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Peripheral Artery Disease: causes and consequences

Coronary Artery Disease: causes and consequences

Pharmacological Therapy

This section explores guideline recommendations and the current evidence for the use of the NOACs in 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 guidelines1-3
  • Establishing the origin of AF – VAF or NVAF – is often challenging for physicians,4 and definitions differ in current guidelines on AF5

Current definitions of NVAF and VAF are summarized below.

Current guideline definitions1 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 repair2
VAF AF related to rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves1

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.

Current evidence for NOACs as anticoagulants in patients with VAF
NOAC (phase III pivotal trial)Outcomes from subanalyses in patients with VAFSource
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 VHDEzekowitz 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 VHDAvezum 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 VHDRenda 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 withoutBreithardt G et al. 201413
References
  • Kirchhof P, Benussi S, Kotecha D et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893-2962. Return to content
  • January CT, Wann LS, Alpert JS et al. 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–e76. Return to content
  • You JJ, Singer DE, Howard PA et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e531S–e575S. You JJ, Singer DE, Howard PA et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e531S–e575S. Return to content
  • Molteni M, Polo FH, Primitz L et al. The definition of valvular and non-valvular atrial fibrillation: results of a physicians' survey. Europace 2014;16:1720–1725. Return to content
  • De Caterina R, Camm AJ. What is 'valvular' atrial fibrillation? A reappraisal. Eur Heart J 2014;35:3328–3335. Return to content
  • Whitlock RP, Sun JC, Fremes SE et al. Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e576S–e600S. Return to content
  • Nishimura RA, Otto CM, Bonow RO et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438–2488. Return to content
  • Nishimura RA, Otto CM, Bonow RO et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–289. Return to content
  • Di Biase L. Use of direct oral anticoagulants in patients with atrial fibrillation and valvular heart lesions. J Am Heart Assoc 2016;5:e002776. Return to content
  • Ezekowitz MD, Parise H, Nagarakanti R et al. Comparison of dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease: the RE-LY trial. J Am Coll Cardiol 2014;63:A325. Abstract 1109-115. Return to content
  • Avezum A, Lopes RD, Schulte PJ et al. Apixaban compared with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the ARISTOTLE trial. Circulation 2015;132:624–632. Return to content
  • Renda G, De Caterina R, Carnicelli A et al. Outcomes in 2824 patients with valvular heart disease treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol 2016;67:2194. Abstract 915-06. Return to content
  • Breithardt G, Baumgartner H, Berkowitz SD et al. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial. Eur Heart J 2014;35:3377–3385. Return to content

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