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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

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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

rivaroxaban an oral direct factor xa inhibitor

Rivaroxaban

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

record phase iii program
RECORD: phase III program
  • Rivaroxaban 10 mg od was compared with enoxaparin in 12,729 patients worldwide
record4 study design

S

U

R

G

E

R

Y

RECORD4: study design

Double blind

F

Mandatory

bilateral

venography

Rivaroxaban 10 mg od orally

O

L

6–8 hours post wound closure or adequate hemostasis

L

R

O

W

12–24 hours post wound closure or adequate hemostasis

U

Enoxaparin 30 mg q12h sc

P

Day 42+5

Day 1

Day 13±2

Last dose, 1 daybefore venography

enrolment 131 sites worldwide
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%

study flow
Study flow

Enoxaparin

Rivaroxaban

Enrolled (N=3418)

Randomized (n=3148)

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-inferiority analysis)

878

864

*Patients may be valid for major VTE analysis if only proximal veins were assessed†Patients could have more than one protocol violation

efficacy endpoints
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
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%

ARD† = –3.19% (–5.67, –0.71)

p=0.012

14

12

10

8

Incidence (%)

6

4

10.1%

6.9%

2

0

Enoxaparin30 mg q12h97/959

Rivaroxaban10 mg once daily67/965

Primary efficacy endpoint: total VTE

*Relative risk reduction based on raw incidences; †absolute weighted risk difference (with 95% CI); mITT population, n=1924

secondary efficacy endpoints
Secondary efficacy endpoints

Symptomatic VTE

Major VTE

5

5

4

4

ARD = –0.80% (–1.82, 0.22)

p=0.124

3

3

ARD = –0.47% (–1.16, 0.23)

p=0.187

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)

major bleeding
Major bleeding

5

4

p=0.110

3

Incidence (%)

2

0.7%

0.3%

1

0

Enoxaparin30 mg q12h4/1508

Rivaroxaban10 mg once daily10/1526

On-treatment major bleeding; safety population, n=3034

safety components of bleeding
Safety: components of bleeding

On-treatment bleeding; *1 patient had fatal post-operative upper GI bleed and a fall in hemogloblin leading to transfusion; † 1intraspinal 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
Adverse events

*Events occurring more than 1 day after the last intake of study drug during follow-up; safety population

liver function tests on treatment abnormalities
Liver function tests: on-treatment abnormalities

Safety population, n=3034; ALT, alanine transaminase; ULN, upper limit of normal; TB, total bilirubin;

record4 summary
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%

10.1%

6.9%

1.2%

0.7%

0

p=0.124

p=0.187

p=0.110

RRR 31%

p=0.012

All p-values based on absolute weighted risk differences

record4 conclusions
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