Systematic Review and Adjusted Indirect Comparison Meta-Analysis of Oral Anticoagulants in Atrial Fibrillation

University of Connecticut Schools of Pharmacy and Medicine, Storrs and Farmington, CT.
Circulation Cardiovascular Quality and Outcomes (Impact Factor: 5.66). 08/2012; 5(5):711-9. DOI: 10.1161/CIRCOUTCOMES.112.966572
Source: PubMed


Oral anticoagulants such as apixaban, dabigatran, and rivaroxaban are alternatives to warfarin for preventing events in patients with atrial fibrillation. Direct comparative studies between agents are unavailable. Our objective was to conduct an adjusted indirect comparison meta-analysis between new oral agents in atrial fibrillation.

Methods and results:
We searched MEDLINE and Cochrane Central through February 2012 for randomized, controlled trials in patients with atrial fibrillation evaluating apixaban, dabigatran, or rivaroxaban versus warfarin. For dabigatran, only data from the Food and Drug Administration-approved dose were included. Outcomes included the composite of stroke or systemic embolism, any stroke, and major bleeding among, others. Outcomes were initially pooled using standard random-effects methods, producing risk ratio and 95% confidence intervals. Adjusted indirect comparisons using these pooled estimates were then performed. A total of 44 733 patients from 4 studies were analyzed. Most analyses yielded no differences between agents. Dabigatran lowered risk of composite outcome (risk ratio, 0.75; 95% confidence interval, 0.57-1.00), ischemic stroke (0.67; 0.48-0.93), and hemorrhagic stroke (0.45; 0.45-0.99) versus rivaroxaban. No differences in all strokes or mortality were seen. Apixaban lowered the risk of major bleeding (0.74; 0.60-0.91) and gastrointestinal bleeding (0.58; 0.41-0.82) versus dabigatran and major bleeding versus rivaroxaban (0.68; 0.55-0.83), but increased systemic emboli versus rivaroxaban (3.86; 1.17-12.75).

Significant differences in efficacy and safety parameters may exist between oral anticoagulant agents in patients with atrial fibrillation. Apixaban lowers the risk of major and gastrointestinal bleeding versus dabigatran and rivaroxaban. Dabigatran lowers the composite of stroke or systemic emboli, and ischemic stroke versus rivaroxaban. Head-to-head clinical trials are required to confirm these findings.

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    • "RCTs generally on the basis of a qualitative comparison in the Results section, with select studies using a quantitative comparison [44] [46] [47]. Differences that informed decisions regarding the analyses tended to be reported in the Methods section (i.e., subgroup analyses, meta-regressions, or specific sensitivity analyses ) [36] [43] [45] [48]. Testa et al. [50] was the only study that identified differences only in the Discussion section, which reflects a limitation of this study. "
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    ABSTRACT: To critically appraise published network meta-analyses (NMAs) evaluating the efficacy or safety of the new oral anticogulants (NOACs) dabigatran, rivaroxaban, and apixaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). A systematic literature review was performed to identify the relevant NMAs using MEDLINE, EMBASE, Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. The synthesis studies were evaluated using the "Questionnaire to assess the relevance and credibility of the NMA." Eleven NMAs evaluating NOACs among adults with nonvalvular AF were identified. Most NMAs included three large phase III randomized controlled trials, comparing NOACs to adjusted-dose warfarin (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], and Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]). The main differences identified related to potential treatment effect modifiers regarding the mean time spent in therapeutic range (TTR) in the warfarin arm, the risk of stroke or systemic embolism across the trials (mean CHADS2 score: C = congestive heart failure, H = hypertension, A = older than age 75 years, D = diabetes mellitus, S2 = prior stroke or history of transient ischemic attack) or primary versus secondary prevention, and type of populations used in the analysis. Kansal et al. [Kansal AR, Sharma M, Bradley-Kennedy C, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada: comparative efficacy and cost-effectiveness. Thromb Haemost 2012;108:672-82] appropriately adjusted the ROCKET-AF TTR to match the RE-LY population on the basis of individual patient data. Meta-regressions are not expected to minimize confounding bias given limited data, whereas subgroup analyses had some impact on the point estimates for the treatment comparisons. Results of the synthesis studies were generally comparable and suggested that the NOACs had similar efficacy, although some differences were identified depending on the outcome. The extent to which differences in the distribution of TTR, CHADS2 score, or primary versus secondary prevention biased the results remains unclear. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.
    Value in Health 01/2015; 18(2). DOI:10.1016/j.jval.2014.10.012 · 3.28 Impact Factor
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    • "[7] [15] Also of note, although none of these have been directly compared in head-to-head trials, data from indirect treatment comparisons have indicated that apixaban lowers the risk of major bleeding compared with dabigatran and rivaroxaban. [16] [17] [18] This key finding reflects direct evidence in support of apixaban from two studies: the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial [19] and the Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial. [20] In ARISTOTLE, apixaban reduced the risk of stroke or systemic embolism (SE) compared with warfarin (hazard ratio [HR] 0.79, 95% confidence interval [CI], 0.66 to 0.95; P = 0.01), the risk of all-cause death (HR 0.89; 95% CI, 0.80 to 0.99; P = 0.047) and was associated with fewer adverse events such as major bleeding (HR 0.69, 95% CI 0.60 to 0.80; P b 0.001). "
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    ABSTRACT: Introduction Atrial fibrillation (AF), one of the major risk factors for stroke, imposes a substantial burden to the Swedish health care system. Apixaban has demonstrated superiority to warfarin and aspirin in stroke prevention amongst patients with AF in two large randomised clinical trials. The aim of this study was to assess the economic implications of apixaban against warfarin and aspirin in these patients from a Swedish societal perspective. Materials and Methods A Markov cohort model was constructed to characterise the consequences of anticoagulant treatment with regards to thromboembolic and bleeding events, as well as the associated health care costs, life-years and quality-adjusted life years (QALYs) for patients with AF treated with apixaban, warfarin or aspirin. Incremental cost-effectiveness ratios (ICERs) per QALY gained of apixaban relative to warfarin (among patients suitable for warfarin treatment) and aspirin (among patients unsuitable for warfarin treatment) were calculated. Costs (in 2011 SEKs) and QALYs were discounted at 3% per annum. Results The model estimated the ICER of apixaban versus warfarin amongst patients who are suitable for warfarin therapy to be SEK 33,458/QALY gained and that of apixaban versus aspirin amongst those unsuitable for warfarin therapy to be SEK 41,453/QALY gained. Probabilistic sensitivity analyses indicate that apixaban is an optimal treatment option compared with warfarin and aspirin, when the willingness-to-pay is above SEK 35,000 and SEK 45,000 per QALY, respectively. Conclusions Apixaban was found to be a cost-effective alternative to warfarin and aspirin for stroke prevention in patients with AF in Sweden.
    Thrombosis Research 08/2014; 134(2). DOI:10.1016/j.thromres.2014.05.027 · 2.45 Impact Factor
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    • "The drug is also indicated in the prevention of stroke and systemic embolic disorders in adults with non-valvular atrial fibrillation who present one or more risk factors (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, previous stroke or transient ischemic attack episodes) (10,20,21). Rivaroxaban shows high bioavailability following oral administration, and a rapid onset of action (22). The peak plasma concentrations are reached 1.5-2 hours after administration. "
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    ABSTRACT: For over 50 years, vitamin K antagonists such as warfarin (Aldocumar®) and acenocoumarol (Sintrom®) have been the gold standard for reducing the risk of cerebrovascular events. In the last 5 years alternative anticoagulants have been evaluated that act directly upon a concrete target within the coagulation cascade, thereby affording a more predictable anticoagulant effect. The present study offers an update on the new oral anticoagulants and reviews the implications referred to the dental care of patients administered these substances. An exhaustive PubMed-Medline and Cochrane Library search was made of the main alternatives to conventional oral anticoagulation, covering those studies published in English and Spanish over the last 10 years. Specialized textbooks and pharmaceutical catalogs were also consulted. A total of 184 articles were identified, of which 76 met the inclusion criteria. The new oral anticoagulants dabigatran, rivaroxaban and apixaban are safe and effective, and offer a series of advantages, including rapid action, no need for constant monitoring, few drug and food interactions, and a broad therapeutic margin. These drugs are expensive, however, and some lack a specific antidote, while others must be administered twice a day. Regarding the dental treatment of patients receiving these drugs, suspension or modification of the background medication is not required when performing invasive dental procedures, except where indicated by the prescribing physician. The new oral anticoagulants do not pose significantly greater risks than conventional oral anticoagulants when providing invasive dental treatment, and their suspension is not strictly required in such situations. Key words:Dabigatran, rivaroxaban, apixaban, dental, hemostasis.
    Journal of Clinical and Experimental Dentistry 12/2013; 5(5):e273-e278. DOI:10.4317/jced.51226
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