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ISSN: 2475-3211
Journal of Diabetic Complications & Medicine
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Safety and Efficacy of New Oral Anticoagulants in Patients with Atrial Fibrillation: A Literature Review

Shweta Bhatia*, Supneet Sandhu and Dharinder Tayal

Anovus Institute of Clinical Research, Chandigarh, India

Corresponding Author:
Dr. Shweta Bhatia
BAMS, M.Sc., Faculty and Executive Assistant
Anovus Institute of Clinical Research, Chandigarh, India
Tel: 8288014374
E-mail:
[email protected]

Received date: September 09, 2015; Accepted date: October 27, 2015; Published date: November 06, 2015

Citation: Bhatia S, Sandhu S, Tayal D (2015) Safety and Efficacy of New Oral Anticoagulants in Patients with Atrial Fibrillation: A Literature Review. J Diabetic Complications Med 1:101. doi: 10.4172/2475-3211.1000101

Copyright: © 2015 Bhatia S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Background: TraditionallyVitamin K antagonists (VKAs), such as warfarin, have been used to reduce the
risks of stroke and systemic embolism in patients with atrial fibrillation (AF). However, they are associated with increased risk of haemorrhage. Thus, there is a need for new oral anticoagulant agents that are effective, safe, and convenient to use. Recent, observational and randomized controlled clinical trials, have examined the long-term use and efficacy of new oral anticoagulants. However, their results pertaining to important secondary efficacy end points as well as safety outcomes were inconclusive.
Aim: We, therefore, performed a systematic review to examine the long-term efficacy and safety of the new oral anticoagulants namely; dabigatran, rivaroxaban and apixaban in patients with AF.
Methods: In total 286 abstracts have been screened and 21 articles have been selected and considered as relevant for this epidemiological review. The primary efficacy endpoint was the incidence of stroke or systemic embolism. The primary safety endpoint was the incidence of major bleeding.
Results: We observed that dabigatran and rivaroxaban are more efficacious than warfarin for the prevention of stroke, death and systemic embolism. Also, they decrease the risk for intracranial bleeding and appear to have a favorable safety profile, making them promising alternatives to warfarin.
Conclusions: Overall, our results support the use of the new oral anticoagulants as alternatives to warfarin for long-term anticoagulation therapy in patients with AF.

Keywords

Atrial fibrillation; Warfarin; New oral anticoagualnts; dabigatran; Rivaroxaban; Apixaban; Safety and efficacy

Introduction

Atrial Fibrillation (AF) is the most common sustained cardiac rhythm disturbance characterized by rapid and irregular beating with its increased prevalence in older age [1]. AF also increases the risks of stroke and systemic embolism. Although, traditionally used Vitamin K Antagonists (VKAs), such as warfarin, reduce the risks of stroke and systemic embolism, however, they are associated with increased risk of hemorrhage [1]. Moreover, VKAs are cumbersome to use, because of their multiple interactions with food and drugs and also because of its slow onset of action and the high inter- and intra-individual variability in reaching effective plasma concentrations [2]. In addition to this, because of the narrow therapeutic window of VKAs, frequent laboratory monitoring of antithrombotic activity in individual patients is required [2]. Apart from this, patients with underline medical condition such as renal insufficiency experience inadequate anticoagulation and are at increased risk for ischemic stroke and bleeding during VKAs therapy [3]. In addition to this, AF patients with congestive cardiac failure present increased variability in metabolism of VKAs [4]. Thus, there is a need for new oral anticoagulant agents that are effective, safe, and convenient to use.

New oral anticoagulants are categorized, on the basis of their targets, as direct thrombin or factor Xa inhibitors. Although, we were aware that the combination of catheter ablation techniques with magnetically targeted nanoparticles for ablation of autonomic ganglia involved in initiating and perpetuating AF can be envisioned. We restricted our review to the use of new oral anticoagulants as alternatives to warfarin. Direct thrombin inhibitors include AZD0837 and dabigatran, and direct factor Xa inhibitors include apixaban, betrixaban, edoxaban, LY-517717, rivaroxaban, and ym-150 [5]. New oral anticoagulants act by specifically and directly blocking the activity of thrombin (both free and clot-bound) [5]. The drug profile of new oral anticoagulants is that they have a short half-life of 12-17 h. Also, they have a predictable and consistent anti-coagulant effect, have a low potential for drug -drug interactions and have no drug - food interactions. In addition to this, they do not require routine coagulation monitoring [6].

Recent, observational and randomized controlled clinical trials, have examined the long-term use and efficacy of new oral anticoagulants [7]. Although, these trials established the much ease and primary efficacy of new oral anticoagulants with respect to the primary end point of combined stroke and systemic embolism [7]. Also, their effect in stroke prevention was consistent irrespective of patient baseline characteristics, suggesting that the efficacy results can be applied widely [6]. However, their results pertaining to important secondary efficacy end points as well as safety outcomes were inconclusive or heterogenous [7].

We, therefore, performed a systematic review to examine the longterm efficacy and safety of the new oral anticoagulants in patients with atrial fibrillation (AF). The objective of writing this review was

• To perform a literature review to identify observational studies (or data base studies) for the association between dabigatran or rivaroxaban (new oral anticoagulant) with any of the following events (ischemic stroke, intracranial haemorrhage (ICH), GI bleeding, non-GI bleeding or acute myocardial infarction) in patients with atrial fibrillation.

• To perform a comparative analysis of the efficacy and safety of dabigatran and rivaroxaban in comparison to warfarin in patients with atrial fibrillation.

Study Design

We systematically searched the published medical research for Randomized control trials (RCTs) comparing new oral anticoagulants to warfarin in patients with AF. The Cochrane Library, Embase, MEDLINE, Science Citation Index Expanded, and ProQuest’s Dissertations and Theses databases were searched from inception through July 2011 without language restriction. The following were used as Medical Subject Heading terms and/or keywords: “new oral anticoagulants,” “oral thrombin inhibitors,” “oral factor Xa inhibitors,” “dabigatran,” “rivaroxaban,” “apixaban,” “edoxaban,” “betrixaban,” “ym-150,” and “LY-517717.” We did not restrict our search to studies conducted in patients with AF, to avoid excluding trials that reported subgroup data on patients with AF. The Embase and MEDLINE searches were limited to clinical trials, and the Embase search was further limited to studies performed in humans. The Science Citation Index Expanded and ProQuest searches were limited to full text reports. Clinical trial databases, relevant reviews, and the reference lists of retrieved reports were hand searched for potentially relevant studies not identified in our electronic database search.

The PRISMA statement for reporting systematic reviews and metaanalyses of RCTs5 was used for the method of this study.

Our electronic search identified a total of 3,167 reports (Figure 1). After removing duplicates, we screened titles and abstracts, and the full text of 44 publications was retrieved and evaluated for eligibility. Three trials that met our inclusion criteria were identified and included in the present study. One trial was published as an original report [8] with a follow-up report providing additional data [9]. The other 2 trials were presented as ClinicalTrials.gov entries and were subsequently published in peer-reviewed journals [10,11]. No additional studies were identified from Cochrane systematic reviews, manual searches of the reference lists of retrieved reports, relevant reviews, or clinical trial databases.

diabetic-complications-medicine-Electronic-search-identified

Figure 1: Electronic search identified reports.

The main efficacy outcome of interest was a composite end point of stroke (including hemorrhagic stroke) and systemic embolism. Other efficacy outcomes were ischemic and unidentified stroke, hemorrhagic stroke, all-cause mortality, vascular mortality, and myocardial infarction. The main safety outcome of interest was major bleeding; taking into consideration that the definition of major bleeding complication varied among the studies. Other safety outcomes were gastrointestinal bleeding and intracranial bleeding.

Studies were included if (1) they were (RCTs), (2) they randomized subjects to warfarin, or to non–vitamin K antagonist oral anticoagulants, (3) they were conducted in patients with AF, and (4) they were published in peer reviewed journals. Studies examining ximelagatran were excluded because it has since been removed from the market because of hepatotoxicity [12]. Conference abstracts and presentations were also excluded, because their results may not be final, and such publications undergo more limited peer review. Open-label and blinded studies were included, because warfarin’s need for monitoring makes blinding difficult. Finally, to assess the long-term efficacy and safety of these agents, only RCTs with follow-up durations of >1 year were included. In addition to this the exclusion criteria for our review was (1) presence of a severe heart-valve disorder, (2) stroke within 14 days or severe stroke within 6 months before screening; a condition that increased the risk of haemorrhage, (3) creatinine clearance of less than 30 ml per minute, active liver disease, and pregnancy.

We estimated pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) using Der Simonian and Laird random-effects models, which account for within- and between-study variability. The presence of between-study variability was assessed using the Qstatistic (with p 0.10 considered significant). All analyses were conducted using Stata version 11.0 (Stata Corp LP, CollegeStation, Texas).

Results

Dabigatran and warfarin were found to be significantly superior to warfarin with respect to a composite of stroke or systemic embolism, with no increased risk of major bleeding. In addition, dabigatran and warfarin significantly reduced the risk of death and haemorrhagic stroke, also a benefit signal was seen in reducing the risk of ischemic stroke and myocardial infarction. The below table shows that both Rivaroxaban and Dabigatran were associated with decreased risk of systemic embolism, stroke, haemorrhage and Ischemia (Table 1).

Events Dabigatran* Rivaroxaban* Warfarin* Dabigatranvs warfarin OR (95% CI) P Rivaroxabanvs warfarin OR (95% CI) P RivaroxabanvsDabigatran OR (95% CI) P
Systemic embolism 1.55 1.11 1.70 0.91 (0.75-1.12) <0.001 0.66 (0.53-0.82) <0.001 0.72 (0.58-0.90) 0.004
Stroke 1.45 1.01 1.58 0.92 (0.75-1.114) 0.44 0.64 (0.51-0.81) <0.001 0.70 (0.55-0.88) 0.002
Haemorrhage 0.12 0.10 0.38 0.31 (0.17-0.56) <0.001 0.26 (0.14-0.49) < 0.001 0.85 (0.39-1.83) 0.67
Ischemia 1.35 0.92 1.28 1.12 (0.89-1.41) 0.32 0.76 (0.59-0.98) 0.034 0.68 (0.53-0.87) 0.002

Table 1: Risk of systemic embolism, stroke, haemorrhage and Ischemia in Dabigatran vs. Rivaroxaban vs. Warfarin.

Impact on Myocardial infarction/Acute Coronary Syndrome (MI/ACS)

Of the all drugs, the risk for MI/ACS was lowest for rivaroxaban. The below table shows that the rate of Myocardial Infarction was lower with both dabigatran and rivaroxaban as compared to warfarin (Table 2).

Events Dabigatran* Rivaroxaban* Warfarin* Dabigatranvs warfarin OR (95% CI) P Rivaroxabanvs warfarin OR (95% CI) P RivaroxabanvsDabigatran OR (95% CI) P
Myocardial Infarction 0.73 0.74 0.94 1.15 (0.91-1.71) 0.071 1.18 (0.90-1.81) 0.052 1.02 (0.79-1.41) 0.81

Table 2: Risk of Myocardial Infarction in Dabigatran vs. Rivaroxaban vs. Warfarin.

Major bleeding complications

Overall, the risk of major bleeding complications was comparable between dabigatran and warfarin. Dabigatran was associated with a reduced risk for major bleeding complications. But there was still considerable heterogeneity among the studies. The below table (Table 3) shows that the rate of any major bleeding, Intracranial Bleeding was lower with Dabigatran and Rivaroxaban as compared to warfarin, whereas there was insignificant difference in the rate of Extracranial Bleeding and Major GI bleeding among the three drugs.

Events Dabigatran* Rivaroxaban* Warfarin* Dabigatranvs warfarin OR (95% CI) P Rivaroxabanvs warfarin OR (95% CI) P RivaroxabanvsDabigatran OR (95% CI) P
Any major bleeding 2.74 3.22 3.46 0.79 (0.68-0.92) 0.002 0.93 (0.81-1.07) 0.32 1.17 (1.01-1.36) 0.04
Intracranial Bleeding 0.21 0.30 0.72 0.29 (0.19-0.45) <0.001 0.41 (0.28-0.61) <0.001 1.42 (0.86-2.37) 0.17
Extracranial Bleeding 2.24 2.93 2.73 0.93 (0.79-1.09) 0.38 1.07 (0.92-1.25) 0.36 1.15 (0.99-1.35) 0.08
Major GI bleeding 1.13 1.54 1.03 1.10 (0.86-1.41) 0.43 1.50 (1.19-1.89) <0.001 1.36 (1.09-1.70) 0.007

Table 3: Risk of bleeding in Dabigatran vs. Rivaroxaban vs. Warfarin.

All-cause mortality

The use of dabigatran and rivaroxaban was associated with the reduction in all-cause mortality. The below table (Table 4) shows that the rate of Vascular death and all cause death was lower with Dabigatran and Rivaroxaban as compared to warfarin, however, this reduction in all-cause mortality was not statistically significant.

Events Dabigatran* Rivaroxaban* Warfarin* Dabigatranvs warfarin
OR (95% CI) P
Rivaroxabanvs warfarin
OR (95% CI) P
RivaroxabanvsDabigatran
OR (95% CI) P
 Vascular Death 1.93 2.17 2.29 0.84 (0.69-1.02) 0.87 0.95 (0.78-1.15) 0.37 1.02 (0.89-1.27) 0.71
All cause death 3.20 3.45 3.71 0.86 (0.74-1.00) 0.59 0.93 (0.79-1.08) 0.56 0.97 (0.81-2.04) 0.77

Table 4: Risk of death in Dabigatran vs. Rivaroxaban vs. Warfarin.

Main observations of our studies

The 3 included trials assessed the relative efficacy and safety of a new oral anticoagulant, apixaban, dabigatran, or rivaroxaban, compared to warfarin in patients with AF (Table 5). They were each designed to determine if the study drug was non-inferior to warfarin with respect to the composite end point of all stroke and systemic embolism.

  RE-LY ROCKET-AF ARISTOTLE
  Dabigatran 150mg BID vs. warfarin Rivaroxaban  20mg daily vs. warfarin Apixaban 5 mg BID   vs. warfarin
Study Design
Trial design RCT Open blinded assessment RCT DB DD RCT DB DD
Sample size (n) 18,000+ 14,000+ 18,000+
Inclusion criteria  AF and selected risk factor(s) for embolization AF and CHADS2 ≥2 AF or flutter and CHADS2 ≥1
Key exclusion criteria Valvular AF Use of ASA ≥100 mg/day CrCl<30 ml/min Valvular AF; Use of ASA >100 mg/day CrCl<30 ml/min Valvular AF Need for ASA >165 mg/day SCr>2.5mg/dL or CrCl<25ml/min
Follow-up (mean) 2 yr 1.9 yr 1.8 yr
Outcome Definitions
Primary Efficacy Composite of systemic embolism and stroke (ischemic or hemorrhagic)
Major Bleeding ISTH: fatal/critical organ bleed; decrease ≥2g/dLHbg or transfusion of ≥2U blood
Mortality All causes
Baseline Characteristics
Age (years) 71 (mean) 73 (median) 70 (median)
Female (%) 36.4% 39.7% 35.2 %
CHADS2(mean) 2.1 3.5 2.1
Previous embolic episode(%) 20% (stroke or TIA only) 55% (stroke,TIA, systemic embolism) 19% (stroke, TIA, systemic embolism)
TTR (%) (Standard 60-65%) 64% 55% 62%

Table 5: Comparative analysis of three major studies.

In ARISTOTLE, 18,201 patients with non-valvular AF were randomized to either apixaban 5 mg twice daily or to warfarin. In RE-LY, 18,113 patients with non-valvular AF were randomized to 1 of 3 treatment arms: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin. The 150 mg dose was used in our analysis because it is the dose administered to patients with AF. ROCKET AF compared a 20 mg/day dose of rivaroxaban to warfarin in 14,264 patients with non-valvular AF.

These 3 trials randomized a total of 44,563 patients, 22,327 to new oral anticoagulants and 22,236 to warfarin. The mean length of followup ranged from 657 to 730 days, and the average age ranged from 70 to 73 years. Mean CHADS2 scores were between 2.1 and 3.5. Women constituted 35% to 40% of the study populations, and the mean time in the therapeutic range of warfarin ranged from 55% to 64%.

Quality assessment of included trials was conducted using the Cochrane tool for assessing risk for bias. In RE-LY, patients were unblinded with respect to dabigatran or warfarin assignment.

However, all investigators, coordinating centre members, the steering committee, the event adjudication committee, and the sponsor were blinded during event ascertainment and analyses. As such, the risk for bias for RE-LY was described as low for the domain of blinding.

Efficacy outcomes

In each trial, the new oral anticoagulants were found to be at least non-inferior to warfarin for the composite end point of stroke (including haemorrhagic stroke) and systemic embolism (Table 6). ARISTOTLE and RE-LY further demonstrated the superiority of apixaban and dabigatran, respectively, to warfarin with respect to this composite end point. All 3 drugs were associated with a significantly decreased risk for hemorrhagic stroke compared to warfarin. RRs of other secondary efficacy outcomes, including ischemic stroke, all-cause mortality, vascular mortality, and myocardial infarction, were also more or less comparable or inconclusive.

Comparison of Efficacy Results
  RE-LY ROCKETAF ARISTOTLE
Outcome (%/year) Dabigatran 150mg BID       vs. warfarin p Value Rivaroxaban 20mg daily vs. warfarin p Value Apixaban 5 mg BID   vs. warfarin p Value
Primary Outcome Stroke or systemic embolism 1.1 vs. 1.7% p<0.001 NNT 88 2.1 vs. 2.4% p=0.12 1.3 vs. 1.6% p=0.01 NNT 167
Stroke 1.0 vs. 1.6% p<0.001 NNT 88 1.65 vs. 1.96% p=0.09 1.2 vs. 1.5% p=0.01 NNT 175
Ischemic stroke 0.9 vs. 1.3% p=0.03 NNT 132 1.3 vs. 1.4 p=0.58 0.97 vs. 1.05% p=0.42
Hemorrhagic stroke 0.1vs0.4% p<0.001 NNT 182 0.26 vs. 0.44% p=0.02 NNT 333 0.24 vs. 0.47% p<0.001 NNT 238
All cause death 3.6 vs. 4.1% p=0.051 4.5 vs. 4.9% p=0.15 3.5 vs. 3.9 p=0.047 NNT 132
MI/ACS 0.7 vs. 0.5% p=0.048 NNH 239 0.9 vs. 1.1% p=0.12 0.5 vs. 0.6% p=0.37

Table 6: Efficacy comparison of Dabigatran vs Rivaroxaban vs apixaban vs Warfarin.

Safety outcomes

With regard to safety, dabigatran and rivaroxaban were found to have comparable risks for major bleeding to warfarin, while apixaban demonstrated superiority for this outcome. Gastrointestinal bleeding data were heterogenous among the RCTs. The new oral anticoagulants were each associated with a decreased risk for intracranial bleeding compared to warfarin (Table 7).

Comparison of Safety Results
  RE-LY Dabigatran 150mg BID       vs. warfarin ROCKETAF Rivaroxaban 20mg daily vs. warfarin ARISTOTLE Apixaban 5 mg BID   vs. warfarin
Major bleed 3.1 vs. 3.36% p=0.31 3.6 vs. 3.4% p=0.58 2.1 vs. 3.1% p<0.001 NNT 67
Intracranial bleed 0.3 vs. 0.74% p<0.001 NNT 116 0.5 vs. 0.7% p=0.02 NNT 250 0.3 vs. 0.8% p<0.001 NNT 128
GI bleed 1.5 vs. 1.0% p<0.001 NNH 100 3.2 vs. 2.2%** p=0.001 NNH 100 0.76 vs. 0.86% 0.37

Table 7: Safety comparison of Dabigatran vs Rivaroxaban vs Warfarin.

Discussion

This study a systematic review of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. It was observed that the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favourable safety profile, making them promising alternatives to warfarin [13].

Warfarin is largely underused because of concerns over the need for systematic monitoring and the risk for bleeding associated with its use [14,15]. Only 50 to 60% of patients with AF indicated for anticoagulation therapy are estimated to receive it [16]. There is consequently a need for new agents that can function as alternatives to warfarin for long-term anticoagulation in AF [13]. Given the recent approval of dabigatran and rivaroxaban for stroke prevention in patients with AF by the United States Food and Drug Administration, it is essential that evidence comparing the novel treatment alternatives to warfarin be available to inform clinical decisions [13].

Previous studies seeking to identify a safe and effective alternative to warfarin for patients with atrial fibrillation have all had specific limitations. The combination of clopidogrel and aspirin was more effective than aspirin alone [17] but less effective than warfarin [18]. Subcutaneous idraparinux was more effective than warfarin but was associated with a substantially higher risk of bleeding [19]. Ximelagatran, an earlier direct thrombin inhibitor, appeared to be similar to warfarin with respect to efficacy and safety but was found to be hepatotoxic [20]. In our serial measurement of liver function, we did not find evidence of hepatotoxicity with dabigatran or rivaroxaban or apixaban.

We found that the new oral anticoagulants reduced the risk for a composite end point of stroke and systemic embolism compared to warfarin. New oral anticoagulants were also found to be associated with a lower risk for key secondary efficacy outcomes, including ischemic and unidentified stroke, haemorrhagic stroke, all-cause mortality, and vascular mortality, compared to warfarin. We found no conclusive outcome with respect to major bleeding and gastrointestinal bleeding but found a substantial decrease in the risk for intracranial bleeding. Overall, our results support the use of the new oral anticoagulants as alternatives to warfarin for long-term anticoagulation therapy in patients with AF.

The trials included in this study had a number of similar conclusions that strengthen our results particularly regarding the efficacy outcomes. Dabigatran and rivaroxaban significantly reduced stroke or systemic embolism even with the higher dose of dabigatran, moreover, the main benefit was a reduction in haemorrhagic stroke. Importantly, we found small significant absolute and relative risk reductions in mortality.

As far as safety is concerned, bleeding is an important concern in anticoagulation therapy. Although warfarin has been shown to lower the risk for stroke and thromboembolism, it is associated with an increased risk for potentially life-threatening bleeding events [21,22]. Our results suggest that new oral anticoagulants lower the risk for intracranial bleeding and, although not conclusive, may decrease the overall risk for major bleeding events in patients with AF. The risk of major bleeding was reduced with dabigatran in the RE-LY while rivaroxaban did not result in lower rates of protocol-defined major bleeding compared to warfarin in the ROCKET-AF.

Evaluation for a summarised risk for major bleeding complications among these studies has been challenging because of the marked variation in study protocol and endpoint definition. Although there was little difference in major bleeding complications when compared with control, the rates were higher for rivaroxaban [23] and apixaban [24,25] in ACS patients. Likely, several of these patients were receiving antiplatelet therapy, and probably treated with these two agents. Additional studies are required to confirm these findings and to assess the efficacy of its use at these doses [21,22].

Also, major bleeding complication rates have been noted to increase by 40 – 70% among those receiving aspirin plus clopidogrel in the RE-LY trial [26].

Majority of these ACS patients were receiving dual antiplatelet agents. Therefore, extreme caution has to be exercised when considering combining antiplatelet and antithrombotic agents because of the high bleeding risk.

Even so, the favourable net clinical benefit of dabigatran and rivaroxaban over warfarin suggested by this study (lower stroke and at least similar major bleedings), with the additional practical advantage of no requirement for INR monitoring or dose adjustment, is quite evident. On the other side, shortcomings of NOACs compared to warfarin include the short half-life, thus potentially increasing the risk of stroke or systemic embolism due to poor drug adherence, lack of coagulation assays to precisely measure the anticoagulation effect, lack of antidote for reversing anticoagulation in emergent situations, and costs. Importantly, dabigatran and rivaroxaban are not currently recommended in AF patients with other reasons for warfarin therapy, such as those with prosthetic heart valves.

Our review showed that as compared to rivaroxaban, dabigatran was associated with increased risk for acute coronary events. The excess risk associated with dabigatran was comparable to the findings of the earlier meta-analysis [27]. Therefore, it appeared that the coronary risk differed between oral direct thrombin inhibitors and anti-Xa agents. Although, the variation in the use of antiplatelet agents could have accounted for some of these differences, it was interesting to note that as compared to rivaroxaban, dabigatran was associated with a higher risk for MI/ACS in clinical studies of ACS patients [28-30]. Majority of them would have been treated with at least one antiplatelet agent. Therefore, based on these findings, those with heightened coronary risk, the use of anti-Xa agents may be preferable to direct thrombin inhibitors.

The benefit of dabigatran may be explained in part by the twicedaily dosing regimen. Since dabigatran has an elimination halflife of 12 to 17 hours, twice-daily dosing reduces variability in the anticoagulation effect, especially as compared with the anticoagulation effect of warfarin, which is difficult to control [31,32]. Warfarin broadly inhibits coagulation (inhibiting factors II, VII, IX, and X and proteins C and S). By selectively inhibiting only thrombin, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding.

Several phase II trials have demonstrated either a comparable risk or a reduced trend of major and clinically relevant bleeding associated with the new agents compared to warfarin. Edoxaban, a new factor Xa inhibitor, was associated with similar bleeding risks as warfarin in patients with AF at once-daily dosages [21,22]. Its efficacy and safety at these dosages are being investigated in a large phase III trial [33]. A study conducted in Japanese patients with AF reported a decreased incidence of major and clinically relevant bleeding events in patients receiving apixaban compared to those receiving warfarin [34]. AZD0837, another new direct thrombin inhibitor, has also shown a trend toward lower risks for major and clinically relevant bleeding at specific doses in patients with AF [25,26]. Furthermore, there was discordance in the main findings of SPORTIF III [35] and SPORTIF V [32]. Although, both studies were similar in design, there were important dissimilarities. SPORTIF III 25 was conducted in Europe, Asia plus Australasia and SPORTIF V 26 was performed in North America. The design of the latter study [32] was double-blind but SPORTIF III was an open-label trial [36]. Of note, the primary endpoint, consisting of stroke and systemic embolism, was 2.3% per year for the warfarin group and 1.6% per year for the ximelagatran group in SPORTIF III [35]. Conversely, it was 1.2% per year for the warfarin group and 1.6% per year for the ximelagatran group in SPORTIF V [32]. There were also differences in the occurrence of major bleeding complications. The authors attributed the differences to better dose regulation, control of hypertension or hyperlipidaemia, and other differences in patient characteristics or management or chance [32]. Additional studies are required to confirm these findings and to assess the efficacy of its use at these doses. In patients after acute venous thromboembolism, dabigatran was associated with a substantially lower risk for major and clinically relevant bleeding compared to warfarin [36]. Studies of apixaban and rivaroxaban in patients after acute venous thromboembolism showed comparable risks for bleeding to low–molecular weight heparin followed by a vitamin K antagonist [37-40,35].

Our study had 3 potential limitations. First, there was heterogeneity among the included trials. They examined different oral anticoagulants, and some of the between-trial differences may be due to the use of different agents. There was also some heterogeneity with respect to the study designs and included populations. Therefore, we used random effects models that account for between-study heterogeneity. Second, patients in clinical trials are often at lower overall risk for adverse events than patients seen in every- day clinical practice. Although this may affect the generalizability of our results, it likely did not result in bias. Third, patients taking warfarin in the included studies were more likely to be within its therapeutic range than in real practice.

With >50000 patients in the present study, our analysis may have overemphasized the statistical significance of small, nonclinically relevant differences between the compared drugs. Finally, heterogeneity was present especially regarding bleeding endpoints. To account for this issue, random-effects models were privileged. Despite these limitations, a notable improvement in survival and other hard clinical outcomes was observed, with no heterogeneity issues, which is particularly interesting for patients with AF. The trials included in this review had a number of similar conclusions that strengthen our results particularly regarding the efficacy outcomes.

In patients with non-valvular AF, NOACs decrease the composite of stroke or systemic embolism, hemorrhagic stroke and mortality compared to warfarin, with no significant increase of major bleeding [6].

Based on these results, NOACs approved from regulatory agencies should be used as first-line agents for antithrombotic management of patients with non-valvular AF.

Acknowledgement

Both the authors reviewed the manuscript. Dr. Shweta Bhatia is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. No competing financial conflict of interest exists. Authors are thankful and acknowledge the help rendered by Dr. Balneek Cheema. The results presented in this paper have not been published anywhere previously in whole or part.

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