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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 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

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 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.

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: 838847

Note: The editorial process for this article was fully handled by Prof. Christian
Weber, Editor-in-Chief.

Introduction

Dose selection

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia (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 adherence 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. However, 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.

Dabigatran is administered as a prodrug (dabigatran etexilate),

which is metabolised to the active form, dabigatran. Renal excretion 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 reduced 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] 3050 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-glycoprotein (P-gp)-inhibitors such as systemic ketoconazole, cyclosporine, itraconazole and tacrolimus (5). In the US, a 75 mg bid
dose of dabigatran is approved for use in patients with CrCL 1530
ml/min and can be considered in patients with moderate renal impairment who are also treated with dronedarone or systemic ketoconazole (6).
Prior to commencing treatment with dabigatran, renal function should be checked in all patients and CrCL calculated using

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Huisman et al. Dabigatran a new oral anticoagulant for use in patients with AF

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 performed.
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 indicated, or if a decline in renal function is suspected (e.g. hypovolaemia, dehydration, certain comedications).

Switching treatment
A potential cause for concern among clinicians is in switching patients between different anticoagulant treatments. Suggested approaches are summarised in Table 3. If switching a patient from

Figure 1: Clinical flowchart for the use of dabigatran for stroke prea

vention in AF (as per European prescribing guidelines) (5). see grey

box in figure. bCrCL can be estimated using the Cockcroft-Gault equation: =
(140 age) x (weight (kg) x (constant)/serum creatinine (M), where constant is 1.23 for men and 1.04 for women. cTable 2 summarises factors associated with a high risk of bleeding. A HAS-BLED score of 3 in patients with

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 converting from dabigatran to VKAs, the start time of the VKA is adjusted according to the CrCL. This is due to the prolonged anticoagulant 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 dabigatran treatment. However, it may be indicated in certain situations,
such as suspected overdose, emergency situations, in the perioperative setting, in the event of bleeding or to identify patients at increased bleeding risk due to excessive dabigatran exposure, or in
patients with progressive or severe renal dysfunction. The anticoagulant tests can be broadly categorised as qualitative (i.e. suit-

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 function. 110 mg bid dose can be considered in patients with associated gastritis, oesophagitis or gastroesophageal reflux, irrespective of age or renal function. CrCL, Creatinine clearance; EU, European Union; NYHA, New York Heart
Association.

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Huisman et al. Dabigatran a new oral anticoagulant for use in patients with AF

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. bGastrointestinal bleeding could be
life threatening or nonlife threatening. CI, confidence interval; yr, year.

able for detection of excess anticoagulant activity) or quantitative.

Guidance for cut-off values for coagulation assays indicative of increased bleeding risk is summarised in Table 4. Clinicians
should be aware that a blood sample taken 2 hours (h) after dabigatran dosage (peak level) will have a higher result in all clotting
tests compared with samples taken at 1012 h (trough level).
The INR test is not recommended for monitoring as it is insensitive 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 Hemochron point-of-care device compared with laboratory INR testing (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
the baseline value although there is some variability due to differ-

VKAs

Dabigatran

Onset of action

Slow (36 to 72 hours)

Rapid (2 hours)

Offset of action

Long (24 to 192 hours depending on type used)

Short, half-life dependent (1214 hours)

Dosing

Individualised

Fixed dose

Dose adjustment

Frequent

Rare

Monitoring

Required; patient adherence and convenience can be problematic

Only in special situations

Food and alcohol

Interaction

No interaction

Drug interactions

Frequent

Few

Thrombosis and Haemostasis 107.5/2012

Table 1: Limitations of
vitamin K antagonists
(VKA) in comparison
with dabigatran.

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Huisman et al. Dabigatran a new oral anticoagulant for use in patients with AF

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 indicates no clinically relevant anticoagulant effect of dabigatran.
Once again, there is some variability depending on the coagulometer and the thrombin reagent used for the 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 anticoagulant 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 (corresponding 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 fragile 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 surgical 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 versus risk of thrombosis. Clinicians should take account of the patients renal function and the bleeding risk of the procedure in decisions regarding the timing of discontinuation (5) (Table 5). If possible, discontinue dabigatran 12 days (CrCL 50 ml/min or more) or
23 days (CrCL less than 50 ml/min) before invasive or surgical pro-

proaches for switching

to and from dabigatran (based on EU
label) (5).

Demographic

Age 75 years

Factors increasing dabigatran

plasma levels

Major:
Moderate renal impairment (CrCL 3050 ml/
min)
P-gp inhibitor co-medication
Minor:
Low body weight (<50 kg)

Quantitative measurement

Table 3: Suggested ap-

Table 2: Factors identified in clinical trials which may increase the

bleeding riska.

Conversion

Pharmacodynamic interactions ASA

NSAID
Clopidogrel
Diseases/procedures with
special haemorrhagic risks

Congenital or acquired coagulation disorders

Thrombocytopenia or functional platelet defects
Active ulcerative GI disease
Recent GI bleeding
Recent biopsy or major trauma
Recent ICH
Brain, spinal, or ophthalmic surgery
Bacterial endocarditis

For special patient populations requiring a reduced 110 mg bid dose, see Figure 1. ASA, acetylsalicylic acid; CrCL, Creatinine clearance; P-gp, P-glycoprotein; GI, gastrointestinal; ICH, intracranial haemorrhage; NSAID, non-steroidal
anti-inflammatory drug.

cedures. 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 212 h after the
last dose of dabigatran), the risk of bleeding needs to be weighed
against the clinical need for the procedure. Ideally, surgical inter-

Start times recommenced

From VKAs to dabigatran

Discontinue VKA and start dabigatran when INR <2

From dabigatran to VKAsa

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 1530 ml/min, start VKA 1 day before stopping dabigatranb

From dabigatran to parenteral

Start parenteral anticoagulant 12 h after last dose of dabigatran

From parenteral to 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.

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

Table 4: Anticoagulation measurement for dabigatran in patients administered 150 mg twice-daily for AFa.
Test

Increased risk of
bleeding

Expected value at
peak concentration
(2 h post dose)

aPTT

>80 s at trough
> 23 x baseline value
(23 x baseline value)

Hemoclot (diluted TT)

>65 s at trough

INR

Not applicableb

ECT

34 x baseline value

3 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 percentile of trough plasma concentration to double the risk of bleeding was 215 ng/
mL. Baseline aPTT range in RE-LY was 2240 s. Baseline ECT range in healthy
volunteer studies was 2834 s (Boehringer Ingelheim, Data on file); bINR is insensitive and unreliable for dabigatran. aPTT, activated partial thromboplastin
time; ECT, ecarin clotting time; h, hours; INR, international normalised ratio;
s, seconds.

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 discontinuing dabigatran, prophylactic doses of low-molecularweight heparin (LMWH) can be considered after surgery prior to
restarting dabigatran.

Re-starting dabigatran
Re-initiation of dabigatran following completion of surgery depends 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

Renal function
(CrCL in ml/min)

Estimated half-life
(hours)

on the dose prescribed) 14 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 combination with higher peak plasma concentrations and overall exposure (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 excreted 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 consideration 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 concentrates (e.g. non-activated or activated), recombinant factor VIIa or
concentrates of coagulation factors II, IX or X in reversing the anticoagulant 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 dabigatran 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 activates thrombin or prothrombin independent of the prothrombinase complex. Thus, the lack of effect of dabigatran on anticoagu-

Timing of discontinuation after last dose of

dabigatran before elective surgery
Standard bleeding
risk

High
bleeding riska

80

13

24 h before

2 days before

50 to <80

15

12 days before

23 days before

30 to <50

18

23 days before (>48 h)

4 days before

Table 5: Discontinuation rules before

elective invasive or
surgical procedures.

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

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 binding of dabigatran (35%), suggests that dialysis may be useful although 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 approach.

Managing overdose
In vitro studies show that dabigatran is adsorbed by activated charcoal therapy (12). Although this has not been tested in vivo, a reasonable approach would be to administer charcoal within 12 h of
intake (overdose) to limit or prevent absorption in the gastrointestinal tract. Beyond 2 h use of charcoal is not useful. Haemoperfusion over a charcoal filter has also been suggested as a possible approach (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 administration 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 eligible 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 concurrent dabigatran has not been studied and may increase the risk
of bleeding (5). There are few anecdotal reports. De Smedt et al. reported successful use of rtPA in a patient 4.5 h after onset of an ischaemic stroke and 7 h after receiving dabigatran (29). Matute et
al. (30) reported use of tPA 15 h after dabigatran when plasma concentration of dabigatran was low and aPTT was normal, suggesting absence of anticoagulant effect, which could have favoured the
absence of complications. In both of the above cases anticoagulation tests suggested a low risk of bleeding.
In patients who are considered possible candidates for thrombolysis, measurement of the aPTT, TT, or ECT are appropriate initial tests. A normal result from one of these assays generally indicates 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 recommendation 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 ischaemic stroke were excluded if the event had occurred within the
previous two weeks. However, there is no reason to assume that dabigatran 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 patient 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 35 days after a mild stroke, 57 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 artery 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. Activated 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 antiplatelet therapy prior to elective percutaneous coronary intervention (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, treatment should be delayed for at least 12 h after the last dose of dabigatran 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

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 anticoagulation for at least three weeks before and four weeks after cardioversion is recommended (1). VKAs have a number of disadvantages in this setting, notably the delayed onset of action and difficulties 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 procedure 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. Transesophageal echocardiogram following a standard protocol may be
performed before the procedure according to local operating procedures.
At present, there are limited clinical data for the use of dabigatran in catheter ablation in patients with symptomatic drug-resistant AF (37). Current guidelines recommend the use of LMWH or
intravenous UFH post-ablation as a bridge to resumption of systemic anticoagulation, which should be continued for a minimum
of three months (1). Some centres do not interrupt anticoagulation for the ablation procedure. Whether anticoagulant therapy
should be continued post-ablation depends on the individuals
risk factors for stroke. If there is sufficient risk to warrant oral anticoagulation for their AF preablation, oral anticoagulation therapy
should be continued indefinitely post-ablation regardless of apparent 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 dabigatran in conjunction with mechanical heart valves (40, 41). A
phase II study (the RE-ALIGN trial) to investigate the use of dabigatran (150 mg, 220 mg and 300 mg bid) in patients with mechanical 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 dabigatran is dyspepsia which typically affects 510% of patients. In RELY, about 2% of dabigatran-treated patients discontinued treatment due to dyspepsia-like symptoms (classified in the trial as abdominal 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 contains hundreds of pellets of tartaric acid each coated with dabigatran etexilate. Dissolution of these pellets produces a local acidic environment resulting in an optimal pH for drug absorption. However, it is not known whether this is the cause of dyspepsia. This effect 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 patients 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). Moreover, 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 recent 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, enoxaparin 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 remained 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 considered 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 (excess of five events/1,000/year). Therefore we recommend that patients 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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Huisman et al. Dabigatran a new oral anticoagulant for use in patients with AF

Dabigatran has a low potential for drug interactions. Dabigatran 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, verapamil 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) compared with that observed in healthy volunteer studies (49). Further,
the combination of P-gp inhibitors with dabigatran did not influence the overall benefits of dabigatran for stroke prevention,
major bleeding events or intracranial haemorrhage relative to warfarin. 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 pantoprazole may slightly reduce dabigatran exposure and peak concentrations although these effects are not likely to reduce the efficacy of dabigatran. In RE-LY, use of PPIs decreased exposure by
12.5% with no impact on efficacy outcomes (50). Table 6 provides 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 concomitant aspirin or clopidogrel in RE-LY, there was an increased risk of
major bleeding (HR 1.76, 95% CI 1.552.00), which was similar for
dabigatran 110 mg, 150 mg or warfarin (51). Data are lacking concerning 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 breaking, chewing or emptying the contents can increase oral bioavailability 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 dabigatran 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 haemorrhage, subcutaneous haemorrhage, haematuria, or bloody
stools) and to call them immediately if such episodes develop.

Table 6: Guidance for use of dabigatran with other drugs (as per EU
label) (5).
Drug interactions and
dosing recommendation
No adjustment required

Effect on dabigatran exposure

due to drug interaction

Atorvastatin

18%

Diclofenac

No effect

Pantoprazole

30%a

Clopidogrel

3040%a

Digoxin

No effect

Use lower dose (110 mg bid)

20150% a,b

Verapamil

Use with caution and assess bleeding risk

Quinidine

50% a

Amiodarone

60% a

Clarithromycin

19% a

Not recommended
Dronedarone

100%a (58)

Rifampicin

67%a

Carbamazepine, phenytoin

(% not reported)

Protease inhibitors
(e.g. ritonavir, tipranavir,
nelfinavir and saquinavir)

Exposure not reportedc

Contraindicated
150%a

Systemic ketoconazole

Itraconazole, tacrolimus and cyclo- (% not reported but likely to be similar

sporin
to ketoconazole based on in vitro data)
Exposure refers to reported area under the plasma concentration curve.
Based 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 dabigatran; 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.
a

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).

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846

Huisman et al. Dabigatran a new oral anticoagulant for use in patients with AF

Conflicts 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, Biotronik, 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 honoraria for
participation in clinical trials, contribution to advisory boards or
oral presentations from Abbott, Allergan, AstraZeneca, Bayer Vital,
BMS, Boehringer Ingelheim, CoAxia, Daichii-Sankyo, D-Pharm,
EV3, Fresenius, GlaxoSmithKline, Janssen Cilag, Knoll, MSD,
Medtronic, MindFrame, Neurobiological Technologies, Novartis,
Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Thrombogenics, Wyeth and Yamanouchi. Financial support for research projects was provided by AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis and Talecris. The Department of Neurology at the University Duisburg-Essen received
research grants from the German Research Council (DFG), German Ministry of Education and Research (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 Boehringer Ingelheim.

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