Transcript Results of the RECORD3 study

Comparison of rivaroxaban – an oral, direct Factor Xa
inhibitor – and subcutaneous enoxaparin for
thromboprophylaxis after total knee replacement
Alexander GG Turpie
On behalf of Kenneth A Bauer, Scott D Berkowitz, Fred D Cushner,
Bruce L Davidson, Michael Gent, Louis M Kwong, Michael R Lassen,
Paul A Lotke, Frank Misselwitz, William D Fisher and the RECORD4
Study Investigators
Disclosures for Alexander GG Turpie
Research support/P.I.
Bayer Schering Pharma
Employee
N/A
Consultant
Bayer Schering Pharma, GSK, sanofi-aventis, Portola,
Pfizer, Takeda
Major stockholder
N/A
Speakers bureau
GSK
Honoraria
Bayer Schering Pharma, sanofi-aventis, Portola,
Pfizer, Takeda
Scientific advisory board
Bayer Schering Pharma, sanofi-aventis, Portola
Rivaroxaban:
an oral, direct Factor Xa inhibitor
 Once daily
O
O
N
O
 Predictable pharmacokinetics
and pharmacodynamics
N
O
Cl
S
H
N
O
Rivaroxaban
 High oral bioavailability
 Rapid onset of action
 Fixed dose
 No requirement for
coagulation monitoring
Rivaroxaban binds directly to the active
site of Factor Xa (Ki 0.4 nM)
Roehrig et al., 2005; Perzborn et al., 2005; Kubitza et al., 2005; 2006; 2007
RECORD: phase III program
 Rivaroxaban 10 mg od was compared with enoxaparin in 12,729
patients worldwide
Duration of
rivaroxaban therapy
Dose and duration of
enoxaparin therapy
THR
5 weeks
40 mg od; 5 weeks
THR
5 weeks
40 mg od; 2 weeks
TKR
2 weeks
40 mg od; 2 weeks
TKR
2 weeks
30 mg q12h; 2 weeks
Study
RECORD4: study design
Double blind
R
S
Rivaroxaban 10 mg od orally
U
R 6–8 hours post wound closure or adequate hemostasis
G
E 12–24 hours post wound closure or adequate hemostasis
R
Y
Enoxaparin 30 mg q12h sc
Day 1
Mandatory
bilateral
venography
F
O
L
L
O
W
U
P
Day 13±2
Last dose, 1 day
before venography
Day 42+5
Enrolment: 131 sites worldwide
Pakistan 1.2%
India 15.7%
Sri Lanka 1.7%
Israel 2.0%
Bulgaria 1.4%
United States 49.0%
Poland 7.8%
Lithuania 2.0%
Sweden 1.1%
Denmark 2.2%
Mexico 6.1%
Canada 9.8%
US and Canada = 58.8%
Study flow
Enoxaparin
Enrolled (N=3418)
Rivaroxaban
1564
Randomized (n=3148)
1584
1508
Safety population
1526
1122
mITT population for major VTE*
1112
959
878
mITT population for primary efficacy
(superiority analysis)
PP population for primary efficacy†
(non-inferiority analysis)
*Patients may be valid for major VTE analysis if only proximal veins were assessed
†Patients could have more than one protocol violation
965
864
Patient demographics
Enoxaparin
Rivaroxaban
30 mg q12h
(n=1508)
10 mg once daily
(n=1526)
Female, n %
967
64.1%
1007 66.0%
Age*, years (range)
64.7 (24–89)
64.4 (21–87)
Weight*, kg (range)
84.4 (35–171.5)
84.7 (38–190)
Body mass index*, kg/m2 (range)
30.7 (13.7–62.4)
30.9 (17.9–74.2)
Race, n %
– Caucasian
1032 68.4%
1008 66.1%
– Black
65 4.3%
88 5.8%
– Asian
289 19.2%
289 18.9%
– Hispanic
116 7.7%
137 9.0%
– American Indian
5 0.3%
1 0.1%
– Other/data missing
2 0.1%
3 0.2%
*Mean
values
Efficacy endpoints
Primary
 Total VTE: any DVT, non-fatal PE, and all-cause mortality up
to day 13±4
Secondary
 Major VTE: proximal DVT, non-fatal PE, and VTE-related death
 DVT: any, proximal, and distal
 Symptomatic VTE
Safety endpoints
Main
 Major bleeding starting after the first blinded dose and
up to 2 days after last dose
 Bleeding that was fatal, into a critical organ, or required re-operation
 Extra-surgical-site bleeding associated with a drop in hemoglobin
≥2 g/dL or requiring transfusion of ≥2 units blood
Other





Any bleeding on treatment*
Non-major bleeding*
Hemorrhagic wound complications*
Cardiovascular adverse events
Liver enzyme levels
All endpoints were adjudicated centrally by independent, blinded committees
*Up to 2 days after last dose of study medication
Primary efficacy endpoint: total VTE
RRR* = 31.4%
14
ARD† = –3.19% (–5.67, –0.71)
Incidence (%)
12
p=0.012
10
8
6
4
10.1%
6.9%
Enoxaparin
30 mg q12h
97/959
Rivaroxaban
10 mg once daily
67/965
2
0
*Relative risk reduction based on raw incidences; †absolute weighted risk difference (with 95% CI);
mITT population, n=1924
Secondary efficacy endpoints
Symptomatic VTE
5
5
4
4
3
ARD = –0.80% (–1.82, 0.22)
p=0.124
2
1
0
Incidence (%)
Incidence (%)
Major VTE
3
ARD = –0.47% (–1.16, 0.23)
p=0.187
2
1
2.0%
1.2%
Enoxaparin
30 mg q12h
22/1112
Rivaroxaban
10 mg once daily
13/1122
ARD, absolute weighted risk difference (with 95% CI)
0
1.2%
0.7%
Enoxaparin
30 mg q12h
18/1508
Rivaroxaban
10 mg once daily
11/1526
Major bleeding
5
Incidence (%)
4
p=0.110
3
2
0.7%
1
0.3%
0
Enoxaparin
30 mg q12h
4/1508
On-treatment major bleeding; safety population, n=3034
Rivaroxaban
10 mg once daily
10/1526
Safety: components of bleeding
n%
Any bleeding
Enoxaparin
Rivaroxaban
30 mg q12h
(n=1508)
10 mg once daily
(n=1526)
142 9.4%
160 10.5%
4 0.3%
10 0.7%
Fatal
0
1*
Critical† (intraspinal, intracraneal, retroperitoneal)
2
1
Leading to fall in hemoglobin
0
4§
Leading to transfusion
0
4§
Leading to re-operation
2‡
5
Major bleeding
Non-major bleeding
138 9.2%
155 10.2%
Clinically relevant non-major bleeding
30 2.0%
39 2.6%
Other non-major bleeding
112 7.4%
124 8.1%
On-treatment bleeding; *1 patient had fatal post-operative upper GI bleed and a fall in
hemogloblin leading to transfusion; † 1 intraspinal and 1 intracranial bleed with enoxaparin, 1
retroperitoneal bleed with rivaroxaban; ‡1 subject received only placebo and no active
enoxaparin; §all 4 patients had a fall in hemogloblin leading to transfusion; safety population,
n=3034
Adverse events
Enoxaparin
30 mg q12h
(n=1508)
n %
Rivaroxaban
10 mg once daily
(n=1526)
Any adverse event
1312
87.0%
1319
86.4%
On treatment
1216
80.6%
1222
80.1%
During follow-up
239
15.8%
244
16.0%
11
0.7%
7
0.5%
On treatment
8
0.5%
2
0.1%
During follow-up
3
0.2%
5
0.3%
6
0.4%
6
0.4%
3
0.2%
4
0.3%
6
0.4%
6
0.4%
Cardiovascular adverse events*
Any post-operative wound-related
infection
On treatment
Death
*Events occurring more than 1 day after the last intake of study drug during follow-up;
safety population
Liver function tests:
on-treatment abnormalities
n/N %
Enoxaparin
30 mg q12h
(n=1508)
Rivaroxaban
10 mg once daily
(n=1526)
ALT >3× ULN
38/1451 2.6%
19/1470 1.3%
ALT >5× ULN
15/1460 1.0%
5/1478 0.3%
ALT >10× ULN
2/1463 0.1%
1/1480 0.1%
ALT >3× ULN + TB >2× ULN
3/1464 0.2%
1/1481 0.1%
Safety population, n=3034; ALT, alanine transaminase; ULN, upper limit of normal;
TB, total bilirubin;
RECORD4: summary
12
Total VTE
Enoxaparin 30 mg q12h
Rivaroxaban 10 mg once daily
Incidence (%)
10
8
6
4
Major VTE
Symptomatic
VTE
2
0
10.1%
6.9%
RRR 31%
2.0%
1.2%
p=0.124
p=0.012
All p-values based on absolute weighted risk differences
1.2%
0.7%
p=0.187
Major bleeding
0.3%
0.7%
p=0.110
RECORD4: conclusions
Rivaroxaban demonstrated:
 Superior efficacy for the primary endpoint (total VTE)
 Low rate of major and symptomatic VTE events
 Similar safety profile to enoxaparin
 No statistically significant difference in major bleeding
 Cardiovascular adverse events low and balanced between groups
 No difference in the frequency of abnormal LFTs