62

tion in the Outpatient Setting Evidence-based Synthesis Program

eer Review Comments and Responses

Author Response

the literature related to the questions you sought to answer. 

onal and the product is truly authoritative.

Thank you

about how warfarin is due to be replaced at any moment

ongs in an ESP because this is not part of the evidence base 

ing warfarin, at least for some patients, for at least the next 10 

ative agent has received FDA approval.

We have deleted many of the messages about potential alternatives to warfarin (see additional responses below).

ve review of anticoagulation management in the outpatient 

Thank you

thods Clearly Described

y described. NR*

NRNR

 thoughtful, thorough, and well written report that provides 

of three decades of research on management of oral 

dressed by the review are clinically quite relevant, in certain 

he analysis to address the clinical circumstances in a 

r. The management of oral anticoagulation is simplistically 

ation and maintenance. As the authors of this review have 

mplications is during this period [initiation]. Once stability is 

s oriented toward minimizing variation in the INR related to 

ation of drugs, changes in diet, etc. Research suggests the 

s latter phase also predicts likelihood of complications. The 

n this review treats these phases as one continuous process. tudies, i.e., AC clinics and PST, and the risk factors for 

ent according to the phase studied.

 confounding effects of computerized dosing programs, 

re considered. My bias is that much of any beneficial effect of 

e of protocols. Can you ascertain if some of the “control” clinics 

using such tools?

Thank you. b. We have reviewed the studies cited in the report and have added information about initiation and maintenance phases in the Overview of Included Studies sections for KQ1 and KQ2. c. We have added information about possible processes of care that might have accounted for observed differences under KQ1a.
63

tion in the Outpatient Setting Evidence-based Synthesis Program

bias shown in support of the direct thrombin inhibitors class and 

 yet to be approved for release to the US market (see pages 

Summary for example); these statements are all speculative 

e included in an evidence based report. A more benign and 

nsidered that could be used once in the Executive Summary: 

may offer the same clinical efficacy and safety profile as 

ss monitoring are currently being evaluated for the US market. 

products may significantly alter the standard for anticoagulation 

nitoring”. 

Thank you for the suggested wording. We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.NR

eport to support the conclusions regarding direct thrombin 

bigatran (see pages iii, iv, vi, and 46). This drug has not 

or use in the US and the report does not draw on any FDA 

drug. There have been several drugs that showed exceptional 

ls that have either been withdrawn from the market or had 

e to problems found during post-marketing surveillance. Stating 

s are “poised to become the preferred treatment for long term 

towards this class of drugs that is not supported by evidence 

on page 46 (“The long term safety of these new agents is not 

ded in the executive summary. I would recommend removing 

 inhibitors from the report. If it is included, I would recommend 

s is currently in clinical trials and the role in therapy has not 

t the usage of warfarin.

We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.NR

ished Studies

NRNRNR
64

tion in the Outpatient Setting Evidence-based Synthesis Program

have been included specifically:

Med 1993;118:511-520 (addresses several risk factors 

ng variability in INR)

mb Haemost 2008;6:451-460 (addresses variability in INR as 

;136:1503-1513 (addressed variability in INR as a risk factor)

bility in INR Is important during the maintenance phase and 

he review.

Fihn 1993 was excluded, because it was outside of the search window (1996 or later).Information for both Van Leeuwen 2008 and LeTourneau 2009 has now been added to the KQ3 section.

ge THIINRS to THINRS NR

s diminishing the usefulness of this review with the assumption 

s will replace warfarin for anticoagulation since they do not 

 It seems premature to make this assumption based on 

ile these studies report the efficacy of the new drug in clinical 

eness (or cost-effectiveness) of these therapies in non-clinical 

een.

We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.

have been completed and the main study paper is planned 

010. An inquiry on whether the unpublished results can be 

eta-analysis could be sent to the CSPCC in Palo Alto.

We have been in contact with the CSPCC and including unpublished data is not an option.
65

tion in the Outpatient Setting Evidence-based Synthesis Program

thesis showed insufficient evidence to conclude that ACC care 

boembolic events, or major bleeding events than usual care, 

concluded that better quality anticoagulation control typically 

r better outcomes. This is discussed in Philips and Ansell 

ines (2008). This review does discuss other reviews (pg. 46) 

ssed in the Executive Summary. 

ave focused on quality and safety have supported AC clinics 

Event Alert Issue 41; AHRQ Report #43, Part III, Chpt. 9). 

e iv that states “there is insufficient evidence for the VA to 

entation of ACCs” I would recommend stating further that this 

of other organizations or expand on how the conclusion of the 

m conclusions of other organizations and experts in the field.

g that this synthesis of the literature did not consider the cost

ource utilization and therefore the conclusion that there is 

d solely on evidence regarding clinical outcomes and does not 

costs, and resource utilization. As the VA does manage a large 

n AC clinics HSR&D may want to consider a study that looks at 

nt within the VA system and include these factors.

a. We have chosen to present the results from our review in the Executive Summary leaving comparisons to other studies in the Discussion section. In agreement with the ACCP Guidelines, we have noted the limited nature of the evidence in the Executive Summary.b. We have reviewed these documents. The Joint Commission Alert is based on a few studies (not a comprehensive review). The AHRQ Report was completed in 2001 and therefore does not include many of the studies cited in our review.c. We are limited to reaching conclusions based on the evidence.d. Cost-effectiveness was outside the scope of the report as defined by the Key Questions. We searched for but were unable to identify evidence-based data on resource utilization. Patient satisfaction results are included in our review. We agree that a study that includes costs and resource utilization would be worthwhile and we have added a statement to that effect in the Conclusions and Recommendations for Key Question 1.

hors indicate that the review may be of limited value because 

of direct thrombin inhibitors. Although this may well be true, 

agonists have been prevalent for 3 decades. Although these 

utic ratio, they have an efficacy in preventing stroke of nearly 

lmost any other drug in regular therapeutic use. Given the fact 

y inexpensive, must typically be taken for many years, and has 

ot be dislodged all that soon.

We have added a statement to the “Background” section of the Executive Summary and the “Discussion and Recommendations” section of the full report. We have deleted all other statements about direct thrombin inhibitors.
66

tion in the Outpatient Setting Evidence-based Synthesis Program

vidence Tables

mized Controlled Trials for Anticoagulation Clinic versus Usual Care (KQ1)

Indication for anticoagulationEntrance criteriaDuration of follow-upMean age% MaleInception Cohort/Time on OAC prior to enrollment

Intervention Group (n)Control Group (n)Total sample size (N)

Outcomes evaluated* Study quality

Atrial fibrillationAge ≥ 65, atrial fibrillation, enrolled in 1 of 6 managed care organizations Mean Age: 76+ 7% Male: 49A follow-up period of the 9 months immediately after theanticoagulation service had attained the minimum enrollmentInception: unclear

Intervention Cluster:  referred to ACC:173,  not referred to ACC: 190Control Cluster: 317N=6802 Practice clusters within each site were randomized to either access or no access to an ACC. The intervention clusters did not HAVE to refer pts to the ACC.

iii. VTE

iv. Bleeding

vii. Time in Therapeutic 

Range

Allocation concealment: NABlinding: NRIntention-to-treat: NRDropouts reported: yes

nces 

ces 

wa, 

Mixed indicationsAll patients expected to be on warfarin ≥ 3moMean Age: 61+ 15 years% Male: 58Follow-Up: 3 monthsInception (< 1 month): 81%

Intervention: ACC: 112Control: family physician:109N = 221

i. All cause mortality

ii. Event related 

mortality

iii. VTE

iv. Bleeding

v. Patient Satisfaction

vii. Time in Therapeutic 

Range

Allocation concealment: yesBlinding: clinical event adjudication committee blinded Intention-to-treat: yesDropouts reported: yes
67

tion in the Outpatient Setting Evidence-based Synthesis Program

d 

Mixed indicationsAll patients, age ≥ 18, requiring ≥ 3mo of warfarin therapyMean Age: 59 + 14 years% Male: 45Follow-Up: max 2 years, average length cannot be determinedInception cohort: see page 602

Intervention: pharmacist-managed ACC: 69Control: hematologist-managed ACC: 69N = 138

i. All cause mortality

iii. VTE

iv. Bleeding

v. Patient Satisfaction

vii. Time in Therapeutic 

Range

xi. Hospitalization

xii. Outpatient Utilization

xiii. ER Utilization

Allocation concealment: unclearBlinding: NRIntention-to-treat: noDropouts reported: yes

mbolic events)

nge

viii.% of INRs in Therapeutic Rangeix. INR Variabilityx. # of Total INR Valuesxi. Hospitalizationxii. Outpatient Utilizationxiii.ER Utilizationxiv. Outpatient Laboratory Utilizationxv. Long-term Care Admission 

(after related event)
68

tion in the Outpatient Setting Evidence-based Synthesis Program

ational Studies for Anticoagulation Clinic versus Usual Care (KQ1)

 design

tion for anticoagulation

nce criteria

on of follow-up

agee

eption/time on OAC prior to enrollment

Intervention Group (n)Control Group (n)Total sample size (N)

Outcomes evaluated*

ective Cohort

indications

ents discharged from hospital requiring long 

arfarin.

-Up: 3 mos

Age: 56.9

e: 57

on: NR

Intervention: Hospital discharges requiring long term anticoagulation referred to anticoagulation clinic. The ACC was led by a pharmacist and included patient education via manuals, videos and compliance aids. (68)Control: Random sample of hospital discharges requiring long term warfarin but not referred to anticoagulation clinic (68)N = 136

xi. Hospitalization

pective CohortIndications

ents, requiring ≥3mo of warfarin therapy, 

 least one outpatient visit

-Up: NR

Age: NR (90% < 65)

e: 53

on: 100%

Intervention: ACC which was led by a pharmacist and included intensive patient education; no dosing algorithm (183)Control: Usual medical care (145)N = 328

iii. VTEiv. Bleedingvii. Time in Therapeutic 

Range

viii. % of INRs in Therapeutic 

Range

xi. Hospitalizationxiii. ER Utilization

pective Cohortindications

coagulation patients during study period 

ed

-Up: NR

Age: 63 + 15

e: 42

on: No/NR

Intervention: Anticoagulation patients during the period 11/1/1996 to 10/31/1997 followed in a pharmacist-run anticoagulation clinic which included POC testing (41)Control: Anticoagulation patients during the period 11/1/1996 to 10/31/1997 followed in a family medicine clinic that did not perform POC testing (75)N = 116

iii. VTEviii. % of INRs in Therapeutic 

Range

xi. Hospitalizationxiii. ER Utilization

pective Cohortindications

, on warfarin, ≥2 INR values during 6 mo 

tion period

-Up: 6 months

Age: 67.8

e: 53

on:NR

Intervention: Anticoagulation therapy managed by a centralized, telephonic clinical pharmacy anticoagulation service manned by pharmacists available 24/7; patient education provided (3323)Control: Anticoagulation therapy managed per usual personal physician. (3322)N = 6645

i. All cause mortalityii. Event related mortalityiii. VTEiv. Bleedingvii. Time in Therapeutic Range
69

tion in the Outpatient Setting Evidence-based Synthesis Program

ective cohort

brillation

on anticoagulation 

-Up: NR

Age: 61.8

e: 59

on: NR

Intervention: referred to anticoagulation clinic (details not provided) (66)Control: followed by usual care which consists of follow-up by cardiology outpatient clinic (138)N = 204

iii. VTE

iv. Bleeding

viii. % of INRs in Therapeutic 

Range

pective Cohort

brillation

sectional cohort with chronic NVAF, age >18, 

um 60 days of AC

-Up: 12 months

Age: NR

e: NR

on: NR

Intervention: Patients of anticoagulation clinics using local protocols were followed in Italy and Spain. ACC management was defined as care provided in a systematic way by personnel focusing specifically on AC management (395)Control: Patients of routine medical care using local protocols were followed in the US, Canada and France (1116)N = 1511

vii. Time in Therapeutic 

Range

viii. % of INRs in Therapeutic 

Range

ective Cohort

indications

ents treated with warfarin in two regions of 

rn Sweden.

-Up: 1.8 years (mean), 4 yrs max

Age: 69

e: 58

on cohort: NR

Intervention: Anticoagulation clinic, no details provided (1537)Control: Primary healthcare centre (1194)N = 2731

iv. Bleeding

pective Cohort

Fibrillation

on anticoagulation

-Up: 12 mos

Age: NR

e: 55

on: No

Intervention: ACC run by an RN mostly by phone, supervised by a cardiologist; intensive pt education on first visit. (351)Control: Usual care by internists, GPs or cardiologists. (756)N = 1107

iii. VTE

iv. Bleeding

vii. Time in Therapeutic 

Range

c events)

vii. Time in Therapeutic Rangeviii. % of INRs in Therapeutic Rangeix. INR Variabilityx. # of Total INR Valuesxi. Hospitalizationxii. Outpatient Utilization

xiii. ER Utilizationxiv. Outpatient Laboratory Utilizationxv. Long-term Care Admission (after 

related event)
70

tion in the Outpatient Setting Evidence-based Synthesis Program

w of individual short-term (<12 months) randomized, controlled trials investigating PST/PSM (KQ2)

ions for anticoagulation

ce criteria

on of follow-up

agee

 of time on OAC prior to enrollment

Intervention group (n)Control group (n)Total sample size (N)Type of vitamin K antagonist

Outcomes evaluated* Study quality

s with a disease or condition requiring 

 OAC

hs

years

ale

 years (mean)

ar (pts were not previously treated in 

 clinics)

Intervention: PSM (n=90)Control: PC clinic (n=89)N=179Phenprocoumon

iii. Thromboembolic events

iv. Major bleeding events

v. Patient satisfaction/

quality of life

vii. INR variability

Allocation concealment: adequateBlinding: lab techs doing the INRs were blindedIntention-to-treat: yesDropouts reported: yes

s aged ≥65 years, residing in 

oga County, OH, starting on OAC with 

ent planned for ≥10 days

hs

8 years (range 65-94)

ale

 (inception cohort)

Intervention: PST (n=163)Control: PC clinic (n=162)N=325Warfarin

i. All-cause mortality

iii. Thromboembolic events

iv. Major bleeding events

viI. % time within 

therapeutic range

Allocation concealment: unclearBlinding: two authorreviewers who were blinded to group assignment adjudicated bleedingeventsIntention-to-treat: yesDropouts reported: yes

pporting patients receiving long-term 

hs (each pt followed 3 mos in each 

ent)

6 years (range 21-71)

ale

 years (mean) (not inception)

Intervention: PSM (n=50)Control: AC clinic (n=50)(Total N=50)Phenprocoumon and acenocoumarol

iii. Thromboembolic events

iv. Major bleeding events

v. Patient satisfaction/

quality of life

vi. % time within 

therapeutic range

vii. % INR values within 

therapeutic range

Allocation concealment: adequateBlinding: NRIntention-to-treat: unclearDropouts reported: yes
71

tion in the Outpatient Setting Evidence-based Synthesis Program

s aged ≥18 years, on long-term OAC 

months previously, with good vision 

anual dexterity, and with INR within 0.5 

et value at least 60% of the time over 

or 12 months

hs

rs

ale

orted (not inception)

Intervention: PSM (n=30)Control: AC clinic (n=26)N=56Warfarin

iv. Major bleeding events

v. Patient satisfaction/

quality of life

vi. % time within 

therapeutic range

vii. % INR values within 

therapeutic range

Allocation concealment: unclearBlinding: noIntention-to-treat: noDropouts reported: yes

s aged 18-75, requiring long-term 

with ≥3 months experience on OAC

eeks (mean)

rs

ale

orted (not inception)

Intervention (1): PST (n=52)Intervention (2): PSM (n=47)Control (1): AC clinic patients aware of the study and receiving education about OAC (n=60)Control (2): AC clinic patients not aware of the study (n=161)N=320Phenprocoumon and acenocoumarol

iii. Thromboembolic events

iv. Major bleeding events

v. Patient satisfaction/

quality of life

vi. % time within

therapeutic range

vii. % INR values within 

therapeutic range

Allocation concealment: adequateBlinding: physicians evaluating andcorrecting the proposed dosing schedules for group A and group B Intention-to-treat: yesDropouts reported: yes

ibrillation

s aged ≥65 years without dementia, 

farin for ≥12 months, with a target INR 

with an INR standard deviation of >

r prior 6 months

hs

 age 73 yrs (range: 65-93)

ale

orted (not inception)

Intervention: PST (n=44)Control (1): ACC patients aware of the study and receiving education about OAC (n=41)Control (2): ACC patients not aware of the study (n=40)N=125Warfarin

iii. Thromboembolic events

iv. Major bleeding events

v. Patient satisfaction/

quality of life

vi. % time within

therapeutic range

Allocation concealment: unclearBlinding: NRIntention-to-treat: noDropouts reported: yes
72

tion in the Outpatient Setting Evidence-based Synthesis Program

s age > 18 years on warfarin for >

h with target INR range 2-3 or 2.5-

hout mental incompetence or known 

oagulable disorders

hs

rs

ale

with > 6 months OAC

Intervention: PSM (n=70)Control: PC clinic (n=70)N=140Warfarin

iii. Thromboembolic events

iv. Major bleeding events

v. Pt Satisfaction

vi. % time within

therapeutic range

vii. % INR values within

therapeutic range

Allocation concealment: adequateBlinding: noIntention-to-treat: yesDropouts reported: yes

s aged ≥18 years attending the 

gulation clinic at University College 

 Hospital, on OAC for ≥8 months, 

evious record of good compliance

hs

rs (range 26-83) (unclear if mean or 

)

ale

orted (not inception)

Intervention: PST (n=44)Control: AC clinic (40) N=84Warfarin

iv. Major bleeding events

v. Pt Satisfaction

vi. % time within

therapeutic range

Allocation concealment: unclearBlinding: noIntention-to-treat: unclearDropouts reported: yes

brillation

s on OAC for atrial fibrillation, without 

ism or other addictions

mos

3years

ale

orted

Intervention: PSM (n=101)Control: PC clinic (n=101)N=202Not reported

iii. Thromboembolic events

iv. Major bleeding events

vi. % time within 

therapeutic range (# of days)

vii. % INR values within 

therapeutic range

Allocation concealment: unclearBlinding: noIntention-to-treat: unclearDropouts reported: unclear

s aged ≥18 years on OAC for ≥8 

ys (mean)

3.7 years

ale

 years (mean)

orted (not inception)

Intervention: PSM (n=50)Control: PC/AC clinic (n=50)N=100Warfarin and phenprocoumon

i. All-cause mortality

iii. Thromboembolic events

iv. Major bleeding events

vi. % time within

therapeutic range

viii. INR variability

Allocation concealment: noBlinding: noIntention-to-treat: no Dropouts reported: yes
73

tion in the Outpatient Setting Evidence-based Synthesis Program

s aged ≥18 years on long-term 

r ≥8 months, without history of poor 

ance, intellectual impairment, or known 

 alcohol dependency

hs

s (22-88)

ale

orted (not inception)

Intervention: PSM (n=55)Control: PST (n=49)N=104Warfarin

vi. % time within

therapeutic range

Allocation concealment: unclearBlinding: noIntention-to-treat: unclearDropouts reported: yes

placement

s undergoing mechanical valve 

ment at Clermont-Ferrand University 

l

 weeks (mean)7 years

ale

orted (recruited when undergoing 

eplacement)

Intervention: PST (n=33)Control: AC clinic (n=34)N=67Fluindione and acenocoumarol

i. All-cause mortality

iii. Thromboembolic events

iv. Major bleeding events

vi. % time within 

therapeutic range

vii. % INR values within 

therapeutic range

viii. INR variability

Allocation concealment: unclearBlinding: noIntention-to-treat: unclearDropouts reported: yes

s on OAC for ≥2 months who had 

 access.

hs

14.3 years 

ale

orted (not inception)

Intervention: PSM (n=132 completed both arms,72 initially)Control: AC clinic (n=132,60 initially)N=162Warfarin

iii. Thromboembolic events

iv. Major bleeding events

vi. % time within

therapeutic range

Allocation concealment: adequate (pharmacycontrolled)Blinding: noIntention-to-treat: noDropouts reported: yes

ic events)

viii. % of INRs in Therapeutic Rangeix. INR Variabilityx. # of Total INR Valuesxi. Hospitalizationxii. Outpatient Utilizationxiii. ER Utilization
74

tion in the Outpatient Setting Evidence-based Synthesis Program

w of individual long-term (≥12 months) randomized, controlled trials investigating PST/PSM (KQ2)

cations for anticoagulation

ance criteria

ation of follow-up

n age

ale

ption cohort/ time on OAC prior to 

llment

Intervention (n)Control (n) Total sample size (N)Type of vitamin K antagonist

Outcomes evaluated* Study quality

V replacement

ance criteria not reported

 months (mean)

eportedeportedeported

Intervention: PSM (n=75) (dosing unclear)Control: PC clinic (n=75)N=150Not reported

iii. Thromboembolic eventsiv. Major bleeding eventsvii. % INR measurements 

within therapeutic range

Allocation concealment: unclearBlinding: NRIntention-to-treat: unclearDropouts reported: unclear

V replacement

ents undergoing MHV replacement from 

94-10/1997 at a German institution

l f/u: 38 mos

-term f/u: 9.3 +/- 2.8 years

ears 

 male

ption Cohort

Intervention: PSM (n=579 in 2001; 488 in 2007)Control: PC clinic (n=576 in 2001; 442 in 2007)N (2001)=1155N (2007)=930Phenprocoumon

i. All-cause mortality(2007)ii. Event-related mortality 

(2007)

iii. Thromboembolic events 

(2001)

iv. Major bleeding events 

(2001)

vii. % INR values within 

therapeutic range (2001)

Allocation concealment: unclearBlinding: NRIntention-to-treat: unclearDropouts reported: yes

V replacement

ents who had undergone MHV 

cement by the author and were < 85 yo 

out visual difficulties

onths

ears (range: 26-85)

 male

eported

Intervention: PSM (n=51)Control: PC or AC clinic (n=49)N=100Warfarin

i. All-cause mortalityii. Event-related mortalityiii. Thromboembolic eventsiv. Major bleeding eventsvi. % time within therapeutic

range

Allocation concealment: unclearBlinding: NRIntention-to-treat: unclearDropouts reported: yes
75

tion in the Outpatient Setting Evidence-based Synthesis Program

d

nts aged ≥18 years on warfarin for ≥6 

hs with treatment indicated for ≥12 hs, with a target INR of 2.5-3.5onths

ears

male

eported (not inception)

Intervention: PSM (n=337)Control: AC clinic (n=280)N=617Warfarin

i. All-cause mortalityii. Event-related mortalityiii. Thromboembolic eventsiv. Major bleeding eventsv. Patient satisfaction/quality 

of life

vi. % time within therapeutic 

range

Allocation concealment: adequateBlinding: noIntention-to-treat: yesDropouts reported: yes

d

nts aged ≥18 years on long-term OAC 

3 months, without severe physical or 

al illnessonths (median f/u)

ears

male

ears (median, IQR 2.0-12.0)

ception NR

Intervention: PSM (n=368)Control: AC clinic (n=369)N=737acenocoumarol

i. All-cause mortalityiii. Thromboembolic eventsiv. Major bleeding eventsvi. % time within therapeutic 

range

vii. % INR values within 

therapeutic range

viii. INR variability (INR 

distance, table 2)

Allocation concealment: adequateBlinding: complications diagnosed and evaluated by a third physician not involved in the trial and unaware of patients’ study groupIntention-to-treat: yesDropouts reported: yes

d

nts aged ≥60 years, on long-term 

, without severe cognitive problems or 

nal illness

 1.2 years (mean)

6.3 years

male

7.1 years (mean)

nception

Intervention: PSM (n=99)Control: AC/PC clinic (n=96)N=195Phenprocoumon and acenocoumarol

i. All-cause mortalityii. Event-related mortality 

(see table 4 p. 1096)

iii. Thromboembolic eventsiv. Major bleeding eventsvi. % time within therapeutic 

range

vii % INR values within 

therapeutic range

viii. INR variability

Allocation concealment: adequateBlinding: complications evaluated by two independent physicians not involved in the trial and unaware of patients’ study group.Intention-to-treat: yesDropouts reported: yes
76

tion in the Outpatient Setting Evidence-based Synthesis Program

 replacement

nts undergoing MHV replacement in a 

man hospital

ars

years

male

eported (randomized at time of valve 

cement)

Intervention: PSM (n=470)Control: PC clinic (n=295)(crossovers were allowed)N=765Warfarin

iii. Thromboembolic eventsiv. Major bleeding eventsvii. % INR values within 

therapeutic range

viii. INR variability

Allocation concealment: unclearBlinding: NRIntention-to-treat: noDropouts reported: no

 replacement

nts undergoing MHV replacement in a 

h hospital with knowledge of computers 

he internet.

onths 

ears

eported

ption cohort (randomized at time of valve 

cement)

Intervention: PSM (n=29)Control: AC clinic (n=29)N=62Not reported

i. All-cause mortalityiii. Thromboembolic eventsiv. Major bleeding eventsv. Pt Satisfaction /quality of 

life

vi. % time within therapeutic 

range

Allocation concealment: unclearBlinding: NRIntention-to-treat: noDropouts reported: yes

d 

nts with MHV replacement or atrial 

ation and competent in device use

4.75 years

9 years

male

an inception cohort (mean time on OAT 

to enrollment not reported)

Intervention: PST (n=1,465)Control: AC clinic (n=1,457)N=2922Warfarin

i. All-cause mortalityiii. Thromboembolic eventsiv. Major bleeding eventsv. Pt Satisfaction /quality of 

life

vi. % time within therapeutic 

range

Allocation concealment: adequate Blinding: major outcomes assessed by independent adjudicators Intention-to-treat: yesDropouts reported: yes

c events)

ange

x. # of Total INR Valuesxi. Hospitalizationxii. Outpatient Utilizationxiii. ER Utilization
77

tion in the Outpatient Setting Evidence-based Synthesis Program

of Individual Studies – Risk Factors for Serious Bleeding (KQ3)

gn

s for anticoagulation

criteria

f follow-up (years)

N (cases)Mean age% Male Definition of Serious Bleeding

Serious Bleeding Outcomes by Risk Factors 

ve cohort study using 

ive Datasets

ending a VA anticoagulation clinic 

001 and 2002

Administrative Data from January 1, 

cember 31, 2002

N(cases): 1,269 (42)Mean age:67.9 (SD=11.4)92% Male

Patient was hemo-dynamically unstable, required a transfusion, had an intracranial hemorrhage, or died.

Risk Index (Bleeding Risk Index) *

Low: 0.8% /PYr (95% CI; 0-4.2)Med: 2.5%/PYr (95%CI;1.6-3.7)High: 10.6% /PYr (95% CI; 6.4-16.6)Warfarin Duration (p=.08)*

New User (n/N): 2.2% (11/502)Prior User (n/N): 4.0% (31/767)

e-control study using 

ive Datasets

ontinuous warfarin users from April 

March 31, 2001

 year

N(cases): 1,798 (361)Mean age:77 (SD=6.8)49% Male

Patient was admitted to the hospital with any diagnosis of upper GI hemorrhage

Other Med Use***

NSAID: OR=1.9 (95%CI;1.4-3.7)Cox-2 InhibitorsCelecoxib: OR=1.7 (95%CI;1.2-3.6)Rofecoxib: OR=2.4 (95%CI;1.7-3.6)

ve cohort studies (derivation 

on cohorts) using data primarily 

cords 

cohort of patients who started 

warfarin therapy upon discharge 

al between 1977 and 1983

nception cohort of consecutive 

o started warfarin therapy upon 

rom hospital between 1986 and 

or both groups was presented up 

Derivation cohort:N(cases): 565 (65)Mean age:61(SD=14)47% MaleValidation cohort:N(cases): 264 (22)Mean age:60(SD=16)47% Male

Overt bleeding that led to the loss of at least 2.0 units in 7 days or less, or was otherwise life-threatening (eg, intracranial bleeding)

Results from Derivation cohort:Risk Index (Outpatient Bleeding Risk Index)*Risk of major bleeding at 12 monthsLow: 3%Intermediate: 12%High: 48%Warfarin Duration (follow-up time not time on warfarin)Cumulative events at 1 month: 3%Cumulative events at 12 months: 11 %Cumulative events at 48 months: 22%Results from Validation cohort:Risk Index (Outpatient Bleeding Risk Index)*Risk of major bleeding at 12 monthsLow: 3%Intermediate: 8%High: 30%Warfarin Duration (follow-up time not time on warfarin) Cumulative events at 1 month: 2%Cumulative events at 12 months: 8 %Cumulative events at 48 months: 12%Results from Combined Cohorts:Stratifying by increased Age and Comorbidity (components of OBRI) shows increased the major bleeding
78

tion in the Outpatient Setting Evidence-based Synthesis Program

e Cohort (vitamin K antagonist arm 

rfarin or acenocoumarol)

th atrial fibrillation at risk for 

bolism

0.9 years (SD=0.5)

N(cases): 2293(29)Mean age: 70.2 (SD=9.165% Male

Bleeding that was fatal, intracranial, or affected another critical anatomical site, or overt bleeding with a drop of hemoglobin ≥20 g/L or requiring transfusion of two or more units of Erythrocytes.

Risk Index (CHADS2 score) *

Low: 0.8% /PYr

 Moderate: 1.0% /PYr High: 2.5% /PYr

aring rate-control and rhythm

tegies in patients with atrial 

 were eligible for warfarin at 

nd most continued their warfarin 

average of 3.5 years (range 0 – 5.9 

N(cases): 4060 (260)Mean age:70 (SD=9)61% Male

Major bleeding was either CNS hemorrhage, or outside the CNS bleeding that required transfusion of ≥2 units of blood, hospitalization in an intensive care unit, and/or discontinuation of anticoagulant or antiplatelet Therapy.

Age: (per year): HR=1.05(95%CI;1.04,1.07)***

Comorbidities:CHF: HR=1.43(95%CI;1.09,1.89)***Diabetes: HR=1.44(95%CI;1.07,1.93)***Hepatic or Renal Disease: HR=1.93(95%CI;1.27,2.93)***Other Med Use:Aspirin Use: HR=2.01(95%CI;1.45,2.77)***Rate Control vs. Rhythm-control strategiesNo difference (p=0.45)

lysis of two large RCTs using just 

n arms of each trial

ere adults with nonvalvular atrial 

p to 24 months

N(cases): 3665 (136)Mean age: ~71<65: 22%65-75: 40%>75: 38%70% Male

Major bleeding was: fatal bleeding; clinically overt bleeding associated with a reduction in hemoglobin level of 20 g/L or more; clinically overt bleeding requiring transfusion of 2 or more units of whole blood or erythrocytes; intracerebral bleeding; and bleeding involving a critical anatomic site.

Age: (Greater 75): HR=1.26(95%CI;1.03,1.52)***

Comorbidities:Hepatic Disease: HR=4.88(95%CI;1.55,15.39)***Other Med Use:Aspirin Use: HR=2.41(95%CI;1.69,3.43)***Statins Use: HR=0.60(95%CI;0.41,0.87)***Warfarin Duration: *Cumulative incidence of major bleeding, % (95% CI)*3 Months: 0.8 (0.5-1.0)12 Months: 2.6 (2.1-3.2)24 Months: 4.7 (3.8-5.5)

e-control study using administrative 

were age 66+ with atrial fibrillation 

prescribed warfarin between April 1, 

December 31, 2001

average of 2 years 

N(cases): 16,618 (1518)Mean age:77 (SD=7)46% Male

Cases were admitted to a hospital with a diagnosis of upper gastrointestinal or intracranial hemorrhage.

Other Med Use:Long-term Warfarin Users (>6 months)Statins Use: OR=0.82(95%CI;0.67,1.00)***Recent Warfarin Users (<6 months)Statins Use: OR=1.02(95%CI;0. 78,1.34)***
79

tion in the Outpatient Setting Evidence-based Synthesis Program

dy using Administrative Datasets

th nonvalvular atrial fibrillation

2.4 years (IQR=1.8-2.8)

15,300 person years (170 cases)Mean age:71 (SD=15)53% Male

Intracranial hemorrhages unless they were associated with major head trauma (e.g., neurosurgical procedure, motor vehicle accident, and skull fracture).Major extracranial hemorrhages defined as fatal, requiring transfusion of two or more units of packed blood cells, or hemorrhage into a critical anatomic site.

New vs. Prior Warfarin

Intracranial hemorrhages 1st Month: 0.92% /PYr

Afterward: 0.46% /PYrRR: 2.0 (95% CI ; 0.6–6.7)*Major Extracranial hemorrhages 1st Month: 1.2% /PYrAfterward: 0.61% /PYrRR: 2.0 (95% CI ; 0.7–5.8)*AgeIntracranial hemorrhages ≥80 v. <80: RR=1.8 (95%CI;1.1–3.1)***Major Extracranial hemorrhages Per 10 years: RR=1.3 (95%CI;1.1–1.7)***

dy using Administrative Datasets

th nonvalvular atrial fibrillation

2.4 years (IQR=1.8-2.8)

~15,000 person years (167 cases)Mean age:71 (SD=15)53% Male

Intracranial hemorrhages unless they were associated with major head trauma (e.g., neurosurgical procedure, motor vehicle accident, and skull fracture).Major extracranial hemorrhages defined as fatal, requiring transfusion of two or more units of packed blood cells, or hemorrhage into a critical anatomic site.

Gender:All major hemorrhagesMen 1.1% vs. Women 1.0%*Men: RR=1.25 (95% CI;0.91–1.67)***Intracranial hemorrhages Men 0.55% vs. Women 0.36%*Men: RR=2.0 (95% CI;1.11–3.33)***

retrospective and prospective 

ies

ending a combination of VA and 

ffiliated clinics anticoagulation clinic 

80 and 1993

Retrospective study data from 

90; prospective study data collected 

990 and 1993.

N (cases): 2376(259)Mean age: 58.373.4% Male

Overt gastrointestinal bleeding; occult gastrointestinal bleeding if endoscopic or radiographic studies were done; gross hematuria prompting cytoscopy or intravenous urography or lasted more than 2 days; hemoptysis.

Age group*Serious Bleeding RR(95%CI)*<50 yrs: 9.3%/PYr ref50-59 yrs: 7.1%/PYr 1.2 (0.9-1.6)60-69 yrs: 6.6%/PYr 1.3 (1.0-1.7)70-79 yrs: 5.1%/PYr 1.3 (1.0-1.7)80-89 yrs: 4.4%/PYr 0.9 (0.5-1.5)Life-threatening or fatal RR(95%CI)*<50 yrs: 0.8%/PYr ref50-59 yrs: 1.3%/PYr 1.3 (0.4-4.1)60-69 yrs: 1.1%/PYr 1.5 (0.5-4.0)70-79 yrs: 0.7%/PYr 0.9 (0.3-3.1)80-89 yrs: 3.4%/PYr 4.5 (1.3-15.6)

d multicenter study (combined 

and double-blinded studies)

atients with nonvalvular AF

1.4 years (16.5 months) average 

xposure

N (cases): 3653(125) Mean age: ~7170% Male

Fatal; involved a critical anatomical site; or overt and associated with a decrease in hemoglobin level of 20 g/L or transfusion of at least 2 U of blood.

Warfarin vs Warfarin +aspirin (p=.01)*

Warfarin (n/N): 2.3% (100/3172)Warfarin + aspirin (n/N): 3.9% (25/481)
80

tion in the Outpatient Setting Evidence-based Synthesis Program

dy using medical records from the 

gistry of Atrial Fibrillation data set.

atients with confirmed atrial 

o a maximum of 1000 days after 

ospitalization

N (cases): 1604(67) Mean age: ~80~43% Male

Major bleeding defined using ICD9-CM codes Risk Index (HEMORR2HAGES) Bleeds per 100 patient-years (95%CI)

Score:0: 1.9 (0.6-4.4)

1: 2.5 (1.3-4.3)2: 5.3 (3.4-8.1)3: 8.4 (4.9-13.6)4: 10.4 (5.1-18.9)≥5: 12.3 (5.8-23.1)Risk Index (OBRI): Low: 1.1 (0.3-4.3)

Moderate: 4.9 (3.6-6.5)High: 8.8 (5.6-14.0)Risk Index (Kuijer 1999):Low: 2.9 (1.3-6.5)Moderate: 5.2 (4.0-6.7)High: 7.5 (2.8-19.9)Risk Index (Kearon 2003):Score:0: 2.5 (1.1-6.1)

1: 2.5 (1.4-4.3)2: 6.5 (4.5-9.4)3: 9.3 (5.7-15.3)≥4: 15.3 (6.4-36.8)

al cohort study plus a nested case

lysis

om the UK General Practice 

atabase) who had a first ever 

escription for AF during the study 

continued treatment for more than 

was approximately 1 year (3740.8 

rs of warfarin exposure)

N (cases): 4152(46)Age range: ~7058% Male

Idiopathic bleeds that resulted in hospitalization within 30 days or death within 7 days following bleeding event

Warfarin +concomitant drug [incidence rate = 

cases/100 PYAR]*Total: 1.2

Warfarin alone: 0.9Concomitant (all): 1.8 Allopurinol: 3.4Amiodarone: 1.2Aspirin: 2.4Levothyroxine: 0.9Metronidazole: 38.5

Miconazole: 41.7Omeprazole: 3.2

Paracetamol: 3.8Paracetamol + Dextropropoxyphene: 4.1

d multicenter study (combined 

and double-blinded studies)

atients with nonvalvular AF

p to 24 months

N (cases): 3624 (NA)Mean age: ~7169.7% Male

Major bleeding Warfarin arm*

Women vs men: -0.35%/yr difference (P=0.491)Men: 91 events, 2.57%/yrWomen ≥ 75: 2.60%/yrWomen < 75: 1.83%/yr
81

tion in the Outpatient Setting Evidence-based Synthesis Program

sis of 6 randomized trials of 

 aspirin + warfarin. All published 

8 none of which were largest alone 

ded

th prosthetic cardiac valves (4 

 with coronary risk factors (1 trial), 

h AF (1 trial)

N (cases): 3874(31) Mean age: NANA % Male

Intracranial hemorrhage Warfarin vs Warfarin +aspirin (p=.08)*

Warfarin (n/N): 0.46% (9/1947)Warfarin + aspirin (n/N): 1.14% (22/1927)

e randomized study (warfarin arm 

th AF and at least 1 additional risk 

roke

p to 24 months (median 1.3 years)

N (cases): 3371 (93)Mean age: 70.2 (SD=9.5)66% Male

Bleeding associated with: death; drop in hemoglobin of at least 2 g/dL; significant hypotension with the need for inotropic agents bleeding requiring surgical intervention (other than vascular site repair); symptomatic intracranial hemorrhage; intraocular hemorrhage causing loss of vison; or the requirement for a transfusion of at least 2 U of blood.

Risk Index (CHADS2 score)*

0: 0.00/100 pt-yrs1: 1.48/100 pt-yrs2: 2.89/100 pt-yrs3: 2.58/100 pt-yrs4: 2.92/100 pt-yrs5: 0.90/100 pt-yrs6: 6.85/100 pt-yrsCHADS2=1: 1.36%/yrCHADS2>1: 2.75%/yrOAC-naïve*CHADS2=1: 1.81%/yrCHADS2>1: 3.76%/yrOAC-experienced*CHADS2=1: 1.33%/yrCHADS2>1: 2.47%/yr

ve cohort study

ending Univ of Washington Med 

gulation clinics

2.2 years (mean)

N (cases): 185(28)Mean age: 59.9 (SD=15.7)63.8% Male

Serious bleeding: overt gastrointestinal bleeding; occult gastrointestinal bleeding if endoscopic or radiographic studies were performed; gross hematuria that prompted cystoscopy or intravenous urography or lasted more than 2 days; hemoptysis; blood transfusions of 2 units or more.

CYP2C9 Genotype*Variant: 10.92% /PYrWild-type: 4.89% /PYr

ve longitudinal cohort study: 

 warfarin + antiplatelet combination 

ending Kaiser Permanente 

nticoagulation clinics

4.6 yr (SD=4.0)

N (cases): 4183(55)Mean age: 70.7(SD=12.553.3% Male

Major hemorrhage: required the transfusion of two or more units of RBCs; caused a decrease in hemoglobin concentration of ≥ 2 g/dL; or involved any intracranial, intraarticular, intraocular, or retroperitoneal sites

Warfarin vs Warfarin + antiplatelet (p=.003)*

Warfarin (n/N): 0.9% (23/2560)Warfarin + antiplatelet (n/N): 2.0% (32/1623)
82

tion in the Outpatient Setting Evidence-based Synthesis Program

based retrospective cohort study 

eview

Olmsted County, MN who had 

 mitral value replacement 

8.2 yr (SD=6.1)

N (cases): 112(27)Mean age: 57 (SD=16)40% Male

Bleeding causing death, hospitalization, permanent injury or transfusion

Cancer HR 4.01 (95%CI; 1.89-8.52)**

INR SD (Variability) HR 2.48 (95%CI; 1.11-5.55)**

e cohort study: influence 

es on risk for hemorrhagic 

ns

rticipating in the Pharmacogenetic 

n of Anticoagulation Therapy 

hort study

14.9 mo (SD=10.7)

N (cases): 446(44)Mean age: 60.6 (SD=15.6)51.3% Male50.9% African American

Major hemorrhage Incidence rate by genotype*

CYP2C9Total: 7.93/100 PYrWild type: 5.67/100 PYrVariant: 15.74/100 PYrVKORC1 1173C/TTotal: 8.0/100 PYr“CC”: 7.4/100 PYrAny “T”: 8.9/100 PYr

 analysis of a prospective cohort ence of kidney function on risk for 

c complications

rticipating in the Pharmacogenetic 

n of Anticoagulation Therapy 

hort study

16.2 mo (mean)

N (cases): 565(64)Mean age: 61 (SD=16)51.1% Male47.6% African American

Major hemorrhage Incidence rate by GFR*

Overall: 8.4/100 PYrGFR≥60: 6.2/100 PYrGFR=30-59: 8.3/100 PYrGFR<30: 30.5/100 PYr

e cohort study

th at least at 3 month duration 

lan were recruited from several 

nics

4.2 years 

N(cases):719(73)Mean age: 70 (SD=11)63% Male

Fatal bleeding and/or symptomatic bleeding in a critical area or organ and/or bleeding causing a fall in hemoglobin level of 2 g/dL or more

UnadjustedGender:*Men: RR=0.8 (95% CI;0.5–1.2)hsCRP:*Per 1 SD: 1.0 (95% CI;0.8–1.3)MV AdjustedAge***Per 10 years: RR=1.4 (95%CI;1.1–1.7)Thrombomodulin:***Per 1 SD: 1.4 (95% CI;1.2–1.7)
83

tion in the Outpatient Setting Evidence-based Synthesis Program

e cohort with nested case-control 

tion of INR and severe bleeding 

on on indication for warfarin 

rfarin treatment or on anticoagulant 

d: 12/2001 – 8/2005

nt-years follow-up

N(cases):1523(33 in 29 patients)Median (interquartile range) age: 66 (57; 74)63% Male

WHO criteria: lethal, lifethreatening, permanently disabling, or leading to hospital admission (ED admissions excluded) or prolongation of hospital stay

First 165 days of treatment vs. beyond 165RR 1.1 (95%CI; 0.5-2.3)First treatment month vs. beyond 1 monthRR 2.4 (95%CI; 1.0-6.0)Age HR 1.02 (95%CI; 0.98-1.06)***Male sex HR 2.8 (95%CI; 1.1-7.3)***Target INR HR 1.3 (95%CI; 0.03-50)***Aver. Warfarin Dose (mg/d) HR 0.97 (95%CI; 0.79-1.2)***Time Outside Ther. INR interval HR 1.2 (95%CI; 0.95-1.5)***Interacting drugs at start of tx (yes/no) HR 2.3 (95%CI; 1.1-4.9)***INR at time of event (28cases;56 controls) OR 1.9 (95%CI; 1.1-3.4)

ve cohort

on on indication for warfarin 

t course of treatment (if multiple 

om start of treatment at VAMC 

31/89 and 3/31/94 to end of 

r 7/1/94; mean duration of follow

s (range: 1 day to 60 mos)

N(cases):565(40)Mean Age 65.1 (SD=10.9)98.5% Male

Landefeld’s bleeding severity index – major hemorrhage defined based on patient survival, amount of blood lost, and physical consequences of the hemorrhage

GI bleeding RR 2.1 (95%CI; 0.93-4.9)***

Comorbid Condition RR 1.6 (95%CI; 0.86-3.1)***Stroke RR 1.2 (95%CI; 0.50-2.9)***Age ≥65 yrs RR 1.0 (95%CI; 0.53-1.9)***Atrial Fibrillation RR 1.0 (95%CI; 0.47-2.1)***Alcohol abuse RR 2.7 (95%CI; 1.4-5.4)***Chronic renal insufficiency RR 2.6 (95%CI; 1.3-5.2 )***Previous GI bleed RR 2.4 (95%CI;1.1-6.0)***NOTE: other factor not significant in univariate analyses include: gender(p=.63), NSAID (p=.78), aspirin (p=.56), diabetes (p=.27)

ve cohort of patients attending 

shington Med Ctr anticoagulation 

on on indication for warfarin 

d known CYP2C9 and VKORC1

tatus

nticoagulation clinic between 4/3/90 

1 with confirmed initial warfarin 

ate and at least 2 clinic visits

sian or African race

N(cases):172(31)Mean age: 59.864.5% Male

Serious and life-threatening bleeds according to Fihn, 1993 definition

Genetics***CYP2C9 (Variant vs Wild-type)HR 3.18 (95%CI; 1.30-7.78)VKORC1 (vs. AB)AA: HR 1.21 (95%CI; 0.38-3.82) BB: HR 0.83 (95%CI; 0.33-2.09) 
84

tion in the Outpatient Setting Evidence-based Synthesis Program

e cohort

on on indication for warfarin 

ontinuing users of warfarin; over 

between 5/1/02 and 5/31/03; 24 

w-up

N(cases):2370 (111)Mean age: ~78 (all over 65)23% Male

Any hospitalization due to warfarin-related bleeding (meeting specified criteria and reviewed by independent reviewers)

Duration of Warfarin Use*New users of warfarin: 4.5 /100 PY (95% CI; 2.9-6.8)Chronic users of warfain: 4.7/100PY (95%CI; 3.7-5.8)First month of follow-up vs. all other months:*RR 0.9 (95%CI; 0.4-1.8)Age No association***MedsNSAID/ASA (vs. neither)***RR 1.4 (95%CI; 0.9-2.1)Number of Current medications (vs. 1-3 meds)***4-8 Meds: RR 1.5 (95%CI; 0.8-3.0)≥9 Meds: RR 2.2 (95%CI; 1.0-4.6)Primary Indication***Valve condition requiring warfarin (vs. other indications): RR 3.02 (95%CI; 1.91-4.78)Anticoagulation clinic (vs. non-specialized clinic):RR 1.63 (95%CI 0.84-3.14)

e cohort

ation

 anticoagulation clinic between 

2/07

ars follow-up; median time of 

1 years (range: 3 mos-9.5 yrs)

N(cases):662 (32 with 17 cerebral)Median age: 75 yrs (range: 49-94)64% Male

Fatal, intracranial, ocular causing blindness, articular, or retroperitoneal; surgery or transfusion of >2 blood units required; hemoglobin reduced 2 g/dl or more

Risk Index (AFI):*Low: 0Moderate: 1.3/100 PYHigh: 1.4/100 PYRisk Index (ACCP):*Low: 0Moderate: 0High 1.4/100 PYRisk Index (CHADS2):*Low: 0Moderate: 1.0/100 PYHigh: 1.9/100 PYRisk Index (NICE):*Low: 0Moderate: 1.0/100 PYHigh: 1.5/100 PY

e cohort

ation

 anticoagulation clinic between 

2/07

ars follow-up; mean time of follow

s (range: 0.1 -13 yrs)

N(cases):783 (37 with 20 cerebral)Median age: 75 yrs (range: 37-94)65% Male

Fatal, intracranial, ocular causing blindness, articular, or retroperitoneal; surgery or transfusion of >2 blood units required; hemoglobin reduced 2 g/dl or more

Age:*Major bleeding≥80 v. <80: RR=1.9 (95%CI;1.2–2.8)Cerebral bleeding≥80 v. <80: RR=2.1 (95%CI;0.8–5.5)
85

tion in the Outpatient Setting Evidence-based Synthesis Program

ve cohort

r atrial fibrillation

caid patients; 1/1/97 to 5/31/02

w-up 740 days

N(cases):9,345 (1022)Mean age: 72 (SD=13.8)32% Male

Intracranial hemorrhage, and gastrointestinal bleeding requiring hospitalization

Intracranial Hemorrhage:

HR (95% CI) 

Substance abuse 2.4 (1.4, 4.0)*** 

Psychiatric illness 1.5 (1.0, 2.1) ***Social risk factors 0.9 (0.7, 1.3) *Hypertension 1.4 (0.9, 2.2) *CHF 0.9 (0.6, 1.2) *Diabetes mellitus 0.9 (0.7, 1.3) *Liver disease 0.9 (0.4, 2.0) *Renal disease 1.3 (0.9, 1.9) *DVT 0.9 (0.6, 1.5) *Age (per decade) 1.0 (0.9, 1.2) *Sex, male 1.1 (0.8, 1.5) *Race, white 0.8 (0.6, 1.2) *GI Bleeding: HR (95% CI)

Substance abuse 1.4 (1.1, 1.9)*** 

Psychiatric illness 1.2 (1.0, 1.4) ***Social risk factors 1.3 (1.1, 1.5) ***Hypertension 1.1 (1.0, 1.3) *CHF 1.3 (1.1, 1.6) ***Diabetes 1.0 (0.9, 1.2) ***Liver disease 1.3 (1.0, 1.7) ***Renal disease 1.6 (1.4, 1.9) ***DVT 1.2 (1.0, 1.5) ***Age (per decade) 1.0 (1.0, 1.1) *Sex, male 1.1 (0.9, 1.2) *Race, white 0.9 (0.7, 1.0) *
86

tion in the Outpatient Setting Evidence-based Synthesis Program

ol study nested within the Medicaid 

new antihyperlipidemic 

ns in patients on warfarin for at 

ys 

Florida, New York, Ohio, and 

nia Medicaid patients from 1999 to 

low-up appears to be nearly 1 year

Total N=353,489Cases=12,193Mean age: ~6933% Male

ICD-9 code indicating hospitalization for gastrointestinal bleeding.

GI Bleeding

NewPrescription OR (95% CI)***

Fenofibrate No dataGemfibrozil 1.96 (1.19-3.24)Fluvastatin 1.45 (0.68-3.09)Simvastatin 1.33 (1.00-1.78)Atorvastatin 1.29 (1.04-1.61)Pravastatin 0.66 (0.38-1.14)3rd to 4th

Prescription OR (95% CI)***

Fenofibrate 1.31 (0.62-2.79)Gemfibrozil 1.23 (0.61-2.48)Fluvastatin No dataSimvastatin 1.10 (0.79-1.53)Atorvastatin 0.62 (0.46-0.85)Pravastatin 0.54 (0.29-1.01) OR (95% CI)*Male sex 0.95 (0.92-0.99) Age, (ref=<50) 50-59 1.43 (1.32-1.56)  60-69 1.81 (1.68-1.96)  70-79 2.14 (1.99-2.30)  80+ 2.34 (2.18-2.51) Prior GI bleed 3.12 (3.00-3.24) Diabetes 1.62 (1.56-1.68) Liver disease 1.79 (1.72-1.87) CKD 2.57 (2.47-2.68)
87

tion in the Outpatient Setting Evidence-based Synthesis Program

ve Cohort

ation

 ≥ 65 years old; discharged from 

ceiving warfarin therapy between 

99 and between 7/00 and 6/01

Total N=26,345 (~415)Development cohort n=19,875 (~318) Validation cohort n=6,470(~97)Mean age: 88% 70 years or older47% Male

Hospitalized for major acute bleeding event (GI hemorrhage, intracranial hemorrhage)(NOTE: only included events within 90 days of discharge from index AF admission and only the first event for a subject)

Results from Development CohortAge ≥ 70 yrs: HR 1.63 (95%CI; 1.08-2.48Male gender: HR 0.73 (95%CI; 0.58-0.92)Remote bleeding event: HR 1.79 (95%CI; 1.36-2.37)Recent bleeding event: HR 1.85 (95%CI; 1.41-2.44)Alcohol or drug abuse: HR 2.03 (95%CI; 1.07-3.83)Diabetes: HR 1.31 (95%CI; 1.04-1.66)Anemia: HR 2.36 (95%CI: 1.76-3.17)Antiplatelet drug: HR 1.38 (95%CI 1.07-1.78)Results from Validation CohortRisk Index (Shireman 2006): (p<0.0001)Low: 0.9% (cases=35)Moderate: 2.0% (cases=48)High: 5.4% (cases=12)Risk Index (Kuijer 1999): (p=0.74)Moderate: 1.5%High: 1.8%Risk Index (OBRI): (p<0.0001)Moderate: 1.0%High: 2.5%

ol

tory of stroke, taking warfarin, and 

d for warfarin-related ICH; age ≥ 60

history of stroke, taking warfarin, 

h group treated with warfarin as a 

evious stroke or TIA

N(cases): 82(26)Mean age: 7553.% Male

Intracranial hemorrhage Comorbidity

Leukoaraiosis: OR 12.9 (95%CI;2.8-59.8); adjusted OR 8.4 (95%CI; 1.4-51.5)Severe (grade 3 or 4) leukoaraiosis: OR 24.9 (95%CI;4.5-137.4) vs. absence of leukoaraiosis

m of RCT comparing warfarin and 

ar atrial fibrillation

 for warfarin anticoagulation 

w-up 2.6 years

N(cases): 555(34)Mean age: 70 for all patients 69% Male 

Bleeding involving the central nervous system; requiring hospitalization, blood transfusion, and/or surgical intervention; or resulted in permanent functional impairment to any degree

Univariate Risk of Bleeding During Warfarin Treatment:*Age > 75 yr: RR 2.6 (p=0.009)Male gender: RR 0.9ComorbiditiesThromboembolism: RR 1.9CHF: RR 2.0 (p=0.05)Diabetes: RR 1.9 (p=0.09)GI bleeding: RR 1.6Hypertension: RR 1.1Other MedsNSAIDs: RR 1.3Other prescriptions: RR 1.2/drug (p=0.003)OtherTobacco Use: RR 1.9 (p=0.1)Alcohol: RR 1.0
88

tion in the Outpatient Setting Evidence-based Synthesis Program

rol study nested within a cohort of 

h prosthetic heart valves treated 

coagulation clinics between 1985-

 a hemorrhagic event during follow

s were matched 2 per case on age 

N(cases):460(154)

Hemorrhagic events included: intracranial and spinal hemorrhage; or major extracranial hemorrhage leading to death or hospitalization (except hemorrhage that led to hospital admission for diagnostic procedures only). 

INR Time in Range and Variability:**In range & stable = ReferenceIn range & unstable: OR 1.0 (0.5-2.0)Outrange & stable: OR 1.6 (0.9-3.1)Outrange & unstable: OR 2.7 (1.4-4.9)

ve review of patients followed in 

g 4/89

e follow-up of all patients with life

 bleeding during retrospective 

D all patients between 6/90 and 4/93

ated with warfarin for at least 6 

on on indication for warfarin therapy

f follow-up 

N(cases):1,999 (32)Mean age: 58.79 (SD=14.3)75.3% Male

Life-threatening: cardiopulmon-ary arrest, surgical or angio-graphic intervention to stop the bleeding, irreversible sequelae (including MI, ICH, blindness, or fibrothroax), or any 2 of the following: transfusion of ≥ 3 U of blood, hypotension, critical anemia, or acute bleeding

Male gender:* 21 of 32 bleeding cases (66%) vs. 75.3% of study populationPrimary Indication*Mechanical valve: 17/32 (53%) vs. 20% of study populationVTE: 5/32 (16%) vs. 23.9% of study populationAtrial fibrillation: 6/32 (19%) vs. 16.9% of study population

ted; **= Adjusted for Age and/or basic demographics like gender; ***=multivariable adjustment for other covariates thought to be related to