Dabigatran for the prevention and treatment of thromboembolic disorders

Andres Enriquez*, Adrian Baranchuk, Damian Redfearn, Christopher Simpson, Hoshiar Abdollah and Kevin Michael
Division of Cardiology, Queen’s University, Kingston, Ontario, Canada
*Author for correspondence:
Tel.: +1 613 549 6666; extn. 3377
Fax: +1 613 548 1387
[email protected]

Dabigatran, an oral direct thrombin inhibitor, was the first of a new class of drugs referred to as non-vitamin K oral anticoagulants. Dabigatran is better than warfarin for stroke prevention in non-valvular atrial fibrillation (dose of 150 mg twice a day), non-inferior to enoxaparin for venous thromboembolism prevention after orthopedic surgery and non-inferior to warfarin in preventing recurrence after acute venous thromboembolism. The safety profile is similar to standard anticoagulants, with significant reduction observed in intracranial hemorrhage. Other advantages include a rapid onset of action and a predictable pharmacokinetic profile, allowing a fixed-dose regimen without the need for routine anticoagulation monitoring. In the event of bleeding, general support measures are recommended and if severe, the use of non-specific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa must be considered. A specific reversal agent (idarucizumab) is in development.

KEYWORDS: dabigatran . new oral anticoagulants . NOACs . warfarin

Until recently, the vitamin K antagonists (VKA), such as warfarin, were the only oral agents available for the prevention and treat- ment of thromboembolic disease. Warfarin is effective, but has several limitations, including a narrow therapeutic window, slow onset and offset of action, need for strict anticoagulation monitoring and numerous food and drug interactions. In the last years, the introduction of non-vitamin K oral anticoagulants (NOACs) has been a revolution in managing patients at risk of thromboembolism. These include the direct thrombin inhibitor dabiga-
tran (Pradaxa®, Boehringer Ingelheim) and the factor Xa inhibitors, namely rivaroxaban (Xarelto®, Bayer), apixaban (Eliquis®, Pfizer and Bristol-Myers Squibb) and edoxaban (Lixiana®, Daiichi Sankyo). Data from large randomized trials show that NOACs are at least as effective as VKA with similar or lower rates of bleeding and fewer drug and food
interactions. Besides, they have a more predict- able anticoagulant effect, allowing a fixed dose regimen and obviating the need for routine anticoagulation monitoring.
Dabigatran was the first of this new family of anticoagulants to be introduced and, there- fore, the one with more extensive post-

marketing information. The drug was initially approved in 2008 by the European Medicines Agency (EMA) for venous thromboembolism (VTE) prophylaxis after hip or knee replace- ment, and in 2010, the U.S. Food and Drug Administration (FDA) authorized its use for stroke prevention in patients with non-valvular atrial fibrillation (AF). In this article, we review the current evidence and future per- spectives on the use of dabigatran in the pre- vention and treatment of thromboembolic disorders.

Pharmacology
Dabigatran etexilate is an oral prodrug that is rapidly absorbed and converted by serum ester- ases to its active form, dabigatran, a competitive direct inhibitor of thrombin, both free and bound to fibrin [1,2]. The oral bioavailability is low (6–7%) and its absorption is pH-depen- dent, with peak concentrations being slightly decreased by concomitant use of proton pump inhibitors. Plasma levels of dabigatran peak within 2 h of administration and its serum half- life is 12–17 h. The drug is predominantly eliminated unchanged by the kidneys (80%), with the rest eliminated via the bile. Patients with moderate renal dysfunction (creatinine

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clearance [ClCr] <50 ml/min) may exhibit prolonged excretion rates and elevated plasma concentration, and dabigatran is con- traindicated in patients with severe renal dysfunction (ClCr
<30 ml/min) [3]. Cytochrome P450 (CYP450) enzymes are not affected by dabigatran and have no role in its metabolism, pre- cluding interaction with drugs metabolized by this system [1]. Dabigatran etexilate is a substrate of the P-glycoprotein (P-gp) efflux transporter expressed in the intestine and increased levels may result from co-administration of P-gp inhibitors such as quinidine, amiodarone and verapamil [4]. Only 35% of dabiga- tran is bound to plasma proteins and hemodialysis is effective in removing approximately 60% of circulating drug over 2 h [5]. Because of the predictable pharmacokinetic profile of dabigatran, routine coagulation monitoring is not necessary in clinical prac- tice. The pharmacological characteristics of dabigatran and other NOACs are compared in TABLE 1.

Clinical uses
VTE prophylaxis in orthopedic surgery
Patients undergoing elective hip or knee arthroplasty are at sig- nificant risk for VTE, which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). Without effective pro- phylaxis nearly half of these patients will develop VTE, although only 5% of these patients manifest symptoms [6]. Low-molecular-weight heparins, the traditional agents used for prophylaxis, are effective and safe, but require parenteral administration, which may be problematic in some patients. Four Phase III trials have compared dabigatran with enoxaparin for thromboprophylaxis in patients undergoing elective hip or knee replacement: RE-MODEL, RE-MOBILIZE and RE-NOVATE I/II (TABLE 2) [7–10]. Globally, these studies have included more than 10,000 patients and the pooled data sug- gest that dabigatran is as effective as enoxaparin for reduction of VTE (relative risk [RR] 0.71; 95% CI: 0.23–2.12;
p = 0.54) and is associated with similar rates of clinically rele- vant bleeding (RR 1.12; 95% CI: 0.94–1.35; p = 0.21) [11].
Treatment of VTE
The RE-COVER and RE-COVER II trials included patients with acute DVT and PE that were initially treated with paren- teral anticoagulation therapy for a mean of 10 days. Dabigatran at a dose of 150 mg twice a day (b.i.d.) was compared with dose- adjusted warfarin to achieve an international normalized ratio (INR) of 2.0–3.0 and the primary outcome was the 6-month incidence of recurrent, symptomatic, objectively confirmed VTE. In both twin studies, dabigatran 150 mg b.i.d. was non-inferior to warfarin in reducing recurrent thromboembolic events (2.4 vs 2.1% in RE-COVER; p < 0.001 and 2.3 vs 2.2% in RE-
COVER II; p < 0.001) and was associated with lower incidence of overall bleeding, with similar rate of major bleeding and a higher rate of gastrointestinal bleeding [12–14].
Subsequently, the role of dabigatran in the extended treatment of VTE was assessed by the RE-SONATE and RE-MEDY trials, two double-blinded, randomized trials com- paring dabigatran (150 mg b.i.d) with placebo and warfarin,

respectively, in patients with DVT or PE who had completed at least 3 initial months of therapy [15]. In the active-control study (RE-MEDY), dabigatran was non-inferior to warfarin in reducing recurrent VTE (0.9 vs 1.8% in dabigatran and warfa- rin groups respectively; p = 0.06) and was associated with
lower rates of major or clinically relevant bleeding (5.6 vs
10.2%; p < 0.001). In the placebo-control study (RE-SONATE), dabigatran reduced the risk of recurrent VTE by 92% compared to placebo (0.4 vs 5.6%; p < 0.001), with a higher incidence of major or clinically relevant bleeding (5.3 vs 1.8%; p = 0.001).
Based on the results of these four Phase III trials, in 2014,
the FDA approved the use of dabigatran for the acute treat- ment of DVT and PE after parenteral anticoagulant therapy for 5–10 days, and to reduce the risk of recurrent DVT and PE in patients who have been previously treated.

Non-valvular AF
AF is the most common sustained cardiac arrhythmia, with a prevalence of 1–2% in the general population [16], and is asso- ciated with significant morbidity and mortality, conferring a fivefold risk of stroke, threefold incidence of congestive heart failure and twofold rate of death [17]. Compared with control, warfarin reduces the risk of stroke and systemic embolism by 64%, corresponding to an absolute annual risk reduction of 2.7% [18]. A major issue with VKA in the real world is the fact that the INR remains in therapeutic range (2.0–3.0) only 50–60% of the time, with the potential adverse consequences of inadequate anticoagulation levels [19].
The pivotal Randomized Evaluation of Long-term anticoagu- lant therapY (RE-LY) study was a prospective, randomized, open- label, blinded-endpoint, non-inferiority trial that compared dabi- gatran 110 mg b.i.d. (D110) and 150 mg b.i.d. (D150) with dose- adjusted warfarin, aiming for an INR of 2.0–3.0 in patients with non-valvular AF [20]. For the primary efficacy endpoint of stroke or systemic embolism, D150 was superior to warfarin (1.11 vs 1.69% per year, respectively; p < 0.001 for superiority), with similar rate of major bleeding (3.11 vs 3.36% per year, respectively; p = 0.31).
D110 was non-inferior to warfarin (1.53 vs 1.69% per year,
respectively; p < 0.001 for non-inferiority) and was associated with fewer major bleeds (2.71 vs 3.36% per year, respectively; p = 0.003). Rates of intracranial bleeding were lower with both doses of dabigatran (0.74, 0.23 and 0.30% for warfarin, D110 and D150, respectively; p < 0.05 for all comparisons) and gastrointesti-
nal bleeding was significantly increased with D150 (1.51 vs 1.02%; p < 0.001), which was attributed to the acidity of the tarta- ric acid core in the dabigatran capsules. Based on the results of the RE-LY study, dabigatran was approved in 2011 by the FDA and EMA for stroke prevention in non-valvular AF.
Data from meta-analysis also confirm the benefits and safety of dabigatran for this indication. A Cochrane systematic review showed that direct thrombin inhibitors (including 12,355 patients on warfarin) were as efficacious as VKA for the com- posite outcome of vascular death and ischemic events and dabi- gatran 150 mg b.i.d. was superior to warfarin [21].

doi: 10.1586/14779072.2015.1034692 Expert Rev. Cardiovasc. Ther.

Table 1. Pharmacological properties of dabigatran and comparison with other non-vitamin K oral anticoagulants.
Dabigatran Rivaroxaban Apixaban Edoxaban
Dosing
AF 150 mg b.i.d. 20 mg q.d. 5 mg b.i.d. 60 mg q.d.
VTE prophylaxis 220 mg q.d. 10 mg q.d. 2.5 mg b.i.d. 30 mg q.d.
VTE treatment 150 mg b.i.d. 15 mg b.i.d. for 21 days followed by 20 mg q.d. 10 mg b.i.d. for 7 days followed by 5 mg b.i.d. 60 mg q.d.
Molecular weight (Da) 628 436 460 548
Target II Xa Xa Xa
Bioavailability (%) 6 63–79 66 50
Tmax (h) 2–3 2–4 1–3 1–3
T1/2 (h) 12–17 7–13 8–15 9–11
Protein binding (%) 35 95 87 54
Metabolism 80% renal,
20% liver 1/3 renal, 2/3 liver 25% renal,
75% fecal 35% renal,
63% liver
Interactions P-gp inhibitors CYP3A4 inhibitors, P-gp inhibitors CYP3A4 inhibitors, P-gp inhibitors CYP3A4 inhibitors, P-gp inhibitors

Approved indications Prevention of stroke and Prevention of stroke and Prevention of stroke and In Japan for VTE systemic embolism in non- systemic embolism in non- systemic embolism in prophylaxis after hip valvular AF valvular AF non-valvular AF and knee replacement
VTE prophylaxis after hip VTE prophylaxis after hip VTE prophylaxis after hip and knee replacement and knee replacement and knee replacement
Antidotes Idarucizumab (Phase I) Andexanet alfa (Phase I–II) Andexanet alfa Andexanet alfa Ciraparantag (pre-clinical) Ciraparantag (pre-clinical) (Phase II–III) (Phase II)
Ciraparantag (pre-clinical) Ciraparantag (Phase I)
AF: Atrial fibrillation; b.i.d.: twice a day; P-gp: P-glycoprotein; q.d.: Once a day; t1/2: Half-life; tmax: Time to maximal concentration; VTE: Venous thromboembolism. Adapted from [61].

Electrical cardioversion
The available data suggest that cardioversion can be safely per- formed on dabigatran. A post-hoc analysis of the RE-LY showed that the incidence of stroke and systemic embolism after car- dioversion was low and similar in patients on dabigatran and warfarin, with or without transesophageal echocardiography guidance (0.8, 0.3 and 0.6% in D110, D150 and warfarin groups, respectively; D110 vs warfarin p = 0.71; D150 vs war-
farin p = 0.40) [22]. Subsequent retrospective analyses also sup-
port the safety of dabigatran for this indication [23,24]. Similar
to warfarin, the European Society of Cardiology (ESC) guide- lines recommend anticoagulation with dabigatran for ‡3 weeks prior to and ‡4 weeks after cardioversion, regardless of the method used (electrical or pharmacological) [25].

Periprocedural anticoagulation for catheter ablation of AF The optimal anticoagulation strategy in patients undergoing AF ablation is a matter of debate and current evidence favors the uninterrupted administration of warfarin over bridging with heparin [26]. No randomized trials have compared dabiga- tran with warfarin, and data from case series have shown

mixed results, with most studies showing no difference between dabigatran and uninterrupted warfarin [27–29] while others have reported a higher risk of thromboembolic or hem- orrhagic complications with dabigatran [30]. In most of these studies, dabigatran was stopped 12–24 h prior to the proce- dure and restarted within the next 12 h. Maddox et al. found no difference in the risk of bleeding or thromboembolic com- plications with uninterrupted oral anticoagulation either with dabigatran or warfarin [31]. A meta-analysis including 10 studies and 3648 patients showed no difference in thrombo- embolic events or major bleeding [32], while another meta- analysis showed equivalent rates of major bleeding, but a higher frequency of neurological events with dabigatran versus continuous warfarin, which was attributed to fluctuations in the anticoagulant effect associated with dabigatran interrup- tion [33]. Certainly, randomized trials are needed to defini- tively assess the safety and efficacy of periprocedural dabigatran and other NOACs in this setting. It is expected that the availability of an antidote in the near future would allow to safely perform AF ablation without the need to stop the drug.

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Table 2. Summary of randomized clinical trials of dabigatran for different indications.
Trial Experimental design n Efficacy outcomes (% per year) Safety outcomes (% per year) Ref.
Non-valvular AF
RE-LY, 2009 Dabigatran 150 mg b.i.d. or 110 mg
b.i.d. vs warfarin duration 2 years 18113 Stroke/systemic embolism:
. Dabigatran 150 mg superior (1.11 vs 1.69; p < 0.001)
. Dabigatran 110 mg non-inferior (1.53 vs 1.69; p < 0.001) Major bleeding:
. Dabigatran 150 mg no difference (3.11 vs 3.4; p = 0.31)
. Dabigatran 110 mg reduction in major
bleeding (2.71 vs 3.4; p = 0.003) [20]

Prevention of VTE after orthopedic surgery
RE-NOVATE I, Dabigatran 220 or 150 mg q.d. vs enoxaparin 40 mg sc. q.d. for 28–35 days after hip replacement surgery; follow-up 3 months 3494 VTE (symptomatic or venographic) and mortality:
. Dabigatran non-inferior (6.0%
[p < 0.0001 vs enoxaparin], 8.6% [p < 0.0001 vs enoxaparin], and 6.7%, respectively) Major bleeding:
. No difference (2.0% [p = 0.64 vs enoxaparin], 1.3% [p = 0.60 vs enoxaparin], and 1.6%, respectively) [10]

2007

RE-MODEL, Dabigatran 220 or 150 mg q.d. vs enoxaparin 40 mg sc. q.d. for 6–10 days after knee arthroplasty surgery; follow-up 3 months 2076 VTE (symptomatic or venographic) and mortality:
. Dabigatran non-inferior (36.4% [p = 0.0003 vs enoxaparin], 40.5% [p = 0.017 vs enoxaparin], and 37.7%, respectively) Major bleeding:
. No difference (1.5, 1.3 and 1.3% for dabigatran 220 mg b.i.d., dabigatran
150 mg b.i.d. and enoxaparin, respectively) [8]

2007

RE-MOBILIZE, Dabigatran 220 or 150 mg q.d. vs 1896 VTE (symptomatic or venographic): Major bleeding: [7]

2009 enoxaparin 30 mg sc. b.i.d. for 12–15 . Dabigatran inferior (31% [p = 0.02 . No difference (0.6, 0.6 and 1.4% for
days after knee arthroplasty surgery; vs enoxaparin], 34% [p < 0.001 vs dabigatran 220 mg b.i.d., dabigatran
follow-up 3 months enoxaparin], and 25%, respectively) 150 mg b.i.d. and enoxaparin,
respectively)
RE-NOVATE II, Dabigatran 220 mg q.d. vs enoxaparin 2055 VTE (symptomatic or venographic) and Major bleeding: [9]

2011 40 mg sc. q.d. for 28–35 days after hip mortality: . No difference (1.4 vs 0.9%; p = 0.40)
replacement surgery; . Dabigatran non-inferior (7.7 vs 8.8%;
follow-up 3 months p < 0.0001)
Treatment of acute VTE
RE-COVER, Dabigatran 150 mg b.i.d. vs warfarin INR 2–3;
duration 6 months 2539 Recurrent symptomatic VTE and related deaths:
. Dabigatran non-inferior (2.4 vs 2.1;
p < 0.001) Major bleeding:
. No difference (1.6 vs 1.9; HR: 0.82;
95% CI: 0.45–1.48) [12]

2009

RE-COVER II, Dabigatran 150 mg b.i.d. vs warfarin INR 2–3;
duration 6 months 2568 Recurrent symptomatic VTE and related deaths:
. Dabigatran non-inferior (2.3 vs 2.2;
p < 0.001) Major bleeding:
. No difference (1.2 vs 1.7%; HR: 0.69;
95% CI: 0.36–1.32) [13]

2014

AF: Atrial fibrillation; b.i.d.: twice a day; HR: Hazard ratio; INR: International normalized ratio; NA: Non-applicable; q.d.: Once a day; sc.: Subcutaneous; VTE: Venous thromboembolism.

Patients with mechanical heart valves
The RE-ALIGN trial is the only clinical trial to date that has tested the safety and efficacy of NOACs in patients with pros- thetic heart valves. In this randomized, Phase II, open-label trial, patients who had undergone aortic or mitral valve replacement were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin [34]. The study was terminated prematurely because of an excess of thromboembolic and bleeding events in the dabigatran group. Stroke occurred in 5% in the dabigatran group and in no patients in the warfarin group, while major bleeding occurred in 4 and 2%, respec- tively. Warnings about the use of dabigatran in this patient population were subsequently issued by the FDA and EMA. The investigators attributed these findings to inadequate plasma levels of the drug and the relative inability of dabiga- tran to suppress activation of coagulation triggered by exposure of blood to the artificial surface of the valve prosthesis.
Adverse effects & interactions
As with any anticoagulant, bleeding is the major hazard of dabigatran and hemorrhagic stroke the most fearsome compli- cation (discussed subsequently). Among the non-hemorrhagic adverse effects, the most consistent in the RE-LY trial was dys- pepsia, reported in 11.5% in the dabigatran group versus 5.8% in the warfarin group [20]. Dyspepsia symptoms are usually mild, transient and improve with concomitant food intake, H2-blockers or proton pump inhibitors [35,36]. Also, the RE-LY trial showed a non-significant numerical increase in myocardial infarction with dabigatran compared with warfarin [37]. This finding was corroborated by a meta-analysis, mainly driven by the patients from RE-LY (59% of the cohort and 74% of the events), which showed a significant 33% increase in myocardial infarction [38], and has been attributed to a protective effect of warfarin against coronary events [39]. As the use of dabigatran is still relatively recent, pharmacovigilance is important to detect eventual low-frequency reactions not identified in clini- cal trials.
Since dabigatran etexilate is a substrate for the P-gp efflux transporter, caution should be exercised with the concomitant use of P-gp inducers (carbamazepine, phenytoin, rifampicin, St John’s wort) or inhibitors (quinidine, verapamil, clarithro- mycin, dronedarone). CYP450 isoenzymes have no role in the metabolism of dabigatran and are neither induced nor inhib- ited by dabigatran, which precludes interactions with other drugs metabolized by CYP450 isoenzymes and is an advantage over warfarin and factor Xa inhibitors.
Risk of bleeding
Pooled data from randomized trials estimate the annual risk of major bleeding associated with warfarin at around 1–2% [40], but the rates may be higher (approximately 3–4%) in community-based studies which typically include older patients with more comorbidities and less strict dose management [41,42]. In the RE-LY trial, D110 compared with warfarin was associated with a lower risk of major bleeding (2.71 vs

3.36%; p = 0.003), intracranial bleeding (0.23 vs 0.30%;
p < 0.001) and life-threatening bleeding (1.22 vs 1.80%;
p < 0.001), with no difference in gastrointestinal bleeding (1.12 vs 1.02%; p = 0.43) [20]. On the other hand, D150 was associated with similar risks of major bleeding (3.11 vs 3.36%; p = 0.31), with less intracranial (0.30 vs 0.74%;
p < 0.001) and life-threatening bleeding (1.45 vs 1.80%;
p < 0.001) but more gastrointestinal bleeding (1.51 vs 1.02%; p < 0.001). The outcomes of intracranial bleeding were also better in the dabigatran group, with lower rates of fatal bleeds [43]. additionally, in the subgroup of patients requiring urgent surgery, dabigatran was associated with similar rates of periop- erative bleeding compared with warfarin [44]. Rates of major bleeding increase with age; thus, in patients aged <75 years, both doses of dabigatran compared with warfarin are associ- ated with reduced bleeding, but in patients aged ‡75 years,
the lower dose of dabigatran (D110) carries with a similar
risk of bleeding compared with warfarin and the higher dose (D150) is associated with a higher risk of bleeding compared with warfarin [45].
After its approval, the safety of dabigatran in the real world has been tested in three post-marketing cohort studies, which have reached different conclusions. Using data from three Dan- ish nationwide datasets including 4978 patients on dabigatran and 8936 patients on warfarin, Larsen et al. found similar rates of major bleeding between both groups (adjusted hazard ratio [HR]: 0.82 for dabigatran 110 mg b.i.d., CI: 0.59–1.12; adjusted HR: 0.77 for dabigatran 150 mg b.i.d., CI: 0.51–1.13) [46]. Gastrointestinal bleeding was lower with dabigatran 110 mg b.i.d. and similar with dabigatran 150 mg b.i.d., whereas intracranial bleeding was significantly lower with both dabigatran doses. The largest post-approval study to date was released in 2014 by the FDA and involved more than 134,000 Medicare beneficiaries with non-valvular AF [47]. In this cohort of elderly patients, dabigatran was associated with significantly reduced risks of ischemic stroke, intracranial bleed- ing and death compared to warfarin, at the expense of an increased risk of major gastrointestinal bleeding. More recently, a different conclusion was reached by Hernandez et al. using the same database [48]. This was a much smaller cohort (1302 dabigatran users), corresponding to a 5% random sam- ple of Medicare beneficiaries with newly diagnosed AF initiat- ing dabigatran or warfarin. The study period was also shorter (11 months, between October 2010 and October 2011), but the outcomes were adjusted by patient characteristics. After analysis, dabigatran was associated with a higher incidence of major bleeding (HR: 1.58; 95% CI: 1.36–1.83) and a higher risk of gastrointestinal bleeding (HR: 1.85; 95% CI: 1.64–2.07), but a lower risk of intracranial hemorrhage (HR: 0.32; 95% CI: 0.20–0.50). The bleeding risk was higher in African Americans and patients with chronic kidney disease. In all the three analyses, treatment with dabigatran showed a sig- nificantly lower risk of intracranial bleeding; however, the mixed results regarding major bleeding suggest the need for continuous surveillance.

Measurement of anticoagulation effect
For patients treated with VKA, laboratory monitoring is com- monly done by measuring the INR, which is derived from the ratio of the prothrombin time (PT) of the patient to that of a standardized control serum. The PT assay reflects the activity of three of the four vitamin K-dependent clotting factors affected by warfarin (II, VII and X), and is performed by add- ing calcium and thromboplastin, an activator of the extrinsic pathway, to citrated plasma and then measuring the time (in seconds) required for fibrin clot formation.
With dabigatran, given its predictable pharmacological effect and the lack of significant drug interactions, routine coagula- tion monitoring is not required for dose adjustment. However, the assessment of anticoagulant activity may be useful in certain clinical situations, as in the case of overdose, major bleeding or emergency surgery.
Plasma concentrations of dabigatran can be directly measured by liquid chromatography with tandem mass spectrometry, which is considered the gold standard method; however, this technique is only available in specialized centers [49]. Indirect measurements by functional coagulation assays, such as Hemo- clot Thrombin Inhibitors and ecarin clotting time, are the most used in the clinical setting [49]. Each of these assays reflects the direct activity of thrombin in the plasma and shows a linear rela- tionship with dabigatran concentrations [3,50]. The kit-based Hemoclot Thrombin Inhibitors is simple and easier to imple- ment in a general laboratory, but ecarin clotting time seems to be more sensitive [51]. The real problem is that (except for zero value and very high levels) we do not know what to do when intermediate concentrations of dabigatran are measured.
Among routine coagulation tests, the activated partial throm- boplastin time (aPTT) provides a raw estimation of dabigatran anticoagulant activity. Prolongation of the aPTT occurs with increasing dabigatran plasma concentration; however, aPTT may be normal even with dabigatran levels up to 60 ng/ml and the concentration–response curve flattens at higher concentra-
tions (‡200 ng/ml) [52,53]. The PT (and its derived measure, INR) is minimally affected by dabigatran at therapeutic doses and is not recommended for monitoring efficacy of the antico-
agulant effect [52].

Management of bleeding
In case of major bleeding associated with oral anticoagulants, the drug must be immediately discontinued and the efforts should be directed toward the rapid reversal of anticoagulation. As specific antidotes for dabigatran are not yet commercially available, the management of bleeding remains largely support- ive. The drug must be temporarily discontinued and general support measures should be adopted, including mechanical compression, surgical or endoscopic hemostasis, and replace- ment of fluids and blood products if needed [25]. Activated charcoal may reduce the absorption of dabigatran and is recom- mended in case of recent overdose (<2–3 h) [54]. In addition, dabigatran can be partially removed by hemodialysis, especially in patients with renal impairment [5].

The use of non-specific hemostatic agents, including 4-factor prothrombin complex concentrates (PCC) or factor eight inhibitor by-passing activity (FEIBA) (activated PCC; coagulation factors in activated form), should be considered in case of severe bleeding according to cur- rent guidelines [25], although the evidence for this recommendation is weak. Both 4- factor PCC and FEIBA have shown to reduce bleeding induced by dabigatran in animal models [55] and to reverse its anti- coagulant effect in vitro when added to blood samples of healthy volunteers [56].
However, the use of 4-factor PCC failed to correct the coagula- tion tests when administered in vivo to volunteers pre-treated with dabigatran [57]. Recombinant FVIIa has also shown to reduce the bleeding time and prolongation of aPTT associated with dabigatran in animal models [58] and its use has been reported to manage dabigatran-associated post-cardiac surgery bleeding [59], but no controlled studies are available. Antifibrino-

Perioperative management
Management of anticoagulation in patients undergoing elective surgery requires balancing the risk of surgical bleeding versus the risk of thromboembolism associated with the interruption of the drug. Periprocedural bridging with heparin, the traditional approach in patients receiving warfarin, is not required for dabi- gatran, given its rapid onset and offset of action. In patients

lytic medications such as tranexamic acid or aprotinin have proven ineffective in reducing bleeding time with other direct thrombin inhibitors and are not recommended in patients taking dabigatran [60].
Finally, two antidotes with potential benefits for dabigatran- induced bleeding are in different stages of development [61]. The first one, idarucizumab (Boehringer Ingelheim), is a humanized antibody fragment that binds to dabigatran with an affinity approximately 350-times greater than thrombin, pre- venting it from binding to thrombin and neutralizing its anti- coagulant effect [62,63]. Studies in rats demonstrated that dabigatran levels of approximately 200 ng/ml are neutralized within 1 min of the injection of an intravenous bolus of idaru- cizumab [62], and a Phase I study in humans showed that idaru- cizumab 2 and 4 g resulted in immediate reversal of dabigatran-induced anticoagulation assessed by thrombin time, diluted thrombin time (Hemoclot Thrombin Inhibitors), aPTT, ecarin clotting time and activated clotting time [63]. Reversal was complete and sustained in seven of nine subjects administered 2 g and in all subjects administered 4 g. A Phase III study, a Study of the Reversal Effects of Idarucizu- mab on Active Dabigatran (the RE-VERSE AD), is ongoing to determine the effect of idarucizumab in patients with dabigatran-induced bleeding or requiring emergency surgery. The second agent, ciraparantag or PER977 (Perosphere), is a small, synthetic, water-soluble, cationic molecule with a broad spectrum of reversal activity. Ciraparantag binds to unfractio- nated heparin, low-molecular-weight heparin, fondaparinux, dabigatran and to all the new factor Xa inhibitors through hydrogen bonding and charge–charge interactions [64]. In thromboelastographic assays (ex vivo) and in a rat-tail-transec- tion bleeding model, ciraparantag has demonstrated to completely reverse the effect of dabigatran [64], but studies in humans treated with dabigatran are not yet available.

with normal renal function, current recommendations suggest
stopping dabigatran 24 h before procedures with a standard risk of bleeding [3,65,66]. However, the time should be longer in patients with a ClCr <50 ml/min or in procedures with a high bleeding risk, including neurosurgery, cardiac surgery, abdomi- nal surgery or interventions requiring spinal anesthesia (TABLE 3). Timing of resumption of dabigatran after surgery also depends on the bleeding risk. In studies on VTE prophylaxis after ortho- pedic surgery, dabigatran was initiated at half a dose (110 mg) on the evening after surgery, which was followed by a dose of 220 mg once daily starting the next day, and it did not result in increased postoperative bleeding compared to enoxaparin [9,10]. In general, full anticoagulation with dabigatran could be restarted at 24 h after procedures with a low bleeding risk and after 48–72 h for procedures with a high bleeding risk [65].

Expert commentary
The incorporation of NOACs represents a major advancement in the management of thromboembolic disease. Dabigatran has important advantages over warfarin, including a predictable anticoagulant effect, rapid onset and offset of action, fixed oral dosage without the need of coagulation monitoring and limited interactions with other drugs. In addition, randomized trials and the bulk of post-marketing information suggest a favorable benefit-to-risk profile, with similar efficacy and less major and intracranial bleeding.
As demonstrated by the RE-LY trial, dabigatran is better than warfarin for prevention of stroke and systemic embolism in non-valvular AF and is associated with less intracranial hem- orrhage. Based on these data, current guidelines favor dabiga- tran over warfarin in most patients with AF who need oral anticoagulation [24,67,68].
Several Phase III studies also support the use of dabigatran for the prevention and treatment of VTE. Dabigatran is at least

as effective as enoxaparin for VTE prevention after hip or knee replacement, with similar safety profiles, and also compares well with warfarin for the acute and long-term therapy of acute VTE. Oral administration of dabigatran facilitates out-of-hospi- tal thromboprohylaxis.
Not all individuals are candidates for dabigatran and appro- priate patient selection is important. The drug is not recom- mended in patients with severe renal dysfunction (CrCl <15 ml/min) and it should be used with caution in those with a CrCl between 15 and 30 ml/min. Other groups in which dabigatran is contraindicated include patients with mechanical heart valves and pregnant or breastfeeding mothers. All the randomized trials have shown that dabigatran has a similar risk of clinically relevant bleeding as that of warfarin, with approximately 50% reduction of intracranial hemorrhage at the expense of a significant increase in gastrointestinal bleed- ing. In addition, the outcomes of bleeds seem to be better. As a specific antidote is not yet available, supportive measures remain the keystone of management in case of bleeding com- plications. In case of minor bleeding, temporary discontinua- tion or delay of the next dose, in addition to local compression, may be sufficient. For major bleeding, additional measures include fluid replacement and transfusional support (packed red cells, fresh frozen plasma or platelets), surgical or endoscopic hemostasis, and the use of non-specific hemostatic agents such as 4-factor PCC or recombinant factor VIIa. Hemodialysis is an option for drug removal, especially in patients with impaired renal function, and activated charcoal
can be considered in case of recent overdose (<2 h).
Dabigatran is more expensive than warfarin, but this has to be balanced with the costs of monitoring and increased compli- cations associated with warfarin therapy. Incremental cost–effec- tiveness of dabigatran versus warfarin has been demonstrated by several analyses and the benefit seems to be more pro- nounced in patients who have a poor INR control with warfarin [69–71].
There are no head-to-head trials to answer the question of how dabigatran compares to the other NOACs. Indirect com- parisons using warfarin as a common denominator have not shown profound differences in efficacy between dabigatran and apixaban or rivaroxaban [72]. However, dabigatran 150 mg b.i.d. was associated with a significant lower risk of stroke and sys- temic embolism compared with rivaroxaban, as well as less hem- orrhagic stroke. Regarding the safety endpoints, major bleeding was lower with dabigatran 110 mg b.i.d. and apixaban.

Five-year view
Current research efforts are focused on the use of dabigatran for new and non-traditional indications. As the BRUISE CONTROL trial previously changed the paradigm demon- strating that continued warfarin is better than heparin bridg- ing at the time of pacemaker or implantable cardioverter defibrillators implantation [73], the BRUISE CONTROL 2 will examine the safety of device surgery on uninterrupted

dabigatran in patients with AF and moderate-to-high risk of stroke [74]. While dabigatran at a dose of 75 mg b.i.d. was approved by the FDA in patients with severe renal impairment (CrCl 15–30 ml/min), this recommendation was based on pharmacokinetic modeling and simulation. A pro- spective Phase IV study (NCT01896297) is also ongoing to further assess dabigatran pharmacokinetics in this population of patients [75]. Another group with a particularly high bleed- ing risk is that of patients with AF who undergo PCI with stenting and, hence, are candidates for triple antithrombotic therapy. In this setting, the REDUAL-percutaneous coronary intervention (PCI) trial is intended to compare a dual antith- rombotic therapy regimen of dabigatran (150 and 110 mg b. i.d.) plus clopidogrel or ticagrelor with a triple antithrom- botic therapy combination of warfarin plus clopidogrel or ticagrelor plus aspirin [76]. Additional clinical trials are explor- ing the periprocedural anticoagulation with dabigatran in patients undergoing AF ablation (DAPPAR AF, ODIn-AF, NCT01976507) [77–79] and the use of dabigatran in pediatric patients with VTE (NCT01895777) [80]. Finally, despite the unfavorable outcomes shown by the RE-ALIGN for mechani- cal heart valves [34], the use of dabigatran in patients with bioprosthetic (mitral and/or aortic) valves requiring anticoa- gulation has not been answered and is currently being addressed by a prospective Phase II study (DAWA trial) [81].
An important aspect with NOACs and new drugs, in gen- eral, is the development of clinical registries to better assess and monitor their benefits and risks in a real-world setting. It is well known that real-world patients often differ from partici- pants of randomized trials, with lower rates of compliance and less strict monitoring. In this regard, worldwide initiatives like GLORIA-AF [82] and GARFIELD-AF [83] will provide valuable information on the safety and comparative effectiveness of dabigatran and other strategies for stroke prevention in AF.
The development of specific antidotes to reverse the effect of dabigatran in case of severe bleeding or emergency surgery is a field of active research today. The preliminary results with the humanized antibody fragment idarucizumab and the universal antidote ciraparantag are promising and data collection of RE-VERSE AD is expected to be completed by 2017. Thus, the advent of commercially available antidotes is probably a matter of time. Finally, the introduction of rapid assays to determine the intensity of anticoagulant effect will be helpful for better management of patients with bleeding or those requiring surgery and also for dose titration in patients with renal impairment.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

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