Oral Antithrombotics in Non-Valvular Atrial Fibrillation
Oral Antithrombotics in Non-Valvular Atrial Fibrillation
Background Antithrombotic therapy reduces stroke, embolism and mortality in patients with atrial fibrillation (AF); however, meta-analyses have focused on pairwise comparisons of treatments.
Objective To synthesise the evidence from trials using a multiple treatment comparison methods thereby permitting a broader comparison across multiple therapies.
Design, setting, patients Randomised controlled trials in patients with AF of antithrombotics were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through May 2012. We performed a random-effects model within a Bayesian framework using Markov Chain Monte Carlo simulation to calculate pooled OR and 95% credibility intervals (CrI). We also ranked therapies by their likelihood of leading to the best results for the outcomes.
Main outcome measure Multiple endpoints including stroke, embolism, death and bleeding.
Results We identified 20 studies with 79 808 patients allocated to 8 treatments: ASA, ASA plus clopidogrel, vitamin K antagonists (VKAs), dabigatran 110 mg, dabigatran 150 mg, rivaroxaban, apixaban or placebo/control. Compared with placebo/control, dabigatran 150 mg was associated with the lowest risk of stroke (OR=0.25, 0.15–0.43), the composite of ischaemic stroke or systemic embolism (OR=0.26, 0.12–0.54) and mortality (OR=0.53, 0.28–0.88). ASA plus clopidogrel was associated with the highest risk of major bleeding (OR=3.65, 1.22–13.56). In simulated comparisons, the novel oral anticoagulants ranked better than VKA or antiplatelet therapies for prevention of stroke, ischaemic stroke or systemic embolism and mortality.
Conclusions In this network meta-analysis, novel oral anticoagulants were the most promising treatments to reduce stroke, stroke or systemic embolism, and all-cause mortality in patients with AF.
In patients with atrial fibrillation (AF), Vitamin K antagonists (VKAs), such as warfarin, reduce the risk of stroke by 65% compared with placebo, but increase the risk of haemorrhage. Although VKAs are recommended for patients who have AF and at least one risk factor, these drugs have several well-known limitations and the need for frequent laboratory monitoring. As a result, adherence is low, and many patients who take VKAs are inadequately anticoagulated. Antiplatelet agents also appear to significantly reduce the incidence of stroke, but are less effective than oral anticoagulants. A meta-analysis of trials comparing warfarin versus ASA showed better stroke reduction with warfarin, but a higher rate of intracranial bleeding, with no difference in total mortality. In a recent randomised trial, anticoagulant therapy was superior to the combination of clopidogrel plus ASA in reducing stroke, with no difference in bleeding.
Several novel oral anticoagulants have been developed in an attempt to overcome the many challenges faced by clinicians and patients with the use of VKAs. Dabigatran, rivaroxaban and apixaban were each 'at least as good as' warfarin in reducing the risk of stroke or embolism in large phase III randomised clinical trials designed to test whether the new agent was non-inferior to warfarin. Not only did these new agents meet criteria for non-inferiority, but additionally, dabigatran 150 mg twice daily and apixaban 5 mg twice daily were superior to warfarin in reducing the composite of stroke or systemic embolism. Finally, in a fourth trial of a novel anticoagulant, apixaban reduced the risk of stroke or systemic embolism compared with aspirin monotherapy without significantly increasing the risk of major bleeding or intracranial haemorrhage.
In a recent meta-analysis of large phase III trials of novel oral anticoagulants compared with warfarin in patients with AF, statistically significant reductions with novel oral anticoagulants were observed in the primary outcome of stroke or systemic embolism (18% relative reduction), as well as all-cause mortality (9%) and haemorrhagic stroke (49%). However, standard meta-analyses are unable to integrate all available randomised evidence in one analysis that also includes indirect comparisons between therapies. By contrast, network meta-analysis allows a unified, coherent analysis of all randomised controlled trials that compare antithrombotic drugs head to head or with placebo/control while fully respecting randomisation. In the context of a systematic review, a network meta-analysis can compare three or more treatments using both direct comparisons of interventions within randomised controlled trials and indirect comparisons across trials based on a common comparator. The idea underlying multitreatment meta-analysis methodology is that, for any given comparison between two treatments A and B, direct evidence (coming from studies comparing A with B) and indirect evidence (coming from combining studies through an intermediate comparator, eg, A vs C and B vs C studies) can be synthesised into a single effect size. When direct and indirect evidence are available, the two sources of information can be combined as a weighted average.
Thus, we performed a network meta-analysis using available phase II and III trial data to answer the following research questions: What are the relative effects of different classes of antithrombotic drugs in reducing the incidence of stroke, the composite of ischaemic stroke or systemic embolism, death from any cause, and major bleeding in patients with non-valvular AF?
Abstract and Introduction
Abstract
Background Antithrombotic therapy reduces stroke, embolism and mortality in patients with atrial fibrillation (AF); however, meta-analyses have focused on pairwise comparisons of treatments.
Objective To synthesise the evidence from trials using a multiple treatment comparison methods thereby permitting a broader comparison across multiple therapies.
Design, setting, patients Randomised controlled trials in patients with AF of antithrombotics were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through May 2012. We performed a random-effects model within a Bayesian framework using Markov Chain Monte Carlo simulation to calculate pooled OR and 95% credibility intervals (CrI). We also ranked therapies by their likelihood of leading to the best results for the outcomes.
Main outcome measure Multiple endpoints including stroke, embolism, death and bleeding.
Results We identified 20 studies with 79 808 patients allocated to 8 treatments: ASA, ASA plus clopidogrel, vitamin K antagonists (VKAs), dabigatran 110 mg, dabigatran 150 mg, rivaroxaban, apixaban or placebo/control. Compared with placebo/control, dabigatran 150 mg was associated with the lowest risk of stroke (OR=0.25, 0.15–0.43), the composite of ischaemic stroke or systemic embolism (OR=0.26, 0.12–0.54) and mortality (OR=0.53, 0.28–0.88). ASA plus clopidogrel was associated with the highest risk of major bleeding (OR=3.65, 1.22–13.56). In simulated comparisons, the novel oral anticoagulants ranked better than VKA or antiplatelet therapies for prevention of stroke, ischaemic stroke or systemic embolism and mortality.
Conclusions In this network meta-analysis, novel oral anticoagulants were the most promising treatments to reduce stroke, stroke or systemic embolism, and all-cause mortality in patients with AF.
Introduction
In patients with atrial fibrillation (AF), Vitamin K antagonists (VKAs), such as warfarin, reduce the risk of stroke by 65% compared with placebo, but increase the risk of haemorrhage. Although VKAs are recommended for patients who have AF and at least one risk factor, these drugs have several well-known limitations and the need for frequent laboratory monitoring. As a result, adherence is low, and many patients who take VKAs are inadequately anticoagulated. Antiplatelet agents also appear to significantly reduce the incidence of stroke, but are less effective than oral anticoagulants. A meta-analysis of trials comparing warfarin versus ASA showed better stroke reduction with warfarin, but a higher rate of intracranial bleeding, with no difference in total mortality. In a recent randomised trial, anticoagulant therapy was superior to the combination of clopidogrel plus ASA in reducing stroke, with no difference in bleeding.
Several novel oral anticoagulants have been developed in an attempt to overcome the many challenges faced by clinicians and patients with the use of VKAs. Dabigatran, rivaroxaban and apixaban were each 'at least as good as' warfarin in reducing the risk of stroke or embolism in large phase III randomised clinical trials designed to test whether the new agent was non-inferior to warfarin. Not only did these new agents meet criteria for non-inferiority, but additionally, dabigatran 150 mg twice daily and apixaban 5 mg twice daily were superior to warfarin in reducing the composite of stroke or systemic embolism. Finally, in a fourth trial of a novel anticoagulant, apixaban reduced the risk of stroke or systemic embolism compared with aspirin monotherapy without significantly increasing the risk of major bleeding or intracranial haemorrhage.
In a recent meta-analysis of large phase III trials of novel oral anticoagulants compared with warfarin in patients with AF, statistically significant reductions with novel oral anticoagulants were observed in the primary outcome of stroke or systemic embolism (18% relative reduction), as well as all-cause mortality (9%) and haemorrhagic stroke (49%). However, standard meta-analyses are unable to integrate all available randomised evidence in one analysis that also includes indirect comparisons between therapies. By contrast, network meta-analysis allows a unified, coherent analysis of all randomised controlled trials that compare antithrombotic drugs head to head or with placebo/control while fully respecting randomisation. In the context of a systematic review, a network meta-analysis can compare three or more treatments using both direct comparisons of interventions within randomised controlled trials and indirect comparisons across trials based on a common comparator. The idea underlying multitreatment meta-analysis methodology is that, for any given comparison between two treatments A and B, direct evidence (coming from studies comparing A with B) and indirect evidence (coming from combining studies through an intermediate comparator, eg, A vs C and B vs C studies) can be synthesised into a single effect size. When direct and indirect evidence are available, the two sources of information can be combined as a weighted average.
Thus, we performed a network meta-analysis using available phase II and III trial data to answer the following research questions: What are the relative effects of different classes of antithrombotic drugs in reducing the incidence of stroke, the composite of ischaemic stroke or systemic embolism, death from any cause, and major bleeding in patients with non-valvular AF?
