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REVIEW ARTICLE
Year : 2016  |  Volume : 7  |  Issue : 2  |  Page : 33-42

Comparison of benefit between dabigatran and warfarin among patients with atrial fibrillation: A systematic review


Department of Pharmaceutical Practice, College of Pharmacy, Princess Nora bint Abdul Rahman University, Riyadh 11671, Saudi Arabia

Date of Web Publication22-Apr-2016

Correspondence Address:
Amal K Sulieman
Department of Pharmaceutical Practice, College of Pharmacy, Princess Nora bint Abdul Rahman University, P.O. Box 84428, Riyadh 11671
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2045-080X.181039

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  Abstract 

Warfarin is recognized as the standard antithrombotic agent for stroke prevention. However, new oral anticoagulant such as dabigatran constitutes huge improvement to compensate for the limitation of warfarin. A literature review was performed to compare and contrast the overall benefit of dabigatran and warfarin among patients with atrial fibrillation. We utilized HighWire as the data source for randomized controlled trials based on inclusion and exclusion criteria (from January 2007 to September 2013). Descriptive and quantitative information related to stroke and major bleeding were extracted from each trial. After a comprehensive screening of 298 search results, 17 studies which enrolled a total of 127,594 patients were included. Warfarin was found to have higher mean event rates for incidence of stroke, major bleeding, and net clinical benefit compared to dabigatran 110 mg and dabigatran 150 mg. Dabigatran 110 mg has higher rate of stroke and net clinical benefit than dabigatran 150 mg with less major hemorrhage. Overall, dabigatran had higher efficacy and safety profile than warfarin. Further research is required to determine the clinical feasibility of dabigatran in real-life practice.

Keywords: Atrial fibrillation, dabigatran, prevention, stroke, warfarin


How to cite this article:
Sulieman AK. Comparison of benefit between dabigatran and warfarin among patients with atrial fibrillation: A systematic review. Arch Pharma Pract 2016;7:33-42

How to cite this URL:
Sulieman AK. Comparison of benefit between dabigatran and warfarin among patients with atrial fibrillation: A systematic review. Arch Pharma Pract [serial online] 2016 [cited 2019 Sep 15];7:33-42. Available from: http://www.archivepp.com/text.asp?2016/7/2/33/181039


  Introduction Top


Atrial fibrillation (AF) is the most common sustained cardiac arrhythmias, which affects about 2.0% of the general population.[1] It is characterized by an abnormal cardiac rhythm which is due to rapid or irregular electrical impulses in the upper chambers of the heart (atria).[2] As a result, blood cannot be effectively pumped into the lower chambers of the heart (ventricles) and this causes pooling of blood in the atrial appendages.[2] The incidence increases with age and is associated with the presence of structural heart disease.[3] AF is classified based on several defining characteristics such as electrocardiogram pattern, epicardial or endocavitary recordings, mapping of atrial electrical activity, or clinical features.[3] For effective diagnosis, clinicians should determine the frequency and duration of AF.[3] First detected AF can fall into either paroxysmal or persistent.[3] Recurrence and frequency of episodes are the main criteria to classify AF. If the episodes are two or more, then it is defined to be recurrent.[3] If the arrhythmia subsides automatically, it is classified as paroxysmal. However, those sustaining more than 7 days are defined as persistent AF.[3] Recovery of symptoms with pharmacological intervention or direct-current cardioversions does not change the classification.[3] Persistent AF usually leads to permanent AF where the cardioversion fails to treat the symptom.[3] One-third of patients with AF are asymptomatic.[1] The common symptoms include palpitations, dyspnea, fatigue, dizziness, and decreased exercise tolerance.[1] Early diagnosis of asymptomatic AF may lead to effective intervention and lower the risk of complications. The most serious complication of AF is stroke which is due to thromboembolism (TE). The incidence of stroke is more frequent among the elderly patients suffering from AF.[1] Clinically important TE has been reported by about 1–2% of patients within the 1st month after recovery from AF which lasts for more than 48 h.[1] Atrial thrombi can form after AF which in turns cause the disruption of blood flow.[1] Apart from stroke, AF may worsen heart failure and ischemic heart disease.[1] In addition, tachycardia and inefficiency of ventricular filling due to inactive atrial component are the two important symptomatic manifestations in many patients.[1] In some cases, patients can experience syncope. Treatment objectives in patients with AF include rate control, recovery of sinus rhythm, and prevention of TE.[3] These three strategies are not mutually exclusive.[3] Rate control strategy aims to correct the ventricular rate while rhythm control strategy involves the maintenance of normal sinus rhythm.[3] Antithrombotic therapy must be undertaken at all stages of AF to prevent TE and reduce the risk of stroke.[1]

Traditional antiplatelet agents such as aspirin and antithrombotic agents such as warfarin (Vitamin K antagonist, and VKA) are usually indicated for the management of stroke prevention.[3] Aspirin is recommended in low-risk patients as prophylaxis while warfarin is suitable for patients at high risks of stroke.[3] In 2007, Hart et al. published a meta-analysis interpreting the efficacy and safety of antithrombotic agents (including VKAs) in patients with nonvalvular AF.[4] The data were extracted from 29 randomized controlled trials (RCTs).[4] On assessing six trials which compared VKA with placebo, adjusted-dose warfarin was shown to reduce relative risk (RR) of stroke by 64% (95% CI 49–74) versus placebo or control (53 events in 2396 patient-years vs. 133 events in 2207 patient-years).[4] For ischemic stroke alone, adjusted-dose warfarin achieves an RR reduction of 67% (95% CI 54–77).[4] Adjusted-dose warfarin was also found to have 26% (95% CI 3–43) reduction in all-cause mortality when to compare with placebo or control (110 vs. 143 deaths).[4] Despite the documented efficacy of VKAs in stroke prevention, there is evidence of increased risk of bleeding associated with anticoagulation therapy, ranging from minor bruising to serious bleeding events requiring transfusion and to the worst case scenario of fatal intracranial hemorrhage [1],[5] Moreover, fluctuating dose–response relationship complicates the dosing regimen of warfarin.[5] Factors attributed to this phenomenon include genetic polymorphisms and environmental factors such as drug–drug and food–drug interactions.[5] Furthermore, warfarin has delayed onset and offset of action.[5] For high-risk individuals, warfarin has to be concurrently administered with intravenous heparin (”bridging therapy”) for at least 4 days before therapy is initiated.[5] Apart from that, significant drug–drug and drug–food interactions also limit the application of warfarin in clinical context.[5] This is particularly challenging because AF often involves elderly patients who have issues of concomitant administration of multiple medications.[5] The narrow therapeutic window of warfarin (international normalized ratio [INR] of prothrombin times ranging between 2 and 3 in patients with AF is recommended) further restricts its usage.[4]

Therefore, alternative anticoagulants should be sought to address for issues of warfarin.[4] They should reduce stroke risk comparatively with lower risk of hemorrhage, enable fixed dosing, generate more predictable dose–response curve, produce quick onset and offset of action, have lower drug interaction potential and less dietary restriction, and require no dose titration and intensive laboratory monitoring. In this case, direct thrombin inhibitors such as dabigatran and Factor Xa inhibitors such as apixaban are the two new classes of agents that may replace warfarin in clinical setting.

Objective

A literature review was conducted based on RCTs, which compare and contrast the overall benefit of dabigatran and warfarin among patients with AF. This was done by:

  • Examining the efficacy of both antithrombotic therapies
  • Evaluating the safety of use of both antithrombotic therapies
  • Interpreting the net clinical benefits of both antithrombotic therapies.



  Methodology Top


Data sources and search strategy

We conducted a systematic literature search on HighWire database which covered the sources from PubMed database for published articles dated from January 2007 to September 2013. The search strategy involved the use of the following search string: “warfarin” AND “atrial fibrillation” AND “dabigatran” AND “stroke prevention.” Moreover, we manually screened through the reference lists of the available full-text articles and performed forward-tracking of the relevant articles in search of additional studies that fit our review objectives.

Inclusion and exclusion criteria

First, the type of population, choice of intervention and comparison, and primary outcome of the literature were determined.[6] The population to be investigated was patients with AF. Trials comparing head-to-head warfarin and dabigatran were included in the study. Finally, outcomes of interest were stroke and major bleeding which were explained in detail in the endpoint definition.

Only randomized controlled trials in the form of full-text articles or summary abstracts were selected.[6] However, cohort studies with large sample size (n = 50,000) were also considered. Furthermore, human studies presented in English language and population with additional high-risk factors of stroke such as previous stroke or transient ischemic attack (TIA) were also criteria of study inclusion for the review.

Apart from that, studies were excluded if they were (1) observational studies or case reports; (2) trials with no comparator (i.e., warfarin alone); and (3) patients with other coexisting condition such as chronic kidney disease, abnormal liver function, and pregnancy.

The assessment of the literature was done based on the primary and secondary outcomes defined during the literature search.

Endpoint definition

Primary endpoints

  • Stroke, defined as a neurological deficiency, is characterized by an acute focal injury of the central nervous system (CNS) of a vascular origin which lasts for more than 24 h. It includes CNS infarction, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.[7] Likewise, TE is the umbrella term covering stroke, TIA, systemic or pulmonary embolism, and embolic complications to viscera and extremities [6]
  • Major bleeding which involves fatal or life-threatening retroperitoneal, intracranial, intraocular, or intraspinal bleeding; subdural hematomas, or bleeding requiring surgery or transfusion of 2 U or associated with a decrease in hemoglobin of 2.0 g/L.[8]


Secondary endpoints

  • Fatal or nonfatal adverse effects during treatment, excluding hemorrhage [6]
  • All-cause death during treatment or follow-up.[6]


Data interpretation

Due to the complexity associated with the traditional analysis of RR and 95% confidence interval, mean event rate was calculated for the effects of warfarin and dabigatran (110 mg and 150 mg) in terms of TE (i.e., stroke), major bleeding, and net clinical benefit [Table 1]. In this review, event rate was the major determinant of outcome measure. Based on the incidence of each event in the specified study sample, percentage event rate was calculated or adopted from the results. Mean event rate was calculated latter to ease the comparison between warfarin and dabigatran.
Table 1: Event rate of warfarin and dabigatran for stroke, major bleeding, and net clinical benefit

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Three out of 17 studies were excluded from the data interpretation due to the absence of data on dabigatran 110 mg (Ezekowitz et al., Lip et al.) and event rate (Eikelboom et al.).


  Results Top


Search results

The stepwise literature search process was illustrated in [Figure 1]. Initially, 298 entries were generated of which the title and abstract were screened as per the inclusion and exclusion criteria. From these, 235 were excluded because their content was out of the scope of the review. Full-text or abstract of the remaining 63 studies was further analyzed. Seventeen studies met the inclusion or exclusion criteria (15 full-text articles,[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[23] one conference abstracts,[24] and one letter to the editors).[22] [Table 2] summarizes the relevant information retrieved from the selected trials.
Figure 1: PRISMA flow diagram

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Table 2: Description of anticoagulation studies

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Efficacy and safety of dabigatran versus warfarin

The primary efficacy outcome was stroke [Table 3] while the primary safety outcome was major bleeding [Table 4]. Likewise, net clinical benefit which was the composite of non-CNS systemic embolism, pulmonary embolism, hemorrhagic stroke, subdural bleeding, major extracranial bleeding, myocardial infarction, and death [12] was also compared in five studies [Table 5]. Data interpretation of endpoints and net clinical benefit of dabigatran and warfarin were shown in [Table 1].
Table 3: Comparison of primary efficacy endpoint (stroke)

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Table 4: Comparison of primary safety endpoint (major bleeding)

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Table 5: Comparison of net clinical benefit between dabigatran and warfarin

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Stroke

Mean incidence rate for stroke was calculated from 13 studies.[9],[10],[11],[12],[13],[14],[15],[16],[18],[19],[21],[22],[24] Warfarin had the highest mean event rate (0.6) followed by dabigatran 110 mg (0.5) and 150 mg (0.4).

Major Bleeding

Among 14 studies,[9],[10],[11],[12],[13],[14],[15],[16],[18],[19],[21],[22],[24] warfarin caused the highest bleeding rate (mean event rate: 1.2) followed by dabigatran 150 mg (mean event rate: 1.1) and dabigatran 110 mg (mean event rate: 0.9).

Net clinical benefit

Among four studies,[11],[17],[21],[24] warfarin had the highest mean event rate (0.7) followed by dabigatran 110 mg (0.6). Dabigatran 150 mg had the least net clinical benefit (0.5).


  Discussion Top


Based on the mean event rate calculated in the result, warfarin had the highest risk of stroke occurrence compared to dabigatran 110 mg and 150 mg. The results were supported by trials from Connolly et al., Parekh et al., Diener et al., and Hart et al. This suggested the relative inferiority in terms of stroke prevention by warfarin. Subgroup analysis of different doses of dabigatran showed that dabigatran 110 mg is a less effective oral anticoagulant than that of 150 mg, in which the result was coherent with that of Connolly et al. (RR: 1.16; 95% CI: 1.00–1.34; P: 0.052). In terms of major bleeding, warfarin was also associated with the highest risk of significant hemorrhage which limits its applicability in clinical setting (Oldgren et al., Healey et al., and Zhu et al.). On one hand, comparison between both doses of dabigatran revealed the fact that lower dose has higher safety profile than higher dose based on the observation of less hemorrhage events (Yang et al., Hart et al.). Apart from the efficacy and safety parameters, data analysis in terms of net clinical benefit, which is a combination of non-CNS systemic embolism, pulmonary embolism, hemorrhagic stroke, subdural bleeding, major extracranial bleeding, myocardial infarction, and death, also proposed that warfarin has less favorable clinical outcome with high-risk benefit ratio (Eikelboom et al.). In general, the incidence of major bleeding was higher than thromboembolic events in all treatment groups, suggesting the high inherent adverse effect of both warfarin and dabigatran despite attaining therapeutic efficacy. However, we were unable to determine the significance of the result generated because we did not perform statistical analysis on the significance of each mean event rate. To summarize, warfarin is less beneficial than dabigatran based on our findings. Further exhaustive statistical interpretation is required to confirm on the significance of the findings.

Warfarin has been established as the primary antithrombotic agent in relation to the treatment protocol of AF in patient with pronounced risk of stroke or TE.[3] For instance, ACTIVE-W trial provided evidence that antiplatelet agent was inferior to warfarin, suggesting the potential benefit to give warfarin in patients with coagulation disorder.[25] In spite of excellent anticoagulation effect, warfarin was known to be leading into serious hemorrhage complications. To illustrate, there was significantly higher incidence of intracranial bleeding with warfarin (0.74%) compared with dabigatran (110 mg: 0.23%, 150 mg: 0.30%) in the RE-LY trial. This could be attributed to the different mechanism of action of both antithrombotic agents. Tissue factor (TF) is a transmembrane receptor for factor VIIa which has substantial concentration in the brain for additional hemostatic protection.[26],[27] The formation of TF-VIIa complexes as a result of interaction between activated coagulation factor VII and TF is the key initiator for cellular coagulation. Warfarin broadly inhibits carboxylation of coagulation factors II, VII, IX, and X, resulting in diminished production of factor VIIa and the subsequent suppression of TF VIIa-mediated thrombosis.[14] By comparison, dabigatran may preserve the hemostatic mechanisms in the brain by selectively inhibiting thrombin.[14] This leads to less risk of intracranial bleeding observed in the RE-LY trial. However, TF is also found in reasonably high concentration at the site of atherosclerotic plaque.[26],[27] This explains why warfarin appears to be more beneficial than dabigatran in reducing risk of myocardial infarction in the RE-LY trial.

However, warfarin is recognized to have a narrow therapeutic index with highly variable inter- and intra-individual anticoagulant response; therefore, it is necessary to regularly monitor INR and adjust the doses accordingly.[28] Certain factors such as potential drug–drug and drug–food interaction and genetic deficiency of certain enzymes involved in the metabolism of warfarin may lead to slow onset and offset of action. These further complicate the dosing regimen and limit the use of warfarin in clinical setting.[28] Therefore, a new oral anticoagulant with predictable pharmacokinetic and pharmacodynamics profile signifies huge improvement to the current anticoagulation therapy. Dabigatran, a potent direct thrombin inhibitor, is given as an orally available prodrug (dabigatran etexilate). Peak plasma concentration follows 0.5–2 h after administration, leading to rapid onset of action observed. This feature coupled with the simple twice daily dosing offers an ideal alternative for prevention of stroke. In the RE-LY trial, about one-third less risk of intracranial hemorrhage without change in efficacy against thromboembolic occurrence was found in dabigatran compared with warfarin. Overall, it is seen that the main benefits of dabigatran are the immediate onset of action and low risk of intracranial hemorrhage which is perhaps the prime concerns while using anticoagulants among AF patients. All these may advocate the superiority of dabigatran when compared with warfarin.

The main problem associated with dabigatran is the absence of antidote to reverse its antihemostatic effect.[16] This could bring a worse prognosis than warfarin in terms of major hemorrhage. Besides, patient may not be able to tolerate gastrointestinal symptoms presented as a common adverse effect of dabigatran. In the RE-LY trial, rate of discontinuation due to dyspepsia in dabigatran (110 mg: 11.8%; 150 mg: 11.3%) was almost double than that in warfarin (5.8%).[9] In addition, the incidence of gastrointestinal bleeding increased with the higher dabigatran dose with the exception of lower rate at other sites.[9] Generally, lower pH is favorable for the absorption of dabigatran. Hence, dabigatran capsules are formulated to contain dabigatran-coated pellets with a tartaric acid core.[9] This acidity may explain the common dyspeptic symptoms and gastrointestinal hemorrhage associated with dabigatran. In contrast, unabsorbed warfarin does not have bleeding concern because warfarin needs to be metabolized by hepatic enzymes to exert an anticoagulant effect.[19] Moreover, there was an increase of about 10% in mean serum creatinine in patient taking dabigatran in the trial conducted by Lip et al.[23] The inhibition of active renal tubular creatinine secretion via human organic cation transporter 2 protein may be contributing to the increased serum creatinine observed.[23] However, this is unlikely to be a real issue given its modest magnitude.[23] In terms of cost-effectiveness, high dose dabigatran (150 mg) was shown to be inferior (≤42,386 per quantity adjusted life years gained) compared with warfarin in patients whose INR is well managed or in centers that achieve good INR control.[13]

There are several strengths and limitations pertaining to this review. Strength of this review is the inclusion of RCT as the main types of study to generate the findings. Based on the topic, the effect of two interventions (exposure of warfarin and dabigatran) observed in a defined context (patients with AF) would be discussed. Therefore, RCT is preferred because it provides the strongest evidence for concluding net benefit of particular intervention. Next, large sample size of all trials in this review signifies high generalizability and reproducibility of the results. Then, consistent and similar adjudication of endpoints by medical experts was also emphasized in every trial. After that, homogeneity of data was observed in both endpoints.

Nonetheless, there are several important limitations which might compromise the quality of the review. First, most trials included were subgroup analysis of RE-LY trials. Inadequate independent trials in recent years had led to the decision to include subgroup analysis in our findings. Consequently, our analysis might be limited by the similarity in RCT data. Second, the comparison of treatment effects might be limited by the low event rates observed across the trials. This was resolved by implementation of mean event rate in the interpretation of data. Third, there was absence of complete statistical data, especially P value of the endpoints in some studies. This resulted in inadequacy of information to verify the significance of data exhibited, and subsequently, a sound conclusion on the comparison could not be drawn. Therefore, results from our review should be interpreted as hypothesis and should be confirmed with comprehensive statistical interpretation.


  Conclusion Top


Dabigatran (110 mg and 150 mg) was shown to have lower rate of thromboembolic complications and major bleeding than warfarin in patient with AF, suggesting the positive benefit profile of dabigatran in clinical setting. Hence, among patients where warfarin is not appropriate as the first choice, dabigatran can be an alternative. However, clinical significance of dabigatran is doubtful among population of low socioeconomic profile.

Alternatively, rate of hemorrhagic complication in warfarin could be reduced through professional counseling on drug–drug and drug–food interactions, precaution in taking the medication, and importance of adherence. There was also recommendation to compare warfarin and dabigatran in real world setting, especially at clinic operated by pharmacist focusing on warfarin as the mainstay of prevention of TE. In short, further prospective and RCTs are still required to confirm on the significance of these findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Wann LS, Lee R, Santangeli P, Natale A. Managing Atrial Fibrillation Insights Into Pathophysiology, Advances in Treatment. Available from: https://www.chestnet.org/~/media/chesnetorg/Publications/Documents/CHEST%20Physician/Vol%206%202011/0811Supplement.ashx. [Last cited on 2013 Aug 14].  Back to cited text no. 1
    
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Providência R, Albenque JP, Combes S, Bouzeman A, Casteigt B, Combes N, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: A systematic review and meta-analysis. Heart 2014;100:324-35.  Back to cited text no. 6
    
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Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:2064-89.  Back to cited text no. 7
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Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol 2007;100:1419-26.  Back to cited text no. 8
    
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Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.  Back to cited text no. 9
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Ezekowitz MD, Wallentin L, Connolly SJ, Parekh A, Chernick MR, Pogue J, et al. Dabigatran and warfarin in Vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation. Circulation 2010;122:2246-53.  Back to cited text no. 10
    
11.
Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: A subgroup analysis of the RE-LY trial. Lancet Neurol 2010;9:1157-63.  Back to cited text no. 11
    
12.
Hori M, Connolly SJ, Ezekowitz MD, Reilly PA, Yusuf S, Wallentin L; RE-LY Investigators. Efficacy and safety of dabigatran vs. warfarin in patients with atrial fibrillation – Sub-analysis in Japanese population in RE-LY trial. Circ J 2011;75:800-5.  Back to cited text no. 12
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Pink J, Lane S, Pirmohamed M, Hughes DA. Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: Quantitative benefit-harm and economic analyses. BMJ 2011;343:d6333.  Back to cited text no. 13
    
14.
Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: An analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011;123:2363-72.  Back to cited text no. 14
    
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Healey JS, Eikelboom J, Yang S, Themeles E, Connolly SJ, Yusuf S, et al. Response to letters regarding article, Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: Results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation 2013;127:e506.  Back to cited text no. 19
    
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Oldgren J, Ezekowitz MD, Alings M, Diener HC, Reilly PA, Yusuf S, et al. Dabigatran versus warfarin and impact of CHAD2-VASC score on outcome in atrial fibrillation patients: A RE-LY subgroup analysis. J Am Coll Cardiol 2011;14:E7.  Back to cited text no. 24
    
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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