Evidence-based Synthesis Program Department of Veterans Affairs 

Health Services Research & Development Service 

April 2012 

Comparative Effectiveness 

of Warfarin and Newer Oral 

Anticoagulants for the Long-term 

Prevention and Treatment of Arterial 

and Venous Thromboembolism 

Prepared for: 

Department of Veterans Affairs 

Veterans Health Administration 

Quality Enhancement Research Initiative 

Health Services Research & Development Service 

Washington, DC 20420 

Prepared by: 

Evidence-based Synthesis Program (ESP) Center 

Durham Veterans Affairs Healthcare System 

Durham, NC 

John W. Williams Jr., M.D., M.H.Sc., Director 

Investigators: 

Principal Investigator: 

Soheir S. Adam, M.D. 

Co-Investigators: 

Jennifer R. McDuffie, Ph.D. 

Thomas L. Ortel, M.D., Ph.D. 

John W. Williams Jr., M.D., M.H.Sc. 

Research Associate:
 

Avishek Nagi, M.S.
 

Medical Editor:
 

Liz Wing, M.A.
 
 

 

Warfarin and Newer Oral Anticoagulants: 


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

PREFACE 

Quality Enhancement Research Initiative’s (QUERI’s) Evidence-based Synthesis Program 

(ESP) was established to provide timely and accurate syntheses of targeted healthcare topics 

of particular importance to Veterans Affairs (VA) managers and policymakers, as they work to 

improve the health and healthcare of Veterans. The ESP disseminates these reports throughout 

VA. 

QUERI provides funding for four ESP Centers and each Center has an active VA affiliation. The ESP 

Centers generate evidence syntheses on important clinical practice topics, and these reports help: 

• develop clinical policies informed by evidence, 

• guide the implementation of effective services to improve patient 

outcomes and to support VA clinical practice guidelines and 

performance measures, and 

• set the direction for future research to address gaps in clinical 

knowledge. 

In 2009, the ESP Coordinating Center was created to expand the capacity of QUERI Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of QUERI field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov. 

Recommended citation: Adam SS, McDuffie JR, Ortel TL, Nagi A, Williams JW Jr. Comparative 

Effectiveness of Warfarin and Newer Oral Anticoagulants for the Long-term Prevention and 

Treatment of Arterial and Venous Thromboembolism. VA-ESP Project #09-010; 2012. 

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the Durham VA Medical Center, Durham, NC, funded by the 

Department of Veterans Affairs, Veterans Health Administration, Office of Research and 

Development, Quality Enhancement Research Initiative. The findings and conclusions 

in this document are those of the author(s) who are responsible for its contents; the 

findings and conclusions do not necessarily represent the views of the Department 

of Veterans Affairs or the United States government. Therefore, no statement in this 

article should be construed as an official position of the Department of Veterans Affairs. 

Potential conflicts of interest: Dr. Ortel: Grants: GlaxoSmithKline, Eisai, Daichi Sankyo, 

Pfizer; Consultancy: Boehringer Ingelheim. No other investigators have any affiliations 

or financial involvement (e.g., employment, consultancies, honoraria, stock ownership or 

options, expert testimony, grants or patents received or pending, or royalties) that conflict 

with material presented in the report. 

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TABLE OF CONTENTS 

EXECUTIVE SUMMARY 

Background.................................................................................................................................................... 1
 

Methods ......................................................................................................................................................... 2
 

Data Synthesis ............................................................................................................................................... 2
 

Rating the Body of Evidence......................................................................................................................... 3
 

Peer Review................................................................................................................................................... 3
 

Results ........................................................................................................................................................... 3
 

Recommendations for Future Research......................................................................................................... 7
 

Conclusion..................................................................................................................................................... 7
 

Abbreviations Table....................................................................................................................................... 8
 

INTRODUCTION 

Chronic Atrial Fibrillation and Stroke........................................................................................................... 9
 

Venous Thromboembolism............................................................................................................................ 9
 

Mechancial Heart Valves and Thrombosis .................................................................................................. 10
 

Therapeutic Options for Anticoagulation .................................................................................................... 10
 

Objective of This Report ............................................................................................................................. 15
 

METHODS 

Topic Development...................................................................................................................................... 16
 

Analytic Framework.................................................................................................................................... 16
 

Search Strategy............................................................................................................................................ 17
 

Study Selection............................................................................................................................................ 17
 

Data Abstraction .......................................................................................................................................... 18
 

Quality Assessment ..................................................................................................................................... 19
 

Data Synthesis ............................................................................................................................................. 19
 

Rating the Body of Evidence....................................................................................................................... 20
 

Peer Review................................................................................................................................................. 20
 

RESULTS 

Literature Flow ............................................................................................................................................ 21
 

Study Characteristics................................................................................................................................... 23
 

Key Question 1: For patients with chronic nonvalvular atrial fibrillation, what is the comparative 

effectiveness of long-term anticoagulation using newer oral anticoagulants versus warfarin on 

stroke incidence, mortality, health-related quality of life (HRQOL), and patient treatment experience?... 25
 

Key Question 2: For patients with venous thromboembolism, are there differential effects of newer 

oral anticoagulants versus warfarin or low molecular weight heparins on recurrent thromboembolism, 

mortality, HRQOL, and patient treatment experience? ............................................................................... 31
 

Key Question 3: For patients with mechanical heart valves, what is the comparative effectiveness 

of newer oral anticoagulants versus warfarin on the incidence of thromboembolic complications, 

mortality, HRQOL, and patient treatment experience? ............................................................................... 35
 

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Key Question 4: When used for long-term anticoagulation treatment, what is the nature and 

frequency of adverse effects for newer oral anticoagulants versus warfarin?............................................. 35
 

Results From Observational Studies ........................................................................................................... 40
 

Summary of FDA Bulletins......................................................................................................................... 42
 

SUMMARY AND DISCUSSION ................................................................................................................ 43
 

Summary of Evidence by Key Question ..................................................................................................... 43
 

Clinical and Policy Implications ................................................................................................................. 46
 

Strengths and Limitations............................................................................................................................ 48
 

Recommendations for Future Research....................................................................................................... 49
 

REFERENCES ................................................................................................................................................... 50
 

APPENDIX A. SEARCH STRATEgIES ............................................................................................................ 59
 

APPENDIX B. STUDY SELECTION FORM.................................................................................................... 61
 

APPENDIX C. EXCLUDED STUDIES.............................................................................................................. 63
 

APPENDIX D. SAMPLE DATA EXTRACTION FORMS................................................................................. 69
 

APPENDIX E. PEER REVIEw COMMENTS .................................................................................................. 93
 

APPENDIX F. ONgOINg CLINICAL TRIALS ............................................................................................. 105
 

APPENDIX g. CRITERIA USED IN QUALITY ASSESSMENT.................................................................... 108
 

APPENDIX H. gLOSSARY ............................................................................................................................ 112
 

FIgURES 

Figure 1. Analytic framework for the comparative effectiveness of newer oral 

anticoagulants........................................................................................................................... 16
 

Figure 2. Literature flow diagram for RCTs ............................................................................................ 22
 

Figure 3. Literature flow diagram for observational studies and systematic reviews.............................. 22
 

Figure 4. AF: All-cause mortality without ximelagatran......................................................................... 28
 

Figure 5. AF: Ischemic stroke without ximelagatran .............................................................................. 28
 

Figure 6. AF: Hemorrhagic stroke without ximelagatran........................................................................ 28
 

Figure 7. AF: All-cause mortality with ximelagatran.............................................................................. 28
 

Figure 8. AF: Ischemic stroke with ximelagatran.................................................................................... 29
 

Figure 9. AF: Hemorrhagic stroke with ximelagatran............................................................................. 29
 

Figure 10. VTE: All-cause mortality without ximelagatran ...................................................................... 34
 

Figure 11. VTE: Death–thromboembolic without ximelagatran............................................................... 34
 

Figure 12. VTE: Recurrent DVT/PE without ximelagatran ...................................................................... 34
 

Figure 13. VTE: All-cause mortality with ximelagatran ........................................................................... 34
 

Figure 14. VTE: Recurrent DVT/PE with ximelagatran ........................................................................... 35
 

Figure 15. Adverse effects: All-cause mortality without ximelagatran..................................................... 37
 

Figure 16. Adverse effects: Discontinued due to adverse effects without ximelagatran........................... 37
 

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Figure 17. Adverse effects: Major bleeding without ximelagatran ........................................................... 38
 

Figure 18. Adverse effects: Fatal bleeding without ximelagatran............................................................. 38
 

Figure 19. Adverse effects: Gastrointestinal bleeding without ximelagatran............................................ 39
 

Figure 20. Adverse effects: Myocardial infarction without ximelagatran................................................. 39
 

Figure 21. Adverse effects: Liver dysfunction without ximelagatran ....................................................... 40
 

TABLES 

Table 1. Characteristics of oral anticoagulants....................................................................................... 13
 

Table 2. Summary of inclusion and exclusion criteria........................................................................... 18
 

Table 3. Overview of study characteristics for included RCTs.............................................................. 23
 

Table 4. Details of study characteristics................................................................................................. 24
 

Table 5. Summary table for KQ 1—chronic atrial fibrillation ............................................................... 26
 

Table 6. Effects of newer oral anticoagulants compared with adjusted-dose warfarin 

for chronic AF .......................................................................................................................... 27
 

Table 7. Summary table for KQ 2—venous thromboembolism............................................................. 32
 

Table 8. Effects of newer oral anticoagulants compared with adjusted-dose warfarin for 

venous thromboembolism ........................................................................................................ 33
 

Table 9. Risk of mortality and adverse effects overall and by drug class .............................................. 35
 

Table 10. Summary of the strength of evidence for KQ 1—chronic AF ................................................. 44
 

Table 11. Summary of the strength of evidence for KQ 2—venous thromboembolism.......................... 44
 

Table 12. Summary of findings for KQ 4—adverse effects..................................................................... 46
 

Table 13. Evidence gaps and future research ........................................................................................... 49
 

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EVIDENCE REPORT 

INTRODUCTION 

Thromboembolic diseases represent a major public health burden and are associated with 

significant morbidity and mortality. For more than 50 years, vitamin K antagonists (VKAs) 

have been the mainstay of treatment and prophylaxis of thromboembolism. There are many 

indications for VKAs, including primary prevention of systemic embolism in nonvalvular atrial 

fibrillation (AF) and mechanical prosthetic heart valves. Other indications include secondary 

prophylaxis following venous thromboembolism (VTE) and preventing stroke in patients with a 

mural thrombus following myocardial infarction. 

In North America, the most widely recognized VKA is warfarin. In 2004, more than 30 million 

prescriptions for warfarin were written in the United States.1 The advent of warfarin has resulted 

in significant risk reduction for thromboembolic complications in AF,2

 mechanical heart valves,3-5 

and VTE.6 

CHRONIC ATRIAL FIBRILLATION AND STROKE 

Chronic AF affects 2.2 million adults in the United States7 and is associated with older age, 

hypertension, and heart disease—characteristics prevalent in the VA population. In patients with 

AF, the annual risk of stroke without prophylactic anticoagulation is 5 percent and increases to 

7 percent if transient ischemic attacks and silent stroke are taken into account.8 Furthermore, 

the rising incidence of AF and the increasing age of the population are projected to increase 

the stroke burden from 38 million disability-affected life-years in 1990 to 60 million disabilityaffected life-years in 2020.9 The use of anticoagulants significantly reduces the risk of stroke 

or death from AF-related stroke.10,11 Despite long experience with warfarin, it is underutilized. 

Warfarin is currently being prescribed for only 48 to 65 percent of suitable patients with AF.12-14 

Guidelines on the management of AF from the American College of Cardiology/American 

Heart Association/ recommend treatment with aspirin or warfarin according to the degree of 

stroke risk, which can be estimated by the CHADS2 scoring system.15 CHADS2 is a clinical 

score ranging from 0 to 6 used to predict the annual risk of stroke in individuals with chronic 

nonvalvular AF. Guidelines recommend aspirin for patients with a CHADS2 score of 0, aspirin 

or warfarin for those with a score of 1, and warfarin for those with a score greater than or equal 

to 2. In high-risk AF, VKAs decreased the risk of stroke by 80 percent while increasing the risk 

of minor bleeding by 3 percent per year.16 

VENOUS THROMBOEMBOLISM 

The incidence of VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE) 

is 1 in 1000 per year in the general population.17,18 In the United States, the incidence of DVT 

is comparable to the incidence of fatal and nonfatal stroke or myocardial infarction.19,20 DVT is 

associated with an increased risk for PE and postphlebitic syndrome, a condition characterized 

by chronic pain, swelling, and ulceration.21 Untreated PE is associated with a hospital mortality 

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rate of 5.4 to 15 percent.22,23 Furthermore, the cumulative incidence of chronic thromboembolic 

pulmonary hypertension 2 years after the diagnosis of PE is 4 percent.24 Anticoagulation lowers 

the risk of recurrent DVT and PE, postphlebitic syndrome, chronic pulmonary hypertension, and 

death. 

Current guidelines of the American College of Chest Physicians recommend the treatment of 

acute DVT/PE with heparin or low molecular weight heparin, overlapping with an oral VKA for 

at least 3 months. In unprovoked proximal DVT, recurrent DVT, or PE—and in the absence of 

significant risk factors for bleeding—it is recommended that VKAs be continued for 6 months or 

longer.25 

MECHANICAL HEART VALVES AND THROMBOSIS 

Aortic stenosis and mitral regurgitation are the most common valvular disorders in older adults. 

The prevalence of at least moderate aortic stenosis in the general population increases from 

2.5 percent at age 75 to 8.1 percent at age 85.26 Aortic valve replacement is the most common 

heart valve operation, accounting for 60 to 70 percent of all valve surgery performed in the 

elderly. Mitral valve regurgitation affects approximately 2.3 percent of adults aged 60 to 69 

and 5.5 percent of adults older than age 70.27 It is the second most common reason for valve 

surgery in older adults. Mechanical valves have longer durability than bioprosthetic valves 

but are associated with the risks of valvular thrombosis and systemic emboli. Thus, patients 

with mechanical valves require lifelong anticoagulation. Because of their longer durability, 

mechanical heart valves are recommended for younger patients (< 65 years of age) who are 

willing to take oral anticoagulants (e.g., warfarin) and comply with continuous anticoagulation 

monitoring.28 

THERAPEUTIC OPTIONS FOR ANTICOAGULATION 

The pharmacological properties of anticoagulants considered in this report are summarized 

in Table 1. The conventional management of acute VTE requires the use of a parenteral 

anticoagulant for 5 to 7 days, overlapping with longer term warfarin. Parenteral anticoagulants 

used in conjunction with warfarin include unfractionated heparin administered intravenously, 

low molecular weight heparin administered subcutaneously, and fondaparinux administered 

subcutaneously.25 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.29 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.30 

There is much experience with warfarin treatment among patients and care providers alike and, 

although bleeding remains a concern,31 protocols and guidelines are available for reversal of 

overanticoagulation using vitamin K and blood products.32-35 However, warfarin therapy has 

several disadvantages, including its narrow therapeutic window and wide interindividual and 

intraindividual variability in anticoagulant effect. This variability dictates the need for continuous 

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and regular monitoring to maintain patients within the desired therapeutic range. Monitoring 

warfarin therapy is achieved through measurement of the international normalized ratio (INR), 

which is dependent on the prothrombin clotting time. However, despite regular monitoring, 

30 to 50 percent of INR values fall outside target range.36 Furthermore, patients find repeated 

venipuncture for dose monitoring tedious, and health care providers find it costly.37 

Warfarin also interacts with a long list of food, herbal medicines, vitamins, and drugs; and the 

list of drugs is continuously expanding.38 This list should be taken into consideration every time 

there is a change in the patient’s medications. In addition, patients on long-term warfarin therapy 

may need bridging with heparin before a planned procedure. Depending on the procedure, this 

may entail admission to the hospital preoperatively, which is costly and inconvenient for patients. 

Newer Oral Anticoagulants 

The search has been ongoing for novel oral anticoagulants with equal efficacy, a wider 

therapeutic range, and less complex pharmacodynamics, thus precluding the need for routine 

laboratory monitoring. Over the past decade, several newer oral anticoagulants have emerged. 

These anticoagulants fall under two drug classes: (1) factor Xa (FXa) inhibitors and (2) direct 

thrombin inhibitors (DTIs). These drugs characteristically have a predictable anticoagulant 

effect, eliminating the need for routine monitoring. However, patients on newer oral 

anticoagulants should still be monitored for any adverse effects, 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.39,40 Newer anticoagulants have 

a faster onset of action, so there is no need to overlap with a parenteral agent when starting 

thromboprophylaxis—as is the case with warfarin. While the reversal of warfarin is necessary 

in some cases of overanticoagulation, oral anticoagulants from these two classes have a shorter 

half-life, thus minimizing the need for an antidote (Table 1). 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. 

Factor Xa inhibitors 

The coagulation cascade consists of two intertwined pathways—the intrinsic and extrinsic— 

which, when activated, result in a fibrin clot that stops bleeding. Both the intrinsic and extrinsic 

pathways converge in FX activation, making activated FX (FXa) an obvious target for 

anticoagulant therapy. Several FXa inhibitors have been developed for clinical use, including 

rivaroxaban and apixaban. Rivaroxaban was approved in Canada and the European Union for 

thromboprophylaxis after orthopedic surgery. It was approved in July 2011 by the U.S. Food and 

Drug Administration (FDA) for prophylaxis of venous thromboembolism in adults undergoing 

orthopedic surgery. In November 2011, the FDA approved rivaroxaban for stroke prophylaxis 

in patients with AF. Apixaban has also shown promise in clinical trials, and is currently 

under priority review by the FDA.41 Other FXa inhibitors that are currently under clinical 

development include edoxaban and betrixaban. Edoxaban is being evaluated in a large Phase III 

trial, ENGAGE AF TIMI (Effective aNticoaGulation with factor xA next GEneration in Atrial 

Fibrillation–Thrombolysis In Myocardial Infarction study 48), comparing two different doses 

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of edoxaban with warfarin for prevention of stroke in patients with AF.42 The study has finished 

recruitment and is projected to be completed in March 2012. Another ongoing trial is evaluating 

edoxaban for the treatment of VTE. (NCT00986154; see Appendix F, Table F-2) 

Direct thrombin inhibitors 

DTIs are another class of oral anticoagulants rapidly emerging in the clinical arena. Ximelagatran 

was the first DTI to be used clinically but is currently no longer available due to liver toxicity. 

Dabigatran etexilate is an oral, reversible DTI that was approved by the FDA in October 2010 for 

stroke prevention in AF. Renal excretion is the predominant elimination pathway for dabigatran, 

with more than 80 percent of systemically available dabigatran eliminated unchanged.43 This 

capability may prove significant in the AF patient population since renal function declines with 

age, increasing the potential for prolonged elimination in older adults and greater anticoagulant 

effect.44 In contrast to warfarin, dabigatran is not metabolized by the liver’s cytochrome P 450 

(CYP) enzyme system, yielding a better drug interaction profile.43 Dabigatran acts as a substrate 

for the p-glycoprotein transporter system, which makes it more prone to drug-drug interactions. 

Coadministration of dabigatran with other p-glycoprotein substrate drugs, while affecting the 

pharmacokinetics, has not been shown to result in significant changes in coagulation parameters, 

including prothrombin time, activated prothrombin time, and ecarin clotting time.45 Despite this 

lack of change in standard coagulation parameters, bleeding risk may be increased. ZD 0837 is 

another oral DTI under development in Phase II clinical trials. 

Although these two newer classes of oral anticoagulants have the advantage of a predictable 

anticoagulant effect, drug acquisition costs are substantially higher than for warfarin. The cost 

of dabigatran therapy is approximately $3000 per year. This is substantially more than the price 

of warfarin, which is approximately $48 per year, even after adding the modest expense of INR 

testing and provider visits to adjust the dose.46 

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l anticoagulants 

 K Antagonists FXa Inhibitors Direct Thrombin Inhibitors 

Warfarin Rivaroxaban Apixaban Edoxaban Dabigatran Ximelagatran 

of hepatic 

 of vitamin 

ent coagulation 

Direct inhibition of FXa Direct inhibition of FXa Direct inhibition of FXa Direct inhibition of clot- bound and free thrombin (FIIa) Direct inhibition of thrombin (FII) 

0.5–3 3 1.5 2–3 1.6–1.9 

5–9 (9–13 in elderly) 8–13 9–11 14–17 4–5 

80 66 50 6.5 20 

dose based on 

e daily 20 mg; once daily 5 mg; twice daily 30 mg or 60 mg; once daily 150 mg; twice daily Not available in the U.S. 

using INR 

Not required In case of hemorrhage or renal impairment, FXadependent assays may be used47 

Not required due to predictable pharmacokinetics In hemorrhage or renal impairment, FXadependent assays may be used47 

Not required due to predictable pharmacokinetics 

Not required except in subgroups such as patients with renal impairment 48 

Ecarin clotting time can be used if needed49 

Not required 

ted unchanged in 

66% renal elimination 50% renal elimination 45% renal elimination 80% renal elimination Main route of elimination 

 CYP1A2, 

nhibitors 

tamin K50 

Potent CYP3A4 inhibitors and P-glycoprotein inhibitors50 

Potent CYP3A4 inhibitors50 

P-glycoprotein inhibitors43 

P-glycoprotein inhibitors Proton pump inhibitors38 

NA 

, fresh frozen 

rothrombin 

concentrate, 

ant FVIIa51 

FVIIa partially reverses rivaroxaban anticoagulant effect52 

Prothrombin complex concentrate completely reverses its anticoagulant effect53 

No available antidote No available antidote It is partially dialyzable54 NA 

ctive bleeding, 

y, breast 

ocumented 

sitivity55 

nal impairment 

ar filtration rate 

min/1.73m2)39 

Severe active bleeding; severe renal impairment39 

Severe active bleeding; severe renal impairment 

Severe active bleeding; severe renal impairment 

Severe active bleeding, severe renal impairment39 NA 

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 K Antagonists FXa Inhibitors Direct Thrombin Inhibitors 

Warfarin Rivaroxaban Apixaban Edoxaban Dabigatran Ximelagatran 

laxis and treat

f thromboembolic 

cations associ

th AF and or carlve replacement 

laxis and treat

f venous throm

nd its extension, 

ary embolism 

ion in the risk of 

recurrent myo

infarction, and 

oembolic events 

s stroke or sys

mbolization after 

rdial infarction 

Prevention of VTE in patients undergoing orthopedic surgery and prevention of stroke in AF 

None None Prevention of stroke in AF None 

CYP = cytochrome P450; INR = international normalized ratio; NA = not applicable; VTE = venous thromboembolism 

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OBJECTIVE OF THIS REPORT 

The Veterans Health Administration (VHA) System serves a largely older, male population with 

a high prevalence of chronic AF and VTE. Many veterans with chronic AF have risk profiles for 

stroke that, according to current clinical guidelines, place them in a risk group where chronic 

anticoagulation is recommended. Adjusted-dose warfarin has been the preferred approach to 

chronic anticoagulation in the VHA, and in many VHA settings, specialized therapeutic drugmonitoring services provide high-quality warfarin treatment. However, the advent of newer 

anticoagulants with the promise of simplified long-term anticoagulation requires reconsideration 

of current treatment practices. The purpose of this systematic review was to study the 

comparative effectiveness of warfarin and the newer oral anticoagulants used for the long-term 

prevention and treatment of arterial and venous thromboembolism. An evaluation of newer oral 

anticoagulants for VTE prophylaxis in the perioperative period will be the subject of a later 

report. 

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METHODS 

TOPIC DEVELOPMENT 

This review was commissioned by the VA’s Evidence-based Synthesis Program. The topic was 

nominated after a topic refinement process that included a preliminary review of published 

peer-reviewed literature, consultation with internal partners and investigators, and consultation 

with key stakeholders. We further developed and refined the key questions (KQs) based on a 

preliminary review of published peer-reviewed literature in consultation with VA and non-VA 

experts. 

The final key questions (KQs) were: 

Key Question 1. For patients with chronic nonvalvular AF, what is the comparative effectiveness 

of long-term anticoagulation using newer oral anticoagulants versus warfarin on stroke 

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

Key Question 2. For patients with venous thromboembolism, are there differential effects 

of newer oral anticoagulants versus warfarin or low molecular weight heparins on recurrent 

thromboembolism, mortality, HRQOL, and patient treatment experience? 

Key Question 3. For patients with mechanical heart valves, what is the comparative effectiveness 

of newer oral anticoagulants versus warfarin on the incidence of thromboembolic complications, 

mortality, HRQOL, and patient treatment experience? 

Key Question 4. When used for long-term anticoagulation treatment, what is the nature and 

frequency of adverse effects for newer oral anticoagulants versus warfarin? 

ANALYTIC FRAMEWORK 

We followed a standard protocol for all steps of this review; certain methods map to the PRISMA 

checklist.56 Our approach was guided by the analytic framework shown in Figure 1. 

Figure 1. Analytic framework for the comparative effectiveness of newer oral anticoagulants 

Adults with history of 

atrial fibrillation, venous 

thromboembolism, or 

mechanical heart valves 

KQs 

1–3 

KQ 4 

Newer oral 

anticoagulants (DTIs 

and FXa inhibitors) 

versus warfarin 

Rates of arterial 

and venous 

thromboembolic 

events 

Adverse effects of 

treatment 

All-cause mortality and 

thrombosis-related 

mortality, HRQOL, 

patient experience 

Abbreviations: DTI = direct thrombin inhibitors; FXa = factor X inhibitors; HRQOL = health-related quality of life; KQ = key 

question 

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SEARCH STRATEGY 

We searched MEDLINE® (via PubMed®), Embase®, and the Cochrane Database of Systematic 

Reviews for peer-reviewed publications comparing the newer oral anticoagulants to standard care 

(usually VKAs) from January 2001 (the year newer oral anticoagulants were introduced) through 

May 2011. Our search strategy used the National Library of Medicine’s medical subject headings 

(MeSH) keyword nomenclature and text words for newer oral anticoagulants, the conditions of 

interest, and validated search terms for randomized controlled trials.57 Our final search terms 

included new or novel oral anticoagulants; DTIs, including dabigatran, and ximelagatran; FXa 

inhibitors, including edoxaban, rivaroxaban, apixaban, betrixaban, YM150; and the names of the 

conditions of interest—atrial fibrillation, venous thromboembolism, and mechanical heart valves. 

We limited the search to articles published in the English language involving human subjects 18 

years of age and older. The full search strategy is provided in Appendix A. Following peer review 

of the draft report, we conducted a supplemental search of PubMed to identify observational 

studies or systematic reviews that addressed adverse effects of the newer oral anticoagulants. 

We also examined the FDA Web site, Drugs@FDA, to identify safety concerns. These included 

Drug Alerts and Statements (www.fda.gov/Drugs/DrugSafety/ucm215175.htm) and Drug Safety 

Communications (www.fda.gov/Drugs/DrugSafety/ucm199082.htm) in addition to the Advisory 

Committee Briefing Documents, the Center for Drug Evaluation and Research Summary Review, 

and the medical and statistical summary reports on the two newer oral anticoagulants (dabigatran 

and rivaroxaban) that have been FDA-approved. These supplemental searches along with an 

updated search for RCTs in PubMed were conducted in February 2012. We developed our search 

strategy in consultation with an experienced search librarian. 

We supplemented the electronic searches with a manual search of citations from a set of 

key primary and review articles.58-70 The reference list for identified pivotal articles was 

manually hand-searched and cross-referenced against our library in order to retrieve additional 

manuscripts. All citations were imported into two electronic databases (EndNote® Version 

X5; Thomson Reuters, Philadelphia, PA, for referencing and DistillerSR for data abstraction). 

As a mechanism to assess the risk of publication bias, we searched www.clinicaltrials.gov for 

completed but unpublished studies. 

STUDY SELECTION 

Using prespecified inclusion and exclusion criteria, two reviewers assessed titles and abstracts 

for relevance to the KQs. Full-text articles identified by either reviewer as potentially relevant 

were retrieved for further review. Each article retrieved was examined by two reviewers against 

the eligibility criteria (Appendix B). Disagreements on inclusion, exclusion, or major reason for 

exclusion were resolved by discussion or by a third reviewer. 

The criteria to screen articles for inclusion or exclusion at both the title-and-abstract and full-text 

screening stages are detailed in Table 2. We modified these criteria for observational studies of 

adverse effects to include noncomparative studies (i.e., case reports, case series), nonrandomized 

comparative studies (i.e., cohort studies, case-control studies, controlled pre–post studies), and 

studies of any treatment duration. Studies excluded at the full-text review stage are listed with 

the reasons for exclusion in Appendix C. 

17 
 

 

 

 

 

 

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Table 2. Summary of inclusion and exclusion criteria 

Study characteristic Inclusion criteria Exclusion criteria 

Population Adults (≥18 years) of age with a history of 

chronic nonvalvular atrial fibrillation, venous 

thromboembolism, or mechanical heart valve 

replacement 

Pregnant women 

Intervention Newer oral anticoagulants: direct thrombin 

inhibitors and factor Xa inhibitors 

Newer anticoagulants requiring intravenous 

or subcutaneous administration 

Comparator Warfarin or low molecular weight heparin None 

Outcome Any of the following: symptomatic thromboembolic event, mortality, health-related quality 

of life, adverse effects, patient experience 

No relevant outcomes 

Timing • KQ 1 and KQ 3: ≥ 12 months

• KQ 2: ≥ 6 months

< 6 months anticoagulation 

Setting Outpatient settings; may include initial 

hospitalization for acute anticoagulation 

None 

Study design KQs 1–4: Randomized controlled trials (RCTs) 

or secondary data analysis from an RCT 

KQ 4: Observational studies including 

noncomparative and nonrandomized 

comparative studies 

• Cross-sectional studies

• Phase I clinical trials

• Sample size < 50

Publications • English-language only

• Published from 2001 to present

• Peer-reviewed article

• Non-English language publication

• Published before 2001a 

a

Newer oral anticoagulants were first introduced in 2001. 

Abbreviations: KQ = key question; RCT = randomized controlled trial 

DATA ABSTRACTION 

Before general use, the abstraction form templates designed specifically for this report were pilot 

tested on a sample of included articles and revised to ensure that all relevant data elements were 

captured and that there was consistency and reproducibility between abstractors. Select data from 

published reports were then abstracted into the final abstraction form (sample form is in Appendix D) 

by one trained reviewer. All data abstractions were confirmed by a second reviewer. Disagreements 

were resolved by consensus or by obtaining a third reviewer’s opinion when consensus could not be 

reached. We abstracted the following key information for each included study: 

•		 age 

•		 sex 

•		 indication for anticoagulation 

•		 baseline bleeding risk or factors associated with increased risk (e.g., creatinine >1.5, 

history of gastrointestinal bleeding) 

•		 study drug and dosage 

•		 comparator and quality of INR control 

•		 length of treatment 

•		 study design 

• number of subjects and retention data
 

• outcomes/adverse effects
 

•		 for case studies, the sequence of clinical events 

In addition, we examined included articles for subgroup analyses of particular relevance to the 

population served by VHA. 

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QUALITY ASSESSMENT 

Data necessary for assessing quality and applicability, as described in the Agency for Healthcare 

Research and Quality’s (AHRQ’s) Methods Guide for Effectiveness and Comparative 

Effectiveness Reviews,

71 also were abstracted. For RCTs, these key quality criteria consisted 

of (1) adequacy of randomization and allocation concealment, (2) comparability of groups 

at baseline, (3) blinding, (4) completeness of follow up and differential loss to follow up, (5) 

whether incomplete data were addressed appropriately, (6) validity of outcome measures, and 

(7) conflicts of interest. Using these quality criteria, we assigned a summary quality score (good, 

fair, poor) to individual RCTs studies as defined by the AHRQ Methods Guide.

71 The criteria 

were applied for each study by the reviewer abstracting the article; this initial assessment was 

then over-read by a second reviewer. Disagreements were resolved between the two reviewers or, 

when needed, by arbitration from a third reviewer. Observational studies consisted only of case 

studies and were not quality rated. 

DATA SYNTHESIS 

We critically analyzed studies to compare their characteristics, methods, and findings. We 

then determined the feasibility of completing a quantitative synthesis (i.e., meta-analysis) by 

exploring the volume of relevant literature, the completeness of the results reporting and the 

conceptual homogeneity of the studies. When a meta-analysis was appropriate, we used randomeffects models to synthesize the available evidence quantitatively. For three-arm studies that 

included more than one dose of the newer oral anticoagulant, we used data from the treatment 

arm using the standard FDA-approved dose. We conducted sensitivity analyses by (1) including 

the studies that evaluated ximelagatran, a newer anticoagulant that is not available, (2) using the 

other dose of the newer anticoagulant in three-arm studies, and (3) using revised data on adverse 

effects from the trial by Eikelboom et al.72 When there were sufficient studies, we conducted a 

mixed-effects analysis to compare treatment effects by drug class. These later analyses should 

be considered hypothesis-generating because they consist of indirect comparisons (across 

studies that may differ in ways other than the drug class) and thus are subject to confounding. 

Heterogeneity was examined among the studies using graphical displays and test statistics 

(Cochran’s Q and I2); the I

2 describes the percentage of total variation across studies due to 

heterogeneity rather than to chance.73 Heterogeneity was categorized as low, moderate, or high 

based on I

2

 values of 25 percent, 50 percent, and 75 percent respectively. 

The outcomes for this report were binary; we therefore summarized these outcomes by a 

weighted-effect measure for proportions (e.g., risk ratio). We present summary estimates and 95 

percent confidence intervals (CIs). When there were statistically significant treatment differences, 

we estimated the absolute treatment effect by calculating the risk difference. Risk difference was 

calculated using the median event rate from the control treatments and the summary risk ratio.74 

These results are presented in the strength of evidence tables (in the Summary and Discussion 

section). 

Because AF, venous thromboembolism, and mechanical heart valve replacement are distinct 

clinical entities with distinct primary endpoints, we examined the groups of studies as they 

pertained to these diagnoses separately. For KQ 4 (adverse effects), we analyzed common 

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outcomes (e.g., death, major bleeding) across treatment indications. All analyses were conducted 

using Review Manager (RevMan) 5.1.4. (Copenhagen: The Nordic Cochrane Centre, The 

Cochrane Collaboration, 2011). 

RATING THE BODY OF EVIDENCE 

In addition to rating the quality of individual studies, we evaluated the overall quality of the 

evidence for each KQ as described in the Methods Guide.

71 In brief, this approach requires 

assessment of four domains: risk of bias, consistency, directness, and precision. Additional 

domains considered were strength of association (magnitude of effect) and publication bias. 

For risk of bias, we considered basic (e.g., RCT) and detailed study design (e.g., adequate 

randomization). We used results from meta-analyses when evaluating consistency (forest 

plots, tests for heterogeneity), precision (CIs), strength of association (odds ratio [OR]), and 

publication bias (www.clinicaltrials.gov survey). Optimal information size and consideration 

of whether the CI crossed the clinical decision threshold using a therapy were also used when 

evaluating precision.75 These domains were considered qualitatively, and a summary rating of 

high, moderate, low, or insufficient strength of evidence was assigned after discussion by two 

reviewers. This four-level rating scale consists of the following definitions: 

•		 High—Further research is very unlikely to change our confidence on the 

estimate of effect. 

•		 Moderate—Further research is likely to have an important impact on our 

confidence in the estimate of effect and may change the estimate.
	

•		 Low—Further research is very likely to have an important impact on our 

confidence in the estimate of effect and is likely to change the estimate.
	

•		 Insufficient—Evidence on an outcome is absent or too weak, sparse, or 

inconsistent to estimate an effect. 

When a rating of high, moderate, or low was not possible or was imprudent to make, a grade of 

insufficient was assigned.76 We also considered the risk of publication bias. Publication bias was 

addressed through a careful search of www.clinicaltrials.gov (March 2012) for identification of 

any study completed but unpublished or ongoing. We did not use graphical (e.g., funnel plots) 

or test statistics (e.g., Beggs test) because these methods do not perform well with fewer than 10 

studies. 

PEER REVIEW 

A draft version of the report was reviewed by technical experts and clinical leadership. A 

transcript of their comments can be found in Appendix E, which elucidates how each comment 

was considered in the final report. 

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Warfarin and Newer Oral Anticoagulants: 

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RESULTS 

LITERATURE SEARCH 

The flow of articles through the literature search and screening process is illustrated in Figures 

2 and 3. Our search for RCTs (Figure 2) identified 594 unique citations from a combined 

search of MEDLINE via PubMed (n = 338), Embase (n = 178), and the Cochrane Database of 

Systematic Reviews (n = 78). Manual searching of included study bibliographies and review 

articles identified an additional 17 citations for a total of 611 unique citations. After applying 

inclusion and exclusion criteria at the title-and-abstract level, 80 full-text articles were retrieved 

and screened. Of these, 56 were excluded at the full-text screening stage, leaving 24 articles 

(representing 8 unique studies) for data abstraction. 

Our search of the observational literature including systematic reviews via PubMed (Figure 

3) identified 369 unique citations. An additional 8 citations were identified from personal 

communications of experts and bibliographies of included studies for a total of 377 unique 

citations. After applying inclusion and exclusion criteria specifically for observational designs 

at the title-and-abstract level, 28 full-text articles were retrieved and screened. Of these, 10 

contained new data and were abstracted either as unique studies (n = 7)70,77-82 or as additional 

analyses from earlier trials (n = 3).72,83,84 

Appendix C provides a complete listing of published articles excluded at the full-text screening 

stage, with reasons for exclusion. 

Our search of the FDA website, Drugs@FDA, identified two MedWatch reports of adverse 

events with dabigatran (QuarterWatch 10/6/2011 and 1/12/2012) and one FDA Drug Safety 

Communication on dabigatran. We also examined the FDA Advisory Committee Briefing 

Reports, FDA Summary Reviews, and the medical and statistical reviews on dabigatran and 

rivaroxaban. These reports are detailed under KQ 4. 

Finally, we searched www.clinicaltrials.gov, which revealed nine unpublished studies that met 

our eligibility criteria (Appendix F). Of these, four are ongoing trials and two have completed 

data collection within the last 6 months. The other three trials (NCT00645853, NCT00448214, 

NCT00329238) were scheduled for completion more than a year ago (between 2008 and 2010). 

Of these, two examined chronic AF and one examined venous thromboembolism. When the 

sponsors were contacted, we received the following information: (1) A 5-year RCT of AZD0837 

in patients with chronic AF (NCT00645853) was terminated early due to “a limitation in the 

long-term stability of the AZD0837 drug product”; (2) development of darexaban maleate 

(YM150, examined in NCT00448214) was stopped for financial reasons prior to Phase III 

trials; and (3) an abstract reporting longer term outcomes (NCT00329238) from the dabigatran 

RECOVER study85 was presented at the 2011 International Symposium on Hemostasis and 

Thrombosis in Kyoto, Japan. 

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Figure 2. Literature flow diagram for RCTs 

Search results = 611 references Excluded = 531 references 

Excluded at title/abstract level 

Retrieved for full-text review = 

80 references 

Excluded = 56 references 

Not full publication, peer-reviewed, 

or primary data = 23 

Not study population of interest = 2 

New drug or comparator not of interest = 22 

No relevant outcomes reported at ≥ 6 months = 9 

Included = 8 unique studies + 16 

companion articles* 

KQ 1 (AF population) 

5 studies + 14 

companion articles 

KQ 2 (VTE 

population) 

3 studies + 14 

companion articles 

KQ 3 (mechanical 

heart valve 

population) 

No eligible studies 

KQ 4 (adverse 

effects) 

8 studies + 16 

companion articles 

*See Glossary for definition of companion articles. 

Abbreviations: AF = atrial fibrillation; VTE = venous thromboembolism; KQ = key question 

Figure 3. Literature flow diagram for observational studies and systematic reviews 

Search results = 377 references 

Retrieved for full-text review = 

28 references 

Included = 7 unique studies + 3 

companion articles* 

Excluded = 349 references 

Excluded at title/abstract level 

Excluded = 18 references 

Background articles† = 8 

Not population of interest = 4 

Not full publication = 3 

Not good quality = 2 

Outcome not of interest = 1 

KQ 4 (adverse effects) 

7 studies + 3 companion articles 

*See Glossary for definition of companion articles. 

†

Articles excluded but used for information in introduction or discussion. 

Abbreviations: KQ = key question 

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STUDY CHARACTERISTICS 

Randomized Controlled Trials 

We identified 8 randomized studies involving 66,449 subjects.85-92 Five studies evaluated 

newer oral anticoagulants for chronic AF, and three studies examined the treatment of venous 

thromboembolism; no study evaluated newer oral anticoagulants for patients with mechanical 

heart valves. All studies compared newer oral anticoagulants to adjusted-dose warfarin; there 

were no direct comparisons between newer oral anticoagulants. 

Seven studies were conducted in multisite trials that included U.S. sites and one study was 

conducted outside the United States. None of the studies were conducted in VA settings. All 

studies were judged good quality (Appendix G), although there were design features that may 

have affected the findings: (1) patients not blinded to treatment assignment (seven of eight 

studies), (2) uncertainty whether outcomes assessors were blinded to treatment status (one 

study),87 and (3) uncertainty whether all outcomes were reported (one study).89 

For the five studies conducted in patients with chronic AF, key exclusion criteria were marked 

renal impairment (5 studies), aspirin use of more than 100 mg (4 studies) or more than 165 mg 

daily (1 study), uncontrolled hypertension (4 studies), prior stroke (4 studies), significant anemia 

(4 studies), and platelet count lower than 90,000 to 100,000 (4 studies). Exclusion criteria were 

somewhat less stringent for the VTE studies. For the three VTE studies, key exclusion criteria 

were marked renal impairment (3 studies), uncontrolled hypertension (1 study), prior stroke (1 

study), and low platelet count (1 study). Table 3 presents an overview of study characteristics of 

the included studies, and Table 4 provides further details. 

Table 3. Overview of study characteristics for included RCTs 

Study Characteristic Chronic Atrial Fibrillation 

Number of studies (patients) 

Venous Thromboembolism 

Number of studies (patients)a 

Studies 5 (57,908) 3 (8541) 

Factor Xa inhibitors 

Apixaban

 Rivaroxaban 

Direct thrombin inhibitors

 Dabigatran

 Ximelagatran 

1 (18,201) 

1 (14,262) 

1 (18,113) 

2 (7332) 

– 

1 (3449) 

1 (2564) 

1 (2528) 

Study country

 Multiple countries (with U.S.)

 Multiple countries (without U.S.) 

4 

1 

3 

– 

Study duration 

6 months

 6–12 months

 >12 months–2 years 

– 

– 

5 (57,908) 

2 (5092) 

1 (3449) 

– 

Mean age 

Age 50–59 

Age 60–69 

Age 70–75 

– 

– 

5 (57,908) 

3 (8541) 

– 

– 

Funding source

 Industry

 Government 

5 

– 

3 

– 

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Study Characteristic Chronic Atrial Fibrillation 

Number of studies (patients) 

Venous Thromboembolism 

Number of studies (patients)a 

Outcomes reported

 Mortality 

Thromboembolic-related mortality 

Thromboembolic events

 Major bleeding 

Adverse effects

 Health-related quality of life

 Patient treatment experience 

5 

4 

5 

5 

5 

– 

– 

3 

3 

3 

3 

3 

– 

– 

Study quality

 Good 5 3 

a

Represents number of patients randomized but does not include the third treatment arm (110 mg dabigatran) from Connolly et 

al., 2009. 

Table 4. Details of study characteristics 

Study RCT n Qualitya Intervention vs. 

Comparator Outcome Measuresb Adverse Effects 

Chronic nonvalvular AF: KQ 1 and KQ 4 

Albers et n = 3922 Good Ximelagatran (DTI) All-cause mortality Serious adverse events 

al., 200588 36 mg vs. warfarin Death–thromboembolic 

(SPORTIF V event 

study) Stroke–ischemic 

Stroke–hemorrhage 

Peripheral embolism 

Connolly et n = 18113 Good Dabigatran (DTI) All-cause mortality Major bleeding 

al., 200987 150 mg vs. warfarin Death–thromboembolic Fatal bleeding 

(RELY study) event 

Stroke–hemorrhage 

Combined stroke 

Peripheral embolism 

Myocardial infarction 

Intracranial bleeding 

Granger et n = 18201 Good Apixaban (FXa) 5 All-cause mortality Adverse effects drug 

al., 201192 mg vs. warfarin Death–thromboembolic discontinuation 

(ARISTOTLE event Major bleeding study) Stroke–ischemic 

Stroke–hemorrhage 

Combined stroke 

Peripheral embolism 

Major bleeding requiring 

transfusion 

Myocardial infarction 

Intracranial bleeding 

Olsson et n = 3410 Good Ximelagatran (DTI) All-cause mortality NR 

al., 200390 36 mg vs. warfarin Death–thromboembolic 

(SPORTIF III event 

study) Stroke–ischemic 

Stroke–hemorrhage 

Peripheral embolism 

Patel et n = 14264 Good Rivaroxaban (FXa) All-cause mortality Major bleeding 

al., 201191 20 mg vs. warfarin Stroke–ischemic Fatal bleeding 

(ROCKET-AF Stroke–hemorrhage Major bleeding requiring 

study) Combined stroke transfusion 

Myocardial infarction 

Intracranial bleeding 

Venous thromboembolism: KQ 2 and KQ 4 

Bauersachs n = 3449 Good Rivaroxaban (FXa) All-cause mortality Major bleeding 

et al., 200586 20 mg vs. warfarin Death–thromboembolic 

(EINSTEIN- event 

DVT study) Recurrent DVT 

PE 

Recurrent DVT/PE 

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Study RCT n Qualitya Intervention vs. 

Comparator Outcome Measuresb Adverse Effects 

Fiessinger 

et al., 200589 

(THRIVE 

study) 

n = 2528 Good Ximelagatran (DTI) 

36 mg vs. warfarin 

All-cause mortality 

Recurrent DVT 

PE 

Recurrent DVT/PE 

Major bleeding 

Schulman et 

al., 200985 

(RECOVER 

study) 

n = 2564 Good Dabigatran (DTI) 

150 mg vs. warfarin 

All-cause mortality 

Death–thromboembolic 

event 

Recurrent DVT 

PE 

All adverse effects 

Serious adverse events 

Adverse effects drug 

discontinuation 

Major bleeding 

Myocardial infarction 

a

Study quality assessed using key quality criteria described in Methods Guide for Effectiveness and Comparative Effectiveness 

Reviews 

b

Outcomes limited to those with direct relevance to KQs 1, 2, and 4 (i.e., chronic AF, venous thromboembolism, adverse effects). 

Abbreviations: DTI= direct thrombin inhibitors; DVT = deep venous thrombosis; FXa = factor Xa inhibitor; PE = pulmonary 

embolism 

KEY QUESTION 1: For patients with chronic nonvalvular AF, what 

is the comparative effectiveness of long-term anticoagulation using 

newer oral anticoagulants versus warfarin on stroke incidence, 

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

experience? 

We identified five good-quality studies relevant to KQ 1, which involved 57,908 patients. 

All studies were funded by the pharmaceutical industry. These studies compared apixaban,92 

dabigatran,87 rivaroxaban,91 and ximelagatran88,90 to adjusted-dose warfarin. Two studies91,92 

modified the drug dose for patients with impaired renal function. In the study by Granger et al.,92 

this was due to older age (>80 years), lower weight (<60 kg), or high creatinine (>1.5 mg/dl). In 

the study by Patel et al.,91 this was due to creatinine clearance less that 30 mL/minute. The mean 

age of participants in all studies was over 70 years; about 55 percent were men. CHADS2 stroke 

risk scores averaged approximately 2.1 in the studies evaluating dabigatran and apixaban87,92 and 

3.5 in the study evaluating rivaroxaban;91 two studies did not report CHADS2 scores.88,90 Average 

adherence to the intervention drugs was greater than 90 percent for two studies88,90 and in another 

study, 79 percent of participants took at least 80 percent of prescribed medication doses87; two 

studies did not report adherence.91,92 In the control groups, the percentage of time in the INR 

target range was 55 to 68 percent (median 66%). All studies planned outcomes assessment over 

24 months; none reported effects on HRQOL or patient experience. Study characteristics are 

summarized in Table 5. 

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Table 5. Summary table for KQ 1—chronic atrial fibrillation 

Study Characteristic Number of Studies (Patients)a 

Total number of studies (patients) 5 studies (57,908) 

Factor Xa inhibitors, dose 

Apixaban, 5 mg twice daily 1 (18,201) 

Rivaroxaban, 20 mg daily 

Direct thrombin inhibitors, dose

1 (14,262) 

Dabigatran, 150 mg twice daily 1 (18,113) 

Ximelagatran, 36 mg twice daily 2 (7,332) 

Mean age 

50–60 years

 60–70 years 

≥70 years 

– 

– 

5 (57,908) 

Sexb

 Men

 Women 

5 (33107) 

5 (18785) 

Baseline CHADS2 stroke risk scorec 

≤1 3 (10,207) 

2 3 (12,742) 

≥3 3 (20,822) 

NR 2 

Adjusted-dose warfarin range 

Time above range (%) 1 (12%), 4 NR 

Time in range (%) 5 (median 66%, range: 55–68%) 

Time below range (%) 1 (20%), 4 NR 

a

Does not include the third treatment arm (110 mg dabigatran) from Connolly et al., 2009.
 b

Does not match randomized total because some patient characteristics were reported only for those subjects analyzed.
 c

CHADS2 is a clinical score ranging from 0 to 6 used to predict the annual risk of stroke in individuals with chronic nonvalvular 

AF.
 

Abbreviations: NR = not reported 

Meta-Analyses for KQ 1 

We used random-effects model meta-analyses to evaluate the effects of newer oral anticoagulants 

compared with adjusted-dose warfarin on mortality, risk of ischemic and hemorrhagic stroke, 

major bleeding, fatal bleeding, myocardial infarction, liver dysfunction, and drug discontinuation 

due to an adverse event (Table 6, Figures 4–9). For our primary analyses, we excluded the studies 

using ximelagatran since this drug is not available in the U.S. All-cause mortality (summary RR 

0.88; 95% CI, 0.82 to 0.95), hemorrhagic stroke (RR 0.46; CI, 0.31 to 0.68), hemorrhagic or 

ischemic stroke (RR 0.77; CI, 0.67 to 0.88), and fatal bleeding (RR 0.55; CI, 0.41 to 0.76) were 

lower with the newer oral anticoagulants. Tests for heterogeneity suggest important variability 

in treatment effects across studies for death due to thromboembolism, hemorrhagic stroke, drug 

discontinuation due to adverse effects, major bleeding, and myocardial infarction. 

There were too few studies to conduct quantitative analyses for factors that may be associated 

with variable treatment effects. However, a qualitative inspection shows differences in the study 

eligibility criteria that may contribute to differential treatment effects. The study by Patel et 

al.91 found the greatest effect on mortality and enrolled an older patient population with higher 

CHADS2 scores than the other studies.9 Older age is a risk factor for both thrombosis and 

bleeding,22,93 and a higher CHADS2 score is associated with a higher risk of stroke, systemic 

embolism, and death.94 Variation in effects may also be related to different definitions for 

outcomes. For example, adverse effects leading to drug discontinuation include liver disease 

and bleeding. Liver disease was defined in two of three included AF studies as liver enzymes 

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elevated to twice the upper limit of normal,87,92 while one study defined it as three or more times 

the upper limit of normal.91 

We conducted two sensitivity analyses, first by including studies of ximelagatran and second by 

using the data from the dabigatran 110 mg treatment arm instead of the 150 mg treatment arm 

in the study by Connolly et al.87 When the two studies examining ximelagatran are included, 

results are similar except that drug discontinuation due to adverse effects and rates of liver 

dysfunction are significantly higher than rates with adjusted-dose warfarin. Using data from the 

dabigatran 110 mg treatment arm, risk ratios did not differ by more than 10 percent except for 

ischemic stroke (summary RR 1.0; 95% CI, 0.88 to 1.13) and peripheral emboli (RR 1.03; CI, 

0.61 to 1.74). Summary risk ratios and tests for variability in treatment effects across studies are 

summarized in Table 6. There were too few studies to conduct meaningful analyses by drug class 

or statistical tests for publication bias. However, our search of www.clinicaltrials.gov did not 

suggest publication bias. 

Table 6. Effects of newer oral anticoagulants compared with adjusted-dose warfarin for chronic AF 

Outcome 

Summary Risk 

Ratios 

(95% CI) 

Test for 

Heterogeneity 

Summary Risk 

Ratios 

(95% CI) 

Test for 

Heterogeneity 

Non-ximelagatran studies (n = 3) All studies (n = 5) 

All-cause mortality 0.88 (0.82 to 0.95) Q = 0.49, I2

 = 0% 

p = 0.78 0.89 (0.83 to 0.96) Q = 1.15, I2

 = 0% 

p = 0.89 

Death–thromboembolica 

0.77 (0.57 to 1.03) Q = 2.23, I2

 = 55% 

p = 0.14 0.91 (0.61 to 1.36) Q = 7.85, I2

 = 62% 

p = 0.05 

Stroke–ischemic 0.89 (0.78 to 1.02) Q = 1.77, I2

 = 0% 

p = 0.41 0.90 (0.78 to 1.04) Q = 5.30, I2

 = 25% 

p = 0.26 

Stroke–hemorrhagic 0.45 (0.31 to 0.68) Q = 4.18, I2

 = 52% 

p = 0.12 0.47 (0.35 to 0.64) Q = 4.74, I2

 = 16% 

p = 0.31 

Combined stroke 0.77 (0.67 to 0.88) Q = 2.80, I2

 = 29% 

p = 0.25 NA NA 

Peripheral embolisma 

1.17 (0.64 to 2.14) Q = 1.38, I2

 = 28% 

p = 0.24 1.40 (0.78 to 2.51) Q = 3.84, I2

 = 22% 

p = 0.28 

Adverse Effect 

Discontinued due to 

adverse effects 1.26 (0.86 to 1.84) Q = 56.27, I2

 = 96%

 p < 0.001 1.41 (1.05 to 1.89) Q = 76.37, I2

 = 95%

 p < 0.001 

Major bleeding 0.88 (0.70 to 1.09) Q = 15.45, I2

 = 87% 

p < 0.001 0.84 (0.71 to 1.00) Q = 16.44, I2

 = 82% 

p = 0.001 

Fatal bleeding 0.55 (0.41 to 0.76) Q = 0.49, I2

 = 0% 

p = 0.48 0.57 (0.42 to 0.77) Q = 1.57, I2

 = 0% 

p = 0.67 

Myocardial infarction 0.97 (0.72 to 1.30) Q = 6.37, I2

 = 69% 

p = 0.04 0.99 (0.75 to 1.31) Q = 11.52, I2

 = 65% 

p = 0.02 

Liver dysfunction 0.97 (0.82 to 1.15) Q = 1.61, I2

 = 0% 

p = 0.45 2.18 (0.96 to 4.95) Q = 99.92, I2

 = 96% 

p < 0.001 

a

No data for Patel 2011. 

Abbreviation: NA = not applicable 

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Forest Plots for Studies Without Ximelagatran (Atrial Fibrillation) 

Figure 4. AF: All-cause mortality without ximelagatrana 

Figure 5. AF: Ischemic stroke without ximelagatrana 

Figure 6. AF: Hemorrhagic stroke without ximelagatrana 

a

Studies evaluating ximelagatran are shown but not incorporated into the summary risk ratio in Figures 4, 5, and 6. 

Forest Plots for Studies With Ximelagatran (Atrial Fibrillation) 

Figure 7. AF: All-cause mortality with ximelagatran 

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Figure 8. AF: Ischemic stroke with ximelagatran 

Figure 9. AF: Hemorrhagic stroke with ximelagatran 

Subgroup Analyses From Primary Publications 

SPORTIF III and V Trials (Ximelagatran Versus Warfarin) 

In three industry-sponsored, pooled analyses on the combined sample (n = 7329) of the 

SPORTIF III and V trials, the following results were reported: 

•		 There was no significant difference in the primary event rate (stroke or systemic 

embolism) for patients with a history of stroke or transient ischemic attack (TIA) 

compared with those without a prior history of stroke or TIA. Similarly, there was no 

difference between these groups in the incidence of cerebral hemorrhage.95 

•		 Ximelagatran was comparable to warfarin for stroke prevention in adults under age 75 

and those older than age 75. Risk of bleeding with ximelagatran was lower than warfarin 

in both the younger and older subgroups.96 

•		 Patients with markers of heart failure compared to patients without markers of heart 

failure had a higher rate of stroke or systemic embolic events. Ximelagatran was 

comparable to warfarin for these outcomes in patients with or without markers of heart 

failure.97 

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RE-LY Trial (Dabigatran Versus Warfarin) 

In the RE-LY trial, the following results were reported: 

•		 Diener et al. performed a subgroup analysis for the primary outcome, stroke or systemic 

embolism, and seven secondary outcomes in patients with and without a history of 

previous stroke or TIA.98 Treatment effects did not differ significantly by subgroup except 

for the secondary outcome of vascular death. For this outcome, dabigatran 110 mg was 

more effective in the group with prior stroke or TIA compared with those without prior 

stroke or TIA (OR 0.63 versus 0.98, p = 0.038). However, this finding was not replicated 

in the dabigatran 150 mg treatment arm. 

•		 Because therapeutic INR with warfarin anticoagulation control is key for stroke 

prevention, Walletin et al. performed a subgroup analysis to compare treatment effects 

by each sites average INR control level.99 For the 18,024 patients at 906 sites, subgroup 

analyses were completed by grouping sites into quartiles of time in therapeutic range 

(TTR). Analyses were adjusted for differences in baseline characteristics across these 

groups. For the primary outcome of stroke or systemic embolism, there were no 

significant interactions between TTR and the comparative effects of dabigatran and 

warfarin. However, the risk of major bleeding was significantly lower for dabigatran 150 

mg at sites with poor INR control (TTR <57.1%; test for interaction p = 0.03) but not 

significantly different from warfarin at sites with better INR control. In contrast, major 

gastrointestinal bleeding was approximately doubled with dabigatran 150 mg compared 

to warfarin at sites with better TTR (≥65.5%, p = 0.019). Dabigatran 150 mg was also 

more effective than warfarin at sites with poor INR control compared with those with 

good INR control for all vascular events (test for interaction, p = 0.006) and mortality (p 

= 0.05). In summary, these subgroup analyses suggest that the quality of adjusted-dose 

warfarin treatment is associated with the comparative effectiveness of dabigatran for 

several clinically important outcomes. 

•		 In another subgroup analysis that focused on bleeding complications, the effects of 

dabigatran varied by age.72 In patients under age 75, both doses of dabigatran were 

associated with a modestly lower risk of major bleeding in comparison to warfarin. In 

those over age 75, the risk of major bleeding was not significantly different for the 110 

mg dose of dabigatran, but the risk approached a statistically significant higher rate for 

the 150 mg dose compared with warfarin (5.1 versus 4.4%, p = 0.07). Although the risk 

of bleeding increased with lower creatinine clearance (CrCl), there was no interaction 

effect between CrCl and the effect of dabigatran. The authors concluded that the observed 

age effects were not “simply a pharmacokinetic interaction” related to declining CrCl in 

older adults. 

•		 In a separate analysis of data from the RE-LY study, rates of MI, unstable angina, cardiac 

arrest, and cardiac death were reported. In the treatment groups on dabigatran 110 mg, 

150 mg, and adjusted-dose warfarin, myocardial infarction occurred at an annual rate of 

0.82 percent, 0.81 percent, and 0.64 percent (HR 1.29; 95% CI, 0.96 to 1.75; p = 0.09 for 

dabigatran 110 mg and HR 1.27; CI, 0.94 to 1.71;p = 0.12 for dabigatran 150 mg).84 In 

conclusion, there was a nonsignificant increase in myocardial infarction with dabigatran 

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treatment while other myocardial events were not increased. The relative effects of 

dabigatran versus warfarin on myocardial ischemic events were consistent in patients 

with or without a baseline history of myocardial infarction or coronary artery disease. 

ROCKET-AF Trial (Rivaroxaban Versus Warfarin) 

In the ROCKET-AF trial, the following results were reported: 

• A secondary analysis of data from the ROCKET-AF trial evaluated the efficacy and 

safety of rivaroxaban compared to warfarin in patients with moderate renal dysfunction.83 

Around one-fifth of the enrolled population (20.7%) had moderate renal impairment at 

baseline (CrCl 30–49 mL/min). Compared to patients with CrCl ≥50 mL/min, patients 

with moderate renal impairment had higher CHADS2 scores and more cardiovascular 

disease. Patients with moderate renal impairment were treated with a lower dose of 

rivaroxaban (15 mg/day) than those with better renal function (20 mg/day). For patients 

with moderate renal dysfunction, the rates of stroke and systemic embolism were higher 

than in those with CrCl ≥ 50 mL/min, regardless of anticoagulant treatment received. 

Major bleeding and clinically relevant non–major bleeding occurred more frequently 

in those with renal insufficiency than in those without, regardless of randomized 

treatment assigned. Comparative treatment effects for rivaroxaban versus warfarin were 

similar for all major outcomes, including bleeding events, for those with and without 

renal insufficiency. When bleeding rates were analyzed further by site of bleeding, 

patients with impaired renal function who were treated with rivaroxaban had higher 

gastrointestinal bleeding rates than those treated with warfarin (4.1% versus 2.6%, p = 

0.02). 

In summary, subgroup analyses show no differential effects on stroke prevention (interaction 

effects) for individuals with a history of cerebrovascular accidents, impaired renal function, or 

older age. However, these analyses suggest that some bleeding complications with dabigatran 

compared with warfarin may be increased in those older than age 75 and at centers with highquality warfarin treatment. Further, myocardial infarction—but not other myocardial ischemic 

events—showed a non–statistically significant increase with dabigatran. The effects of impaired 

renal function were mixed, showing no interaction effect in one analysis and a differential risk of 

gastrointestinal bleeding with rivaroxaban in another analysis. 

KEY QUESTION 2: For patients with venous thromboembolism, are 

there differential effects of newer oral anticoagulants versus warfarin 

or low molecular weight heparins on recurrent thromboembolism, 

mortality, HRQOL, and patient treatment experience? 

We identified three good-quality studies relevant to KQ 2, which involved 8541 patients; all 

studies were funded by the pharmaceutical industry. These studies evaluated dabigatran (n = 

1),85 rivaroxaban (n = 1),89 and ximelagatran (n = 1)86 versus adjusted-dose warfarin. The mean 

age of participants was between 50 and 55; approximately 56 percent were men. Almost 80 

percent of participants had DVT alone, with most of the remainder having both DVT and PE. 

Average adherence to the intervention drugs was 98 percent in the study evaluating dabigatran,85 

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and in the study evaluating ximelagatran,89 93 percent of participants took at least 80 percent 

of prescribed doses. One study did not report adherence.86 In the control groups, the percentage 

of time in the INR target range was 58 to 61 percent (median 60%). Two studies reported the 

proportion of time below range (21 to 24%) and above range (16 to 19%).85,86 Studies assessed 

outcomes at 6 to 12 months; none reported effects on HRQOL or patient experience. Study 

characteristics are summarized in Table 7. 

Table 7. Summary table for KQ 2—venous thromboembolism 

Study Characteristic Number of Studies (Patients) 

Total number of studies (patients) 3 (8541) 

Factor Xa inhibitor, dose

 Rivaroxaban, 20 mg daily 

Direct thrombin inhibitors, dose

 Dabigatran, 150 mg twice daily

 Ximelagatran, 36 mg twice daily 

1 (3449) 

1 (2564) 

1 (2528) 

Study duration:

 6 months

 12 months 

2 (5092) 

1 (3449) 

Mean age

 50–60 years

 60–70 years 

3 (8541) 

– 

Sex

 Men

 Women 

3 (4763) 

3 (3714) 

DVT/PE etiologya

 Idiopathic/unprovoked 

Active cancer

 Prior VTE 

1 (2138), 2 NR 

3 (655) 

3 (1855) 

Adjusted-dose warfarin range 

Time above range (%) 

Time in range (%) 

Time below range (%) 

2 (16.2–19%), 1 NR 

3 (57.7–61%) 

2 (19–21%), 1 NR 

a

Some subjects may have had more than one risk factor. 

Abbreviations: DVT = deep venous thrombosis; NR = not reported; PE = pulmonary embolism; VTE = venous thromboembolism 

Meta-Analyses for KQ 2 

We used random-effects model meta-analyses to evaluate the effects of newer oral anticoagulants 

compared with adjusted-dose warfarin on mortality, risk of recurrent DVT or PE, major bleeding, 

fatal bleeding, myocardial infarction, liver dysfunction, and drug discontinuation due to adverse 

effects. There was no statistically significant difference for any of these outcomes. For some 

outcomes, such as death due to thromboembolism, fatal bleeding, and myocardial infarction, 

the 95-percent CIs were particularly wide and include the potential for clinically important 

differences. Tests for heterogeneity suggest variability in treatment effects across studies for 

recurrent DVT/PE (moderate) and liver dysfunction (high). 

There were too few studies to conduct quantitative analyses for factors that may be associated 

with variable treatment effects. However, a qualitative inspection shows differences across 

studies in patient characteristics, eligibility criteria, and interventions that may be related to 

differential treatment effects. Individuals with a previous history of VTE have a 25-percent risk 

of recurrence in the first 5 years.100 A higher proportion of patients in the dabigatran study 85 had a 

history of previous VTE than patients in the rivaroxaban study (25 versus 19%).86 The dabigatran 

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study also had a lower threshold to exclude patients for elevations in the alanine transaminase 

level than for the rivaroxaban study.86 Furthermore, all patients in the dabigatran study received 

low molecular weight heparin or unfractionated heparin before starting dabigatran, while patients 

in the rivaroxaban study did not. Low molecular weight heparin and unfractionated heparin can 

cause liver enzyme elevation.101,102 

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. This result appears to be related primarily to higher rates of liver dysfunction with 

ximelagatran. Summary risk ratios and tests for variability in treatment effects across studies 

are summarized in Table 8 (Figures 10–14). There were too few studies to conduct subgroup 

analyses by drug class or statistical tests for publication bias. However, our search of www. 

clinicalTrials.gov did not suggest publication bias. 

Table 8. Effects of newer oral anticoagulants compared with adjusted-dose warfarin for venous 

thromboembolism 

Summary Risk 

Ratios 

(95% CI) 

Test for 

Heterogeneity 

Summary Risk 

Ratios 

(95% CI) 

Test for 

Heterogeneity 

Outcome Non-ximelagatran studies (n = 2) All studies (n = 3) 

All-cause mortality 0.84 (0.59 to 1.18) Q = 0.47, I2

 = 0% 

p = 0.49 0.78 (0.59 to 1.02) Q = 1.01, I2

 = 0% 

p = 0.60 

Recurrent DVT 0.66 (0.37 to 1.15) Q = 1.49, I2

 = 33% 

p = 0.22 0.72 (0.49 to 1.06) Q = 2.02, I2

 = 1% 

p = 0.36 

Death–thromboembolica 

0.56 (0.19 to 1.69) Q = 0.28, I2

 = 0% 

p = 0.60 NA NA 

Recurrent DVT/PE 0.86 (0.55 to 1.33) Q = 1.79, I2

 = 44% 

p = 0.18 0.91 (0.67 to 1.24) Q = 2.43, I2

 = 18% 

p = 0.30 

Adverse Effect 

Discontinued due to 

adverse effects 1.19 (0.93 to 1.51) Q = 1.43, I2

 = 30% 

p = 0.23 1.24 (1.10 to 1.41) Q = 1.73, I2

 = 0% 

p = 0.42 

Major bleeding 0.77 (0.49 to 1.20) Q = 0.14, I2

 = 0% 

p = 0.71 0.69 (0.48 to 0.99) Q = 0.91, I2

 = 0% 

p = 0.63 

Fatal bleeding 0.50 (0.12 to 2.06) Q = 0.31, I2

 = 0% 

p = 0.58 0.41 (0.13 to 1.35) Q = 0.59, I2

 = 0% 

p = 0.75 

Myocardial infarction 2.83 (0.75 to 10.71) Q = 0.44, I2

 = 0% 

p =0.51 3.46 (1.03 to 11.62) Q = 0.98, I2

 = 0% 

p = 0.61 

Liver dysfunction 0.60 (0.27 to 1.34) Q = 6.80, I2

 = 85% 

p = 0.009 1.20 (0.29 to 4.98) Q = 65.83, I2

 = 97% 

p < 0.001 

a

No data for ximelagatran group. 

b

Fiessenger 2005 did not report thromboembolic death
 

Abbreviations: DVT = deep venous thrombosis; NA = not applicable; PE = pulmonary embolism 

33
 
Figure 10. VTE: All-cause mortality without ximelagatrana 

Figure 11. VTE: Death–thromboembolic without ximelagatrana,b 

Figure 12. VTE: Recurrent DVT/PE without ximelagatrana 

a

The study evaluating ximelagatran is shown but not incorporated into the summary risk ratio in Figures 10, 11, and 12. 

b

Fiessenger 2005 did not report thromboembolic death. 

Forest Plots for Studies With Ximelagatran (Venous Thromboembolism) 

Figure 13. VTE: All-cause mortality with ximelagatran 

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Forest Plots for Studies Without Ximelagatran (Venous Thromboembolism) 

NOTE: NO Forest Plot for VTE: Death–thromboembolic with ximelagatran. 

There were no data on this outcome for the ximelagatran group. 

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Figure 14. VTE: Recurrent DVT/PE with ximelagatran
	

KEY QUESTION 3: For patients with mechanical heart valves, what 

is the comparative effectiveness of newer anticoagulants versus 

warfarin on the incidence of thromboembolic complications, mortality, 

HRQOL, and patient treatment experience? 

We did not identify any published studies that compared newer anticoagulants to adjusted-dose 

warfarin in patients with mechanical heart valves. We identified one ongoing trial from our 

search of www.clinicaltrials.gov (Appendix F). 

KEY QUESTION 4: When used for long-term anticoagulation 

treatment, what is the nature and frequency of adverse effects for 

newer anticoagulants versus warfarin? 

We reported the risks of adverse effects separately in KQ 1 and KQ 2 for each treatment 

indication. In this section, we examine the risk of adverse effects for all included randomized 

controlled trials and supplement this by a review of observational studies and FDA alerts. For 

the analysis of trial data, we examined the summary risk ratios, first in all studies and then by 

drug class. We excluded studies of ximelagatran for this analysis because this drug has been 

withdrawn from the market due to adverse effects on liver function. 

The range of adverse effect rates for newer oral anticoagulants in the chronic AF studies and 

VTE studies, respectively, were discontinued due to adverse effects (6.2% to 8.3%; 4.9% to 

9.0%); major bleeding (3.6% to 6.2%; 0.8% to 1.6%); fatal bleeding (0.1% to 0.4%; 0.1% 

reported in one study); myocardial infarction (1.0% to 1.5%; 0.3% reported in one study); and 

liver dysfunction (0.5% to 1.9%; 1.5% to 3.4%). Compared with the VTE studies, the studies 

in patients with chronic AF included older patients who may have had more chronic medical 

conditions and concurrent medications, increasing the risk for adverse effects.94 In addition, the 

treatment duration was longer for the chronic AF studies, which may also increase the absolute 

rates of adverse effects. 

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 

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varied importantly across studies—variability that was not explained by drug class. The 

unexplained variability in effect for this outcome and others with similar findings suggests 

the possibility of important differences between individual drugs, even within drug class. The 

risk of gastrointestinal bleeding was increased with newer oral anticoagulants, with significant 

variability across studies that was not explained by drug class. Overall, the risk of myocardial 

infarction was not different from adjusted-dose warfarin. When analyzed by drug class, the risk 

of myocardial infarction was higher with DTIs than with FXa inhibitors. Drug discontinuation 

due to adverse effects showed a small, non–statistically significant increased risk ratio, but 

the risk of discontinuation varied substantially across studies. When analyzed by drug class, 

DTIs had a higher risk of drug discontinuation compared with FXa inhibitors. The risk of liver 

dysfunction, an adverse effect that led to the withdrawal of ximelagatran from the market, was 

not increased. 

Table 9. Risk of mortality and adverse effects overall and by drug class 

All studies (n = 5) Comparison by Drug Class 

Adverse Effect 

Summary Risk 

Ratios 

(95% CI) 

Tests for 

Heterogeneity 

Summary Risk Ratios 

(95% CI) 

Test for differences 

between drug 

classes 

All-cause mortality 0.88 (0.82 to 0.95) Q = 1.05, I2

 = 0%

 p < 0.90 

DTI: 0.90 (0.79 to 1.01) 

FXa: 0.88 (0.80 to 0.96) p = 0.77 

Discontinued due 

to adverse effects 1.23 (0.94 to 1.61) Q = 57.96, I2

 = 93%

 p < 0.001 

DTI: 1.61 (1.14 to 2.27) 

FXa: 1.04 (0.84 to 1.28) p = 0.03 

Major bleeding 0.86 (0.71 to 1.04) Q = 16.08, I2

 = 75% 

p = 0.003 

DTI: 0.93 (0.82 to 1.06) 

FXa: 0.83 (0.60 to 1.14) p = 0.49 

Fatal bleeding 0.59 (0.46 to 0.77) Q = 1.57, I2

 = 0% 

p = 0.81 

DTI: 0.72 (0.45 to 1.16) 

FXa: 0.55 (0.40 to 0.75) p = 0.35 

Gastrointestinal 

bleeding 1.30 (1.01 to 1.68) Q=12.04, I2

 = 75% 

p = 0.007 

DTI: 1.50 (1.24 to 1.80) 

FXa: 1.14 (0.69 to 1.87) p = 0.05 

Myocardial 

infarctiona 1.02 (0.76 to 1.39) Q = 9.37, I2

 = 57% 

p = 0.05 

DTI: 1.35 (0.99 to 1.85) 

FXa: 0.86 (0.66 to 1.11) p = 0.03 

Liver dysfunction 0.82 (0.61 to 1.11) Q = 14.48, I2

 = 72% 

p = 0.006 

DTI: 0.88 (0.72 to 1.09) 

FXa: 0.76 (0.41 to 1.42) p = 0.65 

a

Only four studies reported this outcome. 

Abbreviations: CI = confidence interval; NA = not applicable 

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Forest Plots for Studies Without Ximelagatran (Adverse Effects) 

Figure 15. Adverse effects: All-cause mortality without ximelagatran 

Figure 16. Adverse effects: Discontinued due to adverse effects without ximelagatran 

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Figure 17. Adverse effects: Major bleeding without ximelagatran 

Figure 18. Adverse effects: Fatal bleeding without ximelagatran 

• 

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Figure 19. Adverse effects: Gastrointestinal bleeding without ximelagatran 

Figure 20. Adverse effects: Myocardial infarction without ximelagatran 

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Figure 21. Adverse effects: Liver dysfunction without ximelagatran 

RESULTS FROM OBSERVATIONAL STUDIES 

We reviewed 377 observational studies on adverse effects of newer oral anticoagulants and 

excluded 349 on the basis of our inclusion/exclusion criteria. We performed a full-text review on the 

remaining 28 studies and included 10 of these for data abstraction. Three of the 10 were subgroup 

analyses from included RCTs and have been discussed previously under KQ 1. Seven of the 10 were 

case studies, and one was a systematic review. These are discussed below by major outcome. 

Bleeding 

Three case reports described bleeding associated with dabigatran treatment; one of these was in 

the context of concurrent use of a thrombolytic medication. 

Splenic hemorrhage 

A 78-year-old woman presented to the emergency department with acute-onset abdominal pain 

and vomiting. She had a past medical history of stroke secondary to AF and had been switched 1 

week earlier from warfarin to dabigatran 100 mg orally twice daily for thromboprophylaxis. She 

denied any history of trauma. A computed tomography (CT) scan revealed extravasation from the 

posterior aspect of the spleen and hemoperitoneum.81 

Cerebral hemorrhage after concurrent thrombolytic treatment 

A 62-year-old diabetic male was started on dabigatran 110 mg twice daily following 

cardioversion for nonvalvular AF. Following the third dose of dabigatran, he developed aphasia 

and right hemiplegia. A CT scan revealed a perfusion deficit in the left middle cerebral artery 

area and no evidence of intracranial hemorrhage. All of his coagulation test values were within 

normal limits apart from a borderline high prothrombin time. He was started on thrombolytic 

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therapy and 12 hours later became comatose. A brain CT scan showed a lobar hemorrhage with 

mass effect. The patient died 2 days later.77 

Gastrointestinal bleeding and epistaxis 

Legrand et al. reported two cases of bleeding in elderly patients on dabigatran treatment.79 The 

first case was an 84-year-old woman who had been on dabigatran 75 mg twice daily for AF for 

a period of 4 months prior to presentation. She presented with rectal bleeding associated with a 

fecaloma. Her CrCl was 32 mL/min and her body weight was 40 kg. She developed a massive 

rectal hemorrhage after digital evacuation of the fecaloma and died of hemorrhagic shock despite 

resuscitation and transfusion of blood and fresh frozen plasma. The trough plasma concentration 

of dabigatran was very high (5600 ng/mL; expected range, 31-225 ng/mL). The second case 

was an 89-year-old woman (weight 45 kg), who was given dabigatran 110 mg twice daily for 

prevention of stroke in AF. At presentation for a scheduled procedure 5 months after starting 

on dabigatran, she reported recurrent episodes of epistaxis of 1 week duration. Preoperative 

laboratory evaluation revealed anemia, prolonged baseline coagulation studies, and elevated 

dabigatran plasma concentration (2670 ng/mL). Her CrCl was low at 29 mL/min. Her procedure 

was cancelled and dabigatran was discontinued with a favorable outcome. 

Thrombosis 

Two case reports described ischemic stroke in patients taking dabigatran and successful treatment 

with thrombolytic medication. 

Ischemic stroke 

One study reported a 48-year-old woman with an acute onset of left-sided hemiplegia and 

hemihypesthesia, who was found to have an ischemic stroke in the area of the right middle 

cerebral artery.78 The patient had a history of AF and was randomized to dabigatran on the RELYABLE study (NCT00808067). She was started on thrombolytic therapy with recombinant tissue 

plasminogen activator almost 7 hours after her last dose of dabigatran. All coagulation tests were 

within normal limits, apart from fibrinogen, which was borderline high. The patient improved 

and suffered no complications. 

Another study reported a 76-year-old woman with a history of diabetes and hypertension, who 

presented with acute right-sided hemiplegia and aphasia.80 The patient was on dabigatran 220 

mg once daily as thromboprophylaxis following knee replacement therapy. She was started on 

thrombolytic therapy 15 hours following her last dose of dabigatran. Treatment was completed 

successfully with no bleeding complications. 

Myocardial Infarction 

We identified a single systematic review that addressed adverse effects for newer oral 

anticoagulants. This review of seven mostly short-term trials evaluated dabigatran for 

heterogeneous indications and found a higher risk of myocardial infarction or acute coronary 

syndrome (OR 1.33; 95% CI, 1.03 to 1.71) compared with warfarin, enoxaparin, or placebo.70 

We did not identify any primary reports of observational studies evaluating MI. 

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Mechanical Valve Thrombosis 

Clinical experience is currently limited as to the efficacy and safety of the newer oral 

anticoagulants for thromboprophylaxis in patients with prosthetic valves. As noted in KQ 3, 

no trials have published outcomes for this indication. We identified a single case report of 

anticoagulation failure with dabigatran. A 62-year-old man with a bileaflet mechanical aortic 

valve (St. Jude Medical) and a history of AF was switched, upon his request, from warfarin to 

dabigatran 150 mg twice daily for thromboprophylaxis.82 Eleven months later, he presented 

with facial droop and hemiparesis, which resolved over 24 hours. An MRI study of the patient’s 

brain showed multiple cerebral ischemic infarcts, and later a transesophageal echocardiogram 

showed a thrombus on the posterior disc of the prosthetic aortic valve. Dabigatran was stopped, 

and the patient was started on phenindione with 100 mg aspirin. A followup transesophageal 

echocardiogram showed disappearance of the thrombus. 

SUMMARY OF FDA BULLETINS 

QuarterWatch is a nonprofit Federally certified Institute for Safe Medication Practice, which 

monitors adverse events reported to the FDA through MedWatch. On October 6, 2011, a report 

by QuarterWatch stated that, within months of its release, dabigatran generated more reports 

(307) than 98.7 percent of other drugs monitored. Reported adverse events were equally divided 

between hemorrhagic and thrombotic events. Only 36 percent of reports listed that dabigatran 

was used for its approved indications. Another 46 percent reported that the drug was used to 

prevent blood clots or stroke in general terms. Furthermore, other reports clearly stated the drug 

was used for off-label indications such as thromboprophylaxis after orthopedic surgery.103 

On January 12, 2012, QuarterWatch released a report of serious adverse events linked to 

dabigatran. During the first quarter of 2011, 932 serious adverse events were linked to dabigatran, 

including 120 deaths, 25 permanent disabilities, and 543 hospitalizations. Of the 932 cases, 505 

involved hemorrhage—more than any other monitored drug, including warfarin. The adverse 

events occurred in elderly patients with a median age of 80 years, compared with 56 years in 

all other monitored drugs. The report raised questions about using a fixed dose for all patient 

populations. Older age and impaired renal function lead to a longer half-life and higher drug levels. 

Currently, dosage adjustment is recommended for only patients with severe renal impairment. 

However, mild and moderate renal impairment can increase dabigatran levels by 50 percent and 

300 percent, respectively. The report recommends that the FDA and the manufacturer reevaluate 

the dose of dabigatran for elderly patients and those with moderate renal impairment.104 

The FDA Advisory Committee Briefing Document on adverse events associated with 

rivaroxaban reported that, in the ROCKET-AF study, the posttreatment discontinuation events 

were higher in patients on rivaroxaban (12.63 per 100 patient years) compared with patients on 

adjusted-dose warfarin (8.36 per 100) (HR 1.51; 95% CI, 1.02 to 2.23). This higher event rate 

may be due to fewer patients transitioning from rivaroxaban to warfarin having a therapeutic INR 

during the period of 3 to 30 days after treatment. This finding points to the need for particular 

care when transitioning patients from short-acting newer oral anticoagulants to warfarin. 

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SUMMARY AND DISCUSSION 

We identified eight good-quality RCTs comparing newer oral anticoagulants to conventional 

anticoagulant therapy with warfarin, either alone or in combination with low molecular weight 

heparin. Of these eight studies, five compared newer oral anticoagulants to warfarin for 

prevention of stroke in nonvalvular AF. Three studies compared newer oral anticoagulants with a 

combination of parenteral anticoagulation and warfarin for management of VTE. Overall, newer 

oral anticoagulants were no worse and were—for some clinical outcomes—superior to adjusteddose warfarin. However, in the absence of head-to-head comparisons between the newer 

anticoagulants, our analysis may have failed to detect important differences between drug classes 

or between individual drugs. Comparative effects on HRQOL and patient experience were not 

reported. The observational literature on adverse effects is sparse, consisting only of case-reports 

describing bleeding and thrombotic events. The FDA has issued alerts that it is evaluating reports 

of serious bleeding with dabigatran, mostly in older adults or those with impaired renal function. 

Our main findings and the strength of evidence (SOE) for each major outcome are summarized 

by key question in the next section. 

SUMMARY OF EVIDENCE BY KEY QUESTION 

Key Question 1—Chronic Atrial Fibrillation 

Table 10 summarizes the findings and SOE for each major outcome. In brief, newer oral 

anticoagulants were associated with a lower rate of all-cause mortality compared with warfarin 

(high SOE). Newer oral anticoagulants were also associated with fewer hemorrhagic strokes 

(moderate SOE). For these outcomes, we estimated the absolute risk difference to be 8 fewer 

deaths and 4 fewer hemorrhagic strokes for every 1000 patients treated with the newer oral 

anticoagulants compared with adjusted-dose warfarin over approximately 2 years of treatment. 

However, VTE-related mortality and ischemic stroke were not significantly lower with newer 

oral anticoagulants. 

For dabigatran, the comparative effects on vascular outcomes were dependent, in part, on the 

quality of adjusted-dose warfarin treatment. 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.99 

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Table 10. Summary of the strength of evidence for KQ 1—chronic AF 

Number 

of Studies 

(Subjects) 

Domains Pertaining to SOE SOE 

Risk of Bias: 

Study Design/

Quality 

Consistency Directness Precision Effect Estimate (95%

CI)a 

All-cause mortality High SOE 

3 (44,442) RCT/Good Consistent Direct Precise RR = 0.88 (0.82 to 0.95) 

RD = 8 (3 to 11) fewer 

deaths/1000 

VTE-related mortality Moderate SOE 

2 (30,299) RCT/Good Some inconsistency Direct Some imprecision RR = 0.77 (0.57 to 1.02) 

Ischemic stroke Moderate SOE 

3 (44,442) RCT/Good Consistent Direct Some imprecision RR = 0.89 (0.78 to 1.02) 

Hemorrhagic stroke Moderate SOE 

3 (44,442) RCT/Good Some inconsistency Direct Some imprecision RR = 0.45 (0.31 to 0.68) 

RD = 4 (2 to 5) 

fewer hemorrhagic 

strokes/1000 

Discontinuation due to adverse effects Low SOE 

3 (44,502) RCT/Good Important 

inconsistency 

Direct Important 

imprecision 

RR = 1.26 (0.86 to 1.84) 

Major bleeding Low SOE 

3 (44,474) RCT/Good Important 

inconsistency 

Direct Some imprecision RR = 0.88 (0.70 to 1.09) 

Abbreviations: CI = confidence interval; RCT = randomized controlled trial; RD = risk difference; RR = risk ratio; SOE = 

strength of evidence 

a

The risk difference and 95% CI are based on the assumed risk for the control group (using the median control group risk across 

studies) and the relative intervention effects (and 95% CI). 

Key Question 2—Venous Thromboembolism 

Table 11 summarizes the findings and SOE for each major outcome. In comparison with the 

chronic AF studies, there are fewer studies and patients enrolled and shorter duration of followup 

for this population. The summary risk ratio favored newer oral anticoagulants for all-cause 

mortality, VTE-related mortality, recurrent VTE, and major bleeding, but in each instance the CI 

included no effect. Overall, these results support the conclusion that newer anticoagulants are no 

worse than adjusted-dose warfarin for major clinical outcomes. 

Table 11. Summary of the strength of evidence for KQ 2—venous thromboembolism 

Number 

of Studies 

(Subjects) 

Domains Pertaining to SOE SOE 

Risk of Bias: 

Study Design/

Quality 

Consistency Directness Precision Effect Estimate 

(95% CI) 

All-cause mortality Moderate SOE 

2 (5988) RCT/Good Consistent Direct Some imprecision RR = 0.84 (0.59 to 1.18) 

VTE-related mortality Low SOE 

2 (5988) RCT/Good Consistent Direct Important imprecision RR = 0.56 (0.19 to 1.69) 

Recurrent DVT/PE Moderate SOE 

2 (5988) RCT/Good Some inconsistency Direct Some imprecision RR = 0.86 (0.55 to 1.33) 

Discontinuation due to adverse effects Moderate SOE 

2 (5988) RCT/Good Consistent Direct Some imprecision RR = 1.19 (0.93 to 1.51) 

Major bleeding Moderate SOE 

2 (5988) RCT/Good Consistent Direct Some imprecision RR = 0.77 (0.49 to 1.20) 

Abbreviations: CI = confidence interval; NA = not applicable; NR = not reported; RCT = randomized controlled trial; RR = risk 

ratio; SOE = strength of evidence 

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Key Question 3—Mechanical Heart Valves 

We did not identify any published studies that compared newer oral anticoagulants to adjusteddose warfarin in patients with mechanical heart valves. Current evidence is insufficient to 

estimate the relative effects of newer anticoagulants compared with warfarin for patients with 

mechanical heart valves. 

Key Question 4—Adverse Effects 

The adverse effects of newer oral anticoagulants compared with adjusted-dose warfarin were 

generally consistent across treatment indications. After excluding the ximelagatran studies, 

the summary risk ratio for discontinuation due to adverse effects was higher for newer 

anticoagulants, but this result was not statistically significant. The effects on bleeding rates are 

complex. Fatal bleeding was significantly lower for newer oral anticoagulants, an effect that 

was consistent across drug classes. Major bleeding was lower for newer oral anticoagulants, but 

this effect was not statistically significant and varied significantly across studies. In contrast, 

gastrointestinal bleeding was increased with newer oral anticoagulants. Gastrointestinal bleeding 

was significantly increased in patients treated with dabigatran and rivaroxaban compared with 

warfarin.99 The efflux of dabigatran by p-glycoprotein transporters into the gastrointestinal tract 

may be a mechanism for this finding.105 Both the clinical trial subgroup analyses and the FDA 

reports suggest that bleeding risk may be increased in older adults and in those with impaired 

renal function. Further, the differential bleeding risk may be related to the quality of warfarin 

anticoagulation. 

Another potential adverse effect is myocardial infarction. We found no increased risk when 

combining results from all studies. However, for dabigatran alone, we found an elevated risk 

(RR = 1.35) that approached statistical significance. A separate meta-analysis, primarily of shortterm trials, found a statistically significant increase in myocardial infarction or acute coronary 

syndrome (OR 1.33; 95% CI, 1.03 to 1.71).70 Liver dysfunction was substantially higher for 

ximelagatran, a drug withdrawn from the market due to this adverse effect. Elevated rates of 

liver dysfunction have not been seen with the other newer oral anticoagulants. The SOE was 

low for several outcomes because CIs included clinically important differences and there was 

unexplained variability in treatment effects. 

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Table 12. Summary of findings for KQ 4—adverse effects 

Outcome Strength of 

Evidence Summary 

Drug 

discontinuation 

due to adverse 

effects 

Low 

Across all indications, discontinuation due to adverse effects was higher 

with newer oral anticoagulants (RR 1.23; 95% CI, 0.94 to 1.61), but the 

95-percent CI was large and included no effect. In subgroup analysis, rates 

of discontinuation were higher for dabigatran compared with FXa inhibitors. 

A clinically important increase in drug discontinuation compared with 

warfarin cannot be excluded. 

Major bleeding 

Fatal bleeding 

Gastrointestinal 

bleeding 

Low 

Moderate 

Moderate 

Across all indications, the risk of major bleeding was lower with newer 

oral anticoagulants (RR 0.86; 95% CI, 0.71 to 1.04), but the 95-percent CI 

was large and included no effect. A clinically important decrease in major 

bleeding compared with warfarin cannot be excluded. In December 2011, 

the FDA issued a notice that it was evaluating reports of serious bleeding 

with dabigatran. 

Across all indications, the risk of fatal bleeding was lower with newer oral 

anticoagulants (RR 0.59; 95% CI, 0.46 to 0.77). Risk difference was 1 

fewer death per 1000 patients. 

Across all indications, the risk of gastrointestinal bleeding was increased 

with newer oral anticoagulants (RR 1.30; 95% CI, 1.17 to 1.49). Risk 

difference was 1 additional gastrointestinal bleed per 1000 patients. 

Myocardial 

infarction Low 

Across all indications, the risk of myocardial infarction was not different with 

newer oral anticoagulants (RR 1.02; 95% CI, 0.76 to 1.39). In a subgroup 

analysis, the risk was increased with dabigatran (RR 1.35; CI, 0.99 to 

1.85) compared with FXa inhibitors (RR 0.86; CI, 0.66 to 1.11); p = 0.03 for 

between-group comparison. 

Liver dysfunction Moderate Across all indications, the risk of liver dysfunction was not different with 

newer oral anticoagulants (RR 0.82; 95% CI, 0.61 to 1.11). 

CLINICAL AND POLICY IMPLICATIONS 

Clinicians have used adjusted-dose warfarin to prevent systemic emboli related to chronic AF, 

recurrent VTE, or mechanical heart valves for decades. The benefits and limitations of warfarin 

are well known. Adjusted-dose warfarin reduces the risk of stroke by 62 percent in patients 

with chronic AF, the most common indication for anticoagulation in veterans, compared with 

a 19-percent reduction with aspirin.74 The primary limitations of warfarin are the variability in 

anticoagulant effect together with drugñdrug and drugñfood interactions that require frequent 

laboratory monitoring. A recent VA multicenter trial showed that home warfarin monitoring 

compared with high-quality conventional monitoring did not affect stroke rate, major bleeding 

episodes, or mortality rates but did lead to small improvements in patient satisfaction and quality 

of life.23 

Our review shows that the newer oral anticoagulants are a viable option for long-term 

anticoagulation. DTIs and FXa inhibitors have the advantage of more predictable 

anticoagulation, fewer drug–drug interactions, and equivalent or better mortality and vascular 

outcomes compared with warfarin. The data are most robust for chronic AF, with fewer studies 

evaluating use to prevent recurrent VTE and no studies in patients with mechanical heart valves. 

The absolute benefits for clinical outcomes are small. For chronic AF, the number needed to 

treat compared with warfarin over a 2-year period is 132 to prevent 1 death, 260 to prevent 1 

46
 
 

 

 

 

 

 

 

 

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hemorrhagic stroke, and 758 to prevent 1 fatal bleeding episode. Because no studies reported 

effects on patient experience and HRQOL, effects on these important outcomes are unknown. 

A recent systematic review74 found that, for most patients, warfarin therapy does not have 

important negative impacts on quality of life. 

Safety and Use of Newer Oral Anticoagulants in VA 

For clinicians and policymakers, important questions remain. These include questions about 

which patients are most likely to benefit and which, if any, of the new drugs are most effective. 

Patients with higher bleeding risks and markedly impaired renal function were excluded from 

these studies. Clinicians should also consider the quality of INR monitoring available to their 

patients. 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 poorquality anticoagulation (TTR <57.1%), while rates of major bleeding were not significantly 

different at sites with higher quality anticoagulation. Hence, better INR controlled 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. A pragmatic concern 

related to adherence is the FDA notification that dabigatran may lose potency if placed in pill 

boxes and that it should be dispensed and stored only in the original bottle or blister package.106 

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. The higher myocardial infarction rate 

could be related to the drug specifically, to differences in the patient sample studied, or to the 

protective effect of warfarin on myocardial infarction.69 Alternatively, increased risk of myocardial 

infarction maybe due to a rebound thrombin effect after the discontinuation of dabigatran, a DTI.105 

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. 

Clinicians may wonder whether the benefits of newer oral anticoagulants observed in chronic 

AF will extend to those patients with mechanical heart valves. While this is possible, we caution 

against extrapolating these data since the INR target for patients with mechanical valves is higher 

and the dosing may differ. A Phase II trial is currently underway comparing three different doses 

of dabigatran. 

Guidelines 

The 2011 American College of Cardiology Guideline update for the management of AF was 

published before the studies evaluating rivaroxaban and apixaban were published. It recommends 

dabigatran as a useful alternative to warfarin in patients with chronic nonvalvular AF who 

do not have severe renal failure or advanced liver disease.9,107 This guideline also noted that 

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patients already taking warfarin with excellent INR control may have little to gain by switching 

to dabigatran. The more recent American College of Chest Physicians guidelines recommend 

dabigatran 150 mg for prevention of stroke in AF over the use of adjusted-dose vitamin K 

antagonists.25 Both the nonprofit QuarterWatch and other groups have raised concern or made 

recommendations for dosing adjusted to age or renal function. 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.108 

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.109 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.110 

Cost and Cost-Effectiveness 

An important disadvantage of the newer oral anticoagulants is their higher drug acquisition costs. 

The cost-effectiveness of dabigatran compared with warfarin for stroke prophylaxis has been 

evaluated in three recent publications.93,94,111 Each of these analyses found dabigatran to be costeffective. However, the studies varied in the factors affecting cost-effectiveness, including drug 

costs used in the analyses, assumptions about the adequacy of warfarin anticoagulation, and the 

baseline risk of bleeding or stroke. Depending on the study, cost-effectiveness increased with lower 

drug costs for the newer oral agents, worse INR control, and higher baseline risk of bleeding or 

stroke. However, none of these analyses considered the possible expansion in the pool of patients 

who might be offered and choose chronic anticoagulation with newer agents. An analysis of 

Medicare beneficiaries showed that only two-thirds of patients with chronic AF who were ideal 

candidates for anticoagulation were discharged on warfarin. Although an expansion in the indicated 

use of anticoagulation would be beneficial clinically, it would increase health care costs since these 

drugs have been shown to be cost-effective, not cost-saving. In an era where health systems and 

individuals are considering costs ever more carefully, a budget impact analysis would be useful 

to VA policymakers. Policymakers will have to consider how best to meet the needs of patients 

while considering health care value. A study by Rose et al. has made the business case for quality 

improvement programs to improve adjusted-dose warfarin treatment as another viable alternative.100 

STRENGTHS AND LIMITATIONS 

Our study has a number of strengths, including a protocol-driven review, a comprehensive 

search, careful quality assessment, and rigorous quantitative synthesis methods. Our study, 

and the literature, also has limitations. An important limitation is the lack of head-to-head 

comparisons of the newer oral anticoagulants and an inability to examine the comparative 

effectiveness across classes (DTIs versus FXa inhibitors) or within class. As the literature grows, 

subgroup analyses or a network meta-analysis that includes studies comparing warfarin with 

placebo or aspirin might better address this question—but this comparison was beyond the scope 

or our review. Based on currently available data, important differences in efficacy or frequency 

of adverse effects could be present but undetected. A limitation of the literature is the relatively 

short-term experience with these drugs. It is possible that additional adverse effects may emerge 

with more widespread and longer duration use. 

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RECOMMENDATIONS FOR FUTURE RESEARCH 

We used the framework recommended by Robinson et al.112 to identify gaps in evidence and 

classify why these gaps exist (Table 13). 

Table 13. Evidence gaps and future research 

Evidence Gap Reason Type of Studies to Consider 

Absence of data for patients with 

mechanical heart valves Insufficient information Multicenter RCTs 

Uncertain effects on patient experience 

and health-related quality of life Insufficient information Multicenter RCTs and/or qualitative studies 

Uncertain relative benefits across and 

within newer oral anticoagulant drug 

classes 

Insufficient information 

Multicenter RCTs comparing newer 

anticoagulants with each other and 

network meta-analyses 

Uncertain effects on health system costs Insufficient information Budget impact analysis 

Effects on thrombosis and systemic 

embolism when newer anticoagulants are 

stopped prior to invasive procedures 

Insufficient information Pharmacokinetic studies; 

observational studies 

Management of patients on newer 

anticoagulants with bleeding 

complications 

Insufficient information RCTs; observational studies 

Adverse effects with long-term use and in 

usual clinical practice Insufficient information Observational studies 

Abbreviation: RCT = randomized controlled trial 

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REFERENCES 

1.	 Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin 

use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 

2007;167(13):1414-9. 

2.		 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. 

Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 

1994;154(13):1449-57. 

3.	 Stein PD, Alpert JS, Bussey HI, et al. Antithrombotic therapy in patients with mechanical 

and biological prosthetic heart valves. Chest. 2001;119(1 Suppl):220S-227S. 

4.	 Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding complications in 

patients with mechanical heart valve prostheses. Circulation. 1994;89(2):635-41. 

5.	 Gohlke-Barwolf C, Acar J, Oakley C, et al. Guidelines for prevention of thromboembolic 

events in valvular heart disease. Study Group of the Working Group on Valvular Heart 

Disease of the European Society of Cardiology. Eur Heart J. 1995;16(10):1320-30. 

6.	 Lagerstedt CI, Olsson CG, Fagher BO, et al. Need for long-term anticoagulant treatment 

in symptomatic calf-vein thrombosis. Lancet. 1985;2(8454):515-8. 

7.		 Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: 

national implications for rhythm management and stroke prevention: the AnTicoagulation 

and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370-5. 

8.	 Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the 

management of patients with atrial fibrillation: full text: a report of the American College 

of Cardiology/American Heart Association Task Force on practice guidelines and the 

European Society of Cardiology Committee for Practice Guidelines (Writing Committee 

to Revise the 2001 guidelines for the management of patients with atrial fibrillation) 

developed in collaboration with the European Heart Rhythm Association and the Heart 

Rhythm Society. Europace. 2006;8(9):651-745. 

9.	 Tzeis S, Andrikopoulos G. Novel Anticoagulants for Atrial Fibrillation: A Critical 

Appraisal. Angiology. 2011. 

10.		 Jorgensen HS, Nakayama H, Reith J, et al. Acute stroke with atrial fibrillation. The 

Copenhagen Stroke Study. Stroke. 1996;27(10):1765-9. 

11.		 Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The 

Framingham Study. Stroke. 1996;27(10):1760-4. 

12.	 Birman-Deych E, Radford MJ, Nilasena DS, et al. Use and effectiveness of warfarin in 

Medicare beneficiaries with atrial fibrillation. Stroke. 2006;37(4):1070-4. 

13.		 Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation management: a prospective 

survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart 

J. 2005;26(22):2422-34. 

50 
Warfarin and Newer Oral Anticoagulants: 


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

14.	 Baker WL, Cios DA, Sander SD, et al. Meta-analysis to assess the quality of warfarin 

control in atrial fibrillation patients in the United States. J Manag Care Pharm. 

2009;15(3):244-52. 

15.	 Smith SC, Jr., Feldman TE, Hirshfeld JW, Jr., et al. ACC/AHA/SCAI 2005 Guideline 

Update for Percutaneous Coronary Intervention-Summary Article: A Report of the 

American College of Cardiology/American Heart Association Task Force on Practice 

Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for 

Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006;47(1):216-35. 

16.		 Atwood JE, Albers GW. Anticoagulation and atrial fibrillation. Herz. 1993;18(1):27-38. 

17.	 Hansson PO, Welin L, Tibblin G, et al. Deep vein thrombosis and pulmonary embolism 

in the general population. ‘The Study of Men Born in 1913’. Arch Intern Med. 

1997;157(15):1665-70. 

18.	 Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. 

The number of VTE events and associated morbidity and mortality. Thromb Haemost. 

2007;98(4):756-64. 

19.	 Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the 

prevention of venous thromboembolism. N Engl J Med. 2009;360(18):1851-61. 

20.	 Oger E. Incidence of venous thromboembolism: a community-based study in Western 

France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne 

Occidentale. Thromb Haemost. 2000;83(5):657-60. 

21.	 Kahn SR. The post-thrombotic syndrome: the forgotten morbidity of deep venous 

thrombosis. J Thromb Thrombolysis. 2006;21(1):41-8. 

22.	 Cogo A, Bernardi E, Prandoni P, et al. Acquired risk factors for deep-vein thrombosis in 

symptomatic outpatients. Arch Intern Med. 1994;154(2):164-8. 

23.	 Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes 

in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 

1999;353(9162):1386-9. 

24.	 Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary 

hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257-64. 

25.	 Guyatt GH, Akl EA, Crowther M, et al. Executive Summary: Antithrombotic Therapy 

and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guildelines. Chest. 2012;141(2 supplement ):7S-47S. 

26.		 Ambler G, Omar R, Royston P, et al. Generic, simple risk stratification model for heart 

valve surgery. Circulation. 2005;112(2):224-31. 

27.	 Singh J, Evans J, Levy D, et al. Prevalence and clinical determinants of mitral, tricuspid, 

and aortic regurgitation (the Framingham Heart Study). Am J Cardiol. 1999;83(6):897-

902. 

51 
Warfarin and Newer Oral Anticoagulants: 


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

28.	 Bonow RC, BA. Kanu, C. de Leon, AC Jr. Faxon, DP. Freed, MD. Gaasch, WH. Lytle, 

BW. Nishimura, RA. O’Gara, PT. O’Rourke, RA. Otto, CM. Shah, PM. Shanewise, JS. 

Smith, SC Jr. Jacobs, AK. Adams, CD. Anderson, JL. Antman, EM. Faxon, DP. Fuster, 

V. Halperin, JL. Hiratzka, LF. Hunt, SA. Lytle, BW. Nishimura, R. Page, RL. Riegel, 

B. ACC/AHA 2006 guidelines for the management of patients with valvular heart 

disease: a report of the American College of Cardiology/American Heart Association 

Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for 

the Management of Patients With Valvular Heart Disease): developed in collaboration 

with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for 

Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. 

Circulation. 2006;114(5):e84-231. 

29.	 Key NS, Kasthuri RS. Current treatment of venous thromboembolism. Arterioscler 

Thromb Vasc Biol. 2010;30(3):372-5. 

30.	 Crowther MA, Berry LR, Monagle PT, et al. Mechanisms responsible for the failure of 

protamine to inactivate low-molecular-weight heparin. Br J Haematol. 2002;116(1):178-

86. 

31.	 Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with 

warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease 

in men at increased risk. The Medical Research Council’s General Practice Research 

Framework. Lancet. 1998;351(9098):233-41. 

32.	 Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal: consensus guidelines, 

on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 

2004;181(9):492-7. 

33.	 Pautas E, Peyron I, Bouhadiba S, et al. Reversal of overanticoagulation in very elderly 

hospitalized patients with an INR above 5.0: 24-hour INR response after vitamin K 

administration. Am J Med. 2011;124(6):527-33. 

34.	 Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K 

antagonists: American College of Chest Physicians Evidence-Based Clinical Practice 

Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S. 

35.	 Denas G, Marzot F, Offelli P, et al. Effectiveness and safety of a management protocol to 

correct over-anticoagulation with oral vitamin K: a retrospective study of 1,043 cases. J 

Thromb Thrombolysis. 2009;27(3):340-7. 

36.	 Jones M, McEwan P, Morgan CL, et al. Evaluation of the pattern of treatment, level of 

anticoagulation control, and outcome of treatment with warfarin in patients with nonvalvar atrial fibrillation: a record linkage study in a large British population. Heart. 

2005;91(4):472-7. 

37.	 Wrigley BJ, Lip GY, Shantsila E. Novel oral anticoagulants: the potential relegation of 

vitamin K antagonists in clinical practice. Int J Clin Pract. 2010;64(7):835-8. 

52 
Warfarin and Newer Oral Anticoagulants: 


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

38.	 Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and 

novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31(3):326-43. 

39.		 Harder S. Renal Profiles of Anticoagulants. J Clin Pharmacol. 2011. 

40.	 Huisman MV, Lip GY, Diener HC, et al. Dabigatran etexilate for stroke prevention 

in patients with atrial fibrillation: Resolving uncertainties in routine practice. Thromb 

Haemost. 2012;107(5). 

41.		 Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N 

Engl J Med. 2011;364(9):806-17. 

42.	 Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor 

edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale 

for the Effective aNticoaGulation with factor xA next GEneration in Atrial FibrillationThrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 

2010;160(4):635-41. 

43.	 Fareed J, Thethi I, Hoppensteadt D. Old Versus New Oral Anticoagulants: Focus on 

Pharmacology. Annu Rev Pharmacol Toxicol. 2011. 

44.	 Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition 

of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 

2008;36(2):386-99. 

45.	 Kazmi RS, Lwaleed BA. New anticoagulants: how to deal with treatment failure and 

bleeding complications. Br J Clin Pharmacol. 2011;72(4):593-603. 

46.	 Avorn J. The relative cost-effectiveness of anticoagulants: obvious, except for the cost 

and the effectiveness. Circulation. 2011;123(22):2519-21. 

47.	 Castellone DD, Van Cott EM. Laboratory monitoring of new anticoagulants. Am J 

Hematol. 2010;85(3):185-7. 

48.	 Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and 

tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male 

subjects. Br J Clin Pharmacol. 2007;64(3):292-303. 

49.	 Liesenfeld KH, Schafer HG, Troconiz IF, et al. Effects of the direct thrombin inhibitor 

dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population 

model analysis. Br J Clin Pharmacol. 2006;62(5):527-37. 

50.		 Potpara TS, Lip GY. New anticoagulation drugs for atrial fibrillation. Clin Pharmacol 

Ther. 2011;90(4):502-6. 

51.	 Schick KS, Fertmann JM, Jauch KW, et al. Prothrombin complex concentrate in surgical 

patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe 

bleeding. Crit Care. 2009;13(6):R191. 

53 
Warfarin and Newer Oral Anticoagulants: 


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

52.	 Piccini JP, Patel MR, Mahaffey KW, et al. Rivaroxaban, an oral direct factor Xa inhibitor. 

Expert Opin Investig Drugs. 2008;17(6):925-37. 

53.	 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. 

54.		 Stangier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the 

pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, 

parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259-68. 

55.	 Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic 

disease. Chest. 1995;108(4 Suppl):335S-351S. 

56.	 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews 

and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. 

57.	 Wilczynski NL, McKibbon KA, Haynes RB. Response to Glanville et al.: How to 

identify randomized controlled trials in MEDLINE: ten years on. J Med Libr Assoc. 

2007;95(2):117-8; author reply 119-20. 

58.		 Lane DA, Lip GYH. Dabigatran in atrial fibrillation: balancing secondary stroke 

prevention against bleeding risk. Lancet Neurology; 2010:1140-1142. 

59.	 Eikelboom JW, Weitz JI. Update on antithrombotic therapy: New anticoagulants. 

Circulation. 2010;121(13):1523-1532. 

60.	 Betriu A. Clinical implications of the results of recent atherothrombotic trials on patient 

management. European Heart Journal, Supplement. 2008;10(I):I30-I32. 

61.	 Cooper NJ, Sutton AJ, Lu G, et al. Mixed comparison of stroke prevention treatments in 

individuals with nonrheumatic atrial fibrillation. Arch Intern Med. 2006;166(12):1269-75. 

62.	 Akl Elie A, Barba M, Rohilla S, et al. Anticoagulation for the long term treatment of 

venous thromboembolism in patients with cancer. Cochrane Database of Systematic 

Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2008. 

63.	 Lip GY, Edwards SJ. Stroke prevention with aspirin, warfarin and ximelagatran in 

patients with non-valvular atrial fibrillation: a systematic review and meta-analysis. 

Thromb Res. 2006;118(3):321-33. 

64.	 Testa L, Andreotti F, Biondi Zoccai GG, et al. Ximelagatran/melagatran against 

conventional anticoagulation: a meta-analysis based on 22,639 patients. Int J Cardiol. 

2007;122(2):117-24. 

65.		 Iorio A, Guercini F, Ferrante F, et al. Safety and efficacy of ximelagatran: metaanalysis of the controlled randomized trials for the prophylaxis or treatment of venous 

thromboembolism. Curr Pharm Des. 2005;11(30):3893-918. 

54 
Warfarin and Newer Oral Anticoagulants: 


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

66.	 Diener HC. Stroke prevention using the oral direct thrombin inhibitor ximelagatran in 

patients with non-valvular atrial fibrillation. Pooled analysis from the SPORTIF III and V 

studies. Cerebrovasc Dis. 2006;21(4):279-93. 

67.	 Lloyd NS, Douketis JD, Moinuddin I, et al. Anticoagulant prophylaxis to prevent 

asymptomatic deep vein thrombosis in hospitalized medical patients: a systematic 

review and meta-analysis (Structured abstract). Journal of Thrombosis and Haemostasis; 

2008:405-414. 

68.	 Carrier M, Le Gal G, Wells PS, et al. Systematic review: case-fatality rates of recurrent 

venous thromboembolism and major bleeding events among patients treated for venous 

thromboembolism (Structured abstract). Annals of Internal Medicine; 2010:578-589. 

69.	 Lip GY, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in 

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

70.	 Uchino K, Hernandez AV. Dabigatran Association With Higher Risk of Acute Coronary 

Events: Meta-analysis of Noninferiority Randomized Controlled Trials. Arch Intern Med. 

2012. 

71.	 Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and 

Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research 

and Quality. Available at: http://www.effectivehealthcare.ahrq.gov/index.cfm/searchfor-guides-reviews-and-reports/?pageaction=displayproduct&productid=318. Accessed 

March 30, 2012. 

72.	 Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of 

dabigatran compared with warfarin in older and younger patients with atrial fibrillation: 

an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) 

trial. Circulation. 2011;123(21):2363-72. 

73.	 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 

2002;21(11):1539-58. 

74.	 MacLean S MS, Jankowski M et al. Patient values and preferences for decision making in 

antithrombotic therapy: A systematic review. . Cochrane Database Syst Rev. 2011;Suppl 

3(233):150. 

75.	 Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines 6. Rating the quality of 

evidence--imprecision. J Clin Epidemiol. 2011;64(12):1283-93. 

76.	 Schunemann HJ, Oxman AD, el.al. BJ. Grading quality of evidence and strength of 

recommendation for diagnostic tests and strategies. BMJ. 2008;336(7653):1106-10. 

77.	 Casado Naranjo I, Portilla-Cuenca JC, Jimenez Caballero PE, et al. Fatal intracerebral 

hemorrhage associated with administration of recombinant tissue plasminogen activator 

in a stroke patient on treatment with dabigatran. Cerebrovasc Dis. 2011;32(6):614-5. 

55 
Warfarin and Newer Oral Anticoagulants: 


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

78.	 De Smedt A, De Raedt S, Nieboer K, et al. Intravenous thrombolysis with recombinant 

tissue plasminogen activator in a stroke patient treated with dabigatran. Cerebrovasc Dis. 

2010;30(5):533-4. 

79.	 Legrand M, Mateo J, Aribaud A, et al. The use of dabigatran in elderly patients. Arch 

Intern Med. 2011;171(14):1285-6. 

80.	 Matute MC, Guillan M, Garcia-Caldentey J, et al. Thrombolysis treatment for 

acute ischaemic stroke in a patient on treatment with dabigatran. Thromb Haemost. 

2011;106(1):178-9. 

81.	 Moore CH, Snashall J, Boniface K, et al. Spontaneous splenic hemorrhage after initiation 

of dabigatran (Pradaxa) for atrial fibrillation. Am J Emerg Med. 2011. 

82.	 Stewart RA, Astell H, Young L, et al. Thrombosis on a Mechanical Aortic Valve whilst 

Anti-coagulated With Dabigatran. Heart Lung Circ. 2012;21(1):53-5. 

83.	 Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with 

rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and 

moderate renal impairment. Eur Heart J. 2011;32(19):2387-94. 

84.	 Hohnloser SH, Oldgren J, Yang S, et al. Myocardial Ischemic Events in Patients with 

Atrial Fibrillation Treated with Dabigatran or Warfarin in the RE-LY Trial. Circulation. 

2012. 

85.	 Schulman S, Eriksson H, Goldhaber SZ, et al. Dabigatran etexilate versus warfarin in the 

treatment of venous thromboembolism. Blood. 2009;114(22). 

86.	 Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous 

thromboembolism. N Engl J Med. 2010;363(26):2499-510. 

87.	 Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with 

atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. 

88.	 Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in 

patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293(6):690-

8. 

89.	 Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagatran vs low-molecular-weight 

heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. 

JAMA. 2005;293(6):681-9. 

90.	 Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran 

compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): 

randomised controlled trial. Lancet. 2003;362(9397):1691-8. 

91.	 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular 

Atrial Fibrillation. N Engl J Med. 2011. 

56 
Warfarin and Newer Oral Anticoagulants: 


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

92.	 Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus Warfarin in Patients 

with Atrial Fibrillation. N Engl J Med. 2011. 

93.	 Rubboli A, Becattini C, Verheugt FW. Incidence, clinical impact and risk of bleeding 

during oral anticoagulation therapy. World J Cardiol. 2011;3(11):351-8. 

94.	 Oldgren J, Alings M, Darius H, et al. Risks for stroke, bleeding, and death in patients 

with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: 

a subgroup analysis of the RE-LY trial. Ann Intern Med. 2011;155(10):660-7, W204. 

95.	 Akins PT, Feldman HA, Zoble RG, et al. Secondary stroke prevention with ximelagatran 

versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V 

clinical trials. Stroke. 2007;38(3):874-80. 

96.	 Ford GA, Choy AM, Deedwania P, et al. Direct thrombin inhibition and stroke prevention 

in elderly patients with atrial fibrillation: experience from the SPORTIF III and V Trials. 

Stroke. 2007;38(11):2965-71. 

97.	 Cleland JG, Shelton R, Nikitin N, et al. Prevalence of markers of heart failure in patients 

with atrial fibrillation and the effects of ximelagatran compared to warfarin on the 

incidence of morbid and fatal events: a report from the SPORTIF III and V trials. Eur J 

Heart Fail. 2007;9(6-7):730-9. 

98.		 Diener HC. Dabigatran compared to warfarin in patients with atrial fibrillation and prior 

TIA or stroke: Results of RE-LY. International Journal of Stroke. 2010;5:40. 

99.		 Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran 

compared with warfarin at different levels of international normalised ratio control 

for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 

2010;376(9745):975-83. 

100.	 Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. 

Arterioscler Thromb Vasc Biol. 2009;29(3):298-310. 

101.	 Hui CK, Yuen MF, Ng IO, et al. Low molecular weight heparin-induced liver toxicity. J 

Clin Pharmacol. 2001;41(6):691-4. 

102.	 Al-Mekhaizeem KA, Sherker AH. Heparin-induced hepatotoxicity. Can J Gastroenterol. 

2001;15(8):527-30. 

103.	 Moore TJ, Cohen MR, Furberg CD. QuarterWatch 2010 Quarter 4: Signals for two newly 

approved drugs and 2010 annual summary. Institute of Safe Medication Practices. Oct 6, 

2011. 

104.	 Moore TJ, Cohen MR, Furberg CD. QuarterWatch 2011 Quarter 1: Signals for dabigatran 

and metoclopramide. Institute of Safe Medication Practices. Jan 12, 2012. 

105.	 Bovio JA, Smith SM, Gums JG. Dabigatran etexilate: a novel oral thrombin inhibitor for 

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

57 
Warfarin and Newer Oral Anticoagulants: 

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

106.	 Food and Drug Administration. FDA Drug Safety Communication: Special storage and 

handling requirements must be followed for Pradaxa (dabigatran etexilate mesylate) 

capsules. 2011. 

107.	 Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on 

the management of patients with atrial fibrillation (update on Dabigatran): a report of the 

American College of Cardiology Foundation/American Heart Association Task Force on 

practice guidelines. Circulation. 2011;123(10):1144-50. 

108.	 Camm AJ. The RE-LY study: Randomized Evaluation of Long-term anticoagulant 

therapY: Dabigatran vs. warfarin. European Heart Journal. 2009;30(21):2554-2555. 

109.	 Cairns JA, Connolly S, McMurtry S, et al. Canadian Cardiovascular Society atrial 

fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial 

fibrillation and flutter. Can J Cardiol. 2011;27(1):74-90. 

110.	 Beasley BN, Unger EF, Temple R. Anticoagulant options--why the FDA approved a 

higher but not a lower dose of dabigatran. N Engl J Med. 2011;364(19):1788-90. 

111.	 Shah SV, Gage BF. Cost-Effectiveness of Dabigatran for Stroke Prophylaxis in Atrial 

Fibrillation. Circulation. 2011. 

112.	 Robinson KA, Saldanha IJ, Mckoy NA. Frameworks for Determining Research Gaps 

During Systematic Reviews. Methods Future Research Needs Report No. 2. (Prepared by 

the Johns Hopkins University Evidence-based Practice Center under Contract No. HHSA 

290-2007-10061-I. Agency for Healthcare Research and Quality. Rockville, MD: AHRQ 

Publication No. 11-EHC043-EF. Available at: www.effectivehealthcare.ahrq.gov/reports/ 

final.cfm. Accessed March 13, 2012. 

58