Treatment of VTE Timeline
Find out how venous thromboembolism treatment guidelines have evolved in line with the clinical development of anticoagulants
First Anticoagulants Introduced
First Anticoagulants Introduced
First Anticoagulants Introduced
First Anticoagulants Introduced
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
Guidelines Recommend Anticoagulants for VTE Treatment
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 disorders4,5
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.
Approval code: PP-XAR-ALL-0545-1
- Murray GD, Best CH. The use of heparin in thrombosis. Ann Surg 1938;108:163–177.
- Galanaud JP, Laroche JP, Righini M. The history and historical treatments of deep vein thrombosis. J Thromb Haemost 2013;11:402–411.
- Hyers TM. Management of venous thromboembolism: past, present, and future. Arch Intern Med 2003;163:759–768.
- Yeh CH, Fredenburgh JC, Weitz JI. Oral direct factor xa inhibitors. Circ Res 2012;111:1069–1078.
- GlaxoSmithKline. Arixtra (Fondaparinux sodium) Prescribing Information. 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf [accessed 29 June 2018].
- Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:454S–545S.
- The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510.
- Schulman S, Kearon C, Kakkar AK et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342–2352.
- The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–1297.
- 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].
- Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141:e419S–e494S.
- Schulman S, Kearon C, Kakkar AK et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–718.
- Agnelli G, Buller HR, Cohen A et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799–808.
- Agnelli G, Buller HR, Cohen A et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699–708.
- The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406–1415.
- 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/hu man/002148/WC500107728.pdf [accessed 24 April 2018].
- Boehringer Ingelheim International GmbH. Pradaxa® (dabigatran etexilate) Summary of Product Characteristics. 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/hu man/000829/WC500041059.pdf [accessed 24 April 2018].
- Schulman S, Kakkar AK, Goldhaber SZ et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764–772.
- 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].
- Kearon C, Akl EA, Ornelas J et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315–352.