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This section explores guideline recommendations and the current evidence for the use of the NOACs in VAF
Current definitions of NVAF and VAF are summarized below.
NVAF was interpreted differently in the designs of the pivotal phase III trials for the NOACs for stroke prevention in patients with AF, with inclusion and exclusion criteria varying with regard to associated VHD as opposed to VAF.5 As a result, it is considered that although a small number of patients with VHD were included in the phase III studies of the NOACs, their overall profile in patient with VAF remains untested.
Of all types of VHD, rheumatic mitral valve disease carries the greatest risk of systemic thromboembolism, and onset of AF further increases this risk6; it is the only type of VHD with recommendations for thromboembolic prophylaxis with an anticoagulant (VKA with target INR 2.5, range 2.0–3.0 in patients with AF and mitral stenosis).6-8 These ‘high-risk’ patients were excluded from the pivotal phase III trials assessing NOACs in patients with AF.
Data regarding associated stroke risk in patients with mitral valve prolapse, mitral valve regurgitation or aortic valve regurgitation are conflicting or limited; there are currently no specific recommendations for thromboembolic prophylaxis in these patient groups. These patients were not specifically excluded from the pivotal phase III trials of the NOACs in patients with AF, and retrospective analyses assessing outcomes from patients with VHD are available (further information on these subanalyses is provided in the following section).
The large phase III studies of the NOACs excluded patients with VAF accompanying mitral stenosis or patients with mechanical prosthetic valves, but did not necessarily exclude those with other types of VHD, such as mitral regurgitation or aortic disease.9 Retrospective analyses of outcomes in patients with VHD and AF involved in these trials (subanalyses) are summarized below. In general, the benefits of all four NOACs (dabigatran, apixaban, edoxaban and rivaroxaban) for stroke prevention were consistent compared with warfarin in patients with and without VHD.
|NOAC (phase III pivotal trial)||Outcomes from subanalyses in patients with VAF||Source|
|Direct thrombin inhibitor|
|Dabigatran (RE-LY)||21.8% (3950/18,113) of RE-LY patients had VHD; dabigatran showed similar efficacy and safety outcomes compared with warfarin in patients with VHD versus those without VHD||Ezekowitz MD et al. 201410|
|Direct Factor Xa inhibitors|
|Apixaban (ARISTOTLE)||26.4% (4808/18,201) of ARISTOTLE patients had moderate or severe VHD or previous valve surgery; apixaban showed similar efficacy and safety outcomes compared with warfarin in patients with VHD versus those without VHD||Avezum A et al. 201511|
|Edoxaban (ENGAGE AF-TIMI 48)||In patients with VHD (n=2824/21,046), edoxaban showed similar efficacy and safety outcomes compared with warfarin in patients with VHD versus those without VHD||Renda G et al. 201612|
|Rivaroxaban (ROCKET AF)||14.1% (2003/14,171) patients had VHD; the efficacy results were similar in patients with and without VHD but rates of major and non-major clinically relevant bleeding were higher in patients with VHD than in those without||Breithardt G et al. 201413|