1. Ruby-1 Safety, Tolerability and Efficacy of Darexaban (YM150) in Patients with Acute Coronary Syndrome: a Phase II Study
Ph Gabriel Steg, J Wouter Jukema,
Gregory YH Lip, Shamir R Mehta, Ronny W Renfurm, Christopher B Granger, on behalf of the Ruby-1 investigators
ClinicalTrials.gov Identifier: NCT

2. Ph. Gabriel Steg - Disclosures
Research grant: Servier
Speaking or consulting: Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi-Sankyo-Lilly, GSK, Medtronic, Merck, Otsuka, Pfizer, Roche, sanofi-aventis, Servier, The Medicines Company
Stockholding: Aterovax
The RUBY-1 trial was supported and funded by ASTELLAS Pharma, Leiderdorp, The Netherlands

3. Enrique Gurfinkel (1957–2011)
Reproduced with permission from Rev Fed Arg Cardiol 2011; 40(2):

4. Long-term event rates post ACS The UK–Belgian GRACE experience
Fox KAA, et al. Eur Heart J 2010;31:2755–2764

5. Acute Coronary Syndrome and Oral Anticoagulation
The management of acute coronary syndrome (ACS) has improved considerably over the past decades, leading to a substantial decline in morbidity and mortality1
Guidelines from the European Society of Cardiology2,3 and the American College of Cardiology/American Heart Association4–6 recommend continuation of dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) for up to 1 year after an ACS event
Despite potent dual antiplatelet therapy, the recurrence of ischaemic events after an ACS event remains high, up to 9.1% at 6 months7
Great interest has been directed towards new oral anticoagulants, such as direct thrombin inhibitors and factor Xa inhibitors8,9
1Fox KA, et al. JAMA 2007;297:1892–1900
2Van de Werf F, et al. Eur Heart J 2008;29:2909–2945
3Bassand JP, et al. Eur Heart J 2007;28:1598–1660
4Antman EM, et al. J Am Coll Cardiol 2004;44:E1–E211
5Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157
6 Anderson JL, et al. Circulation 2011;123:e426–e579
7Fox KA, et al. BMJ 2006;33:1091
8Garcia D, et al. Blood 2010;115: 5–20
9Turpie AGG. Eur Heart J 2007; 29:155–165

6. Darexaban: Direct Factor Xa Inhibitor
Turpie AG. Arterioscler Thromb Vasc Biol 2007;27:1238–1247

7. Profile of Darexaban (YM150)
Darexaban is a direct factor Xa inhibitor with1–7:
Rapid absorption
Rapid and almost complete conversion to darexaban glucuronide by UGTs, as potent as darexaban, the main active moiety
Peak concentration occurs at 1–1.5 hours post-dose
Terminal half-life is 14−18 hours
Balanced excretion routes (renal/faecal: 50/50%)
Strong PK/PD relationship, unaffected by renal and hepatic impairment
No DDIs with CYP3A4/P-glycoprotein inhibitors and inducers
No clinically relevant DDIs with ASA, ASA + clopidogrel, or naproxen
Minimal food interaction
1Iwatsuki Y, et al. Blood (ASH Annual Meeting Abstracts) 2006;108:Abstract 911;
2Kaku S, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:Abstract 3153;
3Saitoh M, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:Abstract 3155;
4Groenendaal D, et al. Blood (ASH Annual Meeting Abstracts) 2010; 116:Abstract 3323;
5Groenendaal D, et al. Poster P-TU-163; ISTH 2011, July 23–28, 2011, Kyoto, Japan;
6Heeringa M, et al. Poster P-TU-164; ISTH 2011, July 23–28, 2011, Kyoto, Japan;
7 Shiraga T, et al. Drug Metab Rev 2011;43:S1

8. Study Objective and Endpoints
The primary objective was to evaluate the safety and tolerability of different doses and dose regimens of darexaban on top of standard treatment (ASA with or without clopidogrel) in the secondary prevention of ischaemic vascular events in patients with recent ACS
The primary endpoint was the incidence of major and/or CRNM bleeding events, during the 6 months of double-blind treatment (defined using a modified ISTH definition1)
Secondary endpoints included the following:
Major bleeding events according to the TIMI bleeding definition2
Composite of all cause mortality, non-fatal myocardial infarction, non-fatal stroke and severe recurrent ischaemia
1. Schulman S, et al. J Thromb Haemost 2005;3:692–694
2. Cannon CP, et al. J Am Coll Cardiol 2001;38:2114–2130

9. Study Design
Prospective, randomized, double-blind, multicentre, multiple-dose, placebo-controlled, parallel-group study (26 weeks) in patients presenting with ACS
Once stabilized, eligible patients were randomized to one of seven parallel study treatment groups
Six dose groups of darexaban and one placebo control group were evaluated

10. Study Flow
After the screening and baseline visits, patients had scheduled visits during the treatment period at Day 3, Weeks 1, 2, 4, 8 and 12, and subsequently every 4 weeks until at least 24 weeks double-blind treatment was completed
In order to ensure the smooth completion of the trial, Amendment 2 was issued, which stated that once the last randomized patient had completed 16 weeks of treatment, any patients who had completed the 24 weeks of double-blind treatment period could proceed to the follow-up visit, 4 weeks later
All patients were to complete at least 24 weeks of double-blind treatment unless they discontinued the study early
The double-blind treatment period was followed by a 4-week follow-up period to capture any potential late appearing safety information
After the end of the double-blind treatment period, or in case of premature discontinuation, patients were to be switched to standard of care open-label warfarin therapy unless medically contraindicated
Treatment with open-label warfarin was to continue throughout the 1-month follow-up period, after which subsequent treatment was at the discretion of the treating physician
ASA was used at a dose of 75–325 mg daily, as per local practice. The lower dose range of ASA (75–81 mg/day) was recommended, or clopidogrel 75 mg/day if ASA was contraindicated or not tolerated, or a combination of ASA 75–325 mg and clopidogrel 75 mg daily
1. Bassand JP, et al. Eur Heart J 2007;28:1598–1660
2. Anderson JL, et al. J Am Coll Cardiol 2007;50: e1–e157
R=randomization

11. Participating Countries

12. Inclusion and Exclusion Criteria
Key inclusion criteria
Age ≥18 years old
Diagnosis of STE-ACS or NSTE-ACS* as index event
Elevated cardiac biomarkers (Troponin T or I, or CK-MB)
Clinically stable and receiving current standard oral antiplatelet therapy
Able to be randomized within 7 days after presentation
Key exclusion criteria
Need for ongoing anticoagulant therapy, thrombolytics, glycoprotein IIb/IIIa antagonists or other antiplatelet drugs
Patient scheduled for invasive procedures with potential for bleeding within 60 days
Active bleeding or high risk of bleeding during the study
Recent stroke or TIA less than 12 months prior to index event
Persistent SBP of ≥160 mmHg and/or DBP of ≥100 mmHg at baseline
Hepatic insufficiency or ALT >2.0x the ULN or total bilirubin >1.5x the ULN
Renal creatinine clearance <60 mL/min
Other inclusion criteria included:
Institutional review board/independent ethics committee-approved written informed consent
Other exclusion criteria included:
Women who were pregnant, breast feeding or of childbearing potential unwilling to use a medically acceptable form of contraception
NVAF secondary to other reversible disorders
Indication for warfarin other than AF (including planned cardioversion)
Diagnosis of left ventricular aneurysm or atrial myxoma
Renal creatinine clearance of <60 mL/min; hepatic insufficiency or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 times the upper limit of normal (ULN) or total bilirubin >1.5 times the ULN
Any concurrent illness that could interfere with treatment or evaluation of safety or completion of this study; previous participation in another clinical trial of an investigational drug (including placebo) or device within 30 days (or the limit set by national law, whichever was longer) of signing informed consent for the present study; participation in any other darexaban clinical trials
Prohibited previous and concomitant medication included thrombolytics, antiplatelet agents, anticoagulants and chronic use of non-steroidal anti-inflammatory drugs, or acetylsalicylic acid use of >100 mg/day
* For patients with NSTE-ACS, at least one additional risk factor for ischaemic events had to be present

13. Statistical Analysis
A sample size of 1264 randomized subjects allowed 91% power to detect a linear trend in the incidence of CRNM and major bleeding versus daily dose, using a two-sided test with 95% confidence level
The primary analysis was performed based upon the modified intention- to-treat dataset (all randomized patients who took at least one dose of study drug)
Primary and secondary variables were analysed while patients were on study treatment and 1 day after discontinuation of treatment
Cumulative risk and 95% CIs at 30 days and 6 months were calculated using Kaplan–Meier estimates
These variables were also inferentially analysed using a Cox regression model, using treatment group and antiplatelet therapy as fixed effects
There was no adjustment for multiple comparisons
Other inclusion criteria included:
Institutional review board/independent ethics committee-approved written informed consent
Other exclusion criteria included:
Women who were pregnant, breast feeding or of childbearing potential unwilling to use a medically acceptable form of contraception
NVAF secondary to other reversible disorders
Indication for warfarin other than AF (including planned cardioversion)
Diagnosis of left ventricular aneurysm or atrial myxoma
Renal creatinine clearance of <60 mL/min; hepatic insufficiency or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 times the upper limit of normal (ULN) or total bilirubin >1.5 times the ULN
Any concurrent illness that could interfere with treatment or evaluation of safety or completion of this study; previous participation in another clinical trial of an investigational drug (including placebo) or device within 30 days (or the limit set by national law, whichever was longer) of signing informed consent for the present study; participation in any other darexaban clinical trials
Prohibited previous and concomitant medication included thrombolytics, antiplatelet agents, anticoagulants and chronic use of non-steroidal anti-inflammatory drugs, or acetylsalicylic acid use of >100 mg/day

14. Subject Disposition
It was planned that at least 160 patients (and up to 165 patients) would be randomized in each darexaban dose regimen group and at least 320 patients (and up to 330 patients) in the warfarin group, for a total of at least 1280 patients (and up to 1320 patients)
Overall, 1867 patients were screened due to a higher than anticipated screen failure rate, and 1312 patients were randomized in the study
Patients were stratified by prior anticoagulant use (warfarin use within 8 weeks prior to baseline visit)
Patients were randomized at the baseline visit (Visit 2) to one of six dose groups of darexaban and one control group of dose-adjusted warfarin in a 1:1:1:1:1:1:2 ratio
Of the 1312 patients randomized, 1306 (99.5%) received study drug, 1297 (98.9%) were included in the Safety Analysis Set (SAF) and Full Analysis Set (FAS) and 1175 (89.6%) were included in the Per Protocol Set (PPS)
Overall, 1174 patients (90.5%) in the SAF completed the follow-up

15. Baseline Characteristics (I)
Darexaban
(n=939)
Placebo
(n=319)
Male, n (%)
759 (80.8)
242 (75.9)
Mean age, years
56.6
57.5
Primary diagnosis for index event, n (%)
STEMI
674 (71.8)
220 (69.0)
NSTEMI
265 (28.2)
99 (31.0)
Use of PCI for index event
703 (74.9)
235 (73.7)
Standard antiplatelet therapy, n (%)
With clopidogrel
906 (96.5)
309 (96.9)
Without clopidogrel
33 (3.5)
10 (3.1)
Time from index event for first dose (mean days)
4.1
4.0
GRACE risk score at presentation (evaluated population)
132.8
Demographic characteristics were generally similar across the treatment groups in the SAF. The majority of patients were male (892 patients, 68.8%) and Caucasian (1031 patients [79.5%]). The mean age was 65 years (30–89 years) and 10.5% were older than 75 years
There were no notable differences across the treatment groups with regard to primary diagnosis of NVAF and time since diagnosis of NVAF
Overall, 699 patients (53.9%) had permanent NVAF, 337 patients (26.0%) had paroxysmal NVAF and 260 patients (20.0%) had persistent NVAF. The median time since diagnosis was 3.9 years (range: 0–55 years)

16. Baseline Characteristics (II)
Darexaban
(n=939)
Placebo
(n=319)
Hypertension, n (%)
566 (60.3)
194 (60.8)
Dyslipidaemia, n (%)
474 (50.5)
153 (47.9)
Type 2, diabetes mellitus, n (%)
217 (23.5)
60 (18.8)
Hx of prior CHF, n (%)
22 (2.3)
8 (2.5)
Hx of stroke/TIA, n (%)
31 (3.3)
6 (1.6)
Hx of prior MI, n (%)
105 (11.2)
45 (14.1)
Hx of CABG, n (%)
25 (2.7)
6 (1.9)
Hx of PCI, n (%)
10 (6.3)
25 (7.8)
Peripheral arterial disease
32 (3.4)
13 (4.0)
Demographic characteristics were generally similar across the treatment groups in the SAF. The majority of patients were male (892 patients, 68.8%) and Caucasian (1031 patients [79.5%]). The mean age was 65 years (30–89 years) and 10.5% were older than 75 years
There were no notable differences across the treatment groups with regard to primary diagnosis of NVAF and time since diagnosis of NVAF
Overall, 699 patients (53.9%) had permanent NVAF, 337 patients (26.0%) had paroxysmal NVAF and 260 patients (20.0%) had persistent NVAF. The median time since diagnosis was 3.9 years (range: 0–55 years)

17. Baseline Characteristics (III)
Darexaban
(n=939)
Placebo
(n=319)
Premature permanent study discontinuation
223 (19.0)
68 (21.3)
Concomitant medications, n (%)
Beta-blockers
859 (91.5)
293 (91.8)
ACE-inhibitors
731 (77.8)
248 (77.7)
Angiotensin receptor blockers
124 (13.2)
43 (13.5)
Statins
897 (95.5)
304 (95.3)
Fibrates
25 (2.7)
10 (3.1)
PPIs
336 (35.8)
99 (31.0)
Demographic characteristics were generally similar across the treatment groups in the SAF. The majority of patients were male (892 patients, 68.8%) and Caucasian (1031 patients [79.5%]). The mean age was 65 years (30–89 years) and 10.5% were older than 75 years
There were no notable differences across the treatment groups with regard to primary diagnosis of NVAF and time since diagnosis of NVAF
Overall, 699 patients (53.9%) had permanent NVAF, 337 patients (26.0%) had paroxysmal NVAF and 260 patients (20.0%) had persistent NVAF. The median time since diagnosis was 3.9 years (range: 0–55 years)

18. Study Discontinuations, Treatment Exposure and Compliance
291 patients (23.1%) discontinued treatment early
Adverse events − 137 patients (47.1%)
Withdrawal of consent − 62 patients (21.3%)
Lost to follow-up − 8 patients (9.3%)
Overall mean exposure to study drug was 21.3 weeks
Mean exposure was 19.7–22.0 weeks in the darexaban groups
Mean exposure was 21.9 weeks in the placebo group
Overall mean compliance to study drugs was 97.9%
Mean compliance was 95.9–99.3% in the darexaban groups
Mean compliance was 98.3% in the placebo group
981 patients (75.6%) in the SAF completed the study and 316 patients (24.4%) discontinued the study. A greater percentage of patients discontinued from the darexaban 60 mg once daily (qd) (54 patients, 33.1%) and warfarin (92 patients, 28.4%) groups compared with the other groups (range: 18.0% [darexaban 30 mg qd] to 23.5% [darexaban 30 mg twice daily {bid}])
The most frequent reason for discontinuation was adverse events (AEs) (128 patients, 9.9%), which occurred slightly more frequently in the darexaban 60 mg qd (22 patients, 13.5%) and warfarin (38 patients, 11.7%) groups than in the other groups (range: 8 patients [5.0%, darexaban 30 mg qd] to 17 patients [10.5%, darexaban 30 mg bid])
Other reasons included: withdrawal of consent (62 patients [4.8%]); protocol deviation (8 [0.06%]); did not meet study participation criteria (25 [1.9%]); lost to follow-up (13 [1.0%]); other reasons (80 [6.2%])
The most frequent reasons for discontinuation during follow-up was withdrawal of consent (60 patients) and AEs (29 patients)
Mean exposure to study drug was weeks; this ranged from weeks (darexaban 60 mg qd) to weeks (darexaban 30 mg qd) in the darexaban groups and was weeks with warfarin
Mean compliance to study drug was 98.3%; this ranged from 98.0% (darexaban 60 mg qd group) to 98.9% (darexaban 15 mg bid and 30 mg qd groups) in the darexaban groups and was 97.8% in the warfarin group
In the first 4 weeks, INR <2 (below the therapeutic range) was more frequent in the darexaban treatment groups (range: 65.2 [30 mg bid] to 85.1% [15 mg bid] of the time) than in the warfarin group (38.9% of the time)
INR within the therapeutic range (2–3) was less frequent in the darexaban groups (range: 14.7 [15 mg bid] to 33.1% [30 mg bid] of the time) than in the warfarin group (47.5% of the time)
Similarly, INR >3 (above the therapeutic range) was less frequent in the darexaban groups (range: 0.2 [15 mg bid] to 3.3% [60 mg bid and 120 mg qd] of the time) than in the warfarin group (13.5%)

19. Primary Safety Endpoint: Major and CRNM Bleeding at 6 months
Using placebo as reference, there was a dose-response relationship (p=0.009) for increased bleeding with increasing darexaban dose
Kaplan–Meier analysis of cumulative risk of major and CRNM bleeding events

20. Cumulative Risk of Any Bleeding Events at 6 Months
Data based on Kaplan–Meier analysis

21. Cumulative Risk of Major and CRNM Bleeding for Darexaban Total Daily Doses at 6 Months
Cumulative incidences are calculated using Kaplan–Meier estimates and presented as relative to 1 (e.g represents 6%)

22. Cumulative Risk of Major and CRNM Bleeding and Any Bleeding Events at 6 Months

23. Main Secondary Endpoint: Cumulative Risk of Composite Efficacy Outcome at 6 Months
Kaplan–Meier analysis of cumulative risk of all cause mortality, non-fatal myocardial infarction, non-fatal stroke and severe recurrent ischaemia

24. Main Secondary Endpoint: Composite Efficacy Outcome at 6 Months
Crude risk of all cause mortality, non-fatal myocardial infarction, non-fatal stroke and severe recurrent ischaemia

25. Adverse Events Darexaban Placebo (n=319) 5 mg bid (n=159) 10 mg
qd (n=159)
15 mg
bid (n=159)
30 mg qd
(n=156)
(n=153)
60 mg
qd (n=153)
All AEs, N (%)
100 (62.9)
102 (64.2)
96 (61.5)
101 (66.0)
99 (64.7)
181 (56.7)
Most common AEs, N (%)*
Hypertension
13 (8.2)
9 (5.7)
6 (3.8)
9 (5.9)
8 (5.2)
16 (5.0)
Cough
7 (4.4)
11 (6.9)
5 (3.1)
6 (3.9)
3 (2.0)
11 (3.4)
Angina pectoris
4 (2.5)
4 (2.6)
9 (2.8)
Epistaxis
2 (1.3)
7 (4.5)
10 (6.5)
5 (1.6)
Chest pain
3 (1.9)
4 (1.3)
Non-cardiac chest pain
7 (2.2)
Increased blood creatinine
6 (1.9)
Haematoma
Serious AEs, N (%)
22 (13.8)
28 (17.6)
26 (16.7)
26 (17.0)
40 (12.5)
Study drug related
3 (0.9)
Overall, 2189 treatment-emergent adverse events (TEAEs) occurred in 758 patients (58.4%) in the SAF: 1571 TEAEs in 561 patients (57.7%) treated with darexaban and 618 TEAEs in 197 patients (60.8%) treated with warfarin
TEAEs occurred to a slightly lesser extent in the darexaban 30 mg bid and 60 mg qd groups than in the other darexaban groups and the warfarin group. However, there were generally no notable differences across the treatment groups with regard to number and types of individual TEAEs
Most TEAEs were of mild or moderate severity in the SAF; 446 patients (34.4%) had 1602 mild TEAEs; 259 patients (20.0%) had 517 moderate TEAEs; and 53 patients (4.1%) had 70 severe TEAEs
Overall, 188 TEAEs led to permanent discontinuation of study drug in 145 patients (11.2%) in the SAF; 124 TEAEs in 100 patients (10.3%) treated with darexaban and 64 TEAEs in 45 patients (13.9%) treated with warfarin
Overall, 532 drug-related TEAEs occurred in 282 patients (21.7%) in the SAF; 379 drug‑related TEAEs in 202 patients (20.8%) treated with darexaban and 153 drug-related TEAEs in 80 patients (24.7%) treated with warfarin. Drug-related TEAEs occurred more frequently in the higher dose darexaban groups and warfarin group (than in the lower dose darexaban groups
Overall, 83 drug-related TEAEs led to permanent discontinuation of study drug in 63 patients (4.9%) in the SAF; 61 drug-related TEAEs in 47 patients (4.8%) treated with darexaban and 22 drug-related TEAEs in 16 patients (4.9%) treated with warfarin.
Overall, 84 hepatic TEAEs occurred in 53 patients (4.1%) in the SAF; 72 events in 44 patients (4.5%) treated with darexaban and 12 events in nine patients (2.8%) treated with warfarin. Hepatic TEAEs occurred more frequently in the higher dose darexaban groups than in the lower dose darexaban groups and the warfarin group
Serious AEs
A total of six patients (0.5%) died during the study, all of whom were treated with darexaban; two patients (1.2%) from the 15 mg bid group and one patient (0.6%) from each of the 30 mg bid, 60 mg qd, 60 mg bid and 120 mg qd groups. Two patients died after the completion of the double-blind treatment period
Overall, 157 treatment-emergent serious AEs (SAEs) occurred in 125 patients (9.6%) in the SAF; 108 SAEs in 84 patients (8.6%) treated with darexaban and 49 SAEs in 41 patients (12.7%) treated with warfarin
Overall, 23 drug-related SAEs occurred in 20 patients (1.5%) in the SAF; 16 drug-related SAEs in 13 patients (1.3%) treated with darexaban and seven drug-related SAEs in seven patients (2.2%) treated with warfarin

26. Laboratory Assessments
Darexaban
Placebo
5 mg
bid
(n=159)
10 mg qd
15 mg
bid (n=159)
30 mg
qd (n=156)
bid (n=153)
60 mg
qd (n=153)
(n=319)
ALT or AST >3x
ULN
5/143
(3.5)
4/149
(2.7)
2/148
(1.4)
1/138
(0.7)
2/139
2/137
(1.5)
7/290
(2.4)
ALT or AST >5x
2/149
(1.3)
2/155
(0.0)
1/146
1/144
2/302
Total bilirubin >2x ULN
1/150
1/151
1/147
2/141
1/141
Total bilirubin >3x ULN
Demographic characteristics were generally similar across the treatment groups in the SAF. The majority of patients were male (892 patients, 68.8%) and Caucasian (1031 patients [79.5%]). The mean age was 65 years (30–89 years) and 10.5% were older than 75 years
There were no notable differences across the treatment groups with regard to primary diagnosis of NVAF and time since diagnosis of NVAF
Overall, 699 patients (53.9%) had permanent NVAF, 337 patients (26.0%) had paroxysmal NVAF and 260 patients (20.0%) had persistent NVAF. The median time since diagnosis was 3.9 years (range: 0–55 years)
All data are n (%)

27. Conclusions
Darexaban, when added to dual antiplatelet therapy after ACS, produces an expected, dose-related 2- to 4-fold increase in bleeding
Bleeding rates were numerically higher in all darexaban arms versus placebo
There was a dose–response relationship for increased bleeding with increasing darexaban dose, which was statistically significant for darexaban 30 mg bid
There was no decrease in efficacy event rates with darexaban
However, as with most Phase II dose-ranging trials of antithrombotic drugs, this study was underpowered for efficacy
Darexaban was well tolerated, with no signs of liver toxicity
ALT, AST and bilirubin levels were similar between placebo and all doses of darexaban
Investigating the potential role of low-dose darexaban in preventing major cardiac events after ACS requires a large Phase III trial

28. Darexaban Global Clinical Development Program
NVAF
OPAL-1 (Asia/Japan) (presented ESC 2010)
OPAL-2 (EU/Japan/Asia)
ACS
RUBY-1 (EU/Asia) N=1278 (completed)
Double-blind, placebo-controlled, Phase IIb dose ranging study
VTE prevention
PEARL-1 and -2 (completed)
Phase IIa and b in TKR
Results to be published Q3/4 2011
ONYX-1 and -2 (completed and published)
ONYX-3 (US/EU): (completed)
Phase IIb, double-blind, enoxaparin-controlled, dose-ranging in THR
Data presented at ISTH 2011

29. Published online today at http://eurheartj.oxfordjournals.org/

30. Acknowledgements
Executive Steering Committee: Ph G Steg (Chair; France), CB Granger (USA), JW Jukema (Netherlands), GYH Lip (UK), S Mehta (Canada), RW Renfurm (non-voting; Astellas, Netherlands)
Steering Committee: S-K Kim (South Korea), S Husted (Denmark), L Janssens (Belgium), C Bode (Germany), F Kovar (Slovakia), P Kala (Czech Republic), I Édes (Hungry), TO Ophuis (Netherlands), N Gratsiansky (Russia), D Brieger (Australia), E Franco (Chile), M Dorobantu (Romania), J Balchanader (India), GYH Lip (UK), A Parkhomenko (Ukraine), E Cardona (Mexico), A Rynkiewicz (Poland), A Dalby, (South Africa), J Nicolau (Brazil), E Gurfinkel (Argentina), J Sinnadurai (Malaysia), A Erglis (Latvia)
Independent Adjudication Committee: CM Gibson (Chair), DS Pinto, Y Pride, JF Dashe (USA)
Data Monitoring Committee: F van de Werf (Chair; Belgium), FWA Verheugt (Netherlands), N Freemantle (UK)
Statistical analysis: A Garcia Hernandez (Astellas, Netherlands)
Editorial assistance: FV Gambling (Medicus International, UK)
Study execution and monitoring: ICON plc (UK)
Study sponsorship: Astellas, (Netherlands)