Lok ortho
THROMBOPROFYLAXIE BIJ MAJEURE ORTHOPEDISCHE CHIRURGIE
Maart 2011
Dr P.Verstraeten
alle 3 componenten van de Virchow- triade betrokken bij Orthopedische chirurgie ! Hypercoagulabele status
Endotheliale lesies
Circulatoire stase
Major orthopaedic surgery is an important risk factor for DVT Group
Prevalence of DVT (%)
Medical patients
10–20
Major gynaecological/ urological/ genital surgery
15–40
Neurosurgery
15–40
Stroke
20–50
Hip/knee replacement surgery/ hip fracture surgery
40–60
Major trauma
40–80
Spinal cord injury
60–80
Adapted from Geerts WH et al. Chest 2008;133:381S–453S, with permission from the American College of Chest Physicians.
Bekende gevolgen van VTE • Fatale longembolie • Verhoogde kans op recidief • Chronisch post-thrombotisch syndroom • Chronische thromboembolische pulmonale hypertensie (2 à 4 %) • Verhoogde morbiditeit en
QOL
• Hoge kosten i.v.m.investigaties en behandeling van symptomatische patients Geerts WH et al. Chest 2008;133:381S–453S.
Cave Mogelijks onderschatting van het probleem door de orthopedisch chirurg : Pten met SS VTE ( vnl.Longembolie!) komen op Urgentie afdeling terecht , of bij de longarts !!
VTE (= DVT en /of LONGEMBOLIE) IN MOS • VTE is de meest frekwente oorzaakvan re-hospitalisatie na THR ingreep.
VTE incidentie
• De meeste symptomatische VTE ‘s gebeuren na ontslag!!
In-hospital prophylaxis
Discharge Most DVTs and PEs occur after discharge Increased risk without prophylaxis
tijd Geerts WH et al. Chest 2008;133:381S–453S; Cohen AT et al. Thromb Haemost 2007;98:756–64.
Cumulative incidence of symptomatic VTE after THR or TKR
Cumulative VTE incidence (%)
2.5
2.0
1.5
1.0
TKR (n = 8236) THR (n = 6639)
0.5
0 0
10
20
30
40
50
60
70
Time after surgery (days) Adapted from Warwick D et al. J Bone Joint Surg Br 2007;89:799–807, with permission and copyright © of the British Editorial Society of Bone and Joint Surgery.
80
90
100
Timing of VTE events after THR or TKR Median time to discharge
50
Time after surgery (days)
Mean time to events 40
30
20
10
0
Total hip replacement
Data from Warwick D et al. J Bone Joint Surg Br 2007;89:799–807.
Total knee replacement
1.5 Cumulative VTE incidence
Prophylaxis (any type)
1.0 0.5
0 0 10 20 30 40 50 60 70 80 90 100 Time after surgery (days)
Patients receiving prophylaxis (%)
2.0
100 90 80 70 60 50 40 30 20 10 0
TKR 2.5 Cumulative VTE incidence
2.0 1.5 1.0
Prophylaxis (any type)
0.5
0 0 10 20 30 40 50 60 70 80 90 100 Time after surgery (days)
Adapted from Warwick D et al. J Bone Joint Surg Br 2007;89:799–807, , with permission and copyright © of the British Editorial Society of Bone and Joint Surgery.
Cumulative VTE incidence (%)
100 90 80 70 60 50 40 30 20 10 0
THR
Cumulative VTE incidence (%)
Patients receiving prophylaxis (%)
The time course of thromboprophylaxis versus the cumulative incidence of VTE
THROMBOPROFYLAXE : bij totale heup / knie prothese (THP / TKP) “UNDERUSED” • Ondanks de aanbevelingen krijgt een aanzienlijk aandeel van de patiënten geen adequate tromboprofylaxe na een THP/TKP – 1995: enquête van de British Orthopaedic Association: 13 tot 15% en 18 tot 33% van de chirurgen gebruikten geen enkele tromboprofylaxe na respectievelijk een THP en TKP – 2007: analyse van de HealthFacts-database: slechts 13.3% van de artsen volgden correct de aanbevelingen voor VTE profylaxe – 2007: Global Orthopaedic Registry: profylaxe na een THP/TKP wordt niet voor de juiste tijdsduur voorgeschreven
Anticoagulantia bij MOS-pten • De anticoagulantia die momenteel beschikbaar zijn voor de preventie van VTE na een THP en TKP zijn : – niet-gefractioneerde heparines (UFH) – heparines met laag moleculair gewicht (LMWH) – fondaparinux – vitamine K-antagonisten (VKA)
• Zij inhiberen onrechtstreeks de vorming en/of de werking van trombine (factor IIa)
Aanbevelingen bij totale heup / knie prothese (THP / TKP) • Er bestaan geen nationale Belgische aanbevelingen voor de preventie van VTE • Folia farmacotherapeutica1: Bij majeure orthopedische operaties wordt een behandeling met antitrombotica aanbevolen; LMWH zijn de referentiebehandeling. Fondaparinux is een alternatief, maar is geen voorkeursmiddel omdat – er minder ervaring is met langdurig gebruik in vergelijking met heparines – de kosten hoger liggen. 1. www.cbip.be
VTE prevention : GUIDELINES Evidence-based clinical practice guidelines: • American College of Chest Physicians (ACCP)1 • International Consensus Statement2 • AAOS
1Geerts
WH et al. Chest 2008;133:381–453S; 2Nicolaides AN et al. Int Angiol 2006;25:101-61.
ACCP guidelines for VTE prevention after major orthopaedic surgery
Eighth ACCP Conference on Antithrombotic Therapy Recommendation
Duration
Level of evidence
Elective total hip replacement
LMWH, fondaparinux, or adjusted-dose VKA
At least 10 days, up to 35 days
1A 1A
Elective total knee replacement
LMWH, fondaparinux, or adjusted-dose VKA
At least 10 days, up to 35 days
1A 2B
Procedure
Acetylsalicylic acid is not recommended by the ACCP as sole prophylaxis in any of these patients. Intermittent pneumatic compression is not recommended as sole method of thromboprophylaxis in patients undergoing THR. Data from Geerts WH et al. Chest 2008;133:381S–453S.
LMWH, low molecular weight heparin; VKA, vitamin K antagonist.
Onbeantwoorde behoeften Verschillende doeltreffende therapeutische modaliteiten zijn momenteel beschikbaar voor de preventie van VTE na een THP/TKP. Ze hebben echter allemaal nadelen, hoofdzakelijk wat betreft toedieningswijze en/of de noodzaak voor biologische monitoring
Therapie
Belangrijkste nadelen
LMWH
Uitstekend evenwicht doeltreffendheidveiligheid / MAAR : - Subcutane injectie - Risico op HIT (controle van de bloedplaatjes)
Fondaparinux
- Subcutane injectie - Meer bloedingen in vergelijking met LMWH
VKA
- Minder doeltreffend dan LMWH - Frequente controle met INR
17
Onbeantwoorde behoeften voor de preventie van VTE : Onbeantwoorde behoeften IDEAAL ANTICOAGULANS : AC met een doeltreffendheids- en veiligheidsprofiel vergelijkbaar met LMWH
Orale toediening Zonder monitoring 18
Nieuwe anticoagulantia
New anticoagulants ORAL
PARENTERAL TF/VIIa
TTP889
TFPI (tifacogin)
X
IX VIIIa
Rivaroxaban Apixaban LY517717 YM150 DU-176b PRT-054021
Va Xa
APC (drotrecogin alfa) sTM (ART-123)
IXa AT
II
Ximelagatran Dabigatran
Fondaparinux Idraparinux DX-9065a Otamixaban
IIa Fibrinogen
Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005
DABIGATRAN ( PRADAXA)
Boehringer Ingelheim
VTE Treatment
Orthopaedic VTE Prevention
Re-cover: treatment of VTE Re-medy: Long-term treatment
Re-novate:THR-prolonged Re-model:TKR (EU) Re-mobilize:TKR (USA) Re-novate II : THR
status : ongoing
(Recover
Status:Completed
Stroke Prevention Atrial fibrillation Pethro Re-ly Status: completed study
Status: completed!
)
Dabigatran etexilate (PRADAXA®)
• Oraal • Prodrug! • Directe thrombine (FIIa) inhibitor : - snel en krachtig - reversiebele binding Dosis : 150 – 220 mgr/dd ( profylaxie) pradaxa
Eerste 3 grote Fase III orthopedie-studies Total VTE and all cause mortality ENOXA REMOBILIZE (THR ; USA)
DABI 150 mgr/d.
DABI 220 mgr/d.
25.3(2.2)
33.7 (3.0)
31.3(3.4)
2x30 mgr REMODEL
37.7(3.5)
40.5(3.8)
36.4(2.6)
( TKR ; EU) RENOVATE
6.7 (3.9)
8.6 (4.3)
6.0 (3.1)
( THR ; UE)
( ) = major VTE
MAJEURE BLOEDINGEN (%)
ENOXA
• REMOBILIZE
DABI 150
DABI 220
1.4
0.6
0.6
• REMODEL
1.3
1.3
1.5
• RENOVATE
1.6
1.3
2.0
(USA)
Pooled analysis : major en clin sign.non-major bleed : 5.0
5.6 %
RIVAROXABAN XARELTO® Bayer
RECORD: phase III programme for VTE prevention • Rivaroxaban 10 mg o.d. administered 6–8 hours post surgery compared with enoxaparin • Same efficacy and safety outcomes • Same independent, blinded adjudication committees Hip replacement
Hip replacement
Knee replacement
Knee replacement
Rivaroxaban 10 mg o.d. for 35 ± 4 days
Rivaroxaban 10 mg o.d. for 35 ± 4 days
Rivaroxaban 10 mg o.d. for 12 ± 2 days
Rivaroxaban 10 mg o.d. for 12 ± 2 days
vs.
vs.
vs.
vs.
Enoxaparin 40 mg o.d. for 35 ± 4 days
Enoxaparin 40 mg o.d. for 12 ± 2 days followed by placebo
Enoxaparin 40 mg o.d. for 12 ± 2 days
Enoxaparin 30 mg b.i.d. for 12 ± 2 days
N = 4541
N = 2509
N = 2531
N = 3148
Data from Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14.
Surgeons are very concerned about bleeding at surgical site .
Although in the case of orthopaedic surgery bleedings are mostly located at the surgical sites, it’s important to note that in these definitions only important bleedings at extra-surgical sites are taking into account.
RENOVATE II (dabigatran)
• 2050 pten met THR • R/ 220 mgr DABI (1/2 dosis 1-4h. Postop) enoxa 40 mgr(start avond voor chirurgie) • 28 à 35 dd behandeling • 1° efficacy : total VTE en “all cause †” • 2°
“
: major VTE +VTE related †
• 1° safety : major bleeding
RESULTATEN : RENOVATE II
DABI
ENOXA
p-value
1° Eff.outcome
7.7 %
8.8 %
(non inf)
2° Eff. outcome
2.2 %
4.2 %
Major bleed
1.4 %
0.9%
p : 0.03 p : 0.40
In het kader van MOS kunnen de nieuwe orale antico’s een aantrekkelijk alternatief zijn : • Vb bij out of hospital profylaxie bij pten met THR • Bij oudere pten met verminderde NF : vb pradaxa in een dosis van 150 mgr dd.(cfr RENOVATE 2)
Conclusies • Patienten die een THR of TKR moeten ondergaan hebben een hoog risico op VTE • Dit risico persisteert gedurende meerdere weken na ontslag uit het ZH • Lange-term ijn complicaties van VTE verhogen de morbiditeit en verminderende “ quality of life” Primaire VTE - preventie is dan ook essentieel !
THE END
Primary efficacy endpoint Total VTE Enoxaparin regimen (%)
Rivaroxaban regimen (%)
p-value
3.7
1.1
< 0.001
< 0.001
18.9
9.6
*RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin.
Data from Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86.
Safety: components of bleeding Major bleeding
Non-major bleeding
Enoxaparin regimen (%)
Rivaroxaban regimen (%)
p-value
Enoxaparin regimen (%)
Rivaroxaban regimen (%)
p-value
0.1
0.3
0.18
5.8
5.8
–
–
0.5
0.6
0.77
4.4
*RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin.
Data from Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86.
4.3
–
Secondary efficacy endpoints Major VTE
Symptomatic VTE
Enoxaparin regimen (%)
Rivaroxaban regimen (%)
p-value
Enoxaparin regimen (%)
Rivaroxaban regimen (%)
p-value
2.0
0.2
< 0.001
0.5
0.3
0.22
2.6
1.0
0.01
2.0
0.7
0.005
*
*RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin. Data from Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86.
Total VTE: summary ARD − 9.2% (−12.4 to −5.9)
p < 0.001
Enoxaparin regimen
20
Rivaroxaban regimen
18
RRR = 49% 18.9%
Incidence (%)
16 14 12 10 8 6
9.6%
ARD −2.6% (−3.7 to −1.5)
p < 0.001
RRR = 70%
4 2 0
3.7% 1.1% 1
Data from 1Eriksson BI et al. N Engl J Med 2008;358:2765–75; 2Kakkar AK et al. Lancet 2008;372:31–9; 3Lassen MR et al. N Engl J Med 2008;358:2776–86.
*RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with shortduration (12 ± 2 days) enoxaparin.
RECORD1, 2 and 3: conclusions In almost 10 000 adult patients undergoing elective hip or knee replacement rivaroxaban compared with enoxaparin showed • Superior efficacy for reducing total VTE: – in head-to-head comparisons with enoxaparin (RECORD1 and 3) – comparing extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin (RECORD2)
• • • • • •
Superior efficacy for reducing major VTE in RECORD1 and 3 Significant reduction of symptomatic VTE in RECORD3 Significant reduction of major and symptomatic VTE in RECORD2 Low and similar rates of bleeding events No evidence of drug-induced liver injury attributable to rivaroxaban Consistently low level of cardiovascular adverse events
Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86.
Major VTE: summary ARD, −4.5% (−6.0 to −3.0)
p < 0.0001
7
Enoxaparin regimen
RRR = 88%
Rivaroxaban regimen
6
Incidence (%)
5
ARD, −1.6% (−2.8 to −0.4)
5.1%
ARD, −1.7
p = 0.01
(−2.5 to −1.0)
4
p < 0.001
*RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with shortduration (12 ± 2 days) enoxaparin.
RRR = 62%
RRR = 88%
3 2.6%
2 2.0%
1 0.2%
0 1Eriksson
0.6%
1
2*
2Kakkar
Data from BI et al. N Engl J Med 2008;358:2765–75; AK et al. Lancet 2008;372:31–9; 3Lassen MR et al. N Engl J Med 2008;358:2776–86.
1.0% 3
ARD, absolute weighted risk difference (95% CI); RRR, relative risk reduction.
Symptomatic VTE: summary Enoxaparin regimen
4
Rivaroxaban regimen 3
ARD, −0.2 (−0.6 to −0.1)
Incidence (%)
p = 0.22
ARD, −1.0
ARD, −1.3
(−1.8 to −0.3)
(−2.2 to −0.4)
RRR = 80%
RRR = 66%
p = 0.004
NS
p = 0.005
2
2.0%
1.2%
1 0.5%
0
*RECORD2 compared extended- duration (35 ± 4 days) rivaroxaban with shortduration (12 ± 2 days) enoxaparin.
0.3% 1
0.2% 2*
0.7%
3
Data from 1Eriksson BI et al. N Engl J Med 2008;358:2765–75; 2Kakkar AK et al. Lancet 2008;372:31–9; 3Lassen MR et al. N Engl J Med 2008;358:2776–86.
The ACCP guidelines and the ICS recommend pharmaceutical prophylaxis after THR Option
ACCP1
ICS2
LMWH
Yes (1A)
Yes (A)*
Fondaparinux
Yes (1A)
Yes (A)*
Oral vitamin K antagonist
Yes (1A)
Yes (A)
IPC ± GCS
Yes (1A)**
Yes (A)**
VFP ± GCS
Yes (1A)**
Yes (A)**
GCS
No (1A)
—
Aspirin
No (1A)
—
Low-dose heparin
No (1A)
—
*Preferred options. **Options for patients at increased risk of bleeding. 1Geerts
Data from WH et al. Chest 2008;133:381–453S; 2Nicolaides AN et al. Int Angiol 2006;25:101-61.
GCS, graduated compression stocking; IPC, intermittent pneumatic compression; VFP, venous foot pump.
The ACCP guidelines and the ICS recommend pharmaceutical prophylaxis after TKR Option
ACCP1
ICS2
LMWH
Yes (1A)
Yes (A)
Fondaparinux
Yes (1A)
Yes (B)
Oral vitamin K antagonist
Yes (1A)
Yes (A)
IPC ± GCS
Yes (1A)**
Yes (B)
VFP ± GCS
Yes (1B)**
Yes (B)
GCS
—
—
Aspirin
No (1A)
—
Low-dose heparin
No (1A)
—
**Options for patients at increased risk of bleeding. Data from 1Geerts WH et al. Chest 2008;133:381–453S; 2Nicolaides AN et al. Int Angiol 2006;25:101-61.
GCS, graduated compression stocking; IPC, intermittent pneumatic compression; VFP, venous foot pump.
Guidelines for VTE prevention in patients undergoing THR recommend up to 35 days of thromboprophylaxis Guideline
Prevention of VTE: the 8th ACCP Conference on Antithrombotic and Thrombolytic Therapy (2008)
Classification
1A
• Thromboprophylaxis for at least 10 days
1A
• Recommend thromboprophylaxis beyond 10 days and up to 35 days
A
• Thromboprophylaxis with LMWH should continue for 4–6 weeks
Geerts WH et al. Chest 2008;133:381–453S.
Prevention of VTE: International Consensus Statement (2006)
Recommendation for duration of therapy
C Nicolaides AN et al. Int Angiol 2006;25:101–61.
Not given
• Thromboprophylaxis with fonadaparinux should continue for 4–6 weeks • Use of IPC or VFP should continue as long as tolerated, and then be replaced by chemical prophylaxis for the rest of the period of risk
IPC, intermittent pneumatic compression; VFP, venous foot pump.
Guidelines for VTE prevention in patients undergoing TKR suggest up to 35 days of thromboprophylaxis Guideline
Prevention of VTE: the 8th ACCP Conference on Antithrombotic and Thrombolytic Therapy (2008)
Classification
1A
• Thromboprophylaxis should continue for at least 10 days
2B
• Suggest thromboprophylaxis extended beyond 10 days and up to 35 days
Geerts WH et al. Chest 2008;133:381–453S.
Prevention of VTE: International Consensus Statement (2006)
Recommendation for duration of therapy
Not given
• Effect of extending prophylaxis using LMWH to 30–42 days beyond hospitalization less than in patients undergoing THR
Nicolaides AN et al. Int Angiol 2006;25:101–61.
IPC, intermittent pneumatic compression; VFP, venous foot pump.
Incidence of symptomatic VTE after THR or TKR without extended thromboprophylaxis Patients with symptomatic VTE (%)
10
In-hospital prophylaxis followed by placebo or no treatment
8
6
4
2
0 Planes Bergqvist Dahl et al. et al. et al. 1996 1996 1997
NPHDO Manganelli Lassen 1998 et al. el al. 1998 1998
Data from Eikelboom JW et al. Lancet 2001;358:9–15.
Hull et al. 2000
Hull et al. 2000
Comp et al. 2001
Total
Extended-duration thromboprophylaxis reduces the incidence of VTE after THR and TKR • Meta-analysis:
In-hospital prophylaxis followed by:
– nine studies (THR/TKR)
30
Placebo/no treatment
– N = 3999 Prevalence (%)
• Extended-duration (30–42 days) prophylaxis reduces venographic DVT and symptomatic VTE
Extended prophylaxis 20
19.6%
10
9.6%
3.3%
1.3%
0
Venographic DVT Data from Eikelboom JW et al. Lancet 2001;358:9–15.
Symptomatic VTE
Use of prophylaxis in patients undergoing THR: data from the Global Orthopaedic Registry USA (n = 1227) Other (n = 2723)
100 95%
92%
Patients (%)
80
92%
81%
60
62%
57% 40
47%
44%
20 1%
12%
0 LMWH
Warfarin
IPC
ACCP (2001)recommended prophylaxis, in accordance with recommended regimen*
ACCP (2001)recommended prophylaxis
*In accordance with recommended timing, duration, and intensity. Adapted from Friedman RJ et al. Curr Med Res Opin 2008;24;87–97.
IPC, intermittent pneumatic compression.
Use of prophylaxis in patients undergoing TKR: data from the Global Orthopaedic Registry 100
99% 96%
93%
USA (n = 2065) Other (n = 2145)
Patients (%)
80 77% 69%
60
61% 53%
40
39%
20 1%
16%
0 LMWH
Warfarin
IPC and LMWH/warfarin
*In accordance with recommended timing, duration, and intensity Adapted from Friedman RJ et al. Curr Med Res Opin. 2008;24;87–97.
11% 3% IPC alone
ACCP (2001)recommended prophylaxis
ACCP (2001)recommended prophylaxis in accordance with recommended regimen*
IPC, intermittent pneumatic compression.
Anticoagulantia • Alle anticoagulantia houden een bloedingsrisico in Belang van het evenwicht doeltreffendheid - veiligheid
NICE 2007
3 grote Fase III orthopedie-studies
Total VTE and all cause mortality ENOXA 25.3
DABI 150o.d. 33.7
DABI 220 o.d. 31.3
REMOBILIZE (THR ; usa) REMODEL 37.7 40.5 36.4 ( TKR ; eu) RENOVATE 6.7 8.6 6.0 ( THR ; eu) * zo ”clinically relevant major VTE events”: geen verschil
MAJEURE BLOEDINGEN ENOXA
DABI 150
DABI 220
• REMOBILIZE
1.4
0.6
0.6
• REMODEL
1.3
1.3
1.5
• RENOVATE
1.6
1.3
2.0
Efficacy endpoints Primary • Total VTE: any DVT, non-fatal PE and all-cause mortality Secondary • Major VTE: proximal DVT, non-fatal PE and VTE-related death • DVT (any, proximal, distal) • Symptomatic VTE Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86.
All outcomes underwent blind adjudication by an independent committee.
Safety endpoints Main • Major bleeding starting after the first blinded dose and up to 2 days after last dose Other • Any bleeding on treatment* • Non-major bleeding* • Haemorrhagic wound complications* • Cardiovascular adverse events • Liver enzyme levels Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86.
*Up to 2 days after last dose of study medication. All outcomes underwent blind adjudication by an independent committee.
RECORD phase III programme: study design Rivaroxaban 10 mg o.d. was compared with enoxaparin in > 12 000 patients undergoing total hip or knee replacement surgery Rivaroxaban regimen (10 mg o.d.)
Enoxaparin regimen
THR
10 mg o.d.; 5 weeks
40 mg o.d.; 5 weeks
* THR
10 mg o.d.; 5 weeks
40 mg o.d.; 2 weeks†
TKR
10 mg o.d.; 2 weeks
40 mg o.d.; 2 weeks
TKR
10 mg o.d.; 2 weeks
30 mg b.i.d.; 2 weeks
*RECORD2 compared extended-duration (35 ± 4 days) rivaroxaban with short-duration (12 ± 2 days) enoxaparin. In
contrast to the other trials, RECORD2 was a comparison of regimens, rather than a drug versus drug comparison. †Followed by oral placebo for 3 weeks. Data from Eriksson BI et al. N Engl J Med 2008;358:2765–75; Kakkar AK et al. Lancet 2008;372:31–9; Lassen MR et al. N Engl J Med 2008;358:2776–86; Turpie AGG et al. Pathophysiol Haemost Thromb 2007/2008;36:A14.
