Efficacy and Safety of the Novel Oral Anticoagulants in Atrial Fibrillation: A Systematic Review and Meta-Analysis of the Literature

Study Questions:

What is the clinical benefit of novel oral anticoagulants (NOACs) compared with vitamin K antagonists for the prevention of stroke or systemic embolism in patients with atrial fibrillation?


The authors performed a meta-analysis of phase II and III randomized controlled trials comparing NOACs with warfarin for atrial fibrillation, using MEDLINE and EMBASE up to July 2012. All articles were independently reviewed by two reviewers, assessing outcomes of overall and cardiovascular mortality, stroke or systemic embolism, ischemic stroke, major and intracranial bleeding, and myocardial infarction (MI). All NOACs were pooled for comparison with warfarin, and relative risks (RRs) for the above outcomes were calculated.


A total of 12 studies were analyzed (three dabigatran, four rivaroxaban, two apixaban, and three edoxaban), in which a total of 54,875 subjects were enrolled. Compared with warfarin, NOACs were associated with a statistically significant reduction in total mortality (5.61% vs. 6.02%; RR, 0.89; 95% confidence interval [CI], 0.83-0.96), cardiovascular mortality (3.45% vs. 3.65%; RR, 0.89; 95% CI, 0.82-0.98), and stroke/systemic embolism (2.40% vs. 3.13%; RR, 0.77; 95% CI, 0.70-0.86). Aggregate data for all NOACs revealed a significant reduction in intracranial hemorrhage (RR, 0.46; 95% CI, 0.39-0.56) and a trend toward reduced major bleeding (RR, 0.86; 95% CI, 0.72-1.02). For these aggregate data, there was no difference observed in MI rate.


The authors concluded that NOACs are associated with an overall clinical benefit compared with vitamin K antagonists. The authors further opined that additional research is required to confirm these findings outside the context of randomized trials.


The data published here differ from prior publications of clinical trials for NOACs versus warfarin in atrial fibrillation, in that data from small phase II studies are included, and the results are aggregated for all of the novel agents. For the clinician, this offers little insight, as the phase II studies are so small that they would not alter the results from the large phase III studies. Furthermore, for the practicing clinician, a better understanding of the risks versus benefits is needed for individual agents, and it is probably not valid to assess the NOACs as a group. Each of the NOACs had individually demonstrated a statistically significant reduction in the incidence of intracranial hemorrhage, so this finding can certainly be generalizable and is a major advantage of the NOACs over warfarin. As for proven mortality and stroke risk reduction versus warfarin, only high-dose dabigatran and apixaban can make that claim based on RCTs, with rivaroxaban falling just short of superiority in the intention-to-treat analysis. Such individual agent comparisons seem the only reasonable data to consider when making patient management decisions. Aggregating data for all NOACs does not make sense, and should not be used to make clinical decisions. Most importantly, as the authors emphasize, real-world data are clearly needed to corroborate that the results obtained in closely monitored clinical trials are reproducible.

Clinical Topics: Anticoagulation Management

Keywords: Myocardial Infarction, Stroke, Intracranial Hemorrhages, Warfarin, Embolism, MEDLINE

< Back to Listings