Treatment of VTE Timeline

Find out how venous thromboembolism treatment guidelines have evolved in line with the clinical development of anticoagulants

First Anticoagulants Introduced

Guidelines Recommend Anticoagulants for VTE Treatment

Heparin introduced

VKAs introduced

LMWHs introduced

Factor Xa inhibitors introduced

Guidelines recommend anticoagulant therapy for the treatment of VTE

Rivaroxaban compared with LMWH/VKA for the treatment of symptomatic VTE

Dabigatran compared with VKA for the treatment of acute VTE

First non-VKA oral antagonist (NOAC) approved for the treatment of VTE and prevention of recurrent VTE

Rivaroxaban compared with LMWH/VKA for the treatment of symptomatic PE

Rivaroxaban approved for the treatment of PE

Guidelines recommend initial LMWH over NOACs for the treatment of acute VTE

Dabigatran compared with VKA for the prevention of recurrent VTE

Apixaban compared with LMWH/VKA for the treatment of VTE

Extended use of apixaban in the treatment of VTE

Edoxaban compared with LMWH/VKA for the treatment of VTE

Apixaban approved for the treatment of VTE and prevention of recurrent VTE

Dabigatran approved for the treatment of VTE and prevention of recurrent VTE

Use of dabigatran in patients with VTE

Edoxaban approved for the treatment of VTE and prevention of recurrent VTE

Guidelines recommend NOACs over VKA therapy for the treatment of VTE

Rivaroxaban compared with acetylsalicylic acid for extended prevention of VTE recurrence

1930s 1930s

Heparin introduced for the treatment and prevention of venous thromboembolism (VTE)¹

1940s 1940s

Vitamin K antagonists (VKAs) used for the treatment of deep vein thrombosis (DVT); classic regimen of acute treatment with parenteral heparin followed by an oral VKA established as the standard treatment for VTE²

1980s 1980s

Development of parenteral low molecular weight heparins (LMWHs) – synthetically derived from unfractionated heparin (UFH)³

2001 2001

Subcutaneous fondaparinux, an indirect Factor Xa inhibitor, approved in the US for the treatment and prevention of thromboembolic disorders^4,5

2008 2008

For patients with acute DVT or pulmonary embolism (PE), the American College of Chest Physicians (ACCP) guidelines recommend initial anticoagulant therapy with subcutaneous LMWH, intravenous or subcutaneous UFH, or subcutaneous fondaparinux, together with early initiated VKA⁶

2009–2010 2009–2010

Rivaroxaban (15 mg twice daily [bid] for 21 days followed by 20 mg once daily [od]), an oral direct Factor Xa inhibitor, found to be effective in the treatment of VTE in the EINSTEIN DVT and EINSTEIN EXT trials. In patients with acute DVT, rivaroxaban was non-inferior to enoxaparin/VKA for the prevention of recurrent VTE, with no increase in major bleeding rates. Extended rivaroxaban treatment reduced the rates of recurrent VTE versus placebo, without increasing the rate of major bleeding, in patients with DVT or PE⁷

2009–2010 2009–2010

Dabigatran (150 mg bid), an oral direct thrombin inhibitor, found to be effective in the treatment of VTE in the RE-COVER trial. In patients with acute VTE initially treated with parenteral anticoagulation, dabigatran was as effective as warfarin in preventing recurrent symptomatic VTE with no increase in major bleeding rates⁸

2011 2011

Rivaroxaban (15 mg bid for 21 days followed by 20 mg od) becomes the first oral direct Factor Xa inhibitor approved in the EU for the treatment of DVT and prevention of recurrent DVT and PE in adults; no pre-treatment with a parenteral anticoagulant is required

2012 2012

Rivaroxaban (15 mg bid for 21 days followed by 20 mg od) shown to be effective in the treatment of PE in the EINSTEIN PE trial. In patients with acute symptomatic PE, rivaroxaban was non-inferior to enoxaparin/VKA in preventing recurrent VTE, with a significantly lower rate of major bleeding⁹

2012 2012

Rivaroxaban (15 mg bid for 21 days followed by 20 mg od) is the first NOAC approved for the treatment of PE (and prevention of recurrent DVT and PE)¹⁰

2012 2012

ACCP guidelines recommend initial parenteral anticoagulant therapy or anticoagulation with rivaroxaban for acute DVT or PE¹¹

2013 2013

Dabigatran (150 mg bid) was associated with non-inferior efficacy versus warfarin (RE-MEDY trial) and placebo (RE-SONATE trial) for the prevention of recurrent VTE during extended treatment in patients with VTE, with no increase in major bleeding¹²

2013 2013

Apixaban (10 mg bid for 7 days followed by 5 mg bid), an oral direct Factor Xa inhibitor, was found to be effective for the treatment of VTE in the AMPLIFY and AMPLIFY-EXT trials. In AMPLIFY, apixaban was non-inferior to enoxaparin/warfarin in preventing recurrent symptomatic VTE in patients with acute VTE, with a significantly lower risk for major bleeding¹³

2013 2013

In AMPLIFY-EXT, extended treatment with apixaban significantly reduced the risk of recurrent VTE versus placebo without increasing bleeding risk¹⁴

2013 2013

In the Hokusai-VTE trial, edoxaban (60 mg/30 mg od) – an oral direct Factor Xa inhibitor – was shown to be non-inferior to warfarin for the prevention of recurrent symptomatic VTE in patients with acute VTE who had initially received heparin, and was associated with a significantly lower rate of bleeding¹⁵

2014 2014

Apixaban (10 mg bid for 7 days followed by 5 mg bid) approved in the EU for the treatment of DVT and PE and for the prevention of recurrence of DVT and PE; no pre-treatment with a parenteral anticoagulant is required¹⁶

2014 2014

Dabigatran (150 mg bid), approved in the EU for the treatment of DVT and PE, and prevention of recurrent VTE; pre-treatment with a parenteral anticoagulant is required¹⁷

2014 2014

The RE-COVER II trial confirmed the efficacy of dabigatran (150 mg bid) compared with warfarin for the treatment of acute VTE in patients pre-treated with LMWH or UFH¹⁸

2015 2015

Edoxaban (60 mg/30 mg od), following initial use of parenteral anticoagulant for at least 5 days, approved in the EU for the treatment of DVT and PE and for the prevention of recurrence of DVT and PE¹⁹

2016 2016

For patients with VTE and no cancer, ACCP guidelines recommend long-term anticoagulant therapy with dabigatran, rivaroxaban, apixaban or edoxaban over VKA therapy²⁰

2017 2017

EINSTEIN CHOICE demonstrates the superiority of rivaroxaban at either 10 or 20 mg once daily over acetylsalicylic acid for long-term secondary prevention of DVT or PE, with no significant increase in bleeding rates (Weitz J et al. 2017). This leads to approval of the 10 mg once-daily dose for extended prevention of VTE recurrence in patients who have completed at least 6 months’ therapy for DVT or PE and who are not considered at high risk of recurrence (rivaroxaban SPC). In those at high risk of recurrent VTE, the 20 mg once-daily dose should still be considered.

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Approval code: PP-XAR-ALL-0545-1

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