Evidence‐based Synthesis

Program ( ) ESP

Safe and Effective Anticoagulat

the Outpatient Setting:

A Systematic Systematic Review of the Evid

Evid

Hanna E. Bloomfield Bloomfield, MD, MPH

Brent C. Taylor, PhD, MPH

September 27th, 2010
Acknowledgements

C

o

‐A th /C ll b t A

uthors/C

oll

a

bora

tors

Nancy Greer, PhDAnge Krause, MD

Technical Expert PaRowena Dolor, MDAd

R MD M

Ange Krause, MDRoderick MacDonald, MS

Preetham Reddy, MD

Adam

Rose, MD, M

Keith Trettin, RPh, 

Indulis Rutks, BAVA Minneapolis ESP Director

Funding provided VA Office of Resea

VA Minneapolis ESP Director DevelopmentTimothy J. Wilt, MD, MPH

Development,

Health Services Re

Development (HSR
Evidence‐based Synthesis Pro

(ESP)

Disclosure

This report is based on research research conducted conducted by the Evidence Evidence‐based 

Program (ESP) Center located at the Minneapolis VA Medical Cente

MN, funded by the Department of Veterans Affairs, Veterans Healt

Administration Administration, Office of Research Research and Development Development, Health Servic

Servic

and Development. The findings and conclusions in this document a

the authors who are responsible for its contents; the findings and c

not necessarily necessarily represent represent the views of the Department Department of Veterans Veterans 

United States government. Therefore, no statement in this article sconstrued as an official position of the Department of Veterans Affa

in estigators investigators ha ev any affiliations affiliations or financial financial in ol ement volvement (e g. ., em

consultancies, honoraria, stock ownership or options, expert testim

patents received or pending, or royalties) that conflict with materia

the report.
Evidence‐based Synthesis Pro

(ESP)

VA Evidence‐based Synthesis (ESP)

Program Overview

• Sponsored by VA Office of R&D and HSR&D.• Established Established to provide provide timely and accurate accurate syntheses/reviews syntheses/reviews 

topics identified by VA clinicians, managers and policy‐maker

work to improve the health and healthcare of Veterans.

• Builds on staff and expertise already in place at the Evidence‐

Practice Centers (EPC) designated by AHRQ. Four of these EPESP Centers:

o Durham VA Medical Center; VA Greater Los Angeles Healt

System; Portland VA Medical Center; and Minneapolis VA 

Center.
Evidence‐based Synthesis Pro

(ESP)

• Provides evidence syntheses on important clinical practice to

to Veterans, and these reports help:

o d l eve op cli i l n ca poli i c es if d n ormed by evidence,

o the implementation of effective services to improve 

outcomes and to support VA clinical practice guidelin

performance measures, and

o guide the direction for future research to address gap

knowledge.

• Broad topic nomination process – e.g. VACO, VISNs, field – fa

ESP Coordinating Center (Portland) through online process:

http://www.hsrd.research.va.gov/publications/esp/TopicNomin
Background

• Long‐term anticoagulation indicated f

prevalent conditions ( g e. . atrial fibrilla

• Vitamin K antagonists (e.g. warfarin) h

narrow therapeutic window

• Frequent testing and dose adjustment• Anticoagulation clinics Î standardize • P t bl or a e d i ev ces Î pati t en self t ti es n

management
KEY QUESTIONS

1) Are specialized anticoagulation clinics (ACC) more 

and safer than care in non‐specialized clinics (e.g

care clinics clinics, physician physician offices) offices) for management management of 

anticoagulation in adults?

2) Is Patient Patient Self Testing Testing (PST), either alone or in com

com

with Patient Self Management (PSM), more effec

safer than standard care?

3) What are the risk factors for serious bleeding in p

chronic anticoagulant therapy?
KQ1: Are specialized anticoagulation clinics (A

effective and safer than care in non‐specialize

• Literature Search

– Included

• Randomized controlled trials or cohort stud

term (>3 months) oral anticoagulation publi

English between 1966 and 2010

– Excluded

• Studies of inpatient or pediatric populations
Literature Flow Diagram for Key Questio

612 articles identifiedin Medline

534 articles excluded

based on review of the

abstract

78 articlesretrieved for full‐text review

68 articles excluded based on fu

review

di 1 article identified by hand‐searc

11 studies

(3 RCT, 8 cohort)
Overview of Studies Studies and Sub

Sub

• 3 RCTs (US, China, and Canada)

– 722 subjects– Mean age 68 (range of study means 59 to 76)

• 8 Cohort Studies (5 in US)

– 3 prospective, 5 retrospective retrospective– 12,768 subjects– Mean age 69 (range of study means, 57 to 74)
Results of RCTs

• Rates of all‐cause mortality, major thromboemboli

and major bleeding did not differ significantly betw

two treatment treatment arms in any of the 3 RCTs.

• In the pooled analysis,

– Total Mortality: Mortality: 5/181 in ACC and 6/178 in UC all from a 

(RR: 0.81, 95%CI: 0.25 to 2.58)

– Major Bleeding: 6/353 in the ACC patients and 8/495 in 

(RR: 1.05, 95%CI: 0.36 to 3.12)

– Major thromboembolism: 11/353 in ACC and 14/495 in 

95%CI: 0.6 to 2.81).
Results of RCTs‐2

• Percent time in therapeutic range

– ACC 59.9%– UC 56.3%– weighted weighted mean difference difference of 3 6%. (rang

differences, 3.3 to 5%)
Results of Cohort Studie

Studie

• Unable to pool outcomes

• Total mortality (N=1 study)

– no significant difference between ACC and UC

• Major thromboembolic events (N=4 studies)

– 1 significantly higher incidence in UC– 1 significantly higher incidence in ACC– 2 studies, p values were not reported

• Major Bleeding (N= 5 studies)

– significantly higher in UC in 1– not significantly different between groups in 1
Results of Cohort Studies Studies

• Percent time in therapeutic range (N=4 

– ACC 63.5%– UC 53.5%– weighted weighted mean difference difference of 10% (range 

differences, 4.3 to 26%)
Conclusions for KQ1

• Evidence for the safety and efficacy of ACC is limite

suggests that ACC may lead to better quality antico

control control as measured measured by time in therapeutic therapeutic range

• There is insufficient insufficient evidence evidence to conclude conclude that ACC 

to fewer deaths, thromboembolic events, or major 

events than care provided in UC

• Results Results from two studies studies suggest suggest that patients patients like 

convenience and enhanced service provided by th
Recommendation for KQ

• There is insufficient evidence for the V

activel

y

promote the im

plementation 
KQ2: Is Patient Self Testing ( ), PST either alone 

combination with Patient Self Management (P

more effective and safer than standard care?

• Literature Search:

– Included:

• Randomized Randomized controlled controlled trials of long‐term ( 

> 

oral anticoagulation published in English bet

and 2010

– Excluded:

• Studies of inpatient or pediatric p po ulations
Literature Flow Diagram for Key Questio

1870 articlesid ifi d identified in M dli e ne

1794 articles excluded

based on review of the

abstract

76 articlesretrieved for full‐

text review

50 articles excluded based on fu4 “articles” identified by hand‐se

30 articlesreporting on 22

RCTs
Overview of Studies Studies and Sub

Sub

• 22 RCTs• Only 2 conducted in the US• 8413 subjects• Only 3 with inception cohorts• Duration of follow‐up < 12 months in 13 studies• Mean age 65 (range of means: 42 to 75)

• 3 studies focused on the elderly

• 75% of subjects were male
Interventions

• 4 evaluated PST only; 16 PSM

• PST/PSM

– Intensive training, 2‐4 sessions of 1‐3 ho

• How to use the machine and how often to c• How to dose (algorithm)• When to call for h l e p

– Access to telephone “hot line”

• Control

– Usual clinic care either in an ACC or MD 
Clinical Outcomes

• Significant 25% reduction in all‐cause mortal

(RR: 0.75, 95% CI: 0.57 to 0.99, P=0.04)

• Significant 41% reduction in major thromboe

(RR: 0.59, 95% CI: 0.45 to 0.77, P<0.0001)

• Without any increase in serious bleeding

(RR 0.91, 95%CI 0.78 to 1.07, P=0.26)
Conclusion for KQ2

• Compared to usual clinic‐based mode

anticoagulation managed with PST/PS

results in fewer deaths and majorthromboembolic events without without any 

in bleeding for a select group of motiv

adult patients patients requiring requiring long termanticoagulation
Recommendations for KQ

• Widespread implementation of this ca

in the US should await stronger stronger evide

evide

effectiveness and cost

‐effectiveness in 

US health care settings settings

• THINRS

–largest study to date, perform
KQ3: What are the risk factors for serious blee

patients on chronic anticoagulant therapy?• Literature Search:

– Included:

• Studies published in English after 1996 that 

rates of serious bleeding events in populatio

were on warfarin therapy

– Excluded:

• Studies <25 cases of serious bleeding

• Studies with p po ulations p y rimarily compose

inpatients, pediatric populations, or non‐wa

anticoagulation
Literature Flow Diagram for Key Questio

681 articles identifiedin Medline

603 articles excluded

based on review of the

abstract

78 articles retrievedfor full‐text review

46 articles excluded based on fu

review

35 articles 3 articles identified by hand‐sear

included
Overview of Included Included Stud

Stud

• 35 articles represent 35 unique studies (17 US stud

– 3 studies with a substantial VA population

• Study designs included

– meta‐analyses– RCTs of additional additional drugs combined combined with warfar

warfar

arms of RCTs analyzed as prospective cohort stu

– observational retrosp /p p ective/prospective cohort – case‐control studies

• Analytical Analytical methods methods ranged from frequencies frequencies of ev

strata of a risk factor to using multivariable models

• Average follow‐up times ranged 1 year to 5 years
Subject Characteristics

• Total N for all combined studies = 453,918 subjects• Wide range in sizes:

– case control study with 26 cases and 56 controls– large administrative database study of Medicare records 

353,489 patients

• Most studies i ldd nc u ed pri il mar y eld l er y popul i at on

average age of approximately 70 years.

• The distribution distribution of gender represented represented in the stud

stud

widely with a maximum of 98.5% male to a minim

male.
Narrative Summary of Predic

Serious Bleeding

• Pooling of statistical results for each predictor was 

since the study designs and analytical methods var

• Quantitative results extracted from the 35 studies 

presented presented in the Appendices Appendices of the Full Report (Ap
Risk Factors for Serious Bleeding Report

Individual Studies

Article Age Gender

Warfarin 

Duration INR

Primary 

Indication

Asp

Article Age Gender Duration INR Indication NSBattistella 200555 √Beyth 199849 √ √DiMarco 200556 √ √Douketis

200660 √√ √

Douketis 200765Fang 200557

√

Fang 200661 √ √Fihn 199647 √...
Risk Factors for Serious Bleeding Re

in the Individual Studies

Risk Factor ArticlesAge 16Gender 9Warfarin Duration 5

INR 2

Primary Indication 2Aspirin/NSAID 11Other Meds 11Risk Index 7Genetics 3Comorbidity 12Other 8
Factors most consistently predictin

increased risk of bleeding bleeding

• Very old age (ex. 75+)• First months following warfarin initiation• Medication Medication use (particularly (particularly aspirin aspirin use)• Comorbid conditions

– History of GI bleeding events or diabetes

• Primary indication for taking warfarin was a 

condition

• Genetic factors (ex. variation in the CYP2C g 

• Bleeding Risk Indexes

– Nine different different Indices Indices reported reported (HEMORR (HEMORR HAG

2HAG

had the most evidence)
Stratifying Patients by Risk 

Bleeding

• For example, In the Outpatient Bleeding Risk Index 

patients get 1 point for each of the following:

– 65 years or older, hi ts ory of GI t t rac bl di ee ng, h

stroke, and one or more comorbid conditions (r

myocardial myocardial infarction infarction, anemia, renal impairmen

impairmen

diabetes mellitus).

– Low= score of 0– Moderate = score 1 or 2– High risk = score 3+
Conclusions for KQ3

• Bleeding risk indices are currently ava

stratifying stratifying patients patients into “low” and “hig

groups.

• However, there is not adequate evide

suggest that any of the bleeding risk i

are meaningfully superior to the othe

• HEMORR HAGES index seems to be th

2HAGES index seems to be th

comprehensive list of potential factor

• OBRI index has been the most frequen

tested model and is more parsimonio

parsimonio
Conclusions for KQ3

• Growing support for the development 

formal methods of risk assessment be

that of simple clinical intuition or judgand the current current risk indices indices provide provide a 

to begin to develop useful clinical sup

tools that can be tweaked tweaked as new risk 

are identified.
Future Research Directio

• Randomizing patients to different leve

treatment based on bleeding risk inde

measurements prior to or during chrowarfarin treatment treatment would provide provide cle

cle

evidence of the utility of incorporating 

factor assessment assessment into the clinical clinical enc

enc

• Decision modeling studies might also 

some information at a lesser cost than RCT
Summary of Recommend

• There is insufficient evidence to recommen

efforts to implement ACCs in VA

• PST/PSM are promising promising but widespread widespread

implementation should await results of stu

US/VA

• Either alone or in combination combination, risk factors factors 

to help clinicians and patients have a dialog 

the risks of warfarin warfarin therapy therapy, but the clinica

clinica

risk indices is largely untested