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; or heparin 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
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. 2014
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. 2015
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. 2016
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
Oral Anticoagulants for Stroke Prevention in Patients with AF
Tap/click icons to reveal content
1989
1990s
2000
2003–2005
2006
2007
2009
2010
2011
2012
2013
2015
2016
1989
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)
1990s
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)
1990s
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)
1990s
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)
2000
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)
2003–2005
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)
2006
Global marketing authorization application for ximelagatran
withdrawn because of potential liver toxicity (Boos CJ et al. 2006)
2007
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)
2009
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)
2010
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)
2010
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)
2011
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)
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)
2011
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)
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)
2012
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)
2012
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)
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)
2013
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)
2015
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)
2016
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)
