Pharmacological Therapy

This section explores guideline recommendations and the current evidence for the use of the NOACs in VAF

In this section:

Defining VAF

  • Oral anticoagulant therapy with VKAs (such as warfarin) has been standard therapy for the prevention of thromboembolism in patients with AF for many years and is recommended by guidelines
  • Establishing the origin of AF – VAF or NVAF – is often challenging for physicians, and definitions differ in current guidelines on AF

Current definitions of NVAF and VAF are summarized below.

Current guideline definitions for NVAF and VAF
Origin of AF Definition according to guidelines
NVAF Cases in which rhythm disturbance occurs in the absence of rheumatic mitral valve disease, a prosthetic heart valve or mitral valve repair
VAF AF related to rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves

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. 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.

Current guideline recommendations in VAF

Of all types of VHD, rheumatic mitral valve disease carries the greatest risk of systemic thromboembolism, and onset of AF further increases this risk; 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). 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).

Evidence for the use of NOACs in VAF

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. 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.

Current evidence for NOACs as anticoagulants in patients with VAF
(phase III
pivotal trial)
Outcomes from subanalyses in patients with VAF Source
Direct thrombin inhibitor
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. 2014
Direct Factor Xa inhibitors
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. 2015
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. 2016
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. 2014

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