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

Flow of study selection.

<p>Flow of study selection.</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

Common estimates where justified and indirect comparisons of all BID or QD dosing regimens of NOACs.

<p>Results are expressed from the respective main dose results of the phase 3 trials <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099276#pone.0099276-Connolly1" target="_blank">[1]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099276#pone.0099276-Giugliano1" target="_blank">[5]</a> in the intent-to-treat analysis for efficacy (Stroke and systemic embolism, ischemic stroke) and in the safety analysis for intracranial hemorrhage. AP, apixaban; BID, twice-daily dosing; CE, common estimate; CI, confidence interval; DE, dabigatran etexilate; EDOX, edoxaban; HR, hazard ratio; QD, once-daily dosing; RIVA, rivaroxaban; SE, systemic embolism; W, warfarin; ^aIn the ROCKET-AF trial, only ischemic strokes, excluding unspecified strokes, are reported. Note: bold and italic font marks significantly superior results.</p

Indirect comparison of BID vs QD with the CEs and results from respective NOACs.

<p>The comparison is conducted based on the results from the generation of CE for the respective end points. If no CE was generated (according to the strict heterogeneity criteria) a comparison of the respective result of the specific NOAC was applied. Legend: AP, apixaban; BID, twice-daily dosing; CE, common estimate; CE BID, common estimate generated by meta-analysis of DE 150 mg BID and AP 5/2.5 mg BID; CE QD, common estimate generated by meta-analysis of RIVA 20/10 mg QD and EDOX 60/30 mg QD; DE, dabigatran etexilate; EDOX, edoxaban; HR (95% CI), hazard ratio (95% confidence interval); ITT, intention-to-treat analysis; NOACs, novel oral anticoagulants; QD, once-daily dosing; RIVA, rivaroxaban; safety, safety set analysis.</p

Reported safety outcomes (HRs [95% CI] vs warfarin) of the respective NOACs in the phase 3 trials [1]–[5] in the safety analysis sets.

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

Main characteristics of NOACs.

<p>NOACs, novel oral anticoagulants.</p

Analysis of results heterogeneity of NOACs vs warfarin.

<p>Given are the main results (including all dosages or the dose with most pronounced efficacy result)^* and grouping by regimen (BID or QD) are displayed. BID, twice-daily dosing; FEM, fixed-effects meta-analysis; NOACs, novel oral anticoagulants; QD, once-daily dosing.</p><p>Note. Bold font marks nearly absence of heterogeneity, i.e., generation of a common estimate is justified.</p><p>*Dose with most pronounced efficacy result: dabigatran 150 mg BID, apixaban 5/2.5 mg BID, rivaroxaban 20/15 mg QD, and edoxaban 60/30 mg QD.</p