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CHEST Supplement

www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT 53S

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

Background: To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physi-cians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, andsystematic review and guideline methodologists.

Methods: Clinical areas were designated as articles, and a methodologist without important intel-lectual or financial conflicts of interest led a panel for each article. Only panel members withoutsignificant conflicts of interest participated in making recommendations. Panelists specified thepopulation, intervention and alternative, and outcomes for each clinical question and definedcriteria for eligible studies. Panelists and an independent evidence-based practice center exe-

cuted systematic searches for relevant studies and evaluated the evidence, and where resourcesand evidence permitted, they created standardized tables that present the quality of the evidenceand key results in a transparent fashion.

Results: One or more recommendations relate to each specific clinical question, and each recom-mendation is clearly linked to the underlying body of evidence. Judgments regarding the qualityof evidence and strength of recommendations were based on approaches developed by the Gradesof Recommendations, Assessment, Development, and Evaluation Working Group. Panel mem-bers constructed scenarios describing relevant health states and rated the disutility associated

with these states based on an additional systematic review of evidence regarding patient valuesand preferences for antithrombotic therapy. These ratings guided value and preference decisionsunderlying the recommendations. Each topic panel identified questions in which resource alloca-tion issues were particularly important and, for these issues, experts in economic analysis pro-vided additional searches and guidance.

Conclusions: AT9 methodology reflects the current science of evidence-based clinical practiceguideline development, with reliance on high-quality systematic reviews, a standardized processfor quality assessment of individual studies and the body of evidence, an explicit process for trans-lating the evidence into recommendations, disclosure of financial as well as intellectual conflictsof interest followed by management of disclosed conflicts, and extensive peer review.

CHEST 2012; 141(2)(Suppl):53S–70S

Abbreviations: ACCP5American College of Chest Physicians; AT85Antithrombotic and Thrombolytic Therapy:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition); AT95AntithromboticTherapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical PracticeGuidelines; GDP5gross domestic product; GRADE5Grades of Recommendation, Assessment, Development, andEvaluation; HSP5Health and Science Policy; PICO5population, intervention, comparator, and outcome; QALY5quality-adjusted life year; RCT5 randomized controlled trial; WHO5 World Health Organization

Methodology for the Developmentof Antithrombotic Therapy andPrevention of Thrombosis Guidelines

Antithrombotic Therapy and Prevention of Thrombosis,

9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

Gordon H. Guyatt , MD , FCCP ; Susan L. Norris , MD , MPH ; Sam Schulman , MD , PhD ; Jack Hirsh , MD , FCCP ; Mark H. Eckman , MD ; Elie A. Akl , MD , MPH , PhD ;Mark Crowther , MD ; Per Olav Vandvik , MD , PhD ; John W. Eikelboom , MBBS ;Marian S. McDonagh , PharmD ; Sandra Zelman Lewis , PhD ; David D. Gutterman , MD , FCCP ;Deborah J. Cook , MD ; Holger J. Schünemann , MD , PhD , FCCP

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

http://www.chestpubs.org/http://www.chestpubs.org/

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54S Methodology for the Guidelines

Chest Physicians Evidence-Based Clinical PracticeGuidelines (8th Edition) (AT8), published in 20081 (Dr Guyatt, Panel Chair, and Dr Schünemann, ViceChair of Methodology); a third methodologist-clinician(Dr Akl); a leading thrombosis expert (Dr Crowther,

Vice Chair for Thrombosis); and two liaisons with theACCP Health and Science Policy (HSP) Committee

who had also served on the previous guideline Exec-

utive Committee (Dr Gutterman, Vice Chair andHSP Liaison, and Dr Lewis, Project Manager).

Articles within AT9 are defined by broad popula-tions (eg, pediatric, obstetric) or clinical conditions(eg, prevention of VTE in medical patients or strokeprophylaxis in atrial fibrillation). In addition, AT9includes three articles addressing the basic science oforal and parenteral anticoagulants and platelet-activedrugs and an article addressing new antithromboticand thrombolytic drugs.

1.0 Composition and Selectionof Topic Panel Members

The ACCP AT9 Executive Committee selectedpanel members for each article. A topic editor and adeputy editor led each of the AT9 panels issuing rec-ommendations. The topic editor was the person pri-marily responsible for each article and was requiredto be a methodologist without serious financial orintellectual conflict of interest for any of the article’srecommendations. In all but one case, the topic edi-tor also was a clinician. The Executive Committeechose these individuals on the basis of their previous

experience with guideline development and, in par-ticular, their familiarity with methods developed bythe Grades of Recommendation, Assessment, Devel-opment, and Evaluation (GRADE) Working Group.2 These topic editors and all panel members wereapproved by the ACCP HSP Committee after reviewof their conflict of interest disclosures (see section 7.0“Disclosing and Managing Conflicts of Interest”).

Criteria for selection of the remainder of the panelmembers, including the deputy editor-thrombosisexpert, were an established record in the relevantclinical or research area, international and gender

representation, and an absence of financial conflictsof interest that were judged unacceptable. Some of thepanelists had prior experience on ACCP guidelines inthis area and represented the thrombosis community,but there was substantial turnover from the previousedition. After an international request for applicationsbroadcast through multiple medical societies, theExecutive Committee nominated individual topic edi-tors and deputy editors and collaborated with them toidentify and nominate other topic panel members.

The ACCP HSP Committee reviewed all nomineesand approved all panel members after review of their

This article describes the methodology used forthe Antithrombotic Therapy and Prevention of

Thrombosis, 9th ed: American College of Chest Phy-sicians Evidence-Based Clinical Practice Guidelines(AT9). This methodology incorporates current evidence-based approaches to the appraisal and synthesis ofevidence and to the formulation of clinical practice rec-ommendations. The process thus ensures explicit, trans-

parent, evidence-based clinical practice guidelines.The objective of AT9 is to optimize patient-

important health outcomes and the processes of carefor patients who have experienced or are at risk forthrombotic events. The targeted users of these guide-lines are health-care providers in both primary andspecialty care who assist patients in making treatmentchoices that optimize benefits, minimize harms andburdens, and are consistent with patient values andpreferences.

Figure 1 summarizes the process for the develop-ment of the AT9 recommendations. The primary

responsibility for AT9 rests with the American Collegeof Chest Physicians (ACCP) AT9 Executive Com-mittee. This committee includes two methodologist-clinicians from the previous iteration, Antithromboticand Thrombolytic Therapy: American College of

Revision accepted August 31, 2011. Affiliations: From the Department of Clinical Epidemiologyand Biostatistics (Drs Guyatt, Akl, Cook, Schulman, and Schünemann)and Department of Medicine (Drs Guyatt, Schulman, Hirsh,Crowther, Eikelboom, Cook, and Schünemann), McMasterUniversity Faculty of Health Sciences, Hamilton, ON, Canada;Department of Medical Informatics and Clinical Epidemiology

(Drs Norris and McDonagh), Oregon Health & Science University,Portland, OR; Division of General Internal Medicine and Centerfor Clinical Effectiveness (Dr Eckman), University of Cincinnati,Cincinnati, OH; Departments of Medicine and Family Medicine(Dr Akl), State University of New York, Buffalo, NY; Departmentof Medicine Gjøvik-Innlandet Hospital Trust and NorwegianKnowledge Centre for the Health Services (Dr Vandvik), Oslo,Norway; Evidence-Based Clinical Practice Guidelines andClinical Standards (Dr Lewis), American College of ChestPhysicians, Northbrook, IL; and Cardiovascular Research Center(Dr Gutterman), Medical College of Wisconsin, Milwaukee, WI.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 educa-

tional grants was also provided by Bristol-Myers Squibb; Pfizer,Inc; Canyon Pharmaceuticals; and sanofi-aventis US.Disclaimer: American College of Chest Physician guidelinesare intended for general information only, are not medical advice,and do not replace professional medical care and physicianadvice, which always should be sought for any medical condi-tion. The complete disclaimer for this guideline can be accessedat http://chestjournal.chestpubs.org/content/141/2_suppl/1SCorrespondence to: Gordon H. Guyatt, MD, FCCP, Departmentof Clinical Epidemiology and Biostatistics, McMaster University,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.11-2288


http://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/1S

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proved as a result of the magnitude of financial conflictsof interest. Articles associated with recommendationsincluded from seven to 14 panel members. We didnot include patients or representatives of specificstakeholder groups on topic panels.

Each topic panel also included a frontline physician working in the relevant area who was neither an expertin thrombosis nor a methodologist or clinical investi-

gator. These individuals were chosen in consultation with the topic editors and the ACCP HSP Committee.These clinicians were charged with the following:(1) proposing important real-world clinical questionson the prevention, diagnosis, and treatment of throm-bosis that were not addressed in AT8 and (2) review-ing the draft manuscripts and recommendations toassess the usability of the guidelines and the feasi-bility of implementation of AT9 recommendations.

To address issues of economic efficiency we includedsix health economist-physicians on the AT9 topicpanels charged with making recommendations. These

resource consultants were selected and approvedthrough identical procedures to those for topic edi-tors and panel members. We describe their rolesmore fully later in this discussion.

2.0 Ensuring Consistency Across Articles

We used a number of strategies to ensure consis-tency across articles, and one of us (M. C.) participatedextensively in the formulation of clinical questionsfor each article. To ensure consistency of judgmentsregarding bleeding, one of us (S. S.) was responsible

for standardizing the approach to bleeding outcomesand participated in multiple topic panels (describedin more detail later in this article). Additionally, toensure consistency in the trade-offs between throm-botic and bleeding events, all articles used the sameratings of values and preferences (also described inmore detail later). Because some of the same evi-dence summaries were relevant to several articles,five individuals were chosen to participate in eachof the articles addressing coronary artery disease,stroke, and peripheral arterial disease.

In AT9, prevention of VTE is addressed in three

articles as opposed to a single article as was done inAT8. The prevention topic editors and deputy editorsand those of the stroke article (which includes throm-boprophylaxis recommendations) participated in mul-tiple conference calls to develop and harmonize theapproach to prevention and to ensure consistencyamong final recommendations.3 Topic editors con-sulted with one another when issues overlapped. Forexample, the decision regarding the use of a vitamin Kantagonist, aspirin, and clopidogrel simultaneously inpatients with atrial fibrillation, valvular disease, andintravascular stents is relevant for the atrial fibrillation,

curricula vitae and conflict of interest disclosures.Of 150 nominees, 137 were approved, 18 wereapproved with management of conflicts of interest(ie, regular disclosures and review of ongoing con-flicts as the process progressed), and 13 were disap-

Figure 1. The steps in the process of development of theAntithrombotic Therapy and Prevention of Thrombosis, 9th ed:American College of Chest Physicians Evidence-Based Clinical

Practice Guidelines. The Executive Committee, comprising system-atic review and guideline methodologists, clinical experts, and ACCPHealth and Science Policy Committee liaisons, coordinated theprocess. Information within parentheses indicates who performedeach step in the process. ACCP5American College of Chest Physi-cians; EPC5Evidence-Based Practice Center; GRADE5Gradesof Recommendations, Assessment, Development, and Evaluation;PICO5population, intervention, comparator, and outcome.



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primary responsibility for defining the scope of theclinical questions that each article would address. Foreach question, the topic editor and deputy editordefined the relevant population, alternative manage-ment strategies (intervention and comparator), andthe outcomes (ie, population, intervention, com-parator, and outcome [PICO] format). Each clinicalquestion provided the framework for formulating

study inclusion and exclusion criteria and guided thesearch for relevant evidence (systematic reviews andoriginal studies). Panels typically restricted includedstudies to randomized controlled trials (RCTs) forintervention questions but included observationalstudies when there was a paucity of RCT data address-ing an intervention and for questions of risk assess-ment. Readers can find these PICO questions in thefirst table of each article. One or more recommenda-tions could be formulated for each clinical question.The next subsections (3.2-3.5) deal with the approachto selection of outcomes.

3.2 Patient-Important and Surrogate Outcomes

The outcomes for each clinical question were cho-sen by the topic editors and their panel members and

were generally consistent across articles. Outcomes were restricted to those of importance to patients.4 Panels considered the burden of anticoagulation ther-apy as a patient-important outcome when its con-sideration could tip the balance of benefits and harms.If we found no data for an outcome consideredat the outset as patient-important, we nevertheless

included uncertainty about the effects of the intervention on that outcome when weighing its benefitsand harms.

In the absence of data on patient-important out-comes, surrogates could contribute to the estimationof the effect of an intervention on the outcomes thatare important. Examples of surrogate outcomesinclude asymptomatic venous thrombosis detectedby venographic or ultrasound surveillance and thepercentage of time that an international normal-ized ratio was in therapeutic range (used as a surro-gate for bleeding and thrombosis in the assessment

of the effectiveness of centralized anticoagulationservices).

The issue of asymptomatic thrombosis detectedby venographic or ultrasound surveillance presentedparticular challenges to the articles addressing VTEprevention in orthopedic and nonorthopedic surgerypopulations, an article addressing nonsurgical pro-phylaxis, and an article addressing stroke preven-tion. We were explicit in considering the trade-offsbetween VTE and bleeding events. An article byGuyatt et al3 in this supplement addresses these issuesin some detail.

coronary, and peripheral arterial disease articles. Topicpanels deferred to the Evidence-Based Managementof Anticoagulant Therapy AT9 topic panel for recom-mendations related to the dosing and monitoring ofanticoagulation therapies.

The AT9 Executive Committee met at least once amonth and regularly issued statements of clarificationof methods to topic editors and deputy editors (eg,

use of fixed- or random-effects models for meta-analysis), conflict of interest, preparation of tables, andissues of style and presentation. All these statements

were communicated directly to the topic editors anddeputy editors and made available in a central repositoryaccessible to all AT9 panelists. The chair of the Exec-utive Committee (G. H. G.) was available for resolvingany challenging issues related to the aforementionedtopics. Between September 2009 and September 2010,two members of the Executive Committee (E. A. A.and S. Z. L.) held regular (every 3 months), separateconference calls with each topic editor and deputy

editor during which they addressed questions andconcerns. Finally, the chair of the Executive Com-mittee reviewed every article to ensure consistency ofevidence presentation, evaluation, and writing style.

In terms of writing style, we used consistent lan-guage to describe effects that did not reach statisticalsignificance. The approach was as follows:

1. For adverse outcomes (such as thrombosis andbleeding), “ A is associated with a trend towardreduced thrombosis” if the lower boundary ofthe CI around a relative effect is 0.7 and the

upper boundary of the CI is

1.1 or if the lowerboundary of the CI is 0.8 and the upperboundary of the CI is 1.05. If the point esti-mate is. 1.0, the language used was, “ A is asso-ciated with a trend toward increased bleeding”if the lower boundary of the CI around a relativeeffect is . 0.9 and the upper boundary of theCI is . 1.3 or if the lower boundary of the CIis. 0.95 and the upper boundary of the CI is. 1.2.

2. “ A appears to have little or no effect on throm-bosis” if the above conditions are not met, and theboundaries of the CI lie between 0.80 and 1.2.

3. For all other results that fail to exclude a relativerisk of 1.0, the language was, “Results failedto demonstrate or exclude a beneficial effect ordetrimental effect of A on thrombosis.” Alterna-tive wording with regard to an association is“failed to establish or refute.”

3.0 Evidence Review

3.1 Defining the Clinical Questions—Population,Intervention, Comparator, and Outcome

The thrombosis expert on the Executive Com-mittee (M. C.) along with the deputy editors took


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cified in footnotes the events attributable to eachcomponent.

We avoided any double-counting of events; forexample, a fatal hemorrhagic stroke would onlybe reported under mortality. We also attempted toreport more specific and homogeneous bleeding out-comes than “major bleeding,” which includes events

with a wide range of patient importance and which

investigators have defined in different ways. Forexample, in Falck-Ytter et al8 in this supplement, bleed-ing outcomes of primary interest were (1) bleedingrequiring reoperation and (2) other major bleeding.Because some authors, particularly in older studies,failed to define subsets of major bleeding, we werenot always able to achieve the desired specificity.

3.6 Identifying the Evidence

To identify the relevant evidence, a team of meth-odologists and medical librarians at the OregonHealth & Science University Evidence-based Prac-tice Center conducted literature searches of Medline,the Cochrane Library, and the Database of Abstractsof Reviews of Effects. For each article, the team con-ducted a search for systematic reviews and anotherfor original studies encompassing the main popula-tions and interventions for that article. These searchesincluded studies indexed from week 1, January 2005,forward because AT8 searches were carried out up tothat date (search strategies are available on request).Many articles supplemented these searches withmore-focused searches addressing specific clinicalquestions. When clinical questions had not been cov-ered in AT8, searches commenced at a date relevantto each intervention.

Titles and abstracts retrieved from bibliographicdatabase searches generally were screened in dupli-cate, and full-text articles were retrieved for furtherreview. Consensus on whether individual studies ful-filled inclusion criteria was achieved for each studybetween two reviewers. If consensus could not beachieved, the topic editor and other topic panelists

were brought into the discussion. Deputy editorsreviewed lists of included studies from the databasesearches in order to identify any potentially missedstudies. Additional studies identified were thenretrieved for further evaluation.

Topic panels also searched the same bibliographicdatabases for systematic reviews addressing each PICOquestion. The quality of reviews was assessed usingprinciples embodied in prior instruments addressingmethodologic quality of systematic reviews,9,10 and

wherever possible, current high-quality systematicreviews were used as the source of summary estimates.Reviews were also used to identify additional studiesto complement the database searches.

3.3 Mortality

Options considered in summarizing mortal events were (1) all-cause mortality and (2) mortality relatedto antithrombotic therapy (ie, deaths from pulmonaryemboli and deaths from bleeding). Advantages of theformer include its being the most patient-importantoutcome and the difficulty of ascertaining cause ofdeath. Difficulties ascertaining cause of death maybe particularly problematic when adjudication isunblinded and therefore open to bias.

The disadvantage of all-cause mortality is that thesignal from antithrombotic therapy-related deathsmay be lost in noise from deaths due to other causes.The decision about which mortal outcome to use(all-cause mortality or antithrombotic therapy-relatedmorality) was left to the authors of individual articles.Availability of data sometimes forced the choice ofless satisfactory mortal outcomes (eg, if death relatedto pulmonary embolus but not death related to bleed-ing was reported). When mortality was one of theselected outcomes, we avoided double-counting by doc-umenting nonfatal events for the remaining outcomes(eg, nonfatal thrombosis, nonfatal major bleeding)rather than all such events (fatal and nonfatal).

3.4 Composite End Points

Many of the primary studies we reviewed, particu-larly in the cardiovascular area, presented evidencein the form of composite end points.5 Particularly

when the patient importance of the component endpoints and the magnitude of effect of the interven-

tion on the components differ, composite end pointscan be misleading.6,7 Therefore, we present resultsand base inferences on the effect of interventions onindividual outcomes.

3.5 Bleeding

In view of the wide variation in how bleeding wasassessed and reported in the included primary studiesacross chapters, one individual (S. S.) was responsiblefor standardizing the approach to bleeding outcomes.He worked closely with the Executive Committeeand the topic editors and deputy editors to ensure theuniform application of the approaches that weredeveloped.

We began by specifying the bleeding outcomesthat we believe patients consider important. We didnot consider minor bleeding as incurring a burdenthat was important in comparison with symptomaticthromboembolic events.

We reported fatal hemorrhage as well as fatal strokeor pulmonary embolism in treatment-related or all-cause mortality. Likewise, hemorrhagic stroke andischemic stroke were reported as “stroke.” We spe-



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higher quality, individual prospective studies mayhave a significant risk of bias and specific retro-spective studies may not. For questions related torisk assessment, we evaluated the risk of bias ofindividual studies using the following criteria: validoutcome assessment, including blinding when appro-priate; adjustment for between-group differences;and minimal loss to follow-up.

4.2 Evaluating Quality of Bodies of Evidence

We assessed evidence across studies on an outcome-by-outcome basis using criteria suggested by theGRADE Working Group.19 We defined quality ofevidence as our confidence in the estimate of theeffect to support a recommendation.19 RCTs startas high-quality evidence and observational studies aslow-quality evidence (Fig 2). Additional factors thataffect this rating of quality include the risk of bias(as detailed earlier in this article); precision, con-sistency, and directness of results; likelihood of pub-lication bias; and presence of very large effects.19 TheACCP adaptation of the GRADE system (Table 4)differs only in that the quality of a body of evidencecan be high (A), moderate (B), or low (C) (Fig 2);GRADE also provides a category for very-low-qualityevidence.

Often, we found that the quality of the evidencediffered across outcomes. For example, in assessingthe quality of evidence for thienopyridines vs warfa-rin in patients undergoing percutaneous coronaryinterventions, we determined the evidence to be ofmoderate quality for mortality, nonfatal myocardialinfarction, and revascularization but of low quality formajor bleeding.

We then made a rating of the quality of the entirebody of evidence bearing on the effect of alternativemanagement strategies for each clinical question. Inother words, we assessed the quality across outcomes,including both benefits and harms. Quality for eachrecommendation was the lowest quality rating of theoutcomes judged as critical (as opposed to important,but not critical).19

4.0 Assessing Studies andSummarizing Evidence

4.1 Evaluating Risk of Bias in Individual Studies

We developed and applied uniform criteria forevaluating the risk of bias associated with individualRCTs based on the criteria recommended by theCochrane Collaboration11 (Table 1). Although all

authors assessed risk of bias for individual studies,because of resource limitations, we summarized theresults of the risk of bias (eg, Table 112 ) for only aminority of the recommendations. Readers can findthese assessments in the online data supplements. Formost recommendations for which we did not developsuch tables, we developed Evidence Profiles (seeTable 213-15) that typically provide information on therisk of bias in footnotes.

We also developed specific criteria for assessingthe risk of bias of observational studies (cohort studies

with concurrent controls, cohort studies with historical

controls, case-control studies, or case series). Again,these were based on the evidence-based domainsrecommended by the Cochrane Collaboration forobservational studies (eg, Table 316-18).

Studies without internal comparisons were termed“cohort studies without internal controls” if they metthe following criteria:

1. A protocol existed before the date of commence-ment of data collection.

2. A definition of inclusion and exclusion criteria was available.

3. The study reported the number of excludedpatients.4. The study conducted a standardized follow-up,

including description of all of the following:schedule of follow-up, investigation of suspectedoutcomes, and criteria used to define outcomes.

5. The study reported all losses to follow-up.

We labeled studies that did not meet these crite-ria as “case series.” We did not make a distinctionbetween prospective and retrospective studies becausealthough prospective studies may on average be of

Table 1 —[Section 4.1] Methodologic Quality of Randomized Trials: Fondaparinux vs No Fondaparinux for the Treatment of Superficial Vein Thrombosis

Author, Year DesignRandomization

Concealed Blinding AnalysisStopping Early

for Benefit

Decoususet al12; CALISTOStudy Group,2010

RCT: randomizationsequence generated“using a computer-generatedrandomization list”

DY: “Through acentral telephonesystem”

Patients: PY ITT: DY for efficacy outcomes(as-treated analysis forsafety outcomes)

NoCaregivers: PY

Data collectors: PYAdjudicators: DY Data for primary efficacy

assessment available for98.7% of randomized patients

Data analysts: PN

CALISTO5Comparison of ARIXTRA in Lower Limb Superficial Thrombophlebitis with placebo; DY5definitely yes; ITT5 intent to treat;PN5probably no; PY5probably yes; RCT5 randomized controlled trial.


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T a b l e 2 — [ S e c t i o n

4 . 1 ] E v i d e n c e P r o fi l e : Q u e s t i o n : S h

o u l d L M W H R a t h e r T h a n V K A b e U

s e d f o r L o n g - t e r m T r e a t m e n t o f V T

E ? a , 1 3 - 1 5

Q u a l i t y A s s e s s m e n t

S u m m a r y o f F i n d i n g s

P a r t i c i p a n t s

( S t u d i e s ) , M e d i a n

F o l l o w - u p

R i s k o f B i a s

I n c o n s i s t e n c y

I n d i r e c t n e s s

I m p r e c i s i o n

P u b l i c a t i o n

B i a s

O v e r a l l Q u a l i t y

o f E v i d e n c e

S t u d y E v e

n t R a t e s ( % )

R e l a t i v e

E f f e c t , R R

( 9 5 % C I )

A n t i c i p a t e d A b s o l u t e E f f e c t s b

W i t h

V K A

W i t h

L M W H

R i s k W i t h V K A

R i s k D i f f e r e n c e W i t h

L M W H ( 9 5 % C I )

O

v e r a l l m o r t a l i t y ( c r i t i c a l o u t c o m e )

2 , 4 9 6 ( 7 R C T s ) ,

6 m o

N o s e r i o u s

r i s k o f b i a s

S e l e c t i v e

o u t c o m e

r e p o r t i n g

n o t s e r i o u s c

N o s e r i o u s

i n c o n s i s t e n c y

N o s e r i o u s

i n d i r e c t n e s s

S e r i o u s

i m p r e c i s i o n

C I i n c l u d e s

i m p o r t a n t

b e n e fi t a n d

h a r m

U

n d e t e c t e d

M o d e r a t e

d u e t o


2 0 2 / 1 , 2 3 1 ( 1 6 . 4

) 2 0 4 / 1 , 2 6 5 ( 1 6 . 1 ) 0 . 9 6 ( 0 . 8 1 - 1 . 1 3 ) 1 6 4 d e a t h s

p e r 1 , 0 0 0 d

7 f e w e r d e a t h s p e r

1 , 0 0 0 ( f r o m 3 1

f e w e r t o 2 1 m o r e )

R e c u r r e n t s y m

p t o m a t i c V T E ( c r i t i c a l o u t c o m e ) : D V T a n d

P E

2 , 7 2 7 ( 8 R C T s ) ,

6 m o

S e r i o u s

r i s k o f b i a s

N o s t u d i e s

w e r e b l i n d e d

N o s e r i o u s


N o s e r i o u s


N o s e r i o u s


U

n d e t e c t e d

M o d e r a t e d u e

t o r i s k o f

b i a s

1 0 5 / 1 , 3 4 9 ( 7 . 8

) 6 7 / 1 , 3 7 8 ( 4 . 9 )

0 . 6 2 ( 0 . 4 6 - 0 . 8 4 )

N o c a n c e r

3 0 V T E s

p e r 1 , 0 0 0 d

1 1 f e w e r V T E p e r

1 , 0 0 0 ( f r o m 5

f e w e r t o 1 6 f e w e r )

N o n m e t a s t a t i c c a n c e r

8 0 V T E s

p e r 1 , 0 0 0 d


1 , 0 0 0 ( f r o m 1 3

f e w e r t o 4 3 f e w e r )

M e t a s t a t i c c a n c e r

2 0 0 V T E

s

p e r 1 , 0 0 0 d


1 , 0 0 0 ( f r o m 3 2

f e w e r t o 1 0 8

f e w e r )

M

a j o r b l e e d i n g ( c r i t i c a l o u t c o m e )

2 , 7 3 7 ( 8 R C T s ) ,

6 m o

N o s e r i o u s

r i s k o f b i a s

L a c k o f

b l i n d i n g n o t

s e r i o u s e

N o s e r i o u s


N o s e r i o u s


S e r i o u s


C I i n c l u d e s

i m p o r t a n t

b e n e fi t a n d

h a r m

U

n d e t e c t e d

M o d e r a t e

d u e t o


5 3 / 1 , 3 5 1 ( 3 . 9 )

4 5 / 1 , 3 8 6 ( 3 . 2 )

0 . 8 1 ( 0 . 5 5 - 1 . 2 )

N o c a n c e r o r n o n m e t a s t a t i c c a n c e r

2 0 b l e e d

s

p e r 1 , 0 0 0 f

4 f e w e r b l e e d s p e r

1 , 0 0 0 ( f r o m 9

f e w e r t o 4 m o r e )

M e t a s t a t i c c a n c e r

8 0 b l e e d

s

p e r 1 , 0 0 0 f

1 5 f e w e r b l e e d s p e r

1 , 0 0 0 ( f r o m 3 6

f e w e r t o 1 6 m o r e )

( C o n t i n u e d )



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T a b l e 2 — C o n t i n u e d

Q u a l i t y A s s e s s m e n t

S u m m a r y o f F i n d i n g s

P a r t i c i p a n t s

( S t u d i e s ) , M e d i a n

F o l l o w - u p

R i s k o f B i a s

I n c o n s i s t e n c y

I n d i r e c t n e s s

I m p r e c i s i o n

P u b l i c a t i o n

B i a s

O v e r a l l Q u a l i t y

o f E v i d e n c e

S t u d y E v e

n t R a t e s ( % )

R e l a t i v e

E f f e c t , R R

( 9 5 % C I )

A n t i c i p a t e d A b s o l u t e E f f e c t s b

W i t h

V K A

W i t h

L M W H

R i s k W i t h V K A

R i s k D i f f e r e n c e W i t h

L M W H ( 9 5 % C I )

P T S ( i m p o r t a n t

o u t c o m e ) : s e l f - r e p o r t e d l e g s y m p t o m s a n d s i g n s

1 0 0 ( 1 R C T ) ,

3 m o

S e r i o u s

r i s k o f b i a s

P a t i e n t s a n d

i n v e s t i g a t o r s

n o t b l i n d e d

N o s e r i o u s


S e r i o u s


P r e d i c t i v e

v a l u e f r o m

3 m o t o

l o n g t e r m

u n c e r t a i n

N o s e r i o u s


U

n d e t e c t e d

L o w d u e

t o r i s k o f

b i a s a n d


3 1 / 4 4 ( 7 0 . 5 )

3 4 / 5 6 ( 6 0 . 7 )

0 . 8 5 ( 0 . 7 7 - 0 . 9 4 ) 2 0 0 P T S

p e r 1 , 0 0 0 g

3 0 f e w e r p e r 1 , 0 0 0

( f r o m 1 2 f e w e r

t o 4 6 f e w e r )

L M W H 5 l o w - m o l e c u l a r - w e i g h t h e p a r i n ;

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 ; R C T 5 r a

n d o m i z e d c o n t r o l t r i a l ; R R 5 r i s k r a t i o ; V K A

5 v

i t a m i n K a g o n i s t . ( K e a r o n C , u n p u b l i s h e d d a t a ) . h

a L i m i t e d t o L M W H r e g i m e n s t h a t u s e d 5

0 % o f t h e a c u t e t r e a t m e n t d o s e d u r i n g t h

e e x t e n d e d p h a s e o f t r e a t m e n t .

b T i m e f r a m e i s 6 m o f o r a l l o u t c o m e s e x c e

p t P T S , w h i c h i s 2 y .

c O n e s t u d y d i d n o t r e p o r t d e a t h s : b o r d e r l i n e d e c i s i o n .

d C o n t r o l e v e n t r a t e s f r o m c o h o r t s t u d y b y

P r a n d o n i e t a l , 1 3 a d j u s t e d t o 6 - m o t i m e f r a m

e .

e O u t c o m e l e s s s u b j e c t i v e : b o r d e r l i n e d e c i s i o n .

f C o n t r o l e v e n t r a t e s f r o m c o h o r t s t u d i e s b

y P r a n d o n i e t a l 1 3 a n d B e t h e t a l 1 4 a

d j u s t e d t

o 6 - m o t i m e f r a m e .

g C o n t r o l e v e n t r a t e c o m e s f r o m o b s e r v a t i o n a l s t u d i e s i n r e v i e w b y K a h n e t a l 1 5 a

d j u s t e

d t o 2 - y t i m e f r a m e . A l l p a t i e n t s w o r e p r e s s u r e s t o c k i n g s .

h M e t a - a n a l y s i s i s b a s e d o n R C T s a s r e f e r e n c e d i n t h e a r t i c l e t e x t . T h e c o n t r o l e v e n t r a

t e f o r m o r t a l i t y c o m e s f r o m t h i s m e t a - a n a l y s i s .


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4.3 Estimating Relative and Absolute Effects

Most patient-important outcomes in this guidelineare binary or yes-no outcomes (death, stroke, VTE,myocardial infarction, bleeding). In general, relativeeffects are similar across subgroups of patients,including those with varying baseline risk.20,21 Theevidence summaries (Evidence Profiles and Sum-mary of Findings tables described later in this article),therefore, include a presentation of relative effects(where possible as relative risks because they areeasier to understand than ORs) of intervention vs con-trol management strategies.

Trading off desirable and undesirable consequences(eg, thrombosis vs bleeding) requires, however, esti-mates of absolute effect. For example, in patients

with atrial fibrillation, warfarin results in a 66% rela-tive risk reduction in nonfatal stroke. This comes at acost of inconvenience, lifestyle restrictions, and riskof bleeding. For patients with a CHADS (congestiveheart failure, hypertension, age 75 years, diabetesmellitus, stroke) score of 3, the 66% relative riskreduction translates into an absolute reduction of6.3% (63 in 1,000) per year. Virtually all patients

will consider this worthwhile. On the other hand, forpatients with a CHADS score of 0, the 66% reductiontranslates into an absolute risk reduction of only 0.5%(5 in 1,000) per year. Many patients may consider thisreduction not worth the undesirable consequences of

warfarin use. We calculated absolute effects by applying relative

risks to estimates of control group risk. For instance,if control group risk of thrombosis is 4% and relativerisk with an intervention is 50%, then the absolutedifference between intervention and control is 4% of50% or 2%, and the number needed to treat to pre-

vent an episode of thrombosis is 100/2 or 50. In manycases, the Summary of Findings tables present effectsas events prevented (or caused) per 1,000 patients.In this hypothetical example, the effect would be20 events per 1,000 patients.

Whenever valid prognostic data were availablefrom observational studies, they were used to esti-mate control group risks. When credible resultsfrom observational and prognostic studies were notavailable, risk estimates from control groups of RCTs

were used.

4.4 Considering Subgroup-Specific Relativeand Absolute Effects

Whenever we identified credible evidence that therelative effects vary across distinguishable subgroupsof patients (ie, interaction between the interventionand a patient characteristic), we considered the respec-tive relative effects separately. We then calculatedthe associated absolute effects.

T a b l e 3 — [ S e c t i o n 4 . 1 ] M e t h o d o l o g i c Q u a l i t y o f O b s e r v a t i o

n a l S t u d i e s : C o h o r t S t u d i e s o f t h e T

r e a t m e n t o f H e p a r i n - I n d u c e d T h r o m b o c y t o p e n i a

A u t h o r / Y e a r

I n t e r v e n t i o n / C o n t r o l

S t u d y D e s i g n


S e t t i n g S i m i l a r


T i m e F r a m e S i m i l a r

A d j u s t m e n t

E f f e c t i v e l y B l i n d e d

A s s e s s m e n t o f O u t c o m e s

L o s s t o

F o l l o w - u p

C o m m e n t s

L u b e n o w

e t a l 1 6 / 2 0 0 5

L e p i r u d i n : b o l u s 0 . 4 m g / k g a ;

0 . 1 5 m g / k g

C o h o r t w i t h

h i s t o r i c a l

c o n t r o l s

V e r y

N o t c l o s e

N o n e

N o

N o n e

C a s e s a n d c o n t r o l s b o t h

r e q u i r e d p o s i t i v e t e s t i n g

f o r H I T a n t i b o d i e s .

C o n t r o l : v a r i e d ( d a n a p a r o i d ,

n 5 2

4 ; p h e n o p r o c o u m

o n ,

n 5 2

1 ; o t h e r , n 5 3

0 )

L e w i s

e t a l 1 7 / 2 0 0 3

A r g a t r o b a n : 2 m g / k g p e r m

i n b

( n o b o l u s )

C o h o r t w i t h

h i s t o r i c a l

c o n t r o l s

S o m e w h a t

N o t c l o s e

N o n e

N o

N o n e

H I T a n t i b o d y d a t a f o r c a s e s

w e r e n o t p r o v i d e d .

C o n t r o l : v a r i e d ( t y p i c a l l y

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

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

n )

L e w i s

e t a l 1 8 / 2 0 0 1

A r g a t r o b a n : 2 m g / k g p e r m

i n b

( n o b o l u s )

C o h o r t w i t h

h i s t o r i c a l

c o n t r o l s

V e r y

N o t c l o s e

N o n e

N o

N o n e

S i x t y - fi v e p e r c e n t o f c a s e s a n d

c o n t r o l s t e s t e d p o s i t i v e f o r

H I T a n t i b o d i e s ( r e m a i n d e r

t e s t e d n e g a t i v e o r w e r e n o t

t e s t e d ) .

C o n t r o l : v a r i e d ( t y p i c a l l y

d i s c o n t i n u a t i o n o f h e p a r i n

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

n )

A P T T 5 a c t i v a t e d p a r t i a l t h r o m b o p l a s t i n t i m e ; H I T 5 h e p a r i n - i n d u c e d t h r o m b o c y t o p

e n i a .

a A P T T a d j u s t e d t o 1 . 5 t o 2 . 5 t i m e s b a s e l i n

e A P T T ( o r t h e m e a n l a b o r a t o r y n o r m a l r a n

g e i f t h e b a s e l i n e A P T T w a s u n a v a i l a b l e ) .

b A P T T a d j u s t e d t o 1 . 5 t o 3 . 0 t i m e s b a s e l i n

e A P T T .



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prevention for patients with atrial fibrillation is likelyclose to 50% across risk groups, this translates into anabsolute risk reduction of , 1% per year in the lowest-risk groups and 5% per year in the highest-risk groups.

Even when the relative effect is the same, the abso-lute magnitude of treatment effects may differ inpatients with varying levels of risk. For instance, althoughthe relative risk reduction of warfarin vs aspirin in stroke

Figure 2. GRADE approach to rating quality of evidence. See Figure 1 legend for expansion ofabbreviation.

Table 4 —Strength of the Recommendations Grading System

Grade of RecommendationBenefit vs Risk and

BurdensMethodologic Strength of Supporting

Evidence Implications

Strong recommendation,high-quality evidence (1A)

Benefits clearly outweighrisk and burdens or vice

versa.

Consistent evidence from randomizedcontrolled trials without importantlimitations or exceptionally strongevidence from observational studies.

Recommendation can apply to mostpatients in most circumstances. Furtherresearch is very unlikely to change ourconfidence in the estimate of effect.

Strong recommendation,moderate-qualityevidence (1B)


versa.

Evidence from randomized controlledtrials with important limitations(inconsistent results, methodologicflaws, indirect or imprecise) or verystrong evidence from observationalstudies.

Recommendation can apply to mostpatients in most circumstances.Higher-quality research may well havean important impact on our confidencein the estimate of effect and maychange the estimate.

Strong recommendation,low- or very-low-qualityevidence (1C)


versa.

Evidence for at least one criticaloutcome from observational studies,case series, or randomized controlledtrials, with serious flaws or indirectevidence.

Recommendation can apply to mostpatients in many circumstances.Higher-quality research is likely tohave an important impact on ourconfidence in the estimate of effectand may well change the estimate.

Weak recommendation,high-quality evidence (2A)

Benefits closely balanced with risks and burden.

Consistent evidence from randomizedcontrolled trials without important

limitations or exceptionally strongevidence from observational studies.

The best action may differ dependingon circumstances or patient or societal

values. Further research is very unlikelyto change our confidence in the estimateof effect.

Weak recommendation,moderate-qualityevidence (2B)

Benefits closely balanced with risks and burden.

Evidence from randomized controlledtrials with important limitations(inconsistent results, methodologicflaws, indirect or imprecise) or verystrong evidence from observationalstudies.

Best action may differ depending oncircumstances or patient or societal

values. Higher-quality research may well have an important impact on ourconfidence in the estimate of effect andmay change the estimate.

Weak recommendation,low- or very-low-qualityevidence (2C)

Uncertainty in the estimatesof benefits, risks, andburden; benefits, risk,and burden may beclosely balanced.

Evidence for at least one criticaloutcome from observational studies,case series, or randomized controlledtrials, with serious flaws or indirectevidence.

Other alternatives may be equallyreasonable. Higher-quality research islikely to have an important impact onour confidence in the estimate of effectand may well change the estimate.


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T a b l e 5 — [ S e c t i o n 4 . 1 ] D e s c r i p t i v e T a b l e : R a n d o m i z e d C o n t r o l l e d T

r i a l s o f F o n d a p a r i n u x v s N o F o n d a p a r i n u x f o r t h e T r e a t m e n t o f S u p e r fi c i a l V e i n T h r o m b o s i s

A u t h o r / Y e a r

P a t i e n t s

I n t e r v e n t i o n

C o n t r o l

O u t c o m e s

R e s u l t s

D e c o u s u s e t a l 1 2 ;

C A L I S T O S t u d y

G r o u p / 2 0 1 0

P a t i e n t s a g e d 1 8 y e a r s w i t h a c u t e s y m p t o m a t i c ,

o b j e c t i v e l y c o n fi r m e d S V T o f t h e l e g s

E x c l u s i o n c r i t e r i a :

- S y m p t o m s . 3 w

k

- D V T o r P E a t p r

e s e n t a t i o n

- S V T f o l l o w i n g s c

l e r o t h e r a p y , I V l i n e

- S V T w i t h i n 3 c m

o f t h e s a p h e n o f e m o r a l j u n c t i o n

- S V T w i t h i n t h e p

a s t 3 m o , D V T o r P E w i t h i n t h e p a s t 6 m o

- T r e a t e d f o r c a n c e r w i t h i n t h e p a s t 6 m o

- A n t i t h r o m b o t i c t h e r a p y f o r . 4

8 h o r N S A I D f o r . 7

2 h

f o r c u r r e n t e p i s o d e o f S V T

- L i g a t i o n o r s t r i p p i n g

- M a j o r s u r g e r y w i t h i n 3 m o

- B l e e d i n g r i s k

- P r e g n a n t o r c h i l d b e a r i n g a g e w o m e n n o t u s i n g

r e l i a b l e c o n t r a c e p t i o n

F o n d a p a r i n u x , 2 . 5 m g

s u b c u t a n e o u s o n c e

d a i l y f o r 4 5 d U s e

o f G C S e n c o u r a g e d

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

P l a c e b o

f o r 4 5 d

P r i m a r y e f fi c a c y o u t c o m e :

- C o

m p o s i t e o f s y m p t o m a t i c e v e n t s u p t o d a y 4 7 :

d e a t h f r o m a n y c a u s e , s y m p t o m a t i c D V T o r P E ,

s y m

p t o m a t i c e x t e n s i o n t o t h e s a p h e n o f e m o r a l

j u n c t i o n , r e c u r r e n c e o f S V T

P r i m a r y e f fi c a c y o u t c o m e :

1 3 / 1 , 5 0 2 v s 8 8 / 1 , 5 0 0 ;

R R , 0 . 1 5 ; 9 5 % C I ,

0 . 0 8 - 0 . 2 6

S e c o n d a r y e f fi c a c y o u t c o m e s :

- C o m p o s i t e o f s y m p t o m a t i c e v e n t s u p t o d a y 7 7

- E a c h c o m p o n e n t o f p r i m a r y e f fi c a c y o u t c o m e s

- C o

m p o s i t e o f s y m p t o m a t i c P E o r D V T

- S u r g e r y f o r S V T

C o m p o s i t e o f D V T a n d

P E u p t o d a y 7 7 : 4 / 1 , 5 0 2

v s 2 2 / 1 , 5 0 0 ; R R , 0 . 1 8 ;

9 5 % C I , 0 . 0 6 - 0 . 5 3

S a f e t y o u t c o m e s ( u p t o d a y 4 7 o r u p t o d a y 7 7 ) :

- M a j o r b l e e d i n g

- N o

n m a j o r , m i n o r , t o t a l b l e e d i n g

- A r t e r i a l t h r o m b o e m b o l i c e v e n t

A l l o t h e r e f fi c a c y o u t c o m e s :

P , . 0

5 ; m a j o r b l e e d i n g

b y d a y 4 7 , o n e e v e n t

p e r g r o u p ; R R , 1

G C S 5 g r a d u a t e d c o m p r e s s i o n s t o c k i n g s ;

N S A I D 5 n o n s t e r o i d a l a n t i i n fl a m m a t o r y d r u g ; P E 5 p u l m o n a r y e m b o l i s m ; R R 5 r i s k r a

t i o ; S V T 5 s u p e r fi c i a l v e i n t h r o m b o s i s . S e e

T a b l e 1 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 .

We included control group risks and absoluteeffect estimates for different groups in the sum-maries of effect when (and only when) two conditions

were present. First, we required validated prognosticmodels or, at the very least, credible strategies forclinicians to easily identify higher- and lower-riskpatients. Second, we identified varying risk groupsonly when recommendations differed in strength or

direction between groups. Both conditions were met,for instance, in the atrial fibrillation recommenda-tions in which strong recommendations in favor ofanticoagulation were restricted to the higher-riskpatients.

4.5 Conducting Meta-analyses

When pooled estimates of effects were not avail-able from existing high-quality systematic reviews,

we performed meta-analyses if the data were suffi-ciently homogeneous. When pooling two studies,

we used a fixed-effects model. When three or morestudies were available for generating a pooled esti-mate, we used a random-effects model as the primaryanalysis and a fixed-effects model as a secondaryanalysis. If there were discrepancies between thetwo, we considered the following reasons: If there

was substantial heterogeneity leading to wider CIs with the random-effects model, we considered thatmodel more trustworthy, and if the discrepancy wasdue to a single large dominant study with a resultsubstantially different from smaller studies, we con-sidered the fixed-effects model more trustworthy.

We also assessed statistical heterogeneity using botha x 2 test and I 2 as well as assessed possible explana-tions of heterogeneity considering a priori-generatedhypotheses.22

4.6 Summary Tables

When resources permitted, we used a standardizedapproach for summarizing the evidence and method-ology of individual studies (examples in Tables 1, 2, 5).These summaries appear in the online data supple-ments. Wherever possible, we report nonfatal events(eg, nonfatal stroke) so that there is no overlap with

the number of fatal events reported.For a large number of recommendations, we sum-

marized the quality of the body of evidence (Fig 2)and estimates of relative and absolute effect of alter-native management strategies using the methodsof the GRADE Working Group.23 Evidence Profilessummarize the quality of the body of evidence and

when evidence comes from randomized trials, gener-ally include a presentation of reviewer assessment ofrisk of bias, precision, consistency, directness, andpublication bias associated with each outcome (eg,see Table 2). As specified in GRADE methodology,19



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the overall quality of evidence represents the lowestquality of any critical outcome.

Evidence Profiles can be found in the online datasupplement. The format for these tables was deter-mined through a formal survey of panelists thatevaluated the panelists’ preferences for alternativepresentations and the impact of these presentationson their understanding of the evidence. The text in the

printed version of the AT9 recommendations includesmore succinct Summary of Findings tables (eg, seeTable 624), which include the overall quality assess-ment as well as the relative and absolute effect sizesfor each outcome. Use of an associated computerprogram facilitated the production of the EvidenceProfiles and Summary of Findings tables.25

5.0 Values and Preferences

Making trade-offs between desirable and unde-

sirable consequences of alternative managementstrategies—the fundamental process of makingrecommendations—requires making value and pref-erence judgments. For antithrombotic therapy guide-lines, this trade-off involves, in most instances, areduction in thrombotic events compared with anincrease in bleeding events. Ideally, the values andpreferences applied to this decision would be theaverage values and preferences of the patient popula-tion. We know, however, that patient values for healthoutcomes vary substantially from patient to patient.Knowledge of the extent to which patient values and

preferences vary is one factor in deciding on thestrength of a recommendation. The greater the vari-ability in values and preferences, the more likely a

weak recommendation is appropriate.23 To inform these decisions, we conducted a system-

atic review of the literature bearing on patient valuesand preferences regarding antithrombotic therapy.26 The methodology of conducting such studies remainsto be fully developed, and the area remains under-investigated. Nevertheless, the results of the reviewprovided guidance for the values and preferencesthat we adopted for these guidelines.26

As an additional strategy for achieving meaningful value and preference decisions by each topic paneland to facilitate consistency across articles, we con-ducted a values rating exercise. Topic editors anddeputy editors constructed patient scenarios for keyoutcomes of thrombosis and bleeding relevant to theirarticles. Then informed by the systematic review of

values and preferences, panelists used thesescenarios to rate each outcome from 0 (death) to 100(full health). The mean values of these ratingsguided the trade-offs between thrombotic and bleed-ing events and, thus, the determination of strong

T a b l e 6 — [ S e c t i o n 4 . 6 ] S u m m a r y o f F i n d i n g s T a b l e : P r a s u g r e l 1 A s p i r i n v s C l o p i d o g r e l 1 A s p i r i n i n P a t i e n t s W i t h a R e c e n t A C S

a n d P C I 2 4

A n t i c i p a t e d A b s o l u t e E f f e c t s ( 1 - y T i m e F r a m e )

O u t c o m e s

N o . o f P a r t i c i p a n t s ( S t u d i e s ) , M e a n

F o l l o w - u p

Q u a

l i t y o f t h e E v i d e n c e

( G R A D E )

R e l a t i v e E f f e c t ,

R R ( 9 5 % C I )

R i s k W i t h C l o p i d o g r e l

R i s k D i f f e r e n c e W i t h P r a s u g r e l ( 9 5 % C I )

V a s c u l a r m o r t a l i t y

1 3 , 6 0 8 ( 1 s t u d y ) , 1 4 . 5 m o

M o d e r

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

0 . 8 9 ( 0 . 7 - 1 . 1 2 )

2 4 d e a t h s p e r 1 , 0 0 0 a

3 f e w e r d e a

t h s p e r 1 , 0 0 0 ( f r o m 7 f e w e r

t o 3 m o r e )

N o n f a t a l M I

1 3 , 6 0 8 ( 1 s t u d y ) , 1 4 . 5 m o

H i g h

0 . 7 6 ( 0 . 6 7 - 0 . 8 5 )

9 5 M I p e r 1 , 0 0 0 a

2 2 f e w e r M

I p e r 1 , 0 0 0 ( f r o m 3 3 f e w e r

t o 1 4 f e w

e r )

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

1 3 , 6 0 8 ( 1 s t u d y ) , 1 4 . 5 m o

M o d e r

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

1 . 0 2 ( 0 . 7 1 - 1 . 4 5 )

1 0 s t r o k e s p e r 1 , 0 0 0 a

0 f e w e r s t r o k e s p e r 1 , 0 0 0 ( f r o m 3 f e w e r

t o 5 m o r e

M a j o r e x t r a c r a n i a l b l e e d N o n - C A B G -

r e l a t e d T I M I m a j o r b l e e d i n g

1 3 , 4 5 7 ( 1 s t u d y ) ; m e d i a n , 1 4 . 5 m o

H i g h

1 . 3 2 ( 1 . 0 3 - 1 . 6 8 )

2 2 m a j o r b l e e d s p e r 1 , 0 0 0 a

6 m o r e m a j o r b l e e d s p e r 1 , 0 0 0 ( f r o m

0 m o r e t o 1 2 m o r e )

T h e a n t i c i p a t e d a b s o l u t e e f f e c t i s e x p r e s s e d a s r i s k d i f f e r e n c e ( a n d i t s 9 5 % C I ) a n d i s

b a s e d o n t h e b a s e l i n e r i s k i n t h e c o m p a r i s o

n g r o u p a n d t h e r e l a t i v e e f f e c t o f t h e i n t e r v

e n t i o n ( a n d i t s 9 5 % C I ) . H i g h

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

a t e o f e f f e c t ; m o d e r a t e q u a l i t y , f u r t h e r r e s e a r c h i s l i k e l y t o h a v e a n i m p o r t a n t i m p a c t o n

o u r c o n fi d e n c e i n t h e e s t i m a t e

o f e f f e c t a n d m a y c h a n g e t h e e s t i m a t e ; l o w q u a l i t y , f u r t h e r r e s e a r c h i s v e r y l i k e l y t o h a v e a n i m p o r t a n t i m p a c t o n o u r c o n fi d e n c e

i n t h e e s t i m a t e o f e f f e c t a n d i s l i k e l y t o c h a n g e t h e e s t i m a t e ; a n d v e r y - l o w

q u a l i t y , w e a r e v e r y u n c e r t a i n a b o u t t h e

e s t i m a t e . A C S 5 a c u t e c o r o n a r y s y n d r o m e

s ; C A B G 5 c o r o n a r y a r t e r y b y p a s s g r a f t ; G

R A D E

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