Scientific Poster Session and Clinical Update - Center for ...
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Scientific Poster Session and Clinical Update - Center for ...
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HROMBOSIS<br />
THROMBOSIS<br />
<strong>Scientific</strong> <strong>Poster</strong> <strong>Session</strong><br />
<strong>and</strong> <strong>Clinical</strong> <strong>Update</strong><br />
ABSTRACTS<br />
Selected meeting abstracts from ISTH 2007, ASH 2007, <strong>and</strong> published journal articles<br />
This activity is supported by an<br />
unrestricted educational grant from<br />
Scios <strong>and</strong> Bayer HealthCare.
Contents<br />
Low-Molecular Weight Heparin<br />
enoxaparin<br />
Pregnant Patients with Mechanical Heart Valves .......................................................................2<br />
Chemotherapy-induced Thrombocytopenia ................................................................................3<br />
EXCLAIM ...................................................................................................................................4<br />
Oral Direct Thrombin Inhibitor<br />
Dabigatran etexilate<br />
BISTRO I .....................................................................................................................................6<br />
BISTRO II ....................................................................................................................................7<br />
Prevention of Venous Thromboembolism ............................................................................ 8-10<br />
Oral Direct Factor Xa Inhibitors<br />
YM150<br />
Prevention of Venous Thromboembolism .................................................................................12<br />
apixaban<br />
Treatment of Acute Symptomatic Deep Vein Thrombosis .........................................................13<br />
rivaroxaban (baY 59-7939)<br />
Prevention of Venous Thromboembolism ........................................................................... 14-15<br />
RECORD I .................................................................................................................................16<br />
RECORD II ................................................................................................................................17<br />
RECORD III ......................................................................................................................... 18-19<br />
Once- or Twice-Daily Dosing Treatment of Deep Vein Thrombosis ............................................20<br />
Pharmacokinetics <strong>and</strong> Pharmacodynamics ........................................................................ 21-22<br />
Patients with Heparin-Induced Thrombocytopenia ...................................................................23
enoxaparin
Dose-Escalated Low Molecular Weight Heparin Provides<br />
Effective Anticoagulation <strong>for</strong> Women with Mechanical Heart<br />
Valves during Pregnancy: A Single-Centre Experience<br />
Quinn J, Brooks R, Walker F, Peebles D, Cohen H (Intr. by David C Linch)<br />
Haematology, University College London Hospitals, London, United Kingdom; Cardiology, University College London Hospitals,<br />
London, United Kingdom; Obstetrics <strong>and</strong> Gynaecology, University College London Hospitals, London, United Kingdom<br />
Abstract #1873 appears in Blood, Volume 110, issue 11, November 16, 2007<br />
introDUCtion<br />
Effective anticoagulation <strong>for</strong> women with mechanical heart<br />
valves during pregnancy remains a major challenge. The use<br />
of st<strong>and</strong>ard dosage low molecular weight heparin (LMWH) is<br />
associated with an unacceptable incidence of morbidity <strong>and</strong><br />
mortality <strong>for</strong> this patient group.<br />
MethoDs<br />
In this prospective audit of anticoagulation management,<br />
we report pregnancy outcome <strong>for</strong> a cohort of women with<br />
mechanical heart valves, who received anticoagulation with<br />
a higher dosage LMWH regimen. We audited 12 consecutive<br />
pregnancies in 10 women (mean age 27.8 (18-41) years) with<br />
mechanical heart valves (mitral 4, aortic 2, aortic <strong>and</strong> mitral<br />
2, systemic tricuspid AV valve 2). Past obstetric history (on<br />
warfarin) included 6 fetal losses: 2 miscarriages
The Feasibility <strong>and</strong> Safety of Anticoagulation during<br />
Chemotherapy Associated Thrombocytopenia <strong>for</strong><br />
Thrombotic Complications of Malignancy<br />
Polizzotto MN, Opat SS<br />
Department of Haematology, Alfred Hospital, Melbourne, Victoria, Australia<br />
Abstract #1872 appears in Blood, Volume 110, issue 11, November 16, 2007<br />
introDUCtion<br />
The optimal management of patients with hematological<br />
malignancies who require therapeutic anticoagulation <strong>for</strong><br />
thromboembolic disease or prosthetic cardiac valves while<br />
receiving myelosuppressive chemotherapy has not been<br />
established. In particular, the role of anticoagulation during<br />
chemotherapy-induced thombocytopenia, with its attendant<br />
increased risk of bleeding, is undefined.<br />
MethoDs<br />
We describe the feasibility <strong>and</strong> safety of a dynamic dosing<br />
strategy <strong>for</strong> continuous anticoagulation during chemotherapyinduced<br />
thrombocytopenia. Sixty patients with haematological<br />
malignancies who required anti-coagulation <strong>for</strong> venous<br />
thromboembolism or prosthetic cardiac valves while<br />
receiving chemotherapy were assessed. All were receiving<br />
myelosuppressive chemotherapy <strong>for</strong> a haematological<br />
malignancy (27 Acute myeloid or promyelocytic leukaemia;<br />
18 non-Hodgkin lymphoma; 9 plasma cell myeloma; 6 Acute<br />
lymphoblastic leukaemia), <strong>and</strong> required anticoagulation<br />
<strong>for</strong> either proven deep venous thrombosis (catheter-related<br />
thrombosis in 32 patients; non-catheter associated deep<br />
venous thrombosis in 18) or pulmonary embolus (9) or<br />
prosthetic cardiac valves (1). Three patients underwent<br />
allogeneic stem cell transplantation <strong>and</strong> 7 autologous stem<br />
cell transplantation. Median time from diagnosis of the<br />
thromboembolic disease to commencement chemotherapy<br />
was 10 days (range 0–40). Patients were anticoagulated with<br />
subcutaneous enoxaparin 1mg/kg body weight twice daily<br />
while the platelet count was ≥50x109/L <strong>and</strong> 0.5mg/kg once<br />
daily to maximum of 40mg while it was
Consistent Venous Thromboembolism Risk Reduction by Extended-<br />
Versus St<strong>and</strong>ard-Duration Enoxaparin Prophylaxis in Subgroups of<br />
Acutely Ill Medical Patients in the EXCLAIM Study<br />
Tapson VF, Hull RD, Schellong SM, Monreal M, Samama MM, Turpie AGG, Yusen RD (Intr. by Graham F Pineo)<br />
Duke University Medical <strong>Center</strong>, Durham, NC, USA; University of Calgary, Foothills Hospital, Calgary, AB, Canada;<br />
Hospital Carl Gustav Carus, Dresden, Germany; Hospital Germans Trias i Pujol, Barcelona, Spain; Hotel Dieu, University Hospital, Paris, France;<br />
McMaster University, HHSC McMaster Clinic, Hamilton, ON, Canada; Washington University School of Medicine, St. Louis, MO, USA<br />
Abstract #1863 appears in Blood, Volume 110, issue 11, November 16, 2007<br />
introDUCtion<br />
In the EXCLAIM study, extended-duration enoxaparin<br />
prophylaxis reduced the relative risk of VTE in acutely ill<br />
medical patients by 44% compared with placebo, following<br />
st<strong>and</strong>ard-duration prophylaxis (2.8% vs 4.9%; RR 0.56;<br />
95% CI 0.39–0.80; p=0.0011). We assessed the benefits of<br />
extended-duration enoxaparin prophylaxis in subgroups of<br />
acutely ill medical patients with the most prominent primary<br />
diagnoses enrolled in EXCLAIM.<br />
MethoDs<br />
Patients enrolled in EXCLAIM had: recent reduced mobility<br />
(≤3 days) due to a medical illness, age ≥40 years, <strong>and</strong><br />
anticipated level 1 (total bed rest or sedentary without<br />
bathroom privileges) or level 2 (level 1 with bathroom<br />
privileges) reduced mobility with further risk factors.<br />
Eligible patients received enoxaparin 40mg SC once-daily<br />
<strong>for</strong> 10 ±4 days, <strong>and</strong> were then double-blind r<strong>and</strong>omized<br />
<strong>and</strong> received enoxaparin 40mg SC once-daily (n=2013) or<br />
placebo (n=2027) <strong>for</strong> a further 28 ±4 days. Asymptomatic<br />
DVT were diagnosed by bilateral compression ultrasound<br />
after completion of the r<strong>and</strong>omized treatment. Suspected<br />
cases of symptomatic DVT or PE were confirmed by objective<br />
tests. Fatal PE were confirmed by autopsy where possible.<br />
Univariate logistic regressions were conducted to estimate<br />
treatment effects in patient subgroups. The primary safety<br />
endpoint was major bleeding.<br />
resUlts<br />
Baseline characteristics were similar between treatments<br />
within each primary diagnosis subgroup, <strong>and</strong> the considered<br />
primary diagnoses accounted <strong>for</strong> >80% of the enrolled<br />
population. The reduced VTE incidence associated with<br />
extended-duration enoxaparin prophylaxis was consistent<br />
across subgroups of patients with different primary diagnoses<br />
(Table). The incidence of major bleeding was generally higher<br />
in patients receiving extended-duration prophylaxis (Table).<br />
ConClUsion<br />
Extended enoxaparin prophylaxis consistently reduced VTE<br />
risk in acutely ill medical patients with the most prominent<br />
primary diagnoses compared with placebo following st<strong>and</strong>ardduration<br />
prophylaxis. Major bleeding was generally higher in<br />
the extended-duration enoxaparin arm, but rates of bleeding<br />
were low. These findings are consistent with the primary<br />
findings of the EXCLAIM study which demonstrated the<br />
clinical benefit of the extended-duration enoxaparin regimen.<br />
Table: VTE <strong>and</strong> major bleeding in patient subgroups receiving extended-duration vs st<strong>and</strong>ard-duration prophylaxis/placebo<br />
Primary diagnosis Incidence of VTE (%)*<br />
Extended Enox<br />
St<strong>and</strong>ard Enox/<br />
Placebo<br />
Odds Ratio<br />
[95% CI]**<br />
Incidence of Major Bleeding (%)***<br />
Extended Enox<br />
St<strong>and</strong>ard Enox/<br />
Placebo<br />
Odds Ratio<br />
[95% CI]<br />
Heart failure, NYHA class III or IV 3.1 4.7 0.64 [0.29-1.39] 0.0 0.2 N/A<br />
Acute respiratory insufficiency 2.2 3.7 0.60 [0.27-1.34] 0.6 0.2 3.15 [0.33-30.4]<br />
Post ischemic stroke 2.1 8.3 0.24 [0.06-0.91] 0.6 0.0 N/A<br />
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]<br />
*N=3347 evaluable patients; **Alpha adjustment <strong>for</strong> an interim analysis; ***N=4040 treated patients<br />
Copyright American Society of Hematology. Reprinted with<br />
permission from the American Society of Hematology, which<br />
does not endorse any particular uses of this document. The<br />
American Society of Hematology is not responsible <strong>for</strong> the<br />
completeness or the accuracy of the translation.
oral DireCt<br />
throMbin inhibitor
Dose Escalating Safety Study of a New Oral Direct<br />
Thrombin Inhibitor, Dabigatran Etexilate, in Patients<br />
Undergoing Total Hip Replacement: BISTRO I<br />
Eriksson BI, Dahl OE, Ahnfelt L, Kälebo P, Stangier J, Nehmiz G, Hermansson K, Kohlbrenner V.<br />
J Thromb Haemost 2004;2(9):1573-80.<br />
introDUCtion<br />
Dabigatran etexilate (BIBR 1048) is an oral direct thrombin<br />
inhibitor undergoing evaluation <strong>for</strong> the prevention of venous<br />
thromboembolism (VTE) following total hip replacement.<br />
Following oral administration, dabigatran etexilate is rapidly<br />
converted to its active <strong>for</strong>m dabigatran (BIBR 953 ZW).<br />
MethoDs<br />
In a multicenter, open-label, dose-escalating study, 314<br />
patients received oral doses of dabigatran etexilate (12.5, 25,<br />
50, 100, 150, 200 <strong>and</strong> 300 mg twice daily or 150 <strong>and</strong> 300<br />
mg once daily) administered 4-8 h after surgery, <strong>for</strong> 6-10 days.<br />
Dose escalation was based on clinical <strong>and</strong> pharmacokinetic<br />
data. The primary safety outcome was major bleeding. The<br />
primary efficacy outcome included venographic deep vein<br />
thrombosis (DVT), symptomatic DVT <strong>and</strong> pulmonary embolism<br />
during the treatment period.<br />
resUlts<br />
No major bleeding event was observed in any group, but<br />
two patients at the highest dose (300 mg twice daily)<br />
suffered bleeding from multiple sites associated with<br />
reduced renal clearance <strong>and</strong> prolonged pharmacodynamic<br />
(PD) parameters. A dose-response was demonstrated <strong>for</strong><br />
minor bleeding events. Of the 289 treated patients, 225<br />
patients had evaluable venograms. The overall incidence of<br />
DVT was 12.4% (28/225 patients). There was no consistent<br />
relationship between the dose <strong>and</strong> incidence of DVT, the<br />
highest incidence in any group being 20.8% (5/24 patients).<br />
The lowest dose (12.5 mg twice daily) showed a high rate<br />
of proximal DVT [12.5% (3/24)] <strong>and</strong> no increase in PD<br />
parameters. Peak <strong>and</strong> trough plasma concentrations, area<br />
under the dabigatran plasma concentration-time curve <strong>and</strong><br />
PD parameters also increased in proportion with the dose.<br />
Higher dabigatran plasma concentrations were associated<br />
with lower DVT rates. Approximately 20% of the patients<br />
had low plasma concentrations after the first dose suggesting<br />
further optimization of the preliminary tablet <strong>for</strong>mulation<br />
is required.<br />
ConClUsions<br />
Dabigatran etexilate demonstrates an acceptable safety<br />
profile, with a therapeutic window above 12.5 mg <strong>and</strong> below<br />
300 mg twice daily. The low number of VTE events within<br />
each treatment group indicates a satisfactory antithrombotic<br />
potential, although the study was not powered <strong>for</strong> an efficacy<br />
analysis. Additional studies are ongoing to optimize oral<br />
absorption <strong>and</strong> the efficacy/ safety balance.
A New Oral Direct Thrombin Inhibitor, Dabigatran<br />
Etexilate, Compared With Enoxaparin <strong>for</strong> Prevention<br />
of Thromboembolic Events Following Total Hip or Knee<br />
Replacement: the BISTRO II R<strong>and</strong>omized Trial<br />
Eriksson BI, Dahl OE, Büller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kälebo P,<br />
Reilly P <strong>for</strong> the BISTRO II Study Group.<br />
J Thromb Haemost 2005;3(1):103-11.<br />
introDUCtion<br />
Dabigatran etexilate is an oral direct thrombin inhibitor<br />
undergoing evaluation <strong>for</strong> the prevention of venous<br />
thromboembolism (VTE) following orthopedic surgery.<br />
MethoDs<br />
In a multicenter, parallel-group, double-blind study, 1973<br />
patients undergoing total hip or knee replacement were<br />
r<strong>and</strong>omized to 6-10 days of oral dabigatran etexilate<br />
(50, 150 mg twice daily, 300 mg once daily, 225 mg<br />
twice daily), starting 1-4 h after surgery, or subcutaneous<br />
enoxaparin (40 mg once daily) starting 12 h prior to surgery.<br />
The primary efficacy outcome was the incidence of VTE<br />
(detected by bilateral venography or symptomatic events)<br />
during treatment.<br />
resUlts<br />
Of the 1949 treated patients, 1464 (75%) patients were<br />
evaluable <strong>for</strong> the efficacy analysis. VTE occurred in 28.5%,<br />
17.4%, 16.6%, 13.1% <strong>and</strong> 24% of patients assigned to<br />
dabigatran etexilate 50, 150 mg twice daily, 300 mg once<br />
daily, 225 mg twice daily <strong>and</strong> enoxaparin, respectively.<br />
A significant dose-dependent decrease in VTE occurred<br />
with increasing doses of dabigatran etexilate (P
The Oral Direct Thrombin Inhibitor, Dabigatran Etexilate,<br />
is Effective <strong>and</strong> Safe <strong>for</strong> Prevention of Major Venous<br />
Thromboembolism Following Major Orthopedic Surgery<br />
Caprini JA 1 , Hwang E 2 , Hantel S 3 , Schnee J 4 , Eriksson BI 5<br />
1 Department of Surgery, Evanston Northwestern Healthcare, <strong>and</strong> Northwestern University Feinberg School of Medicine, Northfield, IL; 2 Medical<br />
Data Services/Biostatistics, Boehringer-Ingelheim, Ridgefield, CT, United States; 3 Medical Data Services/Biostatistics, Boehringer Ingelheim,<br />
88397 Biberach an der Riss, Germany; 4 Cardiovascular <strong>Clinical</strong> Operations, Boehringer-Ingelheim, Ridgefield, CT, United States; 5 Orthopaedics<br />
Department, Sahlgrenska University Hospital/Östra, SE-41685 Göteborg, Sweden<br />
Abstract O-W-050 presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Major venous thromboembolism (VTE) <strong>and</strong> VTE related death,<br />
the composite of proximal deep venous thrombosis (DVT),<br />
symptomatic pulmonary embolism (PE) <strong>and</strong> VTE related<br />
death, is a well recognized important clinical endpoint in VTE<br />
prevention studies. A pre-specified pooled analysis of major<br />
VTE <strong>and</strong> VTE related death after major orthopedic surgery,<br />
was per<strong>for</strong>med across the >8000 patient phase III primary<br />
VTE prevention program of dabigatran etexilate (RE-MODEL,<br />
RE-MOBILIZE <strong>and</strong> RE-NOVATE Studies).<br />
MethoDs<br />
Each of the double blind, r<strong>and</strong>omized studies compared 220<br />
<strong>and</strong> 150 mg of dabigatran etexilate, once-daily following a<br />
half-dose on the day of surgery, to enoxaparin. Enoxaparin<br />
was given 40 mg once-daily in the two mainly European<br />
studies, <strong>and</strong> 30 mg twice daily in the mainly North American<br />
study. Treatment duration was 6-15 days post knee replacement<br />
<strong>and</strong> 28-35 days post hip replacement. Definitive diagnostic<br />
testing was required <strong>for</strong> all suspected symptomatic VTE<br />
events. Bilateral venography was per<strong>for</strong>med at the end of the<br />
treatment period.<br />
resUlts<br />
Major VTE <strong>and</strong> VTE related death occurred in 3.3% of the<br />
enoxaparin group (69 of 2096) versus 3.0% (62 of 2033)<br />
of the dabigatran etexilate 220 mg group (risk difference,<br />
-0.2%; 95% confidence interval [CI], -1.3%, 0.9%) <strong>and</strong><br />
3.8%, (78 of 2071) of the 150 mg group (0.5%; 95% CI,<br />
-0.6% to 1.6%). Major bleeding events were infrequent,<br />
<strong>and</strong> occurred at comparable rates across all treatment groups:<br />
enoxaparin 1.4% (39 of 2716), dabigatran 220 mg 1.4%<br />
(38 of 2682), <strong>and</strong> dabigatran 150 mg 1.1% (29 of 2737).<br />
ConClUsions<br />
Dabigatran etexilate was efficacious <strong>and</strong> comparable to<br />
enoxaparin in the prevention of major VTE <strong>and</strong> VTE related<br />
mortality after knee <strong>and</strong> after hip replacement.
Dabigatran Etexilate is Effective <strong>and</strong> Safe <strong>for</strong> the Extended Prevention<br />
of Venous Thromboembolism Following Total Hip Replacement<br />
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<br />
1 Department of Othopaedics, Sahlgrenska University Hospital, Göteborg, Sweden; 2 International Surgical Thrombosis Forum, Thrombosis<br />
Research Institute, London, United Kingdom; 3 Department of Anaesthesia, Paris 5 University Hospital, Paris, France; 4 Department of Othopaedics,<br />
University Hospital Stiftung Friedrichsheim, Frankfurt, Germany; 5 Department of Othopaedics, Academic Medical <strong>Center</strong>, Amsterdam,<br />
Netherl<strong>and</strong>s; 6 Department of Musculoskeletal Science, Royal Liverpool University Hospital, Liverpool, United Kingdom; 7 Medical Department,<br />
Boehringer Ingelheim, Alkmaar, Netherl<strong>and</strong>s; 8 Medical Department, Boehringer Ingelheim, Bibarach, Germany; 9 Medical Department, Boehringer<br />
Ingelheim, Ridgefield, United States; 10 Department of Vascular Medicine, Academic Medical <strong>Center</strong>, Amsterdam, Netherl<strong>and</strong>s<br />
Abstract O-W-049 presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Prophylaxis beyond hospital discharge is recommended to<br />
reduce the risk of venous thromboembolism (VTE) after hip<br />
replacement surgery. Oral thrombo-prophylaxis not requiring<br />
monitoring is an advantage in orthopaedic patients. Dabigatran<br />
etexilate is an oral direct thrombin inhibitor under evaluation<br />
<strong>for</strong> this indication.<br />
MethoDs<br />
In a double-blind non-inferiority Phase III study, we<br />
r<strong>and</strong>omized 3494 patients undergoing total hip replacement<br />
to treatment <strong>for</strong> 28 to 35 days with dabigatran etexilate,<br />
220 mg or 150 mg once-daily, starting with a half-dose 1 to<br />
4 hours after surgery, or subcutaneous enoxaparin 40 mg<br />
once-daily, starting the evening be<strong>for</strong>e surgery. We evaluated<br />
the composite of total venous thromboembolism <strong>and</strong> death<br />
from all-causes (primary efficacy outcome), <strong>and</strong> major<br />
bleeding, during treatment. All efficacy <strong>and</strong> safety outcome<br />
events were centrally adjudicated by blinded independent<br />
committees. Patients were followed-up <strong>for</strong> 3 months<br />
after surgery.<br />
resUlts<br />
The median treatment duration was 33 days, with 87%<br />
of patients receiving treatment <strong>for</strong> 28 to 35 days. The<br />
primary efficacy outcome occurred in 6.7% (60 of 897) of<br />
the enoxaparin recipients versus 6.0% (53 of 880) of the<br />
dabigatran etexilate 220 mg patients (absolute difference,-<br />
0.7%; 95% confidence interval [CI], -2.9 to 1.6) <strong>and</strong> 8.6%<br />
(75 of 874) in those who received 150 mg (1.9%; 95% CI,<br />
-0.6 to 4.4). Both doses were non-inferior to enoxaparin<br />
according to predefined criteria. There was no significant<br />
difference in major bleeding rates between the groups (1.6%,<br />
2.0% <strong>and</strong> 1.3%, respectively). The incidence of liver enzyme<br />
elevations <strong>and</strong> acute coronary events during the treatment<br />
or during the follow-up period did not differ significantly<br />
between the groups.<br />
ConClUsions<br />
Oral dabigatran etexilate once daily, administered <strong>for</strong> a<br />
median of 33 days, was as effective as enoxaparin in<br />
reducing the risk of venous thromboembolism after total<br />
hip replacement surgery, with a similar safety profile.
Dabigatran Etexilate Versus Enoxaparin in Preventing Venous<br />
Thromboembolism Following Total Knee Arthroplasty<br />
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 ,<br />
Hantel S 12 , Schnee J 11<br />
1 Orthopaedic Surgery, Charleston Orthopaedic Associates, Charleston; 2 Vascular Surgery, Evanston Northwestern Healthcare, Skokie; 3 Medicine,<br />
VA Hospital, Oklahoma City; 4 Medicine, Cornell Medical College, New York; 5 Medicine, University of Rochester, Rochester, United States;<br />
6 Medicine, McMaster Medical <strong>Center</strong>, Hamilton, Canada; 7 Orthopaedic Surgery, UT Southwestern Medical <strong>Center</strong>, Dallas; 8 Orthopaedic Surgery,<br />
University of Conneticut, Farmington; 9 Medicine, Methodist Hospital, Houston; 10 Medicine, University of Oklahoma, Oklahoma City; 11 <strong>Clinical</strong><br />
Operations; 12 Biostatistics, Boehringer Ingelheim, Ridgefield, United States<br />
Abstract O-W-051 presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Oral venous thromboembolic prophylaxis without monitoring<br />
or dose adjustment is an advantage <strong>for</strong> patients. Dabigatran<br />
etexilate (D), an oral direct thrombin inhibitor, is being<br />
evaluated <strong>for</strong> its prophylactic effects following orthopedic<br />
surgery in a series of clinical studies<br />
MethoDs<br />
This phase III, double-blind, non-inferiority study, r<strong>and</strong>omized<br />
2615 patients to 12-15 days treatment with D150mg qd,<br />
D220mg qd, or enoxaparin (E) 30mg bid. D was given as a<br />
half dose the day of surgery (6-12 hours post-surgery) <strong>and</strong> E<br />
was started 12-24 hours post-surgery. The primary efficacy<br />
endpoint was a composite of proximal DVT, distal DVT, PE<br />
<strong>and</strong> all-cause mortality (VTE). The primary safety endpoint<br />
was major bleeding events (MBE). Patients had bilateral<br />
venography at the termination of therapy. Efficacy <strong>and</strong> safety<br />
events were adjudicated by blinded independent committees.<br />
73% of patients were evaluable <strong>for</strong> VTE.<br />
resUlts<br />
VTE rates were 33.7% (D150), 31.1% (D220) <strong>and</strong> 25.3%<br />
(E; p=0.0009, D150mg vs E; p=0.02, D220 vs E). Rates of<br />
the composite of proximal DVT, PE <strong>and</strong> VTE-related mortality<br />
(Major VTE) were 3.0% (D150), 3.4% (D220), <strong>and</strong> 2.2%<br />
(E, p=ns). MBE rates were 0.6% (D150), 0.6% (D220) <strong>and</strong><br />
1.4% (E). Elevated ALT (>3xULN) was infrequent <strong>and</strong> similar<br />
in all groups (D150, 1.0%; D220, 0.7%; E, 0.9%).<br />
10<br />
ConClUsions<br />
Treatment with D220 or D150 qd was not as effective<br />
as E bid in preventing VTE, but did preserve 61% <strong>and</strong><br />
50%, respectively, of the putative efficacy of E compared<br />
to placebo. Differences were predominantly due to<br />
asymptomatic distal DVTs, since Major VTE occurred at<br />
similar rates in all treatment groups. Dabigatran etexilate<br />
was safe <strong>and</strong> well tolerated when given orally starting<br />
6-12 hours following total knee arthroplasty.
oral DireCt<br />
FaCtor xa<br />
inhibitors<br />
11
YM150, an Oral Direct Factor Xa Inhibitor, as Prophylaxis <strong>for</strong><br />
Venous Thromboembolism in Patients with Elective Primary Hip<br />
Replacement Surgery. A Dose Escalation Study.<br />
Eriksson BI, Turpie AGG, Lassen MR, Prins MH, Agnelli G, Gaillard ML, Meems B.<br />
Blood 2005;106: Abstract 1865<br />
introDUCtion<br />
Activated factor X (FXa) is a pivotal blood coagulation factor<br />
positioned at the crossroads of the extrinsic <strong>and</strong> intrinsic<br />
coagulation cascade. Inhibitors of FXa are anticoagulants that<br />
could be used in the prevention <strong>and</strong> treatment of thrombosis<br />
<strong>and</strong> venous thromboembolism (VTE).<br />
MethoDs<br />
YM150 is a once daily, orally active FXa inhibitor. A<br />
r<strong>and</strong>omized, enoxaparin-controlled, dose escalation study<br />
was per<strong>for</strong>med in 174 patients undergoing elective primary<br />
hip replacement surgery to assess safety <strong>and</strong> efficacy of<br />
7-10 days of treatment with oral doses of YM150 (3, 10,<br />
30, or 60 mg once daily starting 6-10 h after surgery) or s.c.<br />
enoxaparin (40 mg once daily starting 12 h be<strong>for</strong>e surgery).<br />
Safety is defined as major <strong>and</strong>/or clinically relevant non-major<br />
bleeding, <strong>and</strong> efficacy as venous thromboembolism detected<br />
by m<strong>and</strong>atory bilateral venography on the last treatment<br />
day <strong>and</strong>/or symptomatic VTE. The study was open-label<br />
with blinded evaluation of all outcomes by an independent<br />
Adjudication Committee.<br />
resUlts<br />
There were no major bleeds. Three clinically relevant nonmajor<br />
bleeds were reported, 1 (2.9%; 95% CI: 0-16%) in<br />
the 3 mg <strong>and</strong> 2 (5.7 %; 1-19%) in the 10 mg YM150 dose<br />
groups. No trend was observed in the incidence of minor<br />
bleeds with dose of YM150 in the range 10 mg to 60 mg<br />
daily. The proportion of patients with minor bleeding events<br />
in the enoxaparin group (22%; 95% CI: 10-39%) was similar<br />
to that in the YM150, 60 mg daily group (24%; 11-41%).<br />
147 patients (84%) were considered to have an evaluable<br />
venogram. The incidences of VTE were 52% (95% CI: 31-<br />
72%), 39% (22-57%), 23% (9-40%), <strong>and</strong> 19% (7-37%) <strong>for</strong><br />
the respective 3, 10, 30, <strong>and</strong> 60 mg YM150 once daily dose<br />
groups in comparison with 39% (22-57%) <strong>for</strong> enoxaparin.<br />
12<br />
Logistic regression analysis revealed a statistically significant<br />
dose-related trend (P=0.006) <strong>for</strong> patients reaching the VTE<br />
endpoint during YM150 treatment. No trend in any of<br />
the measured safety parameters was observed with study<br />
treatment (YM150 or enoxaparin) or dose of YM150.<br />
ConClUsions<br />
Oral, once daily doses of YM150, 10 mg to 60 mg<br />
administered 6 to 10 h after primary hip replacement, were<br />
shown to be safe, well tolerated <strong>and</strong> effective in this study.
Late Breaking <strong>Clinical</strong> Trial: A Dose Finding Study of<br />
the Oral Direct Factor Xa Inhibitor Apixaban in the<br />
Treatment of Patients with Acute Symptomatic Deep<br />
Vein Thrombosis-The Botticelli Investigators<br />
Büller HR<br />
Department of Vascular Medicine, Academic Medical <strong>Center</strong>, Amsterdam, Netherl<strong>and</strong>s<br />
Abstract O-S-003 presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Apixaban is a new, direct-acting inhibitor of coagulation<br />
Factor Xa. It binds to the active site of Factor Xa without<br />
requiring anti-thrombin. The efficacy <strong>and</strong> safety of this<br />
compound was evaluated in patients with confirmed deep<br />
vein thrombosis (DVT).<br />
MethoDs<br />
Patients were allocated r<strong>and</strong>omly to 1 of 3 double-blind<br />
regimens of apixaban (5 mg BID,10 mg BID, or 20 mg<br />
QD), or conventional treatment with low molecular weight<br />
heparin or fondaparinux followed by open-label vitamin K<br />
antagonist (VKA) (dose adjusted to an INR 2.0-3.0). Treatment<br />
continued <strong>for</strong> 84-91 days. A bilateral venous compression<br />
ultrasound (CUS) of the legs <strong>and</strong> a perfusion lung scan (PLS)<br />
were obtained within 36 hours from r<strong>and</strong>omization <strong>and</strong> at<br />
12 weeks. The primary efficacy outcome was the composite<br />
of symptomatic recurrent venous thromboembolism (VTE)<br />
<strong>and</strong> deterioration of the thrombotic burden as assessed by<br />
repeat bilateral CUS <strong>and</strong> PLS. The principal safety outcome<br />
was the composite of major <strong>and</strong> clinically relevant nonmajor<br />
bleeding. All outcomes were evaluated by a central,<br />
independent <strong>and</strong> blinded, adjudication committee (CIAC).<br />
resUlts<br />
A total of 520 patients were r<strong>and</strong>omized. For apixaban<br />
5 mg BID, 10 mg BID, 20 mg QD, <strong>and</strong> <strong>for</strong> VKA, the primary<br />
efficacy outcome rates were 6.0%, 5.6%, 2.6%, <strong>and</strong> 4.2%,<br />
respectively, <strong>and</strong> the principal safety outcome rates were<br />
8.6%, 4.5%, 7.3%, <strong>and</strong> 7.9%, respectively. The rates of<br />
symptomatic VTE were 2.6%, 3.2%, 1.7%, <strong>and</strong> 2.5%,<br />
respectively, <strong>and</strong> the rates of major bleeding were 0.8%,<br />
0, 0.8%, <strong>and</strong> 0, respectively.<br />
13<br />
ConClUsions<br />
This oral direct factor Xa inhibitor that can be given as the<br />
sole treatment in a fixed dose appears to be a very attractive<br />
alternative to st<strong>and</strong>ard therapy in patients with DVT.
BAY 59-7939: An Oral, Direct Factor Xa Inhibitor <strong>for</strong> the<br />
Prevention of Venous Thromboembolism in Patients After<br />
Total Knee Replacement. A Phase II Dose-Ranging Study<br />
Turpie AGG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kälebo P, Misselwitz F, Gent M <strong>for</strong> the OdiXa-Knee Study Group<br />
J Thromb Haemost 2005;3(11):2479-86.<br />
introDUCtion<br />
BAY 59-7939, a novel, oral, direct factor Xa inhibitor,<br />
is in clinical development <strong>for</strong> the prevention of venous<br />
thromboembolism (VTE), a frequent complication<br />
following orthopaedic surgery.<br />
MethoDs<br />
In a multicenter, parallel-group, double-blind, doubledummy<br />
study, 621 patients undergoing elective knee<br />
replacement were r<strong>and</strong>omly assigned to oral BAY 59-<br />
7939 (2.5, 5, 10, 20, <strong>and</strong> 30 mg b.i.d., initiated 6-8 h<br />
postsurgery), or subcutaneous enoxaparin (30 mg b.i.d.,<br />
initiated 12-24 h postsurgery). Treatment was continued<br />
until m<strong>and</strong>atory bilateral venography 5-9 days after surgery.<br />
The primary efficacy endpoint was a composite of any<br />
deep vein thrombosis (proximal <strong>and</strong>/or distal), confirmed<br />
non-fatal pulmonary embolism <strong>and</strong> all-cause mortality<br />
during treatment. The primary safety endpoint was major,<br />
postoperative bleeding during treatment.<br />
resUlts<br />
Of the 613 patients treated, 366 (59.7%) were evaluable <strong>for</strong><br />
the primary efficacy analysis. The primary efficacy endpoint<br />
occurred in 31.7%, 40.4%, 23.3%, 35.1%, <strong>and</strong> 25.4% of<br />
patients receiving 2.5, 5, 10, 20, <strong>and</strong> 30 mg b.i.d. doses of<br />
BAY 59-7939, respectively (test <strong>for</strong> trend, P=0.29), compared<br />
with 44.3% in the enoxaparin group. The frequency of major,<br />
postoperative bleeding increased with increasing doses of<br />
BAY 59-7939 (test <strong>for</strong> trend, P=0.0007), with no significant<br />
difference between any dose group compared with enoxaparin.<br />
Bleeding endpoints were lower <strong>for</strong> the 2.5-10 mg b.i.d.<br />
doses compared with higher doses of BAY 59-7939.<br />
14<br />
ConClUsions<br />
Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939,<br />
early in the post operative period, showed potential efficacy<br />
<strong>and</strong> an acceptable safety profile, similar to enoxaparin, <strong>for</strong><br />
the prevention of VTE in patients undergoing elective total<br />
knee replacement.
Oral, Direct Factor Xa Inhibition with BAY 59-7939<br />
<strong>for</strong> the Prevention of Venous Thromboembolism<br />
After Total Hip Replacement<br />
Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, Misselwitz F, Kälebo P <strong>for</strong> the ODIXa-HIP Study Investigators<br />
J Thromb Haemost 2006;4(1):121-8.<br />
introDUCtion<br />
Joint replacement surgery is an appropriate model <strong>for</strong><br />
dose-ranging studies investigating new anticoagulants.<br />
The objective of this study is to assess the efficacy <strong>and</strong><br />
safety of a novel, oral, direct factor Xa (FXa) inhibitor—BAY<br />
59-7939—relative to enoxaparin in patients undergoing<br />
elective total hip replacement.<br />
MethoDs<br />
In this double-blind, double-dummy, doseranging study,<br />
patients were r<strong>and</strong>omized to oral BAY 59-7939 (2.5, 5,<br />
10, 20, or 30 mg b.i.d.), starting 6-8 h after surgery, or s.c.<br />
enoxaparin 40 mg once daily, starting on the evening be<strong>for</strong>e<br />
surgery. Treatment was continued until m<strong>and</strong>atory bilateral<br />
venography was per<strong>for</strong>med 5-9 days after surgery.<br />
resUlts<br />
Of 706 patients treated, 548 were eligible <strong>for</strong> the primary<br />
efficacy analysis. The primary efficacy endpoint was the<br />
incidence of any deep vein thrombosis, non-fatal pulmonary<br />
embolism, <strong>and</strong> all-cause mortality; rates were 15%, 14%,<br />
12%, 18%, <strong>and</strong> 7% <strong>for</strong> BAY 59-7939 2.5, 5, 10, 20, <strong>and</strong> 30<br />
mg b.i.d., respectively, compared with 17% <strong>for</strong> enoxaparin.<br />
The primary efficacy analysis did not demonstrate any<br />
significant trend in dose-response relationship <strong>for</strong> BAY 59-<br />
7939. The primary safety endpoint was major, postoperative<br />
bleeding; there was a significant increase in the frequency of<br />
events with increasing doses of BAY 59-7939 (P=0.045), but<br />
no significant differences between individual BAY 59-7939<br />
doses <strong>and</strong> enoxaparin.<br />
15<br />
ConClUsions<br />
When efficacy <strong>and</strong> safety were considered together, the<br />
oral, direct FXa inhibitor BAY 59-7939, at 2.5-10 mg b.i.d.,<br />
compared favorably with enoxaparin <strong>for</strong> the prevention of<br />
venous thromboembolism in patients undergoing elective<br />
total hip replacement.
Oral Rivaroxaban Compared with Subcutaneous Enoxaparin<br />
<strong>for</strong> Extended Thromboprophylaxis After Total Hip Arthroplasty:<br />
The RECORD1 Trial<br />
Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, B<strong>and</strong>el TJ, Muehlhofer E, Misselwitz F<br />
William Geerts Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; Aarhus University Hospital, Aarhus, Denmark; Medical<br />
University of South Carolina, Charleston, SC, USA; Institute <strong>for</strong> Experimental Oncology <strong>and</strong> Therapy Research, TU, Munich, Germany;<br />
Leiden University Medical <strong>Center</strong>, Leiden, Netherl<strong>and</strong>s; Barts <strong>and</strong> the London School of Medicine, London, United Kingdom; Thrombosis<br />
Research Institute, London, United Kingdom; Bayer HealthCare, Wuppertal, Germany; University of Toronto, Toronto, Canada<br />
Abstract #6 appears in Blood, Volume 110, issue 11, November 16, 2007<br />
introDUCtion<br />
Thromboprophylaxis <strong>for</strong> at least 10 days <strong>and</strong> <strong>for</strong> up to 4–5<br />
weeks is recommended after total hip arthroplasty (THA).<br />
Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced<br />
clinical development <strong>for</strong> the prevention <strong>and</strong> treatment<br />
of thromboembolic disorders. RECORD1 was a phase III,<br />
multinational, r<strong>and</strong>omized, double-blind, double-dummy<br />
trial, conducted to determine the efficacy <strong>and</strong> safety of oral<br />
rivaroxaban, compared with subcutaneous enoxaparin, <strong>for</strong> 5<br />
weeks of thromboprophylaxis in patients undergoing THA.<br />
Methods Patients received rivaroxaban 10 mg beginning<br />
6–8 hours after surgery <strong>and</strong> once daily (od) thereafter, or<br />
enoxaparin 40 mg od, beginning the evening be<strong>for</strong>e surgery<br />
(restarting 6–8 hours after surgery). Therapy continued<br />
<strong>for</strong> 35 ± 4 days <strong>and</strong> m<strong>and</strong>atory, bilateral venography was<br />
conducted the next day. The primary efficacy endpoint was<br />
the composite of any deep vein thrombosis (DVT), nonfatal<br />
pulmonary embolism (PE), <strong>and</strong> all-cause mortality. The<br />
primary efficacy analysis was a test <strong>for</strong> non-inferiority in the<br />
per-protocol (PP) population, followed by a test <strong>for</strong> superiority<br />
in the modified intention-to-treat (mITT) population.<br />
The main secondary efficacy endpoint was major venous<br />
thromboembolism (VTE): the composite of proximal DVT,<br />
non-fatal PE <strong>and</strong> VTE-related death. Major <strong>and</strong> non-major<br />
bleeding during the active treatment period were the primary<br />
<strong>and</strong> secondary safety endpoints, respectively.<br />
DVT, non-fatal PE, <strong>and</strong><br />
all-cause mortality<br />
16<br />
resUlts<br />
A total of 4541 patients were r<strong>and</strong>omized; 4433 were eligible<br />
<strong>for</strong> the safety population, 3153 <strong>for</strong> the mITT population, <strong>and</strong><br />
3029 <strong>for</strong> the PP population. The criteria <strong>for</strong> non-inferiority<br />
were met <strong>and</strong> testing <strong>for</strong> superiority was per<strong>for</strong>med.<br />
Rivaroxaban significantly reduced the incidence of the primary<br />
efficacy endpoint (p
Extended Thromboprophylaxis with Rivaroxaban Compared with<br />
Short-Term Thromboprophylaxis with Enoxaparin after Total Hip<br />
Arthroplasty: The RECORD2 Trial.<br />
Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, B<strong>and</strong>el TJ, Misselwitz F, Barts SH<br />
The London School of Medicine, London, United Kingdom; Thrombosis Research Institute, London, United Kingdom; Rambam Medical <strong>Center</strong>,<br />
Haifa, Israel; Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; Frankfurt-Höchst Clinic, Frankfurt, Germany; Methodist <strong>and</strong> St.<br />
Luke’s Hospitals, Houston, TX, USA; Bayer HealthCare AG, Wuppertal, Germany; Institute <strong>for</strong> Experimental Oncology <strong>and</strong> Therapy Research, TU,<br />
Munich, Germany<br />
Abstract #307 appears in Blood, Volume 110, issue 11, November 16, 2007<br />
introDUCtion<br />
Venous thromboembolism (VTE) is a common, potentially<br />
fatal complication of major orthopaedic surgery.<br />
Pharmacologic thromboprophylaxis is recommended <strong>for</strong><br />
patients undergoing total hip arthroplasty (THA) <strong>for</strong> a<br />
minimum of 10 days, <strong>and</strong> up to 35 days. However, extended<br />
thromboprophylaxis is not universally used. There<strong>for</strong>e, this<br />
trial was conducted to evaluate the potential benefits of<br />
extended thromboprophylaxis after THA. RECORD2 is the<br />
largest, prospective, r<strong>and</strong>omized clinical trial conducted to<br />
date, in this indication.<br />
MethoDs<br />
This global, phase III, double-blind trial, was designed<br />
to compare short-term thromboprophylaxis with a low<br />
molecular weight heparin –enoxaparin –with extended<br />
thromboprophylaxis <strong>for</strong> up to 5 weeks with a novel, oral,<br />
direct Factor Xa inhibitor –rivaroxaban after THA. Patients<br />
received subcutaneous enoxaparin 40 mg once daily (od),<br />
beginning the evening be<strong>for</strong>e surgery, continuing <strong>for</strong> 10–14<br />
days (short-term prophylaxis), <strong>and</strong> followed by placebo until<br />
day 35±4, or oral rivaroxaban 10 mg od beginning 6–8<br />
hours after surgery <strong>and</strong> continuing <strong>for</strong> 35±4 days (extended<br />
prophylaxis). M<strong>and</strong>atory, bilateral venography was conducted<br />
at the end of the extended treatment period. The primary<br />
efficacy endpoint was the composite of any deep vein<br />
Short-term s.c. enoxaparin<br />
40 mg od % (n/N)<br />
17<br />
thrombosis (DVT), non-fatal pulmonary embolism (PE), <strong>and</strong><br />
all-cause mortality. The main secondary efficacy endpoint<br />
was major VTE; the composite of proximal DVT, non-fatal PE,<br />
<strong>and</strong> VTE-related death. Major <strong>and</strong> non-major bleeding during<br />
double-blind treatment were the primary <strong>and</strong> secondary<br />
safety endpoints, respectively. A total of 2509 patients were<br />
r<strong>and</strong>omized; 2457 were included in the safety population <strong>and</strong><br />
1733 in the modified intention-to-treat (mITT) population.<br />
resUlts<br />
Extended thromboprophylaxis with rivaroxaban was<br />
associated with a significant reduction in the incidence of<br />
the primary efficacy endpoint <strong>and</strong> major VTE, compared with<br />
short-term thromboprophylaxis with enoxaparin (Table). The<br />
incidences of major <strong>and</strong> non-major bleeding were similar in<br />
both groups (Table).<br />
ConClUsions<br />
In conclusion, extended duration rivaroxaban was significantly<br />
more effective than short term enoxaparin <strong>for</strong> the prevention<br />
of VTE, including major VTE, in patients undergoing THA.<br />
Furthermore, this large trial demonstrated that extended<br />
thromboprophylaxis provides substantial benefits <strong>for</strong> patients<br />
undergoing THA, <strong>and</strong> that the oral, direct Factor Xa inhibitor<br />
rivaroxaban provides a safe <strong>and</strong> effective option <strong>for</strong> such<br />
a strategy.<br />
Extended oral rivaroxaban<br />
10 mg od % (n/N)<br />
Relative risk<br />
reduction (%)<br />
P-value <strong>for</strong> difference<br />
DVT, non-fatal PE, <strong>and</strong><br />
all-cause mortality a 9.3% (81/869) 2.0% (17/864) 79% P
Late Breaking <strong>Clinical</strong> Trial: Rivaroxaban: An Oral, Direct Factor Xa<br />
Inhibitor <strong>for</strong> the Prevention of Venous Thromboembolism in Total<br />
Knee Replacement Surgery—Results of the RECORD 3 Study<br />
Lassen MR 1 , Turpie AGG 2 , Rosencher N 3 , Borris LC 4 , Ageno W 5 , Lieberman JR 6 , B<strong>and</strong>el TJ 7 , Misselwitz F 7<br />
1 Dept. Orthopaedics, Hoersholm Hospital, Hoersholm, Denmark; 2 McMaster University, Hamilton, Canada; 3 Dept. Anaesthesiology, Cochin<br />
Hospital, Paris, France; 4 Dept. Orthopaedics, Aarhus University Hospital, Aarhus, Denmark; 5 Dept. <strong>Clinical</strong> Medicine, University of Insubria,<br />
Varese, Italy; 6 Dept. Orthopaedic Surgery, UCLA, Los Angeles, United States; 7 Bayer HealthCare AG, Wuppertal, Germany<br />
Abstract O-S-006B presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Rivaroxaban is a novel, oral, direct Factor Xa inhibitor.<br />
RECORD 3 is a phase III trial evaluating rivaroxaban<br />
10 mg once daily in patients undergoing total knee<br />
replacement (TKR).<br />
MethoDs<br />
This double-blind trial r<strong>and</strong>omized 2531 patients undergoing<br />
TKR to rivaroxaban 10 mg or enoxaparin 40 mg once daily.<br />
Enoxaparin was started be<strong>for</strong>e surgery, <strong>and</strong> rivaroxaban 6–8<br />
hours after surgery; both were continued <strong>for</strong> 10–14 days.<br />
The primary outcome was venous thromboembolism (VTE)<br />
diagnosed by m<strong>and</strong>atory venography, symptomatic VTE <strong>and</strong><br />
all-cause mortality. The safety outcome was major bleeding.<br />
resUlts<br />
1254 patients were r<strong>and</strong>omized to rivaroxaban <strong>and</strong> 1277<br />
to enoxaparin: 824 <strong>and</strong> 878, respectively, were evaluable<br />
<strong>for</strong> primary efficacy outcome; this occurred in 9.6% of the<br />
rivaroxaban group <strong>and</strong> 18.9% of the enoxaparin group (RRR<br />
49%; p
Rivaroxaban <strong>for</strong> Prevention of Venous Thromboembolism<br />
after Total Knee Arthroplasty: Impact on Healthcare Costs<br />
Based on the RECORD3 Study.<br />
Kwong L, Lees M, Sengupta N (Intr. by Frank Misselwitz)<br />
Harbor-UCLA Medical <strong>Center</strong>, Torrance, CA, USA; Bayer HealthCare, Uxbridge, United Kingdom; Scios, Inc./Johnson & Johnson, CA, USA<br />
Abstract #1874 appears in Blood, Volume 110, issue 11, November 16, 2007<br />
introDUCtion<br />
Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in<br />
advanced clinical development <strong>for</strong> the prevention <strong>and</strong><br />
treatment of thromboembolic disorders, including the<br />
prophylaxis <strong>for</strong> venous thromboembolism (VTE) after major<br />
orthopaedic surgery. In RECORD3, the first pivotal phase III<br />
study, rivaroxaban 10 mg once daily had superior efficacy<br />
to enoxaparin 40 mg once daily <strong>for</strong> the reduction of VTE<br />
following total knee arthroplasty (TKA). Mean duration of<br />
prophylaxis was 12.1 days. The primary endpoint (deep vein<br />
thrombosis [DVT], pulmonary embolism [PE], <strong>and</strong> all-cause<br />
mortality) occurred in 9.6% of the rivaroxaban group <strong>and</strong><br />
in 18.9% of the enoxaparin group (RRR 49%; p
Treatment of Proximal Deep Vein Thrombosis (DVT):<br />
Rivaroxaban Once or Twice Daily had Similar Efficacy <strong>and</strong><br />
Safety to St<strong>and</strong>ard Therapy in Phase II Studies<br />
Büller HR, 1 Agnelli G 2<br />
1 Vascular Medicine, Academic Medical <strong>Center</strong>, Amsterdam, Netherl<strong>and</strong>s; 2 Internal <strong>and</strong> Vascular Medicine,<br />
University of Perugia, Perugia, Italy<br />
Abstract O-W-052 presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Rivaroxaban – an oral, direct Factor Xa inhibitor – was<br />
evaluated in two dose-ranging studies relative to st<strong>and</strong>ard<br />
therapy – heparin/LMWH+vitamin K antagonist (INR 2–3)<br />
– <strong>for</strong> the treatment of patients with acute, symptomatic,<br />
proximal DVT without pulmonary embolism (PE).<br />
MethoDs<br />
In EINSTEIN-DVT (n=543), patients received rivaroxaban 20,<br />
30 or 40 mg once daily (od) or st<strong>and</strong>ard therapy, <strong>and</strong> in<br />
ODIXa-DVT (n=613), patients received rivaroxaban 10, 20<br />
or 30 mg twice daily (bid), 40 mg od or st<strong>and</strong>ard therapy.<br />
The efficacy outcome in EINSTEIN-DVT was symptomatic,<br />
recurrent DVT or symptomatic PE (recurrent venous<br />
thromboembolism [VTE]), <strong>and</strong> asymptomatic deterioration on<br />
ultrasonography (US) or perfusion lung scan, at 3 months. In<br />
ODIXa-DVT, the efficacy outcome at 3 weeks was thrombus<br />
regression on US without recurrent VTE, <strong>and</strong> at 3 months was<br />
recurrent VTE <strong>and</strong> asymptomatic deterioration on US.<br />
resUlts<br />
Efficacy outcomes at 3 months are shown in the table.<br />
Thrombus regression at 3 weeks occurred in 53.0%,<br />
59.2%, 56.9%, 43.8% <strong>and</strong> 45.9% of patients receiving<br />
rivaroxaban 20, 40, or 60 mg bid, 40 mg od or st<strong>and</strong>ard<br />
therapy, respectively.<br />
ODIXa-DVT (bid study)<br />
Rivaroxaban (total daily dose)<br />
20<br />
ConClUsions<br />
Rivaroxaban, given od or bid <strong>for</strong> 3 months, was as effective<br />
<strong>and</strong> safe as st<strong>and</strong>ard therapy <strong>for</strong> the treatment of acute,<br />
symptomatic DVT. Thrombus regression at 3 weeks was<br />
greater with rivaroxaban bid than od, suggesting bid dosing<br />
may provide an advantage shortly after DVT <strong>for</strong>mation.<br />
Comparison of bleeding rates at 3 months with rivaroxaban<br />
od <strong>and</strong> bid suggested that od dosing may confer a slight<br />
advantage. There<strong>for</strong>e, phase III studies of rivaroxaban <strong>for</strong><br />
the treatment of VTE will investigate an initial, intensified<br />
bid regimen followed by convenient, long-term rivaroxaban<br />
20 mg od.<br />
20 mg 30 mg 40 mg 60 mg St<strong>and</strong>ard therapy<br />
Efficacy outcome (%) 1.1 – 1.1/3.0* 1.0 1.0<br />
EINSTEIN-DVT (od study)<br />
Major bleeding (%) 1.7 – 1.7/1.7* 3.3 0<br />
Efficacy outcome (%) 6.1 5.4 6.6 – 9.9<br />
Major bleeding (%) 0.7 1.5 0 – 1.5<br />
*Results are shown as 20 mg<br />
bid/40 mg od.
Pharmacokinetics (PK) <strong>and</strong> Pharmacodynamics (PD) of<br />
Rivaroxaban: A Comparison of Once- <strong>and</strong> Twice-Daily Dosing in<br />
Patients Undergoing Total Hip Replacement (THR)<br />
Eriksson BI 1 , Misselwitz F 2 , Mueck W 2<br />
1 Department of Orthopaedics, Sahlgrenska University Hospital, Gothenburg, Sweden; 2 N/A, Bayer HealthCare AG, Wuppertal, Germany<br />
Abstract P-M-659 presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa<br />
inhibitor in clinical development <strong>for</strong> the prevention <strong>and</strong><br />
treatment of thromboembolic disorders. Two phase IIb, dosefinding<br />
studies investigated rivaroxaban <strong>for</strong> the prevention of<br />
venous thromboembolism (VTE) after THR: one with twicedaily<br />
(bid) <strong>and</strong> one with once-daily (od) dosing.<br />
MethoDs<br />
Non-linear, mixed-effect population modeling was used<br />
to analyze the PK <strong>and</strong> PD of rivaroxaban, including<br />
the maximum (Cmax) <strong>and</strong> minimum (Ctrough) plasma<br />
concentrations of rivaroxaban, <strong>and</strong> prothrombin time (PT).<br />
The analysis was restricted to the rivaroxaban 5, 10, <strong>and</strong><br />
20 mg total daily dose groups from each study due to the<br />
favourable efficacy <strong>and</strong> safety of these doses, relative to<br />
enoxaparin (n=758).<br />
resUlts<br />
Rivaroxaban PK were described well by an oral, onecompartment<br />
model. Age <strong>and</strong> renal function influenced<br />
clearance, <strong>and</strong> body weight influenced volume of distribution;<br />
however, these effects were moderate, <strong>and</strong> within the<br />
variability of the study population. In both studies, Cmax <strong>and</strong><br />
Ctrough plasma concentrations of rivaroxaban at steady state<br />
increased dose dependently (table). Cmax values were higher,<br />
<strong>and</strong> Ctrough values were lower in the od study than in the<br />
bid study; however, the 90% confidence intervals overlapped.<br />
Rivaroxaban (mg)<br />
5 10 20<br />
bid C max (μg/l) 39.7 (29.2–73.4) 65 (46.2–105) 141 (101–218)<br />
od C max (μg/l) 69 (49–112) 124 (88.1–194) 222 (160–360)<br />
bid C trough (μg/l) 8.6 (1.7–26.5) 15.4 (4.7–46.2) 34.9 (7.9–99.7)<br />
od C trough (μg/l) 4.5 (0.7–37.7) 9.1 (1.3–37.8) 22.4 (4.3–95.7)<br />
21<br />
This suggests that od dosing should not lead to a greater<br />
risk of bleeding (at Cmax) or VTE (at Ctrough) than bid<br />
dosing. In the PD analysis, PT correlated linearly with<br />
rivaroxaban plasma concentrations.<br />
ConClUsions<br />
The PK <strong>and</strong> PD of rivaroxaban are predictable in patients<br />
undergoing THR after od or bid dosing. Combined with<br />
favourable efficacy <strong>and</strong> safety results of od rivaroxaban, these<br />
findings allowed selection of a convenient od dosing regimen.<br />
Values are medians (90%<br />
confidence intervals).
Rivaroxaban Has Predictable Pharmacokinetics (PK) <strong>and</strong><br />
Pharmacodynamics (PD) When Given Once or Twice Daily <strong>for</strong> the<br />
Treatment of Acute, Proximal Deep Vein Thrombosis (DVT).<br />
Mueck W, Agnelli G, Büller H (Intr. by Frank Misselwitz)<br />
<strong>Clinical</strong> Pharmacology, Bayer HealthCare AG, Wuppertal, Germany; University of Perugia, Perugia, Italy;<br />
Academic Medical Centre, Amsterdam, Netherl<strong>and</strong>s<br />
Abstract #1880 appears in Blood, Volume 110, issue 11, November 16, 2007<br />
introDUCtion<br />
Rivaroxaban is an oral, direct Factor Xa inhibitor in<br />
clinical development <strong>for</strong> the prevention <strong>and</strong> treatment of<br />
thromboembolic disorders. Two large, phase IIb, dose-finding<br />
studies investigating rivaroxaban <strong>for</strong> the treatment of acute,<br />
proximal DVT, showed that rivaroxaban once daily (od) <strong>and</strong><br />
twice daily (bid) had similar efficacy <strong>and</strong> safety profiles to<br />
st<strong>and</strong>ard therapy. In order to characterize the population<br />
PK/PD of rivaroxaban <strong>for</strong> DVT treatment, a population model<br />
was developed based on data from healthy subjects.<br />
MethoDs<br />
Sparse PK/PD samples from 870 patients across the two<br />
studies were analyzed using non-linear, mixed-effect<br />
population modeling (NONMEM), version V level 1.1.<br />
The program analyzed population data to give estimates of<br />
mean values <strong>and</strong> variability in the population. Prothrombin<br />
time (PT) was determined at a central laboratory <strong>and</strong><br />
was used in the PD investigation. For the PK profile, data<br />
was pooled from both clinical trials <strong>and</strong> specific exposure<br />
parameters <strong>for</strong> rivaroxaban, such as area under the plasma<br />
concentration–time curve (AUC), maximum <strong>and</strong> minimum<br />
plasma concentrations (Cmax <strong>and</strong> Ctrough, respectively)<br />
were predicted <strong>for</strong> each patient according to the dosing<br />
regimen received.<br />
Predicted rivaroxaban PK parameters<br />
Parameter Rivaroxaban total daily dose<br />
20 mg 30 mg 40 mg 60 mg<br />
n (od/bid) 134/117 134/- 252/114 -/119<br />
od C max (mcg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) –<br />
22<br />
resUlts<br />
The PK of rivaroxaban were well described by an oral, onecompartment<br />
model, with demographic factors influencing<br />
clearance (age, renal function) <strong>and</strong> volume of distribution<br />
(age, body weight, gender); variations due to these factors<br />
were moderate, suggesting fixed dosing may be possible. Comedications<br />
(e.g. diuretics, NSAIDs, aspirin) had no relevant<br />
effects on the PK of rivaroxaban. Rivaroxaban Cmax <strong>and</strong><br />
Ctrough concentrations increased dose dependently (Table).<br />
As expected, Cmax was higher <strong>and</strong> Ctrough was lower after<br />
od dosing compared with bid dosing, at equivalent total<br />
daily doses; however, 90% confidence intervals overlapped,<br />
suggesting that od dosing with rivaroxaban should not<br />
expose patients to a greater risk of bleeding (at Cmax) or VTE<br />
(at Ctrough) than bid dosing. <strong>Clinical</strong>ly relevant rivaroxaban<br />
plasma concentrations correlated linearly with PT, confirming<br />
that it would be suitable <strong>for</strong> measuring rivaroxaban exposure,<br />
if necessary. Conclusions: The PK <strong>and</strong> PD of rivaroxaban<br />
were predictable with od <strong>and</strong> bid dosing, <strong>and</strong> affected by<br />
expected demographic factors in patients receiving it <strong>for</strong><br />
DVT treatment. Combined with efficacy <strong>and</strong> safety results,<br />
this analysis aided the selection of an initial, intensified bid<br />
regimen followed by convenient, long-term rivaroxaban 20<br />
mg od, <strong>for</strong> investigation in phase III studies in this indication.<br />
Copyright American Society of Hematology. Reprinted with permission from the American Society of<br />
Hematology, which does not endorse any particular uses of this document. The American Society of<br />
Hematology is not responsible <strong>for</strong> the completeness or the accuracy of the translation.<br />
bid C max (mcg/L)* 211.5 (130.3–360.7) – 320.9 (209.9–517.9) 400.6 (244.2-749.5)<br />
od C trough (mcg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) –<br />
bid C trough (mcg/L)* 65.1 (17.2–193.6) – 104.2 (31.3–277.8) 143.1 (46.6–347.9)<br />
*Values are shown as means<br />
(90% confidence intervals)
Potential of the Factor Xa Inhibitor Rivaroxaban <strong>for</strong><br />
the Anticoagulation Management of Patients With<br />
Heparin-Induced Thrombocytopenia<br />
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<br />
1 Thoracic <strong>and</strong> CV Surgery; 2 Pathology, Loyola University Medical <strong>Center</strong>, Maywood, United States; 3 Bayer Healthcare<br />
AG, Wuppertal, Germany; 4 Loyola University Medical <strong>Center</strong>, Maywood, United States<br />
Abstract P-M-648 presented at ISTH July 6-12, 2007, Geneva, Switzerl<strong>and</strong>.<br />
introDUCtion<br />
Rivaroxaban (BAY 59-7939; Bayer) is an orally bioavailable,<br />
small-molecule, direct factor Xa inhibitor (XaI) in advanced<br />
clinical trials <strong>for</strong> the prevention <strong>and</strong> treatment of thromboembolic<br />
disorders. The purpose of this study was to determine<br />
the potential of this agent as an anticoagulant <strong>for</strong> patients<br />
with heparin-induced thrombocytopenia (HIT). Rivaroxaban<br />
is structurally different from heparin, LMW heparins, <strong>and</strong><br />
fondaparinux <strong>and</strong>, there<strong>for</strong>e, it is not expected to interact<br />
with pre-<strong>for</strong>med HIT antibodies.<br />
MethoDs<br />
Sera from 89 patients with ELISA positive HIT antibodies that<br />
induced platelet activation in the diagnostic 14C-Serotonin<br />
Release Assay (SRA) were included in this study. Rivaroxaban<br />
was tested in a total of 152 different HIT antibody/donor<br />
platelet combinations using three types of platelet function<br />
HIT assays (SRA, platelet aggregation, flow cytometry).<br />
resUlts<br />
Rivaroxaban had no cross-reactivity with any of the HIT<br />
antibodies as shown by the lack of platelet activation, platelet<br />
aggregation, platelet microparticle generation, <strong>and</strong> P-selectin<br />
up regulation. Further studies demonstrated that rivaroxaban<br />
did not promote the release of PF4 from platelets as did<br />
heparin <strong>and</strong> LMW heparin. Rivaroxaban did not bind to PF4.<br />
23<br />
ConClUsions<br />
Taken together these results provide strong evidence that<br />
rivaroxaban is not immunogenic <strong>for</strong> HIT <strong>and</strong> can be effectively<br />
used <strong>for</strong> anticoagulation of patients with HIT without risk of<br />
adverse platelet activation <strong>and</strong> associated thrombotic side<br />
effects from HIT antibody activation. As a XaI, rivaroxaban<br />
has advantages over current strategies <strong>for</strong> the anticoagulant<br />
management of HIT patients, such as improved safety/<br />
bleeding risk <strong>and</strong> oral bioavailability that allows <strong>for</strong> extended<br />
patient management.
notes<br />
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