Annu.Rev.Med.2011.62:41-57.Downloadedfromwww.annualreviews.orgbyMr.
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`JeffreyDillardon11/20/15.Forpersonaluseonly.
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`Annu. Rev. Med. 2011. 62:41-57
`
`First published online as a Review in Advance on
`December 9, 2010
`
`The Annual Review ofMedicine is online at
`med.annualreviews.org
`This a11icle’s doi:
`10.1 146/annurev-med—062209-095 1 59
`
`Copyright © 2011 by Annual Reviews.
`All rights reserved
`0066-4219/11/0218—0041$20.00
`
`Novel Oral Factor Xa
`
`and Thrombin Inhibitors
`
`in the Management
`of Thromboembolism
`
`Bengt I. Eriksson,1 Daniel]. Quinlan}
`and John W. Eikelboom3
`
`1DeparUnent of Orthopaedics, Sahlgrenska University Hospital, Molndal, Sweden;
`email: b.eriksson@o1thop.gu.se
`2Depamnent of Radiology, Kings College Hospital, London, United Kingdom;
`email: dan.quinlan@consultoberon.com
`3Thrombosis Service, McMaster University, Hamilton General Hospital, Ontario, Canada;
`email: eikelbj@mcmaster.ca
`
`Keywords
`
`anticoagulants, factor Ila inhibitors, factor Xa inhibitors, thrombin
`inhibitors
`
`Abstract
`
`The last decade has seen the evaluation of several new oral antico-
`
`agulants that directly target thrombin or activated factor X (FXa). All
`demonstrate a rapid onset of action, a low potential for food and drug in-
`teractions, and a predictable anticoagulant eifect that obviates the need
`for routine coagulation monitoring. Those agents at the most advanced
`stages of clinical development are a direct thrombin inhibitor, dabiga—
`tran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran
`and rivaroxaban are approved in more than 70 countries for prevention
`ofvenous thromboembolism in patients undergoing elective hip or knee
`arthroplasty, and apixaban is being considered for approval by regula-
`tory agencies for this indication. Dabigatran was shown in a large phase
`III trial to be more elfective and safer than warfarin for the prevention
`of stroke or systemic embolism in patients with atrial fibrillation and
`has recently been approved for this indication. Edoxaban, an oral FXa
`inhibitor, is also being evaluated in phase III clinical trials. This review
`summarizes the pharmacology, clinical trial results, and fiiture role of
`the new oral anticoagulants in clinical practice.
`
`BMS 2008
`CFAD V. BMS
`
`'
`
`|PR2Q’1I5-01723
`
`

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`VKA: vitamin K
`
`antagonist
`FII21: activated
`factor II
`
`FXa: activated
`factor X
`
`DTI: direct thrombin
`inhibitor
`
`VTE: venous
`thromboembolism
`
`AF: atrial fibrillation
`
`INTRODUCTION
`
`Unfractionated heparin and warfarin have
`been available for more than 50 years but have
`important limitations. Several new parenteral
`anticoagulants,
`including
`low-molecular-
`weight heparins and the synthetic pentasac-
`charide fondaparinux, have been introduced as
`replacements for unfractionated heparin, but
`the development of new oral agents to replace
`warfarin and other vitamin K antagonists
`(VKAs) has been much slower. Efforts to find
`a replacement for VKAs have focused on the
`development of nonpeptidic, orally available,
`small molecules that directly inhibit one of
`two key serine proteases in the coagulation
`cascade, thrombin [activated factor II (FIIa)]
`and activated factor X (FXa). Dabigatran
`etexilate, a direct thrombin inhibitor (DTI),
`and rivaroxaban, a selective FXa inhibitor,
`are approved in more than 70 countries for
`the prevention of venous thromboembolism
`(VTE) in patients undergoing hip or knee
`arthroplasty. In addition, the recently reported
`RE-LY and RE-COVER trials comparing
`dabigatran with warfarin for stroke prevention
`in atrial fibrillation (AF) and for the treat-
`ment and secondary prevention of VTE (1,
`2),
`respectively, and the EINSTEIN trials
`comparing rivaroxaban with warfarin for the
`treatment and secondary prevention of VTE
`(3, 4), demonstrate the potential of the new oral
`anticoagulants to replace VKAs for long-term
`treatment. Two other oral factor Xa inhibitors,
`apixaban and edoxaban, are in advanced stages
`of clinical development but neither has yet
`been approved for use.
`In this article, we review the limitations of
`the VKAs that prompted the development of
`new oral agents, summarize the pharmacolog-
`ical characteristics of the new oral anticoagu-
`lants, critically review the results of phase III
`randomized controlled trials that have evalu-
`
`ated their effectiveness, and evaluate the oppor-
`tunities for new oral anticoagulants in dilferent
`clinical indications.
`
`LINIITATIONS OF VITAMIN K
`ANTAGONISTS
`
`VKAs, such as warfarin, are the only orally ac-
`tive anticoagulants that are licensed for long-
`term use, but they have important limitations.
`VKAs have a slow onset of action, a narrow
`therapeutic window, and an unpredictable an-
`ticoagulant effect resulting from multiple food
`and drug interactions and genetic polymor-
`phisms that affect drug metabolism (CYP2 C9)
`and vitamin K turnover (VKORC1). Because
`VKAs have a slow onset of action, patients who
`require an immediate anticoagulant elfect re-
`quire bridging therapy with a rapidly acting
`agent (e.g., heparin). Because VKAs interact
`with food and drugs, patients must take dietary
`precautions, and prescribers must take special
`care when modifying concomitant drug ther-
`apy. Because of their unpredictable anticoagu-
`lant elfects, VKAs require routine coagulation
`monitoring and dose adjustment to maintain
`the international normalized ratio (INR) within
`the target range (5).
`The need for bridging anticoagulation, di-
`etary and drug restrictions, and routine coag-
`ulation monitoring is inconvenient for patients
`and costly for the health care system, and so it
`has contributed to the underuse of VKAs. Even
`
`when VKAs are appropriately used for stroke
`prevention in patients with AF, the INR is fre-
`quently outside of the therapeutic range, lead-
`ing to ineffective anticoagulation or increased
`bleeding risk (6). Poor anticoagulant control
`in patients with AF receiving VKA therapy for
`stroke prevention (where “poor” control is de-
`fined as <60% of the time in a target INR range
`of 2-3) doubles the frequencies of stroke, ma-
`jor bleeding, and death compared with those
`achieving good control (>75 % of the time with
`an INR of 2-3) (7). An effective and safe re-
`placement for VKAs with a more rapid onset of
`action, a low potential for food and drug inter-
`actions, and a predictable anticoagulant effect
`that obviates the need for routine coagulation
`monitoring is urgently required.
`
`42
`
`Eriktron 0 Quinlan 0 Ei/zelboam
`
`

`
`FEATURES OF NOVEL ORAL
`ANTICOAGULANTS
`
`The new oral anticoagulants in the most ad-
`vanced stages of development inhibit either
`thrombin or FXa (Figure 1).
`Thrombin plays a central role in blood coag-
`ulation and thrombus (clot) formation by con-
`verting fibrinogen to fibrin and amplifying its
`own generation by feedback activation of fac-
`tors V, VIII, and XI. Thrombin also is the most
`potent platelet agonist. DTIs directly neutral-
`ize thrombin by occupying the catalytic bind-
`ing site, fibrinogen binding site, or both. DTIs
`also inhibit both fluid-phase and fibrin-bound
`thrombin. Clinical results with parenteral DTIs
`(e.g., hirudin, bivalirudin, argatroban) and a
`previously developed oral DTI (ximelagatran)
`validate thrombin as a target for new oral
`anticoagulants (8, 9).
`FXa, which is located at the junction of the
`intrinsic and extrinsic pathways, is another tar-
`get for new oral anticoagulants. FXa binds to
`FVa on the surface of activated platelets to form
`the prothrombinase complex, which converts
`prothrombin to thrombin. Inhibitors of FXa at-
`tenuate thrombin generation, thereby prevent-
`ing the conversion of fibrinogen to fibrin. Oral
`FXa inhibitors bind directly to the active site of
`FXa and block the interaction with its substrate.
`
`In contrast to indirect FXa inhibitors, such as
`fondaparinux, direct FXa inhibitors inactivate
`free FXa and FXa incorporated within the pro-
`thrombinase complex equally well. Clinical re-
`sults with the parenteral agent, fondaparinux,
`validate FXa as a target for new oral anticoag-
`ulants (10, 11).
`Advantages of the new oral anticoagulants
`over VKAs include a rapid onset of action, no
`
`
`
`
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`Annu.Rev.Med.2011.62:41-57.Downloadedfromwww.annualreviews.orgbyMr.
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`Steps in coagulation
`
`Coagulation pathway
`
`Drugs
`
`Initiation
`
`@
`
`X
`
`IX
`
`Propagation
`
`\W|Xa/
`
`Va
`
`Rivaroxaban
`Apixaban
`(_________ _ _ Edoxaban
`YM1 50
`Betrixaban
`TAK—442
`
`Fibrin formation
`
`<--------- -- Dablgatran etexllate
`AZD0837
`
`Fibrinogen j> Fibrin
`
`Figure 1
`New oral anticoagulants and their targets in the coagulation pathway.
`
`significant food interactions, low potential for
`drug interactions, and a predictable anticoag-
`ulant effect that obviates the need for routine
`
`coagulation monitoring (Table 1). Because of
`their rapid onset of action, the new oral anti-
`coagulants have the potential to be used both
`in acute and chronic settings. The pharmaco-
`logical characteristics of the new oral anticoag-
`ulants that are most advanced in clinical devel-
`
`opment are compared in Table 2.
`
`DIRECT THROMBIN
`INHIBITORS
`
`Ximelagatran, the prodrug of melagatran, was
`the first orally available small—molecule re-
`versible DTI to undergo clinical evaluation.
`Although ximelagatran proved to be an effec-
`tive oral anticoagulant, prolonged therapy with
`ximelagatran resulted in idiosyncratic hepatic
`
`Table 1 Advantages of new oral anticoagulants compared with vitamin K antagonists
`
`Advantage
`Rapid onset of action
`Predictable anticoagulant elfect
`Specific coagulation enzyme target
`Low potential for food interactions
`Low potential for drug interactions
`
`Clinical implications
`No need for bridging
`No need for routine coagulation monitoring
`Low risk of olf—target adverse elfects
`No dietary precautions
`Few drug restrictions
`
`ww7v.annualrevie71/Lorg 0 New 0mlAntitoagulantr
`
`43
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`Table 2 Comparison of the pharmacological characteristics of new oral direct thrombin and FXa inhibitors in late-stage
`clinical development“
`
`Parameter
`Target
`oralbioavauabuiry
`Dosing
`Pro-drug
`Ha1f—Iife<h>
`
`monitoring
`
`Reneleleeranee
`Potential drug
`interactions
`Involvement of CYP
`Clinical status
`
`Edoxebau
`Feetorxe
`50%
`Fixed, once daily
`No
`9-11
`
`Rifampicin, quinidine, amiodarone,
`potent P-gp inhibitors
`
`Approved in >70 countries“
`
`Potent inhibitors of
`CYP3A4 and P—gpb
`CYP3A4
`Approved in >70
`countries“
`
`Potent CYP3A4
`inhibitorsb
`CYP3A4
`Phase 111
`
`35%
`Potent inhibitors of
`CYP3A4 and P-gp
`CYP3A4
`Phase III
`
`“The table does not include data for AZD0837, betrixaban, YMISO, and TAK-442, which remain in early stages of clinical development.
`bCYP, cytochrome P-450 isoenzymes; P-gp, P-glycoprotein. Strong inhibitors of both CYP3A4 and P-gp include azole antifungals (e.g., ketoconazole,
`itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Potent CYP3A4 inhibitors include azole antifiingals, macrolide
`antibiotics (e.g., clarithromycin), and protease inhibitors (e.g., atanazavir).
`°Approved for the prevention of venous thromboembolism after hip and knee arthroplasty. Dabigatran is also approved in the U.S. and Canada for stroke
`prevention in patients with AF. Phase III trials are ongoing in other clinical indications.
`
`toxicity, and it was subsequently withdrawn
`from the market in 2006. Ximelagatran did
`however have many desirable properties, and
`experience with the drug demonstrated that an
`oral anticoagulant specifically targeting throm-
`bin without routine monitoring could be as
`effective as VKAs in the prevention and treat-
`ment of VTE and stroke prevention in pa-
`tients with AF, with no increase in bleeding.
`Confirmation of the suitability of thrombin as
`a target comes from subsequent studies with
`dabigatran, which, unlike ximelagatran, is not
`hepatotoxic.
`
`Dabigatran Etexilate
`
`Dabigatran etexilate is the prodrug of dabiga-
`tran, which reversibly inhibits the active site of
`thrombin. Oral bioavailability is ~6%. Follow-
`ing oral administration, dabigatran etexilate is
`rapidly converted to dabigatran by esterases in
`the blood and liver with peak plasma concentra-
`tions achieved 2-3 h after oral administration.
`
`Dabigatran is not metabolized and does not
`inhibit cytochrome P-45 0 (CYP) isoenzymes
`
`Erikrron 0 Quinlan 0 Ei/zelboom
`
`(12). About 80% of the drug is excreted un-
`changed via the kidneys with the remainder
`conjugated and excreted via the biliary system.
`Dabigatran is contraindicated in patients with
`severe renal impairment [creatinine clearance
`(CLCR) <3 0 mL/min]. For patients undergoing
`hip or knee arthroplasty who have moderate re-
`nal impairment (CLCR 3 0-50 mL/min), a lower
`dose (150 mg once daily) is recommended in
`place of the usual dose of 220 mg once daily (1 3).
`The half-life of dabigatran is 12-14 h, which
`permits once- or twice-daily dosing (12).
`Dabigatran etexilate is a substrate for the ef-
`flux transporter P-glycoprotein (P-gp) in the
`intestine, and coadministration of a P-gp in-
`hibitor increases blood levels of dabigatran by
`decreasing efliux of the prodrug. Amiodarone
`and verapamil are moderately potent inhibitors
`of P-gp and increase blood levels of dabigatran
`by ~50%. Consequently, a lower dose of dabi-
`gatran (150 mg once daily) is recommended for
`VTE prevention in patients taking amiodarone
`or verapamil. Quinidine is a strong P-gp in-
`hibitor and should not be used in conjunction
`with dabigatran (13).
`
`

`
`Based on promising results in phase II
`trials, dabigatran was investigated in four large
`phase III trials for prevention of VTE after
`total hip arthroplasty [RE-NOVATE (14),
`n = 3,494; RE-NOVATE II (15), n = 2,055]
`and total knee arthroplasty [RE-MODEL (16),
`n = 2076; RE-MOBILIZE (17), n = 2,615].
`RE-NOVATE
`and RE-MODEL were
`
`conducted mainly in Europe and used the
`European approved dose of enoxaparin (40 mg
`once daily with the first dose given in the
`evening before surgery) as the comparator,
`whereas RE-MOBILIZE was conducted pre-
`dominantly in the United States and Canada
`and used the North American—approved dose
`of enoxaparin (30 mg twice daily starting 12
`to 24 h after surgery) as the comparator. RE-
`NOVATE II is the most recently completed
`trial and involved patients from both Europe
`and North America. In the first three trials,
`two doses, 220 mg and 150 mg once daily,
`were compared with enoxaparin. Both RE-
`MODEL and RE-NOVATE demonstrated
`
`noninferiority for
`
`the primary outcome,
`)
`
`Figure 2
`Pooled estimates of the results of randomized
`
`controlled trials comparing the elfects of new oral
`anticoagulants versus enoxaparin on total venous
`thromboembolism (VTE) and all—cause mortality,
`and major bleeding among patients undergoing hip
`or knee arthroplasty. The new anticoagulant
`regimens evaluated in the trials were dabigatran
`220 mg once daily (14-17), rivaroxaban 10 mg once
`daily (18-21), and apixaban 2.5 mg twice daily
`(22-24) and the comparator regimens were
`enoxaparin 40 mg once daily or 30 mg twice daily.
`Elfect estimates were calculated using the Mantel-
`Haenszel method under a fixed—elfects model and
`
`are presented as risk ratios and 95% CIs (log scale).
`In panel a, “efficacy” refers to total VTE and
`all—cause mortality. *Heterogeneity: p = 0.12,
`I2 = 49%; overall elfect: p = 0.58. ’[Heterogeneity:
`p = 0.0003, 12 = 84%; overall elfect: p < 0.00001.
`iHeterogeneity: p = 0.0001, 12 = 89%; overall
`effect: p < 0.00001. In panel 17, “bleeding risk”
`refers to major bleeding as defined in the individual
`trials. *Heterogeneity: p = 0.24, I2 = 28%; overall
`effect: p = 0.66. ’[Heterogeneity: p = 0.70,
`I2 = 0%; overall elfect: p = 0.07. iHeterogeneity:
`p = 0.16, I2 = 45%; overall elfecr: p = 0.21.
`
`
`
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`Annu.Rev.Med.2011.62:41-57.Downloadedfromwww.annualreviews.orgbyMr.
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`
`which was a composite of symptomatic or
`asymptomatic deep vein thrombosis (DVT),
`nonfatal pulmonary embolus (PE) (hereafter
`_
`called total V IE), and all-cause mortality,
`with p-values of 0.0003 and <0.0001, respec-
`tively (Figure 2a). These data formed the
`basis for approval of the drug by European
`and Canadian regulators in 2008. The third
`trial, RE-MOBILIZE, did not demonstrate
`
`DVT: dee vein
`thmmbosisp
`
`a Efficacy
`
`Dabigatran
`RE—MODEL
`RE-MOBILIZE
`RE-NOVATE
`RE-NOVATE II
`Overall
`
`-I,-
`:-o-
`—I4.—
`—I-l—
`':|'
`
`E
`Rivaroxaban
`jlj I
`RECORD1
`:
`RECORD2 —-Z
`RECORD3
`—|— I
`RECORD4
`—I— I
`I
`Overall
`-0-
`l
`
`Apixaban
`ADVANCE—1
`ADVANCE—2
`ADVANCE—3
`Overall
`
`0.1
`
`E
`—ll—
`—I— l
`—-—
`
`—I— :
`Favors oral drug
`I
`1.0
`Risk ratio (log scale)
`
`Favors enoxaparin
`
`Risk ratio (95% CI)
`0.97 (0.82-1.13)
`1.23 (1.03-1.47)
`0.90 (0.63-1.29)
`0.88 (0.63—1 .22)
`1.03 (0.93—1.15)*
`
`0.30 (0.18—0.51)
`0.21 (0.13-0.35)
`0.51 (0.39-0.65)
`0.69 (0.51 -0.92)
`0.46 (0.39—0.54)’r
`
`1 .02 (0.78—1 .32)
`0.62 (0.51-0.74)
`0.36 (0.23—o.s6)
`0.67 (0.58—0.77)=l=
`
`10.0
`
`b Bleeding risk
`
`Dabigatran
`RE—MODEL
`RE-MOBILIZE
`RE-NOVATE
`RE-NOVATE II
`Overall
`
`Rivaroxaban
`RECORD1
`RECORD2
`RECORD3
`RECORD4
`Overall
`
`Apixaban
`ADVANCE—1
`ADVANCE—2
`ADVANCE—3
`Overall
`
`
`
`Risk ratio (95% CI)
`1.14 (0.46-2.78)
`0.42 (0.15-1.19)
`1.29 (0.70-2.37)
`1.54 (0.67—3.55)
`1.09 (0.74—1.61)*
`
`3.02 (0.61 -14.95)
`1 .00 (0.06—l 5.98)
`1 .1 8 (0.40-3.52)
`2.47 (0.78—7.86)
`1.85 (0.94—3.63)'l'
`
`0.50 (0.24-1.02)
`0.65 (0.28—1.49)
`1.22 (0.65-2.26)
`0.78 (0.52—1.16)$
`
`0.1
`
`1.0
`Risk ratio (log scale)
`
`10.0
`
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`PE: pulmonary
`embolus
`
`ACS: acute coronary
`syndrome
`
`noninferiority for the primary outcome (2 5.3 %
`for enoxaparin versus 31.1% for 220 mg, risk
`difference +5.8%, 95% CI, 0.8—10.8; p = 0.02
`and 33.7% for 150 mg, risk difference +8.4%,
`95% CI, 3.4—13.3; p = 0.0009). However, both
`treatments were similar for the secondary com-
`posite outcome, major VTE (symptomatic or
`asymptomatic proximal DVT, nonfatal or fa-
`tal PE) plus VTE-related mortality (3 .4% with
`220 mg, 3.0% with 150 mg, and 2.2% with
`enoxaparin) and symptomatic DVT (0.8%,
`0.7%, and 0.6%). There were no differences
`in bleeding rates (Figure 2b), hepatic en-
`zyme elevations, or acute coronary syndrome
`(ACS) events between the two treatments. The
`RE-NOVATE II trial showed that five weeks
`
`of treatment with dabigatran 220 mg once daily
`was as effective as enoxaparin 40 mg once daily
`for prevention of total VTE events and all-
`cause mortality (p < 0.0001 for noninferiority)
`in patients undergoing hip arthroplasty with a
`similar risk of bleeding (15). Treatment with
`dabigatran was, however, superior to enoxa-
`parin for the secondary composite outcome of
`major VTE plus VTE-related mortality (2.2%
`for dabigatran versus 4.2% for enoxaparin,
`p = 0.029).
`The long-term use of dabigatran for the
`prevention of stroke in patients with AF, as
`a replacement for VKAs, was investigated in
`RE-LY, a prospective randomized multina-
`tional phase III trial with blinded evaluation of
`all outcomes (1). Two blinded doses of dabiga-
`tran (110 mg or 150 mg twice daily) were com-
`pared with open-label warfarin (targeted INR
`2-3) in 18,113 patients with nonvalvularAF and
`at least one other major risk factor for throm-
`boembolism. The minimum follow-up was one
`year.
`
`After a median follow-up of two years, the
`rate of stroke or systemic embolism (including
`hemorrhagic stroke) was similar in the warfarin
`group (1.69% per year) and the group that
`received dabigatran 110 mg twice daily (1.53 %
`peryear, p < 0.001 for noninferiority), and sig-
`nificantly lower in the group given dabigatran
`150 mg twice daily (1.11% per year, [1 < 0.001
`for both noninferiority and
`superiority)
`
`En’/arson 0 Quinlan 0 Ei/zelboom
`
`(Figure 3). The major bleeding risk associated
`with dabigatran 150 mg twice daily was compa-
`rable to that observed with warfarin (3.1% per
`year versus 3.4% per year, p = 0.31), whereas
`dabigatran 110 mg twice daily was associated
`with a significantly lower rate of major bleeding
`than warfarin (2.7% per year, p = 0.003) (1).
`For both doses of dabigatran,
`the rates of
`intracranial, life-threatening, minor, and total
`bleeding were significantly lower than with
`warfarin. Dabigatran 150 mg twice daily sig-
`nificantly increased gastrointestinal bleeding
`compared with warfarin, and both doses of
`dabigatran were associated with higher rates of
`myocardial infarction (MI) than warfarin [dabi-
`gatran 110 mg twice daily: 0.72% (p = 0.07);
`dabigatran
`150 mg twice
`daily:
`0.74%
`(p = 0.048); warfarin 0.53 %]. The mechanism
`of increased MI remains uncertain. The mor-
`
`tality rate was 4.13 % per year in the warfarin
`group compared with 3.75% per year with
`110 mg ofdabigatran (p = 0.13) and 3.64% per
`year with 150 mg of dabigatran (p = 0.051).
`There was no signal for liver toxicity or other
`adverse events with dabigatran except for an
`increase in dyspepsia compared with warfarin.
`In contrast to previous trials,
`in which the
`vast majority of patients were on VKAs at the
`time of trial entry, RE-LY included a balanced
`representation ofwarfarin-naive (<2 months of
`VKA) and warfarin-experienced patients. Con-
`sistent benefits of dabigatran were seen whether
`patients were warfarin-naive or experienced.
`Patients in the dabigatran groups who com-
`pleted RE-LY were offered the possibility of
`continuing in the open-label long-term safety
`extension trial, RELY-ABLE. More than 6,000
`patients have been enrolled for up to 28 months
`of treatment, with results expected in 2011.
`The use of dabigatran for treatment and sec-
`ondary prevention ofVTE, as a replacement for
`VKAs, has been studied in RE-COVER, which
`compared six months of dabigatran 15 0 mg
`twice dailywith warfarin (dosed to achieve a tar-
`get INR of 2-3) preceded by initial treatment
`(5-10 days) with an approved parenteral anti-
`coagulant for treatment of acute symptomatic
`VTE (2). Rates of the primary efficacy outcome,
`
`

`
`I
`l
`Dabigatran (1 10 mg)
`—I-l-
`Stroke or systemic embolism
`-I- E
`Major bleeding
`Hemorrhagic stroke élj :
`Death
`-01-
`I
`
`I
`Dabigatran (150 mg)
`—I— E
`Stroke or systemic embolism
`-If
`Major bleeding
`Hemorrhagic stroke élj I
`
`Death
`
`0.1
`
`Favors dabigatran
`
`Favors warfarin
`
`-I-l
`E
`1.0
`Relative risk (log scale)
`
`Relative risk (95% Cl)
`0.91 (0.74—1.11)
`0.80 (0.69—0.93)
`0.31 (0.i7—0.56)
`0.91 (0.80—1.03)
`
`0.66 (0.53—0.82)
`0.93 (0.81—1.07)
`0.26 (0.14—0.49)
`
`0.88 (0.77—1.00)
`
`10.0
`
`
`
`
`
`Annu.Rev.Med.2011.62:41-57.Downloadedfromwww.annualreviews.orgbyMr.
`
`
`
`JeffreyDillardon11/20/15.Forpersonaluseonly.
`
`Figure 3
`Results of the RE—LY trial for the primary outcome event of stroke or systemic embolism, major bleeding
`and important safety endpoints (hemorrhagic stroke), and death (1). Point estimates and 95% CIs are shown.
`
`recurrent symptomatic VTE and VTE-related
`death, were 2.4% and 2.1% in the dabigatran
`and warfarin groups, respectively (p < 0.001
`for noninfeiioiity). Rates of major bleeding
`were 1.6% and 1.9% in the dabigatran and war-
`farin groups, respectively; rates of any bleed-
`ing were 16.1% and 21.9%, respectively (p <
`0.05). The results of additional phase III trials
`in VTE treatment (RE-COVER II, 12 = 2,550)
`and secondary prevention of VTE (two trials,
`12 = 4,095) will be available in 2011 (Table 3).
`A phase II dose-ranging trial assessing the
`safety and efficacy of dabigatran in the preven-
`tion of ischemic events in subjects with ACS has
`been reported (26). Dabigatran was associated
`with low rates of major bleeding, the primary
`outcome of the study, but it is unclear whether
`a phase III trial will be performed for this
`indication.
`
`AZD0837
`
`AZD083 7 is the prodrug of AR-H06763 7, with
`oral bioavailability of 22 % to 55%. It has supe-
`rior pharmacological properties compared with
`its predecessor, ximelagatran, and appears to be
`devoid of liver toxicity. Plasma levels of AR-
`H067637 peak 0.7-1.5 h after oral administra-
`tion, and the mean half-life is 9 h after single
`oral doses (15-750 mg) ofAZD0837 in solution
`(12). An extended-release formulation has been
`developed, potentially enabling once-daily
`
`significant peak-to-trough
`
`dosing without
`variability.
`Limited phase II trials evaluating AZD083 7
`have been completed (12), exposing >900 pa-
`tients to at least three months of treatment
`
`(longest exposure ~16 months). ASSURE, a
`phase III trial comparing AZD0837 (175 mg
`once daily) to warfarin for the prevention of
`stroke or systemic embolism in patients with
`AF, was halted in 2008 because of stability prob-
`lems with the oral formulation. Although this
`issue was subsequently resolved, it is unclear
`whether there will be further development of
`AZD0837.
`
`ORAL FACTOR Xa INHIBITORS
`
`Rivaroxaban
`
`Rivaroxaban is an orally active FXa inhibitor
`with oral bioavailability reported to be >80%
`(12). Absorption is rapid with maximal antico-
`agulant effects achieved 2-4 h after oral dos-
`ing. Rivaroxaban has a dual mechanism of ex-
`cretion; one third is cleared as unchanged drug
`via the kidneys, one third is metabolized by the
`liver via CYP3A4-dependent and -independent
`pathways with the metabolites then excreted in
`the feces, and one third is metabolized in the
`liver with the inactive metabolites then elimi-
`
`nated via the kidneys. Rivaroxaban has a half-
`life of 5-9 h in young subjects, increasing to
`
`71/w71/.annualreview.r.0rg 0 New 0mlAntitoagulant.r
`
`47
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`
`
`Annu.Rev.Med.2011.62:41-57.Downloadedfromwww.annualreviews.orgbyMr
`
`
`
`JeffreyDillardon11/20/15Forpersonaluseonly
`
`11-13 h in elderly subjects. In subjects with
`moderate renal impairment, overall exposure
`is 50% higher than that in controls (12). Ri-
`varoxaban is generally administered once daily,
`although the drug is given twice daily for the
`initial treatment of patients with VTE and in
`patients with ACS.
`Intestinal excretion of rivaroxaban is me-
`
`diated in part by P-gp, because potent P-gp
`inhibitors increase drug levels (12). Concomi-
`tant administration of potent inhibitors of both
`P-gp and CYP3A4, such as ketoconazole and
`ritonavir, is contraindicated because they sub-
`stantially increase plasma drug levels (2 7).
`Based on promising results in phase II tri-
`als, rivaroxaban was investigated in four large
`phase III trials for prevention ofVTE after total
`hip arthroplasty [RECORD1 (18), 12 = 4,541;
`RECORD2 (19), 12 = 2,509] and total knee
`arthroplasty [RECORD3 (20), n = 2,531;
`RECORD4 (21), n = 3,148]. The RECORD1,
`-2, and -3 trials used enoxaparin 40 mg once
`daily as the comparator, whereas RECORD4
`used enoxaparin 30 mg twice daily as the
`comparator. RECORD1, -3, and -4 compared
`equivalent durations of treatment with both
`drugs; the RECORD2 trial compared a 31-
`to 39-day course of rivaroxaban versus a 10-
`to 14-day course of enoxaparin followed by
`21 to 25 days of placebo. In all four trials,
`the dose of rivaroxaban was 10 mg once daily,
`started 6-8 h after wound closure. All four
`
`trials demonstrated superiority for rivaroxaban
`over enoxaparin for the primary outcome, a
`composite of total VTE and all-cause mor-
`tality (Figure 2a). There were no significant
`differences in the rates of major bleeding
`(Figure 211) or hepatic enzyme elevations
`between the two treatments.
`In both the
`
`RECORD2 and -3 trials, rivaroxaban signif-
`icantly reduced the incidence of symptomatic
`VTE compared with enoxaparin. Pooled
`analyses of the RECORD trials revealed a
`small but significant increase in major plus
`clinically relevant nonmajor bleeding with
`rivaroxaban (28). The phase III
`trial data
`formed the basis for European and Canadian
`approval in 2008. Approval by the US. Food
`
`and Drug Administration (FDA) was deferred
`pending long-term safety data.
`The use of rivaroxaban for the secondary
`prevention ofVTE, as a replacement for VKAs,
`has been studied in EINSTEIN-EXT, which
`compared rivaroxaban 20 mg once daily ver-
`sus placebo in patients who had completed 6-
`12 months of anticoagulant treatment for their
`acute episode of VTE (3). Rates of the primary
`elficacy outcome after a median of six months
`treatment, recurrent symptomatic VTE, were
`1.3 % and 7.1% in the rivaroxaban and placebo
`groups, respectively (risk reduction 82%, p <
`0.0001). Rates ofmajor bleedingwere 0.7% and
`0% in the rivaroxaban and placebo groups, re-
`spectively, and the composite ofmajor and clin-
`ically relevant nonmajor bleeding were 6.0%
`and 1.2%, respectively (p < 0.001).
`Phase II dose-ranging trials assessing the
`safety and efficacy of rivaroxaban in the pre-
`vention of ischemic events in subjects with
`ACS (29) and patients with symptomatic DVT
`(30) have been reported. A large phase III
`trial
`(12 =
`14,266) comparing rivaroxaban
`(20 mg once daily) versus warfarin for pre-
`vention of stroke or systemic embolism in pa-
`tients with AF (31) completed enrollment in
`May 2010, and the results are expected to be
`presented in November 2010. A phase III trial
`comparing rivaroxaban (15 mg twice daily for
`3 weeks followed by 20 mg once daily for 3-
`12 months) versus enoxaparin followed byVKA
`for the treatment of acute symptomatic DVT
`without symptoms of PE (EINSTEIN-DVT,
`12 = 3,465) demonstrated that patients treated
`with rivaroxaban had a similar rate of symp-
`tomatic recurrent VTE (fatal or nonfatal, 2.1%
`versus 3.0%, p < 0.0001 for non-inferiority)
`and bleeding (defined as the composite of ma-
`jor and clinically relevant nomnajor bleeding,
`8.1% in both treatment groups, p = 0.77) as
`those treated with standard therapy (4). Ongo-
`ing phase III trials (Table 2) are investigating
`rivaroxaban in PE treatment (12 = 4,000), pri-
`mary prevention of VTE in acutely ill medi-
`cal patients (n = 8,000), and the prevention
`of recurrent ischemia in patients with ACS
`(12 = 16,000).
`
`wwu/.annualreview.r.0rg 0 New 0mlAntitoagulant.r
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`49
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`Annu.Rev.Med.2011.62:41-57.Downloadedfromwww.annualreviews.orgbyMr
`
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`
`Apixaban
`
`Apixaban is an orally active, reversible in-
`hibitor of FXa. Absorption is rapid with maxi-
`mal plasma concentrations achieved 1-3 h after
`oral administration (12). Lower peak-to-trough
`concentration ratios are observed with twice-
`
`daily versus once-daily dosing regimens, result-
`ing in a preference for twice-daily dosing. The
`drug has a mean half-life of 8-15 h in healthy
`young subjects.
`Apixaban and its metabolites are excreted
`by multiple elimination pathways, including re-
`nal excretion (25%), hepatic metabolism via
`CYP3A4-dependent mechanisms, and intesti-
`nal excretion (~5 5 %). The multiple elimina-
`tion pathways raise the possibility that patients
`with hepatic or renal impairment can be treated
`with apixaban. Concomitant treatment with po-
`tent inhibitors of CYP3A4 such as ketoconazole
`
`is contraindicated in apixaban-treated patients
`(12).
`Based on promising results observed in a
`phase II study in patients undergoing knee
`arthroplasty, apixaban was investigated in three
`large phase III trials for prevention of VTE
`after total knee arthroplasty [ADVANCE-1
`(22), n = 3,195; ADVANCE-2 (23), n =
`3,057] and hip arthroplasty [ADVANCE-3,
`12 = 5,407 (24)]. ADVANCE-1 used enoxa-
`parin 30 mg twice daily as the comparator,
`whereas ADVANCE-2 and -3 used enoxaparin
`40 mg once daily as the comparator. In all three
`trials, the dose of apixaban was 2.5 mg twice
`daily, started in the morning of the day after
`surgery. In ADVANCE-1, a 12-day course of
`apixaban had efficacy similar to an equal du-
`ration of treatment with enoxaparin with to-
`tal VTE plus all-cause mortality rates of 9.0%
`and 8.8%, respectively. Major bleeding rates
`were 0.7% with apixaban and 1.4% with enoxa-
`parin (p = 0.053). Despite similar efficacy,
`apixaban did not meet the prespecified non-
`inferiority goal because the event rates in the
`control group were much lower than expected.
`In ADVANCE-2, the same apixaban regimen
`significantly reduced total VTE plus all-cause
`mortality compared with enoxaparin (15.1%
`
`and 24.4%, respectively; p < 0.0001) and was
`associated with a similar risk of bleeding (ma-
`jor bleeding, 0.6% and 0.9%, respectively; p =
`0.30). In ADVANCE-3, five weeks of treat-
`ment with apixaban in patient