Alexander GG Turpie

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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

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Disclosures for Alexander GG Turpie
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Rivaroxaban an oral, direct Factor Xa inhibitor

• Once daily
• Predictable pharmacokinetics and pharmacodynamics
• 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
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RECORD phase III program

• Rivaroxaban 10 mg od was compared with enoxaparin
  in 12,729 patients worldwide

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RECORD4 study design
Double blind
F
Mandatory bilateral venography
Rivaroxaban 10 mg od orally
O
L
68 hours post wound closure or adequate
hemostasis
L
R
O
W
1224 hours post wound closure or adequate
hemostasis
U
Enoxaparin 30 mg q12h sc
P
Day 425
Day 132
Day 1
Last dose, 1 daybefore venography
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Enrolment 131 sites worldwide
Pakistan 1.2
India 15.7
Sri Lanka 1.7
Israel 2.0
United States 49.0
Bulgaria 1.4
Poland 7.8
Lithuania 2.0
Sweden 1.1
Denmark 2.2
Mexico 6.1
US and Canada 58.8
Canada 9.8
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Study flow
Rivaroxaban
Enoxaparin
Enrolled (N3418)
Randomized (n3148)
1564
1584
Safety population
1508
1526
mITT population for major VTE
1122
1112
mITT population for primary efficacy(superiority
analysis)
959
965
PP population for primary efficacy(non-inferiori
ty analysis)
878
864
Patients may be valid for major VTE analysis if
only proximal veins were assessedPatients could
have more than one protocol violation
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Patient demographics
Mean values
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Efficacy endpoints

• Primary
• Total VTE any DVT, non-fatal PE, and all-cause
  mortality up to day 134
• Secondary
• Major VTE proximal DVT, non-fatal PE, and
  VTE-related death
• DVT any, proximal, and distal
• Symptomatic VTE

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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
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Primary efficacy endpoint total VTE
Relative risk reduction based on raw incidences
absolute weighted risk difference (with 95 CI)
mITT population, n1924
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Secondary efficacy endpoints
Symptomatic VTE
Major VTE
5
5
4
4
ARD 0.80 (1.82, 0.22) p0.124
3
3
ARD 0.47 (1.16, 0.23) p0.187
Incidence ()
Incidence ()
2
2
1
1
2.0
1.2
0.7
1.2
0
0
Enoxaparin30 mg q12h 22/1112
Rivaroxaban10 mg once daily 13/1122
Enoxaparin30 mg q12h 18/1508
Rivaroxaban10 mg once daily 11/1526
ARD, absolute weighted risk difference (with 95
CI)
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Major bleeding
5
4
p0.110
3
Incidence ()
2
0.7
0.3
1
0
Enoxaparin30 mg q12h4/1508
Rivaroxaban10 mg once daily10/1526
On-treatment major bleeding safety population,
n3034
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Safety components of bleeding
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, n3034
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Adverse events
Events occurring more than 1 day after the last
intake of study drug during follow-up safety
population
16
Liver function tests on-treatment abnormalities
Safety population, n3034 ALT, alanine
transaminase ULN, upper limit of normal TB,
total bilirubin
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RECORD4 summary
Total VTE
12
Enoxaparin 30 mg q12h
Rivaroxaban 10 mg once daily
10
8
Incidence ()
6
SymptomaticVTE
4
Major VTE
Major bleeding
2
0.7
0.3
2.0
1.2
6.9
10.1
1.2
0.7
0
p0.110
p0.124
p0.187
RRR 31
p0.012
All p-values based on absolute weighted risk
differences
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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