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THROMBOSIS
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 U/ml). Of note, she had a past history of pulmonary embolism
Effective anticoagulation for women with mechanical heart and was heterozygous for the G20210A prothrombin gene
valves during pregnancy remains a major challenge. The use mutation. There were no other valve-related thrombotic
of standard dosage low molecular weight heparin (LMWH) is events. Minor bleeding occurred during 3 pregnancies. There
associated with an unacceptable incidence of morbidity and were 5 major bleeding episodes in 4 patients: 3 antepartum
mortality for this patient group. (1 with placenta praevia) and 1 post-partum haemorrhage
plus 1 abdominal wound haematoma.
MethoDs
In this prospective audit of anticoagulation management, ConClUsions
we report pregnancy outcome for a cohort of women with Our data suggest that in this patient group escalated dose
mechanical heart valves, who received anticoagulation with LMWH provides effective anticoagulation. These patients
a higher dosage LMWH regimen. We audited 12 consecutive require meticulous anticoagulant monitoring and close
pregnancies in 10 women (mean age 27.8 (18-41) years) with surveillance for bleeding and thrombotic complications
mechanical heart valves (mitral 4, aortic 2, aortic and mitral within a multidisciplinary setting, with urgent intervention
2, systemic tricuspid AV valve 2). Past obstetric history (on when indicated.
warfarin) included 6 fetal losses: 2 miscarriages <12 weeks
and 4 terminations including one therapeutic at 22 weeks
gestation because of an intracerebral fetal haemorrhage.
resUlts
In 11/12 pregnancies treated with LMWH, warfarin was
discontinued at <6 weeks and in 1/12 at 8 weeks. LMWH
(dalteparin 7, enoxaparin 5) +/- low-dose aspirin (4) was
then started at full therapeutic dosage (subcutaneous 12
hourly) with regular monitoring to maintain anti-Xa levels
at 1.0-1.2U/mL (0.8-1.2 in the first 4/12 pregnancies). This
necessitated stepwise increases in LMWH with median doses
(12 hourly) pre-delivery 11,750IU for dalteparin and 95mg
for enoxaparin, representing a median 47.7% increase
over initial dosage. 11/12 pregnancies on LMWH resulted
in live births (median BW 2.5 kg (range 1.0-3.7) at median
gestation 36 (range 26-38 weeks) with 1 IUFD at 37 weeks.
One patient had non-fatal valve-related thrombosis at 26
weeks associated with a sub-therapeutic anti-Xa level (0.64
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.
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 regularly only in patients with elevated serum creatinine
The optimal management of patients with hematological (4 patients) or body mass index (1 patient).
malignancies who require therapeutic anticoagulation for
thromboembolic disease or prosthetic cardiac valves while resUlts
receiving myelosuppressive chemotherapy has not been Median number of days of chemotherapy-induced
established. In particular, the role of anticoagulation during thrombocytopenia <150x109/L was 20 (range 1–84);
chemotherapy-induced thombocytopenia, with its attendant <50x109/L 12 (0–41), and <20x109/L was 2 (0–30).
increased risk of bleeding, is undefined. Enoxaparin was delivered at full dose on 31% of
thrombocytopenic days (median per patient 12 days,
MethoDs range 5–23), at reduced dose on 63% of days (median
We describe the feasibility and safety of a dynamic dosing per patient 20 days, range 0–68), and withheld on 6% of
strategy for continuous anticoagulation during chemotherapy- days (median per patient 1 day, range 0–8). Of days where
induced thrombocytopenia. Sixty patients with haematological enoxaparin was withheld, 45% were for procedures; 20%
malignancies who required anti-coagulation for venous bleeding; and 35% other reasons, including refractory
thromboembolism or prosthetic cardiac valves while thrombocytopenia <20x109/L. Serious bleeding complications
receiving chemotherapy were assessed. All were receiving during anticoagulation were uncommon. Three patients
myelosuppressive chemotherapy for a haematological (5%) experienced major bleeding episodes: two developed
malignancy (27 Acute myeloid or promyelocytic leukaemia; gastrointestinal bleeding requiring endoscopic intervention
18 non-Hodgkin lymphoma; 9 plasma cell myeloma; 6 Acute and transfusion while receiving reduced dose anticoagulation
lymphoblastic leukaemia), and required anticoagulation with platelet counts of 20–50 x109/L; one developed
for either proven deep venous thrombosis (catheter-related bleeding requiring surgical intervention at an existing wound
thrombosis in 32 patients; non-catheter associated deep site when the platelet count was 19 x109/L, but had not
venous thrombosis in 18) or pulmonary embolus (9) or received enoxaprin that day. Minor bleeding, including
prosthetic cardiac valves (1). Three patients underwent bruising at the sites of injections and menorrhagia was
allogeneic stem cell transplantation and 7 autologous stem common. No further thromboembolic complications were
cell transplantation. Median time from diagnosis of the identified in any patient.
thromboembolic disease to commencement chemotherapy
was 10 days (range 0–40). Patients were anticoagulated with ConClUsions
subcutaneous enoxaparin 1mg/kg body weight twice daily This study suggests that dynamically dosed anticoagulation
while the platelet count was ≥50x109/L and 0.5mg/kg once is safe and feasible during thrombocytopenia following
daily to maximum of 40mg while it was <50x109/L; platelets chemotherapy, including conditioning for stem cell
were transfused to maintain a count ≥20x109/L. Patients were transplantation, in patients who are carefully selected and
clinically assessed daily for clinical evidence of bleeding or closely monitored. This strategy was not associated with
thrombosis, and underwent regular radiological screening for excessive bleeding and appeared effective in preventing
thrombotic complications. Plasma anti-Xa levels were assayed further thromboembolic complications.
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.
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 Univariate logistic regressions were conducted to estimate
In the EXCLAIM study, extended-duration enoxaparin treatment effects in patient subgroups. The primary safety
prophylaxis reduced the relative risk of VTE in acutely ill endpoint was major bleeding.
medical patients by 44% compared with placebo, following
standard-duration prophylaxis (2.8% vs 4.9%; RR 0.56; resUlts
95% CI 0.39–0.80; p=0.0011). We assessed the benefits of Baseline characteristics were similar between treatments
extended-duration enoxaparin prophylaxis in subgroups of within each primary diagnosis subgroup, and the considered
acutely ill medical patients with the most prominent primary primary diagnoses accounted for >80% of the enrolled
diagnoses enrolled in EXCLAIM. population. The reduced VTE incidence associated with
extended-duration enoxaparin prophylaxis was consistent
MethoDs across subgroups of patients with different primary diagnoses
Patients enrolled in EXCLAIM had: recent reduced mobility (Table). The incidence of major bleeding was generally higher
(≤3 days) due to a medical illness, age ≥40 years, and in patients receiving extended-duration prophylaxis (Table).
anticipated level 1 (total bed rest or sedentary without
bathroom privileges) or level 2 (level 1 with bathroom ConClUsion
privileges) reduced mobility with further risk factors. Extended enoxaparin prophylaxis consistently reduced VTE
Eligible patients received enoxaparin 40mg SC once-daily risk in acutely ill medical patients with the most prominent
for 10 ±4 days, and were then double-blind randomized primary diagnoses compared with placebo following standard-
and received enoxaparin 40mg SC once-daily (n=2013) or duration prophylaxis. Major bleeding was generally higher in
placebo (n=2027) for a further 28 ±4 days. Asymptomatic the extended-duration enoxaparin arm, but rates of bleeding
DVT were diagnosed by bilateral compression ultrasound were low. These findings are consistent with the primary
after completion of the randomized treatment. Suspected findings of the EXCLAIM study which demonstrated the
cases of symptomatic DVT or PE were confirmed by objective clinical benefit of the extended-duration enoxaparin regimen.
tests. Fatal PE were confirmed by autopsy where possible.
Table: VTE and major bleeding in patient subgroups receiving extended-duration vs standard-duration prophylaxis/placebo
Odds Ratio Odds Ratio
Primary diagnosis Incidence of VTE (%)* Incidence of Major Bleeding (%)***
[95% CI]** [95% CI]
Standard Enox/ Standard Enox/
Extended Enox Extended Enox
Placebo Placebo
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 with lower DVT rates. Approximately 20% of the patients
Dabigatran etexilate (BIBR 1048) is an oral direct thrombin had low plasma concentrations after the first dose suggesting
inhibitor undergoing evaluation for the prevention of venous further optimization of the preliminary tablet formulation
thromboembolism (VTE) following total hip replacement. is required.
Following oral administration, dabigatran etexilate is rapidly
converted to its active form dabigatran (BIBR 953 ZW). ConClUsions
Dabigatran etexilate demonstrates an acceptable safety
MethoDs profile, with a therapeutic window above 12.5 mg and below
In a multicenter, open-label, dose-escalating study, 314 300 mg twice daily. The low number of VTE events within
patients received oral doses of dabigatran etexilate (12.5, 25, each treatment group indicates a satisfactory antithrombotic
50, 100, 150, 200 and 300 mg twice daily or 150 and 300 potential, although the study was not powered for an efficacy
mg once daily) administered 4-8 h after surgery, for 6-10 days. analysis. Additional studies are ongoing to optimize oral
Dose escalation was based on clinical and pharmacokinetic absorption and the efficacy/ safety balance.
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
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 ConClUsions
Dabigatran etexilate is an oral direct thrombin inhibitor Oral administration of dabigatran etexilate, commenced early
undergoing evaluation for the prevention of venous in the postoperative period, was effective and safe across a
thromboembolism (VTE) following orthopedic surgery. range of doses. Further optimization of the efficacy/safety
balance will be addressed in future studies.
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<0.0001).
Compared with enoxaparin, VTE was significantly lower in
patients receiving 150 mg twice daily [odds ration (OR) 0.65,
P=0.04], 300 mg once daily (OR 0.61, P=0.02) and 225 mg
twice daily (OR 0.47, P=0.0007). Compared with enoxaparin,
major bleeding was significantly lower with 50 mg twice daily
(0.3% vs. 2.0%, P=0.047) but elevated with higher doses,
nearly reaching statistical significance with the 300 mg once-
daily dose (4.7%, P=0.051).
The Oral Direct Thrombin Inhibitor, Dabigatran Etexilate,
is Effective and Safe for Prevention of Major Venous
Thromboembolism Following Major Orthopedic Surgery
Caprini JA1, Hwang E2, Hantel S3, Schnee J4, Eriksson BI5
1
Department of Surgery, Evanston Northwestern Healthcare, and Northwestern University Feinberg School of Medicine, Northfield, IL; 2Medical
Data Services/Biostatistics, Boehringer-Ingelheim, Ridgefield, CT, United States; 3Medical Data Services/Biostatistics, Boehringer Ingelheim,
88397 Biberach an der Riss, Germany; 4Cardiovascular Clinical Operations, Boehringer-Ingelheim, Ridgefield, CT, United States; 5Orthopaedics
Department, Sahlgrenska University Hospital/Östra, SE-41685 Göteborg, Sweden
Abstract O-W-050 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion ConClUsions
Major venous thromboembolism (VTE) and VTE related death, Dabigatran etexilate was efficacious and comparable to
the composite of proximal deep venous thrombosis (DVT), enoxaparin in the prevention of major VTE and VTE related
symptomatic pulmonary embolism (PE) and VTE related mortality after knee and after hip replacement.
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 replace-
ment and 28-35 days post hip replacement. Definitive diag-
nostic 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).
Dabigatran Etexilate is Effective and Safe for the Extended Prevention
of Venous Thromboembolism Following Total Hip Replacement
Eriksson BI1, Dahl OE2, Rosencher N3, Kurth AA4, v. Dijk N5, Frosticks SP6, Hettiarachchi R7, Hantel S8, Schnee J9,Büller HR10
1
Department of Othopaedics, Sahlgrenska University Hospital, Göteborg, Sweden; 2International Surgical Thrombosis Forum, Thrombosis
Research Institute, London, United Kingdom; 3Department of Anaesthesia, Paris 5 University Hospital, Paris, France; 4Department of Othopaedics,
University Hospital Stiftung Friedrichsheim, Frankfurt, Germany; 5Department of Othopaedics, Academic Medical Center, Amsterdam,
Netherlands; 6Department of Musculoskeletal Science, Royal Liverpool University Hospital, Liverpool, United Kingdom; 7Medical Department,
Boehringer Ingelheim, Alkmaar, Netherlands; 8Medical Department, Boehringer Ingelheim, Bibarach, Germany; 9Medical Department, Boehringer
Ingelheim, Ridgefield, United States; 10Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
Abstract O-W-049 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion ConClUsions
Prophylaxis beyond hospital discharge is recommended to Oral dabigatran etexilate once daily, administered for a
reduce the risk of venous thromboembolism (VTE) after hip median of 33 days, was as effective as enoxaparin in
replacement surgery. Oral thrombo-prophylaxis not requiring reducing the risk of venous thromboembolism after total
monitoring is an advantage in orthopaedic patients. Dabiga- hip replacement surgery, with a similar safety profile.
tran etexilate is an oral direct thrombin inhibitor under evalu-
ation 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.
Dabigatran Etexilate Versus Enoxaparin in Preventing Venous
Thromboembolism Following Total Knee Arthroplasty
Friedman RJ1, Caprini JA2, Comp PC3, Davidson BL4, Francis CW5, Ginsberg J6, Huo M7, Lieberman J8, Muntz JE9, Raskob GE10, Clements ML11,
Hantel S12, Schnee J11
1
Orthopaedic Surgery, Charleston Orthopaedic Associates, Charleston; 2Vascular Surgery, Evanston Northwestern Healthcare, Skokie; 3Medicine,
VA Hospital, Oklahoma City; 4Medicine, Cornell Medical College, New York; 5Medicine, University of Rochester, Rochester, United States;
6
Medicine, McMaster Medical Center, Hamilton, Canada; 7Orthopaedic Surgery, UT Southwestern Medical Center, Dallas; 8Orthopaedic Surgery,
University of Conneticut, Farmington; 9Medicine, Methodist Hospital, Houston; 10Medicine, University of Oklahoma, Oklahoma City; 11Clinical
Operations; 12Biostatistics, Boehringer Ingelheim, Ridgefield, United States
Abstract O-W-051 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion ConClUsions
Oral venous thromboembolic prophylaxis without monitoring Treatment with D220 or D150 qd was not as effective
or dose adjustment is an advantage for patients. Dabigatran as E bid in preventing VTE, but did preserve 61% and
etexilate (D), an oral direct thrombin inhibitor, is being 50%, respectively, of the putative efficacy of E compared
evaluated for its prophylactic effects following orthopedic to placebo. Differences were predominantly due to
surgery in a series of clinical studies asymptomatic distal DVTs, since Major VTE occurred at
similar rates in all treatment groups. Dabigatran etexilate
MethoDs was safe and well tolerated when given orally starting
This phase III, double-blind, non-inferiority study, randomized 6-12 hours following total knee arthroplasty.
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
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 Logistic regression analysis revealed a statistically significant
Activated factor X (FXa) is a pivotal blood coagulation factor dose-related trend (P=0.006) for patients reaching the VTE
positioned at the crossroads of the extrinsic and intrinsic endpoint during YM150 treatment. No trend in any of
coagulation cascade. Inhibitors of FXa are anticoagulants that the measured safety parameters was observed with study
could be used in the prevention and treatment of thrombosis treatment (YM150 or enoxaparin) or dose of YM150.
and venous thromboembolism (VTE).
ConClUsions
MethoDs Oral, once daily doses of YM150, 10 mg to 60 mg
YM150 is a once daily, orally active FXa inhibitor. A administered 6 to 10 h after primary hip replacement, were
randomized, enoxaparin-controlled, dose escalation study shown to be safe, well tolerated and effective in this 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 non-
major 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
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 ConClUsions
Apixaban is a new, direct-acting inhibitor of coagulation This oral direct factor Xa inhibitor that can be given as the
Factor Xa. It binds to the active site of Factor Xa without sole treatment in a fixed dose appears to be a very attractive
requiring anti-thrombin. The efficacy and safety of this alternative to standard therapy in patients with DVT.
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 non-
major 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
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 ConClUsions
BAY 59-7939, a novel, oral, direct factor Xa inhibitor, Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939,
is in clinical development for the prevention of venous early in the post operative period, showed potential efficacy
thromboembolism (VTE), a frequent complication and an acceptable safety profile, similar to enoxaparin, for
following orthopaedic surgery. the prevention of VTE in patients undergoing elective total
knee replacement.
MethoDs
In a multicenter, parallel-group, double-blind, double-
dummy 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 enoxapa-
rin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d.
doses compared with higher doses of BAY 59-7939.
14
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 ConClUsions
Joint replacement surgery is an appropriate model for When efficacy and safety were considered together, the
dose-ranging studies investigating new anticoagulants. oral, direct FXa inhibitor BAY 59-7939, at 2.5-10 mg b.i.d.,
The objective of this study is to assess the efficacy and compared favorably with enoxaparin for the prevention of
safety of a novel, oral, direct factor Xa (FXa) inhibitor—BAY venous thromboembolism in patients undergoing elective
59-7939—relative to enoxaparin in patients undergoing total hip replacement.
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
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 resUlts
Thromboprophylaxis for at least 10 days and for up to 4–5 A total of 4541 patients were randomized; 4433 were eligible
weeks is recommended after total hip arthroplasty (THA). for the safety population, 3153 for the mITT population, and
Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced 3029 for the PP population. The criteria for non-inferiority
clinical development for the prevention and treatment were met and testing for superiority was performed.
of thromboembolic disorders. RECORD1 was a phase III, Rivaroxaban significantly reduced the incidence of the primary
multinational, randomized, double-blind, double-dummy efficacy endpoint (p<0.001) and major VTE (p<0.001),
trial, conducted to determine the efficacy and safety of oral compared with enoxaparin, in the mITT population (Table).
rivaroxaban, compared with subcutaneous enoxaparin, for 5 The incidence of major and non-major bleeding events was
weeks of thromboprophylaxis in patients undergoing THA. similar in both groups (Table).
Methods Patients received rivaroxaban 10 mg beginning
6–8 hours after surgery and once daily (od) thereafter, or ConClUsions
enoxaparin 40 mg od, beginning the evening before surgery Rivaroxaban was significantly more effective than enoxaparin
(restarting 6–8 hours after surgery). Therapy continued for extended prophylaxis after THA, with a similar safety
for 35 ± 4 days and mandatory, bilateral venography was profile. This is the first pivotal trial to demonstrate the
conducted the next day. The primary efficacy endpoint was efficacy and safety of a fixed, unmonitored dose of an
the composite of any deep vein thrombosis (DVT), non- oral, direct Factor Xa inhibitor–rivaroxaban–for extended
fatal pulmonary embolism (PE), and all-cause mortality. The thromboprophylaxis after THA.
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.
P-value for
Rivaroxaban 10mg od % (n/N) Enoxaparin 40 mg od % (n/N) Relative risk reduction % (95% CI)
difference
DVT, non-fatal PE, and
1.1% (18/1595) 3.7% (58/1558) 70% (49–82%) P<0.001
all-cause mortality
Major VTE 0.2% (4/1686) 2.0% (33/1678) 88% (66–96%) P<0.001
Major bleeding 0.3% (6/2209) 0.1% (2/2224) - P=0.178
Non-major bleeding 5.8% (128/2209) 5.8% (129/2224) - P=1.000
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.
16
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 thrombosis (DVT), non-fatal pulmonary embolism (PE), and
Venous thromboembolism (VTE) is a common, potentially all-cause mortality. The main secondary efficacy endpoint
fatal complication of major orthopaedic surgery. was major VTE; the composite of proximal DVT, non-fatal PE,
Pharmacologic thromboprophylaxis is recommended for and VTE-related death. Major and non-major bleeding during
patients undergoing total hip arthroplasty (THA) for a double-blind treatment were the primary and secondary
minimum of 10 days, and up to 35 days. However, extended safety endpoints, respectively. A total of 2509 patients were
thromboprophylaxis is not universally used. Therefore, this randomized; 2457 were included in the safety population and
trial was conducted to evaluate the potential benefits of 1733 in the modified intention-to-treat (mITT) population.
extended thromboprophylaxis after THA. RECORD2 is the
largest, prospective, randomized clinical trial conducted to resUlts
date, in this indication. Extended thromboprophylaxis with rivaroxaban was
associated with a significant reduction in the incidence of
MethoDs the primary efficacy endpoint and major VTE, compared with
This global, phase III, double-blind trial, was designed short-term thromboprophylaxis with enoxaparin (Table). The
to compare short-term thromboprophylaxis with a low incidences of major and non-major bleeding were similar in
molecular weight heparin –enoxaparin –with extended both groups (Table).
thromboprophylaxis for up to 5 weeks with a novel, oral,
direct Factor Xa inhibitor –rivaroxaban after THA. Patients ConClUsions
received subcutaneous enoxaparin 40 mg once daily (od), In conclusion, extended duration rivaroxaban was significantly
beginning the evening before surgery, continuing for 10–14 more effective than short term enoxaparin for the prevention
days (short-term prophylaxis), and followed by placebo until of VTE, including major VTE, in patients undergoing THA.
day 35±4, or oral rivaroxaban 10 mg od beginning 6–8 Furthermore, this large trial demonstrated that extended
hours after surgery and continuing for 35±4 days (extended thromboprophylaxis provides substantial benefits for patients
prophylaxis). Mandatory, bilateral venography was conducted undergoing THA, and that the oral, direct Factor Xa inhibitor
at the end of the extended treatment period. The primary rivaroxaban provides a safe and effective option for such
efficacy endpoint was the composite of any deep vein a strategy.
Short-term s.c. enoxaparin Extended oral rivaroxaban Relative risk
P-value for difference
40 mg od % (n/N) 10 mg od % (n/N) reduction (%)
DVT, non-fatal PE, and
9.3% (81/869) 2.0% (17/864) 79% P<0.001
all-cause mortalitya
Major VTEb 5.1% (49/962) 0.6% (6/961) 88% P<0.001
Major bleedingc 0.1% (1/1229) 0.1% (1/1228) - P=0.980
Non-major bleedingc 5.5% (67/1229) 6.5% (80/1228) - P=0.246
mITT population; bmITT population valid for major VTE analysis; cSafety population
a 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.
17
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 MR1, Turpie AGG2, Rosencher N3, Borris LC4, Ageno W5, Lieberman JR6, Bandel TJ7, Misselwitz F7
1
Dept. Orthopaedics, Hoersholm Hospital, Hoersholm, Denmark; 2McMaster University, Hamilton, Canada; 3Dept. Anaesthesiology, Cochin
Hospital, Paris, France; 4Dept. Orthopaedics, Aarhus University Hospital, Aarhus, Denmark; 5Dept. Clinical Medicine, University of Insubria,
Varese, Italy; 6Dept. Orthopaedic Surgery, UCLA, Los Angeles, United States; 7Bayer 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<0.001). Major VTE (the major secondary efficacy
endpoint: proximal DVT + PE + VTE-related death) occurred
in 1% and 2.6%, respectively (RRR 62%; p=0.01), and
symptomatic VTE occurred in 1% and 2.7%, respectively.
In the rivaroxaban and enoxaparin groups, major bleeding
rates were 0.6% and 0.5%, and any bleeding 4.9% and
4.8%, respectively.
ConClUsions
Rivaroxaban was significantly more effective than enoxaparin
in the prevention of VTE after TKR in this study. Bleeding was
similarly low in both groups. This study with rivaroxaban is
the first demonstration of the effectiveness and safety of a
fixed, unmonitored regimen of an oral Factor Xa inhibitor in
antithrombotic therapy.
18
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 inject for out-patient use. For costing purposes, the duration
Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in of hospitalization was 5 days. In the UK, full blood counts
advanced clinical development for the prevention and should be taken every 3 days while receiving enoxaparin.
treatment of thromboembolic disorders, including the
prophylaxis for venous thromboembolism (VTE) after major resUlts
orthopaedic surgery. In RECORD3, the first pivotal phase III The total cost associated with healthcare resource use in
study, rivaroxaban 10 mg once daily had superior efficacy the US was $290 per patient with enoxaparin and $98
to enoxaparin 40 mg once daily for the reduction of VTE with rivaroxaban (excluding rivaroxaban and enoxaparin
following total knee arthroplasty (TKA). Mean duration of drug costs). This implies a resource use saving of $192
prophylaxis was 12.1 days. The primary endpoint (deep vein per patient due to the improved health outcomes with
thrombosis [DVT], pulmonary embolism [PE], and all-cause rivaroxaban. This improvement was driven primarily by the
mortality) occurred in 9.6% of the rivaroxaban group and reduced costs of hospitalization for symptomatic events. In
in 18.9% of the enoxaparin group (RRR 49%; p<0.001; the UK, the total cost of resource use per patient was £48
modified intention-to-treat), and symptomatic VTE occurred ($78) with enoxaparin and £5 ($8) with rivaroxaban. The
in 1.0% and 2.6%, respectively. There was no difference in reduced healthcare cost of £43 ($70) per patient was driven
major bleeding between rivaroxaban and enoxaparin. This equally by reduced hospitalization and reduced monitoring.
analysis was designed to show the impact of this efficacy The substantial difference in cost impact is due to higher
improvement on healthcare costs from a payer s perspective. US hospitalization costs. These results exclude the impact
Preventing DVT, PE, and all-cause mortality (primary endpoint) of post-thrombotic syndrome (PTS), the estimated 5-year
and symptomatic VTE events have economic benefits, rate of which is 21% in asymptomatic patients and 30%
because fewer healthcare resources are required. in symptomatic patients. Estimated costs for PTS treatment
is more than $11,000 in the USA, and £4,000 ($6472) in
MethoDs the UK. Given the reduced incidence of both asymptomatic
The impact of rivaroxaban on healthcare resources in the and symptomatic events with rivaroxaban, there would be
US and UK were assessed using the resource utilization in even further savings in healthcare costs associated with
the RECORD3 trial, and the reduced administration cost rivaroxaban, due to a reduction in PTS.
associated with an oral therapy. Only non-drug costs borne
by the healthcare sector were included in the analysis. The ConClUsions
cost of symptomatic VTE was taken from published sources The clinical results shown by rivaroxaban for the prevention
in the US, and from the 2007 NICE Guidelines in the UK. of VTE after TKA also result in savings to healthcare costs.
It was assumed that asymptomatic events had no impact With more than 600,000 US patients having hip or knee
on healthcare costs. It was also conservatively assumed arthroplasty annually, these potential cost savings
that nurses spend three minutes per day administering a are significant.
subcutaneous enoxaparin dose and training patients to self-
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.
19
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 G2
1
Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; 2Internal and Vascular Medicine,
University of Perugia, Perugia, Italy
Abstract O-W-052 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion ConClUsions
Rivaroxaban – an oral, direct Factor Xa inhibitor – was Rivaroxaban, given od or bid for 3 months, was as effective
evaluated in two dose-ranging studies relative to standard and safe as standard therapy for the treatment of acute,
therapy – heparin/LMWH+vitamin K antagonist (INR 2–3) symptomatic DVT. Thrombus regression at 3 weeks was
– for the treatment of patients with acute, symptomatic, greater with rivaroxaban bid than od, suggesting bid dosing
proximal DVT without pulmonary embolism (PE). may provide an advantage shortly after DVT formation.
Comparison of bleeding rates at 3 months with rivaroxaban
MethoDs od and bid suggested that od dosing may confer a slight
In EINSTEIN-DVT (n=543), patients received rivaroxaban 20, advantage. Therefore, phase III studies of rivaroxaban for
30 or 40 mg once daily (od) or standard therapy, and in the treatment of VTE will investigate an initial, intensified
ODIXa-DVT (n=613), patients received rivaroxaban 10, 20 bid regimen followed by convenient, long-term rivaroxaban
or 30 mg twice daily (bid), 40 mg od or standard therapy. 20 mg od.
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.
Rivaroxaban (total daily dose)
20 mg 30 mg 40 mg 60 mg Standard therapy
ODIXa-DVT (bid study)
Efficacy outcome (%) 1.1 – 1.1/3.0* 1.0 1.0
Major bleeding (%) 1.7 – 1.7/1.7* 3.3 0
EINSTEIN-DVT (od study)
Efficacy outcome (%) 6.1 5.4 6.6 – 9.9
*Results are shown as 20 mg
Major bleeding (%) 0.7 1.5 0 – 1.5
bid/40 mg od.
20
Pharmacokinetics (PK) and Pharmacodynamics (PD) of
Rivaroxaban: A Comparison of Once- and Twice-Daily Dosing in
Patients Undergoing Total Hip Replacement (THR)
Eriksson BI1, Misselwitz F2, Mueck W2
1
Department of Orthopaedics, Sahlgrenska University Hospital, Gothenburg, Sweden; 2N/A, Bayer HealthCare AG, Wuppertal, Germany
Abstract P-M-659 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion This suggests that od dosing should not lead to a greater
Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa risk of bleeding (at Cmax) or VTE (at Ctrough) than bid
inhibitor in clinical development for the prevention and dosing. In the PD analysis, PT correlated linearly with
treatment of thromboembolic disorders. Two phase IIb, dose- rivaroxaban plasma concentrations.
finding studies investigated rivaroxaban for the prevention of
venous thromboembolism (VTE) after THR: one with twice- ConClUsions
daily (bid) and one with once-daily (od) dosing. The PK and PD of rivaroxaban are predictable in patients
undergoing THR after od or bid dosing. Combined with
MethoDs favourable efficacy and safety results of od rivaroxaban, these
Non-linear, mixed-effect population modeling was used findings allowed selection of a convenient od dosing regimen.
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, one-
compartment 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 Cmax (μg/l) 39.7 (29.2–73.4) 65 (46.2–105) 141 (101–218)
od Cmax (μg/l) 69 (49–112) 124 (88.1–194) 222 (160–360)
bid Ctrough (μg/l) 8.6 (1.7–26.5) 15.4 (4.7–46.2) 34.9 (7.9–99.7)
Values are medians (90%
od Ctrough (μg/l) 4.5 (0.7–37.7) 9.1 (1.3–37.8) 22.4 (4.3–95.7)
confidence intervals).
21
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 resUlts
Rivaroxaban is an oral, direct Factor Xa inhibitor in The PK of rivaroxaban were well described by an oral, one-
clinical development for the prevention and treatment of compartment model, with demographic factors influencing
thromboembolic disorders. Two large, phase IIb, dose-finding clearance (age, renal function) and volume of distribution
studies investigating rivaroxaban for the treatment of acute, (age, body weight, gender); variations due to these factors
proximal DVT, showed that rivaroxaban once daily (od) and were moderate, suggesting fixed dosing may be possible. Co-
twice daily (bid) had similar efficacy and safety profiles to medications (e.g. diuretics, NSAIDs, aspirin) had no relevant
standard therapy. In order to characterize the population effects on the PK of rivaroxaban. Rivaroxaban Cmax and
PK/PD of rivaroxaban for DVT treatment, a population model Ctrough concentrations increased dose dependently (Table).
was developed based on data from healthy subjects. As expected, Cmax was higher and Ctrough was lower after
od dosing compared with bid dosing, at equivalent total
MethoDs daily doses; however, 90% confidence intervals overlapped,
Sparse PK/PD samples from 870 patients across the two suggesting that od dosing with rivaroxaban should not
studies were analyzed using non-linear, mixed-effect expose patients to a greater risk of bleeding (at Cmax) or VTE
population modeling (NONMEM), version V level 1.1. (at Ctrough) than bid dosing. Clinically relevant rivaroxaban
The program analyzed population data to give estimates of plasma concentrations correlated linearly with PT, confirming
mean values and variability in the population. Prothrombin that it would be suitable for measuring rivaroxaban exposure,
time (PT) was determined at a central laboratory and if necessary. Conclusions: The PK and PD of rivaroxaban
was used in the PD investigation. For the PK profile, data were predictable with od and bid dosing, and affected by
was pooled from both clinical trials and specific exposure expected demographic factors in patients receiving it for
parameters for rivaroxaban, such as area under the plasma DVT treatment. Combined with efficacy and safety results,
concentration–time curve (AUC), maximum and minimum this analysis aided the selection of an initial, intensified bid
plasma concentrations (Cmax and Ctrough, respectively) regimen followed by convenient, long-term rivaroxaban 20
were predicted for each patient according to the dosing mg od, for investigation in phase III studies in this indication.
regimen received.
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.
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 Cmax (mcg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) –
bid Cmax (mcg/L)* 211.5 (130.3–360.7) – 320.9 (209.9–517.9) 400.6 (244.2-749.5)
od Ctrough (mcg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) –
*Values are shown as means
bid Ctrough (mcg/L)* 65.1 (17.2–193.6) – 104.2 (31.3–277.8) 143.1 (46.6–347.9)
(90% confidence intervals)
22
Potential of the Factor Xa Inhibitor Rivaroxaban for
the Anticoagulation Management of Patients With
Heparin-Induced Thrombocytopenia
Walenga JM1, Jeske WP1, Prechel M1, Hoppensteadt D2, Swank J1, Sheen L1, Misselwitz F3, Messmore H4, Bakhos M1
1
Thoracic and CV Surgery; 2Pathology, Loyola University Medical Center, Maywood, United States; 3Bayer Healthcare
AG, Wuppertal, Germany; 4Loyola University Medical Center, Maywood, United States
Abstract P-M-648 presented at ISTH July 6-12, 2007, Geneva, Switzerland.
introDUCtion ConClUsions
Rivaroxaban (BAY 59-7939; Bayer) is an orally bioavailable, Taken together these results provide strong evidence that
small-molecule, direct factor Xa inhibitor (XaI) in advanced rivaroxaban is not immunogenic for HIT and can be effectively
clinical trials for the prevention and treatment of thromboem- used for anticoagulation of patients with HIT without risk of
bolic disorders. The purpose of this study was to determine adverse platelet activation and associated thrombotic side
the potential of this agent as an anticoagulant for patients effects from HIT antibody activation. As a XaI, rivaroxaban
with heparin-induced thrombocytopenia (HIT). Rivaroxaban has advantages over current strategies for the anticoagulant
is structurally different from heparin, LMW heparins, and management of HIT patients, such as improved safety/
fondaparinux and, therefore, it is not expected to interact bleeding risk and oral bioavailability that allows for extended
with pre-formed HIT antibodies. patient management.
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.
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notes
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