The 50-year quest to replace Jeffrey Weitz

Anticoagulants are used for the prevention and treatment of venous and arterial to check that the appropriate level of anticoagulation is reached and maintained in , the leading cause of morbidity and mortality in the Western world. patients receiving warfarin. Consequently, warfarin is underused, and the level of Warfarin — the prototype oral — is a antagonist that has been anticoagulation is often suboptimal even when it is administered. These drawbacks in clinical use since the 1950s. Although they are effective, vitamin K antagonists have highlight the need for new oral . The first to be approved — in 2010 DRUG several drawbacks, the most notable of which is the propensity to cause . — as an alternative to warfarin was , a direct inhibitor. Clinical Other limitations include a slow onset of action, interactions with multiple other studies of the direct factor Xa inhibitors and have been DISCOVERY and interpatient variability in drug response. As a result, regular monitoring is required completed and could form the basis for regulatory approval as alternatives to warfarin.

Comparative of new oral anticoagulants compared to warfarin Venous and arterial thrombosis 'PFQVJGNKWO 8GUUGNYCNN Thrombotic disorders The cascade Warfarin Dabigatran Rivaroxaban Apixaban Arterial thrombosis. The primary trigger of Prodrug No Yes No No No (KDTKP Pulmonary This is classically divided into three pathways. The extrinsic pathway (also known as the Bioavailability Over 90% 6% 80% 60% 50% this is rupture of an atherosclerotic plaque, ▶ pathway) initiates coagulation. This pathway is triggered when vessel injury Dosing Once daily Once or Once or twice Twice daily Once daily which exposes material that activates twice daily daily and triggers coagulation. The coagulation exposes tissue factor, or when endothelial cell activation results in the tethering of tissue Half-life 36–42 hours 12–14 hours 7–11 hours 12 hours 9–11 hours 2NCVGNGVU Acute coronary factor-bearing monocytes or cell fragments known as microparticles. Tissue factor binds to Renal None 80% 66% (33% 25% 35% cascade (see far right) is initiated by tissue excretion unchanged and factor, which is expressed by lipid-rich syndrome activated factor VII (FVIIa) and this complex then activates FX and FIX. 33% as inactive Most heart attacks and metabolites) 8CUEWNCTKPLWT[ &COCIGFUWTHCEG macrophages that are exposed in the core of 2NCVGNGV are caused by Atrial fibrillation Coagulation Yes No No No No monitoring the ruptured plaque. Activated platelets clump TKEJ thrombosis, which is VJTQODWU Drug–drug Numerous P-gp CYP3A4 and CYP3A4 CYP3A4 together to form aggregates that are held superimposed on ruptured interactions P-gp and P-gp atherosclerotic plaques. together by . The resultant -rich — a common 6KUUWGHCEVQT (8++C (8++ (s) Vitamin K, None None None None can then occlude the artery and Strokes can also heart rhythm (:++C (:++ plasma, occur when clots in the prothrombin abnormality — is concentrates Supplement to Nature Publishing Group journals Publishing Group Supplement to Nature block flow. heart break off and a risk factor for become lodged in thrombosis. It Advantages of new oral anticoagulants and their clinical implications arteries in the brain. accounts for (:+C (:+ Advantage Clinical implications 8GUUGNYCNN one-fifth of 5OQQVJ .QYOQNGEWNCTYGKIJVJGRCTKP Rapid onset of action No need for bridging therapy OWUENGEGNNU all strokes. 'PFQVJGNKWO 7PHTCEVKQPCVGFJGRCTKP Predictable anticoagulant effect No need for routine coagulation monitoring 8KVCOKP-CPVCIQPKUVU (+:C (+: Specific coagulation targeted Low risk of off-target adverse effects %JQNGUVGTQN &KTGEV(:CKPJKDKVQTU (8+++C Low potential for food interactions No dietary precautions needed &KTGEVVJTQODKPKPJKDKVQTU Low potential for drug interactions Few drug restrictions .KRKFTKEJOCETQRJCIGU HQCOEGNNU  (:C VTE occurs when a blood clot (: Oral anticoagulants in Phase III clinical trials and beyond 6KUUWGHCEVQT GZRTGUUKPIVKUUWGHCEVQT Peripheral forms in a vein. Such clots (8C Drug Structure Highest Indications (acronym (KDTKPTKEJ commonly occur in the deep veins arterial disease phase* of key Phase III trials) VJTQODWU 2NCVGNGVCEVKXCVKQP 0CVWTG4GXKGYU^&TWI&KUEQXGT[ of the leg or pelvis; this is known (++C VJTQODKP (++ RTQVJTQODKP Direct thrombin inhibitors ▶ as a DVT. Parts of these clots can Dabigatran‡ Approved • VTE prevention Virchow’s triad. Named after the German Deep vein (Pradaxa; (RE-NOVATE I and II; break free and migrate to the Boehringer CH3 RE-MODEL; physician (1821–1902), lungs, where they can lodge in a thrombosis Ingelheim) N RE-MOBILIZE) NH2 O • VTE treatment this triad describes the three conditions lung artery and cause a pulmonary (KDTKP (KDTKPQIGP N HN (RE-COVER I and II; that contribute to thrombosis. embolism. DVT can occur after %TQUUNKPMGF HO N NH RE-MEDY; RE-SONATE) surgery or in patients who are ȮDTKPVJTQODWU • SPAF (RE-LY; RELY-ABLE) (:+++ (:+++C O N immobilized because of medical illnesses. The intrinsic pathway (also known as the contact pathway) amplifies FX activation. In 2NCVGNGVU Direct factor Xa inhibitors 0CVWTG4GXKGYU^&TWI&KUEQXGT[ addition to direct activation of FX, the tissue factor–FVIIa complex also activates FIX. FIXa, #NVGTGFXGUUGNNYCNN Rivaroxaban Approved • VTE prevention together with its cofactor FVIIIa, then activates FX to generate additional FXa. Both of these (Xarelto; (RECORD1–4) 4GFDNQQFEGNNU O • VTE treatment Schering (EINSTEIN-DVT; For over 50 years, anticoagulants suchNatur ase warfarinReviews | Drug Discoandvery other pathways converge at the final common pathway. FXa, together with its cofactor FVa, forms O Pharma) O N N Cl EINSTEIN-PE; 6KUUWGHCEVQT H S vitamin K antagonists have been used to prevent or treat many of , a complex that efficiently activates prothrombin (FII) to generate thrombin N EINSTEIN-EXT) O • SPAF (J-ROCKET AF; these disorders. The new oral anticoagulants can overcome many (FIIa). Thrombin converts , a soluble , into fibrin monomers that polymerize ROCKET-AF) 6JTQODQUKU O . Venous thrombi are rich in • ACS (ATLAS-TIMI-51) 0CVWTG4GXKGYU^&TWI&KUEQXGT[ of the limitations of vitamin K antagonists. By simplifying long-term to form fibrin strands. FXIIIa crosslinks the fibrin strands to stabilize the thrombus. fibrin and contain fewer platelets than arterial Apixaban 4KXCTQZCDCP Approved • VTE prevention

▶ anticoagulation therapy, more patients could be treated with the This panel shows the target points of various anticoagulants. Of note, vitamin K antagonists $#; (Eliquis; O (ADVANCE 1–3; ADOPT) thrombi. They form in areas where blood flow is #DPQTOCNDNQQFȯQY +PETGCUGFEQCIWNCDKNKV[ new agents. In addition, because novel oral anticoagulants produce — such as warfarin — target multiple factors, as do the (unfractionated and Bristol-Myers O • VTE treatment Squibb/ N N NH2 (AMPLIFY; AMPLIFY-EXT) sluggish. Such altered blood flow activates the a more predictable level of anticoagulation than warfarin, they are LMWH, which are given by injection when an immediate anticoagulant effect is needed). Pfizer) • SPAF (AVERROES; N ARISTOTLE) O N , which triggers coagulation and easier to administer and are potentially safer and more efficacious. By contrast, the new anticoagulants specifically target either FXa or thrombin. 0CVWTG4GXKGYU^&TWI&KUEQXGT[ • ACS (APPRAISE-2; subsequent fibrin generation. study terminated)

O CH3 Late 1950s: , a specific0CVWTG4GXKGYU ^&TWI&KUEQXGT[ 1920s: cattle eating 1948: warfarin, a 1989: initial crystal 1990: tick anticoagulant 2006: 2008: dabigatran and rivaroxaban first 2011: ongoing Phase III trials are Edoxaban #RKZCDCP Phase III • VTE treatment thrombin inhibitor, isolated from withdrawn from the likely to pave the way for the $/5 CH3 (HOKUSAI) spoiled sweet clover noted derivative, structure of protein and antistasin used approved as alternatives to LMWH for O N • SPAF (ENGAGE-AF CH3 leech saliva; served as a prototype market owing to § approval of other agents (see TIMI-48) to have bleeding disorder marketed as a thrombin reported to validate FXa as a target short-term VTE prevention Cl for the design of thrombin inhibitors potential toxicity table) as alternatives to warfarin O N S N 0CVWTHNG4GXKGYU^&TWI&KUEQXGT[ H N HN H3C N O O

1920 1940 1950 1960 1980 1990 2004 2006 2008 2010 2011 'FQZCDCP Phase II/III • VTE prevention (YM150) &7DHO • ACS O O N CH H 3 HN N 1941: substance responsible for 1950s: warfarin used 1980s: FXa identified as a 2004: ximelagatran, the first oral 2010: dabigatran approved as 2011: apixaban approved as 0CVWTG4GXKGYUO ^&TWI&KUEQXGT[ bovine bleeding disorder identified as as an anticoagulant 1960: first clinical trials potential target for new direct thrombin inhibitor, licensed in an alternative to warfarin for an alternative to LMWH for of anticoagulants § § dicoumarol, a in humans anticoagulants the EU for short-term VTE prevention use in SPAF short-term VTE prevention *Indicates the highest phase reached for any indication in any country. ‡Dabigatran is administered as the prodrug dabigatran etexilate. ;/FCTGZCDCP;/

About Boehringer Ingelheim GmbH. Research into an oral direct thrombin inhibitor began in In contrast to warfarin, Pradaxa® does not require routine coagulation monitoring or dose Abbreviations Affiliations the early 1990s on the Research and Development Campus of Boehringer Ingelheim in Biberach, adjustments, is not affected by food and has a low potential for drug–drug interactions. ACS, ; CYP3A4, cytochrome P450 3A4; DVT, Lassen M.R. et al. Apixaban versus enoxaparin for thromboprophylaxis Jeffrey Weitz is at the Thrombosis and Atherlerosclerosis Research Institute, Germany. Dabigatran etexilate was first synthesized in 1996. This was the starting point for an Dabigatran etexilate is approved for clinical use in stroke risk reduction in non-valvular AF in ; EU, European Union; LMWH, low molecular weight after hip replacement. N. Engl. J. Med. 363, 2487–2498 (2010). McMaster University, Ontario, Canada. http://www.taari.ca unprecedented development program, including extensive Phase III clinical testing investigating many countries around the globe, including the USA, Canada, Europe and Japan. It is also heparin; P-gp, P ; SPAF, stroke prevention in atrial Schulman S, et al. Dabigatran versus warfarin in the treatment of acute venous He has served as a consultant and has received honoraria from Bayer, § Pradaxa® in multiple indications requiring anticoagulation. Among these, RE-LY® was the largest approved in 83 countries for prevention of venous thromboembolic events in adults undergoing fibrillation; VTE, venous thromboembolism. After orthopaedic surgery. thromboembolism. N. Engl. J. Med. 361, 2342–2352 (2009). Bristol-Myers Squibb, Boehringer Ingelheim, Daiich Sankyo, Pfizer and Takeda. atrial fibrillation (AF) study ever completed, which compared two doses of dabigatran etexilate elective total hip or surgery. Boehringer Ingelheim is one of the world’s 20 References Turpie, A.G. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis Bauersachs, R. et al. Oral rivaroxaban for symptomatic venous after total knee arthroplasty (RECORD4): a randomised trial. Lancet 373, Designed by Susie Lanni; edited by Charlotte Harrison; copyedited leading pharmaceutical companies (http://www.boehringer-ingelheim.com). Since its inception (110mg and 150mg bid), administered in a blinded manner, with open label warfarin. The RE-LY® thromboembolism N. Engl. J. Med. 363, 2499–2451 (2010). 1673–1680 (2009). by Mariam Faruqi. trial demonstrated superiority of the 150 mg dose and non-inferiority of the 110 mg dose of in 1885, the family-owned company is committed to researching, developing, manufacturing and Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial Wallentin L, et al. Efficacy and safety of dabigatran compared © 2011 Nature Publishing Group. Pradaxa® over the 50-year old standard of care, warfarin, in preventing stroke in AF. This was marketing novel products of high therapeutic value for human and veterinary medicine. fibrillation. N. Engl. J. Med. 17, 1139–1151 (2009). with warfarin at different levels of international normalised ratio http://www.nature.com/nrd/posters/warfarin achieved without additional overall bleeding with the higher dose and significantly less bleeding Headquarters are in Ingelheim, Germany, and it operates globally with 145 affiliates and over Connolly, S. J. et al. Apixaban in patients with atrial fibrillation. control for stroke prevention in atrial fibrillation: an analysis of with the lower dose. Importantly, significantly less intracranial bleeding with both doses was seen. 42,000 employees. N. Engl. J. Med. 364, 806–817 (2011). the RE-LY trial. Lancet 376, 975–983 (2010).

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