Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

APPENDIX A. SEARCH STRATEGIES 

Table A-1. Search strategy for RCTs (PubMed, February 2012) 

Step Category Terms Result 

1 Newer 

anticoagulants 

dabigatran OR desirudin OR ximelagatran OR edoxaban OR rivaroxaban 

OR apixaban OR betrixaban OR YM150 OR razaxaban OR “factor Xa 

inhibitors” OR “factor Xa inhibitor” OR “fxa inhibitors” OR “fxa inhibitor” 

OR “direct thrombin inhibitor” OR “direct thrombin inhibitors” OR DTIs OR 

“novel anticoagulants” OR “new anticoagulants” OR “novel anticoagulant” 

OR “new anticoagulant” OR “newer anticoagulants” OR “newer 

anticoagulant” AND 

3289 

2 Disorders of 

interest 

“Venous Thrombosis”[Mesh:noexp] OR “Venous 

Thromboembolism”[Mesh] OR “Pulmonary Embolism”[Mesh] OR “Atrial 

Fibrillation”[Mesh] OR “Heart Valve Prosthesis”[Mesh] OR “Aortic 

Valve”[Mesh] OR “Mitral Valve”[Mesh] OR deep vein thrombosis OR AF 

OR dvt OR PE OR pulmonary embolism OR mechanical heart valve OR 

mechanical heart valves OR “mechanical valve” OR “mechanical valves” 

OR “mechanical mitral” OR “mechanical aortic” OR thromboembolism 

AND 

217463 

3 Study designs randomized controlled trial[Publication Type] OR random* 711597 

4 Combine results 

and apply limits 

#1 AND #2 AND #3 

English, Publication Date from 2001 to 2011 

320 

Table A-2. Search strategy for observational studies (February 2012)
	

Step Category Terms Results 

1 Newer 

anticoagulants 

Dabigatran[tiab] OR desirudin[tiab] OR edoxaban[tiab] OR 

rivaroxaban[tiab] OR apixaban[tiab] OR betrixaban[tiab] OR YM150[tiab] 

OR razaxaban[tiab] OR “dabigatran etexilate”[Supplementary Concept] 

OR “desirudin”[Supplementary Concept] OR “edoxaban”[Supplementary 

Concept] OR “rivaroxaban”[Supplementary Concept] OR 

“apixaban”[Supplementary Concept] OR “betrixaban”[Supplementary 

Concept] OR “razaxaban hydrochloride”[Supplementary Concept] 

OR “factor Xa, Glu-Gly-Arg-”[Supplementary Concept] OR 

“KFA1411”[Supplementary Concept] AND 

1112 

2 Disorders of 

interest 

“Venous Thrombosis”[Mesh:noexp] OR “Venous Thromboembolism”[Mesh] 

OR “Pulmonary Embolism”[Mesh] OR “Atrial Fibrillation”[Mesh] OR 

“Heart Valve Prosthesis”[Mesh] OR “Aortic Valve”[Mesh] OR “Mitral 

Valve”[Mesh] OR “deep vein thrombosis”[tiab] OR “atrial fibrillation”[tiab] 

OR dvt[tiab] OR “pulmonary embolism”[tiab] OR “mechanical heart 

valve”[tiab] OR “mechanical heart valves”[tiab] OR “mechanical 

valve”[tiab] OR “mechanical valves”[tiab] OR “mechanical aortic”[tiab] OR 

thromboembolism[tiab] AND 

145374 

3 Study designs (“evaluation studies”[Publication Type] OR “evaluation studies as 

topic”[MeSH Terms] OR “evaluation study”[tiab] OR evaluation studies[tiab] 

OR “intervention studies”[MeSH Terms] OR “intervention study”[tiab] OR 

“intervention studies”[tiab] OR “case-control studies”[MeSH Terms] OR 

“case-control”[tiab] OR “cohort studies”[MeSH Terms] OR cohort[tiab] 

OR “longitudinal studies”[MeSH Terms] OR “longitudinal”[tiab] OR 

longitudinally[tiab] OR “prospective”[tiab] OR prospectively[tiab] OR 

“retrospective studies”[MeSH Terms] OR “retrospective”[tiab] OR “follow 

up”[tiab] OR “comparative study”[Publication Type] OR “comparative 

study”[tiab] OR “Case Reports”[Publication Type] OR “case report”[tiab] 

OR “case series”[tiab] OR observational[tiab]) NOT (Editorial[ptyp] OR 

Letter[ptyp] OR Comment[ptyp]) 

4927238 

59
 
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Step Category Terms Results 

3 Combine results 

and apply limits 

#1 AND #2 AND #3 

Publication Date from 2001 to 2012 

278 

4 Additional study 

designs 

“Case Reports”[Publication Type] OR “Case-Control Studies”[Mesh]) OR 

“Cohort Studies”[Mesh] OR “case report”[tiab] OR cohort[tiab] OR casecontrol[tiab] OR “case series”[tiab] 

2841521 

5 Combine results 

and apply limits 

#1 AND #2 AND #4 Publication Date from 2001 to 2012 47 

Table A-3. Search strategy for systematic reviews (PubMed, February 2012)
	

Step Category Terms Results 

1 New oral 

anticoagulants 

Dabigatran[tiab] OR desirudin[tiab] OR edoxaban[tiab] OR 

rivaroxaban[tiab] OR apixaban[tiab] OR betrixaban[tiab] OR YM150[tiab] 

OR razaxaban[tiab] OR “dabigatran etexilate”[Supplementary Concept] 

OR “desirudin”[Supplementary Concept] OR “edoxaban”[Supplementary 

Concept] OR “rivaroxaban”[Supplementary Concept] OR 

“apixaban”[Supplementary Concept] OR “betrixaban”[Supplementary 

Concept] OR “razaxaban hydrochloride”[Supplementary Concept] 

OR “factor Xa, Glu-Gly-Arg-”[Supplementary Concept] OR 

“KFA1411”[Supplementary Concept] 

1121 

2 Disorders of 

interest 

“Venous Thrombosis”[Mesh:noexp] OR “Venous Thromboembolism”[Mesh] 

OR “Pulmonary Embolism”[Mesh] OR “Atrial Fibrillation”[Mesh] OR 

“Heart Valve Prosthesis”[Mesh] OR “Aortic Valve”[Mesh] OR “Mitral 

Valve”[Mesh] OR “deep vein thrombosis”[tiab] OR “atrial fibrillation”[tiab] 

OR dvt[tiab] OR “pulmonary embolism”[tiab] OR “mechanical heart 

valve”[tiab] OR “mechanical heart valves”[tiab] OR “mechanical 

valve”[tiab] OR “mechanical valves”[tiab] OR “mechanical aortic”[tiab] OR 

thromboembolism[tiab] 

145502 

3 Study designs Systematic[sb] 170174 

3 Combine results 

and apply limits

 Search #1 AND #2 AND #3 

Publication Date from 2001 to 2012 

64 

60
 
Warfarin and Newer Oral Anticoagulants: 

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APPENDIX B. STUDY SELECTION FORM 

Criteria for Inclusion and Exclusion of RCTs 

Inclusion criteria: 

•		An RCT or a secondary data analysis from an RCT comparing a newer anticoagulant to 

an eligible comparator (warfarin and LMWH are the two comparators we are accepting 

for the various key questions) 

•		Sample population with history of chronic nonvalvular AF, deep venous 

thromboembolism, or mechanical valve replacement. Atrial fibrillation may be assessed 

by any accepted threshold on any valid diagnostic tool (e.g., electrocardiogram and/or 

echocardiogram). 

•		Sample population ≥18 years of age 

•		Outpatient setting (community clinic, medical clinic or office, or transitioning from 

inpatient for acute treatment to long-term outpatient management) 

•		Random allocation to the intervention groups 

•		Reports at least one of the included outcomes: 

○		 KQs 1–3: The main outcome is a thromboembolic event. Thromboembolic 

events must be documented radiologically and produce clinical symptoms. 

Asymptomatic thromboembolism (e.g., detected on surveillance imaging) will not 

be included. 

○		 KQs 1–3: Other outcomes are mortality, health-related quality of life, and patient 

treatment experience—the latter two measured by a validated instrument. 

○		 KQ 4: Adverse effects will be specific to the interventions examined and will 

include bleeding complications, myocardial infarction, and gastrointestinal 

adverse effects. 

•		Study duration of at least 6 months (KQ 2 acute treatment) or at least 12 months (KQ 1, 

KQ 2 chronic treatment, KQ 3, KQ 4) 

•		Peer-reviewed publication 

Exclusion criteria: 

•		Non-English language publication

•		Cross-sectional studies 

•		Pregnant population

•		Studies with sample size <50

•		Studies with <6 months postrandomization outcomes 

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Eligibility Criteria for Observational Studies

• Patients: chronic atrial fibrillation or VTE treated with an oral DTI or FXa inhibitor 

• Comparator: none or adjusted-dose warfarin

• Outcomes: adverse events 

• Timing: ≥ 3months use 

• Setting: any outpatient

• Study designs: 

○ Comparative: secondary analyses from RCTs (including patient level metaanalysis), cohort studies (prospective or retrospective-including analyses of claims 

databases), case control, cross-sectional. 

○ Noncomparative: case-reports, case-series. 

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APPENDIX C. EXCLUDED STUDIES 

All citations listed in Tables C-1 and C-2 were reviewed in their full-text version and excluded 

for the reason indicated. An alphabetical reference list follows each table. 

Table C-1. Excluded RCTs with reasons 

Reference 

Not full 

publication, 

peer-reviewed, 

or primary data 

Not study 

population of 

interest 

New drug or 

comparator not 

of interest 

No relevant 

outcomes 

reported at ≥6 

months 

Adams 2005 X 

Ageno 2005 X 

Agnelli 2009 X 

Amadeus Investigators 2008 X 

Anonymous 2004 X 

Anonymous 2009 X 

Berry 2005 X 

Botticelli Investigators 2008 X 

Buller 2007 X 

Buller 2007 X 

Buller 2007 X 

Camm 2009 X 

Chung 2011 X 

Cohen 2006 X 

Connolly 2011 X 

Connolly 2010 X 

Dahl 2010 X 

Deitcher 2006 X 

EAFT Study Group 1993 X 

Eriksson 2005 X 

Eriksson 2003 X 

Fiessinger 1996 X 

Halperin 2005 X 

Halperin 2005 X 

Hankey 2004 X 

Hankey 2009 X 

Hankey 2011 X 

Harenberg 2002 X 

Hart 1999 X 

Heidbuchel 2010 X 

Hull 2006 X 

Kaul 2005 X 

Kubitza 2006 X 

Kwok 2004 X 

Lee 2003 X 

Lip 2009 X 

Lopez-Beret 2001 X 

Meyer 2002 X 

Olsson 2010 X 

Paikin 2011 X 

Party 2010 X 

Persist Investigators 2004 X 

Petersen 2003 X 

Prandoni 2010 X 

Prins 2009 X 

Rother 2010 X 

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Reference 

Not full 

publication, 

peer-reviewed, 

or primary data 

Not study 

population of 

interest 

New drug or 

comparator not 

of interest 

No relevant 

outcomes 

reported at ≥6 

months 

Salam 2004 X 

Schulman 2005 X 

Segal 2001 X 

SPIAF Investigators 1996 X 

SPIAF Investigators 1991 X 

Taylor 2001 X 

Wahlander 2006 X 

Wallentin 2010 X 

Weitz 2010 X 

Weitz 2010 X 

Abbreviations: EAFT = European Atrial Fibrillation Trial; SPIAF = Stroke Prevention in Atrial Fibrillation 

LIST OF EXCLUDED RCTs 

Adams HP. Prevention of embolism among patients 

with atrial fibrillation. Curr Neurol Neurosci Rep. 

2005;5(1):9-12. 

Ageno W, Turpie AG. Clinical trials of deep vein 

thrombosis prophylaxis in medical patients. Clin 

Cornerstone. 2005;7(4):16-22. 

Agnelli G, Eriksson BI, Cohen AT, et al. Safety 

assessment of new antithrombotic agents: lessons from 

the EXTEND study on ximelagatran. Thromb Res. 

2009;123(3):488-97. 

Amadeus Investigators. Comparison of idraparinux 

with vitamin K antagonists for prevention of 

thromboembolism in patients with atrial fibrillation: 

a randomised, open-label, non-inferiority trial. The 

Lancet. 2008;371(9609):315-321. 

Anonymous. Results of THRIVE treatent study show 

that ximelagatran is safe and effective against throbosis. 

J Support Oncol. 2004;2(1):56. 

Anonymous. Dabigatran: safer, more effective 

and easier to use than warfarin. Cardiovasc J Afr. 

2009;20(5):311-2. 

Berry C, Norrie J, McMurray JJ. Ximelagatran 

compared with warfarin for the prevention of systemic 

embolism and stroke. An imputed placebo analysis. 

Cardiovasc Drugs Ther. 2005;19(2):149-51. 

Botticelli Investigators. Efficacy and safety of the oral 

direct factor Xa inhibitor apixaban for symptomatic 

deep vein thrombosis. The Botticelli DVT dose-ranging 

study. Journal of thrombosis and haemostasis : JTH; 

2008:1313-8. 

Buller HR, Cohen AT, Davidson B, et al. Idraparinux 

versus standard therapy for venous thromboembolic 

disease. New England Journal of Medicine. 

2007;357(11):1094-1104. 

Buller HR, Cohen AT, Davidson B, et al. Extended 

prophylaxis of venous thromboembolism with 

idraparinux. New England Journal of Medicine. 

2007;357(11):1105-1112. 

Buller HR, Cohen AT, Davidson B, et al. Idraparinux 

versus standard therapy for venous thromboembolic 

disease. N Engl J Med. 2007;357(11):1094-104. 

Camm AJ. The RE-LY study: Randomized Evaluation 

of Long-term anticoagulant therapY: Dabigatran vs. 

warfarin. European Heart Journal. 2009;30(21):2554-

2555. 

Chung N, Jeon HK, Lien LM, et al. Safety of edoxaban, 

an oral factor Xa inhibitor, in Asian patients with 

non-valvular atrial fibrillation. Thromb Haemost. 

2011;105(3):535-44. 

Cohen AT, Davidson BL, Gallus AS, et al. Efficacy 

and safety of fondaparinux for the prevention of 

venous thromboembolism in older acute medical 

patients: randomised placebo controlled trial. BMJ. 

2006;332(7537):325-327. 

Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban 

in patients with atrial fibrillation. N Engl J Med. 

2011;364(9):806-17. 

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly 

identified events in the RE-LY trial. N Engl J Med. 

2010;363(19):1875-6. 

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Dahl OE, Huisman MV. Dabigatran etexilate: advances 

in anticoagulation therapy. Expert Rev Cardiovasc Ther. 

2010;8(6):771-4. 

Deitcher SR, Kessler CM, Merli G, et al. Secondary 

prevention of venous thromboembolic events in patients 

with active cancer: enoxaparin alone versus initial 

enoxaparin followed by warfarin for a 180-day period. 

Clin Appl Thromb Hemost. 2006;12(4):389-96. 

EAFT (European Atrial Fibrillation Trial) Study 

Group. Secondary prevention in non-rheumatic atrial 

fibrillation after transient ischaemic attack or minor 

stroke. Lancet. 1993;342(8882):1255-62. 

Eriksson H, Lundstrom T, Wahlander K, et al. 

Prognostic factors for recurrence of venous 

thromboembolism (VTE) or bleeding during longterm secondary prevention of VTE with ximelagatran. 

Thromb Haemost. 2005;94(3):522-7. 

Eriksson H, Wahlander K, Gustafsson D, et al. A 

randomized, controlled, dose-guiding study of the 

oral direct thrombin inhibitor ximelagatran compared 

with standard therapy for the treatment of acute deep 

vein thrombosis: THRIVE I. J Thromb Haemost. 

2003;1(1):41-7. 

Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al. 

Once-daily subcutaneous dalteparin, a low molecular 

weight heparin, for the initial treatment of acute deep 

vein thrombosis. Thromb Haemost. 1996;76(2):195-9. 

Halperin JL. Anticoagulation for atrial fibrillation in the 

elderly. Am J Geriatr Cardiol. 2005;14(2):81-6. 

Halperin JL. Ximelagatran: oral direct thrombin 

inhibition as anticoagulant therapy in atrial fibrillation. 

J Am Coll Cardiol. 2005;45(1):1-9. 

Hankey GJ. At last, a RE-LYable alternative to warfarin 

for atrial fibrillation. Int J Stroke. 2009;4(6):454-5. 

Hankey GJ, Eikelboom JW. Dabigatran etexilate: 

a new oral thrombin inhibitor. Circulation. 

2011;123(13):1436-50. 

Hankey GJ, Klijn CJ, Eikelboom JW. Ximelagatran or 

warfarin for stroke prevention in patients with atrial 

fibrillation? Stroke. 2004;35(2):389-91. 

Harenberg J, Ingrid J, Tivadar F. Treatment of venous 

thromboembolism with the oral thrombin inhibitor, 

ximelagatran. Isr Med Assoc J. 2002;4(11):1003-5. 

Hart RG, Benavente O, McBride R, et al. 

Antithrombotic therapy to prevent stroke in patients 

with atrial fibrillation: a meta-analysis. Ann Intern Med. 

1999;131(7):492-501. 

Heidbuchel H, Verhamme P. Dabigatran for stroke 

prevention in atrial fibrillation: from RE-LY to daily 

clinical practice. Acta Cardiol. 2010;65(5):491-7. 

Hull RD, Pineo GF, Brant RF, et al. Long-term 

low-molecular-weight heparin versus usual care in 

proximal-vein thrombosis patients with cancer. Am J 

Med. 2006;119(12):1062-72. 

Kaul S, Diamond GA, Weintraub WS. Trials and 

tribulations of non-inferiority: the ximelagatran 

experience. J Am Coll Cardiol. 2005;46(11):1986-95. 

Kubitza D, Haas S. Novel factor Xa inhibitors for 

prevention and treatment of thromboembolic diseases. 

Expert Opin Investig Drugs. 2006;15(8):843-55. 

Kwok L, Boucher M. Ximelagatran for prevention and 

treatment of venous thromboembolism. Issues Emerg 

Health Technol. 2004(57):1-4. 

Lee AY, Levine MN, Baker RI, et al. Low-molecularweight heparin versus a coumarin for the prevention 

of recurrent venous thromboembolism in patients with 

cancer. N Engl J Med. 2003;349(2):146-53. 

Lip GY, Rasmussen LH, Olsson SB, et al. Oral direct 

thrombin inhibitor AZD0837 for the prevention 

of stroke and systemic embolism in patients with 

non-valvular atrial fibrillation: a randomized doseguiding, safety, and tolerability study of four doses 

of AZD0837 vs. vitamin K antagonists. Eur Heart J. 

2009;30(23):2897-907. 

Lopez-Beret P, Orgaz A, Fontcuberta J, et al. Low 

molecular weight heparin versus oral anticoagulants in 

the long-term treatment of deep venous thrombosis. J 

Vasc Surg. 2001;33(1):77-90. 

Meyer G, Marjanovic Z, Valcke J, et al. Comparison 

of low-molecular-weight heparin and warfarin for the 

secondary prevention of venous thromboembolism in 

patients with cancer: a randomized controlled study. 

Arch Intern Med. 2002;162(15):1729-35. 

Olsson SB, Rasmussen LH, Tveit A, et al. Safety 

and tolerability of an immediate-release formulation 

of theoral direct thrombin inhibitor AZD0837 in 

the prevention of stroke and systemic embolism in 

patients with atrial fibrillation. Thromb Haemost. 

2010;103(3):604-12. 

Paikin JS, Haroun MJ, Eikelboom JW. Dabigatran for 

stroke prevention in atrial fibrillation: the RE-LY trial. 

Expert Rev Cardiovasc Ther. 2011;9(3):279-86. 

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Paty I, Trellu M, Destors JM, et al. Reversibility of 

the anti-FXa activity of idrabiotaparinux (biotinylated 

idraparinux) by intravenous avidin infusion. J Thromb 

Haemost. 2010;8(4):722-9. 

Persist Investigators. A novel long-acting synthetic 

factor Xa inhibitor (SanOrg34006) to replace warfarin 

for secondary prevention in deep vein thrombosis. A 

Phase II evaluation. J Thromb Haemost. 2004;2(1):47-

53. 

Petersen P, Grind M, Adler J. Ximelagatran versus 

warfarin for stroke prevention in patients with 

nonvalvular atrial fibrillation. SPORTIF II: a doseguiding, tolerability, and safety study. J Am Coll 

Cardiol. 2003;41(9):1445-51. 

Prandoni P, Taher A. Insights from the dabigatran 

versus warfarin trial in patients with venous 

thromboembolism (the RE-COVER trial). Expert Opin 

Pharmacother. 2010;11(6):1035-7. 

Prins MH, Guillemin I, Gilet H, et al. Scoring 

and psychometric validation of the Perception of 

Anticoagulant Treatment Questionnaire (PACTQ(copyright)). Health and Quality of Life Outcomes. 

2009;7. 

Rother J, Crijns H. Prevention of stroke in patients 

with atrial fibrillation: the role of new antiarrhythmic 

and antithrombotic drugs. Cerebrovasc Dis. 

2010;30(3):314-22. 

Salam AM. Ximelagatran for stroke prevention in atrial 

fibrillation. Therapy; 2004:49-52. 

Schulman S, Lundstrom T, Walander K, et al. 

Ximelagatran for the secondary prevention of venous 

thromboembolism: a complementary follow-up 

analysis of the THRIVE III study. Thromb Haemost. 

2005;94(4):820-4. 

Segal JB, McNamara RL, Miller MR, et al. 

Anticoagulants or antiplatelet therapy for nonrheumatic atrial fibrillation and flutter. Cochrane 

Database of Systematic Reviews. 2001(1). 

Stroke Prevention in Atrial Fibrillation Investigators. 

Stroke Prevention in Atrial Fibrillation Study Final 

Results. Circulation. 1991;84(2):527-39.
	

Stroke Prevention in Atrial Fibrillation Investigators. 

Bleeding During Antithrombotic Therapy in 

Patients With Atrial Fibrillation. Arch Intern Med. 

1996;156(4):409-16. 

Taylor FC, Cohen H, Ebrahim S. Systematic review 

of long term anticoagulation or antiplatelet treatment 

in patients with non-rheumatic atrial fibrillation. BMJ. 

2001;322(7282):321-6. 

Wahlander K, Eriksson H, Lundstrom T, et al. Risk 

of recurrent venous thromboembolism or bleeding 

in relation to thrombophilic risk factors in patients 

receiving ximelagatran or placebo for long-term 

secondary prevention of venous thromboembolism. 

British Journal of Haematology; 2006:68-77. 

Wallentin L, Ezekowitz MD, Eikelboom J, et al. 

Efficacy and safety of dabigatran compared to warfarin 

at different levels of INR control for stroke prevention 

in 18,113 patients with atrial fibrillation in the RE-LY 

trial. Circulation. 2010;120(21):2158. 

Weitz JI, Cao C, Eriksson BI, et al. A dose-finding study 

with TAK-442, an oral factor Xa inhibitor, in patients 

undergoing elective total knee replacement surgery. 

Thromb Haemost. 2010;104(6):1150-7. 

Weitz JI, Connolly SJ, Patel I, et al. Randomised, 

parallel-group, multicentre, multinational phase 2 study 

comparing edoxaban, an oral factor Xa inhibitor, with 

warfarin for stroke prevention in patients with atrial 

fibrillation. Thromb Haemost. 2010;104(3):633-41. 

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Table C-2. Excluded observational studies 

Reference Background 

only 

Not full 

publication 

Not study 

population of 

interest 

No relevant 

outcomes 

(adverse 

effects) 

reported at >2 

weeks from 

drug initiation 

Not good 

quality 

Aalbers 2010 X 

Anonymous 2011 X 

Baruch 2011 X 

Beyer-Westendorf 2011 X 

Bovio 2011 X 

Camm 2009 X 

Coleman 2012 X 

Cotton 2011 X 

Eerenberg 2011 X 

Gerotziafas 2005 X 

Jacobs 2012 X 

Kaeberich 2011 X 

Lip 2010 

Loke 2011 X 

McKellar 2011 X 

Poultside 2012 X 

Roskell 2010 X 

Tzeis 2011 X 

Watanabe 2012 X 

LIST OF EXCLUDED OBSERVATIONAL STUDIES
 

Aalbers J. Rivaroxaban equals warfarin treatment 

in atrial fibrillation patients at high risk of stroke. 

Cardiovasc J Afr. 2010;21(6):342-3. 

Anonymous. New insights and results from the RE-LY 

trial. Cardiovasc J Afr. 2011;22(5):284-6. 

Baruch L, Sherman O. Potential inaccuracy of pointof-care INR in dabigatran-treated patients. Ann 

Pharmacother. 2011;45(7-8):e40. 

Beyer-Westendorf J, Buller H. External and internal 

validity of open label or double-blind trials in oral 

anticoagulation: better, worse or just different? J 

Thromb Haemost. 2011;9(11):2153-8. 

Bovio JA, Smith SM, Gums JG. Dabigatran etexilate: 

a novel oral thrombin inhibitor for thromboembolic 

disease. Ann Pharmacother. 2011;45(5):603-14. 

Camm. Dabigatran: safer, more effective and easier to 

use than warfarin. Cardiovasc J Afr. 2009;20(5):311-2. 

Coleman CI, Sobieraj DM, Winkler S, et al. Effect of 

pharmacological therapies for stroke prevention on 

major gastrointestinal bleeding in patients with atrial 

fibrillation. Int J Clin Pract. 2012;66(1):53-63. 

Cotton BA, McCarthy JJ, Holcomb JB. Acutely 

injured patients on dabigatran. N Engl J Med. 

2011;365(21):2039-40. 

Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. 

Reversal of rivaroxaban and dabigatran by prothrombin 

complex concentrate: a randomized, placebo-controlled, 

crossover study in healthy subjects. Circulation. 

2011;124(14):1573-9. 

Gerotziafas GT, Samama MM. Heterogeneity of 

synthetic factor Xa inhibitors. Curr Pharm Des. 

2005;11(30):3855-76. 

Jacobs JM, Stessman J. Dabigatran: Do We Have 

Sufficient Data?: Comment on “Dabigatran Association 

With Higher Risk of Acute Coronary Events”. Arch 

Intern Med. 2012. 

Kaeberich A, Reindl I, Raaz U, et al. Comparison of 

unfractionated heparin, low-molecular-weight heparin, 

low-dose and high-dose rivaroxaban in preventing 

thrombus formation on mechanical heart valves: 

results of an in vitro study. J Thromb Thrombolysis. 

2011;32(4):417-25. 

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Lip GY, Lane DA. Does warfarin for stroke 

thromboprophylaxis protect against MI in atrial 

fibrillation patients? Am J Med. 2010;123(9):785-9. 

Loke YK, Kwok CS. Dabigatran and rivaroxaban for 

prevention of venous thromboembolism--systematic 

review and adjusted indirect comparison. J Clin Pharm 

Ther. 2011;36(1):111-24. 

McKellar SH, Abel S, Camp CL, et al. Effectiveness 

of dabigatran etexilate for thromboprophylaxis of 

mechanical heart valves. J Thorac Cardiovasc Surg. 

2011;141(6):1410-6. 

Poultsides LA, Gonzalez Della Valle A, Memtsoudis 

SG, et al. Meta-analysis of cause of death 

following total joint replacement using different 

thromboprophylaxis regimens. J Bone Joint Surg Br. 

2012;94(1):113-21. 

Roskell NS, Lip GY, Noack H, et al. Treatments for 

stroke prevention in atrial fibrillation: a network metaanalysis and indirect comparisons versus dabigatran 

etexilate. Thromb Haemost. 2010;104(6):1106-15. 

Tzeis S, Andrikopoulos G. Novel Anticoagulants for 

Atrial Fibrillation: A Critical Appraisal. Angiology. 

2011. 

Watanabe M, Siddiqui FM, Qureshi AI. Incidence 

and management of ischemic stroke and intracerebral 

hemorrhage in patients on dabigatran etexilate 

treatment. Neurocrit Care. 2012;16(1):203-9. 

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75

APPENDIX D. SAMPLE DATA EXTRACTION FORMS

              

                  

                 

 

 

 

 

 

Warfarin and Newer Oral Anticoagulants: 

Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program 

APPENDIX D. SAMPLE DATA EXTRACTION FORMS 

Elements abstracted from RCTs 

Study abstracted (Author, year, ID#) 

Companion Study Ref IDs (Author, Year) 

Form 1 

Study Sites 

Single Center Multicenter Not reported/unclear 

Geographical Location 

Single Center: 

Enter City and State (if U.S.); Country (If outside the U.S.).
 

Multicenter:
 

Enter number of sites. Enter NR, if not reported.
 

Select all applicable geographical locations.
 

U.S. Canada UK Europe S. America C. America Asia 

Africa Australia/NZ. Middle East Not reported/Unclear Other 

Funding Source 

Check all that apply:
 

Government Private Foundation Industry Not Reported Other
 

69
 
 

 

 

 

 

Study Design 

1. Patient Level RCT 

2. Other 

Comparator Setting (check all that apply): 

Specialized anticoagulation clinic 

Other 

Not 

Reported/unclear 

Enrollment Approach 

Check all that apply: 

Consecutive patients 

Convenience sample 

Other 

Not 

Reported/unclear 

Study Inclusion and Exclusion Criteria 

1) Age range (years) 

2) Diagnosis 

DVT/PE 

Symptomatic? 

Yes No 

       Warfarin and Newer Oral Anticoagulants: 


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70
 
      

 

 

 

 

 

 

 

 

 

 

Objectively confirmed? 

Yes No 

Afib
 

EKG?
 

Yes No 

3) Intended duration of Anticoagulation therapy? (check one choice) 

Choose an item.
 

Check all exclusion criteria used in the study (check all that apply) 

Asymptomatic 

Yes No 

Alcohol or Drug Abuse 

Upper age limit Age 

Medical instability Type 

Anemia (give cut-off) 

Antiplatelet treatment 

ASA (give dosage) 

Clopidogrel 

NSAIDS 

Dipyridamole/ASA 

Clinically significant liver disease 

transaminase study threshold 

High risk of bleeding Define: 

71
 

Warfarin and Newer Oral Anticoagulants: 


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Clinically significant kidney disease 

eGFR (ml/min) study threshold 

Platelet count (threshold) 

 

 

Heparin (unfractionated) 

LMWH 

ANTICOAGULATION TREATMENT 

Yes No Acute Treatment 

“Duration of acute treatment” # days 

 

 

 

Yes No d) Were there dose modifications for sub-populations 

72
 

Warfarin and Newer Oral Anticoagulants: 


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Study Enrollment/Study Completion 

Note: Patients who are eligible, but refuse participation should be counted in the “eligible" 

number. 

Assessed for eligibility (N): 

Eligible (N):
 

Randomized (N):
 

Completed follow-up (N): 

Comments: 

Newer Anticoagulant Drug and Standard dosing 

a) Drug Name: Choose an item. 

b) Dose mg
 

c) Frequency Choose an item.
 
 

      

 

 

 

 

 

Warfarin and Newer Oral Anticoagulants: 

Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program 

Newer Anticoagulant intended duration of treatment. 

Choose an item. 

If others: 

Comparator Anticoagulant Drug and Dosing 

a) Comparator Drug Name Choose an item. 

b) If a=adjusted dose Warfarin, then INR range low 

high 

If a= any other answer, then Dose mg 

c) Frequency Choose an item. 

Comparator Anticoagulant intended duration of treatment. 

Choose an item. 

Visit frequency monitoring 

On average at least monthly? 

Yes No 

73
 
      

 

Warfarin and Newer Oral Anticoagulants: 


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Form 2 

Baseline Characteristics 

Dichotomous variables 

Primary AC Comparator 1 Comparator 2 

Intervention Choose an item. Choose an item. 

Choose an item. 

N= N= N= 

GENDER 

Female 

Not 

reported 

Male 

Not 

reported 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

White 

Not 

reported 

N= 

%= 

N= 

%= 

N= 

%= 

RACE 

Blacks 

Not 

reported 

N= 

%= 

N= 

%= 

N= 

%= 

74
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

for the Long‐term Prevention and Treatment of Arterial and

Venous Thromboembolism Evidence‐based S nthesis

81

              

                  

                 

 

 

Warfarin and Newer Oral Anticoagulants: 


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y Program

RACE 

Latino/Hispanic 

Asian 

Not 

reported 

Not 

reported 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

RACE 

Other * 

(includes Native 

American, Pacific 

Islander, etc.) 

Not 

reported 

N= 

%= 

N= 

%= 

N= 

%= 

Antiplatelet 

drug use 

ASA (>80 

mg daily) 

Not 

reported 

N= 

%= 

N= 

%= 

N= 

%= 

Clopidogrel 

Not 

reported 

N= 

%= 

N= 

%= 

N= 

%= 

75
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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82

              

                  

                 

 

 

N= N= N= 

NSAIDS 

%= %= %= Not
 

reported
 

Aggrenox 

N= N= N=

Antiplatelet Not

drug use
 reported %= %= %= 

N= N= N= 

Dipyridamole 

%= %= %= Not
 

reported
 

N= N= N= 

History of Ischemic 

heart disease
 %= %= %= 

Define: ischemic
	

OR
	

angina 

History of OR

acute coronary
	

syndrome (ACS)
	

heart disease 

Not
 

reported
 

Warfarin and Newer Oral Anticoagulants: 


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76
 
      

 

 

 

 

Impaired 

Renal 

Function 

Define: Moderate 

Define: Severe 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

N= 

%= 

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

Not 

reported 

Comments: 

Continuous variables 

Primary AC Intervention 

Choose an item. 

N= 

Comparator 1 

Choose an item. 

N= 

Comparator 2 

Choose an item. 

N= 

Age (years) 

Not 

reported 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

eGFR/ 

Creatinine 

Clearance (mL/min) 

Not 

reported 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

Obesity? 

Choose an item. 

Not 

reported 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

Choose an item. 

77
 
      

 

 

 

 

Time from index 

event 

Not 

Choose an item. Choose an item. Choose an item. 

reported Choose an item. Choose an item. Choose an item. 

Comments: 

Do these key questions apply to this article, yes/no? 

KQ 1: 

For patients with chronic nonvalvular AF, what is the comparative effectiveness of long-term 

anticoagulation using newer anticoagulants versus warfarin on stroke incidence, mortality, 

health-related quality of life (HRQOL), and patient treatment experience? 

Yes No 

KQ 2:

 For patients with venous thromboembolism, are there differential effects of newer 

anticoagulants versus warfarin or low molecular weight heparins (LMWHs) on recurrent 

thromboembolism, mortality, HRQOL, and patient treatment experience? 

Yes No 

KQ3 does not appear because no studies of mechanical heart valves. 

KQ 4: 

When used for long-term anticoagulation treatment, what is the nature and frequency of adverse 

effects for newer anticoagulants versus warfarin? 

Yes No 

Considering all baseline characteristics, are there significant baseline imbalances between the 

groups? 

Yes No 

Comments: 

Warfarin and Newer Oral Anticoagulants: 


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78
 
      

 

 

 

 

 

 

 

 

 

Form 3a: Atrial Fibrillation 

Risk factor screen type 

CHADS 2 CHADS 2 VASC No CHADS 

Comparative 

Analysis 

Choose an 

item. 

Primary AC 

Intervention 

Choose an item. 

N= 

Comparator 1 

Choose an item. 

N= 

Comparator 2 

Choose an item. 

N= 

Comparative analysis 

New vs Comp 

Comp vs New 

CHADS total 

score 

Not 

reported 

Mean 

SD 

Mean 

SD 

Mean 

SD 

Choose an item. 

Choose an item. 

CHADS 

score=1 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

CHADS 

score=2 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

CHADS 

score=3 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

CHADS score 

>=4 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 


 

Warfarin and Newer Oral Anticoagulants: 


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79
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86

              

                  

                 

 

 

 

 

 

 

 

Warfarin and Newer Oral Anticoagulants: 


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Prior TE 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Cancer 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Known 

Thrombophilic 

condition 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Pregnancy, 

post-partum or 

OBGYN 

complications 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Recent 

surgery/trauma 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Immobilization 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Estrogen 

therapy 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

80
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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87

              

                  

                 

 

Warfarin and Newer Oral Anticoagulants: 


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Others 

condition 

Not 

reported 

N 

% 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

If No CHADS, please record the following: 

Age >75 years 

Not 

reported 

Mean 

SD 

Mean 

SD 

Mean 

SD 

Choose an item. 

Choose an item. 

Diabetes 

Mellitus 

Not 

reported 

Mean 

SD 

Mean 

SD 

Mean 

SD 

Choose an item. 

Choose an item. 

HF 

Not 

reported 

Mean 

SD 

Mean 

SD 

Mean 

SD 

Choose an item. 

Choose an item. 

HTN 

Not 

reported 

Mean 

SD 

Mean 

SD 

Mean 

SD 

Choose an item. 

Choose an item. 

Comments: 

81
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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88

              

                  

                 

   

   

   

   

 

  

  

     

  

   

   

  

  

     

  

   

   

  

  

     

  

   

   

   

        

   

   

        

   

   

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

Form 3b: VTE 

If DVT/PE, risk factors-Indication for anticoagulation 

Total Primary AC

Intervention

Choose an item.

N=

Comparator 1

Choose an item.

N=

Comparative analysis

New vs Comp 

Comp vs New 

DVT

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

PE

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

DVT/PE

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

Prior TE

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

Cancer

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

82
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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89

              

                  

                 

        

   

   

            

   

   

        

   

   

        

   

   

   

        

   

   

   

        

   

   

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

Known

Thrombophilic

condition

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

Pregnancy, post‐

partum or

OBGYN

complications

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

Recent

surgery/trauma

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

Immobilization

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

Estrogen therapy

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

Others condition

Not 

reported 

N

%

N

%

N

%

Choose an item.

Choose an item.

83
 
      

 

 

Form 4a: Outcome Measures Reported 

Yes No Unclear 

Central Adjudication 

Timing of the outcome data reported in the table below [Repeat this table as needed

24 months 12 months 6 months Other 

Primary AC Intervention 

Choose an item. 

Comparator 1 

Choose an item. 

Com

Choo

 

 

 

 

 

 

 

 

 

 

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

] 

N= N= 

parator 2 

se an item. 

N= 

Adherence: 

newer AC, 

defined as 

1) % above 

cut-off 

OR 

2) Average, % 

of medication 

taken 

OR 

Not 

reported 

% 

N 

% 

% 

N 

% 

% 

N 

% 

Adherence: If comparator= Warfarin, % time in therapeutic range: 

 Below range: 

 Above range: 

Not 

reported 

84
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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91

              

                  

                 

 

 

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

Primary AC Intervention 

Choose an item. 

N= 

Comparator 1 

Choose an item. 

N= 

Comparative analysis 

new vs comp 

comp vs new 

Death all cause 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Death TE 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Stroke 

Ischemic 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Peripheral arterial 

embolism 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Stroke Hemorrhage 

Not 

reported 

N 

% 

N 

%

Choose an item. 

Choose an item. 

85
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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92

              

                  

                 

 

Warfarin and Newer Oral Anticoagulants: 


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Combined Stroke 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Quality of life 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Comment: 

86
 
      

 

   

       

mYes m No m Unclear Central Adjudication 

Timing of the outcome data reported in the table below [Repeat this table a

m 24 months m 12 months m 6 months m Other 

Primary AC Intervention

Choose an item.

Comparator 1

Choose an item.    

   

  

     

     

   

  

      

  

  

     

     

  

                  

                                                                           

                                                                                  

                                                                                  

           

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

Form 4b: Outcome Measures Reported 

s needed] 

N= N=

Comparator 2

Choose an item.

N=

Adherence:

newer AC,

defined as

1) % above cut‐

off

OR

2) Average, %

of medication

taken

OR

Not 

reported 

%

N

%

%

N

%

%

N

%

Adherence: If comparator= Warfarin, % time in therapeutic range:

% Below range:

% Above range:

Not 

reported 

87
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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94

              

                  

                 

   

       

   

   

     

     

  

  

   

     

  

  

   

     

  

  

   

     

  

  

     

  

  

   

     

  

  

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

Primary AC Intervention

Choose an item.

N=

Comparator 1

Choose an item.

N=

Comparator 2

Choose an item.

N=

Death all cause

Not 

reported 

N

%

N

%

N

%

Death TE

Not 

reported 

N

%

N

%

N

%

Stroke Ischemic

Not 

reported 

N

%

N

%

N

%

Peripheral arterial

embolism

Not 

reported 

N

%

N

%

N

%

Stroke Hemorrhage

Not 

reported 

N

%

N

%

N

%

Combined Stroke

Not 

reported 

N

%

N

%

N

%

88
 
Comparative Effectiveness of Warfarin and Newer Oral Anticoagulants

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95

              

                  

                 

     

     

  

  

Warfarin and Newer Oral Anticoagulants: 


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Quality of life

Not 

reported 

N

%

N

%

N

%

89
 
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96

              

                  

                 

 

24 months 12 months 6 months Other 

Primary AC Intervention 

Choose an item. 

N= 

Comparator 1 

Choose an item. 

 

 

 

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

Form 5 

Adverse Event Outcomes 

Timing of the outcome data reported in the table below [Repeat this table as needed] 

N= 

Comparative analysis 

new vs comp 

comp vs new 

Any adverse events 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Serious adverse 

events 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Adverse event-drug 

discontinuation 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

90
 
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97

              

                  

                 

Major bleeding-total 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Major bleeding-fatal 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Major bleedingrequire 

transfusion 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Myocardial 

infarction 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

LFT >3X ULN 

Choose an item. 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Intracranial 

bleeding 

Not 

reported 

N 

% 

N 

% 

Choose an item. 

Choose an item. 

Warfarin and Newer Oral Anticoagulants: 


Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program
 

91
 
Warfarin and Newer Oral Anticoagulants: 

Long-term Prevention and Treatment of Arterial and VTE Evidence-based Synthesis Program 

Elements Abstracted From Observational Studies 

• Study design

• Setting/study sites

• Geographic location

• Patient demographics 

○ Age 

○ Race/ethnicity 

○ Gender 

○ Diagnosis 

○ Important medical history (e.g., CHADS score, EGR) 

○ Comorbidities 

• Types of adverse effects reported 

• Suspected agent

• Degree of certainty that agent was causative

• Duration of illness 

• Was patient hospitalized? 

• Was episode fatal? 

• Did episode resolve?

• Other necessary description of episode 

92
 
agulants: 


ment of Arterial and VTE Evidence-based Synthesis Program
 

R REVIEW COMMENTS

Comment Response 

 scope, and methods for this review clearly described? 

nts from reviewer 1. Thank you. nts from reviewer 2. Thank you. 

was “Methods, scope, and objectives are sufficiently described.” Thank you. 

was “Very clear, comprehensive report of the current literature.” Thank you. 

tion of bias in our synthesis of the evidence? 

nts from reviewer 1. Thank you. 

nts from reviewer 2. Thank you. 

ntified all relevant studies (published and unpublished), the identified 

quality, and author’s analysis of the data does not appear to be 

bvious source of bias. However, the analysis is potentially misleading 

her the findings from clinical trials for all new anticoagulants - thus 

erences (in efficacy or safety) that might exist between these new 

– figure 14 suggests there are significant differences in medication 

)... or diminishing the effect a medication or class of medication may 

es relative to warfarin. At the very least, the reader should be alerted 

 in the analytical methods (e.g. the analysis, as constructed, assumes 

ants” are substantially similar and were treated as a single class of 

We conducted additional analyses and presented results by drug class. However, these analyses consist of 

indirect comparisons (across studies that may differ in other ways, such as differences in the patient population or quality of adjusted-dose warfarin) and should be considered hypothesis generating. We added statements in the Discussion section and both the global Summary and Strengths and Limitations sections. 

a comprehensive review of the current literature with sound results, 

 written in a biased manner favoring the newer anticoagulants 

ancing the disadvantages and unknowns. Recommend revising 

d in describing the findings and including disadvantages and 

es provided below: 

1: potential benefits of newer anticoagulants are over-stated, and 

are not included (i.e., dabigatran is associated with higher GI 

arin; downside is that there is not a readily available means of 

g effect of newer agents in cases of emergency such as bleeding or 

e/surgery needed). There is also more recent concern raised by FDA 

ncies outside of US about serious bleeding events with dabigatran, 

lderly and renally impaired. 

We have performed a secondary search of the observational literature and the FDA Web site looking 

specifically for reports of adverse events. These data are included under KQ 4 and in the Executive Summary. 

93
agulants: 


ment of Arterial and VTE Evidence-based Synthesis Program
 

Comment Response 

n the trial of dabigatran for chronic AF, myocardial infarction was Thank you for pointing out this factual error that was an 

nrolled sample had higher CHADS2 scores than other trials.” First, artifact of editing. The ROCKET study did have a higher 

orrect; mean CHADS2 score for RE-LY ~2.1; mean CHADS2 mean CHADS score, and this factual error has been 

5. Second, the “but...” phrase does not explain the increase in MI. corrected. 

n assessment of stroke risk in patients with AF. While it is true that the CHADS2 score is an assessment 

of stroke risk in patients with AF, many of the risk 

factors used in this assessment (e.g., HTN, DM, history of vascular disease) are risk factors for myocardial infarction too. We have clarified this point in the discussion. 

It is misleading to state that the newer agents are free from 

ore accurate, fair and balanced to state that there is not a need 

gulant monitoring”. All patients on anticoagulants should 

sx bleeding, stroke, AEs, medication adherence. In addition, 

oagulants require monitoring of renal function (i.e., dabigatran, 

Agreed. We have modified this statement to state: “These drugs characteristically have a predictable anticoagulant effect, eliminating the need for routine monitoring. 

However, patients on newer anticoagulants should still be monitored for any adverse events, including bleeding. Bleeding risk is increased with concurrent use of antiplatelet medications, older age, and renal impairment since most of these drugs are eliminated through the kidneys. (Harder 2011)” 

 related adverse events were not included in KQ4; these events 

 often with dabigatran. 

We have now addressed GI bleeding and GI-related events in KQ 4. 

of KQ1: only the favorable outcomes of the newer anticoagulants 

y be stated that there was no significant difference found in VTE 

d ischemic stroke. 

Agreed. The following statement was added to the paragraph: “However, VTE-related mortality and 

ischemic stroke were not significantly lower with newer oral anticoagulants.” 

94
agulants: 


ment of Arterial and VTE Evidence-based Synthesis Program
 

Comment Response 

of KQ1: bleeding outcomes and INR control – “The difference 

outcomes are dependent in part upon the quality of adjusted

ment; these studies reported rates of time in therapeutic range 

those observed in the VHA.” Statement is misleading and an 

s is. First, it would be more accurate to state that it is the MEAN or 

om the clinical trials. Second, VHA national data show that ~70% of 

.8 and 3.3. The method used to calculate TTR in the clinical trials 

re limits the ability to directly compare numbers. The take home 

at outcomes with dabigatran vs. warfarin were similar when INR 

urther, outcomes with dabigatran were better when INR control 

rol in the rivaroxaban study was poorer than typical standard. 

the statement to include these limitations. Also suggest adding 

 control in VHA appears to be at least as good as the mean TTR in 

The discussion of bleeding rates has been revised to: “While anticoagulation control in the VHA appears 

to be at least as good as that found in clinical trials, the ROCKET-AF study had a mean TTR that was worse than typical standards. In the RE-LY study, the advantages of dabigatran were greater at sites with poor INR control than at those with good INR control for all vascular events, nonhemorrhagic events, and mortality. Warfarin and dabigatran showed comparable outcomes in centers with good mean TTR.” 

of KQ1: “Except for discontinuations due to adverse effects, other 

red newer anticoagulants but were not statistically significant.” The 

t favor newer anticoagulants and should be stated here. 

The statement was revised to: “Except for discontinuations due to adverse effects, other outcomes 

also favored newer anticoagulants; however, they were not statistically significant.” 

f KQ2: Agree with conclusion; however similarly as for KQ1, only the 

wer anticoagulants is included. It should also be stated that rate of DC 

er with newer anticoagulants, though not statistically significant. 

We have added this text: “When the study examining ximelagatran was included, results were similar except that drug discontinuation due to adverse effects was significantly higher than rates with adjusted-dose warfarin.” 

of KQ4: same incorrect statement about the dabigatran, higher 

mment above. 

ROCKET-AF had a higher mean CHADS2, and the text has been corrected to reflect this. 

of KQ4: “Fatal bleeding was significantly lower for newer 

e chronic AF studies, and the point estimate favored these drugs 

n patients with VTE and major bleeding in both groups.” For the 

re not statistically significant. Statement currently is unbalanced, 

orting to the newer anticoagulants. 

We agree and have changed the statement to: “The newer oral anticoagulants were associated with a consistent decrease in mortality (0.88; 95% CI, 0.82 to 0.95), without significant variability across studies or differences between drug classes. Similarly, rates of 

fatal bleeding were consistently lower with newer oral anticoagulants (Table 9). There was a non–statistically significant reduction in major bleeding, but this effect varied importantly across studies—variability that was not explained by drug class.” 

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Comment Response 

ible that the newer agents may improve patient experience and 

nt is biased; a more balanced statement is that it is unknown 

s may improve patient experience and HRQOL. 

This statement has been rephrased to: “Because no studies reported effects on patient experience and HRQOL, effects 

on these important outcomes are unknown.” 

at patients with high bleeding risk were excluded from clinical 

t paragraph it goes on to recommend these newer agents in patients 

age risk of bleeding. I don’t agree with this statement and it is not 

nce. 

Agreed. We have changed the wording to: “In the RELY study, the advantages of dabigatran were greater 

at sites with poor INR control than at those with good INR control for all vascular events, nonhemorrhagic events, and mortality. Warfarin and dabigatran showed comparable outcomes in centers with good mean TTR.” 

only part of the recommendation from ACCP/AHA on dabigatran 

te also states that: because of BID dosing and greater risk of 

Es with dabigatran, patients already taking warfarin with excellent 

ave little to gain by switching to dabigatran. 

The discussion has been updated to include the point that patients already taking warfarin and who have excellent INR control may have little to gain by switching. 

and Policy Implications: It is not balanced in that this section 

cussion of the unknowns or disadvantages of newer anticoagulants. 

mes in the setting of lower adherence – Adherence in clinical trials 

ikely to be lower in real-world setting. Given the short half-life 

 and the fact that patients discontinue them more frequently, the 

s of lower adherence rates are unknown (but potentially important, 

k).; 2) Higher GI bleeds, GI adverse effects with dabigatran; 

rates with the newer anticoagulants vs. warfarin in the elderly 

nd extremely applicable to the VA population; 4) higher MI with 

We have added the following text: “In a prespecified subgroup analysis, Wallentin et al.99 found that the 

advantage of dabigatran over warfarin in terms of major bleeding rates was evident only at sites with poor-quality anticoagulation (TTR <57.1%), while rates of major bleeding were not significantly different at sites with higher quality anticoagulation. Hence, better INR control led to similar bleeding rates between both groups. In the VHA, time in treatment exceeds this threshold, but newer oral anticoagulants could have important advantages for individual patients who have difficulty maintaining a therapeutic INR. However, since newer oral anticoagulants are dosed twice daily, compared with once daily dosing of warfarin, better outcomes would not be expected if poor medication adherence were the cause of the subtherapeutic INR.” (continued) 

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Comment Response 

Also: “Although newer oral anticoagulants are associated with a lower risk of fatal bleeding compared with warfarin, 

this advantage may be tempered by the increased risk of gastrointestinal bleeding with dabigatran.70,84,91,99 The FDA is currently evaluating reports of high rates of serious bleeding. The reports of bleeding appear to be concentrated in older adults and those with impaired renal function. Another worrisome finding is elevated rates of myocardial infarction with dabigatran, although the strength of evidence for this finding is low.” And: “VA should carefully consider the potential benefits and harms, along with patients at higher risk for adverse effects when establishing eligibility criteria for newer oral anticoagulants.” 

pecified subgroup analysis, Wallentin et al.22 found that major 

dabigatran were lower than warfarin at sites where time in 

as low (<57.1%); rates were not significantly different at sites 

anticoagulation.” This statement is somewhat misleading by not 

major GI bleeding was significantly HIGHER with dabigatran 

NR control was good. Also, for the primary endpoint of stroke or 

 outcomes were similar with dabigatran and warfarin when INR 

n other words, dabigatran was not superior to warfarin when INR 

Agreed. We have rephrased the statement to: “In a prespecified subgroup analysis, Wallentin et al.99 found 

that the advantage of dabigatran over warfarin in terms of major bleeding rates was evident only at sites with poor-quality anticoagulation (TTR <57.1%), while rates of major bleeding were not significantly different at sites with higher quality anticoagulation. Hence, better INR control led to similar bleeding rates between both groups. In the VHA, time in treatment exceeds this threshold, but newer oral anticoagulants could have important advantages for individual patients who have difficulty maintaining a therapeutic INR. However, since newer oral anticoagulants are dosed twice daily, compared with once daily dosing of warfarin, better outcomes would not be expected if poor medication adherence were the cause of the subtherapeutic INR.” 

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Comment Response 

ished or unpublished studies that we may have overlooked? 

nts from reviewer 1. Thank you. 

hnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in 

al fibrillation treated with dabigatran or warfarin in the RE-LY trial. 

 DOI: 10.1161/?CIRCULATIONAHA.111.055970. Available at: 

rnals.org. 

ndez AV. Dabigatran association with higher risk of acute coronary 

ysis of noninferiority randomized controlled trials. Arch Intern 

10.1001/archinternmed.2011.1666. Available at: http://archinte. 

man J. Dabigatran: Do we have sufficient data? Arch Intern Med 

01/archinternmed.2011.1721. Available at: http://archinte.ama-assn. 

The cited articles were published after our draft report was submitted. However, in response to peer review, we conducted a secondary search for observational studies and recent meta-analyses that address adverse effects of the newer anticoagulants. The updated data on myocardial ischemic events (Hohnloser et al.) are included in a newly conducted sensitivity analysis. The meta-analysis by Uchino et al. is cited in the Discussion section. The article by Jacobs et al was reviewed but is an editorial and not eligible for inclusion. 

m aware. Thank you. 

nts from reviewer 4. Thank you. 

onal suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report. 

on that the review covers warfarin and newer oral anticoagulants. This has been clarified throughout the document. 

tment experience.’ Patient experience is a more inclusive set of outcomes 

than patient satisfaction. It has been defined as: The sum 

of all interactions, shaped by an organization’s culture that influence patient perceptions across a continuum of care. 

differences in bleeding when stratifying data based on age or 

 ≥ 80 vs. < 80)? 

From Eikelboom et al. 2011: 18113 patients in RE-LY study randomized to 110 mg, 150 mg dabigatran BID, or 

warfarin for a median followup of 2 years: 

• Risk of major bleeding with 150 mg dabigatran was 

lower than warfarin in those <75 years of age (2.12% vs. 3.04%; P<0.001) and a trend toward higher risk of major bleeding in those ≥75 (4.37%; P=0.07; P for 5.10 % vs. interaction <0.001). 

• In patients with AF, both doses of dabigatran are 

associated with lower risk of major bleeding in patients <75 years of age. In those ≥75, intracranial bleeding risk is lower, but extracranial bleeding risk is the same or higher in both doses of dabigatran. 

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Comment Response 

resented on LMWHs. Remove this from KQ or reword to indicate 

d with warfarin. Also, how many VTEs were DVTs versus PEs? 

ble to DVTs and PEs? 

Agreed. It may be confusing although it is common practice to overlap warfarin with LMWH or other parenteral anticoagulants. We have changed the wording 

of KQ 2 to: “For patients with venous thromboembolism, are there differential effects of newer oral anticoagulants versus warfarin on recurrent thromboembolism, mortality, HRQOL, and patient treatment experience?” 

EAs could help address uncertain effects on health care systems in 

EAs involving dabigatran noted, but none involving other agents. 

In the literature search performed for the Budget Impact Analysis we plan to conduct, we did not find any CEAs on new oral anticoagulants other than Dabigatran. 

has significant interactions with herbal supplements in addition to 

Agreed. This interaction has been noted in the report. 

s are still concerned about inability to reverse effects of newer 

atients at higher risk of bleeding even though half-lives are shorter 

 76 years old and h/o GI bleed). 

Agreed. We have added the statement: “However, there are valid concerns about the lack of specific antidotes for newer oral anticoagulants that would prevent the timely reversal of their anticoagulant effect in a bleeding patient. 

This is especially worrisome in elderly patients and those with renal disease, where drug clearance may be longer and the anticoagulant effects prolonged.” 

page 13): What is the data source? We have changed the heading to “Precautions.” 

): Clarify that data on primary VTE prevention s/p surgery are not 

We have added a statement that a later report will summarize the data on newer anticoagulants used for primary VTE prevention. 

or clarify inclusion of LMWHs We have adjusted Figure 1 as suggested. 

ndard of care was usually warfarin, rather than VKAs Warfarin is one of the vitamin K antagonists. 

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Comment Response 

ns: The risk of major bleeding is unclear with newer agents in patients 

major bleed (e.g., older elderly, h/o major bleed, renal insufficiency, 

We have refined the discussion to state: “Gastrointestinal bleeding was significantly increased in patients treated with dabigatran and rivaroxaban compared with warfarin.(Wallentin 2010) The efflux of dabigatran by 

p-glycoprotein transporters into the gastrointestinal tract may be a mechanism for this finding. (Bovio 2011) The European Society of Cardiology recommends dabigatran at a dose of 150 mg be used in patients with a low risk of bleeding, while the lower dose of 110 mg is reserved for those with a high risk of bleeding.(Camm 2010) In Canada, dabigatran is approved for the prevention of stroke in AF, and dabigatran 110 mg twice daily is recommended for elderly patients 80 years of age or older or those at a high risk of bleeding.(Cairns 2011) In the United States, the FDA has only approved the 150 mg dose and recommends a dose of 75 mg twice daily for patients with CrCl of 15 to 30 mL/min. (Beasley 2011)” 

ic Options for Anticoagulation, Paragraph 1, Line 6 – additional 

includes decreased risk of HIT. Line 8 – additional LMWH 

 it is not completely reversible by protamine. 

We have added the following statement: “Unfractionated heparin requires hospital admission and continuous monitoring and carries the risk of heparin-induced thrombocytopenia. The advantages of low molecular 

weight heparin include longer half-life, better bioavailability, a predictable dose-response that minimizes the need for laboratory monitoring, and a decreased risk of heparin-induced thrombocytopenia.(Key 2010) The disadvantages of low molecular weight heparin include the need for subcutaneous administration once or twice daily, which patients find painful and inconvenient. Further, protamine sulfate only partially reverses heparin’s anticoagulant effect. (Crowther 2002)” 

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Comment Response 

Point of care INR testing is simple and relatively inexpensive. 

 and 5 – bridging also with LMWH, generally performed in an 

which is more convenient for the patient and less costly to the 

red to admission). Paragraph 2, Line 10 – Although a shorter t1/2 

red to warfarin, a lack of antidote for DTI and Xa inhibitors is e hemorrhage or emergent surgery, whereas the effect of warfarin 

pidly with PCC. Paragraph 4 – Line 4 – May consider additional 

ng post-marketing bleeding in Pradaxa and 12/7/2011 FDA Safety 

This FDA Safety Announcement and several others have been addressed under KQ 4. 

h 1, Line 2 – Consider noting that dabigatran is susceptible to Pgp 

ons. 

Thank you. This observation has been added both to the text and the appropriate table. 

6, Row 8 – Typo Should read Ecarin clotting time. Row 10 – PPIs not 

e insert. 

The reference has been changed to a more recent one that does include PPIs. 

1 – May be worthwhile adding additional row listing precautions. “Contraindications” has been changed to “Precautions.” 

h 2, Line 7/8 – Do the authors have a citation for the two statements 

are related to # medical conditions and # medications and that 

nt may increase absolute rates of adverse events? 

Oldgren 2011 has been added to the text in the “Metaanalyses for KQ 1” section, 2nd paragraph, 4th sentence. 

h 3, Line 10 – Is this true? I thought Rocket-AF had higher average 

Agreed. This text has been corrected. 

h 1, Line 6 – See previous comment regarding CHADS2 score and 

LY. 

We have corrected this text. 

h 1, Line 5 – Should also add aspirin + clopidogrel. Paragraph 2, 

ewer drug interactions are noted, but new information may emerge. 

1 – The shorter t1/2 life of new anticoagulants may be problematic in 

ompliant behavior (ie – increase in death rates after discontinuation of 

-AF). 

The ACTIVE-W trial of ASA plus clopidogrel was stopped early due to inferiority compared with warfarin. Other studies are ongoing. We decided not to add this 

detail as it may distract the reader from the main point that warfarin is superior to antiplatelet agents. 

e fact that all of the new anticoagulants are considered as a 

as individual agents (or, at the very least, two distinct classes 

ch of these new agents have unique pharmacological and 

operties. While the efficacy of these agents in clinical trials appears 

r (for both a-fib and VTE treatment indications), the adverse event 

files clearly were not (dabigatran had a relatively higher incidence 

... rivaroxaban was associated with relatively higher rate of GI 

xaban was not associate with either of these adverse events). Thus 

g, analyzing, and summarizing the results of the clinical trials of 

s of medications (DTIs and direct Xa inhibitors) is not appropriate. 

Thank you for this comment. Our analysis assumes a class effect. Although each drug has unique pharmacological 

and pharmacokinetic properties, they are all developed as anticoagulants. However, we have revised our analytic approach to analyze by drug class when there were sufficient studies for meaningful analyses. Further, we have revised the results and discussion to emphasize when the results were variable across drugs or drug class and to point out that our analyses is limited because we cannot reliably detect differences between individual drugs. 

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Comment Response 

OCKET-AF study (Patel 2011 – reference 74) is consistently listed as 

bles and figures; was this a typographical error? 

The report has been revised to ensure that studies are consistently listed by author/year in the tables and figures. 

ction to be complete: Though not very commonly used, UFH may be 

VTE treatment as well as IV: “unfractionated heparin administered 

The statement has been revised to state that UFH is typically given intravenously. 

dding: warfarin’s interaction with certain disease states in addition to 

CHF, thyroid, acute infection) 

Thank you for the suggestion, but we decided to omit this detail as we believe the current text makes it abundantly clear that interindividual and intraindividual variability in warfarin response, along with food and drug interactions, is a disadvantage. 

er adding: dabigatran’s advantage over warfarin in the lack of drug

so, while dabigatran doesn’t interact with drugs via CYP enzyme 

wer but significant interactions through P-gp transporter system. 

Agreed. We have added the following statement: “Dabigatran acts as a substrate for the p-glycoprotein transporter system, which makes it more prone to drugdrug interactions.” It is also present in the table. 

CT time is best measure of anticoagulant effect of dabigatran, 

 not widely available outside of a research setting at this time. 

Agreed. This has been added to the report. 

ontraindications: Warfarin and severe renal impairment – I could not 

s to be true. Reviewed the Harder reference provided where it directs 

information. The link provided in the reference in the Harder article 

ent as a precaution, not contraindication. Also per US PI, severe renal 

 a contraindication. These patients likely have higher risk of bleeding 

es of warfarin but it is not a contraindication to use 

Agreed. We have changed the heading to “Precautions.” 

mplementation Questions 

cal performance measures, programs, quality improvement measures, patient care services, or conferences that will be 

 If so, please provide detail. 

reviewer 1. NA reviewer 2. NA 

reviewer 3. NA 

f this report are unclear at this time. Acknowledged 

 recommendations on how this report can be revised to more directly address or assist implementation needs. 

reviewer 1. NA 

tside of the scope and stated objective of the review, it would be 

 more comprehensive discussion of the major clinical trials including 

al applicability 

We feel that it is outside the scope of this review to discuss the major trials separately. 

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Comment Response 

reviewer 3. NA 

e revised to read more balanced; it is biased toward the newer 

ribing the potential disadvantages and unknowns. 

Agreed. We have revised the report to be more balanced, and we highlight the potential disadvantages of the newer oral anticoagulants. For example, we state: “Wallentin et al. found that the advantage of dabigatran 

over warfarin in terms of major bleeding rates was only evident at sites with poor-quality anticoagulation (time in therapeutic range <57.1%), while rates of major bleeding were not significantly different at sites with higher quality anticoagulation. Hence, better INR control led to similar bleeding rates between both groups. In the VHA, time in treatment exceeds this threshold, but newer anticoagulants could have important advantages for individual patients who have difficulty maintaining a therapeutic INR. However, since newer anticoagulants are dosed twice daily, compared with once daily dosing warfarin, better outcomes would not be expected if poor medication adherence were the cause of the subtherapeutic INR. A pragmatic concern related to adherence is the FDA notification that dabigatran may lose potency if placed in pill boxes and that it should only be dispensed and stored in the original bottle or blister package. Although newer anticoagulants are associated with a lower risk of fatal bleeding compared to warfarin, this advantage may be tempered by the increased risk of gastrointestinal bleeding with dabigatran. The FDA is currently, evaluating reports of high rates of serious bleeding. The reports of bleeding appear to be concentrated in older adults and those with impaired renal function. Another worrisome finding is elevated rates of myocardial infarction with dabigatran, although the strength of evidence for this finding is low.” And we have added a word of caution: “VA should carefully consider the potential benefits and harms, along with patients at higher risk for adverse effects when establishing eligibility criteria for newer anticoagulants.” 

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Comment Response 

with contact details of any additional individuals/stakeholders who should be made aware of this report. 

reviewer 1. NA reviewer 2. NA 

reviewer 3. NA 

reviewer 4. NA 

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OING CLINICAL TRIALS 

rial fibrillation interventions (KQ 1) 

VA/DoD population? Intervention Comparator Sponsor and ClinicalTrials.gov ID Funding Start/Stop Status 

No AZD0837 Vitamin K AstraZeneca Oct 2007–May 2009 Completed 

antagonists (warfarin) NCT00645853 

No Dabigatran dose 1 Dabigatran dose 2 Boehringer Ingelheim Nov 2008–Apr 2013 Ongoing, not 

high dose twice daily low dose twice daily Pharmaceuticals recruiting 

NCT00808067 

No Dabigatran etexilate, Dabigatran Biotronik Feb 2008–Feb 2015 Recruiting 

warfarin etexilate, warfarin 

NCT00559988 

No YM150 Warfarin Astellas Pharma Inc. Mar 2007–Oct 2008 Completed 

NCT00448214 

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enous thromboembolism interventions (KQ 2) 

VA/DoD population? Intervention Comparator Sponsor and ClinicalTrials.gov ID Funding Start/Stop Status 

No Dabigatran etexilate Warfarin Boehringer Ingelheim Apr 2008–May 2011 Completed, 

Pharmaceuticals recent 

NCT00680186 

No Dabigatran Warfarin Boehringer Ingelheim May 2006–Oct 2010 Completed, 

Pharmaceuticals abstract 

presented, but 

NCT00329238 no publication to 

date 

No Xarelto Enoxaparin followed Bayer Mar 2007–Oct 2011 Completed, 

(rivaroxaban, by vitamin K recent BAY59-7939) antagonist NCT00439777 

No LMW Heparin/ LMW Heparin/ Daiichi Sankyo Inc. Oct 2009–Sep 2012 Recruiting 

Edoxaban Warfarin 

NCT00986154 Methods paper 

published 

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echanical heart valve interventions (KQ 3) 

VA/DoD population? Intervention Comparator Sponsor and ClinicalTrials.gov ID Funding Start/Stop Status 

No Dabigatran etexilate Warfarin Boehringer Ingelheim Oct 2011–Aug 2012 Recruiting 

Pharmaceuticals NCT01452347 

No Placebo for Active comparator: Bristol-Myers Squibb July 2008–Mar 2013 Recruiting 

enoxaparin 

Placebo for warfarin 

Enoxaparin NCT00643201 Warfarin 

Apixaban 

Placebo for apixaban 

No DU-176b plus Warfarin tablets plus Daiichi Sankyo Inc. Nov 2008–Feb 2012 Ongoing; 

warfarin placebo DU-176b methods paper 

tablets NCT00781391 published 

No Dabigatran None- open label, Boehringer Ingelheim Dec 2003–Jan 2009 Terminated; has 

nonrandomized Pharmaceutical results 

Phase II study 

NCT00157248 

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APPENDIX G. CRITERIA USED IN QUALITY ASSESSMENT 

General Instructions:
 

For each risk of bias item, rate as “Yes,” “No,” or “Unclear.” After considering each of the 

quality items, give the study an overall quality rating of good, fair, or poor.
 

Detailed Quality Items:
 

If an item is rated as “No,” describe why in the comments column. 

Randomization and allocation concealment: 

a.	 *Randomization adequate? Was the allocation sequence adequately generated? 

Not o No o Yes o reported/Unclear 

b.	 *Allocation concealment? Was allocation adequately concealed? 

Not o No o Yes o reported/Unclear 

Outcomes: 

a.	 *Outcome assessors blinded (hard outcomes)? Were Outcome assessors blind to 

treatment assignment for “hard outcomes” such as mortality? 

Not o No o Yes o reported/Unclear 

b.	 *Outcome assessors blinded (soft outcomes)? Were Outcome assessors blind to 

treatment assignment for “soft outcomes” such as symptoms? 

Not o No o Yes o reported/Unclear 

c.	 Lack of measurement bias? Were the measures used reliable and valid? If so, 

choose “Yes,” indicating no important measurement bias. 

Not o No o Yes o reported/Unclear 

Data analysis: 

a. *All outcomes reported? Are reports of the study free of suggestion of selective 

outcome reporting (systematic differences between planned and reported findings)? 

Not o No o Yes o reported/Unclear 

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b.	 *Incomplete outcome data adequately addressed ? 

m Yes (no systematic differences between groups in withdrawals from study and 

no high overall loss to follow-up; all eligible, randomized patients are included in 

m No analysis (ITT) 

m Not reported/Unclear 

c.	 Adequate power for main effects? 

Not o No o Yes o reported/Unclear 

Results: 

a.	 Other selection bias? Were systematic differences observed in baseline characteristics and prognostic factors across the groups compared? 

Not o No o3 Yes o reported/Unclear 

b. *Comparable groups maintained? (Includes crossovers, adherence, and contamination). Consider issues of crossover (e.g., from one intervention to another), 

adherence (major differences in adherence to the interventions being compared), 

contamination (e.g., some members of control group get intervention), or other 

systematic differences in care that was provided. 

Not o No o Yes o reported/Unclear 

Conflict of interest: 

a.	 Was there the absence of potential important conflict of interest? The focus here 

is financial conflict of interest. If no financial conflict of interest (e.g., if funded 

by government or foundation and authors do not have financial relationships with 

drug/device manufacturer), then answer “Yes.” 

Not o No o Yes o reported/Unclear 

* Items contained in Cochrane Risk of Bias Tool 

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Overall study rating: 

Choose an item.
 

Please assign each study an overall quality rating of “Good,” “Fair,” or “Poor” based on the 

following definitions: 

A “Good” study has the least bias, and results are considered valid. A good study has a clear 

description of the population, setting, interventions, and comparison groups; uses a valid 

approach to allocate patients to alternative treatments; has a low dropout rate; and uses 

appropriate means to prevent bias, measure outcomes, and analyze and report results. 

A “Fair” study is susceptible to some bias but probably not enough to invalidate the results. 

The study may be missing information, making it difficult to assess limitations and potential 

problems. As the fair-quality category is broad, studies with this rating vary in their strengths and 

weaknesses. The results of some fair-quality studies are possibly valid, while others are probably 

valid. 

A “Poor” rating indicates significant bias that may invalidate the results. These studies have 

serious errors in design, analysis, or reporting; have large amounts of missing information; or 

have discrepancies in reporting. The results of a poor-quality study are at least as likely to reflect 

flaws in the study design as to indicate true differences between the compared interventions. 

Comments: 

m Form status: 

m Fully complete - ready for export 

Not ready for export - should be discussed further/ changes reconciled with the abstractor 

Table G-1 lists the rating for each risk of bias item as well as the overall rating for each of the 

included studies. 

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 of the included studies 

 et al., 

05 Bauersachs et al., 2010 Connolly et al., 2009 Fiessinger et al., 2005 Granger et al., 2011 Olsson et al., 2003 Patel et al., 2011 Schulman et al., 2009 

es Yes Yes Yes NR/unclear Yes Yes Yes 

es Yes Yes Yes No Yes NR/unclear Yes 

es Yes NR/unclear Yes Yes Yes Yes Yes 

es Yes NR/unclear Yes Yes Yes Yes Yes 

es Yes Yes Yes Yes Yes Yes Yes 

es Yes Yes NR/unclear Yes Yes Yes Yes 

es NR/unclear Yes Yes Yes Yes No Yes 

es Yes Yes Yes Yes Yes Yes Yes 

o No No Yes No No No No 

es Yes Yes NR/unclear Yes Yes Yes Yes 

o No No No No No No No 

od Good Good Good Good Good Good Good 

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APPENDIX H. GLOSSARY 

Abstract screening 

The stage in a systematic review during which titles and abstracts of articles identified in the 

literature search are screened for inclusion or exclusion based on established criteria. Articles 

that pass the abstract screening stage are promoted to the full-text review stage. 

ClinicalTrials.gov 

A registry and results database of federally and privately supported clinical trials conducted in 

the United States and around the world. ClinicalTrials.gov provides information about a trial’s 

purpose, location, and participant characteristics among other details. 

Cochrane Database of Systematic Reviews 

A bibliographic database of peer-reviewed systematic reviews and protocols prepared by the 

Cochrane Review Groups in The Cochrane Collaboration. 

Companion article 

A publication from a trial that is not the article containing the main results of that trial. It may be 

a methods paper, a report of subgroup analyses, a report of combined analyses, or other auxiliary 

topic that adds information to the interpretation of the main publication. 

Confidence interval (CI) 

The range in which a particular result (such as a laboratory test) is likely to occur for everyone 

who has a disease. “Likely” usually means 95 percent of the time. Clinical research studies are 

conducted on only a certain number of people with a disease rather than all the people who have 

the disease. The study’s results are true for the people who were in the study but not necessarily 

for everyone who has the disease. The CI is a statistical estimate of how much the study findings 

would vary if other different people participated in the study. A CI is defined by two numbers, 

one lower than the result found in the study and the other higher than the study’s result. The size 

of the CI is the difference between these two numbers. 

Cytochrome P-450 (CYP) enzyme system 

A family of liver enzymes that serve two major functions: (1) biosynthesis of steroids, fatty 

acids, and bile acids and (2) metabolism of endogenous and a wide variety of exogenous 

substrates, such as toxins and drugs. They are classified into CYP gene family and subfamilies; 

for example, CYP1, CYP2 and CYP3 are responsible for most drug metabolism. 

Data abstraction 

The stage of a systematic review that involves a pair of trained researchers extracting reported 

findings specific to the research questions from the full-text articles that met the established 

inclusion criteria. These data form the basis of the evidence synthesis. 

Deep vein thrombosis (DVT) 

A blood clot that develops in the deep veins of the legs. 

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Direct thrombin inhibitors (DTIs) 

A new class of anticoagulants that bind directly to thrombin and block its interaction with its 

substrates. 

DistillerSR 

An online application designed specifically for the screening and data extraction phases of a 

systematic review. 

Efflux transporter p-glycoprotein 

Transporters that pump out unwanted toxic substances through specific efflux pumps. 

P-glycoprotein is the most common efflux transporter that allows drug molecules to pass through 

membranes. 

Embase 

The Excerpta Medica database (EMBASE) produced by Elsevier, a major biomedical and 

pharmaceutical database indexing over 3500 international journals in the following fields: 

drug research, pharmacology, pharmaceutics, toxicology, clinical and experimental human 

medicine, health policy and management, public health, occupational health, environmental 

health, drug dependence and abuse, psychiatry, forensic medicine, and biomedical engineering 

or instrumentation. There is selective coverage for nursing, dentistry, veterinary medicine, 

psychology, and alternative medicine. 

Exclusion criteria 

The criteria, or standards, set out before a study or review. Exclusion criteria are used to 

determine whether a person should participate in a research study or whether an individual 

study should be excluded in a systematic review. Exclusion criteria may include age, previous 

treatments, and other medical conditions. 

Factor Xa (FXa) inhibitor 

A new class of anticoagulants that bind directly to factor Xa and block its interaction with other 

substrates. 

Full-text review 

The stage of a systematic review in which a pair of trained researches evaluates the full-text of 

study articles for potential inclusion in the review. 

GRADE 

Grading of Recommendations Assessment, Development, and Evaluation (GRADE), a system of 

assessing the quality of medical evidence and evaluating the strength of recommendations based 

on the evidence. 

Inclusion criteria 

The criteria, or standards, set out before the systematic review. Inclusion criteria are used 

to determine whether an individual study can be included in a systematic review. Inclusion 

criteria may include population, study design, sex, age, type of disease being treated, previous 

treatments, and other medical conditions. 

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Mitral stenosis 

A heart valve disorder that involves the mitral valve, which separates the upper and lower 

chambers on the left side of the heart. Stenosis refers to a condition in which the valve does not 

open fully, restricting blood flow. 

Nonvalvular atrial fibrillation (AF) 

An abnormal cardiac rhythm that occurs at the absence of mitral stenosis. AF is characterized by 

rapid uncoordinated firing of electrical impulses in the upper chambers of the heart (atria), which 

prevents the blood from being effectively pumped into lower chamber of the heart (ventricles). 

Optimal information size 

The number of patients that need to be included in a pooled analysis (meta-analysis) to provide 

sufficient power to detect the smallest clinically important difference in treatment effect. 

PRISMA 

Preferred Reporting Items for Systematic Reviews and Meta-Analyses, an evidence-based 

minimum set of items for reporting in systematic reviews and meta-analyses. 

Publication bias 

The tendency of researchers to publish experimental findings that have a positive result, 

while not publishing the findings when the results are negative or inconclusive. The effect of 

publication bias is that published studies may be misleading. When information that differs 

from that of the published study is not known, people are able to draw conclusions using only 

information from the published studies. 

PubMed® 

A database of citations for biomedical literature from MEDLINE®, life science journals, and 

online books in the fields of medicine, nursing, dentistry, veterinary medicine, the health care 

system, and preclinical sciences. 

Pulmonary embolism (PE) 

Blocking of the pulmonary artery (lungs) or one of its branches by a clot. 

Randomized controlled trial 

A prospective, analytical, experimental study using primary data generated in the clinical 

environment. Individuals similar at the beginning of the trial are randomly allocated to two or 

more treatment groups and the outcomes the groups are compared after sufficient followup time. 

Properly executed, the RCT is the strongest evidence of the clinical efficacy of preventive and 

therapeutic procedures in the clinical setting. 

RevMan 

Review Manager, a software program used for preparing and maintaining Cochrane systematic 

reviews. 

Risk 

A way of expressing the chance that something will happen. It is a measure of the association 

between exposure to something and what happens (the outcome). Risk is the same as probability, 

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but it usually is used to describe the probability of an adverse event. It is the rate of events (such 

as breast cancer) in the total population of people who could have the event (such as women of a 

certain age). 

Statistical significance 

A mathematical technique to measure whether the results of a study are likely to be true. 

Statistical significance is calculated as the probability that an effect observed in a research study 

is occurring because of chance. Statistical significance is usually expressed as a P-value. The 

smaller the P-value, the less likely it is that the results are due to chance (and more likely that 

the results are true). Researchers generally believe the results are probably true if the statistical 

significance is a P-value less than 0.05 (p<.05). 

Strength of evidence (SOE) 

A measure of how confident reviewers are about decisions that may be made based on a body 

of evidence. SOE is evaluated using one of four grades: (1) High confidence that the evidence 

reflects the true effect; further research is very unlikely to change reviewer confidence in the 

estimate of effect; (2) moderate confidence that the evidence reflects the true effect; further 

research may change the confidence in the estimate of effect and may change the estimate; (3) 

low confidence that the evidence reflects the true effect; further research is likely to change the 

confidence in the estimate of effect and is likely to change the estimate; and (4) insufficient; the 

evidence either is unavailable or does not permit a conclusion. 

Systematic review 

A summary of the clinical literature. A systematic review is a critical assessment and evaluation 

of all research studies that address a particular clinical issue. The researchers use an organized 

method of locating, assembling, and evaluating a body of literature on a particular topic using a 

set of specific criteria. A systematic review typically includes a description of the findings of the 

collection of research studies. The systematic review may also include a quantitative pooling of 

data, called a meta-analysis. 

Venous thromboembolism (DVT/PE) 

Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the blood stream. 

Vitamin K antagonist (warfarin) 

An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation 

factors; i.e., I, VII, IX and X. 

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