Preventive Cardiology
`
`A Once-Daily, Oral, Direct Factor Xa Inhibitor,
`Rivaroxaban (BAY 59-7939), for Thromboprophylaxis After
`Total Hip Replacement
`
`Bengt I. Eriksson, MD, PhD; Lars C. Borris, MD; Ola E. Dahl, MD, PhD; Sylvia Haas, MD;
`Menno V. Huisman, MD, PhD; Ajay K. Kakkar, MD, PhD; Eva Muehlhofer, MD;
`Christoph Dierig, PhD; Frank Misselwitz, MD, PhD; Peter Kälebo, MD, PhD;
`for the ODIXa-HIP Study Investigators
`
`Background—Rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor— could be an alternative to heparins and
`warfarin for the prevention and treatment of thromboembolic disorders.
`Methods and Results—This randomized, double-blind, double-dummy, active-comparator– controlled, multinational,
`dose-ranging study assessed the efficacy and safety of once-daily rivaroxaban relative to enoxaparin for prevention of
`venous thromboembolism in patients undergoing elective total hip replacement. Patients (n⫽873) were randomized to
`once-daily oral rivaroxaban doses of 5, 10, 20, 30, or 40 mg (initiated 6 to 8 hours after surgery) or a once-daily
`subcutaneous enoxaparin dose of 40 mg (given the evening before and ⱖ6 hours after surgery). Study drugs were
`continued for an additional 5 to 9 days; mandatory bilateral venography was performed the following day. The primary
`end point (composite of any deep vein thrombosis, objectively confirmed pulmonary embolism, and all-cause mortality)
`was observed in 14.9%, 10.6%, 8.5%, 13.5%, 6.4%, and 25.2% of patients receiving 5, 10, 20, 30, and 40 mg
`rivaroxaban, and 40 mg enoxaparin, respectively (n⫽618, per-protocol population). No significant dose–response
`relationship was found for efficacy (P⫽0.0852). Major postoperative bleeding was observed in 2.3%, 0.7%, 4.3%, 4.9%,
`5.1%, and 1.9% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban, and 40 mg enoxaparin, respectively (n⫽845,
`safety population), representing a significant dose–response relationship (P⫽0.0391).
`Conclusions—Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total hip
`replacement, with the convenience of once-daily oral dosing and without the need for coagulation monitoring. When
`both efficacy and safety are considered, these results suggest that 10 mg rivaroxaban once daily should be investigated
`in phase III studies. (Circulation. 2006;114:2374-2381.)
`
`Key Words: anticoagulants 䡲 coagulation 䡲 embolism 䡲 prevention 䡲 thrombosis
`
`C urrently,
`
`low-molecular-weight heparins (LMWHs)
`and vitamin K antagonists are used routinely for
`thromboprophylaxis after major orthopedic surgery.1 Al-
`though they effectively reduce the incidence of deep vein
`thrombosis (DVT) and pulmonary embolism (PE),1 a
`number of limitations restrict their use. Vitamin K antag-
`onists, although orally administered, have a slow onset of
`action, interpatient variability, need for frequent monitor-
`ing, and potential drug interactions,1 whereas LMWHs are
`administered parenterally.
`
`Editorial p 2313
`Clinical Perspective p 2381
`
`Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa
`(FXa) inhibitor. It has high oral bioavailability (relative
`bioavailability ⬇80%),2 a rapid onset of action, and predict-
`able, dose-proportional pharmacokinetics and pharmacody-
`namics.2,3 It has a half-life of 5 to 9 hours and is excreted
`rapidly, predominantly via renal elimination (66% of the total
`dose, with 36% of the dose excreted unchanged) and also by
`
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` by guest on April 16, 2018
` by guest on April 16, 2018
` by guest on April 16, 2018
` by guest on April 16, 2018
`
`Received May 26, 2006; revision received August 10, 2006; accepted September 8, 2006.
`From the Department of Orthopaedics, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden (B.I.E.); Department of Orthopaedics, Aarhus
`University Hospital, Aarhus, Denmark (L.C.B.); Thrombosis Research Institute, London, UK (O.E.D., A.K.K.); Institute for Experimental Oncology and
`Therapy Research, Munich, Germany (S.H.); Department of General Internal Medicine and Endocrinology, Leiden University Medical Center, Leiden,
`the Netherlands (M.V.H.); Centre for Surgical Sciences, Barts and the London School of Medicine, London, UK (A.K.K.); Bayer HealthCare AG,
`Wuppertal, Germany (E.M., C.D., F.M.); and Department of Radiology, Östra Hospital, Gothenburg, Sweden (P.K.).
`The online-only Data Supplement, which contains a list of the ODIXa-HIP Study Investigators, can be found at http://circ.ahajournals.
`org/cgi/content/full/CIRCULATIONAHA.106.642074/DC1.
`Correspondence to Bengt I. Eriksson, MD, PhD, Department of Orthopaedics, Sahlgrenska University Hospital/Östra, SE-416 85 Gothenburg, Sweden.
`E-mail b.eriksson@orthop.gu.se
`© 2006 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/CIRCULATIONAHA.106.642074
`
`2374
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`MYLAN - EXHIBIT 1041
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`

`Eriksson et al
`
`Once-Daily Oral Rivaroxaban for Thromboprophylaxis
`
`2375
`
`the biliary/fecal route.3– 6 Two phase II studies (n⫽1343)
`were performed to evaluate the efficacy and safety of a
`twice-daily regimen of rivaroxaban for 5 to 9 days, relative to
`the LMWH enoxaparin, for the prevention of venous throm-
`boembolism (VTE) in patients undergoing major orthopedic
`surgery.7,8 A wide (4-fold) dose range of rivaroxaban (total
`daily doses of 5 to 20 mg) compared favorably with
`enoxaparin.
`Further evidence suggests that rivaroxaban may be suitable
`for once-daily administration. Phase I studies in healthy
`subjects showed that single doses of rivaroxaban have phar-
`macodynamic effects that persist for 24 hours.2,9,10 Further-
`more, via inhibition of Factor Xa activity, rivaroxaban ulti-
`mately diminishes thrombin generation. Rivaroxaban
`significantly inhibited peak and total amounts of thrombin
`generated and prolonged time to thrombin generation 24
`hours after dosing in healthy subjects.9
`Together, these studies led to the initiation of the Oral,
`Direct Factor Xa Inhibitor, BAY 59-7939, Given Once Daily
`in Patients Undergoing Total Hip Replacement (ODIXa-OD-
`HIP) study. This phase II study was performed to investigate
`the efficacy and safety of oral rivaroxaban administered once
`daily relative to that of subcutaneous enoxaparin in patients
`undergoing elective total hip replacement.
`
`Methods
`
`Study Design
`The ODIXa-OD-HIP study was a randomized, double-blind, double-
`dummy, active-comparator– controlled, multinational, dose-ranging
`study to assess the efficacy and safety of oral rivaroxaban (Bayer
`HealthCare AG, Wuppertal, Germany) administered once daily
`relative to that of subcutaneous enoxaparin (Clexane/Lovenox,
`sanofi-aventis, Paris, France) for the prevention of VTE in patients
`undergoing elective, primary total hip replacement. The study was
`conducted in accordance with the Declaration of Helsinki. All study
`documentation was reviewed and approved by local independent
`ethics committees.
`After written, informed consent was obtained, patients scheduled
`for elective, primary total hip replacement surgery were randomized
`to receive oral rivaroxaban or subcutaneous enoxaparin. Oral rivar-
`oxaban (5, 10, 20, 30, or 40 mg) was administered 6 to 8 hours after
`surgery and once daily thereafter (every 24⫾2 hours) for an
`additional 5 to 9 days (within 2 hours of food). Enoxaparin 40 mg
`(0.4-mL prefilled syringes) was administered on the evening before
`surgery, at least 6 to 8 hours after wound closure in accordance with
`European practice, and then once daily every evening according to
`hospital routine for an additional 5 to 9 days. Patients received
`matching placebo tablets or injections, so that each patient received
`2 tablets and an injection every evening. Mandatory bilateral
`venography was performed the day after the last dose of study drug.
`Patients attended a clinical follow-up visit 30 to 60 days later.
`Further thromboprophylaxis after venography was at the discretion
`of the investigator.
`
`Patients
`Men aged ⱖ18 years and postmenopausal women scheduled for
`elective, primary total hip replacement surgery were enrolled.
`Exclusion criteria included DVT, PE, myocardial infarction, tran-
`sient ischemic attack, or ischemic stroke during the 6 months before
`the study. Also excluded were patients with intracerebral, intraocu-
`lar, or gastrointestinal bleeding in the previous 6 months; patients
`taking drugs that might have affected the study outcome, such as
`other anticoagulants, platelet-aggregation inhibitors, or any other
`drug influencing coagulation (except nonsteroidal antiinflammatory
`drugs with a half-life ⬍17 hours); patients with severe hypertension,
`
`impairment, medical conditions that may
`severe liver or renal
`interfere with the study, or body weight ⬍45 kg; and patients who
`abuse alcohol or drugs. Intermittent pneumatic compression was not
`permitted during the treatment period.
`
`Outcome Measures
`Efficacy
`The primary efficacy end point—the composite of the incidence of
`any DVT (proximal and/or distal); nonfatal, symptomatic, objec-
`tively confirmed PE; and all-cause death—was evaluated 6 to 10
`days after surgery, or earlier if the patient was symptomatic.
`Secondary efficacy end points included major VTE (defined as the
`composite of the incidence of proximal DVT; symptomatic, objec-
`tively confirmed PE; and VTE-related death) and symptomatic VTE.
`
`Safety
`The primary safety end point was the incidence of major bleeding,
`starting after the first postoperative dose of study drug but no later
`than 2 days after the last dose of study drug. Major bleeding was
`defined as follows11: fatal bleeding; bleeding into a critical organ
`(including retroperitoneal,
`intracranial,
`intraocular, or intraspinal
`bleeding); bleeding warranting treatment cessation; or clinically
`overt bleeding associated with a fall in hemoglobin ⱖ2 g/dL within
`24 hours, leading to transfusion of at least 2 units of blood, or leading
`to reoperation. Other bleeding end points included clinically rele-
`vant, non–major bleeding events (defined as multiple-source bleed-
`ing; spontaneous hematoma ⬎25 cm2; excessive wound hematoma;
`macroscopic hematuria [spontaneous or lasting ⬎24 hours if asso-
`ciated with an intervention]; spontaneous rectal bleeding; epistaxis,
`gingival bleeding, or bleeding after venipuncture for ⬎5 minutes;
`hemoptysis; or hematemesis) and minor bleeding events (those that
`did not fulfill the criteria for major bleeding or clinically relevant,
`non–major bleeding events). Postoperative blood loss (via drain) and
`transfusion volumes were documented during the treatment period.
`Other safety assessments included hematology and clinical chem-
`istry laboratory tests, including liver function and coagulation tests.
`
`Assessments
`Patients were screened for DVT with standardized, mandatory,
`bilateral venography the day after their last dose of study drug (ie, 6
`to 10 days after surgery), or sooner if signs and symptoms were
`present.11 The venography method used was the Rabinov and Paulin
`technique,12–14 with a standardized methodology in which a mini-
`mum of 9 films were used for each leg, each from a different
`projection. All venograms were assessed centrally by the Venogra-
`phy Adjudication Committee (Department of Radiology, Östra
`Hospital, Gothenburg, Sweden). Symptomatic PE was confirmed by
`pulmonary angiography, spiral computed tomography, or perfusion/
`ventilation lung scintigraphy plus chest radiography. In cases of
`death, an autopsy was performed if possible. All symptomatic VTEs
`and deaths occurring during the treatment or follow-up period were
`assessed centrally by the VTE Adjudication Committee (Central
`Clinic, O¨ stra Hospital, Gothenburg, Sweden). All bleeding events
`were assessed centrally by the Bleeding Event Adjudication Com-
`mittee. All adjudication committees were independent and blinded to
`treatment allocation.
`An independent Data and Safety Monitoring Board continuously
`monitored efficacy and safety in this study. The Data and Safety
`Monitoring Board could unblind patients’ study drug allocation and,
`in cases of insufficient efficacy or unacceptable safety, recommend
`amendment of the study protocol, which included discontinuation of
`the study or a treatment arm, according to prespecified criteria.
`
`Sample Size Calculation
`According to the initial study protocol, patients were randomized
`evenly (1:1:1:1:1) to receive 1 of 4 doses of rivaroxaban (10, 20, 30,
`or 40 mg once daily [OD]) or enoxaparin (40 mg OD). However,
`after the study was initiated, the results of 2 phase IIb studies
`investigating twice-daily doses of rivaroxaban became available and
`showed that rivaroxaban 2.5 mg twice daily was more effective than
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`2376
`
`Circulation
`
`November 28, 2006
`
`Assessed for eligibility
`877
`
`Randomized
`873
`
`4 patients
`excluded
`
`Not treated/
`no data: 25
`
`No adequate evaluation
`of efficacy: 152
`No venography: 82
`Non-evaluable
`venogram: 69
`Evaluable venogram
`inadequate: I
`Protocol violations' 25
`
`Rivaroxaban*
`713
`
`Enoxaparin
`160
`
`Safety analysis)
`688
`
`Safety analysist
`157
`
`Primary efficacy
`ana ysis
`511
`
`Primary efficacy
`ana ysis
`107
`
`Not treated)
`no data: 3
`
`No adequate evaluation
`of efficacy. 43
`No venography: 28
`Non-evaluable
`venagnsm: t4
`Evaluable venogram
`inadequate:)
`Protocol violations, 7
`
`Figure 1. Flow of patients though the
`ODIXa-OD-HIP study. *Patients were
`randomized to receive 1 of 5 doses of
`rivaroxaban (5, 10, 20, 30, or 40 mg OD).
`†Patients eligible for the safety analysis
`had at least 1 dose of study drug and
`data allowing safety assessment.
`
`anticipated in patients who had undergone major orthopedic sur-
`gery.7,8 As a result, a 5-mg OD dose of rivaroxaban was included in
`the protocol after the study was initiated. On the basis of event rates
`of the primary efficacy end point of 10% to 25%, and assuming a
`linear trend in the dose–response relationship and a 23% invalidity
`rate, 135 subjects were required in each dose group to provide 90%
`power to detect a dose trend in the primary efficacy analysis. To
`achieve similar numbers of patients in each dose group despite the
`late start of the 5-mg OD dose group, patients were randomized
`2:1:1:1:1:1 to 5, 10, 20, 30, and 40 mg rivaroxaban OD and 40 mg
`enoxaparin, respectively.
`
`Statistical Analysis
`
`Efficacy
`The primary efficacy analysis—to determine a trend in the dose–
`response relationship between rivaroxaban and the primary efficacy
`end point—was performed in the per-protocol (PP) population with
`a logistic regression model,
`including the total daily dose of
`rivaroxaban and the country in which the patient was treated as
`explanatory variables. An identical supportive analysis was per-
`formed in the intention-to-treat (ITT) population.
`A similar analysis, using logistic regression with the total daily
`dose of rivaroxaban as a covariate, was performed in the PP
`population to determine a trend in the dose–response relationship
`between rivaroxaban and major VTE (a secondary efficacy end
`point; because of the expected low incidence of major VTE, country
`effects were not considered in this analysis).
`The PP population comprised patients who had received at least
`one dose of study medication and had data allowing assessment of
`safety (ie, the safety population), who had undergone surgery, had an
`adequate VTE assessment (adequate bilateral venography 6 to 10
`days after surgery, or confirmed DVT, PE, or death up to 10 days
`after surgery) performed no later than 36 hours after the last dose of
`study drug, and who did not show any major protocol violations. All
`tests were 2 sided, with a type I error rate of ␣⫽5%.
`
`Safety
`The incidence of major bleeding was analyzed in the safety popu-
`lation with a logistic regression model, including the total daily dose
`of rivaroxaban as a covariate. In addition, each dose of rivaroxaban
`was compared with enoxaparin with the Fisher exact
`test. All
`statistical analyses were performed with SAS software, version 8.2
`(SAS Institute Inc, Cary, NC).
`
`The authors had full access to and take full responsibility for the
`integrity of the data. All authors have read and agree to the
`manuscript as written.
`
`Results
`
`Study Population
`Between November 2004 and July 2005, 877 patients were
`enrolled in this study, at 48 centers in 11 countries (Europe
`and Israel); 873 patients were randomized to receive rivar-
`oxaban or enoxaparin (Figure 1; for further details, see the
`Data Supplement Figure). Twenty-one randomized patients
`did not receive study drug (18 in the rivaroxaban dose groups
`and 3 in the enoxaparin group). Of the remaining 852
`patients, 695 received rivaroxaban (128, 142, 140, 143, and
`142 patients received 5, 10, 20, 30, and 40 mg OD, respec-
`tively) and 157 received enoxaparin. The safety population
`comprised 845 patients (7 patients withdrew from the study
`before surgery). The primary analysis was performed
`in the PP population, which comprised 618 patients: 511
`patients receiving rivaroxaban (94, 113, 106, 104, and 94
`patients in the 5-, 10-, 20-, 30-, and 40-mg OD dose groups,
`respectively) and 107 patients receiving enoxaparin (Figure
`1). A total of 29% of all randomized patients (255/873) were
`excluded from the primary efficacy analysis. The main reason
`for exclusion was inadequate evaluation of efficacy, which
`occurred in 195 patients, 110 of whom did not undergo
`bilateral venography, and venograms were considered inad-
`equate for interpretation in 83 patients. In 2 patients, venog-
`raphy was performed before the prespecified time window,
`ie, before the fifth postoperative day. Other reasons for
`exclusion included protocol violations, such as violating the
`time interval between doses of study drug and taking prohib-
`ited medications.
`All groups were well balanced with respect to age, sex,
`weight, body mass index, and the duration of surgery (Table
`1). Almost all patients were white; there were 3 nonwhite
`patients (2 Asian, 1 Hispanic). The mean interval between
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`

`Eriksson et al
`
`Once-Daily Oral Rivaroxaban for Thromboprophylaxis
`
`2377
`
`TABLE 1. Baseline Characteristics and Surgery Details for Study Patients (Safety Population; nⴝ845)
`
`Characteristics
`
`Age, mean (range), y
`Female, n (%)
`Weight, mean (range), kg
`Body mass index, mean (range), kg/m2
`Surgery details
`Cemented hip prosthesis, n (%)
`Duration of surgery, mean⫾SD, min
`Type of anesthesia
`General, n (%)
`Regional,* n (%)
`
`*Spinal and epidural anesthesia.
`
`5 mg OD
`(n⫽128)
`64.8 (28–84)
`72 (56)
`76.6 (45–118)
`27.4 (17–46)
`
`10 mg OD
`(n⫽142)
`64.0 (27–87)
`89 (63)
`75.6 (45–111)
`26.9 (18–49)
`
`Rivaroxaban
`
`20 mg OD
`(n⫽139)
`65.0 (27–93)
`82 (59)
`75.7 (47–120)
`27.1 (18–41)
`
`30 mg OD
`(n⫽142)
`65.4 (31–86)
`73 (51)
`78.4 (49–130)
`27.5 (20–43)
`
`40 mg OD
`(n⫽137)
`64.7 (27–83)
`81 (59)
`77.6 (50–126)
`27.5 (19–40)
`
`37 (28.9)
`85⫾33
`
`64 (50)
`62 (48)
`
`55 (38.7)
`89⫾30
`
`49 (35)
`93 (65)
`
`50 (36.0)
`85⫾31
`
`42 (30)
`96 (69)
`
`58 (40.8)
`89⫾34
`
`56 (39)
`84 (59)
`
`57 (41.6)
`89⫾31
`
`42 (31)
`95 (69)
`
`Enoxaparin
`
`40 mg OD
`(n⫽157)
`65.6 (30–89)
`101 (64)
`74.9 (45–116)
`27 (16–39)
`
`64 (40.8)
`84⫾28
`
`60 (38)
`97 (62)
`
`surgery and first oral dose of rivaroxaban was 7 hours. The
`mean duration of treatment was 7 days for rivaroxaban and 8
`days for enoxaparin—the difference is explained by the
`initiation of enoxaparin on the day before surgery and the
`initiation of rivaroxaban after surgery.
`
`Efficacy Outcomes
`The primary efficacy end point (composite of any DVT, PE,
`and all-cause death) was observed in 14.9%, 10.6%, 8.5%,
`13.5%, and 6.4% of patients receiving 5, 10, 20, 30, and 40
`mg rivaroxaban OD, respectively, compared with 25.2% of
`patients receiving enoxaparin (Table 2). Although there was a
`tendency toward a lower incidence of the primary efficacy
`end point with increasing doses of rivaroxaban (Table 2,
`Figure 2), statistical analysis did not detect a trend in this
`dose–response relationship (P⫽0.0852). Similar results were
`obtained in the ITT population (data not shown). No rivar-
`oxaban dose arm was discontinued because of lack of
`efficacy.
`No deaths were reported during the study (treatment and
`follow-up). Although there were no PEs reported in the PP
`
`population (Table 2), there was a PE in a patient in the ITT
`population who received 40 mg rivaroxaban OD, and one in
`a patient receiving 10 mg rivaroxaban OD who was only
`eligible for the safety analysis. There was one report of
`symptomatic DVT during the treatment period (1 distal DVT
`in the enoxaparin group [PP population]), and 3 during the
`follow-up period (2 proximal DVTs: 20 mg and 40 mg
`rivaroxaban; and 1 PE: 40 mg rivaroxaban).
`The observed incidence of the secondary efficacy end
`point, major VTE (composite of proximal DVT, PE, and
`VTE-related death), was similar to enoxaparin in all rivar-
`oxaban dose groups, except the 5-mg OD group, in which the
`incidence was 8.5%, compared with 2.8% for enoxaparin
`(Table 2). Statistical analysis demonstrated a significant trend
`in the dose–response relationship between rivaroxaban and
`major VTE (P⫽0.0072).
`
`Safety Outcomes
`The primary safety end point—major postoperative bleed-
`ing—was observed in 2.3%, 0.7%, 4.3%, 4.9%, and 5.1% of
`patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban OD,
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`
`TABLE 2.
`
`Efficacy End Points and Their Composites (PP Population; nⴝ618)
`
`Parameter
`
`Primary efficacy end point,* n (%)
`95% CI
`DVT, n (%)
`Proximal, n (%)
`Distal only, n (%)
`PE, n (%)
`Death, n (%)
`Major VTE,† n (%)
`95% CI
`
`5 mg OD
`(n⫽94)
`14 (14.9)
`8.4, 23.7
`14 (14.9)
`8 (8.5)
`6 (6.4)
`0
`0
`8 (8.5)
`3.7, 16.1
`
`10 mg OD
`(n⫽113)
`12 (10.6)
`5.6, 17.8
`12 (10.6)
`3 (2.7)
`9 (8.0)
`0
`0
`3 (2.7)
`0.6, 7.6
`
`Rivaroxaban
`
`20 mg OD
`(n⫽106)
`9 (8.5)
`4.0, 15.5
`9 (8.5)
`1 (0.9)
`8 (7.5)
`0
`0
`1 (0.9)
`0.0, 5.1
`
`30 mg OD
`(n⫽104)
`14 (13.5)
`7.6, 21.6
`14 (13.5)
`2 (1.9)
`12 (11.5)
`0
`0
`2 (1.9)
`0.2, 6.8
`
`40 mg OD
`(n⫽94)
`6 (6.4)
`2.4, 13.4
`6 (6.4)
`1 (1.1)
`5 (5.3)
`0
`0
`1 (1.1)
`0.0, 5.8
`
`Enoxaparin
`
`40 mg OD
`(n⫽107)
`27 (25.2)
`17.3, 34.6
`27 (25.2)
`3 (2.8)
`24 (22.4)
`0
`0
`3 (2.8)
`0.6, 8.0
`
`*Components of primary efficacy end point: any DVT; nonfatal, symptomatic, objectively confirmed PE (no reports); and all-cause
`death (no reports).
`†Components of major VTE (a secondary efficacy end point): proximal DVT; nonfatal, symptomatic, objectively confirmed PE (no
`reports); and death associated with VTE (no reports).
`
`0004
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`

`2378
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`Circulation
`
`November 28, 2006
`
`• DVT, PE, and all-cause death
`• Major, post-operative bleeding
`
`40
`
`7 30 -
`
`a) 20-
`
`' --------------
`
`10-
`
`•
`--------------------- -• -----
`
`0
`
`0
`
`10
`5
`30
`20
`Total daily dose (mg) of rivaroxaban
`
`30
`
`5
`-20 cti
`co
`o co
`
`Fo"
`
`-0
`
`Figure 2. Dose–response relationships between rivaroxaban and
`the primary efficacy end point (DVT, non-fatal PE, all-cause
`death; PP population) and the primary safety end point (major
`postoperative bleeding events; safety population). The solid
`lines are the dose–response curves for rivaroxaban, estimated
`by logistic regression including total daily dose as a covariate.
`The dotted lines represent the 95% CIs for safety. The hatched
`lines represent the 95% CIs for efficacy.
`
`respectively, compared with 1.9% of patients receiving enox-
`aparin (Table 3). There was a significant dose trend for major
`postoperative bleeding (P⫽0.0391; Figure 2). There were no
`significant differences in the incidences of major postopera-
`tive bleeding between any rivaroxaban dose and enoxaparin;
`however, this study was not powered to detect differences
`between individual rivaroxaban doses and enoxaparin.
`No bleeding into a critical organ was reported, and all
`major postoperative bleeding events were confined to the
`surgical site. The majority of major bleeding events were due
`to clinically overt bleeding associated with a fall in hemo-
`globin ⱖ2 g/dL within 24 hours and/or leading to transfusion
`of at least 2 units of blood. The incidences of the secondary
`
`bleeding end points are also shown in Table 3. In general,
`proportions of patients requiring blood transfusions were
`similar across all rivaroxaban dose groups and for enoxapa-
`rin, and the volume of blood transfused was also similar
`(Table 4). No dose arm was stopped because of safety
`concerns.
`Treatment-emergent increases (up to 7 days after the last
`dose of study drug) in alanine aminotransferase (ALT) or
`aspartate aminotransferase (AST) levels ⬎3⫻ the upper limit
`of normal (ULN) occurred in 3.0% to 5.4% and 3.4% to 6.2%
`of patients, respectively, in the rivaroxaban groups, compared
`with 7.1% of patients in the enoxaparin group (10/140 and
`10/141 patients, respectively; Table 5). There did not seem to
`be dose dependency between rivaroxaban and increased liver
`enzymes.
`One patient in the 30-mg rivaroxaban OD group had a
`combination of ALT ⬎3⫻ ULN and bilirubin ⬎2⫻ ULN 3
`hours after receiving his first dose of study medication.
`Bilirubin returned to within normal limits the next day. ALT
`levels decreased despite continued study drug administration:
`They were ⬍3⫻ ULN on the last day of administration and
`within normal limits at the follow-up visit (34 days after
`receiving the last dose of study drug).
`In addition, 1 patient in the 10-mg rivaroxaban OD group
`who had normal ALT and AST levels at baseline had raised
`ALT and AST 3 days after surgery (approximately 2⫻ ULN;
`bilirubin was within normal limits). The patient received
`study medication for 7 days after surgery, according to the
`protocol. Liver enzymes continued to rise during the
`follow-up period, with ALT and AST ⬎3⫻ ULN 59 days
`after receiving the last dose of study drug, and 14 days later.
`An ultrasound examination 99 days after surgery revealed
`cholecystolithiasis.
`
`Discussion
`The ODIXa-OD-HIP study demonstrated that oral rivaroxa-
`ban given once daily postoperatively was equally efficacious
`
`TABLE 3. Bleeding End Points (Safety Population; nⴝ845)
`
`Rivaroxaban
`
`Enoxaparin
`
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`
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` by guest on April 16, 2018
`
`Bleeding Classification
`
`5 mg OD
`(n⫽128)
`3 (2.3)
`0.5, 6.7
`
`10 mg OD
`(n⫽142)
`1 (0.7)
`0.0, 3.9
`
`20 mg OD
`(n⫽139)
`6 (4.3)
`1.6, 9.2
`
`30 mg OD
`(n⫽142)
`7 (4.9)
`2.0, 9.9
`
`40 mg OD
`(n⫽137)
`7 (5.1)
`2.1, 10.2
`
`40 mg OD
`(n⫽157)
`3 (1.9)
`0.4, 5.5
`
`Major postoperative bleeding*, n (%)
`95% CI
`Components of major bleeding†
`Fatal/critical bleeding, n (%)
`Bleeding leading to reoperation, n (%)
`Clinically overt bleeding leading to
`treatment cessation, n (%)
`Clinically overt bleeding with a fall in
`hemoglobin, n (%)
`Clinically overt bleeding leading to
`blood transfusion, n (%)
`5 (3.2)
`4 (2.9)
`3 (2.1)
`1 (0.7)
`3 (2.1)
`2 (1.6)
`Clinically relevant non–major bleeding, n (%)
`6 (3.8)
`14 (10.2)
`8 (5.6)
`6 (4.3)
`5 (3.5)
`5 (3.9)
`Minor bleeding, n (%)
`*Bleeding starting after the first postoperative dose of study drug, but not ⬎2 days after the last administration of study drug.
`†Patients may have events that fall into ⬎1 category.
`
`0
`0
`0
`
`2 (1.6)
`
`0
`0
`0
`
`0
`
`0
`1 (0.7)
`1 (0.7)
`
`0
`1 (0.7)
`0
`
`0
`0
`1 (0.7)
`
`0
`0
`0
`
`4 (2.9)
`
`6 (4.2)
`
`5 (3.6)
`
`1 (0.6)
`
`3 (2.3)
`
`1 (0.7)
`
`5 (3.6)
`
`6 (4.2)
`
`6 (4.4)
`
`3 (1.9)
`
`0005
`
`

`

`Eriksson et al
`
`Once-Daily Oral Rivaroxaban for Thromboprophylaxis
`
`2379
`
`TABLE 4. Blood Transfusions and Volume of Postoperative Blood Loss (Safety Population; nⴝ845)
`
`Patients receiving blood transfusions, n (%)
`Volume, mean⫾SD, mL
`Patients with volume in drain (postoperative), n (%)
`Volume, mean⫾SD, mL
`
`5 mg OD
`(n⫽128)
`72 (56.3)
`317⫾400
`107 (83.6)
`582⫾438
`
`10 mg OD
`(n⫽142)
`85 (59.9)
`342⫾356
`115 (81.0)
`491⫾442
`
`Rivaroxaban
`
`20 mg OD
`(n⫽139)
`85 (61.2)
`404⫾422
`114 (82.0)
`538⫾592
`
`30 mg OD
`(n⫽142)
`82 (57.7)
`391⫾456
`119 (83.8)
`469⫾514
`
`40 mg OD
`(n⫽137)
`81 (59.1)
`416⫾460
`112 (81.8)
`470⫾364
`
`Enoxaparin
`
`40 mg OD
`(n⫽157)
`93 (59.2)
`409⫾455
`126 (80.3)
`454⫾441
`
`across an 8-fold dose range (5 to 40 mg OD), with efficacy
`similar to enoxaparin (40 mg OD) for the prevention of VTE
`after elective hip replacement surgery. The rate of major
`bleeding was similar to enoxaparin in the 5- and 10-mg OD
`dose groups.
`The observed incidence of the primary efficacy end point
`(the composite of DVT, PE, and all-cause death) was slightly
`lower than observed in a similar phase II dose-finding study
`investigating rivaroxaban given twice daily in patients under-
`going hip replacement surgery7: 14.9%, 10.6%, and 8.5%
`with total daily doses of 5, 10, and 20 mg rivaroxaban OD,
`respectively (present study), compared with 15.4%, 13.8%,
`and 11.9%, respectively (twice-daily study). The incidence
`with enoxaparin (25.2%; 95% confidence interval [CI] 17.3,
`34.6) was higher than observed in the twice-daily rivaroxaban
`phase II study (17.0%; 95% CI 10.4, 25.5),7 despite the use of
`the same rigorous assessment technique and the same central
`adjudication committee.
`There was a flat dose–response relationship between rivar-
`oxaban and the primary efficacy end point (P⫽0.0852). This
`could be explained by the higher-than-expected efficacy
`achieved in the lower dose groups (higher than assumed for
`sample size calculations).
`A total of 71% of randomized patients received study drugs
`and were eligible for the primary efficacy analysis (PP
`population). This validity rate is similar to those reported in
`other clinical trials investigating anticoagulants in patients
`undergoing orthopedic surgery: 70% and 79% of patients
`were valid for the primary analysis in the PENTATHLON15
`and European Pentasaccharide Hip Elective SUrgery Study
`(EPHESUS)16 studies with fondaparinux, respectively; 72%
`and 74% in the Boehringer Ingelheim Study in ThROmbosis
`(BISTRO) I17 and II18 studies with dabigatran, respectively;
`and 77% and 79% in the MElagatran for THRombin inhibi-
`tion in Orthopaedic surgery (METHRO) II19 and III20 studies
`with ximelagatran, respectively.
`The observed incidence of major VTE (which comprised
`proximal DVT because there were no reports of death or PE
`
`during the study) was lower with all doses of rivaroxaban,
`except the 5-mg OD dose, compared with enoxaparin. Fur-
`thermore, there was a significant dose–response relationship
`between rivaroxaban and major VTE (P⫽0.0072). Except for
`the 5-mg OD dose, there was a similar incidence of major
`VTE in this study (8.5%, 2.7%, 0.9%, 1.9%, and 1.1% for the
`5-, 10-, 20-, 30-, and 40-mg rivaroxaban groups, respectively)
`compared with the phase II twice-daily dosing study with
`rivaroxaban (2.9%, 0.9%, 1.0%, and 3.0% for total daily
`doses of 5, 10, 20, and 40 mg rivaroxaban, respectively).7
`Because of its limited efficacy for the prevention of major
`VTE, and despite its efficacy for the prevention of the
`primary end point, 5 mg rivaroxaban OD was defined as the
`lowest effective dose.
`The incidence of proximal DVT observed with enoxaparin
`(2.8%) was lower than that observed in previous studies that
`used 40 mg enoxaparin OD (5.2%),18 which was similar to
`that observed in the rivaroxaban phase II twice-daily dosing
`study (4.7%).7 The incidence of symptomatic VTE events
`was low during treatment and follow-up after short-term
`rivaroxaban (6 to 10 days).
`There was a significant dose trend for major postoperative
`bleeding
`across
`the
`rivaroxaban
`treatment
`groups
`(P⫽0.0391). The observed incidences were similar in the 5-
`and 10-mg rivaroxaban OD dose groups and the enoxaparin
`group (2.3% and 0.7% versus 1.9%, respectively). The ob-
`served incidences in the 20-, 30-, and 40-mg rivaroxaban OD
`dose groups were higher than with enoxaparin, but no dose
`group was discontinued because of excessive bleeding. Im-
`portantly, there were no fatal bleeding events or bleeding into
`a critical organ, all major bleeding events were confined to
`the surgical site, and only 2 patients (1 in each of the 20- and
`30-mg rivaroxaban OD groups) required reoperation.
`The incidence of major postoperative bleeding was similar
`in this study, after once-daily dosing (2.3%, 0.7%, 4.3%,
`4.9%, and 5.1% for rivaroxaban doses of 5, 10, 20, 30, and 40
`mg OD), to that seen with twice-daily dosing in the previous
`phase II study (0.8%, 2.2%, 2.3%, and 4.5% for total daily
`
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` by guest on April 16, 2018
`
`TABLE 5. Patients With Liver Aminotransferase Levels >3ⴛ ULN (Safety Population; nⴝ845)
`
`Rivaroxaban
`
`Enoxaparin
`
`40 mg OD
`(n⫽157)
`10/140 (7.1)
`10/141 (7.1)
`
`Laboratory Parameter
`ALT ⬎3⫻ ULN, n/N* (%)
`AST ⬎3⫻ ULN, n/N* (%)
`*Number of patients with specified laboratory abnormality/total number of patients who had laboratory tests.
`
`5 mg OD
`(n⫽128)
`5/119 (4.2)
`4/119 (3.4)
`
`10 mg OD
`(n⫽142)
`5/133 (3.8)
`5/134 (3.7)
`
`20 mg OD
`(n⫽139)
`4/133 (3.0)
`6/133 (4.5)
`
`30 mg OD
`(n⫽142)
`7/129 (5.4)
`8/129 (6.2)
`
`40 mg OD
`(n⫽137)
`5/127 (3.9)
`5/127 (3.9)