`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Introduction
`
`Pharmacology
`
`Preclinical pharmacologic
`studies in animal models
`
`Pharmacokinetic and
`pharmacodynamic studies
`in humans
`
`Clinical trials
`
`Potential disadvantages
`of apixaban
`
`7.
`
`Expert opinion and conclusions
`
`Drug Evaluation
`
` Apixaban, an oral direct Factor Xa
`inhibitor: awaiting the verdict
` Jennifer Carreiro & Jack Ansell †
` Lenox Hill Hospital, New York, USA
`
` For the last half-century, despite its many limitations warfarin has been the
`mainstay of treatment for patients with venous and arterial thromboembolic
`disease. During the past decade, a number of new oral anticoagulant
`agents have been developed that may offer an alternative to warfarin.
`Emerging data suggest that Factor Xa may be a target for inhibition.
`Apixaban is one such agent. It is a potent, selective, reversible, and orally
`bioavailable FXa inhibitor that demonstrates antithrombotic efficacy, with a
`favorable pharmacokinetic profile. At present, the safety and efficacy of
`apixaban for the prophylaxis and treatment of venous thromboembolism is
`being evaluated in Phase II and Phase III trials involving nearly 25,000
`patients. Trials are also underway involving over 20,000 patients for secondary
`prevention after acute coronary syndromes and the prevention of stroke in
`patients with non-valvular atrial fibrillation. This review article discusses the
`discovery, pharmacokinetics, attributes, and current clinical trials of this
`emerging drug.
`
` Keywords: anticoagulation , apixaban , factor Xa inhibitors , oral anticoagulants
`
` Expert Opin. Investig. Drugs (2008) 17(12):1937-1945
`
` 1. Introduction
`
` For the last half-century, heparin and warfarin have been the mainstays of
`treatment for patients with venous and arterial thromboembolic disease. The
`administration of warfarin is limited because of its narrow therapeutic index,
`slow onset of therapeutic effect, numerous dietary and drug interactions, and a
`need for monitoring as well as dose adjustments. For over 60 years [1] , warfarin
`has been the only available oral anticoagulant, despite its many limitations.
`During the past decade, new oral anticoagulant agents have been developed that
`may offer an attractive alternative to warfarin. The era of anticoagulation, requiring
`labor-intensive monitoring and treatment, may soon be ending due to a number
`of antithrombotic compounds currently being investigated in clinical trials [2] .
`Emerging data suggest that Factor Xa and thrombin are favorable targets for
`inhibition by new anticoagulants because of their central location in the common
`pathway of the coagulation cascade, blocking both intrinsic and extrinsic pathways.
` Figure 1 lists many of the current investigational agents and their targeted
`coagulation factors.
` Serine proteases play an important role in coagulation and the thrombotic
`process, such as venous thromboembolism, stroke and other cardiovascular disorders [3] .
`There is evidence to suggest that FXa may represent a better target for inhibition
`than thrombin [4] . In animal models, direct Factor Xa inhibitors produce less
`bleeding than direct thrombin inhibitors when given in doses with similar
`antithrombotic activity [5-10] . This is based on an understanding of the amplified
`nature of coagulation, where smaller doses of an anticoagulant drug are needed
`to block coagulation progression earlier in the sequence of reactions (i.e., one
`molecule of FXa catalyzes the formation of almost 1000 thrombin molecules) [11] .
`Secondly, some evidence suggests that direct thrombin inhibitors may be associated
`
`10.1517/13543780802528625 © 2008 Informa UK Ltd ISSN 1354-3784
`All rights reserved: reproduction in whole or in part not permitted
`
`1937
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`
`
`Apixaban
`
`XII
`
`Oral Xa and IIa inhibitors
`
`XI
`
`IX
`
`VIII
`
`VII
`
`New oral IIa inhibitors
`Dabigatran (Boehringer Ingelheim)
`Ximelagatran (AstraZeneca)
`AZD0837 (AstraZeneca)
`
`New oral xa inhibitors
`Rivaroxaban (Bayer/Ortho McNeil)
`Apixaban (Bristol Myers Squibb/Pfizer)
`DU-176b (Daiichi Sankyo)
`YM150 (Astellas)
`LY517717 (Lilly)
`Betrixaban (Portola)
`
`X
`
`V
`
`II
`
`I
`
`Fibrin clot
`
` Figure 1 . New anticoagulant drugs targeted to factors Xa or IIa.
`
`with a rebound hypercoagulable state that does not appear
`to be associated with FXa inhibitors [12] . Thirdly, FXa inhibitors
`incompletely block thrombin generation, and some existing
`thrombin has anti-inflammatory functions that can potentially
`maintain hemostasis [13] as well as the potential to activate
`the protein C system and add to an antithrombotic potential.
`Lastly, in vitro assays have found that Factor Xa is progres-
`sively inhibited over a much wider concentration range than
`thrombin, suggesting that FXa inhibitors may have a wider
`therapeutic window than thrombin inhibitors [14] . This
`means that it would be easier to maintain a patient’s anti-Xa
`concentration within the therapeutic range.
` A number of direct-acting, oral Factor Xa inhibitors are
`in development. Apixaban is one such agent. It is a potent,
`selective, reversible, and orally bioavailable FXa inhibitor
`that demonstrates antithrombotic efficacy with a favorable
`pharmacokinetic profile. Apixaban not only inhibits free
`Factor Xa but also inactivates Factor Xa in the prothrombinase
`complex and Xa bound to platelets. At present, trials are
`underway involving about 47,000 patients examining apixaban’s
`safety and efficacy in the prophylaxis and treatment of
`venous thromboembolism, and stroke prevention for patients
`with atrial fibrillation (AF). This review article discusses the
`discovery, pharmacokinetics, and current clinical trials of this
`emerging drug.
`
` 2. Pharmacology
`
` Apixaban was designed as a follow-up compound to the oral,
`direct FXa inhibitor razaxaban. Razaxaban was a selective
`
`oral direct Factor Xa inhibitor that was discontinued based
`on less than optimal pharmacologic properties [15] . Efforts
`to identify a suitable follow-up compound to razaxaban
`focused on modification of the carboxamido linker. Cyclization
`of the carboxamido linker to the novel bicyclic tetrahydro-
`pyrazolopyridinone scaffold (see Figure 2 ), modification of
`the P 1 moieties, and optimization of the terminal P 4
`ring proved to have exceptionally potent FXa binding
`activity [6] . These three modifications led to the discovery of
`1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)
`phenyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-
`3-carboxamide, also known as apixaban. Apixaban exhibits a
`high degree of FXa potency, selectivity, and efficacy and
`has an improved pharmacokinetic profile relative to razaxaban,
`without the bleeding risk. Apixaban is a selective inhibitor to
`Factor Xa with > 30,000-fold selectivity over other coagulation
`proteases [16] . Direct Factor Xa inhibitors bind to Factor Xa
`with 1:1 stoichiometry and block the interaction of Factor
`Xa with Factor II. It is a small molecule with a molecular
`weight of 460.
`
` 3. Preclinical pharmacologic studies in
`animal models
`
` The preclinical pharmacokinetic and metabolic attributes of
`apixaban feature a small volume of distribution, a low systemic
`clearance, good oral bioavailability, multiple elimination
`pathways and minimal potential for drug–drug interactions.
`In the rabbit AV shunt thrombosis model, apixaban inhibited
`thrombus formation in a dose-dependent manner and did
`
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`
`
`Carreiro & Ansell
`
`N
`
`N
`
`N
`
`F
`
`NH
`
`O
`
`P4
`
`SO2NH2
`
`B.
`
`F3C
`
`N
`
`N
`
`A.
`
`Scaffold
`
`NH
`
`O
`
`N
`
`N
`
`R
`
`P1
`
`meta R = C(NH)NH2 110
`
`meta R = CH2NH2 210
`
`ortho R = CH2NH2 312a
`
`fXa Ki = 0.013 nM
`Trypsin Ki = 16 nM
`fXa Ki = 0.15 nM
`Trypsin Ki = 60 nM
`fXa Ki = 0.87 nM
`Trypsin Ki = 1500 nM
`
`O
`
`N
`
`NH2
`
`(Razaxaban) 47a
`fXa Ki = 0.15 nM
`Trypsin Ki = 5000 nM
`
`C.
`
`O
`
`N
`
`N
`
`H2N
`
`O
`
`O
`
`N
`
`N
`
`O
`
` Figure 2 . The pharmacology for apixaban chemical discovery (adapted from [6] ) and apibaxan structure. A. Precursor molecules
`to razaxaban, which contains a sulfonamide group. B. Razaxaban structure. C. Apixaban structure (fXa K i = 0.08 nM).
`
`not affect bleeding time [9,10,16] . Apixaban has an IC 50 value
`of 329 nM [6] . Apixaban is absorbed in chimpanzees, dogs
`and rats with a mean oral bioavailability of 51, 88 and 34%,
`respectively [7] . The mean volume of distribution of apixaban
`is 0.17, 0.29 and 0.31 l/kg in chimpanzees, dogs and rats,
`respectively, suggesting that apixaban is distributed (30 – 50%)
`to blood where the therapeutic action resides [17] . The small
`volume is not due to extensive plasma protein binding but
`possibly attributed to limited extravascular tissue distribution,
`given that the unbound fraction is approximately 5, 8 and 4%
`in chimpanzee, dog and rat serum, respectively [17] . The
`systemic clearance is < 3% of hepatic blood flow in chim-
`panzees (0.018 l/h/kg) and dogs (0.052 l/h/kg), and < 10%
`in rats (0.26 l/h/kg) [17] . Consistent with this low clearance,
`the in vitro metabolic clearance of apixaban is low, as indicated
`
`by the lack of significant metabolism in chimpanzee and dog
`liver microsomes.
` The elimination of apixaban involves multiple pathways,
`including renal and intestinal excretion. The biliary clearance
`is low in dogs, accounting for approximately 2% of the systemic
`clearance [17] . Apixaban shows weak activity against various
`P 450 isozymes (IC 50 > 25 µM) [6] . No glutathione adduct with
`apixaban was formed in dog and rat [17] . No teratogenicity
`was observed in rat or rabbit models [18] . In animal models,
`apixaban was as effective as lepirudin, and more effective
`than aspirin for the prevention of arterial thrombosis; it
`prolonged the bleeding time less than lepirudin and aspirin
`at antithrombotic doses [9] .
` The combination of apixaban and aspirin or apixaban, aspirin
`and clopidogrel has been studied in a rabbit model. The
`
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`
`Apixaban
`
`study found that combining apixaban and antiplatelet agents
`reduced the formation of occlusive arterial thrombosis [8] .
` Control thrombus weight was 8.6 ± 0.9 mg. The addition
`of aspirin to apixaban significantly reduced the thrombus
`weight from 7.4 ± 0.5 to 5.3 ± 0.3, and the further addition
`of aspirin and apixaban to clopidogrel produced a significant
`additional reduction in thrombus weight from 5.3 ± 0.3 to
`0.7 ± 0.1 mg. The addition of aspirin and apixaban did not
`increase bleeding time (BT) compared with the control. How-
`ever, the combination of clopidogrel and aspirin with apixaban
`produced a significant increase in BT of 2.1 times control.
`
` 4. Pharmacokinetic and pharmacodynamic
`studies in humans
`
` In vitro properties of apixaban show that it is a highly selective
`and potentially potent antithrombotic agent in human blood
`from healthy volunteers. Detailed kinetic analysis of apixaban
`inhibition of human FXa showed that it is a readily reversible
`competitive inhibitor with a synthetic tripeptide substrate
`with a K i of 0.08 nM. K i is a measure of how potent a drug
`is to produce half maximum inhibition. The human serum
`protein binding as measured by equilibrium dialysis for
`apixaban was 87% [6] . Weak affinity is observed for thrombin
`( K i 3.1 µM), plasma kallikrein ( K i 3.7 µM)), and chymotrypsin
`( K i 3.5 µM), trypsin ( K i > 12 µM) and all other serine
`proteases [6] . The unbound fraction is approximately 13%
`in humans [17] .
` The pharmacokinetic profile of apixaban is consistent with
`rapid oral absorption and bioavailability. It is well absorbed
`from the gastrointestinal tract, and peak plasma levels are
`achieved in about 3 h. The effective half-life is 8 – 11 h when
`given twice daily and 12 – 15 h for a once-daily regimen [19] .
`This
`is consistent with achievement of
`steady-state
`concentrations by day 3 with modest accumulation (1.3- to
`1.9-fold for b.i.d. and 1.3- to 1.5-fold for q.d.). Lower
`peak-to-trough concentration ratios are observed with b.i.d.
`versus q.d. dosing regimens. There is no food effect on
`apixaban absorption following the consumption of a hig- fat,
`high-calorie meal [20] . Apixaban absorption is not likely to
`be affected by medications that alter gastric pH, based on
`apixaban’s physical-chemical properties. Apixaban has no
`ionizable groups and therefore does not exhibit pH-dependent
`aqueous solubility. Apixaban exhibits a dual mechanism of
`excretion, with about 25% being excreted via the kidneys,
`while the remainder appears in the feces [17] . Apixaban has
`multiple elimination pathways that make it applicable for
`use in patients with renal failure and liver failure.
` The major metabolic pathway of apixaban metabolism
`is the O -demethylation forming a phenol metabolite; it is
`primarily metabolized by CYP3A4 [17] . A Phase I study
`evaluating the effects of ketoconazole, a known potent inhibitor
`of CYP3A4, on apixaban pharmacokinetics found a twofold
`increase of apixaban [21] . These results suggest that concomitant
`administration of ketoconazole or other potent 3A4 inhibitors
`
`with apixaban should be avoided unless discontinued 14 days
`prior to the administration of apixaban. The effects of apixaban
`and moderate CYP3A4 inhibitors (i.e., cimetidine, diltiazem,
`selective serotonin receptor inhibitors) should be used with
`caution, but have not been studied. The effect of apixaban
`and the statins, which are also metabolized by 3A4, is not
`known. Apixaban has not been found to interact with
`CYP1A2, 2C19, 2C9, and 2D6 [17] .
` Three studies have examined the safety and tolerability
`of apixaban co-administered with antiplatelet agents in a
`limited number of healthy volunteers: CV1855002 Part B,
`CV185005, and CV185015 [21] . CV185002 Part B examined
`the interaction of apixaban 5 mg b.i.d. with aspirin 325 mg q.d.
`in 17 healthy subjects. CV185005 examined the interaction
`of apixaban (5 mg b.i.d. or 10 mg q.d.) with clopidogrel
`75 mg q.d. in 35 healthy volunteers. CV185015 examined
`the co-administration of apixaban 20 mg q.d. with both
`aspirin 162 mg q.d. and clopidogrel 75 mg q.d. in 30 healthy
`subjects. In CV185002 Part B and CV185005, apixaban
`was co-administered with the antiplatelet agent following an
`initial lead-in period with the antiplatelet agent alone.
`There were no changes in INR or activated partial thrombo-
`plastin time (aPTT) beyond those attributed to apixaban
`alone, nor in ex vivo platelet aggregation measurements
`or bleeding time (BT) beyond those attributed to aspirin or
`clopidogrel alone [19] . No major bleeding events occurred in
`these studies. Possible interactions between apixaban and
`anticoagulants, including heparin, LMWH, and IIb/IIIa
`inhibitors, have not been evaluated in clinical trials.
` Other studies have examined other possible drug interac-
`tions in likely co-medications in a clinical setting. Patients
`with AF, for example, may be taking digoxin for rhythm
`control. There was no interaction between apixaban 20 mg
`once daily for 10 days and the pharmacokinetic of digoxin [22] .
`Administration of apixaban at doses up to 50 mg once daily
`for 3 days had no effect on the QTc interval in healthy
`patients [23] . No dose-limiting adverse effects were noted.
` Apixaban causes concentration-dependent prolongation of
`the FXa mediated clotting assays. Apixaban inhibits Factor
`Xa activity in a dose-dependent manner, accompanied by
`mild prolongations in the INR and aPTT in a concentra-
`tion-dependent fashion. The human plasma concentration
`required to produce a doubling of the clotting time in vitro
`is 3.6 µM for prothrombin time (PT), 7.4 µM for aPTT
`and 0.4 µM for HepTest [13] . However, its effect on these
`tests is minimal at concentrations that are likely to be
`therapeutic. At doses that achieved similar 80% levels of
`thrombosis inhibition, apixaban caused less prolongation of
`bleeding times than warfarin [7,16] . Finally, apixaban has no
`effect on human platelet aggregation [9] . The mPT clotting
`time assay is a modification of the standard PT assay to
`more sensitively detect the effects of direct FXa inhibitors.
`For example, apixaban 10 mg q.d. produced a mPT 2.3-fold
`increase from baseline, 1.2-fold elevation in INR, and only
`1.1-fold increase in aPTT [21] . Given the modest changes
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`
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`
`2.5 mg
`BID
`
`5 mg
`QD
`
`5 mg
`BID
`
`10 mg
`QD
`
`10 mg
`BID
`
`20 mg
`QD
`
`Enox Warf
`
`30
`
`25
`
`20
`
`%
`
`15
`
`10
`
`05
`
` Figure 3 . Incidence of adjudicated VTE plus death from any cause (dark grey bars) and total bleeding events (light bars)
`for b.i.d. and q.d. doses of apixaban and the comparators.
` ENOX: Enoxaparin; VTE: Venous thromboembolism; Warf: Warfarin.
`
`observed in INR and aPTT, these coagulation tests are not
`useful for monitoring apixaban.
`
` 5. Clinical trials
`
` 5.1 Thromboprophylaxis in orthopedic surgery
` The APROPOS [24] trial was a Phase II study examining the
`efficacy of apixaban in preventing deep vein thrombosis
`(DVT) and pulmonary embolism (PE) in patients undergoing
`total knee replacements (TKR). The study was randomized,
`double-blinded, and examined 1238 patients. Patients receiving
`apixaban were randomized to one of six doses from 2.5 mg b.i.d.
`to 20 mg once daily and were compared with both enox-
`aparin 30 mg b.i.d. and warfarin (with a target INR
`of 1.8 – 3.0). Patients received treatment for 10 – 14 days,
`commencing 12 – 24 h after surgery with apixaban or enox-
`aparin, and on the evening of surgery with warfarin. The
`primary efficacy outcome was a composite of VTE diagnosed
`with mandatory venography and all-cause mortality during
`treatment. The primary safety outcome was major bleeding.
`A significantly lower incidence of DVT or PE occurred in
`the apixaban group than those receiving enoxaparin (p < 0.02)
`or warfarin (p < 0.001) (9 vs 15.6 vs 26%, respectively).
`At the lowest apixaban dose tested (5 mg total daily dose),
`the primary outcome rates for apixaban 2.5 mg b.i.d.
`and 5 mg q.d. were 9% (95% confidence interval [CI],
`5.1 – 17.0) and 11.3% (95% CI, 5.8 – 19.4), respectively,
`compared with 15.6% (95% CI, 9.4 – 23.8) in the enoxaparin
`group and 26.6% (95% CI, 18.6 – 35.9) in the warfarin group.
`All apixaban groups had a lower event rate of developing
`DVT or PE (0 – 2.7%) than either comparator ( Figure 3 ).
`A significant dose-related increase in the incidence of total
`adjudicated bleeding events was noted in the once-daily
`(p = 0.01) and twice-daily (p = 0.02) apixaban groups; there
`
`was no difference observed between q.d. and b.i.d. regimens.
`The optimal dose of apixaban was determined to be either
`2.5 mg twice daily or 5 mg once daily, both of which had a
`promising benefit–risk profile compared with the current
`standards of care following TKR.
` Apixaban is currently undergoing a number of Phase III studies
`identified in Table 1 . At the time of this writing, ADVANCE 1
`has concluded enrolment; results will be available in late
`2008. The other orthopedic studies are currently ongoing.
`
` 5.2 Thromboprophylaxis in patients with
`medical illnesses
` The ADOPT trial is a Phase III study comparing the
`effectiveness of apixaban to enoxaparin for the prevention of
`DVT in hospitalized patients (see www.clinicaltrials.gov,
`identifier NCT00457002). The study is randomized, double-
`blinded study enrolling 7502 patients. Patients receiving
`apixaban 2.5 mg twice daily plus placebo for 30 days will be
`compared to patients taking enoxaparin 40 mg subcutaneous
`for 6 – 14 days plus placebo for 30 days. The study is estimated
`to be completed in March 2009.
`
` 5.3 Thromboprophylaxis in advanced
`metastatic cancer
` An ongoing Phase II randomized, double-blind (subject,
`investigator) study is currently examining the role of apixaban
`in preventing thromboembolic events in patients undergoing
`advanced or metastatic cancer treatment (www.clinicaltrials.
`gov, identifier NCT00320255). Demonstration of a favorable
`benefit–risk profile could lead to significant reduction in
`this serious and sometimes fatal complication of ongoing
`cancer and its treatment. The study is estimated to enroll
`160 patients and its projected completion is October 2008.
`Patients in the experimental arm will receive apixaban 5 mg
`
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`
`
`Apixaban
`
` Table 1 . Apixaban clinical trials.
`
` Study
`
` Phase
`
` Indication
`
` Population N, duration
`
` Apixaban dose
`
` Comparator
`
` Status
`
`VTE prevention
`
`VTE prevention
`
`Total knee replacement
`1238, 10 days
`Acute DVT
`520, 3 months
`
`2.5 mg b.i.d. to
`20 mg q.d.
`5 mg b.i.d. to
`20 mg q.d.
`
`Enoxaparin
`Warfarin
`LMWH-VKA
`
`Post-ACS
`
`Post-ACS
`1715, 6 months
`
`2.5 mg b.i.d. to
`20 mg q.d.
`
`Placebo
`
`Completed
`
`Completed
`
`Completed
`
`2.5 mg b.i.d.
`
`Placebo
`
`Recruiting
`
`VTE prevention
`
`VTE prevention
`
`Metastatic cancer
`160, 3 months
`Total knee replacement
`3000, 10 days
`
`2.5 mg b.i.d.
`
`VTE prevention
`
`Total knee replacement
`3000, 10 days
`
`2.5 mg b.i.d.
`
`VTE prevention
`
`Total hip replacement
`4000, 35 days
`
`2.5 mg b.i.d.
`
`Enoxaparin
`30 mg, q12h
`
`Enoxaparin
`40 mg q.d.
`
`Enoxaparin
`40 mg q.d.
`
`Closed
`
`Recruiting
`
`Recruiting
`
`CV185010
`APROPOS
`CV185017
`BOTTICELLI
`NCT00252005
`
`CV185023
`APPRAISE
`NCT00313300
`CV185027
`NCT00320255
`CV185034
`ADVANCE-1
`NCT00371683
`CV185047
`ADVANCE-2
`NCT00452530
`CV185035
`ADVANCE-3
`NCT00423319
`CV185036
`ADOPT
`NCT00457002
`CV185030
`ARISTOTLE
`NCT00412984
`CV185048
`AVERROES
`NCT00496769
`AMPLIFY
`NCT00643201
`AMPLIFY-EXT
` NCT00633893
`
`2
`
`2
`
`2
`
`2
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`VTE prevention
`
`Acute medical illness
`6500, 30 days
`
`2.5 mg b.i.d.
`
`Enoxaparin/placebo
`
`Recruiting
`
`Stroke prevention
`
`Non-valvular AF
`15,000, 18 months
`
`Stroke prevention
`
`Non-valvular AF
`5600, 18 months
`
`5 mg b.i.d.
`
`Warfarin
`
`Recruiting
`
`5 mg b.i.d.
`
`Aspirin
`
`Recruiting
`
`VTE treatment
`
`Extended VTE
`treatment
`
`Acute DVT/PE, 3625,
`6 months
`DVT/PE after initial
`therapy; 2438
`
`10 mg b.i.d./
`5 mg b.i.d.
`5 mg b.i.d./
`2.5 mg b.i.d.
`
`Enoxaparin/warfarin
`
`Recruiting
`
`Placebo
`
`Recruiting
`
` ACS: Acute coronary syndrome; AF: Atrial fi brillation; b.i.d.: Twice daily; DVT: Deep vein thrombosis; LMWH-VKA: Low molecular weight heparin- vitamin K
`antagonist; PE: Pulmonary embolism; q.d.: Once daily; VTE: Venous thromboembolism.
`
`once daily for 12 weeks compared with placebo. The
`primary outcome measure is the occurrence of a bleeding
`event; its secondary measure is symptoms compatible with
`venous thromboembolism.
`
` 5.4 Thromboprophylaxis in the prevention
`of cardiovascular events
` The prevention of cardiovascular events was examined in the
`APPRAISE trial [25] , a Phase II, randomized, double-blind
`study, which has now been completed (www.clinicaltrials.gov,
`NCT00313300). The purpose of the study was to determine
`whether apixaban was safe in people who have recently
`(< 7 days) had an acute coronary syndrome (ACS) being
`treated with dual antiplatelet therapy. The study included
`1715 patients with experimental groups receiving apixaban
`10 mg once daily or apixaban 2.5 mg twice daily, compared
`with a placebo group for 26 weeks. Apixaban 10 mg b.i.d.
`
`and apixaban 20 mg q.d. was discontinued early due
`to excess bleeding in patients receiving apixaban and dual
`antiplatelet therapy. The primary outcome measures were
`major and clinically relevant bleeding and secondary measures
`included nonfatal myocardial infarction, severe recurrent
`ischemia, non-hemorrhagic stroke, or death. The study
`evaluated the effect of apixaban with concomitant ACS
`treatments such as aspirin (< 165 mg/day), clopidogrel, beta-
`blockers, ACE inhibitors or ARBs, calcium blockers, nitrates,
`and statins. The study found that patients taking apixaban
`2.5 mg b.i.d. had no significant reduction in ischemic events
`(7.6%, HR 0.73; 95% CI, 0.44 – 1.19; p = 0.21) or
`increased bleeding risk (5.7%, HR 1.78; 95% CI, 0.91 – 3.48;
`p = 0.09) compared with the placebo (8.7% ischemic and
`3% bleeding events). Patients taking apixaban 10 mg daily
`demonstrated a promising trend (although not significant)
`toward a reduction in ischemic events (6.0%, HR 0.61;
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`95% CI, 0.35 – 1.04; p = 0.07); however, there was a
`significant increase in bleeding risk (7.9%, HR 2.45; 95% CI,
`1.31 – 4.61; p = 0.005) compared with the control. The risk
`of bleeding and reduction in ischemic events were similar
`among patients taking a single aspirin or dual antiplatelet
`therapy (aspirin plus clopidogrel). In conclusion, APPRAISE
`found that the addition of apixaban to contemporary anti-
`platelet therapy for 6 months following an ACS results in a
`dose-dependent increase in bleeding, and a trend in reduction
`in ischemic events at higher doses.
`
` 5.5 Thromboprophylaxis in the prevention of stroke
`in atrial fi brillation
` Atrial fibrillation affects 1 – 1.5% of the population in the
`developed world [26] . Projected data from the population-
`based studies suggest that the prevalence of AF will grow at
`least threefold by 2050 [27] . The clinical significance of AF
`lies predominantly in a fivefold increased risk of stroke [26] .
`Strokes associated with AF are usually more severe and
`confer increased risk of morbidity, mortality, and poor
`functional outcome.
` ARISTOTLE, a Phase III study, has been initiated to
`evaluate the efficacy and safety of apixaban 5 mg twice daily
`compared with warfarin, for the prevention of stroke and
`systemic embolism in patients with non-valvular AF. Secondary
`outcome measures are confirmed ischemic stroke, hemorrhagic
`stroke, systemic embolism, and all-cause mortality. This
`randomized, double-blind study is expected to enroll 15,000
`patients (see www.clinicaltrials.gov, identifier NCT00412984).
` AVERROES is a Phase III study comparing the efficacy
`of apixaban versus acetylsalicylic acid (ASA) for the prevention
`of stroke or systemic embolism in AF patients who have
`failed or who are unsuitable for warfarin (see www.clinicaltrials.
`gov, identifier NCT00496769). This is a randomized, double-
`blind study that will enroll 6160 to investigate 5600 patients.
`Patients will receive either apixaban 5 mg b.i.d. (or 2.5 mg b.i.d.
`in selected patients) or ASA (81 – 324 mg q.d.). Patients will
`be followed for up to 36 months and the incidence of stroke
`or systemic embolism will be compared in the apixaban
`versus aspirin group. The estimated study completion date
`is April 2010.
`
` 5.6 Treatment of venous thrombosis
` Whereas apixaban has shown promise in the prevention of
`venous thromboembolism following major orthopedic surgery,
`the Botticelli study conducted a dose-ranging study in
`patients with symptomatic deep vein thrombosis [28] . It was
`a Phase II randomized, double-blinded study that examined
`the role of apixaban to treat DVT. The study assessed the
`efficacy of three doses of apixaban 5 mg twice a day, 10 mg
`twice a day and 20 mg once daily versus conventional treatment
`with low-molecular-weight heparin followed by warfarin for
`3 months. The primary efficacy outcome was the symptomatic
`recurrence of venous thromboembolism and asymptomatic
`deterioration of bilateral compression ultrasound or perfusion
`
`Carreiro & Ansell
`
`lung scan. The principal safety outcome was the composite
`of major and clinically relevant, non-major bleeding. The
`study found that the incidence of DVT in all three apixaban
`groups was low and comparable to LMWH and warfarin.
`The primary outcome occurred in 17 of the 358 apixaban-
`treated patients (4.7%; 95% CI, 2.8 – 7.5%] and in five of
`the 118 LMWH/VKA-treated patients (4.2%; 95% CI,
`1.4 – 9.6%). The principal safety outcome occurred in 28
`(7.3%) of the 385 apixaban-treated patients and in 10
`(7.9%) of the 126 LMWH/VKA-treated patients. Apixaban
`did not demonstrate a dose response, making it an attractive
`fixed-dose regimen for meeting the demand to simplify anti-
`coagulant treatment in patients with established venous
`thromboembolism. In summary, apixaban was found to be
`useful in the initial and long-term treatment of acute DVT
`without increasing the incidence of bleed.
` With these results, a Phase III study has recently started
`(June 2008) examining the use of apixaban in the treatment
`of symptomatic DVT and PE (see www.clinicaltrials.gov,
`identifier NCT00643201). It is a randomized, double-
`blinded study examining the reoccurrence of DVT/PE or
`death. Patients will receive apixaban 10 mg tablets b.i.d. for
`7 days followed by either apixaban 5 mg b.i.d. for 6 months
`or warfarin for 6 months. To control for the placebo effect,
`patients receiving apixaban will receive a placebo injection
`until a sham INR ≥ 2; whereas patients receiving warfarin
`will also take a 5 mg placebo apixaban tablet twice daily.
` A second Phase III study is currently underway that will
`evaluate the utility of apixaban for the long-term secondary
`prevention of DVT vein thrombosis and PE (see www.
`clinicaltrials.gov, identifier NCT00633893) after receiving
`6 months of warfarin. It will be a randomized, double-blind,
`placebo control study that is projected to enroll 2438 patients.
`Study arms include patients receiving apixaban 2.5 mg b.i.d.,
`apixaban 5 mg b.i.d. and a placebo group. Patients will be
`followed for 12 months, with the primary outcome measure
`comparing venous thromboembolic recurrence or death. The
`estimated completion date is January 2011.
`
` 6. Potential disadvantages of apixaban
`
` Whenever a new medication is introduced, there is the risk
`that extended use may reveal a serious side effect that was
`not initially evident. Ximelagatran, for example, initially was
`thought to offer promise for unmonitored anticoagulation,
`but was discontinued after it was found to have unexpected
`long-term hepatic toxicity. Because the mechanism responsible
`for this side effect has not yet been identified, it is difficult
`to predict whether other new anticoagulants will have the
`same problem. To date, hepatotoxicity has not been found
`in clinical studies and apixaban has a different target than
`ximelagatran, which was a direct thrombin inhibitor.
` Although new anticoagulants have been designed to be
`given without monitoring, there are some instances where
`monitoring may be helpful. Effective doses of warfarin are
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`Apixaban
`
`associated with specific INR values. Apixaban, in contrast,
`has a variable effect on routine coagulation tests and none of
`the routine tests provide an estimate of drug levels. If a
`patient bleeds on warfarin and the INR is elevated, the
`bleed can be attributed to excessive anticoagulation. If a
`patient develops a DVT in the setting of a subtherapeutic
`INR, then it reflects an inadequate level of anticoagulation
`rather than a treatment failure. This may be difficult to discern
`with a non-monitored drug. Compliance with non-monitored
`anticoagulants may also be difficult to assess.
` Another concern with apixaban is the lack of a specific
`antidote, as there is currently no treatment to reverse it. Since
`the major complication of all anticoagulants is bleeding,
`there is need for a neutralizing agent in the event of significant
`hemorrhage. Treatment of apixaban overdose consists of
`supportive measures. However, because of the relatively short
`half-life of apixaban, with an effective half-life of 10 – 15 h,
`the drug effect dissipates at a rate much quicker than would
`be seen with the vitamin K antagonists.
`
` 7. Expert opinion and conclusions
`
` Current anticoagulants have many limitations and drawbacks.
`Warfarin and heparin rank consistently in the ‘top 10’ lists
`of drugs associated with serious adverse events, emergency
`room vis