Twice- or Once-Daily Dosing of Novel Oral Anticoagulants for Stroke Prevention: A Fixed-Effects Meta-Analysis with Predefined Heterogeneity Quality Criteria

<div><p>Background</p><p>A number of novel oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) are in clinical use for various indications. The dosing regimens differ between twice-daily and once-daily dosing for the prevention of stroke in patients with atrial fibrillation. With the availability of the results from four phase 3 studies (>70,000 patients), we explored whether twice-daily or once-daily dosing provides better risk-benefit balance among novel oral anticoagulants.</p><p>Methods</p><p>We conducted a strict, stepwise, fixed-effects meta-analysis with predefined heterogeneity quality criteria to generate the most appropriate common estimates for twice-daily (BID) or once-daily (QD) dosing regimens. An indirect comparison of these dosing regimens with fixed-effects meta-analysis common estimates (where available), or individual compound results, was done respectively.</p><p>Results</p><p>Comparing indirectly BID vs QD dosing regimens resulted in hazard ratios (HR [95% confidence interval]) for stroke and systemic embolism of 0.75 (0.58–0.96) for dabigatran 150 mg BID, and 0.91 (0.73–1.13) for apixaban BID vs the QD dosing regimen. For ischemic stroke, the HR of BID vs QD was 0.85 (0.69–1.05). For intracranial hemorrhage, BID vs rivaroxaban QD was 0.57 (0.37–0.88) and, vs edoxaban QD, 0.81 (0.54–1.22). Due to heterogeneity, common estimates for major bleeding QD or BID were not justified, therefore indirect comparison of regimens were not possible. All non-vitamin K antagonist oral anticoagulants reduced all-cause mortality vs warfarin with a HR of 0.90 (0.86–0.96) without differences between regimen.</p><p>Conclusions</p><p>Based on the available phase 3 study evidence, the twice-daily dosing regimen of non-vitamin K antagonist oral anticoagulants appears to offer a more balanced risk-benefit profile with respect to stroke prevention and intracranial hemorrhage.</p></div

Imputed placebo analysis.

<p>Comparison of new oral anticoagulants versus imputed placebo on the risk of stroke.</p

Estimated proportion of warfarin benefit by new oral anticoagulants on the risk of stroke.

<p>Estimated proportion of warfarin benefit by new oral anticoagulants on the risk of stroke.</p

Main Characteristics of Trials Evaluating New Oral Anticoagulants for Stroke Prevention in Patients with Nonvalvular Atrial Fibrillation.

<p>D, Dabigatran; R, Rivaroxaban; A, Apixaban; E, Edoxaban; N, number of patients; AF, atrial fibrillation; TIA, transient ischemic attack, TTR = time in therapeutic range (International normalized ratio 2.0 to 3.0); CHF, congestive heart failure; DM, diabetes mellitus; HTN, hypertension; CHADS₂ indicates CHF, hypertension, age, diabetes mellitus, stroke.</p><p>*  =  Stroke or TIA only.</p

Estimated proportion of warfarin benefit by new oral anticoagulants on the risk of all-cause mortality.

<p>Estimated proportion of warfarin benefit by new oral anticoagulants on the risk of all-cause mortality.</p

Search strategy and selection of clinical trial according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement for reporting systematic reviews and meta-analyses.

<p>Search strategy and selection of clinical trial according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement for reporting systematic reviews and meta-analyses.</p

Scheme of the strict, stepwise, fixed-effects meta-analysis with predefined heterogeneity quality criteria.

<p>This stepwise statistical approach was conducted for the identification of groupings that are justified to generate a common estimate (CE) based on the predefined quality criteria of low heterogeneity. If these heterogeneity criteria were not met no CE was generated. Legend: BID, twice-daily dosing; CE, common estimate; I², Higgins' I²<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099276#pone.0099276-Deeks1" target="_blank">[8]</a>; QD, once-daily dosing; Q_peto, χ²-distributed, Cochran's Q <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099276#pone.0099276-Jackson1" target="_blank">[7]</a>.</p

Imputed placebo analysis. Comparison of new oral anticoagulants versus imputed placebo on the risk of all-cause mortality.

<p>Imputed placebo analysis. Comparison of new oral anticoagulants versus imputed placebo on the risk of all-cause mortality.</p

Flow of study selection.

<p>Flow of study selection.</p

Reported efficacy outcomes (HRs [95% CI] vs warfarin) of the respective NOACs in the phase 3 trials [1]–[5] in the intent-to-treat analysis.

<p>AP, apixaban; CI, confidence interval; DE, dabigatran etexilate; EDOX, edoxaban; HR, hazard ratio; RIVA, rivaroxaban. Note. Bold font marks results where the 95% CIs do not cross or touch 1.00.</p><p>*Dose with most pronounced efficacy result. †Includes ischemic strokes only.</p