Papel de la Vitamina K en la prevención de los embolismos

Direct thrombin inhibitors versus vitamin K antagonists for
preventing cerebral or systemic embolism in people with non-
valvular atrial ﬁbrillation (Review)
Salazar CA, del Aguila D, Cordova EG
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2014, Issue 3
http://www.thecochranelibrary.com
Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial
ﬁbrillation (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
14DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Efﬁcacy, Outcome 1 Vascular deaths and ischaemic events. . . . . . . . . . . . 44
Analysis 2.1. Comparison 2 Safety, Outcome 1 Fatal and non-fatal haemorrhages. . . . . . . . . . . . . 45
Analysis 3.1. Comparison 3 Efﬁcacy: sensitivity analyses, Outcome 1 Vascular deaths and ischaemic events. . . . . 46
Analysis 4.1. Comparison 4 Safety: sensitivity analyses, Outcome 1 Fatal and non-fatal haemorrhages. . . . . . 48
Analysis 5.1. Comparison 5 Adverse events, Outcome 1 Adverse events that lead to discontinuation of treatment. . 49
Analysis 5.2. Comparison 5 Adverse events, Outcome 2 Serious adverse events. . . . . . . . . . . . . . 50
Analysis 6.1. Comparison 6 Hepatotoxicity, Outcome 1 ALT or AST > 3x ULN. . . . . . . . . . . . . . 51
Analysis 7.1. Comparison 7 Overall mortality, Outcome 1 Death from all causes. . . . . . . . . . . . . . 52
53APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
56INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iDirect thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial

[Intervention Review]
Direct thrombin inhibitors versus vitamin K antagonists for
preventing cerebral or systemic embolism in people with non-
valvular atrial fibrillation
Carlos A Salazar1, Daniel del Aguila1, Erika G Cordova1
1
Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru
Contact address: Carlos A Salazar, Department of Medicine, Universidad Peruana Cayetano Heredia, Avenida Honorio Delgado 430,
San Martin de Porres, Lima, Peru. caso90@gmail.com.
Editorial group: Cochrane Stroke Group.
Publication status and date: New, published in Issue 3, 2014.
Review content assessed as up-to-date: 22 March 2014.
Citation: Salazar CA, del Aguila D, Cordova EG. Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral
or systemic embolism in people with non-valvular atrial fibrillation. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.:
CD009893. DOI: 10.1002/14651858.CD009893.pub2.
A B S T R A C T
Background
Chronic anticoagulation with vitamin K antagonists (VKAs) prevents ischaemic stroke and systemic embolism in people with non-
valvular atrial fibrillation (AF) but dose adjustment, coagulation monitoring and bleeding limits its use. Direct thrombin inhibitors
(DTIs) are under investigation as potential alternatives.
Objectives
To assess (1) the comparative efficacy of long-term anticoagulation using DTIs versus VKAs on vascular deaths and ischaemic events
in people with non-valvular AF, and (2) the comparative safety of chronic anticoagulation using DTIs versus VKAs on (a) fatal and
non-fatal major bleeding events including haemorrhagic strokes, (b) adverse events other than bleeding and ischaemic events that lead
to treatment discontinuation and (c) all-cause mortality in people with non-valvular AF.
Search methods
We searched the Cochrane Stroke Group Trials Register (July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL),
(The Cochrane Library, May 2013), MEDLINE (1950 to July 2013), EMBASE (1980 to October 2013), LILACS (1982 to October
2013) and trials registers (September 2013). We also searched the websites of clinical trials and pharmaceutical companies and hand-
searched the reference lists of articles and conference proceedings.
Selection criteria
Randomised controlled trials (RCTs) comparing DTIs versus VKAs for prevention of stroke and systemic embolism in people with
non-valvular AF.
Data collection and analysis
All three review authors independently performed data extraction and assessment of risk of bias. Primary analyses compared all DTIs
combined versus warfarin. We performed post hoc analyses excluding ximelagatran because this drug was withdrawn from the market
owing to safety concerns.
1Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial

Main results
We included eight studies involving a total of 27,557 participants with non-valvular AF and one or more risk factors for stroke; 26,601
of them were assigned to standard doses groups and included in the primary analysis. The DTIs: dabigatran 110 mg twice daily and 150
mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once per day (two studies, 233 participants) and ximelagatran
36 mg twice per day (three studies, 3726 participants) were compared with the VKA warfarin (10,287 participants). Overall risk of
bias and statistical heterogeneity of the studies included were low.
The odds of vascular death and ischaemic events were not significantly different between all DTIs and warfarin (odds ratio (OR) 0.94,
95% confidence interval (CI) 0.85 to 1.05). Sensitivity analysis by dose of dabigatran on reduction in ischaemic events and vascular
mortality indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical
significance (OR 0.86, 95% CI 0.75 to 0.99). Sensitivity analyses by other factors did not alter the results. Fatal and non-fatal major
bleeding events, including haemorrhagic strokes, were less frequent with the DTIs (OR 0.87, 95% CI 0.78 to 0.97). Adverse events
that led to discontinuation of treatment were significantly more frequent with the DTIs (OR 2.18, 95% CI 1.82 to 2.61). All-cause
mortality was similar between DTIs and warfarin (OR 0.91, 95% CI 0.83 to 1.01).
Authors’ conclusions
DTIs were as efficacious as VKAs for the composite outcome of vascular death and ischaemic events and only the dose of dabigatran
150 mg twice daily was found to be superior to warfarin. DTIs were associated with fewer major haemorrhagic events, including
haemorrhagic strokes. Adverse events that led to discontinuation of treatment occurred more frequently with the DTIs. We detected
no difference in death from all causes.
P L A I N L A N G U A G E S U M M A R Y
Direct thrombin inhibitors compared with vitamin K antagonists in people with atrial fibrillation for preventing stroke
Question: We wanted to compare the effectiveness and safety of direct thrombin inhibitors (DTIs) with vitamin K antagonists in
people with atrial fibrillation (AF) to prevent stroke.
Background: Non-valvular atrial fibrillation is a type of irregular heartbeat that arises in a heart with normal valves. It increases the risk
of developing blood clots in the heart which can then travel to the brain, leading to a stroke, and to other parts of the body. Warfarin
(a vitamin K antagonist) is a drug that prevents the formation of such clots, thus reducing the risk of stroke. However, the need for
frequent blood tests to adjust the dose and the risk of bleeding limits the use of warfarin. The oral DTIs represent a potential alternative.
We aimed to establish the comparative effectiveness and safety of these new drugs compared with the standard treatment (warfarin)
used for long-term anticoagulation in people with AF.
Study characteristics: We included eight studies, identified up to October 2013, evaluating the effect of DTIs versus warfarin in people
with non-valvular AF. DTIs included were dabigatran 110 mg or 150 mg twice daily (three studies, 12,355 participants), AZD0837
300 mg once a day (two studies, 233 participants) and ximelagatran 36 mg twice daily (three studies, 3726 participants). Of the total
number of participants included in this review 61% were men, and the mean age of participants in all studies was over 70 years. Follow-
up periods after the end of study medication ranged from zero to four weeks.
Key results: We conducted the analyses excluding ximelagatran because this drug was withdrawn from the market owing to toxic effects
on the liver. We evaluated the effectiveness of the treatment by the number of vascular deaths and ischaemic events. We evaluated safety
by the number of (1) fatal and non-fatal major bleeding events, including haemorrhagic strokes, (2) adverse events other than bleeding
and ischaemic events that led to treatment discontinuation, and (3) death from all causes.
There was no difference in the number of vascular deaths and ischaemic events between all DTIs combined and warfarin, although
dabigatran 150 mg twice daily was superior to warfarin for this outcome. Major bleeding events were less frequent with the DTIs, making
them a potentially safer alternative to anticoagulation in people at high risk. The adverse events that led participants to discontinue
treatment were more frequent with the DTIs. Death from all causes was similar between DTIs and warfarin.
Quality of the evidence: We judged the quality of all eight included studies to be adequate to address the main objectives of the review.

B A C K G R O U N D
Non-valvular atrial fibrillation (AF) is estimated to affect fewer
than 1% of individuals below 50 years of age, increasing to 23.5%
in people over 80 years of age (Benjamin 1998). Among people
with AF, 76% have a moderate to high risk of stroke (Singer 2008).
Dose-adjusted warfarin reduces this risk by 62% compared with
placebo but increases the risk of intracranial bleeding (Hart 2007).
Direct thrombin inhibitors (DTIs) constitute a new class of oral
anticoagulants under investigation (Fuster 2006; Squizzato 2009;
Weitz 2003).
Description of the condition
AF is a cardiac arrhythmia caused by multiple re-entrant wave-
forms within the atria of the heart, which impairs atrial contrac-
tion. The resulting left atrial stasis can promote thrombus forma-
tion and subsequent embolic events including stroke and systemic
embolism (Ferro 2004; Kimura 2005). AF increases the risk of
stroke four to five times in all age groups (Friberg 2004; Wolf
1987). Without anticoagulation therapy, the stroke rate among
people with AF can vary from 1.9% to 18% per year, depending
on individual characteristics (CHADS score) (Gage 2004).
Description of the intervention
DTIsbelongtoanewclassof anticoagulantsthatwere developedas
potential alternatives to vitamin K antagonists (VKAs) for chronic
anticoagulation in people with non-valvular AF (Kirchhof 2007).
DTIs offer fixed oral dosing without the need for coagulation
monitoring, as well as rapid onset of action and stable pharma-
cokinetics with little potential for drug interactions (Baetz 2008;
Pengo 2004). Ximelagatran was the first oral DTI to be used clin-
ically but it was withdrawn from the market due to liver toxicity
(Albers 2006; Boudes 2006; EMEA 2006). Dabigatran etexilate is
a DTI that was approved by the US Food and Drug Administra-
tion (FDA) in October 2010 for stroke prevention in people with
non-valvular AF. Dabigatran reaches its plasmatic peak and begins
its anticoagulant action between half an hour and two hours after
oral administration (Baetz 2008). It is primarily eliminated by the
kidneys and it is not metabolised by the cytochrome P450 enzyme
system in the liver, which yields a better drug interaction profile
(Fareed 2012). AZD0837 is another oral DTI under investigation,
not yet licensed for clinical use.
How the intervention might work
Thrombin has a central role in thrombogenesis. DTIs act by in-
terfering with the final step of the coagulation cascade, namely,
the conversion of fibrinogen to insoluble fibrin by thrombin.
Why it is important to do this review
Although there is much experience with VKA treatment, it has
several disadvantages including its narrow therapeutic index and
wide variability of anticoagulation intensity, which requires fre-
quent dose adjustments (Go 2003; Rose 2008). Despite regular
monitoring, 30% to 50% of the time the international normalised
ratio (INR) values fall outside the therapeutic target range (Jones
2005). Moreover, the risk of bleeding remains a pivotal concern
with warfarin therapy, particularly among the elderly (Oldgren
2011). These limitations result in undertreatment of a consider-
able proportion of people with AF who remain at high risk for
stroke (Frykman 2001) and create a need for safer and more con-
venient alternatives. In this context, the evaluation of the efficacy
and safety of the new DTIs is of critical importance.
O B J E C T I V E S
To assess (1) the comparative efficacy of long-term anticoagulation
using DTIs versus VKAs on vascular deaths and ischaemic events
in people with non-valvular AF, and (2) the comparative safety of
long-termanticoagulationusingDTIsversusVKAson(a)fatal and
non-fatal major bleeding events including haemorrhagic strokes,
(b) adverse events other than bleeding and ischaemic events that
lead to treatment discontinuation, and (c) all-cause mortality in
people with non-valvular AF.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) comparing anticoagulation
with direct thombin inhibitors (DTIs) versus vitamin K antago-
nists (VKAs) for preventing cerebral or systemic embolism in peo-
ple with non-valvular AF.
Types of participants
People with non-valvular AF and one or more risk factors for
stroke.
Types of interventions
Administration of DTIs at standard doses (dabigatran 110 mg
twice daily and 150 mg twice daily, AZD0837 300 mg twice daily
and ximelagatran 36 mg twice daily) compared with VKAs (ad-
justed-dose warfarin) for an INR between 2 and 3.

Both doses of dabigatran included in this review are available for
clinical use. The dose of dabigatran 150 mg twice daily has been
approved by the FDA for preventing stroke in people with non-
valvular AF (Beasley 2011). The European Society of Cardiology
recommends both dabigatran 150 mg twice daily and dabigatran
110 mg twice daily for people at low and high risk of bleeding
respectively (Camm 2009). The dose of ximelagatran 36 mg twice
daily was commercially available until 2006 when it was with-
drawn from the market owing to safety concerns. We chose to
include the dose of AZD0837 300 mg twice daily even though
it has not yet been licensed because in the analysis of individual
doses it appeared to have the best efficacy and safety profile among
the different tested doses.
Types of outcome measures
Primary outcomes
1. The composite outcome of vascular deaths and ischaemic
events, including non-fatal ischaemic strokes and transient
ischaemic attacks (TIAs), non-fatal systemic embolic events
(SEE) and non-fatal myocardial infarction (MI). Vascular death
is defined as any death related to a vascular cause not including
fatal haemorrhages or cardiovascular deaths (e.g. sudden
arrhythmia, pump failure). Systemic embolism is defined as any
event of acute non-intracerebral or non-coronary vascular origin
including deep vein thrombosis (DVT) and pulmonary
embolism (PE).
2. The composite outcome of fatal or non-fatal major
bleeding events, including haemorrhagic strokes. We did not
include minor bleeding events.
Secondary outcomes
1. Fatal or non-fatal adverse events other than haemorrhage
and ischaemic events that lead to discontinuation of treatment.
2. Death from all causes during treatment.
Search methods for identification of studies
See the ’Specializedregister’ sectioninthe Cochrane Stroke Group
module. We searched for relevant trials in all languages and, where
necessary, arranged translation of trial reports published in lan-
guages other than English or Spanish.
Electronic searches
We searched the Cochrane Stroke Group Trials Register (last
searched July 2013). In addition, we searched the following
electronic databases: the Cochrane Central Register of Con-
trolled Trials (CENTRAL) (The Cochrane Library, May 2013, Is-
sue 5) (Appendix 1), MEDLINE (Ovid) (1950 to July 2013)
(Appendix 2), EMBASE (Ovid) (1980 to October 2013) (
Appendix 3), and LILACS (Latin American and Caribbean
Health Science Literature) (1982 to October 2013) (Appendix
4). We also searched ClinicalTrials.gov (www.clinicaltrials.gov),
Current Controlled Trials (www.controlled-trials.com), TrialRe-
sults-center (www.trialresultscenter.org), Stroke Trials Directory (
www.strokecenter.org/trials) and the WHO International Clini-
cal Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/
en/) (last searched September 2013).
We developed the search strategies for MEDLINE, EMBASE and
CENTRAL with the help of the Cochrane Stroke Group Trials
Search Co-ordinator and adapted the MEDLINE search strategy
for the other databases.
Searching other resources
In an effort to identify further published, unpublished and ongo-
ing trials we:
1. screened the reference lists of relevant articles;
2. identified and handsearched the following relevant journals
and the proceedings of relevant conferences (last search:
September 2013): Congresses of the European Society of
Cardiology, Scientific sessions of the American Heart
Association, Heart Rhythm Society and Annual Meeting of the
American College of Cardiology;
3. reviewed the websites of the following pharmaceutical
companies for clinical trial results: AstraZeneca (
www.astrazenecaclinicaltrials.com) and Boehringer-Ingelheim (
www.boehringer-ingelheim.com).
Data collection and analysis
All three review authors screened the records obtained from the
electronic searches and excluded obviously irrelevant studies. We
obtained the full text of the remaining papers and the same three
authors selected trials for inclusion based on the selection crite-
ria described previously. We arranged translation of titles and ab-
stracts of articles in languages other than English or Spanish, and
if the title and the abstract potentially met the inclusion criteria
we had the entire text of the article translated. We resolved any
disagreements through discussion and consensus.
Selection of studies
All three review authors independently assessed eligibility of stud-
ies based on prespecified inclusion and exclusion criteria. We re-
solved disagreements by discussion and consensus. We listed stud-
ies excluded at the full-text review stage along with the reasons for
exclusion. See the study flow chart (Figure 1).

Data extraction and management
All three review authors independently extracted data using pre-
designed abstraction forms. We verified these forms to ensure that
all relevantdatawere included.We comparedthe abstractionforms
with each other to ensure reproducibility between abstractors.
Assessment of risk of bias in included studies
All three review authors independently assessed the methodolog-
ical quality of each included study using the domain-based eval-
uation tool described in Chapter 8 of the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). Quality criteria
consisted of (1) random sequence generation, (2) allocation con-
cealment, (3) blinding of participants and personnel (4) blinding
of outcome assessment (5) incomplete outcome data addressed,
(6) selective reporting and (7) other potential biases. Each author
issued a judgement of risk (low, high or uncertain) for each qual-
ity criterion. When a rating of high or low would not have been
feasible or prudent, we assigned a grade of unclear. We resolved
disagreements by discussion. We addressed publication bias using
graphical statistics such as funnel plots. See Figure 2 and Figure 3.
Measures of treatment effect
The outcomes were binary and we summarised the dichotomous
data using odds ratios (ORs). Results are presented with 95%
confidence intervals (CIs).
Unit of analysis issues
The included RCTs had a simple parallel group design. In this
design, the participants are individually randomised to either the
intervention group (DTIs) or the control group (VKAs) and we
collected and analysed a single measurement for each outcome
from each participant. For phase II studies including multiple
treatment arms with different doses of the DTIs, we selected the
data from the treatment arm using the standard or intermediate
doses. See Types of interventions.
Dealing with missing data
We complemented data from the final report of included studies
with: (1) protocol descriptions (e.g. rationale and design articles),
(2) clinical trial registers, (3) editorials and subanalyses of main
studies, and (4) FDA briefing documents. If the missing data could
not be obtained, then we analysed the available data and noted any
assumptions made. We carefully considered missing data when
evaluating potential biases and in the interpretation of results.
Assessment of heterogeneity
We used the I² statistical test (Higgins 2003) to ascertain hetero-
geneity among studies. The I² is expressed as a percentage, and
describes the proportion of variability that is due to heterogeneity
rather than to sampling error. We categorised heterogeneity as fol-
lows: low (I² values less than 25%), moderate (I² above 25% but
less than 50%) and high (I² between 50% and 75%).
Assessment of reporting biases
We performed a comprehensive search for published, unpublished
and ongoing studies that met our eligibility criteria. The evalua-
tion of methodological quality of included studies comprised the
assessment of selective reporting.
Data synthesis
We used either fixed-effect or random-effects models to synthe-
sise the evidence quantitatively, depending on the heterogeneity
across studies. For an analysis with low heterogeneity we planned
to use a fixed-effect meta-analysis. Conversely, for moderate or
high heterogeneity we planned to use a random-effects meta-anal-
ysis. Finally, if the combination of studies resulted in very high
heterogeneity (greater than 75%), we did not perform a combined
analysis.
Subgroup analysis and investigation of heterogeneity
Other than the analysis of grouped and individual doses described
in the Sensitivity analysis section, we could not undertake the
subgroup analyses prespecified in the protocol due to insufficient
data. See Differences between protocol and review.
Sensitivity analysis
We performed the following sensitivity analyses:
1. re-analysis of data using a different statistical approach
(random-effects instead of fixed-effect and vice versa);
2. different doses of DTIs: all tested doses grouped and
isolated.
Post hoc sensitivity analyses included:
1. excluding the studies of ximelagatran;
2. evaluating each drug independently;
3. excluding myocardial infarction (MI) from the primary
efficacy outcome.
R E S U L T S
Description of studies
See Characteristics of included studies; Characteristics of excluded
studies.

Results of the search
We obtained 1025 records through the searches of the electronic
databases and 89 additional references from other sources. Af-
ter removing duplicate records, we screened 1074 records by title
and abstract. We excluded 1042 records as not relevant. We ob-
tained the full text of the remaining 32 papers and of these we ex-
cluded 24. Eight studies are included in the qualitative and quan-
titative synthesis (Lip 2009; Olsson 2010; PETRO 2007; RE-LY
2009; SPORTIF II 2003; SPORTIF III 2003; SPORTIF V 2005;
NCT01136408). We did not identify any ongoing trials. The ﬂow
diagram describing the search process, selection and exclusion is
shown in Figure 1.

Figure 1. Study ﬂow diagram.

Included studies
We identified eight randomised controlled trials (RCTs) that met
the eligibility criteria, which included a total of 27,557 partici-
pants, 26,601 of whom were assigned to standard doses groups and
included in the primary analysis. The direct thrombin inhibitors
(DTIs) dabigatran 110 mg twice daily and 150 mg twice daily
(three studies, 12,355 participants), AZD0837 300 mg once daily
(two studies, 233 participants) and ximelagatran 36 mg twice daily
(three studies, 3726 participants) were compared to the vitamin
K antagonist (VKA) warfarin (10,287 participants). RE-LY 2009
represented 66% of the total population. Three RCTs used dabiga-
tran etexilate (NCT01136408; PETRO 2007; RE-LY 2009). Two
RCTs used AZD0837: Lip 2009 used an extended-release form
and Olsson 2010 used immediate-release pills. Three RCTs used
ximelagatran (SPORTIF II 2003; SPORTIF III 2003; SPORTIF
V 2005). Three included studies were phase III RCTs designed
to assess efficacy and safety (RE-LY 2009; SPORTIF III 2003;
SPORTIF V 2005), while the remaining five were phase II RCTs
that evaluated tolerability and safety of different dosages (Lip
2009; NCT01136408; Olsson 2010; PETRO 2007; SPORTIF II
2003).These latter studies also reported events that were included
in the efficacy analysis. All studies were funded by the pharmaceu-
tical industry.
From the total number of participants included in this review, 61%
were men and the mean age of participants in all studies was over
70 years. The rate of VKA-na ve participants (never previously
exposed to VKAs) was approximately 50% (range 5% to 100%).
The average CHADS score was 2.1 except for PETRO 2007 in
which the average score was 3. The studies of ximelagatran did
not report CHADS scores. In the groups assigned to warfarin,
the international normalised ratio (INR) was maintained within
the therapeutic range between 57% and 71% of the time. In five
studies (Lip 2009; Olsson 2010; PETRO 2007; RE-LY 2009;
SPORTIF II 2003) the different doses of DTIs were administered
in a double-blind modality whereas warfarin was given openly.
NCT01136408 and SPORTIF III 2003 were open-label for both
the DTI and warfarin. SPORTIF V 2005 used a double-dummy
design to blind the administration of both the intervention and
the control drug. In PETRO 2007, the three doses of dabigatran
used (50, 150, and 300 mg twice daily) were combined in a 3 x
3 factorial fashion with no aspirin, 81 mg or 325 mg aspirin once
daily. Aspirin was given openly.
The studies planned outcome assessment over 2.8 to 24 months
for dabigatran, three to 4.7 months for AZD0837 and three to 20
months for ximelagatran. Follow-up periods after discontinuation
of study medication ranged from zero to four weeks.
Excluded studies
We excluded a total of 24 studies. We excluded 15 studies be-
cause they studied populations other than people with AF (e.g.
healthy individuals, people with DVT, with mechanical heart
valves, haemodialysis, people undergoing elective percutaneous
coronary intervention, people with acute coronary syndrome)
(BISTRO 2005; Eikelboom 2013; Eriksson 2007; ESTEEM
2003; NCT01225822; NCT00152971; NCT00246025;
NCT00680186; ; RE-ALIGN 2012; RECOVER 2009;
REDEEM 2011; REMODEL 2007; RENOVATE 2011;
Schulman 2013; Vranckx 2013). We excluded six studies (
ACTIVE 2006; Amadeus Investig 2008; ARISTOTLE 2011;
ENGAGE AF 2010; EXPLORE Xa 2013; ROCKET 2011) be-
cause they did not use a DTI as the intervention. We excluded one
study for not using warfarin as the comparison (NCT00904800).
The international multicentre RELY ABLE 2012 study followed
5851 participants on dabigatran for a further 28 months after
completion of RE-LY 2009. We excluded this study because it had
no comparison group and participants randomised to warfarin in
the original study were not eligible for inclusion. Moreover, par-
ticipants continuing in RELY ABLE 2012 differed in several re-
spects from those who did not: continuing participants were less
likely to have permanent AF, less likely to have heart failure and
less likely to have had a major clinical event during the original
study. SPORTIF IV 2006 is a long-term follow-up study of peo-
ple who participated in SPORTIF II 2003. It was stopped prema-
turely following an adverse event report of serious liver injury in
the EXTEND clinical trial. We excluded the SPORTIF IV 2006
study owing to methodological concerns as it introduced signif-
icant bias: only people completing the first and seventh visit of
SPORTIF II 2003 were eligible for the study, outcome assessment
lost blinding and all three different dose arms were combined into
a single dose of ximelagatran 36 mg bid and analysed together.
Risk of bias in included studies
See Figure 2, Figure 3, Figure 4 and Figure 5.

Figure 2. Funnel plot of comparison: Efﬁcacy outcome: Vascular deaths plus ischaemic events

Figure 3. Funnel plot of comparison: Safety outcome: Fatal and non-fatal haemorrhages
Figure 4. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Figure 5. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

Allocation
Seven of the included studies achieved randomisation sequence
through a computerised interactive system, and three of them
maintained the allocation concealment in the same way. Olsson
2010, PETRO 2007 and SPORTIF V 2005 trials did not mention
how allocation concealment was maintained after the randomisa-
tion. NCT01136408 did not specify how the randomisation se-
quence or allocation concealment was done.
Blinding
Participants taking warfarin needed constant INR monitoring.
Therefore, blinding of both intervention and control groups was
notdone inmoststudies.However, the differentdosesof DTIwere
blinded to the physician and to the participant. Only SPORTIF
V 2005 used a double-dummy design to maintain blinding of
both DTI and warfarin. NCT01136408 and SPORTIF III 2003
were open-label for both intervention and control groups. In RE-
LY 2009, PETRO 2007, SPORTIF II 2003, SPORTIF III 2003
and SPORTIF V 2005 endpoint adjudication was done by an
independent committee blinded to treatment status following the
PROBE design in an effort to compensate for open warfarin.
Incomplete outcome data
RE-LY 2009 showed a rate of discontinuation of treatment of
19.6% and 15% in the dabigatran and warfarin groups respec-
tively. The reasons for discontinuation were uncertain for 208 par-
ticipants in the dabigatran group and 200 in the warfarin group.
This study reported that only 20 (0.11%) participants interrupted
follow-up. In SPORTIF II 2003 47 (18.2%) participants discon-
tinued assigned treatment prematurely. Reasons for discontinua-
tion remained uncertain in 24 participants. SPORTIF III 2003
reported premature discontinuation of study treatment in 309
(18%) participants in the ximelagatran group and 246 (14%) par-
ticipants in the warfarin group. The reasons for discontinuation
were uncertain for 125 participants in the ximelagatran group and
124 in the warfarin group. In this study interrupted follow-up
was seen in 138 (4%) participants. Status could not be ascertained
in 18 of 78 participants assigned to ximelagatran and 17 of 60
participants assigned to warfarin. SPORTIF V 2005 reported that
37% and 33% discontinued treatment prematurely in the xime-
lagatran and warfarin groups respectively. This study reported a
total of 226 (6%) participants who interrupted follow-up. Sta-
tus remained uncertain for 23 of them. Lip 2009 also had a sig-
nificant percentage of discontinuation of treatment in the DTI
group (16.8%) compared with that of the warfarin group (7.9%).
However, the overall follow-up interruption was less than 10%
(8.9% for AZD0837 and 4.7% for warfarin). The treatment dis-
continuation percentages in the other studies were: Olsson 2010:
6.4% and PETRO 2007: 7.5%. NCT01136408 did not report
the number of discontinuations.
Reported outcomes in RE-LY 2009 were complemented with data
from a RE-LY update publication, Conolly 2010 (included in the
RE-LY 2009 references), which reported additional primary effi-
cacy outcome events recorded during routine clinical site closure
visits after the database was locked. Additionally, we used data
from a briefing document submitted to the FDA by Boehringer
Ingelheim, PharmaceuticalsBoehringerIngelheim2010(included
in the RE-LY 2009 references) to obtain the exact number of in-
dividual outcomes included in composite endpoints.
We made assumptions when missing data could not be obtained
and when reported outcomes left room for interpretation. All as-
sumptions followed unified criteria across studies and were made
before the pooled analysis was carried out. These are detailed as
follows:
Dabigatran studies
PETRO 2007
502 participants were randomised, 13 of whom were included
twice in the safety analysis of the study owing to a change in their
aspirin dose, reaching a total of 515 participants analysed. In our
security analysis, we only included the 502 initially randomised
participants.
Two deaths in the dabigatran group were reported in the study
report on the pharmaceutical company website: one of them was
due to heart failure and the other was due to mesenteric ischaemia.
Neither is mentioned in the published report. We included both
deaths in our analysis as death from all causes. We did not include
the death attributed to systemic embolism in the efficacy analysis
because we could not elucidate the dosage arm to which it be-
longed.
One participant had a peripheral embolism and an ischaemic
stroke, which counted as two separate events in our efficacy anal-
ysis.
RE-LY 2009
We included the number of strokes with uncertain classifications
(seven for dabigatran 110 mg twice daily, nine for dabigatran 150
mg twice daily and 10 for warfarin) in the primary efficacy out-
come.
We included both clinical and silent MI in the primary analysis.
We included deaths classified as vascular from unknown causes
(46 for dabigatran 110 mg twice daily, 41 for dabigatran 150 mg
twice daily and 46 for warfarin) as vascular deaths.
NCT01136408
We considered a participant who presented with an ischaemic
stroke with haemorrhagic conversion only as an ischaemic event.

AZD0837 studies
Lip 2009
We counted clinically relevant bleeding events in the safety anal-
ysis.
One participant in the warfarin group presented one major bleed-
ing and one clinically relevant bleeding, which we considered as
two different events in our safety analysis.
We considered one death due to haemorrhage after a skull fracture
as a death from other causes.
Olsson 2010
We included a participant with MI, considered as an adverse event
by the study authors, in the efficacy analysis. A participant who
died of sudden chest pain and for whom an autopsy was not per-
formed is considered in our analysis as a death from other causes.
Ximelagatran studies
SPORTIF II 2003
No assumptions.
SPORTIF III 2003
One participant had both initial ischaemic and subsequent haem-
orrhagic stroke. The former is included in the efficacy analyses and
the latter in the safety analysis as two separate events.
The 10deathsreportedinparticipantswhohadalreadyterminated
the study are not accounted for in any analysis.
SPORTIF V 2005
One participant who had two ischaemic strokes is counted twice
in our efficacy analysis.
Selective reporting
All three review authors assessed selective reporting by cross-check-
ing the results reported in the original articles with those obtained
from online trial registers and from the reports of pharmaceutical
company websites. We included all reported outcome events in
the analyses.
Other potential sources of bias
None detected.
Effects of interventions
Tests for statistical heterogeneity suggested low variability in treat-
ment effects across studies for all outcomes analysed. However, we
judged clinical heterogeneity to be moderate owing to differences
in methodological aspects and variation in definitions of reported
outcomes across studies.
Primary outcomes
Efficacy analysis
See Analysis 1.1 and Analysis 3.1
Vascular deaths and ischaemic events (including ischaemic strokes/
transient ischaemic attacks (TIAs), non-fatal systemic embolic
events (SEE) and non-fatal myocardial infarction (MI)) were not
significantly different between all DTIs and warfarin (odds ra-
tio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). The
analysis of individual drugs within the class showed similar results
for dabigatran versus warfarin (OR 0.92, 95% CI 0.82 to 1.04),
AZD0837 versus warfarin (OR 0.52, 95% CI 0.06 to 4.72) and
ximelagatran versus warfarin (OR 1.02, 95% CI 0.83 to 1.26).
Sensitivity analyses of individual doses of dabigatran showed that
numerically fewer events were observed for both dabigatran doses
but only dabigatran 150 mg twice daily was significantly superior
to warfarin for the primary endpoint (OR 0.86, 95% CI 0.75 to
0.99). When we excluded the studies examining ximelagatran, the
results were unchanged. The analysis excluding MI favoured the
DTIs slightly without reaching statistical significance (OR 0.89,
95% CI 0.79 to 1.00).
Safety analysis
Fatal and non-fatal major haemorrhages, including haemorrhagic
strokes, occurred less frequently with the DTIs compared with
VKAs (OR 0.87, 95% CI 0.78 to 0.97). The sensitivity analyses
revealed that ximelagatran (OR 0.71, 95% CI 0.55 to 0.92) and
the individual dose of dabigatran 110 mg bid (OR 0.82, 95% CI
0.71 to 0.94) contributed most to this result. Numerically, fewer
events were observed with all other comparisons (dabigatran both
doses versus warfarin, dabigatran 150 mg twice daily versus war-
farin, AZD0837 versus warfarin), although none reached statisti-
cal significance.
Secondary outcomes
Adverse events
We excluded studies of ximelagatran for this analysis because this
drug was withdrawn from the market due to adverse effects on
liver function. Importantly, the risk of transaminase elevation to
three times the upper limit of normal was not increased either with
dabigatran all doses versus warfarin (OR 0.91, 95% CI 0.74 to
1.13) or AZD0837 all doses versus warfarin (OR 1.52, 95% CI
0.60 to 3.86).
Adverse events other than bleeding and ischaemic events that led to
treatment discontinuation were significantly more frequent with
the DTIs compared with VKAs (OR 2.18, 95% CI 1.82 to 2.61).
Serious adverse events were also more frequent in the DTI group
(OR 1.31, 95% CI 1.09 to 1.56); these were significantly more

frequent with dabigatran (OR 1.35, 95% CI 1.12 to 1.63) but
not with AZD0837 (OR 0.99, 95% CI 0.57 to 1.71).
All-cause mortality
See Analysis 7.1
Death from all causes occurred to a similar extent in both groups
(OR 0.91, 95% CI 0.83 to 1.01). Death rates were slightly lower
in the DTI group.
D I S C U S S I O N
Summary of main results
Deaths attributed to vascular causes and total ischaemic events
(including ischaemic stroke/transient ischaemic attacks (TIAs),
non-fatal systemic embolic events (SEE) and non-fatal myocar-
dial infarction (MI)) were not significantly different between di-
rect thrombin inhibitors (DTIs) and warfarin. Importantly, the
analysis of individual doses showed that dabigatran 150 mg was
superior to warfarin for this same endpoint.
Bleeding events - namely fatal and non-fatal haemorrhages includ-
ing haemorrhagic strokes - were significantly lower with the DTIs.
The overall estimate was mainly influenced by ximelagatran and
by the dose of dabigatran 110 mg twice daily.
Other outcomes evaluated including adverse events that led to
discontinuation of treatment were significantly more frequent in
the DTI group. Deaths from all causes were comparable between
the DTIs and warfarin.
Overall completeness and applicability of
evidence
Several aspects of this review attest to its completeness: (1) we con-
ducted a thorough search and included data from published and
unpublished studies in the analysis; (2) RE-LY 2009 was comple-
mented with its update publication by Conolly 2010 (included in
RE-LY 2009 references) and by the briefing document prepared by
Boehringer Ingelheim Pharmaceuticals for the FDA (Boehringer
Ingelheim 2010 - included in RE-LY 2009 references), allowing
us to break down composite endpoints accurately with minimal
assumptions.
The assessment of the external validity of our results should take
into consideration the following.
1. The eight studies that met the eligibility criteria were
considered adequate to address the main objectives of the review.
However, studies varied in important aspects: (a) design; (b)
number of randomised participants; (c) duration of study, and
(d) definitions of primary and secondary outcomes.
2. All studies were conducted at multiple sites and included
participants from the US and Canada, Europe, Asia and
Australia. However, fewer black people and Hispanics were
enrolled compared to white people and Asians.
3. Populations were broadly similar for important participant
characteristics relevant to the treatment in evaluation (age, stroke
severity, type of atrial fibrillation (AF), exclusion of people with
marked renal impairment) but they varied in other characteristics
such as percentage of vitamin K antagonist (VKA)-naïve
participants included or concomitant antiplatelet therapy.
4. Time in the therapeutic range (TTR) varied across studies
and across different sites within a given study. However, mean
TTR was compatible with the one seen in sites with good
control of warfarin therapy in everyday clinical practice (Baker
2009), thus avoiding underestimation of the benefits of the
standard therapy.
Although challenging for combined analysis, the clinical hetero-
geneity across studies better supports the external validity of the
results as this variation in participant populations is more likely to
reflect practice in the real world.
Quality of the evidence
We included eight RCTs involving 27,623 participants and three
DTIs. Studies were heterogeneous in their individual quality as-
sessment; see Figure 4 and Figure 5. They also varied in design
(phase II and phase III), primary and secondary analyses (inten-
tion-to-treat (ITT) versus per protocol (PP)) and displayed some
diversity in the reporting of outcomes. Nonetheless, all eight stud-
ies were judged to be adequate to address the main objectives of
the review.
SPORTIF V 2005 and RE-LY 2009 analysed all randomised par-
ticipants according to the ITT principle for primary outcomes.
SPORTIF II 2003 and SPORTIF III 2003 describe an ITT analy-
sis but three participants from each study were randomised and not
analysed. Overall, 16 participants were randomised but not anal-
ysed. The remaining four studies performed a PP analysis only in-
cluding participants who took at least one dose of study treatment.
Secondary outcomes from SPORTIF III 2003 and SPORTIF V
2005 included in the safety analysis were based on an on-treatment
(OT) population that allowed a maximum continuous interrup-
tion of 30 days (or up to 60 days total) without study medication.
Primary safety analyses in RE-LY 2009 used the randomised set
(ITT), and sensitivity analyses using the safety dataset (OT) were
performed.
Potential biases in the review process
The risk of having introduced significant bias into the review pro-
cess is small owing to the fact that all three review authors inde-
pendently performed study selection, data abstraction and assess-

ment of risk of bias, and cross-checked them for reproducibility.
Added to this, we carried out a comprehensive electronic search
complemented with various other sources to minimise overall as-
sumptions.
A limitation of our review is the lack of sufficient data to perform
head-to-head comparisons between different DTIs. Combining
all of them may introduce bias to both the efficacy and safety
analyses, as we observed important differences between drugs that
were not explained by drug class, such as the hepatotoxicity seen
with ximelagatran that was not seen with the other DTIs, and
some unexplained variations in bleeding effects across studies.
Another limitation is the relatively short evaluation periods. An-
ticoagulation in the AF population is intended to be long-term,
and there is therefore a chance that additional adverse events arise
with longer periods of treatment. Moreover, people with AF tend
to be older and to have more comorbidities and polypharmacy,
which increases their risk of developing adverse events.
Importantly, a single study (RE-LY 2009) represented 75% of
the population analysed in our primary results. The dominant
effect that this large study has on the overall estimates should be
considered in the interpretation of results. Important differences
could be present but undetected, given the smaller samples of the
other studies.
Finally, we performed several post hoc sensitivity analyses, which
may appear to introduce bias. However, the rationale for each
analysis is extensively discussed and the findings clearly help in the
interpretation of the protocol-driven composite endpoints.
Publication bias must be considered due to the asymmetry of fun-
nel plots and to the fact that no studies were found published in
a language other than English.
Agreements and disagreements with other
studies or reviews
DTIs represent a major advance in stroke prevention in people
with non-valvular AF, as results from our analyses indicate a trend
towards similar - and perhaps superior - effectiveness and increased
safety. These results are in agreement with the findings from other
recently published meta-analyses: Capodanno 2012, Lip 2012 and
Miller 2012. However, these meta-analyses included drug classes
other than DTIs, such as Factor Xa inhibitors, which are beyond
the scope of our review.
When comparing our results with those from individual trials, it
is important to consider that our primary outcomes were con-
structed in a different way from those from the original studies.
The most relevant difference is that we excluded haemorrhagic
stroke from our primary efficacy outcome. The rationale behind
this exclusion is that AF does not cause haemorrhagic stroke itself,
but anticoagulants do. Moreover, haemorrhagic stroke is not pre-
vented by anticoagulants but rather is associated with their use.
Therefore, haemorrhagic stroke belongs more appropriately to the
primary safety outcome. The introduction of haemorrhagic stroke
in the primary safety endpoint rather than in the primary effi-
cacy endpoint does not undermine its critical clinical relevance. It
merely places it where it more appropriately belongs.
For our composite primary efficacy endpoint of vascular deaths
and ischaemic events, we found no difference between DTIs and
warfarin. However, the sensitivity analysis for individual doses re-
vealed that dabigatran 150 mg twice daily was superior to war-
farin for this same endpoint. This is a concordance with the results
from RE-LY 2009 where the higher dose of dabigatran was found
to be superior to warfarin for their primary efficacy outcome of
stroke and SEE as well as for their outcome of vascular deaths,
particularly those due to strokes. Importantly, our analysis shows
that the benefits of dabigatran over warfarin are maintained even
after removing the influence of including haemorrhagic strokes in
the comparison.
The inclusion of vascular deaths in our primary efficacy endpoint
is also clinically relevant because death may act as a competing risk
factor for stroke/SEE (Schatzkin 1989). In a geriatric population
with considerable comorbidities, the competing risk of death is
especiallyhigh (Berry2010). The inclusionof death inacomposite
endpoint is one way of addressing competing risks.
The efficacy endpoint in our review also included MI. The inclu-
sion of this outcome in the composite endpoint can be controver-
sial as it can be argued that the pathophysiology of MI differs from
that of stroke and other embolic events. However, we deemed this
inclusion appropriate based on its clinical relevance and the fact
that a recent meta-analysis of seven trials that evaluated dabiga-
tran for various indications found a higher risk of MI compared
with warfarin (Uchino 2012). Also, in the RE-LY 2009 trial, the
frequency of MI was greater in participants receiving dabigatran
than in those treated with warfarin. We performed a sensitivity
analysis excluding MI to assess the impact of having included this
outcome in the comparison. As expected, the results tended to
favour the DTIs but without reaching statistical significance.
We also considered pulmonary embolism (PE) and deep vein
thrombosis (DVT) in our primary analysis as systemic embolic
events. The consideration was based on the fact that systemic em-
bolismwasdefinedinthe largestincludedstudyasanacute non-in-
tracerebral and non-coronary vascular event. Although the patho-
physiology of arterial and venous thrombosis differs in many as-
pects, the inclusionof these eventsinthe composite outcome seems
reasonable per study definitions. RE-LY 2009 showed slightly
higher rates of PE events in both dabigatran groups compared with
warfarin but the overall number of these events was low. Both MI
and PE were considered as efficacy outcomes in RE-LY 2009 but
the authors did not include either of them in the primary efficacy
analysis. This is important because the efficacy of the DTI was
comparable to that of warfarin in our analysis even after the in-
troduction of MI and PE in the composite endpoint.
Our safety analysis was designed to evaluate fatal and non-fatal
haemorraghic events referring to major bleeds rather than overall
bleedingevents, because majorbleedscarryimportantclinical con-

sequences relevant to health professionals when deciding whether
or not to use an anticoagulant. A reduction in major bleeding is of
particular clinical relevance, as there is increasing evidence to sup-
port a significant association between a major haemorrhagic event
and adverse prognosis as indicated by an increased risk of death
in people with AF (Sharma 2012). In our safety analysis, DTIs
were found to be superior to warfarin with fewer fatal and non-
fatal haemorraghic events including haemorrhagic strokes. The
sensitivity analyses showed that this favourable result was mainly
influenced by ximelagatran and dabigatran at the dose of 110 mg
twice daily. Interestingly, although numerically fewer major bleed-
ing events were seen in all three SPORTIF trials, none of the indi-
vidual studies found a statistically significant difference between
the DTI and warfarin. In contrast, RE-LY 2009 did report a sig-
nificant reduction in the occurrence of major bleeding events with
both doses of dabigatran compared with warfarin.
In the evaluation of new drugs, the assessment of adverse events
is fundamental. However, the possibility of researcher bias needs
to be considered in this analysis. Researcher bias refers to investi-
gators having more stringent discontinuation criteria for the new
treatment in comparison with a standard drug with which they
have more experience and feel more comfortable. Since warfarin
was given in an open-label fashion in most studies, this bias could
be important. Our analysis included only events that led to treat-
ment discontinuation because participant compliance with long-
term treatment is of critical importance in dealing with chronic
conditions like stroke prevention in AF. Our analysis showed that
the adverse events leading to treatment discontinuation occurred
more frequently with the DTIs compared with warfarin. The most
frequent adverse events were gastrointestinal complaints. Interest-
ingly, the analysis of individual drugs showed that adverse events
leading to treatment discontinuation were significantly more fre-
quent with dabigatran than with AZD0837.
Finally, we found all-cause mortality to be comparable between
DTIs and VKAs. The results are in agreement with RE-LY 2009,
where fewer overall deaths were observed in both dabigatran
groups compared with the warfarin group, although this differ-
ence did not reach statistical significance.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
The odds of preventing a vascular death or ischaemic event (in-
cluding ischaemic stroke, transient ischaemic attack, systemic em-
bolic events and myocardial infarction) did not differ substantially
between the direct thrombins inhibitors (DTIs) and vitamin K
antagonists (VKAs), meaning that DTIs are as efficacious as VKAs
to prevent all these clinically relevant outcomes. Dabigatran 150
mg twice daily was superior to warfarin for this composite end-
point. Fewer major haemorraghic events, including haemorrhagic
strokes, were observed with the DTIs, making these new drugs
easily administered safe alternatives to adjusted-dose warfarin. The
impact of the higher dose of dabigatran on vascular deaths and
ischaemic events is important because it indicates that the advan-
tage of dabigatran compared with warfarin is not limited to effects
on bleeding. Thus, in the not infrequent clinical scenario where
warfarin administration or monitoring poses significant difficul-
ties, DTIs appear promising. Nonetheless, people on DTIs should
still be carefully monitored, as concerns remain with the lack of
drug antidote and compliance, given the need for twice daily ad-
ministration. Several additional factors exist, such as comorbid
conditions including reduced renal function, side-effect profile,
cost and patient preference. Therefore, the need to consider the
balance of benefit and risk in each individual is no less important
than with VKA therapy.
Implications for research
Our review has evaluated all DTIs combined versus warfarin.
However, an important gap in the evidence is the lack of compar-
isons between different drug classes (e.g. DTIs versus Factor Xa
inhibitors) and between different drugs within a class. This should
be assessed in future research through multicentre randomised
controlled trials comparing newer anticoagulants with each other
and through network meta-analyses. Also, the mean evaluation
period across studies was about two years. Since anticoagulation
in people with non-valvular AF is long-term, it is possible that
additional adverse effects may arise with more prolonged use. Ob-
servational studies and US Food and Drug Administration-Euro-
pean Medicines Agency pharmacovigilance should be considered
to address this issue.
Finally, the superiority of dabigatran 150 mg compared with war-
farin came from a post hoc sensitivity analysis and was found to
be borderline statistically significant. Hence, future studies could
assess this finding as a primary analysis.
A C K N O W L E D G E M E N T S
We thank the Cochrane Stroke Group for its guidance and helpful
collaboration during the development of this review. And special
thanks to our parents for their never-ending support.

R E F E R E N C E S
References to studies included in this review
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Lip GY, Rassmusen LH, Olsson SB, Jensen EC, Persson AL,
Ericksson U, et al.Oral direct thrombin inhibitor AZD0837
for the prevention of stroke and systemic embolism in
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of AZD0837 vs. vitamin K antagonists. European Heart
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Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA,
Nagarakanti R, Parcham-Azad K, et al.Dabigatran with or
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∗
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M, Partridge S, et al. Ximelagatran vs warfarin for stroke
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randomized trial. JAMA 2005;293(6):690–8.
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ACTIVE 2006 {published data only}
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Chrolaviscius S, et al.ACTIVE Writing Group of the
ACTIVE Investigators. Clopidogrel plus aspirin versus oral
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Davidson BL, et al.Amadeus Investigators. Comparison
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ENGAGE AF 2010 {published data only}
Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S,
Mendell J, et al. Randomised, parallel-group, multicentre,
multinational phase 2 study comparing edoxaban, an oral
factor Xa inhibitor, with warfarin for stroke prevention in
patients with atrial fibrillation. Thrombosis and Haemostasis
2010;104(3):633–41.
Eriksson 2007 {published data only}
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Dijk CN, Frostick SP, et al.Dabigatran etexilate versus

enoxaparin for prevention of venous thromboembolism
after total hip replacement: a randomised, double-blind,
non-inferiority trial. Lancet 2007;370(9591):949–56.
ESTEEM 2003 {published data only}
Wallentin L, Wilcox RG, Weaver WD, Emanuelsson
H, Goodvin A, Nyström P, et al. Oral ximelagatran for
secondary prophylaxis after myocardial infarction: the
ESTEEM randomised controlled trial. Lancet 2003;362
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EXPLORE Xa 2013 {published data only}
Connolly SJ, Eikelboom J, Dorian P, Hohnloser SH,
Gretler DD, Sinha U, et al. Betrixaban compared with
warfarin in patients with atrial fibrillation: results of a phase
2, randomised, dose-ranging study (Explore-Xa). European
Heart Journal 2013; Vol. 34, issue 20:1498–505.
NCT00152971. Dabigatran etexilate vs enoxa-
parin in prevention of venous thromboembolism
(VTE) post total knee replacement. http://clinical-
trials.gov/ct2/show/NCT00152971?term=Dabiga-
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NCT00246025. A study of BIBR 1048 in prevention of
venous thromboembolism in patients with TKR surgery.
http://clinicaltrials.gov/ct2/show/NCT00246025?term=
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rank=1 (accessed September 2013).
NCT00680186. Phase III study testing efficacy and safety
of oral dabigatran etexilate vs warfarin for 6 months.
Treatment for acute symptomatic venous thromboembolism
(VTE). http://clinicaltrials.gov/ct2/show/NCT00680186?
term=oral+dabigatran+etexilate+vs+warfarin&rank=1
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NCT00904800. AZD0837 Extended Release (ER) Japan
Study. http://clinicaltrials.gov/show/NCT00904800
(accessed September 2013).
NCT01225822. BIBR 1048 dose range finding study in
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Granger CB, Härtter S, et al. A comparison of dabigatran
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and pharmacokinetics of oral dabigatran etexilate in patients
after heart valve replacement (RE-ALIGN). Americal Heart
Journal 2012;163(6):931–7.
RECOVER 2009 {published data only}
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S, Eriksson H, et al. Dabigatran versus warfarin in the
treatment of acute venous thromboembolism. New England
REDEEM 2011 {published data only}
Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J,
Siegbahn A, et al. Dabigatran vs placebo in patients with
acute coronary syndromes on dual antiplatelet therapy: a
randomised, double-blind, phase II trial. European Heart
Journal 2011;32(22):2781–9.
RELY ABLE 2012 {unpublished data only}
Connolly SJ. Randomised comparison of the effects of
two doses of dabigatran etexilate on clinical outcomes
over 4.3 years: results of the RELY-ABLE double-blind
randomised trial. http://www.abstractsonline.com/plan/
ViewAbstract.aspx?mID=2974&sKey=94d74361-5616-
4a16-8a8e-a3739885329a&cKey=770e5366-02c1-4314-
9a37-76ab178d193b&mKey=14145d5b-f96b-4354-8237-
8f0937744ba4 [American Heart Association Scientific
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REMODEL 2007 {published data only}
Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van
Dijk CN, Frostick SP, et al. Oral dabigatran etexilate
vs subcutaneous enoxaparin for the prevention of venous
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MODEL randomised trial. Journal of Thrombosis and
Haemostasis 2007;5(11):2178–85.
RENOVATE 2011 {published data only}
Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S,
Hermansson K, et al. Oral dabigatran versus enoxaparin
for thromboprophylaxis after primary total hip arthroplasty
(RE-NOVATE II*). A randomised, double-blind, non-
inferiority trial. Thrombosis and Haemostasis 2011;105(4):
721–9.
ROCKET 2011 {published data only}
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE,
Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular
atrial fibrillation. New England Journal of Medicine 2011;
365(10):883–91.
Schulman 2013 {published data only}
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or placebo in venous thromboembolism. New England
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AstraZeneca. Long-term treatment with the oral direct
thrombin inhibitor H 376/95, compared to warfarin, as
stroke prophylaxis in patients with atrial fibrillation. An
open 10-year follow-up study. Final report at 7 years
(Supplement to 5-year interim analysis report). AstraZeneca
Synopsis 8 December 2006.
Vranckx 2013 {published data only}
Vranckx P, Verheugt FW, De Maat MP, Ulmans VA,
Regar E, Smits P, et al. A randomised study of dabigatran
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coronary artery disease patients. EuroIntervention 2013;8
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∗
Indicates the major publication for the study

C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Lip 2009
Methods Study design: RCT, dose guiding, safety study
Power calculation: not specified
Number of participants randomised: 955 (AZD0837: 636; VKA: 319)
Number of participants analysed: 949
Number of exclusions post-randomisation: 6
Number of withdrawals and reasons: AZD0837 groups: 56 (8.9%) prematurely discon-
tinued study and 106 (16.8%) prematurely discontinued treatment. VKA group: 15
(4.7%) prematurely discontinued study and 25 (7.9%) prematurely discontinued treat-
ment. The most common adverse events leading to discontinuation of treatment were
gastrointestinal disorders, such as diarrhoea, flatulence, or nausea
ITT analysis: no
Treatment within target INR: 57% to 68%
Source of funding: pharmaceutical: AstraZeneca
Participants Country: Austria, Denmark, Hungary, Ireland, Norway, Poland, Russia, Sweden, UK
Setting/location: hospitals
Number of centres: 95
Age: 68
Sex: 68% male
Inclusion criteria
1. Paroxysmal, persistent or permanent non-valvular AF verified by at least 2 ECGs
in the last year
2. One or more of the following conditions:
◦ previous cerebral ischaemic attack (stroke or TIA > 30 days prior to
randomisation);
◦ previous systemic embolism;
◦ symptomatic congestive heart failure;
◦ impaired left ventricular systolic function;
◦ hypertension requiring anti-hypertensive treatment;
◦ diabetes mellitus;
◦ age ≥ 75 years
Exlusion criteria
1. AF secondary to reversible disorders
2. Known contraindications to VKA treatment
3. MI, stroke or TIA within the last 30 days
4. Presence of a valvular heart disease, mechanical heart valves, active endocarditis,
left ventricular aneurysm or thrombus, atrial myxoma or any condition other than AF
requiring chronic anticoagulation treatment
5. Conditions associated with increased risk of major bleeding
6. Major surgical procedure or trauma within the last 2 weeks
7. Renal impairment (calculated creatinine clearance < 30 mL/minute)
8. Known hepatic disease and/or alanine transaminase (ALT) > 3 times upper limit
of normal
9. Treatment with antiplatelet agent other than aspirin ≤ 100 mg/day or fibrinolytic

Lip 2009 (Continued)
agents within the last 10 days
10. Planned cardioversion or surgery during the study
Interventions Treatments: participants were randomised into 4 parallel groups: 4 groups receiving
AZD0837 extended-release tablets (150, 300, or 450 mg od or 200 mg bid)
Control: VKA (warfarin) with target INR: 2.0 to 3.0
Duration: 142 days
Outcomes Primary outcomes
• bleeding events: number of participants with a bleeding event while on study
drug. Participants with multiple events are counted once
• creatinine: change in creatinine values from baseline to week 12
• ALAT: number of participants while on study drug with ALAT ≥ 3 times upper
limit of normal
• bilirubin: number of participants while on study drugs with bilirubin ≥ 2 times
upper limit of normal
Secondary outcomes
• D-Dimer: change in D-Dimer values from enrolment to week 12 visit for VKA-
naïve participants while on study drug
• APTT: change in APTT from baseline to week 12 visit for VKA-naïve
participants while on study drug
• ECT: change in ECT from baseline to week 12 visit for participants while on
study drug
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Computer-generated scheme
Allocation concealment (selection bias) Low risk Central randomisation through interactive
web response system
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Double-blind for AZD0837 doses but
open for VKA
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk It is mentioned that participant, caregiver
and investigator were blinded; nevertheless
the methodology is not speciﬁed
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk A greater proportion of participants in the
AZD0837 treatment groups (9.2%) dis-
continued study treatment than in the
VKA treatment group (1.6%). The reasons
for treatment abandonment are not speci-

Lip 2009 (Continued)
fied, it is only reported that the most com-
mon reasons for discontinuation were gas-
trointestinal disorders. Nevertheless, par-
ticipants were analysed as if they were in
the original randomisation group
Selective reporting (reporting bias) Unclear risk The study is registered in clinicaltrials.gov
and their outcomes are reported according
to that guideline. Protocol could not be
found
NCT01136408
Methods Study design: RCT, safety study
Number of participants randomised: 174 (dabigatran: 112; VKA: 62)
Number of withdrawals and reasons: not specified
ITT analysis: no
Treatment within target INR: not specified
Source of funding: pharmaceutical: Boehringer Ingelheim
Participants Country: Japan
Setting/location: Boehringer Ingelheim investigational sites and 1 hospital
Age: not specified
Sex: both, proportion not specified
Inclusion criteria
in the last year
◦ hypertension
◦ diabetes mellitus
◦ left-side heart failure
◦ previous ischaemic stroke or TIA
◦ coronary artery disease
3. Age ≥ 20 years
4. Written informed consent
Exlusion criteria
1. Participants diagnosed as having a valvular heart disease by echocardiography, or
participants who had a history of prosthetic valve replacement or valve surgery
2. Participants who were to receive electric defibrillation or pharmacological
defibrillation during the study period
3. Participants who developed stroke or TIA within 30 days before the date of
informed consent
4. Participants who developed MI or were admitted to hospital due to acute

NCT01136408 (Continued)
coronary syndrome or for percutaneous transluminal coronary angioplasty within 3
months before the date of informed consent or participants who underwent coronary
stenting within 6 months before the date of informed consent
5. Participants with atrial myxoma or left ventricular thrombosis
6. Participants with contraindication to anticoagulant therapies
7. Participants scheduled for major surgery or invasive procedure
8. Participants having major bleeding from non-gastrointestinal organs within 6
months before the date of informed consent
9. Participants with uncontrolled hypertension
Interventions Treatments: dabigatran etexilate 110 mg and 150 mg bid
Duration: 84 days
• Frequency of major bleeding event: the percentage of participants with major
bleeding event
• Frequency of clinically relevant bleeding event: the percentage of participants with
clinically relevant bleeding event
• Frequency of nuisance bleeding event: the percentage of participants with
nuisance bleeding event
Secondary outcomes
• Frequency of a composite clinical endpoint: percentage of participants with the
composite clinical endpoint (ischaemic or haemorrhagic stroke (fatal or non-fatal),
TIA, systemic embolism, MI (fatal or non-fatal), other major adverse cardiac events,
and death)
• Frequency of ischaemic or haemorrhagic stroke (fatal and non-fatal)
• Frequency of TIA
• Frequency of systemic embolism
• Frequency of MI (fatal or non-fatal)
• Frequency of other major adverse cardiac events
• Frequency of death
Notes
Risk of bias
bias)
Unclear risk Not speciﬁed
Allocation concealment (selection bias) Unclear risk Not speciﬁed
(performance bias)
All outcomes
High risk Open-label study

NCT01136408 (Continued)
bias)
All outcomes
High risk Open-label study
All outcomes
High risk There is no information regarding treat-
ment discontinuation. Adverse events are
not assessed properly
Selective reporting (reporting bias) Unclear risk The study is registered in clinicaltrials.gov
and their outcomes are reported according
to that guideline. Protocol could not be
found
Olsson 2010
Number of participants randomised: 250 (AZD0837: 167; VKA: 83)
Number of withdrawals and reasons: AZD0837 groups: 8 (4.7%) prematurely discon-
tinued study and 15 (9.0%) prematurely discontinued treatment. VKA group: 1 (1.2%)
prematurely discontinued study and 1 (1.2%) prematurely discontinued treatment. The
most common adverse events leading to discontinuation of treatment were: gastroin-
testinal disorders, such as diarrhoea, ﬂatulence, or nausea; and cardiac disorders with
ischaemic or arrhythmic origin
ITT analysis: no
Treatment within target INR: 60% to 71%
Source of funding: pharmaceutical: AstraZeneca
Participants Country: Denmark, Norway, Sweden
Age: 71
Sex: 78% male
Inclusion criteria
in the last year
◦ hypertension requiring anti-hypertensive treatment
◦ previous cerebrovascular disease
◦ previous systemic embolism
◦ symptomatic congestive heart failure
◦ age ≥ 65 years and coronary artery disease
◦ age ≥ 65 years and diabetes mellitus
Exlusion criteria
1. Age < 18 years

Olsson 2010 (Continued)
2. AF secondary to reversible disorders
3. Valvular heart disease or any condition other than AF requiring chronic
anticoagulation treatment
4. Stroke or TIA and/or systemic embolism within the previous 6 months.
5. Conditions associated with increased risk of bleeding within the last year
6. Major surgical procedure or trauma within the previous 2 weeks
7. Diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥ 180 mmHg
with or without antihypertensive treatment
8. Renal impairment (calculated creatinine clearance < 30 mL/min)
9. Hepatic disease and/or ALT > 2 times upper limit of normal
10. Hepatitis B surface antigen positive antibodies against hepatitis C, Gilbert’s
syndrome, anaemia (Hb < 10g/dL) or platelet count < 100 x 10
/L
11. Treatment with antiplatelet agent other than aspirin (≥ 100 mg/day) within the
previous 10 days or fibrinolytic agents within the previous 30 days
12. Contraindications to warfarin treatment
13. Planned cardioversion or surgery during the study
Interventions Treatments: participants were randomised into 2 groups: AZD0837 150 mg and 350
mg immediate-release tablets bid
Duration: 91 days
Outcomes Adverse events (including bleeding): ECG, vital signs, blood pressure, pulse rate, labo-
ratory values and physical examination
Notes
Risk of bias
bias)
Low risk Computer-generated scheme
Allocation concealment (selection bias) Unclear risk Not specified
(performance bias)
All outcomes
Unclear risk Participants were blinded to the dose re-
ceived of AZD0837, but VKA were given
in an open fashion
bias)
All outcomes
Unclear risk Not specified
All outcomes
Low risk A similar number of participants discontin-
ued the study in the AZD0837 groups (4.
7%) and in the VKA treatment group (1.
2%). The reasons for treatment abandon

Olsson 2010 (Continued)
are well specified, being the most common
gastrointestinal and cardiac disorders
Participants were analysed as if they were
in the original randomisation group
Selective reporting (reporting bias) High risk Protocol can not be found. The study is not
registered in clinicaltrials.gov
PETRO 2007
Number of participants randomised: 502 (dabigatran: 432, VKA: 70)
Number of participants analysed: 515 (13 included twice owing to a change in their
aspirin dose)
Number of exclusions post-randomisation: not specified
Number of withdrawals and reasons: 38 (7.6%) participants discontinued treatment;
29 (6.5%) adverse events all from the dabigatran group and 9 (uncertain allocation): 3
withdrew consent, 1 participant not compliant, 1 with uncertain compliance, 4 withdrew
(percutaneous coronary intervention for coronary artery disease requiring clopidogrel,
angiography planned before trial entry, difficulty with blood draws, personal reasons)
ITT analysis: no
Treatment within target INR: 57.2%
Source of funding: pharmaceutical: Boehringer Ingelheim
Participants Country: Denmark, Netherlands, Sweden, USA
Age: 70 ± 8.3
Sex: 81.9% male
Inclusion criteria
1. Non-rheumatic AF (paroxysmal, persistent, or permanent), documented by ECG
within the past 6 months
2. Coronary artery disease, documented by previous MI, angina, positive stress test,
previous coronary intervention or bypass surgery, or atherosclerotic lesion(s) diagnosed
by coronary angiography is only considered as one of several possible qualifying risk
factors
3. An additional risk factor for stroke, i.e. 1 or more of the following conditions/
events:
◦ hypertension (defined as systolic blood pressure > 140 mmHg and/or
diastolic blood pressure > 90 mmHg) requiring antihypertensive medical treatment
◦ diabetes mellitus (type I and II)
◦ symptomatic heart failure or left ventricular dysfunction (ejection fraction <
40%)
◦ a previous ischaemic stroke or TIA
◦ age > 75 years
◦ history of coronary artery disease
4. Age ≥ 18 years at entry

PETRO 2007 (Continued)
5. Written informed consent
Exclusion criteria
1. Valvular heart disease.
2. Planned cardioversion.
3. Recent (≤ 1 month) MI, stroke or TIA, or participants who have received a
coronary stent within the last 6 months.
4. Intolerance or contraindications to acetylsalicylic acid
5. Any contraindication to anticoagulant therapy
6. Major bleeding within the last 6 months (other than gastrointestinal
haemorrhage)
7. Severe renal impairment (estimated glomerular filtration rate ≤ 30 mL/min)
8. Uncontrolled hypertension (SBP > 180 mmHg and/or DBP > 100 mmHg)
9. Abnormal liver function as defined by aspartate-aminotransferase, alanine-
aminotransferase, serum bilirubin or alkaline phosphatase above the reference range, or
history of liver disease
10. Women who are pregnant or of childbearing potential who refuses to use a
medically acceptable form of contraception throughout the study.
11. Participants who have received an investigational drug within the last 30 days
12. Participants scheduled for major surgery or invasive procedures which may cause
bleeding, or those who have had major surgery or percutaneous coronary intervention
within 6 weeks
13. Participants considered unreliable by the investigator
14. Another indication for anticoagulant treatment
15. Participants suffering from anaemia
16. Participants suffering from thrombocytopenia
17. Any other condition which, at the discretion of the investigator, would not allow
safe participation in the study
18. Concomitant treatment with antiplatelet agents other than ASA
19. Recent malignancy or radiation therapy (≤ 6 month)
Interventions Treatment(s):dabigatranetexilate with dosesof 50, 150and300 mgtwice dailycombined
in a 3 x 3 factorial fashion with no aspirin or 81 mg aspirin or 325 mg aspirin every day
Duration: 84 days
• Number of participants with fatal or life-threatening major bleeding events
(retroperitoneal, intracranial, intraocular, or intraspinal bleeding, or requiring surgical
treatment, or leading to a transfusion of 2 units or more, or leading to a fall in
haemoglobin of 20 g/L or more)
• Number of participants with minor/relevant bleeding events (haematuria, rectal
bleeding, gingival bleeding, skin hematoma of 25cm² or more, nose bleed of more than
5 minutes duration, bleeding leading to a hospitalisation, leading to a transfusion of
less than 2 units or any other clinically relevant bleeding)
• Number of participants with minor/nuisance bleeding events (all bleeding events
not fulfilling one of the criteria for major bleeding event or minor/relevant bleeding
events)
Secondary outcomes:
• A composite clinical endpoint of any thromboembolic or cardiac event, including

Papel de la Vitamina K en la prevención de los embolismos

Papel de la Vitamina K en la prevención de los embolismos

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