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CHEST Supplement

www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e1S

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Guideline panels require the best evidence regard-ing patient values and preferences in making

trade-offs between desirable and undesirable con-sequences of alternative management strategies.1 Wedefine “values and preferences” as a broad term thatincludes patient perspectives, beliefs, expectations,and goals for their health and life, including theprocess that patients go through in weighing thepotential benefits, harms, costs, and burdens associ-ated with different treatment or disease managementoptions.2 Recommendations regarding antithrom-botic therapy typically involve trade-offs betweendecreased risk of thrombosis vs increased bleedingrisk and burden of treatment. To inform recommen-

dations of the Antithrombotic Therapy and Preven-tion of Thrombosis, 9th ed: American College of

Chest Physicians Evidence-Based Clinical PracticeGuidelines, we conducted a systematic review todetermine what is known regarding patient valuesand preferences for and experiences with antithrom-botic therapy (including prophylaxis and treatment).

1.0 Methods

1.1 Eligibility Criteria

We included studies that enrolled individuals potentially at riskof or having direct experience with conditions for which anti-thrombotic therapy may be indicated. We specifically included:

Background: Development of clinical practice guidelines involves making trade-offs betweendesirable and undesirable consequences of alternative management strategies. Although the rel-ative value of health states to patients should provide the basis for these trade-offs, few guidelineshave systematically summarized the relevant evidence. We conducted a systematic reviewrelating to values and preferences of patients considering antithrombotic therapy.

Methods: We included studies examining patient preferences for alternative approaches to anti-thrombotic prophylaxis and studies that examined, in the context of antithrombotic prophylaxisor treatment, how patients value alternative health states and experiences with treatment. Weconducted a systematic search and compiled structured summaries of the results. Steps in theprocess that involved judgment were conducted in duplicate.

Results: We identified 48 eligible studies. Sixteen dealt with atrial fibrillation, five with VTE, four

with stroke or myocardial infarction prophylaxis, six with thrombolysis in acute stroke or myocar-dial infarction, and 17 with burden of antithrombotic treatment.Conclusion: Patient values and preferences regarding thromboprophylaxis treatment appear tobe highly variable. Participant responses may depend on their prior experience with the treat-ments or health outcomes considered as well as on the methods used for preference elicitation.It should be standard for clinical practice guidelines to conduct systematic reviews of patientvalues and preferences in the specific content area. CHEST 2012; 141(2)(Suppl):e1S–e23S

Patient Values and Preferences in DecisionMaking for Antithrombotic Therapy: A Systematic Review

Antithrombotic Therapy and Prevention of Thrombosis,

9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

Samantha MacLean , MSc ; Sohail Mulla , BHSc ; Elie A. Akl , MD , MPH, PhD ;Milosz Jankowski , MD , PhD ; Per Olav Vandvik , MD , PhD ; Shanil Ebrahim, MSc ;Shelley McLeod, MSc ; Neera Bhatnagar , MLIS ; and Gordon H. Guyatt , MD , FCCP

wnloaded From: http://journal.publications.chestnet.org/ on 05/25/2015

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e2S Patient Values for Antithrombotic Therapy

one reviewer screened conference abstracts. We conducted calibra-tion exercises to ensure consistency among reviewers. We retrievedthe full texts of articles judged as potentially eligible by at leastone reviewer. Two reviewers then independently screened all fulltexts for eligibility using a standardized form with explicit inclu-sion and exclusion criteria. Reviewers resolved their disagree-ments by discussion or by consulting a third reviewer (G. H. G.).

1.4 Data Abstraction

In pairs, reviewers independently abstracted the following datafrom each article using a standardized data abstraction form: studydesign; population and health conditions of interest; antithrom-botic medication; outcomes assessed; results; and methodologiccharacteristics of the study, including systematic biases and poten-tial limitations.

1.5 Data Analysis

We planned to conduct a meta-analysis if the treatment out-comes considered were comparable. The variability in methodsand the ways outcomes were measured and presented made thegeneration of pooled estimates impossible. We present the resultsin narrative and tabular form, stratified by the health condition.

2.0 Results

2.1 Included Studies

Of 48 studies selected for inclusion, 16 focused onpatients with atrial fibrillation,3-18 five on patients with

VTE,19-23 four on stroke or myocardial infarction pro-phylaxis,24-27 six on thrombolysis in acute stroke ormyocardial infarction,28-33 and 17 on the burden of anti-thrombotic treatment.34-50 Strategies used to elicit patientpreferences include visual analog scales25,37,42,50 ; stan-dard gamble17,22,23,30 ; time trade-off6-8,15,19-21 ; probability

trade-off technique3,4,9,12,25,26 ; decision aids10,13,14,18,31 ;the presentation of hypothetical scenarios in whichparticipants are asked to make a treatment deci-sion5,11,16,24,32,33 ; and methods used to elicit informationabout treatment burden, such as interviews andsurveys.27,29,35-41,43-50

Of the 48 included studies, 12 provided healthstate utilities or health state valuations obtained fromparticipants with regard to both long-term and short-term outcomes related to thrombolysis and prophy-laxis treatments6-8,15,17,19-23,25,30 (Table 1). Health stateutilities typically are assessed on a scale of 0 to 1, with

0 being equivalent or worse health, and 1 being opti-mal health. A patient or participant’s utility valuereflects his or her opinions or attitudes toward a givenhealth state or outcome. Disutility refers to the bur-den or negative outcomes associated with a particularhealth state.

2.2 Overall Findings

Although there were exceptions,13,14 participantsacross the studies tended to place a higher disutility onstroke than GI bleed3,4,25 and much greater disutility

• Studies that examined patient preferences for antithrom-botic therapy vs no or alternative antithrombotic therapy,

which includes receiving both treatment for thromboem-bolic disease and prophylaxis as defined previously

• Studies that examined in the context of consideration of anti-thrombotic therapy how patients value alternative healthstates and experiences with treatment

• Studies that examined choices patients make when pre-sented with decision aids for management options regardingantithrombotic therapy

We excluded studies of proxy decision makers and health-careprofessionals and studies that were not available in English.

1.2 Search Strategy

We developed electronic search strategies with the help of ahealth-care librarian (N. B.). We searched Medline, Embase,Psychinfo, HealthStar, CINAHL, CENTRAL, and InternationalPharmaceuticals Abstracts between August and September 2009,starting with the dates of inception of each database.

We also searched the gray literature, including the Interna-tional Society for Quality of Life conference abstracts (2000-2008),the Society for Medical Decision Making conference abstractsavailable online (2001, 2004-2008), PapersFirst, and Dissertations

and Theses International. Finally, we reviewed reference lists ofall eligible studies.

1.3 Selection of Studies

Two reviewers independently screened for eligibility the titlesand abstracts of identified articles. S. MacLean served as the firstreviewer, whereas six authors split the task of the second reviewer(S. McLeod, S. Mulla, M. J., E. A. A., P. O. V., and S. E.); only

Revision accepted August 31, 2011. Affiliations: From the Department of Biostatistics and ClinicalEpidemiology (Ms MacLean, Messrs Mulla and Ebrahim, andDrs Akl and Guyatt) and Health Sciences Library (Ms Bhatnagar),McMaster University, Hamilton, ON, Canada; Department of

Internal Medicine (Dr Jankowski), Faculty of Medicine, JagiellonianUniversity Medical College, Krakow, Poland; Division ofEmergency Medicine (Ms McLeod), Department of Medicine,Schulich School of Medicine and Dentistry, The University of

Western Ontario, London, ON, Canada; Department of Medicine(Dr Akl), State University of New York at Buffalo, Buffalo, NY;and Norwegian Knowledge Centre for the Health Services andDepartment of Medicine Gjøvik (Dr Vandvik), Innlandet HospitalTrust, Gjøvik, Norway.Ms MacLean is currently at the University of British Columbia,Faculty of Medicine, School of Population of Public Health. Funding/Support: The Antithrombotic Therapy and Preventionof Thrombosis, 9th ed: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines received support fromthe National Heart, Lung, and Blood Institute [R13 HL104758]and Bayer Schering Pharma AG. Support in the form of educational

grants was also provided by Bristol-Myers Squibb; Pfizer, Inc;Canyon Pharmaceuticals; and sanofi-aventis US.Disclaimer: American College of Chest Physician guidelines areintended for general information only, are not medical advice, anddo not replace professional medical care and physician advice,

which always should be sought for any medical condition. Thecomplete disclaimer for this guideline can be accessed at http:// chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: Samantha MacLean, MSc, McMasterUniversity, 1200 Main St W, Hamilton, ON, L8N 3Z5, Canada;e-mail: [email protected]© 2012 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from theAmerican College of Chest Physicians ( http://www.chestpubs.org/ site/misc/reprints.xhtml).DOI: 10.1378/chest.11-2290


http://chestjournal.chestpubs.org/content/141/2_suppl/1Shttp://chestjournal.chestpubs.org/content/141/2_suppl/1Smailto:[email protected]://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlmailto:[email protected]://chestjournal.chestpubs.org/content/141/2_suppl/1Shttp://chestjournal.chestpubs.org/content/141/2_suppl/1S

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T a b l e 1 —

[ S e c t i o n 2 . 1

] P a r t i c i p a n t H e a l t h S t a t e U t i l i t y V a l u a t i o n s

S t u d y / Y e a r

M e t h o d o f H S U

E l i c i t a t i o n s

U n i t

W e l l W a r f a r i n

( o r U n s p e c i fi e d

V K A )

W

e l l A s p i r i n

S e v e r e

S t r o k e

M o d e r a t e S t

r o k e

M i l d S t r o k e

M a j o r ( o r

U n s p e c i fi e d )

G I B l e e d

M i l d /

N o n f a t a l

G I B l e e d

O t h e r

A l o n s o - C o e l l o

e t a l a / 2 0 0 8

F e e l i n g

t h e r m o m e t e r

( 1 0 0 - p o i n t

s c a l e ) 2 y

M e a n S

D

0 . 6 6 0 . 1 5

0 . 8 0 . 1 9

0 . 2 2 0 . 1 6

0 . 4 7 0 . 1 8

0 . 4

4 0 . 2

D r a n i t s a r i s

e t a l 1 9 / 2 0 0 9

T T O 3 m o

M e d i a n ( 9 5 % C I )

t r a n s f o r m e d t o

S D b

W a r f a r i n

t r e a t m e n t o f

1 0 d : 0 . 8 0

( 0 . 0 2 )

D a l t e p a r i n f o r

1 0 d : 0 . 9 8 ( 0 . 0 2 )

D a l t e p a r i n f o r

3 5 d : 0 . 8 3 ( 0 . 0 2 )

P r o t h e r o e

e t a l 1 5 / 2 0 0 0

T T O 1 y

M e d i a n ( I Q R )

t r a n s f o r m e d

t o S D c

1 0

0 . 1 0

0 . 5 0 . 2 9

B u r d e n w i t h

w a r f a r i n :

0 . 8 0 . 2 2

T h o m s o n

e t a l 1 7 / 2 0 0 0

S G 1 y

M e a n S

D

G P m a n a g e d :

0 . 9 4 8 0 . 0 9

C l i n i c

m a n a g e d :

0 . 8 4 0 . 1 7

0 . 1 9 0 . 2 8

0 . 6 4 0 . 2 7

0 . 8 4 0 . 1 7

G a g e e t a l 8 / 1 9 9 8

T T O 1 0 y

M e a n ( r a n g e ) d

0 . 9 5 ( 0

. 9 2 - 0 . 9 9 )

0 . 9 9 ( 0 . 9 6 - 1 )

0 . 5 1 ( 0 - 0 . 9 9 )

0 . 8 5 ( 0 - 1 )

G a g e e t a l 6 / 1 9 9 5

T T O 1 0 y

M e a n ( r a n g e )


t o S D e

0 . 9 9 0 . 0 2

0 . 9 9 0 . 1

0 . 3 9 0 . 2 5

0 . 7 5 0 . 2 5

G a g e e t a l 7 / 1 9 9 6

T T O / S G 1 y

M e a n ( 1 0 t h a n d

9 0 t h p e r c e n t i l e )

0 . 9 9 ( 0 . 9 5 , 1 )

0 . 9 9 ( 0 . 9 9 , 1 )

0 . 1 1 ( 0 , 0 . 5 1 )

0 . 3 9 ( 0 , 0 . 9 9 )

0 . 7 6 ( 0 . 1 4 , 1 )

L e n e r t a n d

S o e t i k n o 2 2 / 1 9 9 7

S G E n t i r e l i f e

M e a n ( 9 5 % C I )


t o S D

C N S b l e e d :

0 . 6 6 0 . 2

3

M i l d P P S :

1 . 0 0 0 . 0 2

S e v e r e P P S :

0 . 9 3 0 . 0 6

L o c a d i a

e t a l 2 0 , 2 1 / 2 0 0 4

T T O 2 y



t o S D

0 . 9 2 0 . 1 5

C N S : 0 . 3 3

0 . 2 9

G I b l e e d :

0 . 6 5 0 . 2 7

P T S : 0 . 8 2 0 . 2 3

D V T : 0 . 8 4 0 . 2 5

P u l m o n a r y

e m b o l i s m :

0 . 6 3 0 . 3 7

M a n - S o n - H i n g

e t a l 2 5 / 2 0 0 0

V A S ( 1 0 c m ) 5 y

M e a n S

D

0 . 9 3 0 . 1 4

0 . 1 6 0 . 1 6

0 . 7 0 . 1 8

0 . 7 9 0 . 1 8

M I : 0 . 5 7 0 . 2 6

O ’ M e a r a

e t a l 2 3 / 1 9 9 4

S G P a r t i c i p a n t

l i f e e x p e c t a n c y

M e a n ( r a n g e )


t o S D

C N S : 0 . 2 9

0 . 2 5

M i l d P P S :

0 . 9 9 5 0 . 0 3

S e v e r e P P S :

0 . 9 8 2 0 . 0 3

( C o n t i n u e d )



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on stroke than treatment burden.6-8 However, there was little consistency in health state utilities andpreferences for treatment choices both within andacross studies. We outline the range of participantpreferences in categories of presentation. Unlessotherwise indicated, the term “stroke” refers to thenet of nonfatal hemorrhagic and nonfatal throm-botic stroke. The term “bleed” refers to nonfatal GI

bleeding.

3.0 Atrial Fibrillation

3.1 Summary of Findings

Three studies reported compelling findings of ahigher disutility associated with stroke than with bleed.Alonso-Coello et al3 found that 19 of 96 participants(20%) were willing to accept . 35 additional bleedson warfarin for 3% absolute risk reduction of stroke.For this 20%, the disutility associated with one stroke

was equal to the disutility associated with 11.6bleeding episodes. The median threshold that patient-participants were willing to accept was 10 bleeds fora 3% reduction in stroke (range, 1-100). Similarly,Devereaux and colleagues4 found that 57% of partic-ipants were willing to accept 22 additional bleeds toachieve a stroke reduction of 8% (disutility of onestroke equal to 2.8 bleeds). The remaining 43% ofparticipants varied considerably in the number ofadditional instances of bleed that they were willingto accept. The mean number of bleeds that all par-ticipants were willing to accept to achieve this 8%

stroke reduction was 17.4.Man-Son-Hing12 found that given a bleeding risk

of 3% over 2 years, the mean stroke reduction thatparticipants required to accept warfarin was 1.65%over the same time period. Fifty-two percent of par-ticipants would accept warfarin for an absolutedecrease in stroke risk by 1% over 2 years. The lowtreatment threshold in this study may be partly dueto the fact that 90% of participants had been taking

warfarin at the time of the first interview, and all par-ticipants had previously been prescribed warfarin.

A number of studies reported a stroke-to-bleed

preference ratio of , 2.11,13,14 Patients enrolled inthese studies appeared to place a considerably higher

value on avoiding bleeding relative to avoiding strokethan did patients in most other studies.13

Another study conducted by Man-Son-Hing andcolleagues14 randomized 199 participants to a qualita-tive vs quantitative version of a decision aid trial.None of the participants had atrial fibrillation, 31%had experienced aspirin treatment, and 6% had expe-rienced warfarin treatment. The investigators catego-rized participants in both groups as low risk ormoderate risk for stroke. In the low-risk group,

T a b l e 1 —

C o n t i n u e d

S t u d y / Y e a r

M e t h o d o f H S U

E l i c i t a t i o n s

U n i t

W e l l W a r f a r i n

( o r U n s p e c i fi e d

V K A )

W

e l l A s p i r i n

S e v e r e

S t r o k e

M o d e r a t e S t

r o k e

M i l d S t r o k e

M a j o r ( o r

U n s p e c i fi e d )

G I B l e e d

M i l d /

N o n f a t a l

G I B l e e d

O t h e r

S l o t a n d

B e r g e 3 0 / 2 0 0 9

S G E n t i r e l i f e



t o S D

0 . 1 ( 0 . 1 1 )

0 . 7 7 ( 0 . 1 5 )

0 . 9 3 ( 0 . 0 4 )

G P 5 g e n e r a l p r a c t i t i o n e r ; H S U 5 h e a l t h s t a t e u t i l i t y ; I Q R 5 i n

t e r q u a r t i l e r a n g e ; M I 5 m y o c a r d i a l i n f a r c t i o n ; P P S 5 p o s t p h l e b i t i c

s y n d r o m e ; P T S 5 p o s t t h r o m b o t i c s y n d r o m e ; S G 5 s t a n d a r d g a m b l e ;

T T O 5 t i m e t r a d e - o f f ; V A S 5 v

i s u a l a n a l o g s c a l e ; V K A 5 v

i t a m i n K a n t a g o n i s t .

a R e s c a l e d f r o m 0 - 1 0 0 - p o i n t r a t i n g . A l o n s o

- C o e l l o P , M o n t o r i V M , D i a z M G , e t a l , u n p u b l i s h e d d a t a , 2 0 0 8 .

b A s s u m e d n o r m a l d i s t r i b u t i o n ( m e a n 5 m e d i a n ) ; 9 5 % C I / 3 . 9 2 5 S

D .

c I Q R / 1 . 3 4 9 5 S

D .

d G i v e n t h a t t h e s a m p l e s i z e f o r G a g e e t a l 8 i s , 2

5 ( n 5 1

4 ) , w e c a n n o t t r a n s f o r m t h e d

a t a t o S D .

e R a n g e 3 0 . 2 5 5 S

D .


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or intracranial bleed. These omissions make theresults difficult to interpret. To the extent, however,that patients assumed that the functional consequencesof a thrombotic stroke and an intracranial bleed are sim-ilar, the results of this study suggest that many patientsplace a higher value on avoiding an adverse event thatoccurs as a consequence of treatment vs avoiding anevent with the same functional consequences that

occurs as a consequence of not using that treatment.Table 251-54 provides a summary of all studies thatconsidered atrial fibrillation.

4.0 VTE/DVT Therapy


These studies illustrate significant variability inelicited patient values and preferences regardingthrombosis prophylaxis and treatment. Locadia et al20 described extremely large between-patient variability

with regard to participant willingness to accept warfa-rin treatment at varying thresholds of recurrent DVT.In another study by Locadia et al,21 the authors con-cluded that preferences stated in the form of healthstate utilities varied significantly across the threemethods (Table 3).

5.0 VTE/DVT Thrombolysis


A study by O’Meara et al23 found that no participant

values and preferences were consistent with takingstreptokinase, which differs from the findings ofLenert and Soetikno22 where the majority of participantpreferences were consistent with use of streptokinase.Lenert and Soetikno22 explained these differences inresults by arguing that their participants were bettereducated about the risks and benefits of DVT andits treatment, given that participants were presented

with video and audio descriptions. O’Meara et al23

provided only written material to participants; thus,their participants may have lacked a full understandingof the outcomes associated with antithrombotic treat-

ment. Another factor potentially affecting results isthat participants in the Lenert and Soetikno22 study were younger and, thus, potentially less risk averse thanthe participants in the O’Meara et al23 study (Table 4).

[I D ]TB L4[ / ID ]

6.0 Stroke and MyocardialInfarction Prophylaxis


The results of each of these studies illustrate howdesign features and participant characteristics may

participants were told that warfarin, compared withaspirin, resulted in a 1% reduction in stroke and a2.5% increase in bleeds. The majority (69%) of par-ticipants in this group chose aspirin; 4% chose warfa-rin, 14% chose no medication, and 13% were unableto make a treatment decision. The majority whochose aspirin placed an implicit value on strokereduction of , 2.5 times the disutility of bleeding.

In the moderate-risk group, participants were toldthat warfarin, compared with aspirin, results in a 3%absolute risk reduction in stroke and a 2.5% increasein bleeds. The majority (58.1%) of participants in thisgroup chose aspirin; 11% opted for no treatment,12% chose warfarin, and 18.4% were unable to makea treatment decision. The majority who chose aspirinplaced a value on stroke reduction of , 0.83 timesthe value placed on bleeding.

Holbrook and colleagues11 presented participants with information about atrial fibrillation using anaudiotape and booklet. In a typical scenario, warfarin

provided a 6% absolute risk reduction in stroke(9%-3%) and a 4% absolute risk increase in bleed(2%-6%) compared with no treatment. In this sce-nario, 65% of participants chose warfarin, and 35%chose no treatment. For the 65% choosing warfarin,the disutility associated with one stroke was at least1.5 times greater than the disutility associated with amajor bleed.

There are several potential explanations for the variability in results among studies. The first concernsparticipants’ previous experience with antithrombotictreatment. The low treatment threshold in the 1996

study by Man-Son-Hing12 (. 50% had a disutility ofstroke vs bleeding . 3:1) may be partly due to thefact that 90% of the participants had been taking

warfarin at the time of the first interview and that allparticipants had previously been prescribed warfarin.In contrast, participants in the 1999 study by Man-Son-Hing et al13 reported a higher disutility withbleeds. The patients in this study had chosen at enroll-ment in Stroke Prevention in Atrial Fibrillation III(SPAF) 2 years earlier to receive aspirin prophy-laxis alone. Most, if not all, of the participants had notexperienced a stroke during the subsequent 2 years.

Participants may have believed that whatever thegeneral risk of stroke while taking aspirin, their per-sonal risk was lower (and, at least to some extent, theymight have been correct in this deduction)51 (Table 2).

Some studies do not provide enough information toenable us to make reliable inferences regarding patientpreferences. For example, Fuller et al5 did not report

what information they provided patients about the mor-tality associated with stroke and bleed (presumably,their scenarios referred to nonfatal stroke and bleed),nor did they indicate whether they provided any infor-mation about the consequences of a thrombotic stroke



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T a b l e 3 —

[ S e c t i o n 4 . 0 ] V T E / D V T P r o p h y l a x i s a n d T r e a t m

e n t S t u d i e s

S t u d y / Y e a r

P a t i e n t P o p u l a t i o n

S

t u d y D e s i g n

M e t h o d o f P r e f e r e n c e

E l i c i t a t i o n

T

h e r a p y

O u t c o m e s C o n s i d e r e d

C o n t e x t

S u m m a

r y o f R e s u l t s

D r a n i t s a r i s

e t a l 1 9 / 2 0 0 9

2 4 v o l u n t e e r s

( g e n e r a l p u b l i c )

C r o s s - s e c t i o n a l

i n t e r v i e w

T T O

D

1 0 d / D

3 5 d / W

M a j o r b l e e d

S y m p t o m a t i c D V T

M o n i t o r i n g

r e q u i r e m e n t s

V T E p r o p h y l a x i s

T h e d i s u t i l i t y a s s o c i a t e d w i t h o n e e p i s o d e o f D V T w a s

g r e a t e r , o n a v e r a g e , t h a n t h e d i s u t i l i t y a s s o c i a t e d

w i t h 1 . 5 b l e e d s . W h e n

a s k e d d i r e c t l y , 4 5 . 8 % o f

p a t i e n t s c h o s e d a l t e p a r i n f o r 1 0 d w i t h a 6 . 6 %

c h a n c e o f m a j o r G I b l e e d , f o l l o w e d b y w a r f a r i n

( 4 1 . 6 % ) w i t h a 4 . 5 % c h a n c e o f b l e e d , a n d t h e n b y

d a l t e p a r i n f o r 3 5 d ( 1 2

. 5 % ) w i t h a 6 . 6 % c h a n c e o f

b l e e d .

L o c a d i a

e t a l 2 0 / 2 0 0 4

1 2 4 p a t i e n t s

r e c e i v i n g V K A


i n t e r v i e w s

w i t h d e c i s i o n

a n a l y s i s

T T O

V K A

N o n f a t a l s t r o k e

P T S N o t r e a t m e n t

D V T

P u l m o n a r y e m b o l i s m

G I b l e e d

M u s c u l a r b l e e d

T r e a t m e n t w i t h V K A

B u r d e n

V T E t r e a t m e n t

( p r o p h y l a x i s )

A c r o s s a r a n g e o f r a t e s o f r e c u r r e n c e o f D V T w i t h o u t

t r e a t m e n t f r o m 5 % t o

1 5 % ( V T E r i s k r e d u c e d t o

2 % w i t h t r e a t m e n t a n d

a 3 % r i s k o f m a j o r b l e e d i n g

e v e n t ) , p a r t i c i p a n t s ’ t r e a t m e n t t h r e s h o l d s w e r e

v a r i a b l e ( 2 3 % w o u l d a l w a y s c h o o s e t r e a t m e n t , 3 0 %

w o u l d a l w a y s r e j e c t t r e a t m e n t , t h e r e m a i n d e r w o u l d

r e j e c t t r e a t m e n t b e t w e e n 5 % a n d 1 5 % r i s k o f V T E ) .

S e e T a b l e 1 f o r a d d i t i o

n a l H S U s

L o c a d i a

e t a l 2 1 2 0 0 4

5 4 p a t i e n t s

p r e v i o u s l y o r

c u r r e n t l y b e i n g

t r e a t e d w i t h

V K A w h o

p r e v i o u s l y

e x p e r i e n c e d

a t h r o m b o t i c

e v e n t

R e p e a t e d

i n t e r v i e w s

( t w o i n t e r v i e w s

c o n d u c t e d

2 w k a p a r t )

1 . C o n v e n t i o n a l T T O

m e t h o d

2 . C h a i n e d T T O

m e t h o d

3 . R a n k o r d e r i n g

o f h e a l t h s t a t e s

4 . D i r e c t r a t i n g o f

h e a l t h s t a t e s o n a

0 - 1 0 0 s c a l e

V K A

H o s p i t a l i z a t i o n a f t e r a

s e r i o u s a c c i d e n t

D V T

P u l m o n a r y e m b o l i s m

G I b l e e d

M u s c u l a r b l e e d

T r e a t m e n t w i t h o r a l

a n t i c o a g u l a n t

U s e o

f a n t i c o a g u l a n t s

f o r

V T E , P T S ,

m a j o r b l e e d

( p r o p h y l a x i s )

H e a l t h s t a t e v a l u e s d i f f e r e d s i g n i fi c a n t l y a m o n g t h e

t h r e e m e t h o d s . A l l p a r

t i c i p a n t s r a n k e d fi v e h e a l t h

s t a t e s ; t h e a v e r a g e o r d e r i n g o f h e a l t h s t a t e s w a s a s

f o l l o w s :

1 . T r e a t m e n t w i t h o r a l

a n t i c o a g u l a n t s ( H S U 0 . 7 5 -

0 . 9 5 a c r o s s t h r e e m e t h o d s o f H S U e l i c i t a t i o n )

2 . D V T ( H S U 0 . 6 - 0 . 8 5 )

3 . M u s c u l a r b l e e d ( H S

U 0 . 2 - 0 . 6 )

4 . G I b l e e d ( H S U 0 . 1 5 - 0 . 5 )

5 . P u l m o n a r y e m b o l i s m ( H S U 0 . 1 2 - 0 . 5 )

D 5 d a l t e p a r i n . S e e T a b l e 1 a n d 2 l e g e n d s f o r e x p a n s i o n o f o t h e r a b b r e v i a t i o n s .


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T a b l e 4 —

[ S e c t i o n 5 . 0 ] V T E / D V T T h r o m b o l y s i s S t u d i e s

S t u d y / Y e a r

P a t i e n t P o p u l a t i o n

S t u d y D e s i g n

M e t h o d o f P r e f e r e n c e

E l i c i t a t i o n

T h e r a p y

O u t c o m e s

C o n s i d e r e d

C o n t e x t

S u m m a r y o f R e s u l t s

L e n e r t a n d

S o e t i k n o 2 2 / 1 9 9 7

3 0 h e a l t h y w o m e n


c o m p u t e r

i n t e r v i e w s w i t h

d e c i s i o n a n a l y s i s

S G

H / S K / H & S K

S t r o k e

M i l d P T S

S e v e r e P T S

D V T t r e a t m e n t

( t h r o m b o l y s i s )

P a r t i c i p a n t s r a t e d C N S b l e e d w i t h a m e d i a n u t i l i t y o f

0 . 6 6 ( S D , 0 . 2 3 ) , s e v e r e P T S w i t h a m e d i a n u t i l i t y o f

0 . 9 3 ( S D , 0 . 0 6 ) ; a n d m i l d P T S w i t h a m e d i a n u t i l i t y

o f 1 ( S D , 0 . 0 2 ) .

A f t e r a p p l y i n g h e a l t h s t a t e

v a l u a t i o n s i n t o a d e c i s i o n

m o d e l , c o m p a r i n g t h e g

a i n s i n q u a l i t y - a d j u s t e d l i f e

y e a r s f o u n d c o m b i n a t i o n t h e r a p y ( H 1 S

K ) t o b e t h e

o p t i m a l c h o i c e .

S e e T a b l e 1 f o r a d d i t i o n a l

H S U s .

O ’ M e a r a

e t a l 2 3 / 1 9 9 4

3 6 p a r t i c i p a n t s

( 1 6 / 3 6 h a d

e x p e r i e n c e d

V T E )


i n t e r v i e w w i t h

d e c i s i o n a n a l y s i s

S G

H / H & S K

S t r o k e

M i l d P P S

S e v e r e P P S

P r o x i m a l D V T

( t h r o m b o l y s i s )

C o m p a r e d w i t h S K 1 H , h

e p a r i n a l o n e i n c r e a s e d l i f e

e x p e c t a n c y b y 2 9 d o v e r t h e p r e d i c t e d l i f e e x p e c t a n c y

o f 2 0 y . A s w e l l , m a j o r b

l e e d w i t h C N S w a s i n c l u d e d

a s t h e o n l y r e l e v a n t o u t c o m e . S K 1 H

i n c r e a s e s

a b s o l u t e r i s k o f f a t a l C N

S b l e e d b y 0 . 4 % a n d

d e c r e a s e s t h e a b s o l u t e r i s k o f P P S b y 5 . 6 % . G i v e n

p a r t i c i p a n t H S U , p a r t i c

i p a n t s p l a c e d a m u c h h i g h e r

d i s u t i l i t y o n d e a t h ( m e a

n , 0 0

) t h a n P P S ( m e a n ,

0 . 9 8 2 0 . 0 2 5 ) . H e p a r i n

a l o n e w a s p r e f e r r e d b e c a u s e

p a r t i c i p a n t s w e r e u n w i l l i n g t o a c c e p t a s m a l l i n c r e a s e

o f d e a t h t o a v o i d P P S . S

e e T a b l e 1 f o r a d d i t i o n a l

H S U s .

H 5 h e p a r i n ; S K 5 s t r e p t o k i n a s e . S e e T a b l e 1 a n d 2 l e g e n d s f o r e x p a n s i o n o f o t h e r a b b r e v i a t i o n s .



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ment-induced adverse (eg, hemorrhagic stroke)events than avoiding events prevented as a result oftreatment. This latter interpretation is consistent withresults from Fuller et al,5 who examined the relativeaversion to thrombotic and hemorrhagic stroke andfound that patients placed a greater value on avoidingtreatment-induced strokes than on avoiding strokesthat treatment could prevent. This finding could

relate to the concept of loss aversion.55 Stanek et al32 suggested, in contrast with Heyland

et al,31 that participants were most concerned withmortality as opposed to stroke. Participants weremost often unwilling to accept a higher risk of deathin exchange for a reduction in stroke risk. Differ-ences in results may be attributed to participant pop-ulations, methods, and outcomes considered. Forexample, Stanek et al32 used a self-administered ques-tionnaire, whereas Heyland et al31 conducted a face-to-face preference elicitation exercise, with a researchassistant guiding participants through the decision

aid. Given that in Stanek, under conditions of no costand 0% risk of mortality, approximately one-third ofparticipants chose tissue plasminogen activator(which is associated with higher stroke risk), it is pos-sible that at least some of these participants lacked aproper understanding of the risks and outcomesassociated with each treatment. Heyland elicitedpreferences from participants considered at risk formyocardial infarction, whereas Stanek surveyed inpa-tients undergoing diagnostic coronary angiography.Finally, Stanek considered only hemorrhagic stroke,

whereas Heyland included both hemorrhagic stroke

and myocardial infarction (Table 7).

9.0 Treatment Burden and Quality of Life


Warfarin is, for most patients, associated with rela-tively limited impact on quality of life and the abilityto carry out daily activities. Although some patientsreport anxiety or worry over the risks that they incur

while taking warfarin therapy,35-37,40,41 they generallyare satisfied with this treatment.39,46 Other elements

of burden that patients report include dietary modifi-cations and the inconvenience associated with fre-quent blood monitoring. Duration of warfarin therapy

was positively attributed to satisfaction with treat-ment.38,40 Duration of low-molecular-weight heparinor unfractionated heparin therapy was associated

with increased patient quality of life.50 Injection treatments and compression devices are

well tolerated by most patients. However, when giventhe choice, most patients would prefer injectiontreatment because of the discomfort associated withcompression treatment44 (Table 8).

affect reported values and preferences. For example,in the 2001 study by Man-Son-Hing et al,26 enrolleesin the Aspirin for Primary Prevention in the Low-riskElderly (APPLE) pilot study would accept aspirin togain a significantly smaller reduction in first-timestroke risk compared with those who did not enroll.This finding may indicate that individuals who enrollin trials may have higher acceptance for treatment

than those who do not.Results from a 2000 study by Man-Son-Hing et al25

help to defend the claim that differing methods forpreference and health state utility valuations mayaffect reported preferences. Of the 42 participants

who rated preferences using two methods, 43%reported that they would base their decision on theresults of the probability trade-off technique, and17% would base their decision on the decisionanalysis. The remaining 40% had no preferencebetween the two.

Results from a study by Bergus et al24 suggest that

methods used to relay information about risks andbenefits of therapy may significantly affect theirreported preferences. Participants who receivedtreatment benefits following risks were more likelyto accept aspirin than those who received informa-tion in the opposite order. This may relate to the con-cept of loss aversion, which refers to the tendencyfor individuals to prefer avoiding loss in favor of gain-ing benefits.55 The results of a study by Montori et al2 illustrate that similar to other studies, previous expe-rience with a given treatment affects the valuation ofthe outcomes or risks associated with that treatment

(Table 5). [ID ]T BL 5[ /I D ]

7.0 Stroke Thrombolysis


Results from Slot and Berge30 indicate that com-pared with individuals who have not experienced agiven health event, those who have may associate ahigher utility to that event . This factor may be impor-tant to consider when eliciting health state valuationsfor outcomes associated with antithrombotic treat-ment. These studies also illustrate that other factorssuch as age, sex, and living situation affect willingnessto accept or reject treatment options (Table 6).

[ID ]T BL 6[ /I D]

8.0 Myocardial Infarction Thrombolysis


One could infer from the results of Heyland et al 31 that many patients are extremely stroke averse (val-uing avoiding stroke to a considerably greater extentthan avoiding death). More likely, the results suggestthat patients place a higher value on avoiding treat-


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treatment names (placebo, aspirin, and warfarin); themajority of these switches were to aspirin.

11.0 Discussion

We have carried out a systematic review of studiesreporting patient values and preferences with regardto antithrombotic treatment. The results obtained

through this review provide direction for guidelinedevelopers to base recommendations on patient

values. In particular, this review highlights the appar-ently large variability in participant health state valu-ations and the factors, other than the impact ofalternative management strategies on quantity andquality of life, that influence patient decisions.

A number of factors may explain the large vari-ability in patient preferences both within and acrossstudies. First, whether patients had experienced thetreatments under consideration appeared to influ-ence results. Typically, previous exposure with a given

treatment was associated with a preference for con-tinuing that same treatment.12,13,45 Cognitive disso-nance occurs when participants are inclined to modifytheir interpretation of information to ensure that it isconsistent with their previous decision.56 To reducecognitive dissonance, participants who had previouslybeen exposed to the treatments under considerationmay be inclined to continue their treatment, even inthe face of information suggesting that it is not theoptimal choice. Patients who do not want to believethat they have been taking the wrong treatment mayinterpret the evidence presented so that it is consis-

tent with their prior choice.In addition, and perhaps most importantly, the dif-

fering methods used to elicit values and preferencesmay have resulted in differing apparent treatmentpreferences and health state valuations. Few studiesattempted to determine whether methods such asprobability trade-off, decision analysis, and differingmethods for obtaining health state utilities wouldresult in different choices. Indeed, in two studies,20,25 investigators found that methods used to elicit pref-erences significantly affected treatment health state

valuations and treatment thresholds.

The relatively small number of studies, their smallsample sizes, their methodological limitations, andthe large variability in their findings limit the infer-ences that we can confidently draw. We consider thefollowing conclusions, however, as reasonably robust:

1. Values and preferences for antithrombotictreatment and for health states appear to varyappreciably among individuals.

2. Heterogeneity of results across studies—oftendifficult to explain—leaves appreciable uncer-tainty about average patient values.

10.0 Biases and Limitations Associated With Included Studies

There are a number of limitations associated withthe included studies. Only three studies reportedcomprehension screening of potential participants,3,4,12 and two used only the data from participants withconsistent results.6,31 Le Sage and colleagues48 had

research assistants walk through the survey with par-ticipants to ensure that the participants understoodall the questions. It is possible that for those studiesthat did not pretest for comprehension, preferenceselicited using methods such as time trade-off, proba-bility trade-off, and standard gamble may have beencompromised because of a lack of participant under-standing. For example, Thomson et al18 designedtheir study as a three-arm trial, one arm of which elic-ited patient preferences through the standard gamblemethod. After realizing that participants were havingdifficulty understanding the standard gamble, they

dropped that arm of the study.Studies were also inconsistent in the descriptionsof health states presented to participants in terms ofboth the number and the type of health states consid-ered (eg, major bleed, major side effects, stroke). Forexample, Protheroe et al15 grouped major and minorside effects together (not typical), whereas otherstudies did not consider minor side effects at all. As

well, when describing the outcomes associated withstroke, some authors centered their descriptions onthe physical effects,30 whereas others consideredadditional aspects, such as the likelihood of becom-

ing depressed or losing the ability to comprehendlanguage.21 Given the complexity of the treatmentdecision in this context, we do not consider studies tobe biased if they neglected to consider rare or minoroutcomes because including these may overwhelmparticipants and affect the validity of the outcomes.

The methodologic quality of the included studiesis concerning, and most studies are compromised bysome form of selection bias. For example, whetherpatients had previously experienced the condition orhealth events under consideration may have influ-enced their preference. Slot and Berge30 found that

those participants who had previously experienced astroke tended to place a lower disutility on strokethan did those who had not experienced stroke events.Ideally, investigators would have recruited individ-uals recently given a diagnosis of the condition understudy and who had not made a treatment decision.None of the included studies did.

In addition, participants’ prior associations withthe treatments under study may have affected will-ingness to accept specific treatment options. Forexample, Holbrook et al10 found that 36% of partici-pant treatment preferences changed once given the


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made the choices under investigation. Although priorexperiences may result in a better understanding ofthe treatment under consideration, it may introducefactors other than preferences for the health statesdescribed in their responses (particularly cognitivedissonance). Second, in order to gain a better under-standing of whether differing health state descrip-tions significantly affect health state valuations, future

research may test the impact of different descriptionson participant valuations. Ideally, standard descrip-tions of bleed and stroke outcomes would be devel-oped and applied across studies. Finally, researchshould ensure that participants understand the pref-erence elicitation exercise and explore factors thatbear significantly on patient decisions.

Our findings also have implications for guidelinedevelopment. The uncertainty and the variability in

values and preferences among patients suggest thatthe present guideline panels should be circumspectin making strong recommendations. Strong recom-

mendations should be restricted to situations in whichthe desirable consequences of an intervention sub-stantially outweigh the undesirable consequences.

Acknowledgments

Author contributions: As Topic Editor, Ms MacLean oversawthe development of this article, including the data analysis andfindings contained herein.Ms MacLean: served as Topic Editor.Mr Mulla: served as a panelist.Dr Jankowski: served as a panelist.Dr Akl: served as a panelist.Dr Vandvik: served as a panelist.

Mr Ebrahim: served as a panelist.Ms McLeod: served as a panelist.Ms Bhatnagar: served as a panelist.Dr Guyatt: served as a panelist.Financial/nonfinancial disclosures: In summary, the authorshave reported to CHEST the following conflicts of interest:Dr Guyatt is co-chair of the GRADE Working Group, andDrs Akl and Vandvik are members and prominent contributorsto the Grade Working Group. Mss MacLean, McLeod, andBhatnagar; Messrs Mulla and Ebrahim; and Dr Jankowski havereported that no potential conflicts of interest exist with anycompanies/organizations whose products or services may be dis-cussed in this article.Role of sponsors: The sponsors played no role in the develop-ment of these guidelines. Sponsoring organizations cannot recom-mend panelists or topics, nor are they allowed prepublication

access to the manuscripts and recommendations. Guideline panelmembers, including the chair, and members of the Health & Sci-ence Policy Committee are blinded to the funding sources. Fur-ther details on the Conflict of Interest Policy are available onlineat http://chestnet.org. Endorsements: This guideline is endorsed by the AmericanAssociation for Clinical Chemistry, the American College of ClinicalPharmacy, the American Society of Health-System Pharmacists,the American Society of Hematology, and the International Societyof Thrombosis and Hematosis.

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Study results suggest the following average valuesfor the health states of interest:

3. Although there are troubling inconsistenciesacross studies, particularly in Man-Son-Hinget al,14 a reasonable trade-off to assume betweenstroke and bleeds would be a ratio of disutilityof net nonfatal stroke (thrombotic or hemor-

rhagic) to GI bleeds in the range of 2:1 to 3:1.4. There is much less information about the rela-tive disutility of myocardial infarction and bleeds,although it is clear that myocardial infarction hassubstantially less disutility than major stroke(and more than minor stroke). A reasonabletrade-off to assume between myocardial infarc-tion and bleeds would be 1:1 to 2:1.

5. The only conclusion that one can make regardingthe relative disutility of major bleed vs DVT isthat it varies widely among patients.

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Study results suggest the following preferences forthe antithrombotic interventions:

7. For most patients, vitamin K antagonist therapydoes not have important negative effects onquality of life, although many patients worryabout the side effects associated with vitamin Kantagonist treatment.

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less preferred compared with injection treatments.

The present study has several limitations. Given thelarge number of abstracts that were selected for review(N517,086), it was not feasible to seek out articlesthat could not be obtained online. Therefore, thisstudy comprises only articles that could be accessedthrough the electronic library at McMaster University.Eight articles that we deemed potentially relevant

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