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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
Superiority of warfarin over ASA demonstrated
1990s
Warfarin for stroke prevention in patients with AF / SPAF I (1990)
Warfarin for stroke prevention in patients with AF / SPAF II (1994)
Warfarin for stroke prevention in patients with AF / SPAF III (1996)
2000
Warfarin for stroke prevention in patients with AF at increased risk of stroke is demonstrated
2003‒2005
Ximelagatran is approved for stroke prevention in patients with AF
2006
Ximelagatran is withdrawn
2007
Benefit of VKA therapy demonstrated
2009
Dabigatran shown to be at least as effective as warfarin
2010
First NOAC approved for the prevention of stroke and SE in patients with NVAF
Guidelines recommend oral anticoagulant therapy in specific patient populations
2011
Rivaroxaban shown to be non-inferior to warfarin
First NOAC approved for the prevention of stroke and SE in patients with NVAF
Apixaban shown to be superior to warfarin
Apixaban shown to be superior to ASA in patients unsuitable for warfarin
2012
Apixaban approved for stroke and SE prevention in patients with NVAF with ≥1 risk factors
Guidelines recommend oral anticoagulants for patients with AF
Updated guidelines recommend preference for NOACs over warfarin in patients with AF
2013
Edoxaban shown to be non-inferior to warfarin
2015
Edoxaban approved for stroke prevention in patients with NVAF
2016
Guidelines recommend NOACs over VKA therapy for stroke prevention in at-risk patients with AF

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

Show references

Approval code: PP-XAR-ALL-0561-1

  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.
  2. 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.
  3. Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–539.
  4. Ezebowitz MD, James KE, R. M et al. Stroke prevention in atrial fibrillation II study. Lancet 1994;343:1508–1509.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Boos CJ, Lip GYH. Ximelagatran: an eulogy. Thromb Res 2006;118:301–304.
  10. 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.
  11. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.
  12. 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].
  1. 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.
  2. Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.
  3. 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].
  4. Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–992.
  5. Connolly SJ, Eikelboom J, Joyner C et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–817.
  6. 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].
  7. 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.
  8. 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.
  9. Giugliano RP, Ruff CT, Braunwald E et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–2104.
  10. 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].
  11. 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.