Scientific Poster Session and Clinical Update - Center for ...

HROMBOSIS
THROMBOSIS
Scientific Poster Session
and Clinical Update
ABSTRACTS
Selected meeting abstracts from ISTH 2007, ASH 2007, and published journal articles
This activity is supported by an
unrestricted educational grant from
Scios and Bayer HealthCare.

Contents
Low-Molecular Weight Heparin
enoxaparin
Pregnant Patients with Mechanical Heart Valves .......................................................................2
Chemotherapy-induced Thrombocytopenia ................................................................................3
EXCLAIM ...................................................................................................................................4
Oral Direct Thrombin Inhibitor
Dabigatran etexilate
BISTRO I .....................................................................................................................................6
BISTRO II ....................................................................................................................................7
Prevention of Venous Thromboembolism ............................................................................ 8-10
Oral Direct Factor Xa Inhibitors
YM150
Prevention of Venous Thromboembolism .................................................................................12
apixaban
Treatment of Acute Symptomatic Deep Vein Thrombosis .........................................................13
rivaroxaban (baY 59-7939)
Prevention of Venous Thromboembolism ........................................................................... 14-15
RECORD I .................................................................................................................................16
RECORD II ................................................................................................................................17
RECORD III ......................................................................................................................... 18-19
Once- or Twice-Daily Dosing Treatment of Deep Vein Thrombosis ............................................20
Pharmacokinetics and Pharmacodynamics ........................................................................ 21-22
Patients with Heparin-Induced Thrombocytopenia ...................................................................23

enoxaparin

Dose-Escalated Low Molecular Weight Heparin Provides
Effective Anticoagulation for Women with Mechanical Heart
Valves during Pregnancy: A Single-Centre Experience
Quinn J, Brooks R, Walker F, Peebles D, Cohen H (Intr. by David C Linch)
Haematology, University College London Hospitals, London, United Kingdom; Cardiology, University College London Hospitals,
London, United Kingdom; Obstetrics and Gynaecology, University College London Hospitals, London, United Kingdom
Abstract #1873 appears in Blood, Volume 110, issue 11, November 16, 2007
introDUCtion
Effective anticoagulation for women with mechanical heart
valves during pregnancy remains a major challenge. The use
of standard dosage low molecular weight heparin (LMWH) is
associated with an unacceptable incidence of morbidity and
mortality for this patient group.
MethoDs
In this prospective audit of anticoagulation management,
we report pregnancy outcome for a cohort of women with
mechanical heart valves, who received anticoagulation with
a higher dosage LMWH regimen. We audited 12 consecutive
pregnancies in 10 women (mean age 27.8 (18-41) years) with
mechanical heart valves (mitral 4, aortic 2, aortic and mitral
2, systemic tricuspid AV valve 2). Past obstetric history (on
warfarin) included 6 fetal losses: 2 miscarriages

The Feasibility and Safety of Anticoagulation during
Chemotherapy Associated Thrombocytopenia for
Thrombotic Complications of Malignancy
Polizzotto MN, Opat SS
Department of Haematology, Alfred Hospital, Melbourne, Victoria, Australia
Abstract #1872 appears in Blood, Volume 110, issue 11, November 16, 2007
introDUCtion
The optimal management of patients with hematological
malignancies who require therapeutic anticoagulation for
thromboembolic disease or prosthetic cardiac valves while
receiving myelosuppressive chemotherapy has not been
established. In particular, the role of anticoagulation during
chemotherapy-induced thombocytopenia, with its attendant
increased risk of bleeding, is undefined.
MethoDs
We describe the feasibility and safety of a dynamic dosing
strategy for continuous anticoagulation during chemotherapyinduced
thrombocytopenia. Sixty patients with haematological
malignancies who required anti-coagulation for venous
thromboembolism or prosthetic cardiac valves while
receiving chemotherapy were assessed. All were receiving
myelosuppressive chemotherapy for a haematological
malignancy (27 Acute myeloid or promyelocytic leukaemia;
18 non-Hodgkin lymphoma; 9 plasma cell myeloma; 6 Acute
lymphoblastic leukaemia), and required anticoagulation
for either proven deep venous thrombosis (catheter-related
thrombosis in 32 patients; non-catheter associated deep
venous thrombosis in 18) or pulmonary embolus (9) or
prosthetic cardiac valves (1). Three patients underwent
allogeneic stem cell transplantation and 7 autologous stem
cell transplantation. Median time from diagnosis of the
thromboembolic disease to commencement chemotherapy
was 10 days (range 0–40). Patients were anticoagulated with
subcutaneous enoxaparin 1mg/kg body weight twice daily
while the platelet count was ≥50x109/L and 0.5mg/kg once
daily to maximum of 40mg while it was

Consistent Venous Thromboembolism Risk Reduction by Extended-
Versus Standard-Duration Enoxaparin Prophylaxis in Subgroups of
Acutely Ill Medical Patients in the EXCLAIM Study
Tapson VF, Hull RD, Schellong SM, Monreal M, Samama MM, Turpie AGG, Yusen RD (Intr. by Graham F Pineo)
Duke University Medical Center, Durham, NC, USA; University of Calgary, Foothills Hospital, Calgary, AB, Canada;
Hospital Carl Gustav Carus, Dresden, Germany; Hospital Germans Trias i Pujol, Barcelona, Spain; Hotel Dieu, University Hospital, Paris, France;
McMaster University, HHSC McMaster Clinic, Hamilton, ON, Canada; Washington University School of Medicine, St. Louis, MO, USA
Abstract #1863 appears in Blood, Volume 110, issue 11, November 16, 2007
introDUCtion
In the EXCLAIM study, extended-duration enoxaparin
prophylaxis reduced the relative risk of VTE in acutely ill
medical patients by 44% compared with placebo, following
standard-duration prophylaxis (2.8% vs 4.9%; RR 0.56;
95% CI 0.39–0.80; p=0.0011). We assessed the benefits of
extended-duration enoxaparin prophylaxis in subgroups of
acutely ill medical patients with the most prominent primary
diagnoses enrolled in EXCLAIM.
MethoDs
Patients enrolled in EXCLAIM had: recent reduced mobility
(≤3 days) due to a medical illness, age ≥40 years, and
anticipated level 1 (total bed rest or sedentary without
bathroom privileges) or level 2 (level 1 with bathroom
privileges) reduced mobility with further risk factors.
Eligible patients received enoxaparin 40mg SC once-daily
for 10 ±4 days, and were then double-blind randomized
and received enoxaparin 40mg SC once-daily (n=2013) or
placebo (n=2027) for a further 28 ±4 days. Asymptomatic
DVT were diagnosed by bilateral compression ultrasound
after completion of the randomized treatment. Suspected
cases of symptomatic DVT or PE were confirmed by objective
tests. Fatal PE were confirmed by autopsy where possible.
Univariate logistic regressions were conducted to estimate
treatment effects in patient subgroups. The primary safety
endpoint was major bleeding.
resUlts
Baseline characteristics were similar between treatments
within each primary diagnosis subgroup, and the considered
primary diagnoses accounted for >80% of the enrolled
population. The reduced VTE incidence associated with
extended-duration enoxaparin prophylaxis was consistent
across subgroups of patients with different primary diagnoses
(Table). The incidence of major bleeding was generally higher
in patients receiving extended-duration prophylaxis (Table).
ConClUsion
Extended enoxaparin prophylaxis consistently reduced VTE
risk in acutely ill medical patients with the most prominent
primary diagnoses compared with placebo following standardduration
prophylaxis. Major bleeding was generally higher in
the extended-duration enoxaparin arm, but rates of bleeding
were low. These findings are consistent with the primary
findings of the EXCLAIM study which demonstrated the
clinical benefit of the extended-duration enoxaparin regimen.
Table: VTE and major bleeding in patient subgroups receiving extended-duration vs standard-duration prophylaxis/placebo
Primary diagnosis Incidence of VTE (%)*
Extended Enox
Standard Enox/
Placebo
Odds Ratio
[95% CI]**
Incidence of Major Bleeding (%)***
Extended Enox
Standard Enox/
Placebo
Odds Ratio
[95% CI]
Heart failure, NYHA class III or IV 3.1 4.7 0.64 [0.29-1.39] 0.0 0.2 N/A
Acute respiratory insufficiency 2.2 3.7 0.60 [0.27-1.34] 0.6 0.2 3.15 [0.33-30.4]
Post ischemic stroke 2.1 8.3 0.24 [0.06-0.91] 0.6 0.0 N/A
Acute infection without septic shock 3.6 5.3 0.66 [0.36-1.22] 0.8 0.2 5.16 [0.60-44.3]
*N=3347 evaluable patients; **Alpha adjustment for an interim analysis; ***N=4040 treated patients
Copyright American Society of Hematology. Reprinted with
permission from the American Society of Hematology, which
does not endorse any particular uses of this document. The
American Society of Hematology is not responsible for the
completeness or the accuracy of the translation.

oral DireCt
throMbin inhibitor

Dose Escalating Safety Study of a New Oral Direct
Thrombin Inhibitor, Dabigatran Etexilate, in Patients
Undergoing Total Hip Replacement: BISTRO I
Eriksson BI, Dahl OE, Ahnfelt L, Kälebo P, Stangier J, Nehmiz G, Hermansson K, Kohlbrenner V.
J Thromb Haemost 2004;2(9):1573-80.
introDUCtion
Dabigatran etexilate (BIBR 1048) is an oral direct thrombin
inhibitor undergoing evaluation for the prevention of venous
thromboembolism (VTE) following total hip replacement.
Following oral administration, dabigatran etexilate is rapidly
converted to its active form dabigatran (BIBR 953 ZW).
MethoDs
In a multicenter, open-label, dose-escalating study, 314
patients received oral doses of dabigatran etexilate (12.5, 25,
50, 100, 150, 200 and 300 mg twice daily or 150 and 300
mg once daily) administered 4-8 h after surgery, for 6-10 days.
Dose escalation was based on clinical and pharmacokinetic
data. The primary safety outcome was major bleeding. The
primary efficacy outcome included venographic deep vein
thrombosis (DVT), symptomatic DVT and pulmonary embolism
during the treatment period.
resUlts
No major bleeding event was observed in any group, but
two patients at the highest dose (300 mg twice daily)
suffered bleeding from multiple sites associated with
reduced renal clearance and prolonged pharmacodynamic
(PD) parameters. A dose-response was demonstrated for
minor bleeding events. Of the 289 treated patients, 225
patients had evaluable venograms. The overall incidence of
DVT was 12.4% (28/225 patients). There was no consistent
relationship between the dose and incidence of DVT, the
highest incidence in any group being 20.8% (5/24 patients).
The lowest dose (12.5 mg twice daily) showed a high rate
of proximal DVT [12.5% (3/24)] and no increase in PD
parameters. Peak and trough plasma concentrations, area
under the dabigatran plasma concentration-time curve and
PD parameters also increased in proportion with the dose.
Higher dabigatran plasma concentrations were associated
with lower DVT rates. Approximately 20% of the patients
had low plasma concentrations after the first dose suggesting
further optimization of the preliminary tablet formulation
is required.
ConClUsions
Dabigatran etexilate demonstrates an acceptable safety
profile, with a therapeutic window above 12.5 mg and below
300 mg twice daily. The low number of VTE events within
each treatment group indicates a satisfactory antithrombotic
potential, although the study was not powered for an efficacy
analysis. Additional studies are ongoing to optimize oral
absorption and the efficacy/ safety balance.

A New Oral Direct Thrombin Inhibitor, Dabigatran
Etexilate, Compared With Enoxaparin for Prevention
of Thromboembolic Events Following Total Hip or Knee
Replacement: the BISTRO II Randomized Trial
Eriksson BI, Dahl OE, Büller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kälebo P,
Reilly P for the BISTRO II Study Group.
J Thromb Haemost 2005;3(1):103-11.
introDUCtion
Dabigatran etexilate is an oral direct thrombin inhibitor
undergoing evaluation for the prevention of venous
thromboembolism (VTE) following orthopedic surgery.
MethoDs
In a multicenter, parallel-group, double-blind study, 1973
patients undergoing total hip or knee replacement were
randomized to 6-10 days of oral dabigatran etexilate
(50, 150 mg twice daily, 300 mg once daily, 225 mg
twice daily), starting 1-4 h after surgery, or subcutaneous
enoxaparin (40 mg once daily) starting 12 h prior to surgery.
The primary efficacy outcome was the incidence of VTE
(detected by bilateral venography or symptomatic events)
during treatment.
resUlts
Of the 1949 treated patients, 1464 (75%) patients were
evaluable for the efficacy analysis. VTE occurred in 28.5%,
17.4%, 16.6%, 13.1% and 24% of patients assigned to
dabigatran etexilate 50, 150 mg twice daily, 300 mg once
daily, 225 mg twice daily and enoxaparin, respectively.
A significant dose-dependent decrease in VTE occurred
with increasing doses of dabigatran etexilate (P

The Oral Direct Thrombin Inhibitor, Dabigatran Etexilate,
is Effective and Safe for Prevention of Major Venous
Thromboembolism Following Major Orthopedic Surgery
Caprini JA 1 , Hwang E 2 , Hantel S 3 , Schnee J 4 , Eriksson BI 5
1 Department of Surgery, Evanston Northwestern Healthcare, and Northwestern University Feinberg School of Medicine, Northfield, IL; 2 Medical
Data Services/Biostatistics, Boehringer-Ingelheim, Ridgefield, CT, United States; 3 Medical Data Services/Biostatistics, Boehringer Ingelheim,
88397 Biberach an der Riss, Germany; 4 Cardiovascular Clinical Operations, Boehringer-Ingelheim, Ridgefield, CT, United States; 5 Orthopaedics
Department, Sahlgrenska University Hospital/Östra, SE-41685 Göteborg, Sweden
Abstract O-W-050 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Major venous thromboembolism (VTE) and VTE related death,
the composite of proximal deep venous thrombosis (DVT),
symptomatic pulmonary embolism (PE) and VTE related
death, is a well recognized important clinical endpoint in VTE
prevention studies. A pre-specified pooled analysis of major
VTE and VTE related death after major orthopedic surgery,
was performed across the >8000 patient phase III primary
VTE prevention program of dabigatran etexilate (RE-MODEL,
RE-MOBILIZE and RE-NOVATE Studies).
MethoDs
Each of the double blind, randomized studies compared 220
and 150 mg of dabigatran etexilate, once-daily following a
half-dose on the day of surgery, to enoxaparin. Enoxaparin
was given 40 mg once-daily in the two mainly European
studies, and 30 mg twice daily in the mainly North American
study. Treatment duration was 6-15 days post knee replacement
and 28-35 days post hip replacement. Definitive diagnostic
testing was required for all suspected symptomatic VTE
events. Bilateral venography was performed at the end of the
treatment period.
resUlts
Major VTE and VTE related death occurred in 3.3% of the
enoxaparin group (69 of 2096) versus 3.0% (62 of 2033)
of the dabigatran etexilate 220 mg group (risk difference,
-0.2%; 95% confidence interval [CI], -1.3%, 0.9%) and
3.8%, (78 of 2071) of the 150 mg group (0.5%; 95% CI,
-0.6% to 1.6%). Major bleeding events were infrequent,
and occurred at comparable rates across all treatment groups:
enoxaparin 1.4% (39 of 2716), dabigatran 220 mg 1.4%
(38 of 2682), and dabigatran 150 mg 1.1% (29 of 2737).
ConClUsions
Dabigatran etexilate was efficacious and comparable to
enoxaparin in the prevention of major VTE and VTE related
mortality after knee and after hip replacement.

Dabigatran Etexilate is Effective and Safe for the Extended Prevention
of Venous Thromboembolism Following Total Hip Replacement
Eriksson BI 1 , Dahl OE 2 , Rosencher N 3 , Kurth AA 4 , v. Dijk N 5 , Frosticks SP 6 , Hettiarachchi R 7 , Hantel S 8 , Schnee J 9 ,Büller HR 10
1 Department of Othopaedics, Sahlgrenska University Hospital, Göteborg, Sweden; 2 International Surgical Thrombosis Forum, Thrombosis
Research Institute, London, United Kingdom; 3 Department of Anaesthesia, Paris 5 University Hospital, Paris, France; 4 Department of Othopaedics,
University Hospital Stiftung Friedrichsheim, Frankfurt, Germany; 5 Department of Othopaedics, Academic Medical Center, Amsterdam,
Netherlands; 6 Department of Musculoskeletal Science, Royal Liverpool University Hospital, Liverpool, United Kingdom; 7 Medical Department,
Boehringer Ingelheim, Alkmaar, Netherlands; 8 Medical Department, Boehringer Ingelheim, Bibarach, Germany; 9 Medical Department, Boehringer
Ingelheim, Ridgefield, United States; 10 Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
Abstract O-W-049 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Prophylaxis beyond hospital discharge is recommended to
reduce the risk of venous thromboembolism (VTE) after hip
replacement surgery. Oral thrombo-prophylaxis not requiring
monitoring is an advantage in orthopaedic patients. Dabigatran
etexilate is an oral direct thrombin inhibitor under evaluation
for this indication.
MethoDs
In a double-blind non-inferiority Phase III study, we
randomized 3494 patients undergoing total hip replacement
to treatment for 28 to 35 days with dabigatran etexilate,
220 mg or 150 mg once-daily, starting with a half-dose 1 to
4 hours after surgery, or subcutaneous enoxaparin 40 mg
once-daily, starting the evening before surgery. We evaluated
the composite of total venous thromboembolism and death
from all-causes (primary efficacy outcome), and major
bleeding, during treatment. All efficacy and safety outcome
events were centrally adjudicated by blinded independent
committees. Patients were followed-up for 3 months
after surgery.
resUlts
The median treatment duration was 33 days, with 87%
of patients receiving treatment for 28 to 35 days. The
primary efficacy outcome occurred in 6.7% (60 of 897) of
the enoxaparin recipients versus 6.0% (53 of 880) of the
dabigatran etexilate 220 mg patients (absolute difference,-
0.7%; 95% confidence interval [CI], -2.9 to 1.6) and 8.6%
(75 of 874) in those who received 150 mg (1.9%; 95% CI,
-0.6 to 4.4). Both doses were non-inferior to enoxaparin
according to predefined criteria. There was no significant
difference in major bleeding rates between the groups (1.6%,
2.0% and 1.3%, respectively). The incidence of liver enzyme
elevations and acute coronary events during the treatment
or during the follow-up period did not differ significantly
between the groups.
ConClUsions
Oral dabigatran etexilate once daily, administered for a
median of 33 days, was as effective as enoxaparin in
reducing the risk of venous thromboembolism after total
hip replacement surgery, with a similar safety profile.

Dabigatran Etexilate Versus Enoxaparin in Preventing Venous
Thromboembolism Following Total Knee Arthroplasty
Friedman RJ 1 , Caprini JA 2 , Comp PC 3 , Davidson BL 4 , Francis CW 5 , Ginsberg J 6 , Huo M 7 , Lieberman J 8 , Muntz JE 9 , Raskob GE 10 , Clements ML 11 ,
Hantel S 12 , Schnee J 11
1 Orthopaedic Surgery, Charleston Orthopaedic Associates, Charleston; 2 Vascular Surgery, Evanston Northwestern Healthcare, Skokie; 3 Medicine,
VA Hospital, Oklahoma City; 4 Medicine, Cornell Medical College, New York; 5 Medicine, University of Rochester, Rochester, United States;
6 Medicine, McMaster Medical Center, Hamilton, Canada; 7 Orthopaedic Surgery, UT Southwestern Medical Center, Dallas; 8 Orthopaedic Surgery,
University of Conneticut, Farmington; 9 Medicine, Methodist Hospital, Houston; 10 Medicine, University of Oklahoma, Oklahoma City; 11 Clinical
Operations; 12 Biostatistics, Boehringer Ingelheim, Ridgefield, United States
Abstract O-W-051 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Oral venous thromboembolic prophylaxis without monitoring
or dose adjustment is an advantage for patients. Dabigatran
etexilate (D), an oral direct thrombin inhibitor, is being
evaluated for its prophylactic effects following orthopedic
surgery in a series of clinical studies
MethoDs
This phase III, double-blind, non-inferiority study, randomized
2615 patients to 12-15 days treatment with D150mg qd,
D220mg qd, or enoxaparin (E) 30mg bid. D was given as a
half dose the day of surgery (6-12 hours post-surgery) and E
was started 12-24 hours post-surgery. The primary efficacy
endpoint was a composite of proximal DVT, distal DVT, PE
and all-cause mortality (VTE). The primary safety endpoint
was major bleeding events (MBE). Patients had bilateral
venography at the termination of therapy. Efficacy and safety
events were adjudicated by blinded independent committees.
73% of patients were evaluable for VTE.
resUlts
VTE rates were 33.7% (D150), 31.1% (D220) and 25.3%
(E; p=0.0009, D150mg vs E; p=0.02, D220 vs E). Rates of
the composite of proximal DVT, PE and VTE-related mortality
(Major VTE) were 3.0% (D150), 3.4% (D220), and 2.2%
(E, p=ns). MBE rates were 0.6% (D150), 0.6% (D220) and
1.4% (E). Elevated ALT (>3xULN) was infrequent and similar
in all groups (D150, 1.0%; D220, 0.7%; E, 0.9%).
10
ConClUsions
Treatment with D220 or D150 qd was not as effective
as E bid in preventing VTE, but did preserve 61% and
50%, respectively, of the putative efficacy of E compared
to placebo. Differences were predominantly due to
asymptomatic distal DVTs, since Major VTE occurred at
similar rates in all treatment groups. Dabigatran etexilate
was safe and well tolerated when given orally starting
6-12 hours following total knee arthroplasty.

oral DireCt
FaCtor xa
inhibitors
11

YM150, an Oral Direct Factor Xa Inhibitor, as Prophylaxis for
Venous Thromboembolism in Patients with Elective Primary Hip
Replacement Surgery. A Dose Escalation Study.
Eriksson BI, Turpie AGG, Lassen MR, Prins MH, Agnelli G, Gaillard ML, Meems B.
Blood 2005;106: Abstract 1865
introDUCtion
Activated factor X (FXa) is a pivotal blood coagulation factor
positioned at the crossroads of the extrinsic and intrinsic
coagulation cascade. Inhibitors of FXa are anticoagulants that
could be used in the prevention and treatment of thrombosis
and venous thromboembolism (VTE).
MethoDs
YM150 is a once daily, orally active FXa inhibitor. A
randomized, enoxaparin-controlled, dose escalation study
was performed in 174 patients undergoing elective primary
hip replacement surgery to assess safety and efficacy of
7-10 days of treatment with oral doses of YM150 (3, 10,
30, or 60 mg once daily starting 6-10 h after surgery) or s.c.
enoxaparin (40 mg once daily starting 12 h before surgery).
Safety is defined as major and/or clinically relevant non-major
bleeding, and efficacy as venous thromboembolism detected
by mandatory bilateral venography on the last treatment
day and/or symptomatic VTE. The study was open-label
with blinded evaluation of all outcomes by an independent
Adjudication Committee.
resUlts
There were no major bleeds. Three clinically relevant nonmajor
bleeds were reported, 1 (2.9%; 95% CI: 0-16%) in
the 3 mg and 2 (5.7 %; 1-19%) in the 10 mg YM150 dose
groups. No trend was observed in the incidence of minor
bleeds with dose of YM150 in the range 10 mg to 60 mg
daily. The proportion of patients with minor bleeding events
in the enoxaparin group (22%; 95% CI: 10-39%) was similar
to that in the YM150, 60 mg daily group (24%; 11-41%).
147 patients (84%) were considered to have an evaluable
venogram. The incidences of VTE were 52% (95% CI: 31-
72%), 39% (22-57%), 23% (9-40%), and 19% (7-37%) for
the respective 3, 10, 30, and 60 mg YM150 once daily dose
groups in comparison with 39% (22-57%) for enoxaparin.
12
Logistic regression analysis revealed a statistically significant
dose-related trend (P=0.006) for patients reaching the VTE
endpoint during YM150 treatment. No trend in any of
the measured safety parameters was observed with study
treatment (YM150 or enoxaparin) or dose of YM150.
ConClUsions
Oral, once daily doses of YM150, 10 mg to 60 mg
administered 6 to 10 h after primary hip replacement, were
shown to be safe, well tolerated and effective in this study.

Late Breaking Clinical Trial: A Dose Finding Study of
the Oral Direct Factor Xa Inhibitor Apixaban in the
Treatment of Patients with Acute Symptomatic Deep
Vein Thrombosis-The Botticelli Investigators
Büller HR
Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
Abstract O-S-003 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Apixaban is a new, direct-acting inhibitor of coagulation
Factor Xa. It binds to the active site of Factor Xa without
requiring anti-thrombin. The efficacy and safety of this
compound was evaluated in patients with confirmed deep
vein thrombosis (DVT).
MethoDs
Patients were allocated randomly to 1 of 3 double-blind
regimens of apixaban (5 mg BID,10 mg BID, or 20 mg
QD), or conventional treatment with low molecular weight
heparin or fondaparinux followed by open-label vitamin K
antagonist (VKA) (dose adjusted to an INR 2.0-3.0). Treatment
continued for 84-91 days. A bilateral venous compression
ultrasound (CUS) of the legs and a perfusion lung scan (PLS)
were obtained within 36 hours from randomization and at
12 weeks. The primary efficacy outcome was the composite
of symptomatic recurrent venous thromboembolism (VTE)
and deterioration of the thrombotic burden as assessed by
repeat bilateral CUS and PLS. The principal safety outcome
was the composite of major and clinically relevant nonmajor
bleeding. All outcomes were evaluated by a central,
independent and blinded, adjudication committee (CIAC).
resUlts
A total of 520 patients were randomized. For apixaban
5 mg BID, 10 mg BID, 20 mg QD, and for VKA, the primary
efficacy outcome rates were 6.0%, 5.6%, 2.6%, and 4.2%,
respectively, and the principal safety outcome rates were
8.6%, 4.5%, 7.3%, and 7.9%, respectively. The rates of
symptomatic VTE were 2.6%, 3.2%, 1.7%, and 2.5%,
respectively, and the rates of major bleeding were 0.8%,
0, 0.8%, and 0, respectively.
13
ConClUsions
This oral direct factor Xa inhibitor that can be given as the
sole treatment in a fixed dose appears to be a very attractive
alternative to standard therapy in patients with DVT.

BAY 59-7939: An Oral, Direct Factor Xa Inhibitor for the
Prevention of Venous Thromboembolism in Patients After
Total Knee Replacement. A Phase II Dose-Ranging Study
Turpie AGG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kälebo P, Misselwitz F, Gent M for the OdiXa-Knee Study Group
J Thromb Haemost 2005;3(11):2479-86.
introDUCtion
BAY 59-7939, a novel, oral, direct factor Xa inhibitor,
is in clinical development for the prevention of venous
thromboembolism (VTE), a frequent complication
following orthopaedic surgery.
MethoDs
In a multicenter, parallel-group, double-blind, doubledummy
study, 621 patients undergoing elective knee
replacement were randomly assigned to oral BAY 59-
7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h
postsurgery), or subcutaneous enoxaparin (30 mg b.i.d.,
initiated 12-24 h postsurgery). Treatment was continued
until mandatory bilateral venography 5-9 days after surgery.
The primary efficacy endpoint was a composite of any
deep vein thrombosis (proximal and/or distal), confirmed
non-fatal pulmonary embolism and all-cause mortality
during treatment. The primary safety endpoint was major,
postoperative bleeding during treatment.
resUlts
Of the 613 patients treated, 366 (59.7%) were evaluable for
the primary efficacy analysis. The primary efficacy endpoint
occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of
patients receiving 2.5, 5, 10, 20, and 30 mg b.i.d. doses of
BAY 59-7939, respectively (test for trend, P=0.29), compared
with 44.3% in the enoxaparin group. The frequency of major,
postoperative bleeding increased with increasing doses of
BAY 59-7939 (test for trend, P=0.0007), with no significant
difference between any dose group compared with enoxaparin.
Bleeding endpoints were lower for the 2.5-10 mg b.i.d.
doses compared with higher doses of BAY 59-7939.
14
ConClUsions
Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939,
early in the post operative period, showed potential efficacy
and an acceptable safety profile, similar to enoxaparin, for
the prevention of VTE in patients undergoing elective total
knee replacement.

Oral, Direct Factor Xa Inhibition with BAY 59-7939
for the Prevention of Venous Thromboembolism
After Total Hip Replacement
Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, Misselwitz F, Kälebo P for the ODIXa-HIP Study Investigators
J Thromb Haemost 2006;4(1):121-8.
introDUCtion
Joint replacement surgery is an appropriate model for
dose-ranging studies investigating new anticoagulants.
The objective of this study is to assess the efficacy and
safety of a novel, oral, direct factor Xa (FXa) inhibitor—BAY
59-7939—relative to enoxaparin in patients undergoing
elective total hip replacement.
MethoDs
In this double-blind, double-dummy, doseranging study,
patients were randomized to oral BAY 59-7939 (2.5, 5,
10, 20, or 30 mg b.i.d.), starting 6-8 h after surgery, or s.c.
enoxaparin 40 mg once daily, starting on the evening before
surgery. Treatment was continued until mandatory bilateral
venography was performed 5-9 days after surgery.
resUlts
Of 706 patients treated, 548 were eligible for the primary
efficacy analysis. The primary efficacy endpoint was the
incidence of any deep vein thrombosis, non-fatal pulmonary
embolism, and all-cause mortality; rates were 15%, 14%,
12%, 18%, and 7% for BAY 59-7939 2.5, 5, 10, 20, and 30
mg b.i.d., respectively, compared with 17% for enoxaparin.
The primary efficacy analysis did not demonstrate any
significant trend in dose-response relationship for BAY 59-
7939. The primary safety endpoint was major, postoperative
bleeding; there was a significant increase in the frequency of
events with increasing doses of BAY 59-7939 (P=0.045), but
no significant differences between individual BAY 59-7939
doses and enoxaparin.
15
ConClUsions
When efficacy and safety were considered together, the
oral, direct FXa inhibitor BAY 59-7939, at 2.5-10 mg b.i.d.,
compared favorably with enoxaparin for the prevention of
venous thromboembolism in patients undergoing elective
total hip replacement.

Oral Rivaroxaban Compared with Subcutaneous Enoxaparin
for Extended Thromboprophylaxis After Total Hip Arthroplasty:
The RECORD1 Trial
Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Muehlhofer E, Misselwitz F
William Geerts Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; Aarhus University Hospital, Aarhus, Denmark; Medical
University of South Carolina, Charleston, SC, USA; Institute for Experimental Oncology and Therapy Research, TU, Munich, Germany;
Leiden University Medical Center, Leiden, Netherlands; Barts and the London School of Medicine, London, United Kingdom; Thrombosis
Research Institute, London, United Kingdom; Bayer HealthCare, Wuppertal, Germany; University of Toronto, Toronto, Canada
Abstract #6 appears in Blood, Volume 110, issue 11, November 16, 2007
introDUCtion
Thromboprophylaxis for at least 10 days and for up to 4–5
weeks is recommended after total hip arthroplasty (THA).
Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced
clinical development for the prevention and treatment
of thromboembolic disorders. RECORD1 was a phase III,
multinational, randomized, double-blind, double-dummy
trial, conducted to determine the efficacy and safety of oral
rivaroxaban, compared with subcutaneous enoxaparin, for 5
weeks of thromboprophylaxis in patients undergoing THA.
Methods Patients received rivaroxaban 10 mg beginning
6–8 hours after surgery and once daily (od) thereafter, or
enoxaparin 40 mg od, beginning the evening before surgery
(restarting 6–8 hours after surgery). Therapy continued
for 35 ± 4 days and mandatory, bilateral venography was
conducted the next day. The primary efficacy endpoint was
the composite of any deep vein thrombosis (DVT), nonfatal
pulmonary embolism (PE), and all-cause mortality. The
primary efficacy analysis was a test for non-inferiority in the
per-protocol (PP) population, followed by a test for superiority
in the modified intention-to-treat (mITT) population.
The main secondary efficacy endpoint was major venous
thromboembolism (VTE): the composite of proximal DVT,
non-fatal PE and VTE-related death. Major and non-major
bleeding during the active treatment period were the primary
and secondary safety endpoints, respectively.
DVT, non-fatal PE, and
all-cause mortality
16
resUlts
A total of 4541 patients were randomized; 4433 were eligible
for the safety population, 3153 for the mITT population, and
3029 for the PP population. The criteria for non-inferiority
were met and testing for superiority was performed.
Rivaroxaban significantly reduced the incidence of the primary
efficacy endpoint (p

Extended Thromboprophylaxis with Rivaroxaban Compared with
Short-Term Thromboprophylaxis with Enoxaparin after Total Hip
Arthroplasty: The RECORD2 Trial.
Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Bandel TJ, Misselwitz F, Barts SH
The London School of Medicine, London, United Kingdom; Thrombosis Research Institute, London, United Kingdom; Rambam Medical Center,
Haifa, Israel; Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; Frankfurt-Höchst Clinic, Frankfurt, Germany; Methodist and St.
Luke’s Hospitals, Houston, TX, USA; Bayer HealthCare AG, Wuppertal, Germany; Institute for Experimental Oncology and Therapy Research, TU,
Munich, Germany
Abstract #307 appears in Blood, Volume 110, issue 11, November 16, 2007
introDUCtion
Venous thromboembolism (VTE) is a common, potentially
fatal complication of major orthopaedic surgery.
Pharmacologic thromboprophylaxis is recommended for
patients undergoing total hip arthroplasty (THA) for a
minimum of 10 days, and up to 35 days. However, extended
thromboprophylaxis is not universally used. Therefore, this
trial was conducted to evaluate the potential benefits of
extended thromboprophylaxis after THA. RECORD2 is the
largest, prospective, randomized clinical trial conducted to
date, in this indication.
MethoDs
This global, phase III, double-blind trial, was designed
to compare short-term thromboprophylaxis with a low
molecular weight heparin –enoxaparin –with extended
thromboprophylaxis for up to 5 weeks with a novel, oral,
direct Factor Xa inhibitor –rivaroxaban after THA. Patients
received subcutaneous enoxaparin 40 mg once daily (od),
beginning the evening before surgery, continuing for 10–14
days (short-term prophylaxis), and followed by placebo until
day 35±4, or oral rivaroxaban 10 mg od beginning 6–8
hours after surgery and continuing for 35±4 days (extended
prophylaxis). Mandatory, bilateral venography was conducted
at the end of the extended treatment period. The primary
efficacy endpoint was the composite of any deep vein
Short-term s.c. enoxaparin
40 mg od % (n/N)
17
thrombosis (DVT), non-fatal pulmonary embolism (PE), and
all-cause mortality. The main secondary efficacy endpoint
was major VTE; the composite of proximal DVT, non-fatal PE,
and VTE-related death. Major and non-major bleeding during
double-blind treatment were the primary and secondary
safety endpoints, respectively. A total of 2509 patients were
randomized; 2457 were included in the safety population and
1733 in the modified intention-to-treat (mITT) population.
resUlts
Extended thromboprophylaxis with rivaroxaban was
associated with a significant reduction in the incidence of
the primary efficacy endpoint and major VTE, compared with
short-term thromboprophylaxis with enoxaparin (Table). The
incidences of major and non-major bleeding were similar in
both groups (Table).
ConClUsions
In conclusion, extended duration rivaroxaban was significantly
more effective than short term enoxaparin for the prevention
of VTE, including major VTE, in patients undergoing THA.
Furthermore, this large trial demonstrated that extended
thromboprophylaxis provides substantial benefits for patients
undergoing THA, and that the oral, direct Factor Xa inhibitor
rivaroxaban provides a safe and effective option for such
a strategy.
Extended oral rivaroxaban
10 mg od % (n/N)
Relative risk
reduction (%)
P-value for difference
DVT, non-fatal PE, and
all-cause mortality a 9.3% (81/869) 2.0% (17/864) 79% P

Late Breaking Clinical Trial: Rivaroxaban: An Oral, Direct Factor Xa
Inhibitor for the Prevention of Venous Thromboembolism in Total
Knee Replacement Surgery—Results of the RECORD 3 Study
Lassen MR 1 , Turpie AGG 2 , Rosencher N 3 , Borris LC 4 , Ageno W 5 , Lieberman JR 6 , Bandel TJ 7 , Misselwitz F 7
1 Dept. Orthopaedics, Hoersholm Hospital, Hoersholm, Denmark; 2 McMaster University, Hamilton, Canada; 3 Dept. Anaesthesiology, Cochin
Hospital, Paris, France; 4 Dept. Orthopaedics, Aarhus University Hospital, Aarhus, Denmark; 5 Dept. Clinical Medicine, University of Insubria,
Varese, Italy; 6 Dept. Orthopaedic Surgery, UCLA, Los Angeles, United States; 7 Bayer HealthCare AG, Wuppertal, Germany
Abstract O-S-006B presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Rivaroxaban is a novel, oral, direct Factor Xa inhibitor.
RECORD 3 is a phase III trial evaluating rivaroxaban
10 mg once daily in patients undergoing total knee
replacement (TKR).
MethoDs
This double-blind trial randomized 2531 patients undergoing
TKR to rivaroxaban 10 mg or enoxaparin 40 mg once daily.
Enoxaparin was started before surgery, and rivaroxaban 6–8
hours after surgery; both were continued for 10–14 days.
The primary outcome was venous thromboembolism (VTE)
diagnosed by mandatory venography, symptomatic VTE and
all-cause mortality. The safety outcome was major bleeding.
resUlts
1254 patients were randomized to rivaroxaban and 1277
to enoxaparin: 824 and 878, respectively, were evaluable
for primary efficacy outcome; this occurred in 9.6% of the
rivaroxaban group and 18.9% of the enoxaparin group (RRR
49%; p

Rivaroxaban for Prevention of Venous Thromboembolism
after Total Knee Arthroplasty: Impact on Healthcare Costs
Based on the RECORD3 Study.
Kwong L, Lees M, Sengupta N (Intr. by Frank Misselwitz)
Harbor-UCLA Medical Center, Torrance, CA, USA; Bayer HealthCare, Uxbridge, United Kingdom; Scios, Inc./Johnson & Johnson, CA, USA
Abstract #1874 appears in Blood, Volume 110, issue 11, November 16, 2007
introDUCtion
Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in
advanced clinical development for the prevention and
treatment of thromboembolic disorders, including the
prophylaxis for venous thromboembolism (VTE) after major
orthopaedic surgery. In RECORD3, the first pivotal phase III
study, rivaroxaban 10 mg once daily had superior efficacy
to enoxaparin 40 mg once daily for the reduction of VTE
following total knee arthroplasty (TKA). Mean duration of
prophylaxis was 12.1 days. The primary endpoint (deep vein
thrombosis [DVT], pulmonary embolism [PE], and all-cause
mortality) occurred in 9.6% of the rivaroxaban group and
in 18.9% of the enoxaparin group (RRR 49%; p

Treatment of Proximal Deep Vein Thrombosis (DVT):
Rivaroxaban Once or Twice Daily had Similar Efficacy and
Safety to Standard Therapy in Phase II Studies
Büller HR, 1 Agnelli G 2
1 Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; 2 Internal and Vascular Medicine,
University of Perugia, Perugia, Italy
Abstract O-W-052 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Rivaroxaban – an oral, direct Factor Xa inhibitor – was
evaluated in two dose-ranging studies relative to standard
therapy – heparin/LMWH+vitamin K antagonist (INR 2–3)
– for the treatment of patients with acute, symptomatic,
proximal DVT without pulmonary embolism (PE).
MethoDs
In EINSTEIN-DVT (n=543), patients received rivaroxaban 20,
30 or 40 mg once daily (od) or standard therapy, and in
ODIXa-DVT (n=613), patients received rivaroxaban 10, 20
or 30 mg twice daily (bid), 40 mg od or standard therapy.
The efficacy outcome in EINSTEIN-DVT was symptomatic,
recurrent DVT or symptomatic PE (recurrent venous
thromboembolism [VTE]), and asymptomatic deterioration on
ultrasonography (US) or perfusion lung scan, at 3 months. In
ODIXa-DVT, the efficacy outcome at 3 weeks was thrombus
regression on US without recurrent VTE, and at 3 months was
recurrent VTE and asymptomatic deterioration on US.
resUlts
Efficacy outcomes at 3 months are shown in the table.
Thrombus regression at 3 weeks occurred in 53.0%,
59.2%, 56.9%, 43.8% and 45.9% of patients receiving
rivaroxaban 20, 40, or 60 mg bid, 40 mg od or standard
therapy, respectively.
ODIXa-DVT (bid study)
Rivaroxaban (total daily dose)
20
ConClUsions
Rivaroxaban, given od or bid for 3 months, was as effective
and safe as standard therapy for the treatment of acute,
symptomatic DVT. Thrombus regression at 3 weeks was
greater with rivaroxaban bid than od, suggesting bid dosing
may provide an advantage shortly after DVT formation.
Comparison of bleeding rates at 3 months with rivaroxaban
od and bid suggested that od dosing may confer a slight
advantage. Therefore, phase III studies of rivaroxaban for
the treatment of VTE will investigate an initial, intensified
bid regimen followed by convenient, long-term rivaroxaban
20 mg od.
20 mg 30 mg 40 mg 60 mg Standard therapy
Efficacy outcome (%) 1.1 – 1.1/3.0* 1.0 1.0
EINSTEIN-DVT (od study)
Major bleeding (%) 1.7 – 1.7/1.7* 3.3 0
Efficacy outcome (%) 6.1 5.4 6.6 – 9.9
Major bleeding (%) 0.7 1.5 0 – 1.5
*Results are shown as 20 mg
bid/40 mg od.

Pharmacokinetics (PK) and Pharmacodynamics (PD) of
Rivaroxaban: A Comparison of Once- and Twice-Daily Dosing in
Patients Undergoing Total Hip Replacement (THR)
Eriksson BI 1 , Misselwitz F 2 , Mueck W 2
1 Department of Orthopaedics, Sahlgrenska University Hospital, Gothenburg, Sweden; 2 N/A, Bayer HealthCare AG, Wuppertal, Germany
Abstract P-M-659 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa
inhibitor in clinical development for the prevention and
treatment of thromboembolic disorders. Two phase IIb, dosefinding
studies investigated rivaroxaban for the prevention of
venous thromboembolism (VTE) after THR: one with twicedaily
(bid) and one with once-daily (od) dosing.
MethoDs
Non-linear, mixed-effect population modeling was used
to analyze the PK and PD of rivaroxaban, including
the maximum (Cmax) and minimum (Ctrough) plasma
concentrations of rivaroxaban, and prothrombin time (PT).
The analysis was restricted to the rivaroxaban 5, 10, and
20 mg total daily dose groups from each study due to the
favourable efficacy and safety of these doses, relative to
enoxaparin (n=758).
resUlts
Rivaroxaban PK were described well by an oral, onecompartment
model. Age and renal function influenced
clearance, and body weight influenced volume of distribution;
however, these effects were moderate, and within the
variability of the study population. In both studies, Cmax and
Ctrough plasma concentrations of rivaroxaban at steady state
increased dose dependently (table). Cmax values were higher,
and Ctrough values were lower in the od study than in the
bid study; however, the 90% confidence intervals overlapped.
Rivaroxaban (mg)
5 10 20
bid C max (μg/l) 39.7 (29.2–73.4) 65 (46.2–105) 141 (101–218)
od C max (μg/l) 69 (49–112) 124 (88.1–194) 222 (160–360)
bid C trough (μg/l) 8.6 (1.7–26.5) 15.4 (4.7–46.2) 34.9 (7.9–99.7)
od C trough (μg/l) 4.5 (0.7–37.7) 9.1 (1.3–37.8) 22.4 (4.3–95.7)
21
This suggests that od dosing should not lead to a greater
risk of bleeding (at Cmax) or VTE (at Ctrough) than bid
dosing. In the PD analysis, PT correlated linearly with
rivaroxaban plasma concentrations.
ConClUsions
The PK and PD of rivaroxaban are predictable in patients
undergoing THR after od or bid dosing. Combined with
favourable efficacy and safety results of od rivaroxaban, these
findings allowed selection of a convenient od dosing regimen.
Values are medians (90%
confidence intervals).

Rivaroxaban Has Predictable Pharmacokinetics (PK) and
Pharmacodynamics (PD) When Given Once or Twice Daily for the
Treatment of Acute, Proximal Deep Vein Thrombosis (DVT).
Mueck W, Agnelli G, Büller H (Intr. by Frank Misselwitz)
Clinical Pharmacology, Bayer HealthCare AG, Wuppertal, Germany; University of Perugia, Perugia, Italy;
Academic Medical Centre, Amsterdam, Netherlands
Abstract #1880 appears in Blood, Volume 110, issue 11, November 16, 2007
introDUCtion
Rivaroxaban is an oral, direct Factor Xa inhibitor in
clinical development for the prevention and treatment of
thromboembolic disorders. Two large, phase IIb, dose-finding
studies investigating rivaroxaban for the treatment of acute,
proximal DVT, showed that rivaroxaban once daily (od) and
twice daily (bid) had similar efficacy and safety profiles to
standard therapy. In order to characterize the population
PK/PD of rivaroxaban for DVT treatment, a population model
was developed based on data from healthy subjects.
MethoDs
Sparse PK/PD samples from 870 patients across the two
studies were analyzed using non-linear, mixed-effect
population modeling (NONMEM), version V level 1.1.
The program analyzed population data to give estimates of
mean values and variability in the population. Prothrombin
time (PT) was determined at a central laboratory and
was used in the PD investigation. For the PK profile, data
was pooled from both clinical trials and specific exposure
parameters for rivaroxaban, such as area under the plasma
concentration–time curve (AUC), maximum and minimum
plasma concentrations (Cmax and Ctrough, respectively)
were predicted for each patient according to the dosing
regimen received.
Predicted rivaroxaban PK parameters
Parameter Rivaroxaban total daily dose
20 mg 30 mg 40 mg 60 mg
n (od/bid) 134/117 134/- 252/114 -/119
od C max (mcg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) –
22
resUlts
The PK of rivaroxaban were well described by an oral, onecompartment
model, with demographic factors influencing
clearance (age, renal function) and volume of distribution
(age, body weight, gender); variations due to these factors
were moderate, suggesting fixed dosing may be possible. Comedications
(e.g. diuretics, NSAIDs, aspirin) had no relevant
effects on the PK of rivaroxaban. Rivaroxaban Cmax and
Ctrough concentrations increased dose dependently (Table).
As expected, Cmax was higher and Ctrough was lower after
od dosing compared with bid dosing, at equivalent total
daily doses; however, 90% confidence intervals overlapped,
suggesting that od dosing with rivaroxaban should not
expose patients to a greater risk of bleeding (at Cmax) or VTE
(at Ctrough) than bid dosing. Clinically relevant rivaroxaban
plasma concentrations correlated linearly with PT, confirming
that it would be suitable for measuring rivaroxaban exposure,
if necessary. Conclusions: The PK and PD of rivaroxaban
were predictable with od and bid dosing, and affected by
expected demographic factors in patients receiving it for
DVT treatment. Combined with efficacy and safety results,
this analysis aided the selection of an initial, intensified bid
regimen followed by convenient, long-term rivaroxaban 20
mg od, for investigation in phase III studies in this indication.
Copyright American Society of Hematology. Reprinted with permission from the American Society of
Hematology, which does not endorse any particular uses of this document. The American Society of
Hematology is not responsible for the completeness or the accuracy of the translation.
bid C max (mcg/L)* 211.5 (130.3–360.7) – 320.9 (209.9–517.9) 400.6 (244.2-749.5)
od C trough (mcg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) –
bid C trough (mcg/L)* 65.1 (17.2–193.6) – 104.2 (31.3–277.8) 143.1 (46.6–347.9)
*Values are shown as means
(90% confidence intervals)

Potential of the Factor Xa Inhibitor Rivaroxaban for
the Anticoagulation Management of Patients With
Heparin-Induced Thrombocytopenia
Walenga JM 1 , Jeske WP 1 , Prechel M 1 , Hoppensteadt D 2 , Swank J 1 , Sheen L 1 , Misselwitz F 3 , Messmore H 4 , Bakhos M 1
1 Thoracic and CV Surgery; 2 Pathology, Loyola University Medical Center, Maywood, United States; 3 Bayer Healthcare
AG, Wuppertal, Germany; 4 Loyola University Medical Center, Maywood, United States
Abstract P-M-648 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion
Rivaroxaban (BAY 59-7939; Bayer) is an orally bioavailable,
small-molecule, direct factor Xa inhibitor (XaI) in advanced
clinical trials for the prevention and treatment of thromboembolic
disorders. The purpose of this study was to determine
the potential of this agent as an anticoagulant for patients
with heparin-induced thrombocytopenia (HIT). Rivaroxaban
is structurally different from heparin, LMW heparins, and
fondaparinux and, therefore, it is not expected to interact
with pre-formed HIT antibodies.
MethoDs
Sera from 89 patients with ELISA positive HIT antibodies that
induced platelet activation in the diagnostic 14C-Serotonin
Release Assay (SRA) were included in this study. Rivaroxaban
was tested in a total of 152 different HIT antibody/donor
platelet combinations using three types of platelet function
HIT assays (SRA, platelet aggregation, flow cytometry).
resUlts
Rivaroxaban had no cross-reactivity with any of the HIT
antibodies as shown by the lack of platelet activation, platelet
aggregation, platelet microparticle generation, and P-selectin
up regulation. Further studies demonstrated that rivaroxaban
did not promote the release of PF4 from platelets as did
heparin and LMW heparin. Rivaroxaban did not bind to PF4.
23
ConClUsions
Taken together these results provide strong evidence that
rivaroxaban is not immunogenic for HIT and can be effectively
used for anticoagulation of patients with HIT without risk of
adverse platelet activation and associated thrombotic side
effects from HIT antibody activation. As a XaI, rivaroxaban
has advantages over current strategies for the anticoagulant
management of HIT patients, such as improved safety/
bleeding risk and oral bioavailability that allows for extended
patient management.

notes
24

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