OACs for Stroke Prevention in Patients with AF Timeline
Discover the key clinical trials that led to the approval of anticoagulants for stroke prevention in patients with atrial fibrillation
1989 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 acetylsalicylic acid (ASA) or placebo, in patients with chronic non-rheumatic atrial fibrillation (AF)1
1990s 1990s
SPAF I (1990) showed both warfarin and ASA to be superior to placebo for the prevention of stroke in patients with AF2,3
1990s 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 AF4
1990s 1990s
In 1996, SPAF III showed conventional adjusted-dose warfarin to be superior to low-intensity, fixed-dose warfarin plus ASA5
2000 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 stroke6
2003–2005 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 AF7,8
2006 2006
Global marketing authorization application for ximelagatran withdrawn because of potential liver toxicity9
2007 2007
Meta-analysis showed that vitamin K antagonist (VKA) therapy was associated with a significant reduction in stroke rate compared with placebo or ASA in patients with AF10
2009 2009
Ximelagatran becomes the first oral direct thrombin inhibitor licensed in the EU for short-term prevention of VTE12
2010 2010
Twice-daily dabigatran (150 mg/75 mg) is the first non-VKA oral antagonist (NOAC) approved in the US for the prevention of stroke and systemic embolism (SE) in patients with non-valvular AF (NVAF)12
2010 2010
European Society of Cardiology (ESC) guidelines recommend oral anticoagulant therapy (VKA; but non-VKA oral anticoagulants [NOACs] may be considered) for patients with one ‘major’ risk factor or ≥2 ‘clinically relevant or non-major risk factors’ for stroke13
2011 2011
Rivaroxaban (20 mg once daily [od]) shown to be non-inferior to warfarin for stroke prevention in patients with NVAF in the ROCKET AF study. No significant difference in major bleeding was found between the rivaroxaban and warfarin groups14
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 SE in adult patients with NVAF with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack15
2011 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 group16
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 ASA17
2012 2012
Apixaban (5 mg/2.5 mg bid) is approved in the EU for the prevention of stroke and SE in adult patients with NVAF 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)18
2012 2012
American College of Chest Physicians (ACCP) guidelines recommend oral anticoagulation for all patients with AF, except those at low risk of stroke or those with contraindications. Dabigatran preferred over warfarin19
2012 2012
The updated ESC guidelines recommend one of the NOACs rather than dose-adjusted warfarin for most patients with AF at risk of stroke20
2013 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 warfarin21
2015 2015
Once-daily edoxaban (60 mg/30 mg) is approved in the EU for the prevention of stroke in adult patients with NVAF with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack22
2016 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 anticoagulation23
Approval code: PP-XAR-ALL-0561-1
- Petersen P, Boysen G, Godtfredsen J et al. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1989;1:175-179.
- Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation study. N Engl J Med 1990;322:863–868.
- Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–539.
- Ezebowitz MD, James KE, R. M et al. Stroke prevention in atrial fibrillation II study. Lancet 1994;343:1508–1509.
- Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996;348:633–638.
- Segal JB, McNamara RL, Miller MR et al. Prevention of thromboembolism in atrial fibrillation. A meta-analysis of trials of anticoagulants and antiplatelet drugs. J Gen Intern Med 2000;15:56–67.
- Executive Steering Committee of behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691–1698.
- Albers GW, Diener HC, Frison L et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005;293:690–698.
- Boos CJ, Lip GYH. Ximelagatran: an eulogy. Thromb Res 2006;118:301–304.
- Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–867.
- Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.
- Boehringer Ingelheim Pharmaceuticals Inc. Pradaxa® (dabigatran etexilate) Prescribing Information. 2018. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf [accessed 28 March 2018].
- Camm AJ, Kirchhof P, Lip GYH et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–2429.
- Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.
- Bayer AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2018. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf [accessed 21 May 2018].
- Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–992.
- Connolly SJ, Eikelboom J, Joyner C et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–817.
- Bristol-Myers Squibb, Pfizer. Eliquis® (apixaban) Summary of Product Characteristics. 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf [accessed 24 April 2018].
- 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.
- Camm AJ, Lip GYH, De Caterina R et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–2747.
- Giugliano RP, Ruff CT, Braunwald E et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–2104.
- Daiichi Sankyo Europe GmbH. Lixiana® (edoxaban) Summary of Product Characteristics. 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf [accessed 24 April 2018].
- 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.
