Anticoagulant Development Timeline
Explore more than 100 years of anticoagulant therapy using this interactive timeline
Hirudin extracts from the medicinal leech first used for parenteral anticoagulation in the clinic1
Heparin first isolated from dog liver by Jay McLean2
First human trial of heparin conducted3,4
The Swedish company Vitrum AB launches the first unfractionated heparin product for intravenous use5
‘Sweet clover disease’ in cattle leads to the discovery of the naturally occurring vitamin K antagonist (VKA) anticoagulant dicoumarol6
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
Oral warfarin is approved for use as a medication in humans⁷
First randomized clinical trial demonstrating the efficacy of anticoagulant therapy in the treatment of venous thromboembolism (VTE)8
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
Interest in Factor Xa as a potential target for new anticoagulants increases because of its key role in the amplification of coagulation10
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
Ximelagatran becomes the first oral direct thrombin inhibitor licensed in the EU for short-term prevention of VTE12
Ximelagatran withdrawn from the market because of potential liver toxicity13
The oral direct thrombin inhibitor dabigatran is approved in the EU for VTE prevention in adult patients after elective hip or knee replacement surgery14
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
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
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
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
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
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
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
Rivaroxaban, 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 syndrome (ACS) in adult patients with elevated cardiac biomarkers15
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
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
Approval code: G.MKT.GM.XA.12.2017.2016
- Mellanby J. The coagulation of blood: part II. The actions of snake venoms, peptone and leech extract. J Physiol 1909;38:441–503.
- McLean J. The thromboplastic action of cephalin. Am J Physiol 1916;41:250–257.
- Murray DWG, Jaques LB, Perrett TS, Best CH. Heparin and the thrombosis of veins following injury. Surgery 1937;2:163–187.
- Friedman SG. The discovery of heparin. JSM Atheroscler 2016;1:1017.
- 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.
- 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.
- Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol 2006;62:509–511.
- Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med 2001;134:409–417.
- Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost 2008;99:807–818.
- 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].
- 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.
- Boos CJ, Lip GYH. Ximelagatran: an eulogy. Thromb Res 2006;118:301–304.
- 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].
- 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].
- 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].
- 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].
- 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].