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WJC https://www.wjgnet.com 710 December 26, 2021 Volume 13 Issue 12
World Journal of
Cardiology
W J C
Submit a Manuscript: https://www.f6publishing.com World J Cardiol 2021 December 26; 13(12): 710-719
DOI: 10.4330/wjc.v13.i12.710 ISSN 1949-8462 (online)
MINIREVIEWS
Dabigatran in cardiovascular disease management: A
comprehensive review
Ayesha Javed, Muhammad Ajmal, Aaron Wolfson
ORCID number: Ayesha Javed 0000-
0003-3726-2584; Muhammad Ajmal
0000-0002-2463-3035; Aaron Wolfson
0000-0002-9695-185X.
Author contributions: Ajmal M
came up with the idea; Javed A
and Ajmal M drafted the
manuscript; Wolfson A reviewed
and finalized it; Javed A, Ajmal M
and Wolfson A revised the
manuscript.
Conflict-of-interest statement: All
authors have no any conflicts of
interest.
Country/Territory of origin: United
States
Specialty type: Cardiac and
cardiovascular systems
Provenance and peer review:
Invited article; Externally peer
reviewed.
Peer-review report’s scientific
quality classification
Grade A (Excellent): 0
Grade B (Very good): 0
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
Open-Access: This article is an
open-access article that was
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
Ayesha Javed, Department of Internal Medicine, University of Arizona, Tucson, AZ 85719,
United States
Muhammad Ajmal, Department of Cardiology, University of Arizona, Tucson, AZ 85719,
United States
Aaron Wolfson, Department of Cardiology, University of Southern California, Los Angeles, CA
90007, United States
Corresponding author: Muhammad Ajmal, MD, Academic Fellow, Department of Cardiology,
University of Arizona, 1625 N Campbell Ave, Tucson, AZ 85704, United States.
drajmal207@gmail.com
Abstract
Dabigatran, a direct thrombin inhibitor, has robust data for the treatment of deep
venous thrombosis and pulmonary embolism, stroke prevention in non-valvular
atrial fibrillation, and the prophylaxis of venous thromboembolism (VTE) after
knee and hip replacement. Recent studies have evaluated dabigatran to determine
its safety and efficacy in such conditions as VTE in malignancy, coronary artery
disease, mechanical and bioprosthetic valves, and antiphospholipid syndrome.
This article provides a comprehensive review on the role of dabigatran in various
cardiovascular diseases.
Key Words: Dabigatran; Anticoagulation; Thrombus; Bleeding; Atrial fibrillation; Deep
venous thrombosis; Stroke
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Core Tip: Direct oral anticoagulants (DOACs) have plethora of data for the use in
medical field and particulalry in cardiovascular medicine. This review is focused on the
dabigatran which is one of the DOAC and it is prudent for all the physicians to be
familiar with this drug.
Citation: Javed A, Ajmal M, Wolfson A. Dabigatran in cardiovascular disease management: A
comprehensive review. World J Cardiol 2021; 13(12): 710-719
Javed A et al. Dabigatran review
WJC https://www.wjgnet.com 711 December 26, 2021 Volume 13 Issue 12
accordance with the Creative
Commons Attribution
NonCommercial (CC BY-NC 4.0)
license, which permits others to
distribute, remix, adapt, build
upon this work non-commercially,
and license their derivative works
on different terms, provided the
original work is properly cited and
the use is non-commercial. See: htt
ps://creativecommons.org/Licens
es/by-nc/4.0/
Received: April 6, 2021
Peer-review started: April 6, 2021
First decision: September 2, 2021
Revised: September 27, 2021
Accepted: November 25, 2021
Article in press: November 25, 2021
Published online: December 26,
2021
P-Reviewer: Emran TB
S-Editor: Ma YJ
L-Editor: A
P-Editor: Ma YJ
URL: https://www.wjgnet.com/1949-8462/full/v13/i12/710.htm
DOI: https://dx.doi.org/10.4330/wjc.v13.i12.710
INTRODUCTION
Warfarin, a vitamin K antagonist (VKA) and systemic anticoagulant, has been used for
decades in clinical practice for a variety of clinical indications including nonvalvular
atrial fibrillation, deep venous thrombosis (DVT) and pulmonary embolism (PE).
Given warfarin’s indirect mechanism of action, maintaining a goal international
normalized ratio (INR) is a constant challenge. Patients often experience periods of
over- and under-treatment and may therefore be exposed to increased risk for adverse
outcomes. The two classes of direct-acting oral anticoagulants (DOACs) include direct
thrombin inhibitors (DTI) and factor Xa inhibitors and both have emerged as attractive
alternatives to warfarin[1,2]. Dabigitran, a DTI, and three factor Xa inhibitors including
apixaban, edoxaban, and rivaroxaban are currently approved by the Food and Drug
Administration (FDA) for ischemic stroke prevention in non-valvular atrial fibrillation
(AF), treatment of venous thromboembolism (VTE) and the prevention of VTE after
hip and knee arthroplasty[3]. Dabigatran etexilate is a small molecule prodrug that is
rapidly converted by serum esterase to dabigatran, a competitive and reversible direct
inhibitor of thrombin. Dabigatran is predominantly (80%) excreted through the
kidneys and does not require INR[4]. The purpose of this review is to provide a
comprehensive review of the current and potential indications for dabigatran use.
ANTICOAGULATION IN NONVALVULAR ATRIAL FIBRILLATION
Atrial fibrillation is a prothrombotic condition that may lead to thrombus formation in
the left atrial appendage and with subsequent systemic embolization causing a
cerebrovascular accident (CVA) or stroke[2,5]. The efficacy of dabigatran in non-
valvular atrial fibrillation was studied in the Randomized Evaluation of Long-Term
Anticoagulant Therapy (RE-LY) multicenter randomized controlled trial. In this study,
patients were randomized to dabigatran 110 or 150 mg twice daily (BID) vs dose-
adjusted warfarin. Compared to warfarin, dabigatran dosed at 150 mg twice daily was
found to reduce the risk of systemic embolism and similar rates of major hemorrhage.
Dabigatran was the first DOAC that received FDA approval in 2010 and by the
European Medicines Agency (EMA) in 2011 for treatment of non-valvular atrial fibril-
lation. The recommended doses are 150 mg BID for patient with eGFR > 30 mL/min
and 75 mg BID (not tested in the Re-LY trial) for patients with an eGFR of 15-29
mL/min[6]. In a meta-analysis, dabigatran was found to be associated with a lower
risk of ischemic stroke, major bleeding, mortality, a similar risk of myocardial
infarction, and a greater risk of gastrointestinal bleeding when compared to warfarin
[7].
According to the 2019 American Heart Association (AHA)/American College of
Cardiology (ACC)/Heart Rhythm Society (HRS) Focused Update of the 2014
guidelines for the management of atrial fibrillation, dabigatran has a class 1
recommendation (level of evidence A) for the treatment of non-valvular atrial fibril-
lation and, similar to other DOACs, is recommended over warfarin. Dabigatran is
associated with a lower risk of serious bleeding and has been proven to be either non-
inferior or superior to warfarin in preventing stroke and systemic embolism[8].
TREATMENT OF DEEP VEIN THROMBOSIS AND PULMONARY EMBO-
LISM
Venous thromboembolism (VTE) includes the clinical entities of deep venous
thrombosis (DVT) and pulmonary embolism (PE) and is a major cause of morbidity
and mortality. The role of dabigatran in the treatment of acute VTE was evaluated in
the randomized, double-blind Phase III clinical trials of RE-COVER and RE-COVER II.
These trials included patients with DVT and PE who were initially treated with a
parenteral anticoagulant therapy for 5-10 d. Dabigatran at a dose of 150 mg twice daily
was compared to dose-adjusted warfarin with an INR target of 2-3 for a 6-mo period.
In both trials, dabigatran was found to be non-inferior to warfarin in reducing
Javed A et al. Dabigatran review
WJC https://www.wjgnet.com 712 December 26, 2021 Volume 13 Issue 12
recurrent VTE. In both trials, dabigatran and warfarin had similar bleeding rates and
other adverse effects, while patients on dabigatran were more likely to have dyspepsia
as compared to warfarin in the RE-COVER trial, presumably due to the tartaric acid
component.
The extended treatment of VTE was studied in the RE-MEDY and RE-SONATE
trials. The RE-SONATE trial included patients that had been previously treated for an
acute DVT or PE with anticoagulant therapy for 6-18 mo. This trial found that
dabigatran use had a significant reduction in symptomatic VTE and related deaths.
While the RE-MEDY trial included patients, who had been previously treated for an
acute DVT and PE with anticoagulant therapy for 3 to 12-mo, dabigatran 150 mg twice
daily demonstrated noninferiority to dose-adjusted warfarin. An increased risk of
acute coronary syndrome was observed in the RE-MEDY trial although there was no
difference observed in the RE-SONATE trial[9]. In 2014, the FDA approved dabigatran
150 mg twice daily for the treatment of DVT and PE in patients with an eGFR > 30
mL/min while its use is not recommended for patients with a GFR < 30 mL/min.
The American College of Chest Physicians 2016 guidelines recommend dabigatran,
along with other DOACs, over warfarin for the treatment of acute VTE in patients
without cancer (Grade 2B) and recommend 3 mo of treatment for the management of
DVT and PE (Grade 1B)[10]. The American Society of Hematology 2020 guidelines for
VTE recommend DOACs over VKAs (conditional recommendation based on a
moderate certainty in evidence) and this recommendation does not apply to a patient
with low creatinine clearance, moderate to severe liver disease, or antiphospholipid
syndrome. This panel does not suggest one DOAC over another (conditional
recommendation based on low certainty in evidence)[11].
POSTOPERATIVE VTE PROPHYLAXIS AFTER HIP AND KNEE SURGERY
VTE is the third most common cause of cardiovascular death after myocardial
infarction and stroke and has high morbidity and mortality. Major orthopedic
surgeries such as total hip and knee arthroplasty are responsible for 50% of
thromboembolic events in the absence of VTE prophylaxis[12]. Oral dabigatran (220
mg or 150 mg once daily) was compared to subcutaneous enoxaparin for the primary
prevention of VTE in patients undergoing elective total hip or knee arthroplasty in
four randomized, double-blind, non-inferiority trials[13].
Prevention of postoperative thromboembolism after knee replacement
RE-MODEL was a randomized, double-blinded trial conducted in Europe and
included patients undergoing total knee replacement. In this trial, the patients were
assigned to oral dabigatran 150 mg or 220 mg once daily and were compared to
enoxaparin 40 mg subcutaneously once daily. Enoxaparin was given the evening
before surgery while dabigatran was administered 1–4 h after completion of surgery.
Treatment was continued for a total of 6–10 d and patients were assessed for 3 mo after
surgery. The primary outcome (total VTE and mortality during treatment) and safety
outcome (bleeding events) showed no difference between the two therapies.
Dabigatran (150 mg or 220 mg) was as effective as enoxaparin and had a similar safety
profile for the prevention of VTE after total knee replacement surgery[14].
RE-MOBLIZE was a double-blind, randomized trial conducted in the United States
and Canada and used enoxaparin 30 mg twice daily as compared to the 40 mg daily
dose used in the RE-MODEL trial. Patients with unilateral total knee arthroplasty were
randomized to receive dabigatran 220 or 150 mg once daily starting 6 to 12 h after the
surgery, or enoxaparin 30 mg subcutaneously twice daily starting the morning after
surgery. The treatment was continued for 12-15 d. Dabigatran showed inferior efficacy
to enoxaparin 30 mg twice daily while major bleeding rates were found to be similar
[15].
Prevention of postoperative thromboembolism after hip surgery
The RE-NOVATE randomized phase III, double-blinded trial was conducted in
Europe. This trial compared dabigatran 150 mg and 220 mg once daily to enoxaparin
40 mg subcutaneously once daily for the prevention of VTE in patients undergoing
total hip replacement. The treatment duration was 28-35 d. Both dabigatran doses
were found to be non-inferior to enoxaparin and the incidence of major bleeding was
not significantly different[16]. The RE-NOVATE II randomized phase III, double-
blinded trial was the follow-up study to further evaluate the efficacy and safety of the
dabigatran 220 mg dose in a more diverse population. This trial compared dabigatran
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220 mg to enoxaparin 40 mg once daily in patients undergoing total hip arthroplasty.
Patients were randomized to 28–35 d of treatment of dabigatran 220 once daily or
enoxaparin 40 mg subcutaneously. Subcutaneous enoxaparin was given the evening
before surgery while dabigatran 110 mg was given 1–4 h after completion of surgery
followed by a full dose of dabigatran 220 mg the morning after surgery. Dabigatran
was as effective as enoxaparin for preventing VTE and superior to enoxaparin for
reducing the risk of major VTE and major bleeding risk while adverse effects were the
same for both groups[17].
In 2015, the FDA approved dabigatran 110 mg on the day of surgery followed by
220 mg the next day for prophylaxis of DVT and PE in patients undergoing hip
replacement surgery. The recommended duration of prophylaxis is a minimum of 10-
14 d and can be extended up to 35 d. The same dose is being used off-label for the
prophylaxis of VTE after knee replacement[18]. The American College of Chest
Physicians’ guidelines recommend using antithrombotic prophylaxis over no
prophylaxis in patients undergoing total hip and knee arthroplasty and suggest
extending thromboprophylaxis for up to 35 d (Grade 1B recommendation)[19]. The
American Society of Hematology 2019 guidelines also recommends using pharmaco-
logical prophylaxis for patients undergoing hip fracture repair (conditional
recommendation based on very low certainty in evidence) and recommend using
aspirin or a systemic anticoagulant, preferably DOACs, for prophylaxis in patients
undergoing total hip or knee arthroplasty (conditional recommendation based on low
certainty in evidence)[20].
ROLE IN CORONARY ARTERY DISEASE
The randomized controlled RE-DUAL and RE-DEEM trials assessed the efficacy and
safety of DOACs in patients with coronary artery disease (CAD) including acute
coronary syndrome (ACS) and stable CAD in patients with atrial fibrillation. RE-
DUAL was a noninferiority trial that showed dual-pathway therapy with dabigatran
150 mg or 110 mg twice daily plus clopidogrel or ticagrelor reduced the risk of the
primary bleeding outcome compared to triple therapy in patients with atrial fibril-
lation undergoing PCI. This dual-pathway regimen also demonstrated noninferiority
for the secondary efficacy outcome (thromboembolic events, death), although there
was an increase in MI and stent thrombosis in dual pathway therapy when compared
to triple therapy[21]. The RE-DEEM phase II trial investigated the safety and efficacy
of dabigatran in ACS. Patients with STEMI and NSTEMI were randomly assigned to
dabigatran 50 mg twice daily, 75 mg twice daily, 110 mg twice daily, 150 mg twice
daily or placebo. Patients already on DAPT were continued on this regimen until the
end of the study. Dabigatran was found to have no association with ischemic benefit
and showed a dose-dependent increase in the rate of the primary safety outcome
(bleeding rate) when compared to placebo. A Phase III investigation was not
conducted following the RE-DEEM trial[22].
ROLE IN TREATMENT OF VTE WITH CANCER
Patients with cancer are at four-to-seven fold higher risk of developing VTE than those
without cancer. Therefore, VTE is an important cause of morbidity and mortality in
patients with cancer. The role of dabigatran in the treatment of acute VTE was
evaluated in the RE-COVER and RE-COVER II trials as reported above. Data from
these two randomized trials were pooled to determine the primary efficacy (recurrent
VTE and related death) and safety (major and non-major bleeding) outcomes of
dabigatran in active cancer patients who were diagnosed with cancer in the previous 5
years. No significant difference in efficacy between dabigatran and warfarin was
found. Although major bleeding and non-major bleeding events were more frequent in
patients with cancer than without cancer, there were no differences in the safety
outcomes between dabigatran and warfarin[23].
Javed A et al. Dabigatran review
WJC https://www.wjgnet.com 714 December 26, 2021 Volume 13 Issue 12
DABIGATRAN USE IN MECHANICAL AND/OR BIOPROSTHETIC VALVE
REPLACEMENT
In the Dabigatran phase III clinical trials for atrial fibrillation, patients with mechanical
heart valves were excluded. The RE-ALIGN study randomized patients with recent
mechanical aortic or mitral valve replacement in a 2:1 ratio to receive dabigatran or
warfarin. The patients received dabigatran doses of 150 mg, 220 mg or 300 mg twice
daily based on creatinine clearance. The study was discontinued early due to more
bleeding and thromboembolic events in the dabigatran-treated group. The DAWA
study was initiated to evaluate the efficacy and safety of dabigatran in patients with
bioprosthetic mitral and/or aortic valve replacement but the study was terminated
early due to limited enrollment[24,25].
ROLE IN TREATMENT OF LEFT VENTRICULAR THROMBUS
Although DOACs have been used off-label for the treatment of left ventricular
thrombus, there are currently no randomized controlled trials evaluating the safety
and efficacy for this indication. There is conflicting evidence based on various observa-
tional studies and a recent systematic review recommended against DOACs for the
treatment of left ventricular thrombi[26].On the other hand, a single centered,
retrospective, small observational study carried out at tertiary care center found that
dabigatran use in patients with left ventricular thrombus is both safe and effective[27].
Additional studies are needed the clarify the role of dabigatran in the treatment of left
ventricular thrombus.
USE AFTER LEFT ATRIAL APPENDAGE OCCLUSION
Left Atrial Appendage Occlusion (LAAO) is an established alternative to oral antico-
agulation in patients with atrial fibrillation and a contraindication to oral anticoagu-
lation to prevent the risk of stroke. LAAO device placement is associated with
increased postoperative stroke risk and requires anticoagulation after device
implantation[28]. There is no randomized clinical trial to compare the safety and
efficacy of anticoagulants after LAA occlusion. Although warfarin was used after
LAAO in landmark trials DOACs have been used in the real-world setting[29].
ANTIPHOSPHOLIPID SYNDROME
Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia leading
to arterial, venous, and microvascular thrombosis. Post hoc analyses compared
dabigatran with warfarin in patients with APS for the treatment and prevention of
VTE and found no significant difference in symptomatic VTE or VTE-related deaths
between groups. The dabigatran group showed fewer bleeding events, but differences
did not reach statistical significance. The EMA recommends against the use of DOACs
in patients with APS, especially those with triple positive (lupus anticoagulant,
anticardiolipin, and anti-β2-glycoprotein antibodies) disease[30].
CONSIDERATION IN KIDNEY DISEASE
A meta-analysis published by some researchers evaluated the safety and efficacy of
dabigatran, apixaban and rivaroxaban in patients with renal insufficiency. DOAC use
was compared to warfarin in patients with mild (defined as eGFR 50–79 mL/min) and
moderate (defined as eGFR of 30–49 mL/min) renal impairment and found that
DOAC use reduced the risk of stroke, systemic embolism and major and non-major
bleeding[31]. Dabigatran 150 mg twice daily was approved by the FDA for atrial fibril-
lation for patients with eGFR > 30 mL/min and 75 mg twice daily for patients with
eGFR 15-29 mL/min[6]. Based on real-world data, the use of DOACs is strongly
discouraged in patients with end-stage renal disease (ESRD)[31]. After RE-COVER,
RE-COVER II, RE-MEDY, and RE-SONATE trials, the FDA approved dabigatran 150
mg BID (after 5-10 d of parenteral anticoagulation) for the treatment of DVT and PE in
Javed A et al. Dabigatran review
WJC https://www.wjgnet.com 715 December 26, 2021 Volume 13 Issue 12
patients with eGFR > 30 mL/min and recommends against the use in patients with
eGFR < 30 mL/min[9]. In 2015, based on the RE-SONATE and RESONATE II trials,
the FDA approved dabigatran 220 mg once daily for VTE prophylaxis in patients
undergoing hip arthroplasty. This dose is used off-label in patients with knee arthro-
plasty; dabigatran is contraindicated for VTE prophylaxis in patients with eGFR < 30
mL/min[32]. The doses of dabigatran for various indications are shown in Table 1.
CONSIDERATION IN LIVER DISEASE
As all approved DOACs undergo some degree of hepatic metabolism, liver
dysfunction may increase the risk of bleeding. Patients with liver disease have been
excluded from the trials of DOACs, therefore, unlike guidelines for DOAC use in renal
disease, no guidelines are available for patients with liver impairment. Dabigatran has
3%-7% bioavailability and a small fraction is metabolized in the liver while 80% is
excreted through the kidney. Based on pharmacokinetic and pharmacodynamics
studies, the FDA does not recommend dose adjustments for patients with mild or
moderate hepatic impairment. The EMA recommends against dabigatran use in
patients with elevated liver function tests (twice the upper limit of normal)[33].
CONSIDERATION IN OBESITY
The efficacy and safety of DOACs in the obese population have not been investigated
in any large randomized controlled trial. DOACs are as effective as warfarin in phase
III randomized trials of atrial fibrillation and VTE, however, patients weighing ≥ 100
kg were underrepresented and accounted for 20% of enrolled patients. The Scientific
and Standardization Subcommittee of the International Society on Thrombosis and
Hemostasis recommends against the use of DOACs in patients with a BMI > 40 kg/m2
or a weight >120 kg[3,34].
COST-EFFECTIVENESS ANALYSIS
There is no consensus on the most cost-effective DOAC agent and future head-to-head
clinical studies among DOACs are needed. One Canadian study demonstrated
dabigatran to be highly cost-effective among patients with atrial fibrillation for the
prevention of stroke and systemic embolism as compared to other alternatives[35].
Similarly, in the United Kingdom, Belgium, Denmark, and Taiwan studies have
demonstrated dabigatran to be cost-effective in patients with non-valvular atrial fibril-
lation for the prevention of stroke and systemic embolism[35-39]. Dabigatran was
found to be a cost-effective alternative compared to both warfarin and rivaroxaban for
the treatment of acute VTE in the United Kingdom[40]. In one study comparing
rivaroxaban and dabigatran with enoxaparin, dabigatran was found to be more cost-
effective than enoxaparin and less cost-effective than rivaroxaban for thrombopro-
phylaxis in patients undergoing total hip and knee replacements[41].
SAFETY
Dabigatran is associated with a high risk of gastrointestinal bleeding when used at
higher doses. Similarly, bleeding risk increases with in treatment with concomitant
aspirin use or in those with a history of bleeding[42]. According to the Beers criteria,
Dabigatran should be used with caution in patients age 75 and above given an
increased risk of gastrointestinal bleeding[43]. Due to the mechanism of absorption,
dabigatran use is not recommended in patients with a history of gastrointestinal or
bariatric surgery[44,45].
REVERSAL AGENT
Idarucizumab is a humanized monoclonal antibody fragment approved by the FDA
and EMA to reverse the anticoagulant effects of dabigatran. The recommended dose of
Javed A et al. Dabigatran review
WJC https://www.wjgnet.com 716 December 26, 2021 Volume 13 Issue 12
Table 1 Indications and dosage of dabigatran
Indication Renal function Doses
CrCl > 30 mL/min 150 mg BID
CrCl 15-30 mL/min 75 mg BID
Non-valvular atrial fibrillation
CrCl < 15 mL/min Avoid use
CrCl > 30 mL/min 150 mg BIDVenous thromboembolism treatment
CrCl < 30 mL/min Avoid use
CrCl > 30mL/min 110 mg one dose followed by 220 mg dailyVenous thromboembolism prophylaxis following hip/knee replacement surgery
CrCl < 30 mL/min Avoid use
BID: Twice daily.
idarucizumab is 5 g administered as two separate 2.5 g doses intravenously for rapid
reversal of uncontrolled bleeding in dabigatran-treated patients[46]. Glund et al[47]
conducted a randomized, controlled, phase I study in which patients received
idarucizumab 20 mg to 8 g as 1-hour intravenous infusion or 1, 2, or 4 g as 5 min
infusion and was found to be safe and well-tolerated in all administrated doses. In the
multicenter, prospective cohort study, the Reversal Effects of Idarucizumab on Active
Dabigatran (RE-VERSE AD) trial, Idarucizumab was found to reverse the antico-
agulant effect of dabigatran in 88% to 98% of the patients[48].
CONCLUSION
Dabigatran has strong data supported by randomized-controlled trials, observational
studies, systemic reviews, and meta-analysis for its role in stroke prevention in non-
valvular atrial fibrillation, treatment and prophylaxis of VTE, and treatment of VTE in
cancer patients. It has also been used off-label for the treatment of left ventricular
thrombus and post LAAO, but further randomized trials are needed to determine the
safety and efficacy of dabigatran in these indications. Current data do not support the
use of dabigatran in patients with mechanical or bioprosthetic valves and acute or
chronic CAD.
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