoagulation clinics was state of the art.17

SUMMARY – KEY QUESTION 2

This review confirms that patient self testing with or without self management is at least as 

effective and safe as routine care for a select group of motivated adult patients requiring long 

term anticoagulation with Vitamin K antagonists. 
30

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Table 6. Summary of Study Characteristics for Patient Self Testing/Management versus Usual Care 

Studies 

Characteristic Range or Mean %

# studies 

reporting

Overall: number of subjects per study 50 to 2922 (8413 total) 22

Short-term trials (<12 months): number of subjects 

per study 50 to 341 (1935 total) 13

Long-term trials (≥12 months): number of subjects 

per study 62 to 2922 (6478 total) 9

Study dropouts/withdrawals, overall: mean % 

(range) 9 (<1 to 28) 18

Study dropouts/withdrawals, PST/PSM intervention: 

mean % (range) 14 (1 to 43) 15

Age of subjects: mean years (range) 65 (42 to 75) 19

Gender, male: mean % (range) 75 (43 to 98) 20

Race/ethnicity, white: mean % (range) 90 (67 to 92) 2*

Race/ethnicity, non-white/other: mean % (range) 10 (8 to 33)

Indication for anticoagulation, mixed indications:* 

number of subjects per study 50 to 737 (3090 total) 13

Indication for anticoagulation, MHV replacement: 

number of subjects per study 62 to 930 (2074 total) 6

Indication for anticoagulation, atrial fibrillation: 

number of subjects per study 125 to 202 (327 total) 2

Indication for anticoagulation, MHV replacement and 

atrial fibrillation: number of subjects per study 2922 1

Studies conducted in the United States: number of 

subjects per study 325 to 2922 (3247 total) 2

Outcomes Assessed

All-cause mortality: number of subjects per study 56 to 2922 (6820 total) 16

Event-related mortality: number of subjects per 

study 56 to 930 (3302 total) 9

Thromboembolic events: number of subjects per 

study 56 to 2922 (8209 total) 20

Major bleeding events: number of subjects per study 56 to 2922 (8209 total) 20

Percentage of time within therapeutic range: number 

of subjects per study 56 to 2922 (6008 total) 14

Percentage of INR within therapeutic range: number 

of subjects per study 50 to 765 (3857 total) 13

INR variability: number of subjects per study 67 to 765 (2268 total) 6

PST: patient self-testing; PSM: patient self-management; MHV: mechanical heart valve; INR: international 

normalized ratio

*Both studies conducted in the United States
31

tion in the Outpatient Setting Evidence-based Synthesis Program

n Patient Self Testing/Management versus Usual Care Studies

vent

lated 

ortality

Thromboembolic 

events

Major 

bleeding 

events

Patient 

satisfaction & 

quality of life

% time 

within 

therapeutic 

range

% INR 

values 

within 

therapeutic 

range

INR 

variability

% time or 

INR values 

above 

or below 

range

No. of 

INR 

values

Costeffectiveness

domized, controlled trials

√ √ √ √

√ √ √ √ √ √

√ √ √ √ √ √ √√ √ √ √ √ √ √√ √ √ √ √ √ √

√* √* √ √ √

√ √ √ √ √ √ √√ √ √ √√ √ √** √ √ √

√ √ √√ √

√ √ √ √√ √ √ √ √ √
32

tion in the Outpatient Setting Evidence-based Synthesis Program

omized, controlled trials

√ √ √ √

√ √ √ √ √ √√ √ √ √ √ √√ √ √ √ √ √√ √ √ √ √ √ √√ √ √ √ √ √ √ √ √

√ √ √ √ √ √√ √ √ √** √√ √ √ √

6 20 20 11 18 12 8 9 13 3

s **# of days (not % time)
33

tion in the Outpatient Setting Evidence-based Synthesis Program

ents for Patient Self Testing/Management versus Usual Care Studies 

e mortality Event-related mortality (# of deaths) # Thromboembolic events # Major bleeding events Patient satisfaction & quality of life

n Control Intervention Control Intervention Control Intervention Control

domized, controlled trials

1/89 (1.1%) --- --- 1/90 (1.1%)‡ 2/89 (2.2%) 1/90 (1.1%)‡ 1/89 (1.1%) 40-item questionnaire

26/162 (16%) 1/163 (0.6%)‡ 3/162 (1.8%) 14/163 (8.6%)† 21/162 (13.0%) 8/163 (4.9%)*, 17/162 (10.5%) ---

--- --- --- 0/50‡ 1/50 (2%) 0/50 0/50 32-item questionnaire

1/26 (3.8%) 0/30 1/26 (3.8%) 0/30 0/26 0/30‡ 1/26 (3.8%) Patient interview with SEIQoL tool

--- --- ---

PST: 0/52

PSM: 0/47

P/Ed:

0/60

PC:

0/161

PST: 0/52

PSM: 2‡, a

P/Ed: 2‡, a

PC: 1/161

(0.6%)

32-item questionnaire

--- --- --- 0/44 0/41 1/44 (2.3%)‡ 0/41 Surveys with UKSF-36 and EuroQoL

0/70 0/70 0/70 0/70‡ 2/70 (2.9%) 0/70‡ 1/70 (1.4%) ---

0/40 --- --- 0/44 0/40 0/44 0/40 ---

0/101 0/101 0/101 0/101‡ 1/101 (1%) 1/101 (1%) 0/101 ---

0/50 --- --- --- --- --- --- ---

--- --- --- --- --- --- --- ---

0/34 --- --- 0/33 0/34 0/33† 4/34 (11.8%) ---

 

rm 

d

--- --- ---

2/132

(1.5%)

1/132

(0.8%) 0/132

1/132

(0.8%)

Patient satisfaction 

with care
34

tion in the Outpatient Setting Evidence-based Synthesis Program

omized, controlled trials

--- --- ---

0.9*

(%/year)

3.63

(%/year) 4.49* (%/year) 10.88 (%/ year) ---

 

s

At 5 years 

(est.)

55/395

(13.9%)

At 12 

years

142/442

(32.2%)

8/488

(1.6%)‡

7/442

(1.6%)

16/579

(2.8%)*

32/576

(5.6%)

42/579

(7.3%)‡

34/576

(5.9%)

---

4/49 (8.2%) 0/51 1/49 (2.0%) 1/51 (2.0%)‡ 0/49 1/51 (2%)‡, 0/49 ---

11/280

(3.9%)

2/337

(0.6%)‡

1/280

(0.4%)

4/337

(1.2%)‡

3/280

(1.1%)

5/337

(1.5%)‡, 

4/280

(1.4%)

EQ-5D tool; mean 

QALYs

15/369 (4.1%) 3/368 (0.8%)‡ 0/369 4/368‡ (1.1%) 20/369 (5.4%) 4/368‡ (1.1%) 7/369 (1.9%) ---

11/96

(11.5%) 0/99† 3/96 (3.1%) 6/99 (6.1%)†, 13/96 (13.5%) 7/99 (7.1%) 10/96 (10.4%) ---

--- --- --- 14/470‡ (3.0%) 21/295 (7.1%) 32/470‡ (6.8%) 20/295 (6.8%) ---

1/29

(3.4%)

--- --- 0/29 1/29 (3.4%) 1/29 (3.4%) 1/29 (3.4%) SF-36v2

157/1457

(10.8%)

--- ---

33/1465

(2.3%)‡

31/1457

(2.1%)

180/1465

(12.3%)‡

199/1457

(13.7%)

---

stically significant versus control ‡ p value not reported § range or deviation not reported

tients; we were therefore unable to determine a proportion since no denominator was available

nterquartile range (25-75%) PC = primary care PC/Ed = primary care with education PSM = patient self-management 

standard deviation SEM = standard error of the mean
35

tion in the Outpatient Setting Evidence-based Synthesis Program

 for Patient Self Testing/Management versus Usual Care Studies 

ean % Time within 

herapeutic range

Mean % INR values within 

therapeutic range 

INR variability 

(method)

ention Control Intervention Control Intervention Control

domized, controlled trials

- --- --- ---

0.65±1.04*

(mean squared 

INR deviation)

0.83±0.95

6§ 32 --- --- --- ---

- --- 55†, § 49 0.1±0.2‡ (mean difference) 0.12±0.22

4‡ 

 67-81) 77 (95% CI 67-86) 66‡ (95% CI 61-71) 72 (95% CI 65- 80) --- ---

66.9†

62.7-71)

 68.6†

3.7-73.6)

PC/Ed: 67.9

(95% CI 62.9-

73)

PC: 63.5

(95% CI 59.7-

67.3)

PST: 63.9†

(95% CI 59.8-68)

PSM: 66.3†

(95% CI 61-71.5)

PC/Ed: 61.3

(95% CI 55.4-

67.1)

PC: 58.7

(95% CI 55-

62.4)

--- ---

D 14.5)

PC/Ed: 70.4

(SD 24.5)

PC: 63.2 

(SD 25.9)

--- --- --- ---

EM 5.5) 63.2 (SEM 5.8) 64.8† (SEM 5.8) 58.7 (SEM 5.9) --- ---

20, range 

96) 64 (SD 26, range 7-100) --- --- --- ---

- --- 67.8* (SD 17.6) 58.5 (SD 19.8) --- ---

edian)†

69.2-81)

68.9 (median)

(95% CI 59.3-

78.2)

--- --- --- ---
36

tion in the Outpatient Setting Evidence-based Synthesis Program

71.8†

4.9-80.1, 

22.1)

 69.9†

0.8-76.7, 

23.1)

--- --- --- --- ---

D 19) 53 (SD 19) 41.1±39.3* (mean deviation) 62.4±72.6

edian) 

001) 58.6 (median) 87.4 78.2 --- ---

omized, controlled trials

- --- 43.2‡, § 22.3 --- ---- --- 78.3*, § 60.5 --- ---

5*, § 63.8 --- --- --- ---

0†

8.1-72.4)

68

(95% CI 65.2-

70.6)

--- --- --- ---

D 14.3) 64.9 (SD 19.9) 58.6* (SD 14.3) 55.6 (SD 19.6) 0.58±0.18† (INR distance) 0.59±0.27

edian)*

4.7-82)

65.5 (median)

(IQR 55.4-77.2)

68.4 (median)*

(IQR 61.5-77.8)

59.1 (median)

(IQR 50-70.6)

0.16*(IQR 0.09-0.25)

(squared INR deviation)

0.23 (IQR 0.16-

0.36)

- --- 79*, § 65 0.35*, §

(mean variance)

0.39

- --- 72.9 (SD 11)

(p=0.001)

53.9 (SD 14) --- ---

D 14.2) 62.4 (SD 17.1) --- --- --- ---

 not reported § range or deviation not reported

interquartile range (25-75%) PC = primary care PC/Ed = primary care with education 

PST = patient self-testing SD = standard deviation SEM = standard error of the mean
37

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Table 10. Percentage of Time within Therapeutic Range for Patient Self Testing/Management versus 

Usual Care Studies*

Study PST/PSM group Standard care group

Short-term studies (<12 months)

Beyth 200018 (n=325) 56 32

Fitzmaurice 200222 (n=49) 74 77

Gladisseur 200323 (n=320)

PST 66.9 PC/Ed** 67.9

PSM 68.6 PC 63.5

Khan 200425 (n=79) 71.1 70.4

Sunderji 200419 (n=139) 71.8 63.2

Gardiner 200526 (n=88) 61 64

Dauphin 200831 (n=67) 57 53

Long-term studies (≥12 months)

Sidhu 200138 (n=84) 76.5 63.8

Fitzmaurice 200539 (n=617) 70 68

Menedez-Jandula 200541 (n=737) 64.3 64.9

Matchar 201017 (n=2870) 66.2 62.4

Pooled weighted mean (range) 66.1 (56 to 76.5) 61.9 (32 to 77)

*Includes only studies that reported mean percentage of time

**PC = primary care; PC/Ed = primary care with education

Table 11. Percentage of INR Values within Therapeutic Range for Patient Self Testing/Management 

versus Usual Care Studies*

Study PST/PSM group Standard care group

Short-term studies (<12 months)

Cromheecke 200021 (n=50) 55 49

Fitzmaurice 200222 (n=49) 66 72

Gladisseur 200323 (n=320)

PST 63.9 PC/Ed** 61.3

PSM 66.3 PC 58.7

Sunderji 200419 (n=139) 64.8 58.7

Voeller 200527 (n=202) 67.8 58.5

Ryan 200932 (n=132) 87.4*** 78.2***

Long-term studies (≥12 months)

Horstkotte 199834 (n=150) 43.2 22.3

Koertke 200135,36 (n=575) 78.3 60.5

Menedez-Jandula 200541 (n=737) 58.6 55.6

Eitz 200844 (n=765) 79 65

Soliman Hamad 200945 (n=62) 72.9 53.9

Pooled weighted mean (range) 70.5 (43.2 to 87.4) 59.3 (22.3 to 78.2)

*Includes only studies that reported mean percentage of values

**PC = primary care; PC/Ed = primary care with education

***Within 0.75 units of INR of the target INR
38

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program Allocation concealment?

Beyth 2000 (18)

Christensen 06/07 (28,29) –

Cromheecke 2000 (21) +

Dauphin 2008 (31)

Eitz 2008 (44)

Fitzmaurice 2002 (22)

Fitzmaurice 2005 (26) +

Gadisseur 2004 (24) +

Gardiner 2005 (26)

Gardiner 2006 (30)

Horstkotte 1998 (34)

Khan 2004 (40)

Koertke 2001/07 (35,36)

Matchar 2010 (17) +

Menendez-J 2005 (41) +

Ryan 2009 (32) +

Sawicki 1999 (20) +

Sidhu 2001 (38)

Siebenhofer 07/08 (42,43) +

Soliman Hamad 2009 (45)

Sunderji 2004 (19)

Voller 2005 (27)

Blinding (outcomes assessors or evaluation of dosing) +

–

–

–

–

+

–

–

+

+

–

+

+

–

–

–

Intention-to-treat –

–

–

+

+

–

+

+

–

+

+

–

+

Withdrawals described +

+

+

+

–

+

+

+

+

+

+

+

+

+

+

+

+

+

Figure 6. Methodological Quality Summary, Patient Self Testing/Management Studies versus Usual 

Care Studies
39

tion in the Outpatient Setting Evidence-based Synthesis Program

Patient Self Testing/Management versus Usual Care Studies

agulation in the Outpatient Setting 

33

lity, Patient Self Testing/Management versus Standard Care Studies 

s)

 = 0.48); I2 = 0%

0.63)

s)

P = 0.003); I2 = 69%

0.0003)

 (P = 0.02); I2 = 51%

0.0003)

= 0.34, df = 1 (P = 0.56), I2 = 0%

Events

21

1101100

25

5

94

152

60

15

1

273298

Total

163

503330449070

101

581

337488

1465

368

519929

28373418

Events

26

0010100

2811

142157

15

4

11

1

341369

Total

162

503426408970

101

572

280442

1457

369

499629

27223294

Weight

7.2%0.2%0.2%0.2%0.2%0.4%

8.2%

2.7%

31.2%49.1%

3.6%0.7%4.0%0.3%

91.8%

100.0%

Peto, Fixed, 95% CI

0.77 [0.42, 1.44]

7.39 [0.15, 372.38]7.62 [0.15, 384.01]

0.12 [0.00, 5.91]

6.75 [0.13, 341.54]

0.99 [0.06, 15.93]

Not estimableNot estimable

0.87 [0.49, 1.55]

0.38 [0.14, 1.03]0.51 [0.38, 0.68]0.96 [0.76, 1.21]0.42 [0.17, 0.99]0.12 [0.02, 0.89]1.37 [0.60, 3.13]

1.00 [0.06, 16.39]

0.73 [0.61, 0.86]0.74 [0.63, 0.87]

nt Self-Testing/Management Usual Care Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.1 0.2 0.5 1 2 5 10

Favors PST/PSM Favors Usual care
40

tion in the Outpatient Setting Evidence-based Synthesis Program

nts, Patient Self Testing/Management versus Usual Care Studies

agulation in the Outpatient Setting 

34

Events, Patient Self Testing/Management versus Standard Care Studies 

s)

 = 0.45); I2 = 0%

0.02)

s)

 = 0.79); I2 = 0%

0.43)

 (P = 0.43); I2 = 2%

0.17)

= 4.60, df = 1 (P = 0.03), I2 = 78.3%

Events

8000010101

1132

5

42

180

4171

272283

Total

163

5033304444

132

9070

101

663

470337579

1465

368

519929

33984061

Events

17

041001110

2520

4

34

199

70

10

1

275300

Total

162

5034264041

132

8970

101

655

295280576

1457

369

499629

31513806

Weight

4.5%0.7%0.2%0.2%0.2%0.4%0.2%0.2%

6.5%

8.9%1.7%

13.7%63.6%

2.1%0.2%3.0%0.4%

93.5%

100.0%

Peto, Fixed, 95% CI

0.46 [0.20, 1.03]

Not estimable

0.13 [0.02, 0.94]0.12 [0.00, 5.91]

Not estimable

6.90 [0.14, 348.69]

0.14 [0.00, 6.82]

0.99 [0.06, 15.93]

0.14 [0.00, 6.82]

7.39 [0.15, 372.38]

0.43 [0.22, 0.85]

1.00 [0.56, 1.79]1.04 [0.28, 3.89]1.25 [0.78, 1.98]0.89 [0.71, 1.10]0.58 [0.18, 1.90]

7.10 [0.14, 358.35]

0.66 [0.24, 1.78]

1.00 [0.06, 16.39]

0.93 [0.78, 1.11]0.89 [0.75, 1.05]

ent Self-Testing/Management Usual Care Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.1 0.2 0.5 1 2 5 10

Favors PST/PSM Favors Usual care
41

tion in the Outpatient Setting Evidence-based Synthesis Program

olic Events, Patient Self Testing/Management versus Usual Care Studies

agulation in the Outpatient Setting 

35

embolic Events, Patient Self Testing/Management versus Standard Care Studies 

s)

 = 0.65); I2 = 0%

0.08)

s)

P = 0.04); I2 = 52%

0.0001)

 (P = 0.17); I2 = 27%

0.0001)

= 0.00, df = 1 (P = 0.97), I2 = 0%

Events

14

0000002100

1714

4

1633

4160

7895

Total

163

503330994444

132

9070

101

856

470337579

1465

368

519929

33984254

Events

21

1000001221

2821

3

323120

0

13

1

121149

Total

162

503426

221

4041

132

8970

101

966

295280576

1457

369

499629

31514117

Weight

13.6%

0.4%1.3%1.3%0.9%0.4%

17.9%

13.7%

3.0%

19.9%27.1%10.1%

0.4%7.5%0.4%

82.1%

100.0%

Peto, Fixed, 95% CI

0.64 [0.32, 1.28]0.14 [0.00, 6.82]

Not estimableNot estimableNot estimableNot estimableNot estimable

1.96 [0.20, 18.98]

0.50 [0.05, 4.91]0.13 [0.01, 2.15]0.14 [0.00, 6.82]

0.58 [0.32, 1.07]

0.39 [0.19, 0.78]1.11 [0.25, 4.94]0.50 [0.28, 0.88]1.06 [0.65, 1.74]0.25 [0.11, 0.57]

7.10 [0.14, 358.35]

0.43 [0.17, 1.10]0.14 [0.00, 6.82]

0.58 [0.43, 0.77]0.58 [0.45, 0.75]

nt Self-Testing/Management Usual Care Peto Odds Ratio Peto Odds Ratio

Peto, Fixed, 95% CI

0.1 0.2 0.5 1 2 5 10

Favors PST/PSM Favors Usual care
42

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Safe and Effective Anticoagulation in the Outpatient Setting 

Figure 10. Percent Time in Therapeutic Range for Patient Self Testing/Management Studies 

Study name Statistics for each study Difference in means and 95% CI

Difference Lower Upper 

in means limit limit

Fitzmaurice 2002 (22) -3.00 -14.45 8.45

Gadisseur 2003 (23) -1.00 -7.54 5.54

Sunderji 2004 (19) 8.60 -7.07 24.27

Khan 2004 (25) 0.70 -8.15 9.55

Gardiner 2005 (26) -3.00 -12.87 6.87

Dauphin 2008 (31) 4.00 -5.10 13.10

Menendez-J 2005 (41) -0.60 -3.10 1.90

Fitzmaurice 2005 (39) 2.00 -1.41 5.41

Matchar 2010 (17) 3.80 2.65 4.95

1.50 -0.63 3.63

-8.00 -4.00 0.00 4.00 8.00

Favors SC Favors PST/PSM

Figure 10. Percent Time in Therapeutic Range for Patient Self Testing/Management versus Usual 

Care Studies

Figure 11. Percent of INRs within Therapeutic Range for Patient Self Testing/Management versus 

Usual Care Studies

Safe and Effective Anticoagulation in the Outpatient Setting 

Figure 11. Percent of INRs within Therapeutic Range for Patient Self Testing/Management Studies 

Study name Statistics for each study Difference in means and 95% CI

Difference Lower Upper 

in means limit limit

Fitzmaurice 2002 (22) -6.00 -14.82 2.82

Gadisseur 2003 (23) 2.60 -4.62 9.82

Sunderji 2004 (19) 6.10 -10.13 22.33

Voller 2005 (27) 9.30 4.13 14.47

Menendez-J 2005 (41) 3.00 0.52 5.48

Soliman Hamad 2009 (45) 19.00 12.52 25.48

5.91 -0.18 12.01

-8.00 -4.00 0.00 4.00 8.00

Favors SC Favors PST/PSM

Favors SC Favors PST/PSM

Favors SC Favors PST/PSM
43

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

KEY QUESTION 3

What are the risk factors for serious bleeding in patients on chronic anticoagulant therapy?

Literature Search

Using the search strategy shown in the Methods section, we looked for studies published in 

English after 1996 in peer reviewed journals. We included studies that provided rates of serious 

bleeding events in populations who were on warfarin therapy. The rates of serious bleeding 

needed to either be presented by strata of risk factors (e.g., 1% in people less than 50 years and 

1.4% in people over 50 years of age) or using a ratio of risk such as an odds ratio, relative risk 

or hazards ratio (e.g., HR=1.4 for people over age 50 compared to people under age 50). We 

excluded studies that did not report at least 25 cases of serious bleeding, since the precision for 

estimated risk among small studies is limited and observational studies such as those identified in 

this report are too heterogeneous to pool for formal meta-analysis. We excluded reports that dealt 

with inpatients, pediatric populations, or non-warfarin anticoagulation. As shown in Figure 4, we 

screened 681 titles/abstracts and selected 78 for full article review. Of these, we identified a total 

of 32 articles reporting on 33 distinct studies.48-79 We also identified three additional articles by 

hand-searching references cited.80-82

Overview of Included Studies

An overview of the 35 included articles is shown in Appendix B, Table 5. These 35 articles 

represent 35 unique studies (several studies were reported in multiple articles, 1 article included 

a development and validation cohort, a series of articles reported on the warfarin arm of two 

randomized controlled trials, and 1 article reported a meta-analysis of 6 randomized trials). 

There were three multinational studies, 17 US studies (including 3 studies with a substantial 

VA population). Study designs included: meta-analyses, RCTs of additional drugs combined 

with warfarin, warfarin arms of RCTs analyzed as prospective cohort studies, observational 

retrospective/prospective cohort studies, case-control studies, and case-control studies nested 

in cohort studies. Within these different study designs various analytical methods were used, 

ranging from simply reporting frequencies of serious bleeding events by strata of a risk factor to 

using multivariable models to estimate the independent effect of a risk factor after accounting 

for many other potential risk factors and follow-up time. Average follow-up times ranged from 

slightly less than a year to 5 years, with most studies reporting follow-up periods of 1 to 2 years.

Subject Characteristics

A total of 453,918 subjects were included in these studies. Studies ranged in size from a case 

control study with 26 cases and 56 controls to a large administrative database study of Medicare 

records that included 353,489 patients. Since any averages of patient characteristics by study 

will be mostly driven by the few large administrative studies, the value of overall patient 

characteristics is somewhat limited. Most studies included primarily elderly populations with 

an average age of approximately 70 years. The distribution of gender represented in the studies 

varied widely with a maximum of 98.5% male to a minimum of 23% male. 

Predictors of Serious Bleeding

Of the 35 articles we identified that provided evidence regarding the impact of various risk 

factors for predicting serious bleeding events, each article provided a different set of reported 
44

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

risk factors in a diverse range of patient populations, using different lengths of follow-up. These 

differences make statistical pooling of results unreliable, so the evidence is summarized below 

in a narrative format. All of the quantitative results extracted from the 35 studies are presented in 

Appendix B, Table 5. The risk factors reported in each study are displayed in Table 12. 

Age

Overall, there is evidence that older age is associated with increased risk of serious bleeding in 

patients on warfarin. The evidence is not completely consistent across studies and also tends to 

suggest that the association is not linear in that the difference in risk between a 40 and 60 year 

old is likely not the same as the difference in risk between a 60 and 80 year old.

Sixteen articles from 14 unique studies reported results regarding the impact of increased age 

on the risk of serious bleeding events in people on warfarin therapy.48-52,58,61,62,63,65,66,72,74,76,77,79

Increased age was typically found to be associated with increased bleeding risk;48,48,51,58,62,63,66,76,

77,79 however several studies failed to show a significant association between increased age and 

increased risk of serious bleeding events.50,52,61,72,74 Furthermore, in the studies that did show 

a significant age association, the magnitude of the association differed substantially between 

studies. The amount of increased bleeding attributable to increased age ranged from a few 

studies reporting several fold higher rates of bleeding events in the oldest age groups (i.e., those 

over 80) compared to people in their 50s to 60s, while most other studies reported more modest 

to completely null associations. This suggests that the association between patient age and 

bleeding is likely complex and dependent on other factors that act as either confounders or effect 

modifiers. Another difference between studies related to the format in which age was modeled. In 

some studies results were reported from multivariable adjusted models based estimates of a one 

year increase in age, while others used dichotomous comparisons of differences above and below 

an age cut point (e.g., above versus below age 65). Still others simply reported unadjusted rates 

of bleeding across several age categories. 

Gender

Overall, in the studies we identified, gender was not strongly associated with the rate of serious 

bleeding. Only nine articles reported results regarding the impact of gender on the risk of serious 

bleeding events in people on warfarin therapy.48,50,52,59,61,65,66,72,77 Among the studies that reported 

results by gender, most failed to observe a significant association between gender and risk of 

serious bleeding.48,52,59,61,65,77 In a large U.S. study using administrative data, men and women had 

similar rates of overall hemorrhage (RR: 1.25, 95%CI; 0.91–1.67), but men had a two-fold risk 

of intracranial hemorrhage (RR: 2.0, 95%CI; 1.11–3.33).59 Likewise data from two large trials 

show that the rate of major bleeding on warfarin was not significantly different between men 

and women (p=0.49) with men having 0.35% more events per year (a non-significant relative 

difference of approximately 14%).65 One study from Sweden found men had a 2.8 fold higher 

rate of severe hemorrhage (95%CI: 1.1-7.3).72 Conversely, one U.S. study identified a small, 

but statistically significant increased risk of major bleeding in women.66 This study was used to 

develop the bleeding risk index (mentioned below), and this is the one index that incorporates 

female gender as a predictor of bleeding risk.
45

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Aspirin, NSAIDs, and other Medication Use

Aspirin use has been associated with increased risk of bleeding in patients on warfarin and 

the relative increase in risk is likely greater than two-fold. Aspirin is the only predictor we 

investigated for which we identified evidence from randomized controlled trials. A metaanalysis of six RCTs including 3,874 participants, in which 31 cases of intracranial hemorrhage 

developed, showed a 2.4 fold increased risk (95%CI; 1.2-4.8) among those randomized to aspirin 

plus warfarin compared to those randomized to only warfarin.53

When data are available from randomized trials the value of nonrandomized data is reduced. This 

is particularly true for drugs where confounding by indication can occur, such that it is difficult 

to untangle whether it is the drug or the indication for taking the drug that might predispose 

someone to a higher risk of events. Data from studies that did not randomize patients to aspirin 

but still compared rates of bleeding by reported aspirin use have also consistently reported 

increased bleeding in those taking aspirin and the increase has tended to be close to a doubling of 

the risk of serious bleeding events.58,60,62,64,70

The evidence for an increased risk of serious bleeding is not as strong for other medications. 

NSAIDs have been reported, from observational studies, to be associated with increased risks 

of serious bleeding events, but these risks are generally weaker in magnitude (less than twofold increased risk) and less consistently reported than the results from studies of aspirin.45,52,57,74

We found no randomized controlled trials confirming the association of NSAIDs with serious 

bleeding events.

In the studies we identified, few other medications were regularly reported with serious bleeding 

outcomes. A study by Gasse et al. listed several medications which were associated with 

increased risks of bleeding among patients taking their first ever dose of warfarin.60 Several 

medications were associated with increased risk of bleeding some of which were associated with 

very high risks of bleeding (see Appendix B, Table 5), but most of these medications were either 

not reported or not assessed in the other studies we identified.

Warfarin Duration

Serious bleeding events tend to occur most frequently during the initiation of warfarin 

therapy.51,62,63,72 Among the studies that reported the rate of serious bleeding by the duration of 

time on warfarin, the most commonly reported first interval was events at 1 month and then 

typically the rate at 12 months and possibly later was also reported. Only one study reported 

similar rates of bleeding events during the first month compared to all other months.74 This same 

study also found no difference in bleeding rates between new users and chronic warfarin users. 

All four of the studies showed initial bleeding rates that were two to three times higher in the 

first one to three months compared to the rest of follow-up. The absolute magnitude of bleeding 

during the first month varied substantially in magnitude possibly due to differences in the study 

population and definition of serious bleeding. However there was a clear trend for decreasing rate 

of bleeding events after the initial few months of warfarin treatment.

INR — We identified only two studies that reported serious bleeding events by INR 

variability.81,82 Both studies reported that increased INR variability was associated with an 

increase in the risk of serious bleeding. However, in one study the impact of INR variability was 
46

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

only seen among people who spent the greatest amount of time outside of the INR target range of 

2.5-4.0.82

Primary Indication

We identified only two studies that reported serious bleeding events by the primary indication 

for taking warfarin.50,74 Both studies reported that patients taking warfarin because of valve 

conditions were at significantly increased risk of bleeding compared to other patients. While this 

may have little impact for patient care since it is not modifiable, it is a relevant factor to consider 

when evaluating the overall bleeding risk of a population on warfarin.

Genetic Factors

Several recent articles have attempted to predict risk of serious bleeding events using genetic 

polymorphisms in two genes (CYP2C9 and VKORC1).54,71,73 These articles represent two unique 

studies including approximately 631 patients and 75 cases of serious bleeding. Both studies 

reported participants with variant CYP2C9 genotypes having a roughly three-fold greater rate 

of serious bleeding events compared to those with the CYP2C9 wild type genotype.54,71,73 The 

association between the VKORC1 genotypes and serious bleeding was not significant in either 

study.71,73

Co-morbidity

Twelve studies reported on various co-morbidities and their associations with increased risk of 

serious bleeding events.48,50,51,52,55,57,61,62,66,75,79,81 There was not a consistent set of co-morbidities 

that was reported in the studies we indentified, such that the significance of reported associations 

may be due, in part, to publication bias; the co-morbidities most strongly associated with events 

might have been more likely to have been reported. The following factors were all associated 

with bleeding in at least one of the studies: diabetes, kidney impairment, alcohol abuse, history 

of GI bleeds, prior stroke, hypertension, psychiatric illness, liver disease, anemia, leukoaraiosis 

(an age-related change in cerebral white matter), congestive heart failure, cancer, and venous 

thrombosis. Estimating the actual magnitude of each of these conditions’ associations with 

serious bleeding is beyond the scope of this project and would be difficult given the available 

data. Particularly important to the task of estimating the impact of these conditions would be 

untangling the intensity of warfarin therapy and other potential confounding factors that might be 

mediating the associations with serious bleeding events.

Risk Indices

Several bleeding risk indices are currently available for stratifying patients into “low” and “high” 

risk groups. We identified seven articles51,56,66,68,69,78,80 that estimated the risk of serious bleeding 

events in people on warfarin therapy using one or more of nine different risk indices (OBRI,51

Shireman,66 Kuijier,83 AFI, ACCP, CHADS2,

84 HEMORR2HAGES,80 Kearon, NICE). Typically, 

these risk indices place patients into low, intermediate and high risk groups using several risk 

factors. Four of the risk indices (AFI, ACCP, CHADS2, NICE)78 were developed to predict risk of 

stroke, but also provided some evidence about whether or not they also predicted risk of serious 

bleeding complications. The stroke risk models appeared to be inferior to the bleeding risk 

models and likely only provide value for risk stratifying in studies that only have the stroke risk 

indices measured. Therefore, while the results from the stroke models are included in Appendix 
47

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

B, Table 5, we will focus on the indices developed specifically for bleeding risk.

All of the risk indices included a categorical indicator of age as a component, but they differed 

in the age cut point with the age ≥60 used by the Kuijers risk index while others used ≥65, 

≥70, ≥75, or a two level indicator with some increased risk at ≥65 and more risk ≥75. All of the 

indices included some increased risk for comorbidities. The comorbidities varied, particularly 

between the models that were designed specifically to predict stroke versus those designed to 

predict bleeding. The bleeding models tended to include some marker of prior history of bleeding 

events while the stroke models focused more on hypertension, history of stroke or TIA, or other 

vascular diseases. Most included diabetes mellitus as a risk factor and two of three bleeding 

models included female gender as a risk factor.66,83

Risk indices are difficult to compare across different studies. Two articles did however show 

head-to-head comparisons of different bleeding risk indices within the same study.66,80 All of 

the bleeding risk indices were able to separate out groups of people with lower average risks of 

bleeding from those with higher risks of bleeding. Those identified as low risk typically have a 

several-fold lower risk of bleeding events compared to those identified as high risk. The amount 

of separation depended in part on the population. For example, a population where most of the 

patients are generally at a low risk of major bleeding will tend to show little separation, because 

there is not much of a range in risk. Likewise if age is an important factor in risk stratifying 

patients, using a tool with an age cut-off at age 65 for the higher risk group will not be very 

useful in a population where most of the patients are in their 70s or 80s. 

Overall, while there have not been a lot of confirmatory studies of individual risk indices, 

bleeding risk indices were generally successful to some extent in stratifying patients into 

different risk groups. The choice of risk index might depend in part on the overall risk profile 

of the patient population (i.e., if many are well over age 65 then indices with older age cutpoints might be more useful) and the availability of risk factor information (i.e., information on 

genotype status and level of detail on prior medical history).

SUMMARY – KEY QUESTION 3

Several individual risk factors (including very old age, initial warfarin use, INR variability, 

concomitant medications, comorbid conditions, mechanical heart valve, genetics) and 

combinations of risk factors (risk indices) can be used to define low and high risk groups for 

serious bleeding with warfarin use. However, due to the heterogeneity of studies (populations, 

risk factors assessed, risk factor definitions, etc.), it is difficult to reach definitive conclusions 

about the value of risk factor assessment. 
48

tion in the Outpatient Setting Evidence-based Synthesis Program

ous Bleeding Reported in the Individual Studies

Gender

Warfarin 

Duration INR 

Primary 

Indication

Asprin/ 

NSAID

Other 

Meds 

Risk 

Index Genetics Co-morbidity Other

√

√ √

√ √ √

√

√ √

√ √ √ √

√

√

√

√

√

√ √

√

√

√

√

√ √

√ √

√

√

√ √ √ √ √ √ √ √ √ √ √ 

√

√ √ √ √ √

√

√ √ √ 

√ √

√ √ √ √ √

√

√ √ √ √ √

√

√ √ √ √ √

9 5 2 2 11 11 7 3 12 8
49

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

DISCUSSION AND RECOMMENDATIONS

Key Question 1

For management of long-term outpatient anticoagulation in adults, are specialized 

anticoagulation clinics (ACC) more effective and safer than care in non-specialized clinics (e.g., 

primary care clinics, physician offices)? 

Major Clinical Outcomes

The literature available to address this question is limited. We were able to identify 11 studies, 

of which only 3 were RCTs.6,7,8 Except for one study,14 major clinical outcomes occurred more 

frequently in the control than the intervention group (Table 3b). However, pooled results from 

the 3 RCTS showed no significant differences between ACC and UC for deaths, thromboembolic 

events, or major bleeding. Pooling of the observational studies’ results was not possible due to 

heterogeneity among studies in reported outcome metrics. 

Time in Therapeutic Range

All 9 studies that reported this metric (or the related metric, % INRs within therapeutic range) 

found that subjects receiving care in an ACC spent more time within the therapeutic range than 

those who received usual care.6-8,10-14,16 In 4 studies the difference was statistically significant.7,10,12,14 

In the RCTs, the pooled weighted means were only slightly higher for ACC than UC (59.9% 

v.56.3%). In the observational studies, there was a larger spread with ACC patients spending 63.5% 

of the time in therapeutic range compared to 53.5% for subjects in usual care. 

Patient Satisfaction

Measured in 2 of the RCTs, patient satisfaction was found to be significantly higher in patients 

randomized to the ACC intervention than to UC.6,7

Other Reviews

The 2008 ACCP guidelines on Pharmacology and Management of the Vitamin K Antagonists1

included a narrative review of 9 uncontrolled studies, 3 cohort studies, and 2 RCTs. The authors 

concluded that “although the literature ... is not as robust as one would like, and there is great 

heterogeneity between studies, the results are almost always consistent, indicating that care 

provided by an anticoagulation management service results in better outcomes or more stable 

therapy than UC” (p 184s1). Similarly a systematic review and meta-regression published in 200685

found that care provided in community settings resulted in significantly worse anticoagulation 

control (as measured by TTR) than that provided within ACCs (or within clinical trials). This 

review included studies of any design as long as the report included original data measuring serial 

INRs in at least one patient group. A third review and meta-analysis of 36 studies of patients with 

atrial fibrillation found that significantly more time was spent within the therapeutic range when 

patients were cared for in organized settings (i.e., ACCs) as compared with usual care.86 Finally, 

a very recent meta-analysis investigated the effect of study-level factors (e.g., study design, year 

of publication, INR interpolation method) on time in therapeutic range and reported that patients 

managed in ACCs spent significantly more time within the therapeutic range than those managed in 

usual care.87 None of these reviews evaluated clinical outcomes. 
50

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

Key Question 1a

Which components of a specialized anticoagulation clinic are associated with effectiveness/

safety?

None of the included studies reported the association between specific elements of ACC and 

outcomes. Some possible processes of care that might have accounted for observed differences 

in outcomes in these studies included use of both face-to face and telephone interactions with 

patients;13 use of a computerized patient monitoring system that identified patients who were 

delinquent in returning for timely INR determinations;12 the specialized expertise of the ACC 

staff;12 more consistency in ACCs in obtaining regular INRs;11 and frequency of face-to-face 

consultations, methods of dosage adjustment, and provision of written dosage instructions.16

Conclusion and Recommendations for KQ1

The evidence suggests that care provided within ACCs may lead to better quality anticoagulation 

control as measured by time in therapeutic range (a surrogate outcome that has been correlated 

with clinical events),50 but there is insufficient evidence to conclude that ACC care leads to 

fewer deaths, thromboembolic events, or major bleeding events than care provided in usual 

care settings such as primary care clinics. Patients reported that they liked the convenience 

and enhanced service provided by ACCs. There is insufficient evidence for the VA to actively 

promote the implementation of ACCs. Other organizations have suggested greater benefits with 

ACCs; future research should include cost and resource utilization outcomes along with clinical 

outcomes and patient satisfaction measures. Future research should also address whether the 

benefits from ACC are restricted to the initiation of anticoagulation (a high risk period) or also 

continue through the maintenance phase. 

Key Question 2

Is Patient Self Testing (PST), either alone or in combination with Patient Self Management 

(PSM), more effective and safer than standard care delivered in either ACCs or non-specialized 

clinics? 

This analysis of 22 randomized, controlled trials (RCTs) indicates that for selected patients, oral 

anticoagulation therapy delivered through a PST/PSM model results in superior patient outcomes 

compared with oral anticoagulation therapy delivered through usual clinic based models. Patients 

randomized to PST/PSM, had a significant 26% lower risk of death and a significant 42% 

reduction in major thromboembolism without any increased risk of major bleeding events. We 

included between 4-12 more trials and 3500-5000 more patients than other meta-analyses2,46,47,88 

and to our knowledge we are the first to include the largest trial to date, The Home INR Study, a 

VA cooperative studies trial17.

The mechanism by which PST/PSM leads to a reduction in thromboembolic events is thought 

to involve the higher proportion of time spent within the therapeutic range that is achieved with 

more frequent monitoring and dosage adjustments. This assumption has been predicated on 

observational data suggesting that the incidence of bleeding and thromboembolism is correlated 

with the quality of anticoagulation control (i.e., time in therapeutic range or % INR values 

within therapeutic range).89-93 The recent VA trial also found a modest but statistically significant 
51

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

higher percent time within therapeutic range for patients randomized to PST than to usual care 

(absolute difference 3.8 percentage points).17 Our study did not confirm this association, possibly 

because our analysis, which included the largest number of trials to-date, was limited to RCTs 

whereas other reports were either from single RCTs,17,91,94 reviews that included both RCTS and 

observational studies,89 database analyses90,92 or retrospective cohort studies.93

It is important to note that these trials enrolled highly selected populations. Subjects had to have 

the desire and confidence as well as the manual dexterity, visual acuity, and mental faculties 

to use the testing device and either relay those values to their clinic (PST) or perform dose 

adjustment on their own (PSM). In most of the trials, 50% or fewer patients met preliminary 

eligibility criteria, successfully completed the training, and agreed to be randomized. Some of 

the reasons cited for patient unwillingness to participate or continue with the PST/PSM included 

patient-perceived physical limitations, lack of confidence in their ability to follow the protocol, 

difficulty performing measurements, and preference for an alternative method.25,46 However, 

among the randomized patients, the percentage who continued with the intervention throughout 

the study was relatively high (64-98%) and patients in the PST/PSM group generally reported 

higher satisfaction and quality of life than those in usual care. 

Several limitations of this analysis should be acknowledged. First, the methodological quality 

of the included trials was variable; only 5 trials met all of our quality indicators. Second, it is 

unclear whether the apparent benefits of PST/PSM result from the PST/PSM or simply from 

the more intense education that these patients receive. Third, the current data do not address the 

question of whether PST/PSM is safe during the high-risk initiation phase or should only be 

implemented during the maintenance phase. However, it is reassuring to note that in the VA trial 

there was no outcome difference between the group who had been randomized within 3 months 

of starting anticoagulation and the group that had been anticoagulated for more than 3 months.17

Finally, the data on quality of life and patient satisfaction is difficult to interpret due to the wide 

range and variable quality of the outcome measures used. 

Whether the results of this review can be applied to US health care systems is unclear. Only 

2 of the 22 reviewed trials were conducted in the US17,18 and both investigated PST not PSM. 

Furthermore, one of these, the VA trial, did not show a significant benefit among patients 

randomized to PST compared to those randomized to a high quality ACC. The generalizability of 

results from non-US trials to US health care settings is problematic since half of these trials used 

vitamin K antagonists not widely used in the US and several of these have markedly different 

half lives from warfarin.1 Also, since PST/PSM is a complex multi-component intervention, 

it is important to have evidence of effectiveness in typical US healthcare settings. Finally, 

although we did not examine costs, survey data suggest that costs are likely to be a barrier to 

implementation.95 Several cost analyses have concluded that implementing PST/PSM may not be 

cost-effective due to the high cost of the portable monitoring devices and supplies and of patient 

training.2,96

Conclusion and Recommendations for KQ2

This analysis indicates that compared to usual clinic care, patient self testing with or without 

self management is associated with significantly fewer deaths and thromboembolic events 
52

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

without any increase in bleeding complications, for a select group of motivated patients requiring 

long term anticoagulation with Vitamin K antagonists. It should be noted, however, that while 

the strength of evidence was moderate for the thromboembolism and bleeding, it was low for 

mortality. Whether this care model is cost-effective and can be implemented successfully in 

typical US health care settings requires further study. 

Key Question 3

What are the risk factors for serious bleeding in patients on chronic anticoagulant therapy?

Summary

Many factors have been shown to predict an increased risk of serious bleeding; however, 

there is no standard set of variables that is commonly reported such that coming up with a 

comprehensive list of independent risk factors is difficult and involves piecing together results 

from a very heterogeneous group of studies. Factors that seemed most consistently associated 

with serious bleeding included: very old age, the first months following warfarin initiation, other 

medication use (particularly aspirin use), comorbid conditions (such as history of GI bleeding 

events or diabetes), primary indication for taking warfarin was a valve condition, and genetic 

factors (ex. variation in the CYP2C gene). There have also been a number of studies of indices 

that pool together several of the before mentioned risk factors and shown that patients can to 

some extent be categorized into low, intermediate, and higher risk for serious bleeding events. 

Those identified as low risk typically have a several-fold lower risk of bleeding events compared 

to those identified as high risk. The amount of separation depended in part on the population. For 

example a population where most of the patients are generally at a low risk of major bleeding 

will tend to show little separation, because there is not much of a range in risk.

Limitations

Publication bias and the inability to pool results across studies due the heterogeneity of the study 

designs, analytical methods, and risk factors assessed limit the certainty that can be assigned to the 

results presented in this section. Publication bias is a concern when looking at lists of predictors of 

outcomes from observational studies. It is not uncommon for studies to evaluate associations for 

many more factors than they report results, creating a situation where, positive associations with 

bleeding may be more often reported than null associations. This may make some factors look 

artificially more strongly associated than they might be expected to be in real-world circumstances. 

For this reason, it is important to confirm more novel associations in large prospective studies. The 

range of uncertainty around the magnitude of effect for any of these risk factors is also necessarily 

large, since the heterogeneity of the studies precludes anything but a narrative review of the findings.

Conclusion and Recommendations for KQ3

Several factors have been shown to consistently predict an increased risk of bleeding and, when 

pooled together, a subset of these risk factors has been shown to stratify groups of patients into 

lower and higher risk groups. Either alone or in combination, these risk factors can likely be 

used to help clinicians and patients have a dialog about the risks of warfarin therapy. Currently, 

there is not adequate evidence to suggest that any of the bleeding risk indices are meaningfully 

superior to the other indices. The HEMORR2

HAGES index seems to be the most comprehensive 
53

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

list of potential factors, while the OBRI index has been the most frequently tested model and is 

more parsimonious. While neither of these is clearly superior, it does seem that there is growing 

support for the development of more formal methods of risk assessment beyond that of simple 

clinical intuition or judgment, and the current risk indices provide a means to begin to be develop 

useful clinical support tools that can be tweaked as new risk factors are identified.

Future studies might better define the utility of these risk indices by randomizing patients to 

different bleed risk management strategies possibly incorporating different combinations of 

risk factors or bleeding risk indices to assess the potential benefits and harms of different anticoagulation strategies.

Future Directions

The questions addressed in this review may become moot within the next several years. Very 

recent randomized controlled trials suggest that direct thrombin inhibitors, drugs currently being 

evaluated for the United States market, and which do not require intensive monitoring, may be as 

safe and efficacious as vitamin K antagonists. Specifically, in large randomized trials, dabigatran 

has been shown to be equivalent to warfarin for the prevention of thromboembolic events in 

patients with chronic atrial fibrillation97 and deep vein thrombosis.98 The long term safety of these 

new agents is not yet established. In one trial,97 myocardial infarction was more common among 

patients randomized to dabigatran than to warfarin, although this association was only marginally 

significant. Furthermore, liver function abnormalities were observed with use of an older direct 

thrombin inhibitor, ximelagatran,98 although to date this has not been observed with dabigatran. 

Final FDA approval of these products may significantly alter the standard for anticoagulation 

therapy and subsequent monitoring.
54

Safe and Effective Anticoagulation in the Outpatient Setting Evidence-based Synthesis Program

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