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Efficacy and safety of dabigatran in prevention of venous thromboembolism in patients undergoing major orthopedic surgeries: a review

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Abstract

p class="abstract">Thromboprophylaxis with anticoagulants can significantly reduce the risk of patients developing symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) and VTE related mortality post major orthopedic surgeries like total hip and knee replacement surgeries. Dabigatran, a directly acting oral anticoagulant (DOAC) and direct thrombin inhibitor, is an available option for VTE prophylaxis having comparable efficacy to low molecular weight heparins (LMWH), other DOACs and Warfarin, once daily dosing, and comparable safety and bleeding risk to both LMWH and Aspirin. Dabigatran is currently the only DOAC with an available and marketed reversing agent. A review of Dabigatran’s clinical efficacy and safety is presented here. Therefore, Dabigatran represents a balanced thromboprophylaxis option for VTE prevention in patients undergoing major orthopedic surgeries. </p
International Journal of Research in Orthopaedics | January-February 2019 | Vol 5 | Issue 1 Page 196
International Journal of Research in Orthopaedics
Narayanan V et al. Int J Res Orthop. 2019 Jan;5(1):196-200
http://www.ijoro.org
Review Article
Efficacy and safety of dabigatran in prevention of venous
thromboembolism in patients undergoing major
orthopedic surgeries: a review
Varsha Narayanan*, Amit Bhargava
INTRODUCTION
Orthopedic surgeries are high risk factors for developing
postoperative DVT and VTE.
In absence of thromboprophylaxis, confirmed DVT post
lower limb orthopedic surgery is 4060% with 10- 14%
progressing to symptomatic VTE, and around 5%
showing PE, all usually seen post discharge from
hospital.1 One third are proximal DVTs seen more with
hip surgeries with greater risk to embolize. The
cumulative risk of venous thromboembolism lasted for up
to three months (median 21-34 days) and one month
(median 12-20 days) after hip and knee surgery
respectively.2
Increased VTE risk post orthopedic surgeries can be due
to immobilization, prolonged bed rest leading to venous
stasis, surgical manipulations causing endothelial trauma
and hyper-coagulable state, with presence of medical
comorbidities increasing risk further.1,3
Contrary to perception, autopsy studies indicate similar
incidence of PE in Asian and Western countries.4 A
multicentric study for the evaluation of patients at risk for
venous thromboembolism in the acute hospital care
setting (ENDORSE- cross-sectional survey in Asian
countries: India, Thailand, Pakistan, and Bangladesh),
reported similar VTE risk in surgical patients ranging
from 44% to 62%, which was similar to the proportion,
reported for all countries studied (overall: 64%; range:
44%80%).5
ABSTRACT
Thromboprophylaxis with anticoagulants can significantly reduce the risk of patients developing symptomatic deep
vein thrombosis (DVT), pulmonary embolism (PE) and VTE related mortality post major orthopedic surgeries like
total hip and knee replacement surgeries. Dabigatran, a directly acting oral anticoagulant (DOAC) and direct thrombin
inhibitor, is an available option for VTE prophylaxis having comparable efficacy to low molecular weight heparins
(LMWH), other DOACs and Warfarin, once daily dosing, and comparable safety and bleeding risk to both LMWH
and Aspirin. Dabigatran is currently the only DOAC with an available and marketed reversing agent. A review of
Dabigatran’s clinical efficacy and safety is presented here. Therefore, Dabigatran represents a balanced
thromboprophylaxis option for VTE prevention in patients undergoing major orthopedic surgeries.
Keywords:
Dabigatran, Thrombin, Direct oral anticoagulants, Total hip and knee replacement, THR, Anticoagulants,
Venous thromboembolism, Deep vein thrombosis, Pulmonary embolism
Lupin Medical Services and Research, BKC, Mumbai, Maharashtra, India
Received: 28 November 2018
Revised: 13 December 2018
Accepted: 14 December 2018
*Correspondence:
Dr. Varsha Narayanan,
E-mail: drvarsha@rediffmail.com
Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: http://dx.doi.org/10.18203/issn.2455-4510.IntJResOrthop20185147
Narayanan V et al. Int J Res Orthop. 2019 Jan;5(1):196-200
International Journal of Research in Orthopaedics | January-February 2019 | Vol 5 | Issue 1 Page 197
With routine VTE prophylaxis in orthopaedic patients,
fatal PE is uncommon, and the rates of symptomatic VTE
within three months can be reduced to as low as 1-2%.3
Pharmacoprophylaxis options for VTE prevention
recommended include low molecular weight heparins
(LMWH) LMWH, fondaparinux, direct (or newer/non-
vitamin K) oral anticoagulants (DOACs/NOACs -
dabigatran, apixaban, rivaroxaban), low dose
unfractionated heparin (LDUH), adjusted-dose vitamin K
antagonist (Warfarin), and aspirin (AAOS 20116 and
ACCP 2012).7
Aspirin is not recommended to be used alone or as the
only thromboprophylaxis agent in any patient group as
other agents (LMWH, DOACs and warfarin) are more
effective for prevention of VTE (ACCP 2008, SIGN
2010 updated 2015).8,9 LMWH are conventionally first
line anticoagulants in hospitalized patients, however
being injectable, they do not represent a compliant option
for patients once discharged from hospital. Warfarin has
a slow onset and offset and is known to be associated
especially in Asian populations with increased risk of
intracranial hemorrhage (ICH), requires meticulous INR
monitoring, and has associated high food-drug
interactions.4,10
ACCP recommends that in patients undergoing major
orthopaedic surgery who decline or are uncooperative
with injections or a mechanical device like IPCD, the
DOACs dabigatran or apixaban and if unavailable,
rivaroxaban or adjusted-dose VKA should be used rather
than alternative forms of prophylaxis.7
DOACs currently represent the most appropriate and
balanced option for VTE risk reduction in patients
discharged from hospital.
ORAL DIRECT THROMBIN INHIBITOR:
DABIGATRAN
Dabigatran is an oral direct thrombin inhibitor approved
for VTE prophylaxis in orthopedic surgeries. Thrombin
(IIa) is the key and central factor in the coagulation
pathway. Table 1 shows mechanism of action of
dabigatran as well as the dosing and treatment duration of
dabigatran. Dabigatran acts on both free as well as fibrin
bound thrombin as it has a different active binding site
from the exosites used by fibrin and antithrombin, while
LMWH act only on free thrombin.14
Table 1: Dabigatran action and dosing.
Dabigatran: mechanism of action11-13
Dose16
Duration
Inhibits the following actions of thrombin
Conversion of fibrinogen to fibrin
Activation of Factor XIII which cross links fibrin
Feedback activation of factor V, VII and XI
Binding to thrombomodulin to activate protein C
Activation of platelet aggregation
Fibroblast proliferation18
VTE prophylaxis for Orthopedic surgeries:
Once daily dose of 220 mg (2 capsules
of 110mg).
Initiation, if within 1-4 hours of surgery
is recommended with 1 capsule.
It can be taken irrespective of food and
the capsule is to be swallowed intact.
TKR:
10-14 days
THR:
28-35 days
Onset of Dabigatran action occurs in half to 1 hour with a
half-life of 12-14 hours. It does not show CYP dependent
metabolism and drug interactions so can be given even in
moderate hepatic impairment, however interacts with Pgp
inhibitors and due to majority renal clearance, should not
be given if creatinine clearance falls below 30ml/min
(<50 ml/min if concomitant Pgp inhibiting drugs are
being co-administered). Dabigatran is contraindicated in
patients with active pathological bleeding, mechanical or
prosthetic valves and history of hypersensitivity to
Dabigatran and does not have controlled studies in
pregnancy or lactation to recommend its use.15,16
CLINICAL EFFICACY AND SAFETY OF
DABIGATRAN
Three phase III studies compare Dabigatran to standard
dose of Enoxaparin 40mg SC OD to assess VTE rate and
bleeding risk in patients undergoing Hip and Knee
replacement surgery (Table 2). Patients were treated for
6-10 days post TKR and 28-35 days post THR with a 3
month follow up period in all 3 studies. The REMODEL
(TKR) and RENOVATE (THR) studies showed
comparable efficacy and safety in VTE prevention and
bleeding risk of Dabigatran doses to standard 40mg SC
Enoxaparin.17,18 In RENOVATE II, though the total VTE
incidence as well as bleeds (major and clinically relevant
non major - CRNM bleeds) were comparable to
Enoxaparin 40mg OD, the rate of proximal DVT, major
VTE and VTE related mortality was significantly lower
than Enoxaparin (2.1vs 3.9%; P=0.04 and 2.2 vs 4.2%;
P=0.03 respectively).19 This reduced risk of major VTE
and VTE-related mortality was also seen in the Indian
population sub-analyzed in RENOVATE II : 179 Indian
patients (91 Dabigatran; 88 Enoxaparin : 7.9% vs 9.9%).
This showed that in the normal clinical setting,
Dabigatran was an effective and well tolerated option to
LMWH in patients who had undergone THR and TKR
and may offer greater convenience in the outpatient post
discharged patients.20
Narayanan V et al. Int J Res Orthop. 2019 Jan;5(1):196-200
International Journal of Research in Orthopaedics | January-February 2019 | Vol 5 | Issue 1 Page 198
Table 2: Dabigatran vs Enoxaparin studies (data in%: *significant)
Study
Total VTE Symptomatic DVT Symptomatic PE Major VTE+ all cause
mortality
Major bleed CRNM bleed
Dabi
Enoxa
Dabi
Enoxa
Dabi
Enoxa
Dabi
Enoxa
Dabi
Enoxa
Dabi
Enoxa
REMODEL17
(2007)
N=2086 TKR
40.5 (150mg)
36.4 (220mg) 37.7 0.4 (150mg)
0.1 (220mg) 1.2
0.1 (150mg)
0 (220mg) 0.1 3.8 (150mg)
2.6 (220mg) 3.5
1.3 (150mg)
1.5 (220mg)
1.3
6.8 (150mg)
5.9 (220mg)
5.3
RENOVATE
I18
(2007)
N=3463 THR
8.6 (150mg)
6.0 (220mg) 6.7 0.8 (150mg)
0.5 (220mg) 0.1
0.1 (150mg)
0.4 (220mg)
0.3 4.3 (150mg)
3.1 (220mg) 3.9
1.3 (150mg)
2.0 (220mg)
1.6
4.7 (150mg)
4.2 (220mg)
3.5
RENOVATE
II19
(2011)
N=2055; THR
7.7 (220mg) 8.8 0 (220mg) 0.4
0.1 (220mg)
0.2 2.2*
(220mg)
4.2
1.4 (220mg)
0.9
2.3 (220mg)
2
Narayanan V et al. Int J Res Orthop. 2019 Jan;5(1):196-200
International Journal of Research in Orthopaedics | January-February 2019 | Vol 5 | Issue 1 Page 199
Dabigatran and Warfarin have been compared in two
studies (RECOVER and RECOVER II) to assess risk of
VTE recurrence and bleeding risk in patients being
treated for acute VTE.21 In both studies, Dabigatran was
found to have similar effects on VTE recurrence and a
lower risk of bleeding compared with warfarin in 2
studies (RECOVER I,II:.VTE Rate and deaths during 6
months of treatment : 2.4% vs 2.2% while major or
CRNM bleeding rate: 5.3% vs 8.5%; total bleeding rate:
16.1% vs 22.2% for Dabigatran vs Warfarin with more
than twice as many ICH cases in Warfarin group).21
Various metanalysis have also been published for
DOACs. Comparable efficacy is seen among DOACs in
treatment and prevention of recurrence of VTE however
Dabigatran was associated with a significantly lower risk
of ‘major or CRNM bleed’ compared with rivaroxaban
and edoxaban.22 and when compared with Enoxaparin,
the relative risk of clinically relevant bleeding was higher
with rivaroxaban (OR 1.25), and similar with Dabigatran
(OR 1.12).23
When comparing apixaban, aspirin, Dabigatran,
rivaroxaban, warfarin and placebo, the risk of the
composite efficacy outcome (VTE and VTE-related
death) seen on metanalysis was significantly lower with
the DOACs and warfarin INR 2.03.0 compared with
aspirin, with Dabigatran and apixaban being associated
with comparable rate of major and CRNM bleeds to
Aspirin and significantly lower than Warfarin, while
rivaroxaban having higher and comparable rate of major
and CRNM bleeds to Aspirin and Warfarin
respectively.24
The efficacy and safety of DOACs in the geriatric
population (10 RCTs included 25,031 elderly participants
>75 years) showed that DOACs did not cause excess
bleeding (9.3% vs 8.7%; OR = 1.07 for major/CRNM
bleeds of Dabigatran versus conventional therapy:
vitamin K antagonists, LMWH, aspirin, placebo) and
were associated with equal or greater efficacy than
conventional therapy.22 (Overall DOACs resulted in a
significantly lower risk of VTE or VTE-related death
than conventional therapy (3.7% vs 7.0%; OR 0.45) in
geriatric age group.
Dabigatran is the only DOAC to have a reversable agent
currently available in the market: Idarucizumab.
Idarucizumab in studies showed a median maximum
100% percentage reversal of Dabigatran (assessed by
diluted thrombin time/ecarin clotting time) with a median
time to the cessation of bleeding of 2.5 hours and a
median time to surgery of 1.6 hours with 93% normal
hemostasis.25
CONCLUSION
The DOACs or NOACs (Newer Oral Anticoagulants)
represent a more balanced, compliant, and effective
approach for VTE preventions in patients undergoing
lower limb orthopedic surgery especially for patients
discharged from hospital. Dabigatran in comparison to
Enoxaparin (LMWH) has shown comparable efficacy
with better risk reduction of proximal DVT, major VTE
and VTE related mortality with the added advantage of
oral dosing. Dabigatran efficacy is comparable to
Warfarin as well as the other NOACs, and significantly
better efficacy than Aspirin, in VTE prevention. Safety
and bleeding risk of Dabigatran is similar to both LMWH
and aspirin and lower than warfarin. Dabigatran has an
effective available reversible agent. Therefore,
Dabigatran can be a practical option for orthopedic
surgeons for VTE prevention in patients undergoing
lower limb orthopedic surgeries like TKR and THR.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: Not required
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Cite this article as: Narayanan V, Bhargava A.
Efficacy and safety of dabigatran in prevention of
venous thromboembolism in patients undergoing major
orthopedic surgeries: a review. Int J Res Orthop
2019;5:196-200.
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VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT. The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B). Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.
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Background Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. Methods We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. Results A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. Conclusions In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.)
Article
Objectives To evaluate the efficacy and safety of new oral anticoagulants (NOACs) in elderly adults. DesignMeta-analyses of randomized clinical trials (RCTs). SettingPubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 1, 2001, through March 30, 2013. ParticipantsElderly population (75) in RCTs comparing NOACs (rivaroxaban, apixaban, and dabigatran) with conventional therapy. MeasurementsTwo authors reviewed the trials, and odds ratios (ORs) were calculated using a random effects model. ResultsTen RCTs included 25,031 elderly participants. Risk of major or clinically relevant bleeding was not significantly different between NOACs and conventional therapy in elderly adults (OR=1.02, 95% confidence interval=0.73-1.43). Similar results were observed when comparing NOACs and pharmacologically active agents. In atrial fibrillation (AF) trials, NOACs were more effective than conventional therapy in prevention of stroke or systemic embolism in an elderly population with AF. In non-AF trials, NOACs also had a significantly lower risk of venous thromboembolism (VTE) or VTE-related death than conventional therapy in elderly adults. Analysis for individual NOACs showed that the NOAC was noninferior or more effective than conventional therapy for efficacy and safety outcomes. Conclusion In participants of clinical trials aged 75 and older, NOACs did not cause excess bleeding and were associated with equal or greater efficacy than conventional therapy.
Article
Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings. In a randomized, double-blind, double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64-1.80; absolute risk difference, 0.2%; 95% CI, -1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36-1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56-0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76-1.57), for major bleeding of 0.73 (95% CI, 0.48-1.11), and for any bleeding of 0.70 (95% CI, 0.61-0.79). Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE. www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330.