Anticoagulant Development Timeline

Explore more than 100 years of anticoagulant therapy using this interactive timeline

The Discovery and Production of the First Anticoagulant Drugs
The Discovery and Production of the First Anticoagulant Drugs
The Discovery and Production of the First Anticoagulant Drugs
The Discovery and Production of the First Anticoagulant Drugs
The Discovery and Production of the First Anticoagulant Drugs
The Discovery and Production of the First Anticoagulant Drugs
Anticoagulants Approved for Human Use
Anticoagulants Approved for Human Use
Anticoagulants Approved for Human Use
Anticoagulants Approved for Human Use
Anticoagulants Approved for Human Use
Anticoagulants Approved for Human Use
Anticoagulants Approved for Human Use
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
NOACs Approved for Various Thromboembolic Indications
1909
First clinical anticoagulant
1916
Heparin identified
1935
Heparin tested in humans
1936
First intravenous heparin product produced
1939
Discovery of natural VKA dicoumarol
1950s
First synthetic VKA is produced
1954
Warfarin approved for human use in the US
1960
Effectiveness of anticoagulants demonstrated for VTE treatment
1980s
Parenteral LMWH introduced
Concept of Factor Xa inhibitors born
2001
First Factor Xa inhibitor approved
2004
Ximelagatran approved for VTE prevention
2006
Ximelagatran withdrawn
2008
First approval of dabigatran
First approval of rivaroxaban
2010
First NOAC approved for stroke prevention in patients with NVAF
2011
Rivaroxaban approved for stroke prevention in patients with NVAF
Rivaroxaban approved for the treatment of VTE
First approval of apixaban
2012
Apixaban approved for stroke prevention in patients with NVAF
Rivaroxaban approved for treatment of PE
2013
Rivaroxaban approved for prevention of arterial thrombosis in patients following an ACS
2014
Dabigatran and apixaban approved for the treatment of VTE and prevention of recurrent VTE
2015
First approval of edoxaban
2018
Rivaroxaban approved for the prevention of arterial thromnosis in patients with chronic CAD or symptomatic PAD

1909 1909

Hirudin extracts from the medicinal leech first used for parenteral anticoagulation in the clinic1

1916 1916

Heparin first isolated from dog liver by Jay McLean2

1935 1935

First human trial of heparin conducted3,4

1936 1936

The Swedish company Vitrum AB launches the first unfractionated heparin product for intravenous use5

1939 1939

‘Sweet clover disease’ in cattle leads to the discovery of the naturally occurring vitamin K antagonist (VKA) anticoagulant dicoumarol6

1950s 1950s

The VKA – warfarin – a synthetic derivative of dicoumarol used as a pesticide against rats and mice – is found to be effective and relatively safe for preventing thrombosis and thromboembolism6,7

1954 1954

Oral warfarin is approved for use as a medication in humans7

1960 1960

First randomized clinical trial demonstrating the efficacy of anticoagulant therapy in the treatment of venous thromboembolism (VTE)8

1980s 1980s

Development of parenteral low molecular weight heparins (LMWHs) – synthetically derived from unfractionated heparin – that exert their anticoagulant effect indirectly by binding to antithrombin and accelerating inhibition of Factor Xa9

1980s 1980s

Interest in Factor Xa as a potential target for new anticoagulants increases because of its key role in the amplification of coagulation10

2001 2001

Subcutaneous fondaparinux, a synthetic pentasaccharide, is the first indirect Factor Xa inhibitor approved in the US for the treatment and prevention of thromboembolic disorders10,11

2004 2004

Ximelagatran becomes the first oral direct thrombin inhibitor licensed in the EU for short-term prevention of VTE12

2006 2006

Ximelagatran withdrawn from the market because of potential liver toxicity13

2008 2008

The oral direct thrombin inhibitor dabigatran is approved in the EU for VTE prevention in adult patients after elective hip or knee replacement surgery14

2008 2008

Rivaroxaban becomes the first oral direct Factor Xa inhibitor approved in the EU for VTE prevention in adult patients after elective hip or knee replacement surgery15

2010 2010

Twice-daily dabigatran, the first of the non-VKA oral anticoagulants (NOACs), is approved in the US for the prevention of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF)16

2011 2011

Once-daily rivaroxaban 20 mg 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 congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack15

2011 2011

Rivaroxaban (15 mg twice daily [bid] for 21 days followed by 20 mg once daily [od]) is the first NOAC to be approved in the EU for the treatment of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults; no pre-treatment with a parenteral anticoagulant is required15

2011 2011

Apixaban (10 mg bid for 7 days followed by 5 mg bid) – an oral direct Factor Xa inhibitor – is approved in the EU for VTE prevention after elective hip or knee replacement surgery17

2012 2012

Apixaban 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)17

2012 2012

Rivaroxaban (15 mg bid for 21 days followed by 20 mg od) is approved for the treatment of PE – the first NOAC to receive this indication15

2013 2013

Rivaroxaban 2.5 mg twice daily, co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine, is approved in the EU for the secondary prevention of acute coronary syndromes in adult patients with elevated cardiac biomarkers15

2014 2014

Dabigatran and apixaban are approved in the EU for the treatment of DVT and PE and the prevention of recurrent DVT and PE in adults14,17

2015 2015

Edoxaban 60 mg od – a direct Factor Xa inhibitor – 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 congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack and the treatment of DVT and PE and prevention of recurrent DVT and PE in adults18

2018 2018

Rivaroxaban 2.5 mg twice daily is approved in Europe in combination with acetylsalicylic acid for the prevention of atherothrombotic events in patients with chronic CAD or symptomatic PAD at high risk of ischaemic events (rivaroxaban SPC)

Show references

Approval code: PP-XAR-ALL-0544-1

  1. Mellanby J. The coagulation of blood: part II. The actions of snake venoms, peptone and leech extract. J Physiol 1909;38:441–503.
  2. McLean J. The thromboplastic action of cephalin. Am J Physiol 1916;41:250–257.
  3. Murray DWG, Jaques LB, Perrett TS, Best CH. Heparin and the thrombosis of veins following injury. Surgery 1937;2:163–187.
  4. Friedman SG. The discovery of heparin. JSM Atheroscler 2016;1:1017.
  5. Royston D. Anticoagulant and antiplatelet therapy. Pharmacology and Physiology for Anesthesia. doi:10.1016/B978-1-4377-1679-5.00037-5 2013. p. 643–667.
  6. Kresge N, Simoni RD, Hill RL. Hemorrhagic sweet clover disease, dicumarol, and warfarin: the work of Karl Paul Link. J Biol Chem 2005;280:e5–e6.
  7. Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol 2006;62:509–511.
  8. Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med 2001;134:409–417.
  9. Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost 2008;99:807–818.
  10. Yeh CH, Fredenburgh JC, Weitz JI. Oral direct factor xa inhibitors. Circ Res 2012;111:1069–1078.
  11. GlaxoSmithKline. Arixtra (Fondaparinux sodium) Prescribing Information. 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf [accessed 29 June 2018].
  12. Mohapatra R, Tran M, Gore JM, Spencer FA. A review of the oral direct thrombin inhibitor ximelagatran: not yet the end of the warfarin era... Am Heart J 2005;150:19–26.
  1. Boos CJ, Lip GYH. Ximelagatran: an eulogy. Thromb Res 2006;118:301–304.
  2. 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].
  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/hu man/000944/WC500057108.pdf [accessed 21 May 2018].
  4. Boehringer Ingelheim Pharmaceuticals Inc. Pradaxa® (dabigatran etexilate) Prescribing Information. 2018. Available at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&fol derPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf [accessed 28 March 2018].
  5. 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].
  6. 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/hu man/002629/WC500189045.pdf [accessed 24 April 2018].