Comparative pharmacology of new oral anticoagulants compared to warfarin
`Warfarin
`Dabigatran
`Rivaroxaban
`Apixaban
`Edoxaban
`Prodrug
`No
`Yes
`No
`No
`No
`Bioavailability Over 90%
`6%
`80%
`60%
`50%
`Dosing
`Once daily
`Once or
`Once or twice
`Twice daily Once daily
`twice daily
`daily
`12–14 hours
`7–11 hours
`80%
`66% (33%
`unchanged and
`33% as inactive
`metabolites)
`No
`
`Half-life
`Renal
`excretion
`
`36–42 hours
`None
`
`12 hours
`25%
`
`9–11 hours
`35%
`
`Coagulation
`monitoring
`Drug–drug
`interactions
`Antidote(s)
`
`Yes
`
`No
`
`No
`
`No
`
`Numerous
`
`P-gp
`
`None
`
`Vitamin K,
`plasma,
`prothrombin
`concentrates
`
`CYP3A4 and
`P-gp
`None
`
`CYP3A4
`
`None
`
`CYP3A4
`and P-gp
`None
`
`Advantages of new oral anticoagulants and their clinical implications
` Advantage
`Clinical implications
`Rapid onset of action
`No need for bridging therapy
`Predictable anticoagulant effect
`No need for routine coagulation monitoring
`Specific coagulation enzyme targeted
`Low risk of off-target adverse effects
`Low potential for food interactions
`No dietary precautions needed
`Low potential for drug interactions
`Few drug restrictions
`
`Indications (acronym
`of key Phase III trials)
`
`(cid:114)(cid:2)VTE prevention
`(RE-NOVATE I and II;
`RE-MODEL;
`RE-MOBILIZE)
`(cid:114)(cid:2)VTE treatment
`(RE-COVER I and II;
`RE-MEDY; RE-SONATE)
`(cid:114)(cid:2)SPAF (RE-LY; RELY-ABLE)
`
`Oral anticoagulants in Phase III clinical trials and beyond
`Drug
`Structure
`Highest
`phase*
`
`Approved
`
`NH2
`
`NH
`
`HN
`
`CH3
`
`NN
`
`Direct thrombin inhibitors
`Dabigatran‡
`(Pradaxa;
`Boehringer
`Ingelheim)
`
`O
`
`N
`
`HO
`
`O
`
`N
`
`Approved
`
`O
`
`The 50-year quest to replace warfarin
`
`Jeffrey Weitz
`
`DRUG
`DISCOVERY
`
`Anticoagulants are used for the prevention and treatment of venous and arterial
`thrombosis, the leading cause of morbidity and mortality in the Western world.
`Warfarin — the prototype oral anticoagulant — is a vitamin K antagonist that has been
`in clinical use since the 1950s. Although they are effective, vitamin K antagonists have
`several drawbacks, the most notable of which is the propensity to cause bleeding.
`Other limitations include a slow onset of action, interactions with multiple other drugs
`and interpatient variability in drug response. As a result, regular monitoring is required
`
`to check that the appropriate level of anticoagulation is reached and maintained in
`patients receiving warfarin. Consequently, warfarin is underused, and the level of
`anticoagulation is often suboptimal even when it is administered. These drawbacks
`highlight the need for new oral anticoagulants. The first drug to be approved — in 2010
`— as an alternative to warfarin was dabigatran, a direct thrombin inhibitor. Clinical
`studies of the direct factor Xa inhibitors rivaroxaban and apixaban have been
`completed and could form the basis for regulatory approval as alternatives to warfarin.
`
`Pulmonary
`embolism
`
`Acute coronary
`syndrome
`
`Atrial fibrillation
`
`Atrial fibrillation
`— a common
`heart rhythm
`abnormality — is
`a risk factor for
`thrombosis. It
`accounts for
`one-fifth of
`all strokes.
`
`Peripheral
`arterial disease
`
`Deep vein
`thrombosis
`
`The coagulation cascade
`This is classically divided into three pathways. The extrinsic pathway (also known as the
`tissue factor pathway) initiates coagulation. This pathway is triggered when vessel injury
`exposes tissue factor, or when endothelial cell activation results in the tethering of tissue
`factor-bearing monocytes or cell fragments known as microparticles. Tissue factor binds to
`activated factor VII (FVIIa) and this complex then activates FX and FIX.
`
`(cid:56)(cid:67)(cid:85)(cid:69)(cid:87)(cid:78)(cid:67)(cid:84)(cid:2)(cid:75)(cid:80)(cid:76)(cid:87)(cid:84)(cid:91)
`
`(cid:38)(cid:67)(cid:79)(cid:67)(cid:73)(cid:71)(cid:70)(cid:2)(cid:85)(cid:87)(cid:84)(cid:72)(cid:67)(cid:69)(cid:71)
`
`(cid:54)(cid:75)(cid:85)(cid:85)(cid:87)(cid:71)(cid:2)(cid:72)(cid:67)(cid:69)(cid:86)(cid:81)(cid:84)
`
`(cid:40)(cid:56)(cid:43)(cid:43)(cid:67)
`
`(cid:40)(cid:56)(cid:43)(cid:43)
`
`(cid:40)(cid:58)(cid:43)(cid:43)(cid:67)
`
`(cid:40)(cid:58)(cid:43)(cid:43)
`
`(cid:46)(cid:81)(cid:89)(cid:2)(cid:79)(cid:81)(cid:78)(cid:71)(cid:69)(cid:87)(cid:78)(cid:67)(cid:84)(cid:2)(cid:89)(cid:71)(cid:75)(cid:73)(cid:74)(cid:86)(cid:2)(cid:74)(cid:71)(cid:82)(cid:67)(cid:84)(cid:75)(cid:80)
`(cid:55)(cid:80)(cid:72)(cid:84)(cid:67)(cid:69)(cid:86)(cid:75)(cid:81)(cid:80)(cid:67)(cid:86)(cid:71)(cid:70)(cid:2)(cid:74)(cid:71)(cid:82)(cid:67)(cid:84)(cid:75)(cid:80)
`(cid:56)(cid:75)(cid:86)(cid:67)(cid:79)(cid:75)(cid:80)(cid:2)(cid:45)(cid:2)(cid:67)(cid:80)(cid:86)(cid:67)(cid:73)(cid:81)(cid:80)(cid:75)(cid:85)(cid:86)(cid:85)
`(cid:38)(cid:75)(cid:84)(cid:71)(cid:69)(cid:86)(cid:2)(cid:40)(cid:58)(cid:67)(cid:2)(cid:75)(cid:80)(cid:74)(cid:75)(cid:68)(cid:75)(cid:86)(cid:81)(cid:84)(cid:85)
`(cid:38)(cid:75)(cid:84)(cid:71)(cid:69)(cid:86)(cid:2)(cid:86)(cid:74)(cid:84)(cid:81)(cid:79)(cid:68)(cid:75)(cid:80)(cid:2)(cid:75)(cid:80)(cid:74)(cid:75)(cid:68)(cid:75)(cid:86)(cid:81)(cid:84)(cid:85)
`
`(cid:40)(cid:58)(cid:43)(cid:67)
`
`(cid:40)(cid:58)(cid:43)
`
`(cid:40)(cid:43)(cid:58)
`
`(cid:40)(cid:56)(cid:43)(cid:43)(cid:43)(cid:67)
`
`(cid:40)(cid:58)
`
`(cid:40)(cid:43)(cid:58)(cid:67)
`
`(cid:40)(cid:56)(cid:67)
`
`(cid:40)(cid:58)(cid:67)
`
`(cid:50)(cid:78)(cid:67)(cid:86)(cid:71)(cid:78)(cid:71)(cid:86)(cid:2)(cid:67)(cid:69)(cid:86)(cid:75)(cid:88)(cid:67)(cid:86)(cid:75)(cid:81)(cid:80)
`
`(cid:40)(cid:43)(cid:43)(cid:67)(cid:2)(cid:10)(cid:86)(cid:74)(cid:84)(cid:81)(cid:79)(cid:68)(cid:75)(cid:80)(cid:11)
`
`(cid:40)(cid:43)(cid:43)(cid:2)(cid:10)(cid:82)(cid:84)(cid:81)(cid:86)(cid:74)(cid:84)(cid:81)(cid:79)(cid:68)(cid:75)(cid:80)(cid:11)
`
`(cid:40)(cid:75)(cid:68)(cid:84)(cid:75)(cid:80)
`
`(cid:40)(cid:75)(cid:68)(cid:84)(cid:75)(cid:80)(cid:81)(cid:73)(cid:71)(cid:80)
`
`(cid:40)(cid:58)(cid:43)(cid:43)(cid:43)
`
`(cid:40)(cid:58)(cid:43)(cid:43)(cid:43)(cid:67)
`
`(cid:37)(cid:84)(cid:81)(cid:85)(cid:85)(cid:78)(cid:75)(cid:80)(cid:77)(cid:71)(cid:70)
`(cid:558)(cid:68)(cid:84)(cid:75)(cid:80)(cid:2)(cid:86)(cid:74)(cid:84)(cid:81)(cid:79)(cid:68)(cid:87)(cid:85)
`
`(cid:56)(cid:71)(cid:85)(cid:85)(cid:71)(cid:78)(cid:2)(cid:89)(cid:67)(cid:78)(cid:78)
`
`(cid:39)(cid:80)(cid:70)(cid:81)(cid:86)(cid:74)(cid:71)(cid:78)(cid:75)(cid:87)(cid:79)
`
`Thrombotic disorders
`
`(cid:50)(cid:78)(cid:67)(cid:86)(cid:71)(cid:78)(cid:71)(cid:86)(cid:15)
`(cid:84)(cid:75)(cid:69)(cid:74)
`(cid:86)(cid:74)(cid:84)(cid:81)(cid:79)(cid:68)(cid:87)(cid:85)
`
`(cid:40)(cid:75)(cid:68)(cid:84)(cid:75)(cid:80)
`
`(cid:50)(cid:78)(cid:67)(cid:86)(cid:71)(cid:78)(cid:71)(cid:86)(cid:85)
`
`(cid:53)(cid:79)(cid:81)(cid:81)(cid:86)(cid:74)
`(cid:79)(cid:87)(cid:85)(cid:69)(cid:78)(cid:71)(cid:2)(cid:69)(cid:71)(cid:78)(cid:78)(cid:85)
`
`(cid:37)(cid:74)(cid:81)(cid:78)(cid:71)(cid:85)(cid:86)(cid:71)(cid:84)(cid:81)(cid:78)
`
`Stroke
`
`Most heart attacks and
`strokes are caused by
`thrombosis, which is
`superimposed on ruptured
`atherosclerotic plaques.
`Strokes can also
`occur when clots in the
`heart break off and
`become lodged in
`arteries in the brain.
`
`(cid:54)(cid:75)(cid:85)(cid:85)(cid:87)(cid:71)(cid:2)(cid:72)(cid:67)(cid:69)(cid:86)(cid:81)(cid:84)
`
`(cid:46)(cid:75)(cid:82)(cid:75)(cid:70)(cid:15)(cid:84)(cid:75)(cid:69)(cid:74)(cid:2)(cid:79)(cid:67)(cid:69)(cid:84)(cid:81)(cid:82)(cid:74)(cid:67)(cid:73)(cid:71)(cid:85)(cid:2)(cid:10)(cid:72)(cid:81)(cid:67)(cid:79)(cid:2)(cid:69)(cid:71)(cid:78)(cid:78)(cid:85)(cid:11)(cid:2)
`(cid:71)(cid:90)(cid:82)(cid:84)(cid:71)(cid:85)(cid:85)(cid:75)(cid:80)(cid:73)(cid:2)(cid:86)(cid:75)(cid:85)(cid:85)(cid:87)(cid:71)(cid:2)(cid:72)(cid:67)(cid:69)(cid:86)(cid:81)(cid:84)(cid:2)
`
` Virchow’s triad. Named after the German
`▶
`physician Rudolf Virchow (1821–1902),
`this triad describes the three conditions
`that contribute to thrombosis.
`
`VTE occurs when a blood clot
`forms in a vein. Such clots
`commonly occur in the deep veins
`of the leg or pelvis; this is known
`as a DVT. Parts of these clots can
`break free and migrate to the
`lungs, where they can lodge in a
`lung artery and cause a pulmonary
`embolism. DVT can occur after
`surgery or in patients who are
`immobilized because of medical
`illnesses.
`
`(cid:35)(cid:78)(cid:86)(cid:71)(cid:84)(cid:71)(cid:70)(cid:2)(cid:88)(cid:71)(cid:85)(cid:85)(cid:71)(cid:78)(cid:78)(cid:2)(cid:89)(cid:67)(cid:78)(cid:78)
`
`▶
`
`Venous and arterial thrombosis
`
`Arterial thrombosis. The primary trigger of
`this is rupture of an atherosclerotic plaque,
`which exposes material that activates platelets
`and triggers coagulation. The coagulation
`cascade (see far right) is initiated by tissue
`factor, which is expressed by lipid-rich
`macrophages that are exposed in the core of
`the ruptured plaque. Activated platelets clump
`together to form aggregates that are held
`together by fibrin. The resultant platelet-rich
`thrombus can then occlude the artery and
`block blood flow.
`
`Supplement to Nature Publishing Group journals
`
`(cid:56)(cid:71)(cid:85)(cid:85)(cid:71)(cid:78)(cid:2)(cid:89)(cid:67)(cid:78)(cid:78)
`
`(cid:39)(cid:80)(cid:70)(cid:81)(cid:86)(cid:74)(cid:71)(cid:78)(cid:75)(cid:87)(cid:79)
`
`(cid:40)(cid:75)(cid:68)(cid:84)(cid:75)(cid:80)(cid:15)(cid:84)(cid:75)(cid:69)(cid:74)
`(cid:86)(cid:74)(cid:84)(cid:81)(cid:79)(cid:68)(cid:87)(cid:85)
`
`(cid:50)(cid:78)(cid:67)(cid:86)(cid:71)(cid:78)(cid:71)(cid:86)(cid:85)
`
`(cid:114)(cid:2)VTE prevention
`(RECORD1–4)
`(cid:114)(cid:2)VTE treatment
`(EINSTEIN-DVT;
`EINSTEIN-PE;
`EINSTEIN-EXT)
`(cid:114)(cid:2)SPAF (J-ROCKET AF;
`ROCKET-AF)
`(cid:114)(cid:2)ACS (ATLAS-TIMI-51)
`(cid:114)(cid:2)VTE prevention
`(ADVANCE 1–3; ADOPT)
`(cid:114)(cid:2)VTE treatment
`(AMPLIFY; AMPLIFY-EXT)
`(cid:114)(cid:2)SPAF (AVERROES;
`ARISTOTLE)
`(cid:114)(cid:2)ACS (APPRAISE-2;
`study terminated)
`
`Direct factor Xa inhibitors
`Rivaroxaban
`(Xarelto;
`Bayer
`Schering
`Pharma)
`
`O
`
`N
`
`O
`
`N
`
`O
`
`O
`
`N
`
`Apixaban
`(Eliquis;
`Bristol-Myers
`Squibb/
`Pfizer)
`
`N
`
`O
`
`Cl
`
`S
`
`O
`
`HN
`
`Approved
`
`O
`
`NH2
`
`N
`
`N
`
`O
`
`CH3
`
`Phase III
`
`Cl
`
`(cid:114)(cid:2)VTE treatment
`(HOKUSAI)
`(cid:114)(cid:2)SPAF (ENGAGE-AF
`TIMI-48)
`
`Phase II/III
`
`(cid:114)(cid:2)VTE prevention
`(cid:114)(cid:2)ACS
`
`O
`
`CH3
`
`O
`
`CH3
`N
`
`CH3
`
`N
`
`O
`
`HN
`
`HN
`
`NH
`
`O
`
`O
`
`S
`
`N
`
`HN
`
`O
`
`HO
`O
`
`NH
`
`N
`
`Edoxaban
`
`H3C
`
`N
`
`Darexaban
`(YM150)
`
`*Indicates the highest phase reached for any indication in any country. ‡Dabigatran is administered
`as the prodrug dabigatran etexilate.
`
`Affiliations
`Jeffrey Weitz is at the Thrombosis and Atherlerosclerosis Research Institute,
`McMaster University, Ontario, Canada. http://www.taari.ca
`He has served as a consultant and has received honoraria from Bayer,
`Bristol-Myers Squibb, Boehringer Ingelheim, Daiich Sankyo, Pfizer and Takeda.
`
`Designed by Susie Lanni; edited by Charlotte Harrison; copyedited
`by Mariam Faruqi.
`© 2011 Nature Publishing Group.
`http://www.nature.com/nrd/posters/warfarin
`
`(cid:52)(cid:71)(cid:70)(cid:2)(cid:68)(cid:78)(cid:81)(cid:81)(cid:70)(cid:2)(cid:69)(cid:71)(cid:78)(cid:78)(cid:85)
`
`▶
`
`(cid:54)(cid:75)(cid:85)(cid:85)(cid:87)(cid:71)(cid:2)(cid:72)(cid:67)(cid:69)(cid:86)(cid:81)(cid:84)
`
`Venous thrombosis. Venous thrombi are rich in
`fibrin and contain fewer platelets than arterial
`thrombi. They form in areas where blood flow is
`sluggish. Such altered blood flow activates the
`endothelium, which triggers coagulation and
`subsequent fibrin generation.
`
`(cid:54)(cid:74)(cid:84)(cid:81)(cid:79)(cid:68)(cid:81)(cid:85)(cid:75)(cid:85)
`
`(cid:35)(cid:68)(cid:80)(cid:81)(cid:84)(cid:79)(cid:67)(cid:78)(cid:2)(cid:68)(cid:78)(cid:81)(cid:81)(cid:70)(cid:2)(cid:559)(cid:81)(cid:89)
`
`(cid:43)(cid:80)(cid:69)(cid:84)(cid:71)(cid:67)(cid:85)(cid:71)(cid:70)(cid:2)(cid:69)(cid:81)(cid:67)(cid:73)(cid:87)(cid:78)(cid:67)(cid:68)(cid:75)(cid:78)(cid:75)(cid:86)(cid:91)
`
`For over 50 years, anticoagulants such as warfarin and other
`vitamin K antagonists have been used to prevent or treat many of
`these disorders. The new oral anticoagulants can overcome many
`of the limitations of vitamin K antagonists. By simplifying long-term
`anticoagulation therapy, more patients could be treated with the
`new agents. In addition, because novel oral anticoagulants produce
`a more predictable level of anticoagulation than warfarin, they are
`easier to administer and are potentially safer and more efficacious.
`
`The intrinsic pathway (also known as the contact pathway) amplifies FX activation. In
`addition to direct activation of FX, the tissue factor–FVIIa complex also activates FIX. FIXa,
`together with its cofactor FVIIIa, then activates FX to generate additional FXa. Both of these
`pathways converge at the final common pathway. FXa, together with its cofactor FVa, forms
`prothrombinase, a complex that efficiently activates prothrombin (FII) to generate thrombin
`(FIIa). Thrombin converts fibrinogen, a soluble protein, into fibrin monomers that polymerize
`to form fibrin strands. FXIIIa crosslinks the fibrin strands to stabilize the thrombus.
`This panel shows the target points of various anticoagulants. Of note, vitamin K antagonists
`— such as warfarin — target multiple factors, as do the heparins (unfractionated heparin and
`LMWH, which are given by injection when an immediate anticoagulant effect is needed).
`By contrast, the new anticoagulants specifically target either FXa or thrombin.
`
`1920s: cattle eating
`spoiled sweet clover noted
`to have bleeding disorder
`
`1948: warfarin, a
`dicoumarol derivative,
`marketed as a rodenticide
`
`Late 1950s: hirudin, a specific
`thrombin inhibitor, isolated from
`leech saliva; served as a prototype
`for the design of thrombin inhibitors
`
`1989: initial crystal
`structure of
`thrombin reported
`
`1990: tick anticoagulant
`protein and antistasin used
`to validate FXa as a target
`
`2006: ximelagatran
`withdrawn from the
`market owing to
`potential liver toxicity
`
`2008: dabigatran and rivaroxaban first
`approved as alternatives to LMWH for
`short-term VTE prevention§
`
`2011: ongoing Phase III trials are
`likely to pave the way for the
`approval of other agents (see
`table) as alternatives to warfarin
`
`1920
`
`1940
`
`1950
`
`1960
`
`1980
`
`1990
`
`2004
`
`2006
`
`2008
`
`2010
`
`2011
`
`1941: substance responsible for
`bovine bleeding disorder identified as
`dicoumarol, a vitamin K antagonist
`
`1950s: warfarin used
`as an anticoagulant
`in humans
`
`1960: first clinical trials
`of anticoagulants
`
`1980s: FXa identified as a
`potential target for new
`anticoagulants
`
`2004: ximelagatran, the first oral
`direct thrombin inhibitor, licensed in
`the EU for short-term VTE prevention§
`
`2010: dabigatran approved as
`an alternative to warfarin for
`use in SPAF
`
`2011: apixaban approved as
`an alternative to LMWH for
`short-term VTE prevention§
`
`About Boehringer Ingelheim GmbH. Research into an oral direct thrombin inhibitor began in
`the early 1990s on the Research and Development Campus of Boehringer Ingelheim in Biberach,
`Germany. Dabigatran etexilate was first synthesized in 1996. This was the starting point for an
`unprecedented development program, including extensive Phase III clinical testing investigating
`Pradaxa® in multiple indications requiring anticoagulation. Among these, RE-LY® was the largest
`atrial fibrillation (AF) study ever completed, which compared two doses of dabigatran etexilate
`(110mg and 150mg bid), administered in a blinded manner, with open label warfarin. The RE-LY®
`trial demonstrated superiority of the 150 mg dose and non-inferiority of the 110 mg dose of
`Pradaxa® over the 50-year old standard of care, warfarin, in preventing stroke in AF. This was
`achieved without additional overall bleeding with the higher dose and significantly less bleeding
`with the lower dose. Importantly, significantly less intracranial bleeding with both doses was seen.
`
`In contrast to warfarin, Pradaxa® does not require routine coagulation monitoring or dose
`adjustments, is not affected by food and has a low potential for drug–drug interactions.
`Dabigatran etexilate is approved for clinical use in stroke risk reduction in non-valvular AF in
`many countries around the globe, including the USA, Canada, Europe and Japan. It is also
`approved in 83 countries for prevention of venous thromboembolic events in adults undergoing
`elective total hip or knee replacement surgery. Boehringer Ingelheim is one of the world’s 20
`leading pharmaceutical companies (http://www.boehringer-ingelheim.com). Since its inception
`in 1885, the family-owned company is committed to researching, developing, manufacturing and
`marketing novel products of high therapeutic value for human and veterinary medicine.
`Headquarters are in Ingelheim, Germany, and it operates globally with 145 affiliates and over
`42,000 employees.
`
`Abbreviations
`ACS, acute coronary syndrome; CYP3A4, cytochrome P450 3A4; DVT,
`deep vein thrombosis; EU, European Union; LMWH, low molecular weight
`heparin; P-gp, P glycoprotein; SPAF, stroke prevention in atrial
`fibrillation; VTE, venous thromboembolism. §After orthopaedic surgery.
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`thromboembolism N. Engl. J. Med. 363, 2499–2451 (2010).
`Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial
`fibrillation. N. Engl. J. Med. 17, 1139–1151 (2009).
`Connolly, S. J. et al. Apixaban in patients with atrial fibrillation.
`N. Engl. J. Med. 364, 806–817 (2011).
`
`Lassen M.R. et al. Apixaban versus enoxaparin for thromboprophylaxis
`after hip replacement. N. Engl. J. Med. 363, 2487–2498 (2010).
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`© 2011 Macmillan Publishers Limited. All rights reserved
`
`1
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`BMS 2005
`MYLAN v. BMS
`IPR2018-00892
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