This section explores guideline recommendations and the current evidence for the use of the NOACs in VAF
In this section:
- 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
- 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.
|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
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
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.
|Outcomes from subanalyses in patients with VAF||Source|
|Direct thrombin inhibitor|
|Ezekowitz MD et al. 2014|
|Direct Factor Xa inhibitors|
(ENGAGE AF-TIMI 48)
|In patients with VHD
|Breithardt G et al. 2014|
Oral Anticoagulants for Stroke Prevention in Patients with AF
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AFASAK was the first randomized trial to show a significant reduction in thromboembolic complications and vascular mortality with the use of warfarin compared with ASA or placebo, in patients with chronic non-rheumatic AF (Peterson P et al. 1989)
SPAF I (1990) showed both warfarin and ASA to be superior to placebo for the prevention of stroke in patients with AF (Stroke Prevention in Atrial Fibrillation Study Group Investigators. 1990; Stroke Prevention in Atrial Fibrillation Investigators. 1991)
SPAF I was followed by SPAF II in 1994, which showed warfarin to be superior to ASA for the prevention of stroke in patients aged >75 years with AF (Stroke Prevention in Atrial Fibrillation Study Group Investigators. 1994)
In 1996, SPAF III showed conventional adjusted-dose warfarin to be superior to low-intensity, fixed-dose warfarin + ASA (The SPAF III Writing Committee. 1996)
Meta-analysis showed anticoagulation with warfarin to be the cornerstone of stroke prevention in patients with AF and an average or greater risk of stroke (Segal JB et al. 2000)
SPORTIF III and SPORTIF V showed that ximelagatran, the first oral direct thrombin inhibitor (first marketed in 2003), was at least as effective as well-controlled warfarin for stroke prevention in high-risk patients with AF (Executive Steering Committee on behalf of the SPORTIF III Investigators. 2003; SPORTIF Executive Steering Committee for the SPORTIF V Investigators. 2005)
Global marketing authorization application for ximelagatran withdrawn because of potential liver toxicity (Boos CJ et al. 2006)
Meta-analysis showed that VKA therapy was associated with a significant reduction in stroke rate compared with placebo or ASA in patients with AF (Hart RG et al. 2007)
The RE-LY study showed the oral direct thrombin inhibitor, dabigatran (110 mg/150 mg bid) to be at least as effective as warfarin for the prevention of stroke in patients with AF.
The study also showed that dabigatran 110 mg bid was associated with similar efficacy but lower rates of major bleeding, and dabigatran 150 mg bid with superior efficacy but similar rates of major bleeding, versus warfarin (Connolly SJ et al. 2009)
Twice-daily dabigatran (150 mg/75 mg) is the first NOAC approved in the US for the prevention of stroke and systemic embolism in patients with non-valvular AF (dabigatran PI)
ESC guidelines recommend oral anticoagulant therapy (VKA; but NOACs may be considered) for patients with one ‘major’ risk factor or ≥2 ‘clinically relevant or non-major risk factors’ for stroke (Camm AJ et al. 2010)
Rivaroxaban (20 mg od) shown to be non-inferior to warfarin for stroke prevention in patients with AF in the ROCKET AF study.
No significant difference in major bleeding was found between the rivaroxaban and warfarin groups (Patel MR et al. 2011)
Once-daily rivaroxaban (20 mg/15 mg) is the first oral, direct Factor Xa inhibitor approved in the EU for the prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack (rivaroxaban SPC)
Apixaban (5 mg bid) - a direct Factor Xa inhibitor - is shown to be superior to warfarin for the prevention of stroke in patients with AF in the ARISTOTLE trial.
The rate of major bleeding in the ARISTOTLE trial was significantly lower in the apixaban group versus the warfarin group (Granger CB et al. 2011)
The AVERROES trial showed that apixaban significantly reduced stroke risk in patients with AF for whom warfarin was unsuitable, without increasing the risk of major bleeding versus ASA (Connolly SJ et al. 2011)
Twice-daily apixaban (5 mg/2.5 mg) is approved in the EU for the prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors, such as prior stroke or transient ischaemic attack; age ≥75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA class ≥II) (apixaban SPC)
ACCP guidelines recommend oral anticoagulation for all patients with AF, except those at low risk of stroke or those with contraindications. Dabigatran preferred over warfarin (You JY et al. 2012)
The updated ESC guidelines recommend one of the NOACs rather than dose-adjusted warfarin for most patients with AF at risk of stroke (Camm AJ et al. 2012)
The ENGAGE AF-TIMI 48 trial showed the direct Factor Xa inhibitor edoxaban (30 mg/60 mg od) to be non-inferior to warfarin for stroke prevention in patients with AF. Major bleeding rates were significantly lower for edoxaban 60 mg od versus warfarin (Giugliano RP et al. 2013)
Once-daily edoxaban (60 mg/30 mg) is approved in the EU for the prevention of stroke in adult patients with non-valvular AF with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, hypertension, diabetes mellitus, prior stroke or transient ischaemic attack (edoxaban SPC)
ESC/EHRA/ESO guidelines recommend NOAC therapy (apixaban, dabigatran, edoxaban or rivaroxaban) over VKA therapy for stroke prevention in at-risk patients with AF with an indication for oral anticoagulation (Kirchhof P et al. 2016)
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