Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice.

Abstract

Dabigatran etexilate is a new oral anticoagulant recently approved in Europe for the prevention of stroke or systemic embolism in adult patients with non-valvular atrial fibrillation (AF) and at least one risk factor for stroke. With a fast onset of action and a predictable anticoagulant effect obviating the need for coagulation monitoring, dabigatran etexilate offers practical advantages over vitamin K antagonists in clinical practice. However, clinicians may have questions about practical aspects of dabigatran etexilate use including monitoring anticoagulant efficacy, interruption for surgical or invasive procedures and management of bleeding. This review article aims to address these concerns and provide guidance on the use of dabigatran etexilate in special situations, such as acute coronary syndromes and cardiac revascularisation. In addition, cut-off values for different coagulation assay results associated with an increased risk of bleeding are given.

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© Schattauer 2012
Thrombosis and Haemostasis 107.5/2012
Review Article
Dabigatran etexilate for stroke prevention in patients with atrial
fibrillation: Resolving uncertainties in routine practice
Menno V. Huisman1; Gregory Y. H. Lip2; Hans-Christoph Diener3; Martina Brueckmann4; Joanne van Ryn5; Andreas Clemens4
1Departments of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands; 2University of Birmingham Centre for Cardiovascular Sciences, City
Hospital, Birmingham, UK; 3Department of Neurology, University Hospital Essen, Essen, Germany; 4Global Clinical Development and Medical Affairs, Boehringer Ingelheim GmbH
& Co. KG, Ingelheim, Germany, 5Department of CardioMetabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Summary
Dabigatran etexilate is a new oral anticoagulant recently approved in
Europe for the prevention of stroke or systemic embolism in adult pa-
tients with non-valvular atrial fibrillation (AF) and at least one risk fac-
tor for stroke. With a fast onset of action and a predictable anticoagu-
lant effect obviating the need for coagulation monitoring, dabigatran
etexilate offers practical advantages over vitamin K antagonists in clini-
cal practice. However, clinicians may have questions about practical as-
pects of dabigatran etexilate use including monitoring anticoagulant
Correspondence to:
Menno V. Huisman
Department of Thrombosis and Haemostasis
Leiden University Medical Center, Leiden, Netherlands
Tel.: +31 752 62085, Fax: +31 71 5248140
E-mail: M.V.Huisman@lumc.nl
efficacy, interruption for surgical or invasive procedures and manage-
ment of bleeding. This review article aims to address these concerns
and provide guidance on the use of dabigatran etexilate in special situ-
ations, such as acute coronary syndromes and cardiac revasculari-
sation. In addition, cut-off values for different coagulation assay results
associated with an increased risk of bleeding are given.
Keywords
Dabigatran, atrial fibrillation, oral anticoagulant, bleeding
Received: October 18, 2011
Accepted after minor revision: January 29, 2011
Prepublished online: February 8, 2012
doi:10.1160/TH11-10-0718
Thromb Haemost 2012; 107: ■■■
Note: The editorial process for this article was fully handled by Prof. Christian
Weber, Editor-in-Chief.
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac ar-
rhythmia (1), which if untreated is a major risk factor for stroke.
Extensive evidence from randomised trials supports the value of
vitamin K antagonists (VKAs) in reducing the risk of stroke by
about two thirds, even among elderly AF patients, who are at
higher risk (2, 3). However, practical limitations may lead to wide
variation in VKA use (4), as well as patient-related issues with ad-
herence and convenience.
Dabigatran etexilate (hereafter referred to as dabigatran) is the
first oral direct thrombin inhibitor approved for the prevention of
stroke and systemic embolism in patients with non-valvular AF
and one or more risk factors (?Fig. 1) (5, 6). The efficacy and
safety profile of dabigatran, demonstrated by the RE-LY trial (7, 8)
(?Fig. 2), together with practical advantages over VKAs (see
?Table 1), have led to its rapid uptake in clinical practice. How-
ever, there may be some areas of uncertainty in everyday clinical
practice, which this article aims to address. We focus on dosing
guidelines applicable to patients treated in Europe.
Dose selection
Dabigatran is administered as a prodrug (dabigatran etexilate),
which is metabolised to the active form, dabigatran. Renal excre-
tion of unchanged dabigatran is the predominant elimination
pathway, with about 80% excreted unchanged in the urine (9). The
recommended dose regimen is 150 mg twice daily (bid) with or
without food. However, in certain regions including Europe a re-
duced dose of 110 mg bid is recommended or may be considered in
certain patient groups (?Fig. 1), including those with moderate
renal impairment (creatinine clearance [CrCL] 30–50 ml/minute
[min]) or treated concomitantly with verapamil, and the elderly at
higher risk of bleeding (?Table 2) (5). This dose is not approved in
the US (6). In Europe, dabigatran is contraindicated in patients
with severe renal impairment (CrCL <30 ml/min), active clinically
significant bleeding, or if concomitantly treated with certain P-gly-
coprotein (P-gp)-inhibitors such as systemic ketoconazole, cyclo-
sporine, itraconazole and tacrolimus (5). In the US, a 75 mg bid
dose of dabigatran is approved for use in patients with CrCL 15–30
ml/min and can be considered in patients with moderate renal im-
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Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
pairment who are also treated with dronedarone or systemic keto-
conazole (6).
Prior to commencing treatment with dabigatran, renal func-
tion should be checked in all patients and CrCL calculated using
the Cockcroft-Gault formula (10). This represents an obvious
change in clinical practice for patients commencing VKAs when
international normalised ratio (INR) monitoring only is perform-
ed.
Patients should be closely monitored for signs of bleeding
throughout treatment. This is especially important in patients
with multiple risk factors for the use of dabigatran, such as elderly
patients who may have low body weight, impaired renal function
and multiple relevant concomitant medications (11). During
treatment, CrCL should be rechecked periodically as clinically in-
dicated, or if a decline in renal function is suspected (e.g. hypovol-
aemia, dehydration, certain comedications).
Switching treatment
A potential cause for concern among clinicians is in switching pa-
tients between different anticoagulant treatments. Suggested ap-
proaches are summarised in ?Table 3. If switching a patient from
a VKA to dabigatran, it is advisable to monitor the INR closely and
only initiate dabigatran when the INR is less than 2.0. When con-
verting from dabigatran to VKAs, the start time of the VKA is ad-
justed according to the CrCL. This is due to the prolonged anti-
coagulant effect of dabigatran in patients with impaired renal
function. Monitoring using the activated partial thromboplastin
time (aPTT) can be useful to assess when dabigatran anticoagulant
activity is excessively high (see below).
Monitoring anticoagulant effect
Anticoagulant monitoring is not necessary during routine dabig-
atran treatment. However, it may be indicated in certain situations,
such as suspected overdose, emergency situations, in the perioper-
ative setting, in the event of bleeding or to identify patients at in-
Figure 1: Clinical flowchart for the use of dabigatran for stroke pre-
vention in AF (as per European prescribing guidelines) (5). asee grey
box in figure. bCrCL can be estimated using the Cockcroft-Gault equation: =
(140 – age) x (weight (kg) x (constant)/serum creatinine (μM), where con-
stant is 1.23 for men and 1.04 for women. cTable 2 summarises factors as-
sociated with a high risk of bleeding. A HAS-BLED score of ≥3 in patients with
AF is also associated with a high risk of bleeding (1, 56). d110 mg bid dose
recommended in patients taking verapamil, irrespective of age or renal func-
tion. 110 mg bid dose can be considered in patients with associated gastri-
tis, oesophagitis or gastroesophageal reflux, irrespective of age or renal func-
tion. CrCL, Creatinine clearance; EU, European Union; NYHA, New York Heart
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Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
creased bleeding risk due to excessive dabigatran exposure, or in
patients with progressive or severe renal dysfunction. The anti-
coagulant tests can be broadly categorised as qualitative (i.e. suit-
able for detection of excess anticoagulant activity) or quantitative.
Guidance for cut-off values for coagulation assays indicative of in-
creased bleeding risk is summarised in ?Table 4. Clinicians
should be aware that a blood sample taken 2 hours (h) after dabig-
atran dosage (∼peak level) will have a higher result in all clotting
tests compared with samples taken at 10–12 h (trough level).
The INR test is not recommended for monitoring as it is insen-
sitive to dabigatran (12). However, it is sometimes used despite
these recommendations. Recent reports have noted falsely elevated
INR levels for patients on dabigatran measured using the Hemo -
chron® point-of-care device compared with laboratory INR test-
ing (13, 14). It is not known whether this artifactual effect also is
also observed with other point-of-care devices. This problem is the
subject of further study and highlights another reason not to use
INR with dabigatran.
Detection or qualitative measurement
Both the aPTT and Thrombin Time (TT) test may be useful as
qualitative measures to detect an excess of anticoagulant activity
(5, 12). At a dose of 150 mg bid, the aPTT is approximately twice
Association.
Figure 2: Key findings
from RE-LY (7, 8). aData
are shown for all patients
who had at least one
event. All analyses were
based on the time to the
first event. bGastrointes-
tinal bleeding could be
life threatening or non-
life threatening. CI, con-
fidence interval; yr, year.
Table 1: Limitations of
vitamin K antagonists
(VKA) in comparison
with dabigatran.

Onset of action
Offset of action
Dosing
Dose adjustment
Monitoring
Food and alcohol
Drug interactions
VKAs
Slow (36 to 72 hours)
Long (24 to 192 hours depending on type used)
Individualised
Frequent
Required; patient adherence and convenience can be problematic
Interaction
Frequent
Dabigatran
Rapid (2 hours)
Short, half-life dependent (12–14 hours)
Fixed dose
Rare
Only in special situations
No interaction
Few
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Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
the baseline value although there is some variability due to differ-
ent test reagents (15). A trough aPTT >80 seconds (s) (or 2- to
3-fold of baseline value) is associated with a higher risk of bleeding
(5, 12). The TT is a more sensitive test and is significantly raised at
therapeutic doses and thus a normal TT or aPTT measurement in-
dicates no clinically relevant anticoagulant effect of dabigatran.
Once again, there is some variability depending on the coagulo-
meter and the thrombin reagent used for the measurement.
Quantitative measurement
The calibrated Hemoclot® Thrombin Inhibitor assay (Hyphen
BioMed, Neuville-sur-Oise, France) and ecarin clotting time
(ECT) are more sensitive tests suitable for use in monitoring anti-
coagulant activity (12, 16). However, in routine practice it is more
likely that the former will be available. This laboratory-based assay
generally takes a similar time to perform as an aPTT test. A trough
Hemoclot® thrombin inhibitor assay value of 200 ng/ml (cor-
responding to a test result of ∼>65 s) is associated with a higher risk
of bleeding (17). The test can be especially useful when assessing
plasma concentrations and anticoagulation activity in elderly frag-
ile patients or those with impaired renal function although further
studies are required to determine the normal test result range (11).
Interruption of dabigatran before and during
surgery
Temporary discontinuation of dabigatran may be indicated in sur-
gical patients, depending on the urgency of the procedure, level of
bleeding risk and renal function. The decision to stop treatment in
non-urgent or elective surgery depends on the risk of bleeding ver-
sus risk of thrombosis. Clinicians should take account of the pa-
tient’s renal function and the bleeding risk of the procedure in
decisions regarding the timing of discontinuation (5) (?Table 5).
If possible, discontinue dabigatran 1–2 days (CrCL 50 ml/min or
more) or 2–3 days (CrCL less than 50 ml/min) before invasive or
surgical procedures. Longer delays may be needed for patients with
a high bleeding risk including those undergoing major surgery,
spinal puncture, or placement of a spinal or epidural catheter or
port.
Semi-urgent and urgent surgery
In patients requiring semi-urgent surgery (within 2–12 h after the
last dose of dabigatran), the risk of bleeding needs to be weighed
Table 2: Factors identified in clinical trials which may increase the
bleeding riska.
Demographic
Factors increasing dabigatran
plasma levels
Age ≥75 years
Major:
Moderate renal impairment (CrCL 30–50 ml/
min)
P-gp inhibitor co-medication

Minor:
Low body weight (<50 kg)
Pharmacodynamic interactions ASA
NSAID
Clopidogrel
Congenital or acquired coagulation disorders
Thrombocytopenia or functional platelet de-
fects
Active ulcerative GI disease
Recent GI bleeding
Recent biopsy or major trauma
Recent ICH
Brain, spinal, or ophthalmic surgery
Bacterial endocarditis
Diseases/procedures with
special haemorrhagic risks
aFor special patient populations requiring a reduced 110 mg bid dose, see Fig-
ure 1. ASA, acetylsalicylic acid; CrCL, Creatinine clearance; P-gp, P-glycopro-
tein; GI, gastrointestinal; ICH, intracranial haemorrhage; NSAID, non-steroidal
anti-inflammatory drug.
Table 3: Suggested ap-
proaches for switching
to and from dabig-
atran (based on EU
label) (5).
Conversion
From VKAs to dabigatran
From dabigatran to VKAsa
Start times recommenced
Discontinue VKA and start dabigatran when INR <2
Start times for VKAs are based on renal function:
− If CrCL ≥50 ml/min, start VKA 3 days before stopping dabigatran
− If CrCL ≥30 to <50 ml/min, start VKA 2 days before stopping dabigatran
− If CrCL 15–30 ml/min, start VKA 1 day before stopping dabigatranb
Start parenteral anticoagulant 12 h after last dose of dabigatran
Start dabigatran at the same time or up to 2 hours before the next parenteral drug dose. For
continuous infusions of parenteral drugs, start dabigatran at the time of discontinuation of
the continuous infusion.
From dabigatran to parenteral
From parenteral to dabigatran
aBecause dabigatran may contribute to an elevated INR, the INR will better reflect the effect of the VKA after dabigatran has been
stopped for at least 2 days; bApplies to patients treated in the US and for patients in whom the CrCL drops below 30 mL/min. CrCL,
Creatinine clearance; h, hours; INR, International normalised ratio; VKA, vitamin K antagonists.
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Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
against the clinical need for the procedure. Ideally, surgical inter-
vention should be delayed wherever possible until coagulation
screening (using either the aPTT or TT, see above) is normal or
until at least 12 h after the last dose. If urgent surgery is needed
within a few hours after the last dabigatran dose, clinicians should
anticipate likely bleeding complications. Haemodialysis can be
considered to eliminate dabigatran in these patients (see below).
For those patients at risk of post-operative thrombosis after dis-
continuing dabigatran, prophylactic doses of low-molecular-
weight heparin (LMWH) can be considered after surgery prior to
restarting dabigatran.
Re-starting dabigatran
Re-initiation of dabigatran following completion of surgery de-
pends on the nature of the surgery, the urgency for restarting
thromboprophylaxis and the haemostatic state of the patient.
Where wound haemostasis is satisfactory, dabigatran can generally
be re-started with a single capsule (110 mg or 150 mg depending
on the dose prescribed) 1–4 h after surgery with the usual regimen
started the following day. When resuming dabigatran in a patient
with renal impairment it is important to remember that there is a
rapid onset of action with peak levels around 2 h which, in com-
bination with higher peak plasma concentrations and overall ex-
posure (18), may place the patient at risk of bleeding if given too
close following surgery.
Managing bleeding and overdose
At present, there is no specific reversal or antidote agent available
for dabigatran or other novel oral anticoagulants such as apixaban
or rivaroxaban. Specific antidotes are in development, but it will
take time before they are commercially available (19, 20). In the
event of bleeding complications, dabigatran must be discontinued
and the source of bleeding investigated. Since dabigatran is ex-
creted predominantly by the renal route, an adequate diuresis must
be maintained. Standard treatment, e.g. surgical haemostasis and
blood volume replacement is recommended (5), and consider-
ation may be given to the use of fresh whole blood or fresh-frozen
plasma. There is some experimental evidence to support the role of
general haemostatic agents such as prothrombin complex concen-
trates (e.g. non-activated or activated), recombinant factor VIIa or
concentrates of coagulation factors II, IX or X in reversing the anti-
coagulant activity of dabigatran in cases of major/life-threatening
bleeding (12, 21), although their usefulness in clinical settings has
not yet been systematically evaluated. Eerenberg et al. reported that
a single 50 IU/kg bolus of prothrombin complex concentrate
(PCC, Cofact) did not reverse the aPTT, ECT and TT in a small
number of healthy young volunteers (n=12) who received dabi -
gatran 150 mg bid for two days (22). No assessment of bleeding
time was performed and there was no correlation with bleeding
events per se. The study findings were not unexpected as the aPTT
and ECT can remain elevated despite PCC administration. The
aPTT is generally more insensitive to PCCs, which predominantly
influence the extrinsic pathway and are reflected in the PT or INR
(23). In addition, using ECT or TT assays bypasses the additional
prothrombin concentrates, since the stimulus for the assay acti-
vates thrombin or prothrombin independent of the prothrombi-
nase complex. Thus, the lack of effect of dabigatran on anticoagu-
Table 4: Anticoagulation measurement for dabigatran in patients ad-
ministered 150 mg twice-daily for AFa.
Test Increased risk of
bleeding
Expected value at
peak concentration
(2 h post dose)
> 2–3 x baseline value aPTT >80 s at trough
(2–3 x baseline value)
Hemoclot (diluted TT) >65 s at trough
INR
ECT
-
-
3 x baseline value
Not applicableb
3–4 x baseline value
aEvidence based on post-hoc review of pharmacokinetic samples collected from
patients enrolled in RE-NOVATE II (57) (aPTT and Hemoclot) and RE-LY (aPTT
and ECT) (7) trials. After administration of dabigatran 150 bid, the 90th percen-
tile of trough plasma concentration to double the risk of bleeding was ∼215 ng/
mL. Baseline aPTT range in RE-LY was 22–40 s. Baseline ECT range in healthy
volunteer studies was 28–34 s (Boehringer Ingelheim, Data on file); bINR is in-
sensitive and unreliable for dabigatran. aPTT, activated partial thromboplastin
time; ECT, ecarin clotting time; h, hours; INR, international normalised ratio;
s, seconds.
Table 5: Discontinu-
ation rules before
elective invasive or
surgical procedures.
Renal function (CrCL in
ml/min)
Estimated half-life (hours) Timing of discontinuation after last dose of da-
bigatran before elective surgery
Standard bleeding risk High
bleeding riska
2 days before
2–3 days before
4 days before
≥80
≥50 to <80
≥30 to <50
∼13
∼15
∼18
24 h before
1–2 days before
2–3 days before (>48 h)
aTypes of surgery associated with a high risk of bleeding (or major surgery where complete haemostasis may be required) including
but not limited to cardiac surgery, neurosurgery, abdominal surgery, or surgeries involving a major organ. Other procedures such as
spinal anaesthesia may also require complete haemostatic function. h, hour.
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Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
Thrombosis and Haemostasis 107.5/2012 © Schattauer 2012
lation reversal may be due to the assays used to test this. Further
support for this comes from preclinical models where it was shown
that the lack of reversal of anticoagulation does not predict a lack
of bleeding reversal (24).
The use of platelet concentrates may be considered where
thrombocytopenia is present or long-acting antiplatelet drugs (e.g.
aspirin, clopidogrel) have been used. The low plasma protein bind-
ing of dabigatran (∼35%), suggests that dialysis may be useful al-
though there is only limited experience with this (12). If dialysis is
not possible, constant haemoperfusion might also be applicable,
although, once again, there is no clinical experience with this ap-
proach.
Managing overdose
In vitro studies show that dabigatran is adsorbed by activated char-
coal therapy (12). Although this has not been tested in vivo, a rea-
sonable approach would be to administer charcoal within 1–2 h of
intake (overdose) to limit or prevent absorption in the gastrointes-
tinal tract. Beyond 2 h use of charcoal is not useful. Haemoperfu-
sion over a charcoal filter has also been suggested as a possible ap-
proach (25, 26), but has not been tested clinically.
Special situations
Thrombolysis in patients with acute ischaemic stroke
In the setting of acute ischaemic stroke, intravenous adminis-
tration of recombinant tissue plasminogen activator (rtPA) is
proven if given to eligible patients within 4.5 h of symptom onset
(27). Warfarin-treated patients with stroke are not considered eli-
gible for thrombolysis unless the INR ≤1.7, although an increased
risk of symptomatic intracerebral haemorrhage after thrombolytic
treatment has been reported even in those with subtherapeutic
INR levels (28). The use of thrombolysis in patients receiving con-
current dabigatran has not been studied and may increase the risk
of bleeding (5). There are few anecdotal reports. De Smedt et al. re-
ported successful use of rtPA in a patient 4.5 h after onset of an is-
chaemic stroke and 7 h after receiving dabigatran (29). Matute et
al. (30) reported use of tPA 15 h after dabigatran when plasma con-
centration of dabigatran was low and aPTT was normal, suggest-
ing absence of anticoagulant effect, which could have favoured the
absence of complications. In both of the above cases anticoagu-
lation tests suggested a low risk of bleeding.
In patients who are considered possible candidates for throm-
bolysis, measurement of the aPTT, TT, or ECT are appropriate in-
itial tests. A normal result from one of these assays generally indi-
cates that the risk of bleeding is low, although there is also the
possibility that one or more doses of dabigatran may have been
missed. Since the INR is insensitive to dabigatran, a recommen-
dation based on INR is not useful. Whether thrombectomy with
the Penumbra® or Solitaire® revascularisation devices is possible
in patients treated with dabigatran has not been evaluated.
Initiation of dabigatran after transient ischaemic
attack or ischaemic stroke
In RE-LY, patients with transient ischaemic attack (TIA) or is-
chaemic stroke were excluded if the event had occurred within the
previous two weeks. However, there is no reason to assume that da-
bigatran carries a higher bleeding risk than warfarin when initiated
early after the event. Since dabigatran achieves full anticoagulant
activity 2 h post dose it should only be commenced when the pa-
tient is suitable for full anticoagulation. In patients with a TIA, it
seems reasonable that dabigatran can be started as soon as imaging
tests have excluded a cerebral haemorrhage. We recommend that
treatment can be initiated 3–5 days after a mild stroke, 5–7 days
after a moderate stroke and two weeks after a severe stroke (31).
Acute coronary events and coronary intervention
Consideration should be given to discontinuing dabigatran in the
setting of acute myocardial infarction (MI) if invasive procedures
such as percutaneous coronary revascularisation or coronary ar-
tery bypass surgery are indicated. Such patients should be treated
according to current clinical guidelines. If patients are candidates
for thrombolysis, the aPTT, TT and ECT tests are sensitive
measures of dabigatran activity and are recommended where there
is a high bleeding risk, such as coronary revascularisation. Acti-
vated clotting time (ACT), which is sensitive to dabigatran in vitro
may also be used, although relevant ACT prolongation has not
been tested in this clinical setting. A recent study in stable coronary
heart disease patients showed that a short course (three days) of
dabigatran 110 or 150 mg bid given in combination with dual anti-
platelet therapy prior to elective percutaneous coronary interven-
tion (PCI) did not provide sufficient anticoagulation compared
with unfractionated heparin (UFH) given during the procedure
(32). At present, dabigatran should be interrupted before PCI and
replaced by an alternative anticoagulant. Further studies are
necessary to identify the optimal approach for patients receiving
dabigatran who require PCI. If UFH or LMWH is indicated, treat-
ment should be delayed for at least 12 h after the last dose of dabi -
gatran or until the aPTT is less than 1.5 times the upper limit of
normal (ULN). If aPTT is > 1.2 and < 1.5 x ULN, UFH can be
started without a loading dose and LMWH can be initiated. If the
aPTT is > 1.5 x ULN, this should be repeated every 4 h until < 1.5
x ULN at which time heparin or other anticoagulation can be
started.
For patients with AF on an oral anticoagulant who require PCI
stenting, current guidelines advocate the use of bare metal stents
rather than drug-eluting stents due to the shorter duration of triple
oral therapy after the procedure (four weeks vs. 12 months) and
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Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
© Schattauer 2012 Thrombosis and Haemostasis 107.5/2012
the associated lower potential risk of subsequent bleeding events
(33, 34). Triple therapy with aspirin, clopidogrel and dabigatran
after revascularisation can be given for a short period but requires
close observation for bleeding events (35).
Cardioversion and ablation
For patients with AF of >48 h duration, therapeutic anticoagu-
lation for at least three weeks before and four weeks after cardio-
version is recommended (1). VKAs have a number of disadvan-
tages in this setting, notably the delayed onset of action and dif-
ficulties in achieving and maintaining an appropriate degree of
therapeutic anticoagulation before or following the procedure.
Evidence from RE-LY (36) suggests that dabigatran is a reasonable
alternative. Among 1,270 patients who underwent cardioversion,
stroke and systemic embolism rates within 30 days of this pro-
cedure were 0.8% and 0.3% for dabigatran 150 and 110 mg bid
doses, respectively, vs. 0.6% with warfarin. Major bleeding rates
were 1.7%, 0.6%, and 0.6%, respectively. It is therefore likely that
patients can stay on dabigatran while being cardioverted. Trans-
esophageal echocardiogram following a standard protocol may be
performed before the procedure according to local operating pro-
cedures.
At present, there are limited clinical data for the use of dabig-
atran in catheter ablation in patients with symptomatic drug-resis-
tant AF (37). Current guidelines recommend the use of LMWH or
intravenous UFH post-ablation as a bridge to resumption of sys-
temic anticoagulation, which should be continued for a minimum
of three months (1). Some centres do not interrupt anticoagu-
lation for the ablation procedure. Whether anticoagulant therapy
should be continued post-ablation depends on the individual’s
risk factors for stroke. If there is sufficient risk to warrant oral anti-
coagulation for their AF preablation, oral anticoagulation therapy
should be continued indefinitely post-ablation regardless of ap-
parent procedural success (38, 39).
Mechanical heart valves
Currently, the use of dabigatran in patients with mechanical heart
valves cannot be recommended due to the lack of clinical evidence.
In vitro and pre-clinical studies have investigated the use of dabi -
gatran in conjunction with mechanical heart valves (40, 41). A
phase II study (the RE-ALIGN trial) to investigate the use of dabig-
atran (150 mg, 220 mg and 300 mg bid) in patients with mechan-
ical heart valves (aortic or mitral) has just commenced (42). Data
from this trial will help to guide the development programme for
dabigatran in this setting.
Adverse effects and drug interactions
Other than bleeding, the most common adverse effect of dabigat-
ran is dyspepsia which typically affects ∼5–10% of patients. In RE-
LY, about 2% of dabigatran-treated patients discontinued treat-
ment due to dyspepsia-like symptoms (classified in the trial as ab-
dominal pain upper, abdominal pain, abdominal discomfort, or
dyspepsia) compared with 0.6% on warfarin. Dyspepsia related to
dabigatran was mainly graded as mild or occasionally moderate in
severity by the investigators, appeared more likely to occur early
after starting treatment (43), and tended to be transient, often
spontaneously resolving with continued treatment (44) or after
cessation of treatment. One hypothesis for the dyspepsia is that it is
related to the capsule formulation. Each dabigatran capsule con-
tains hundreds of pellets of tartaric acid each coated with dabigat-
ran etexilate. Dissolution of these pellets produces a local acidic en-
vironment resulting in an optimal pH for drug absorption. How-
ever, it is not known whether this is the cause of dyspepsia. This ef-
fect may be managed by giving dabigatran with a large glass of
water, with food or a proton-pump inhibitor (PPI) (26). Although
dyspepsia was not predictive for gastrointestinal (GI) bleeding, we
recommend the use of faecal occult blood testing (e.g. Haemocult)
to exclude this (see below). A prospective observational study is
planned to further evaluate the effect of food and PPIs given in
conjunction with dabigatran (Boehringer Ingelheim, data on file).
In RE-LY, a non-significant increase in risk for MI with both
doses of dabigatran (excess of two events/1,000 patients/year vs.
warfarin) was observed (?Fig. 1). However, it should also noted
that the overall rate of MI in the trial was low, given that 30% of pa-
tients had objective evidence of coronary artery disease at baseline.
Other myocardial ischaemic events were not increased and the
treatment effects of dabigatran were consistent in patients at
higher and lower risk of myocardial ischaemic events (45). More-
over, there were also significantly fewer cardiovascular deaths (five
fewer events/1,000/year) and significantly fewer strokes (six fewer
events/1,000/year) with the higher dose of dabigatran (46). A re-
cent meta-analysis of seven trials (including RE-LY) reported an
absolute increase in MI or acute coronary syndrome events of
0.27% with dabigatran treatment versus control (warfarin, enox-
aparin or placebo) (47). Of note, this analysis included patients
from different clinical indications who had differing risks of MI
and were treated with different comparators. Overall mortality re-
mained in favour of dabigatran. Thus, any possible increase in risk
of MI with dabigatran is unlikely to outweigh the clinical benefits
of dabigatran in most patients. If appropriate, co-administration
of low-dose aspirin (≤100 mg daily) with dabigatran may be con-
sidered for patients with a history of coronary artery disease.
In RE-LY, there was a significantly higher risk of gastrointestinal
bleeding with dabigatran 150 mg bid compared with warfarin (ex-
cess of five events/1,000/year). Therefore we recommend that pa-
tients should be monitored clinically for evidence of lower GI tract
bleeding. Faecal occult blood testing (e.g. Haemocult) within the
first month of initiating treatment is a reasonable option to detect
early signs of bleeding possibly associated with anticoagulant use
(48).
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Page 8

Thrombosis and Haemostasis 107.5/2012 © Schattauer 2012
8
Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
Dabigatran has a low potential for drug interactions. Dabig-
atran does not interact with the cytochrome P450 system. The
main clinically relevant interaction is with drugs that inhibit the
P-gp efflux transporter as the prodrug (dabigatran etexilate) is a
substrate. Thus, plasma concentrations of dabigatran are increased
when given with strong P-gp inhibitors such as amiodarone, ver-
apamil and ketoconazole (5), and reduced when given with potent
inducers such as rifampicin, carbamazepine or phenytoin. Data
from RE-LY indicate that co-administration of P-gp inhibitors
(mainly amiodarone or verapamil) resulted in modest increases in
dabigatran plasma concentrations (12% overall increase) com-
pared with that observed in healthy volunteer studies (49). Further,
the combination of P-gp inhibitors with dabigatran did not in-
fluence the overall benefits of dabigatran for stroke prevention,
major bleeding events or intracranial haemorrhage relative to war-
farin. In view of the relatively small increases in exposure, dose
modification is not required when dabigatran is administered with
amiodarone or quinidine. However, in the European Union, when
co-administered with verapamil, a reduced dose of dabigatran 110
mg bid is recommended. Co-prescription with a PPI such as pan-
toprazole may slightly reduce dabigatran exposure and peak con-
centrations although these effects are not likely to reduce the effi-
cacy of dabigatran. In RE-LY, use of PPIs decreased exposure by
12.5% with no impact on efficacy outcomes (50). ?Table 6 pro-
vides guidance for the use of dabigatran in conjunction with other
drugs based on the European prescribing guidelines (5).
Caution is recommended if considering co-administration of
dabigatran with other anticoagulants or antiplatelet agents due to
the increased risk of bleeding. Among patients receiving concomi-
tant aspirin or clopidogrel in RE-LY, there was an increased risk of
major bleeding (HR 1.76, 95% CI 1.55–2.00), which was similar for
dabigatran 110 mg, 150 mg or warfarin (51). Data are lacking con-
cerning the use of dabigatran in conjunction with new antiplatelet
treatments such as prasugrel and ticagrelor.
Practical aspects
Dabigatran etexilate capsules should be swallowed whole as break-
ing, chewing or emptying the contents can increase oral bioavail-
ability and exposure by up to 75% (5). Once the medication bottle
has been opened, the capsules must be used within 120 days as they
are susceptible to humidity (6).
Compliance with twice-daily dosing is important and should be
addressed by patient education. Patients who miss a dose of dabig-
atran can take the dose up to 6 h before the next scheduled dose. If
this is not possible, the missed dose should be omitted. Patients
should not take a double dose to compensate for missed individual
doses. Clinicians should advise their patients about how to look for
signs of abnormal bleeding (such as epistaxis, gingival haem-
orrhage, subcutaneous haemorrhage, haematuria, or bloody
stools) and to call them immediately if such episodes develop.
Conclusions
Very clearly, many questions remain, and the present review article
nicely complements a recent position document from the Italian
Federation of Thrombosis Centers (FCSA) dealing with the use of
the new oral anticoagulants (52). The latter have clearly changed
our approach to thromboprophylaxis (53), so that in AF, effective
stroke prevention with new oral anticoagulants such as dabigatran
can be offered to patients with one or more stroke risk factors (54,
55).
Table 6: Guidance for use of dabigatran with other drugs (as per EU
label) (5).
Drug interactions and
dosing recommendation
No adjustment required
Atorvastatin
Diclofenac
Pantoprazole
Clopidogrel
Digoxin
Use lower dose (110 mg bid)
Verapamil
Use with caution and assess bleeding risk
Quinidine
Amiodarone
Clarithromycin
Not recommended
Dronedarone
Rifampicin
Carbamazepine, phenytoin
Protease inhibitors
(e.g. ritonavir, tipranavir,
nelfinavir and saquinavir)
Contraindicated
Effect on dabigatran exposure
due to drug interaction
↓ 18%
No effect
↓ 30%a
↑ 30–40%a
No effect
↑ 20–150% a,b
↑ 50% a
↑ 60% a
↑ 19% a
Systemic ketoconazole
Itraconazole, tacrolimus and cyclo-
sporin
Exposure refers to reported area under the plasma concentration curve.
aBased on data in healthy volunteers.bDepends on timing of administration of
and formulation of verapamil. Dabigatran exposure is 150% higher if the first
dose of immediate release formulation verapamil is given 1 hour before dabi -
gatran; lower if given as extended release formulation (70% higher) or with
multiple doses of verapamil (50% increase); and negligible if given 2 hours
after dabigatran (20% increase). Both medications should be taken at the same
time. cProtease inhibitors including ritonavir and its combinations with other
protease inhibitors affect P-gp (either as inhibitor or as inducer). They have not
been studied and are therefore not recommended for concomitant treatment
with dabigatran.
↑ 150%a
↑ (% not reported but likely to be similar
to ketoconazole based on in vitro data)
↑ 100%a (58)
↓ 67%a
↓ (% not reported)
Exposure not reportedc
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© Schattauer 2012 Thrombosis and Haemostasis 107.5/2012
9
Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
Conflict of interest
Menno Huisman has received honoraria for presentations as well
as research grants of Boehringer Ingelheim, Bayer Healthcare,
Pfizer, GSK and Actelion. Gregory Lip has served as a consultant
for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, Bio-
tronik, Portola and Boehringer Ingelheim and has been on the
speakers’ bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim,
and Sanofi-Aventis. Hans-Christoph Diener has received honor-
aria for participation in clinical trials, contribution to advisory
boards or oral presentations from Abbott, Allergan, AstraZeneca,
Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, Daichii-San-
kyo, D-Pharm, EV3, Fresenius, GlaxoSmithKline, Janssen Cilag,
Knoll, MSD, Medtronic, MindFrame, Neurobiological Technol-
ogies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sano-
fi-Aventis, Schering-Plough, Servier, Solvay, Thrombogenics,
Wyeth and Yamanouchi. Financial support for research projects
was provided by AstraZeneca, GlaxoSmithKline, Boehringer In-
gelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syn-
gis and Talecris. The Department of Neurology at the University
Duisburg-Essen received research grants from the German Re-
search Council (DFG), German Ministry of Education and Re-
search (BMBF), European Union, National Institute of Health,
Bertelsmann Foundation and Heinz-Nixdorf Foundation. Hans-
Christoph Diener has no ownership interest and does not own
stocks of any pharmaceutical company. Martina Brueckmann,
Joanne van Ryn, and Andreas Clemens are employees of Boehr-
inger Ingelheim.
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Thrombosis and Haemostasis 107.5/2012 © Schattauer 2012
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Huisman et al. Dabigatran – a new oral anticoagulant for use in patients with AF
For personal or educational use only. No other uses without permission. All rights reserved.
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