Vietata la copia non autorizzata: tutti i diritti del produttore e il materiale sono riservati. Solo per uso privato. Il materiale contenuto in questo file è ad uso esclusivo dei partecipanti al corso ECM residenziale tenutosi il 12 ottobre 2011. Ogni altro uso (uso in pubblico e diffusione) è strettamente proibito senza il permesso esplicito del produttore
Franco PiovellaS.C. ANGIOLOGIA -
MALATTIE TROMBOEMBOLICHEFondazione IRCCS Policlinico San Matteo
Pavia
La Gestione del Tromboembolismo Venoso:La Gestione del Tromboembolismo Venoso:Confronto tra Farmaci Confronto tra Farmaci ““ClassiciClassici””
e Nuove Prospettive Terapeutichee Nuove Prospettive Terapeutiche
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
Tromboembolismo VenosoTromboembolismo Venoso
Il Trattamento del TEV, 2010Il Trattamento del TEV, 2010
UFH (UFH (e.v.e.v., s.c., , s.c., s.c.s.c.
a dosi fisse) a dosi fisse) EBPMEBPMFondaparinuxFondaparinuxTrombolisiTrombolisi
Trattamento a lungo termine
Trattamento esteso
INR 2.0INR 2.0--3.03.0
Antagonisti della vitamina KAntagonisti della vitamina K
INR 2.0INR 2.0--3.0 oppure:3.0 oppure:INR 1.5INR 1.5--1.91.9
≥≥
5 giorni5 giorni almeno tre mesialmeno tre mesi indefinito*indefinito*
* Con rivalutazione del rapporto rischio/beneficio individuale a* Con rivalutazione del rapporto rischio/beneficio individuale ad intervalli periodici d intervalli periodici
Obiettivi del TrattamentoObiettivi del Trattamento
Scopo del trattamento anticoagulante iniziale
Eliminare la generazione di trombinaPrevenire la estensione del tromboPrevenire l’embolia polmonare e le recidive fatali
≥≥
5 giorni5 giorni almeno tre mesialmeno tre mesi indefinito*indefinito*
Trattamento a lungo termine
Trattamento esteso
Obiettivi del TrattamentoObiettivi del Trattamento
Scopo del trattamento anticoagulante a lungo termine
Stabilizzare il tromboPrevenire le recidive precoci
≥≥
5 giorni5 giorni almeno tre mesialmeno tre mesi indefinito*indefinito*
Trattamento a lungo termine
Trattamento esteso
Obiettivi del TrattamentoObiettivi del Trattamento
Scopo del trattamento anticoagulante esteso
Prevenire le recidive tardiveed i nuovi episodi non correlati all’evento iniziale
≥≥
5 giorni5 giorni almeno tre mesialmeno tre mesi indefinito*indefinito*
Trattamento a lungo termine
Trattamento esteso
IIaIIa
XaXa
XIIXII XIIaXIIa
XIXI XIaXIa
Tissue factorTissue factor
IXIX IXaIXa VIIaVIIa VIIVII
VIIIVIII VIIIaVIIIa
XX
VV VaVa
IIII
BersagliBersagli dedei Farmaci Anticoagulantii Farmaci Anticoagulanti
Via Intrinseca(attivazione da contatto)
Via Estrinseca(danno tissutale)
FibrinogenoFibrinogeno FibrinaFibrina
(Trombina)(Trombina)
IIaIIa
XaXa
XIIXII XIIaXIIa
XIXI XIaXIa
Tissue factorTissue factor
IXaIXa VIIaVIIa
VIIIVIII VIIIaVIIIa
VV VaVa
EparinaEparina
IXIX VIIVII
XX
IIII
BersagliBersagli dedei Farmaci Anticoagulantii Farmaci Anticoagulanti
Via Intrinseca(attivazione da contatto)
Via Estrinseca(danno tissutale)
FibrinogenoFibrinogeno FibrinaFibrina
(Trombina)(Trombina)
XIIXII XIIaXIIa
XIXI
Tissue factorTissue factor
IXIX VIIVII
VIIIVIII VIIIaVIIIa
XX
VV VaVa
IIII
EparinaEparina
Antagonisti della Antagonisti della Vitamina KVitamina K
IIaIIa
XaXa
XIaXIa
IXaIXa VIIaVIIa
BersagliBersagli dedei Farmaci Anticoagulantii Farmaci Anticoagulanti
Via Intrinseca(attivazione da contatto)
Via Estrinseca(danno tissutale)
FibrinogenoFibrinogeno FibrinaFibrina
(Trombina)(Trombina)
XIIXII XIIaXIIa
XIXI
Tissue factorTissue factor
IXIX VIIVII
VIIIVIII VIIIaVIIIa
XX
VV VaVa
IIII
Eparine Eparine e LMWHe LMWH
Antagonisti della Antagonisti della Vitamina KVitamina K
IIaIIa
XaXa
XIaXIa
IXaIXa VIIaVIIa
BersagliBersagli dedei Farmaci Anticoagulantii Farmaci Anticoagulanti
Via Intrinseca(attivazione da contatto)
Via Estrinseca(danno tissutale)
FibrinogenoFibrinogeno FibrinaFibrina
(Trombina)(Trombina)
IIaIIa
XIIXII XIIaXIIa
XIXI
Tissue factorTissue factor
IXIX VIIVII
VIIIVIII VIIIaVIIIa
XX
VV VaVa
IIII
Eparine e LMWHEparine e LMWH
Antagonisti della Antagonisti della Vitamina KVitamina K
Inibitori diretti della Inibitori diretti della trombinatrombina IIaIIa
XaXa
XIaXIa
IXaIXa VIIaVIIa
IIa
BersagliBersagli dedei Farmaci Anticoagulantii Farmaci Anticoagulanti
Via Intrinseca(attivazione da contatto)
Via Estrinseca(danno tissutale)
FibrinogenoFibrinogeno FibrinaFibrina
(Trombina)(Trombina)
IIaIIa
Via Intrinseca(attivazione da contatto)
XIIXII XIIaXIIa
XIXI
Tissue factorTissue factor
IXIX VIIVII
VIIIVIII VIIIaVIIIa
Via Estrinseca(danno tissutale)
XX
VV VaVa
IIII
FibrinogenoFibrinogeno FibrinaFibrina
Eparine e LMWHEparine e LMWH
Antagonisti della Antagonisti della Vitamina KVitamina K
Inibitori diretti della Inibitori diretti della TrombinaTrombina
Inibitori del Fattore XaInibitori del Fattore Xa
(Trombina)(Trombina)IIaIIa
XaXa
XIaXIa
IXaIXa VIIaVIIa
IIa
Xa
BersagliBersagli dedei Farmaci Anticoagulantii Farmaci Anticoagulanti
Prevention of DVT in Prevention of DVT in Orthopaedic SurgeryOrthopaedic Surgeryive Hip Replacementive Hip Replacement
--
Data Obtained with VenogrData Obtained with Venogr
Prophylaxis nProphylaxis n°°
of Studies % Tot. DVT RRR, % % Prox. DVT of Studies % Tot. DVT RRR, % % Prox. DVT RRR, %RRR, %(95%C.I.) (95%C.I.) (95%C.I.)(95%C.I.)
Controls (n.t.) 12 54.2 Controls (n.t.) 12 54.2 (50(50--58)58)
--
26.6 26.6 (23(23--31)31)
--
El. StockingsEl. Stockings
44
41.7 41.7 (36(36--48)48)
2323 25.5 25.5 (21(21--31)31)
4 4 AspirinAspirin
66
40.2 40.2 (35(35--45)45)
26 11.4 26 11.4 (8(8--16)16)
5757LD HeparinLD Heparin
1111
30.1 30.1 (27(27--33)33)
4545 19.3 19.3 (17(17--22)22)
2727Warfarin Warfarin 1313
22.1 22.1 (20(20--24)24)
5959
5.2 5.2 (4(4--6)6)
80 80 IPCIPC
77
20.3 20.3 (17(17--24)24)
6363
13.7 13.7 (11(11--17)17)
48 48 Rec. Hirudin Rec. Hirudin 33
16.3 16.3 (14(14--19)19)
7070
4.1 4.1 (3(3--5)5)
8585
DanaparoidDanaparoid 33
15.6 15.6 (12(12--19)19)
71 4.1 71 4.1 (2(2--6)6)
8585AD HeparinAD Heparin
44
14.0 14.0 (10(10--19)19)
7474
10.2 10.2 (7(7--14)14)
6262
ACCP Consensus 2008ACCP Consensus 2008
Prevention of DVT in Prevention of DVT in Orthopaedic SurgeryOrthopaedic Surgeryive Hip Replacementive Hip Replacement
--
Data Obtained with VenogrData Obtained with Venogr
Prophylaxis nProphylaxis n°°
of Studies % Tot. DVT RRR, % % Prox. DVT of Studies % Tot. DVT RRR, % % Prox. DVT RRR, %RRR, %(95%C.I.) (95%C.I.) (95%C.I.)(95%C.I.)
Controls (n.t.) 12 54.2 Controls (n.t.) 12 54.2 (50(50--58)58)
--
26.6 26.6 (23(23--31)31)
--
El. StockingsEl. Stockings
44
41.7 41.7 (36(36--48)48)
2323 25.5 25.5 (21(21--31)31)
4 4 AspirinAspirin
66
40.2 40.2 (35(35--45)45)
26 11.4 26 11.4 (8(8--16)16)
5757LD HeparinLD Heparin
1111
30.1 30.1 (27(27--33)33)
4545 19.3 19.3 (17(17--22)22)
2727Warfarin Warfarin 1313
22.1 22.1 (20(20--24)24)
5959
5.2 5.2 (4(4--6)6)
80 80 IPCIPC
77
20.3 20.3 (17(17--24)24)
6363
13.7 13.7 (11(11--17)17)
48 48 Rec. Hirudin Rec. Hirudin 33
16.3 16.3 (14(14--19)19)
7070
4.1 4.1 (3(3--5)5)
8585
DanaparoidDanaparoid 33
15.6 15.6 (12(12--19)19)
71 4.1 71 4.1 (2(2--6)6)
8585AD HeparinAD Heparin
44
14.0 14.0 (10(10--19)19)
7474
10.2 10.2 (7(7--14)14)
6262
LMWHLMWH 3030 16.1 16.1 (15(15--17)17) 70 5.9 70 5.9 (5(5--7)7) 7878
ACCP Consensus 2008ACCP Consensus 2008
LL’’EPARINA A BASSO PESO MOLECOLARE NEL EPARINA A BASSO PESO MOLECOLARE NEL TRATTAMENTO DELLA TROMBOSI VENOSA PROFONDATRATTAMENTO DELLA TROMBOSI VENOSA PROFONDA
UFH (n)
LMWH (n) p 95% C.I.
PrandoniPrandoni
etet
al. al. 14% (85) 14% (85) 7% (85)7% (85)
p=0.13p=0.13
--0.30.3--15%15%19921992EmorrEmorr. Maggiori. Maggiori 3.5%3.5% 0.1%0.1% p>0.2p>0.2
HullHull
etet
al.al.
6.9% (219)6.9% (219)
2.8% (213)2.8% (213)
p<0.05p<0.05
0.020.02--8.1%8.1%19921992EmorrEmorr. Maggiori. Maggiori 5% 5% 0.5%0.5% p=0.006p=0.006
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
KoopmanKoopman MMW, MMW, PrandoniPrandoni P, Piovella F, P, Piovella F, etet al.al.
Treatment Treatment ofof venousvenous thrombosisthrombosis withwith intravenousintravenous unfractionatedunfractionated heparinheparin administeredadministered in the hospital in the hospital asas comparedcompared withwith subcutaneoussubcutaneous lowlow--molecularmolecular--weightweight
heparinheparin administeredadministered at homeat homeTasman Tasman StudyStudy
N N EnglEngl J J MedMed 1996;334:6821996;334:682--77
LevineLevine M, Gent M, M, Gent M, HirshHirsh J, J, etet al.al.
A A comparisoncomparison ofof lowlow--molecularmolecular--weightweight heparinheparin administeredadministered primarilyprimarily at homeat home withwith unfractionatedunfractionated heparinheparin administeredadministered in the hospital in the hospital forfor proximalproximal
deepdeep--veinvein thrombosisthrombosisCanadian Canadian StudyStudy
N N EnglEngl J J MedMed 1996;334:6771996;334:677--8181
Home treatment of DVT with Home treatment of DVT with LMWHsLMWHs is as effective and safe is as effective and safe as inas in--hospital UFHhospital UFH
% VTE recurrence% VTE recurrence Major bleedingMajor bleeding Overall mortalityOverall mortality
NadroparinNadroparin
UFHUFH6.9%6.9%8.6%8.6%
0.5%0.5%2.0%2.0%
6.9%6.9%8.1%8.1%
Koopman MWM, Prandoni P, Piovella F., et al. Koopman MWM, Prandoni P, Piovella F., et al. N Engl J MedN Engl J Med 1996;334:6821996;334:682––7.7.
The TASMAN study
The Columbus The Columbus InvestigatorsInvestigators
LowLow--molecularmolecular--weightweight heparinheparin in the treatment in the treatment ofof patientspatients withwith venousvenous thromboembolismthromboembolism
Columbus Columbus StudyStudyN N EnglEngl J J MedMed 1997;337:6571997;337:657--6262
SimonneauSimonneau G, G, SorsSors H, H, CharbonnierCharbonnier B, B, etet al.al.
A A comparisoncomparison ofof lowlow--molecularmolecular--weightweight heparinheparin withwith unfractionatedunfractionated heparinheparin forfor acute acute pulmonarypulmonary
embolismembolismThThééssééee StudyStudy
N N EnglEngl J J MedMed 1997;337:6631997;337:663--99
COLUMBUS and THCOLUMBUS and THÉÉSSÉÉE studies. E studies. Main resultsMain results
COLUMBUSCOLUMBUS THTHÉÉSSÉÉEE
LMWH
UFH LMWH UFH(n=510) (n=511) (n=304) (n=308)
Recurrent VTERecurrent VTE 27 (5.3%) 25 (4.9%) 5 (1.6%) 6 (1.9%)
Major bleedingMajor bleeding 16 (3.1%) 12 (2.3%) 6 (2.0%) 8 (2.6%)
MortalityMortality
36 (7.1%) 39 (7.6%) 12 (3.9%) 14 (4.5%)
Columbus Columbus StudyStudyN N EnglEngl J J MedMed 1997;337:6571997;337:657--6262
ThThéésséée Studye StudyN Engl J Med 1997;337:663N Engl J Med 1997;337:663--99
Low Molecular Unfractionated Odds Ratio
Weight Heparin
Heparin
(95% CI)Deep Vein TrombosisDeep Vein TrombosisRecurrent VTE
86/1998 (4.3%)
113/2021 (5.6%)
0.75(0.55-1.01)
Major bleeding
30/2353 (1.3%)
51/2401 (2.1%) 0.60(0.39-0.93)
Mortality
135/2108 (6.4%)
172/2137 (8.0%)
0.78(0.62-0.99)
Pulmonary EmbolismPulmonary EmbolismRecurrent VTE
30/988 (3.0%)
39/895 (4.4%)
0.68(0.42-1.09)
Major bleeding
14/1023 (1.4%)
21/928 (2.3%) 0.67(0.36-1.27)
Mortality
46/988 (4.7%)
55/895 (6.1%) 0.77(0.52-1.15)
Recurrent symptomatic VTE, major bleeding and mortality at threeRecurrent symptomatic VTE, major bleeding and mortality at three months months –– summary of two metasummary of two meta--analyses in deep vein thrombosis analyses in deep vein thrombosis
and pulmonary embolism and pulmonary embolism ––
A. van den Belt et al. 2002, The Cochrane LibraryA. van den Belt et al. 2002, The Cochrane LibraryD. Quinlan et al. 2004, Ann Intern MedD. Quinlan et al. 2004, Ann Intern Med
Anticoagulants in DevelopmentAnticoagulants in Development
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
Adapted from Bates Adapted from Bates Br J HaematolBr J Haematol 20062006
TTP889
TFPI (tifacogin)NAPc2
OralRivaroxabanApixabanEdoxabanBetrixabanYM150
ParenteralFondaparinuxIdraparinuxBiotinylated idraparinux
OralDabigatran
APC (drotrecogin alfa)sTM (ART-123)
Fondaparinux Fondaparinux
DescriptionDescription
* fully synthetic* fully synthetic
* potent and indirect selective Xa inhibitor* potent and indirect selective Xa inhibitor
Clinical evaluationClinical evaluation
* prevention VTE after orthopaedic surgery* prevention VTE after orthopaedic surgery
* treatment of established VTE* treatment of established VTE
* treatment of acute coronary syndromes* treatment of acute coronary syndromes
factor Xa
AT
ArgArgLys
Pentasaccharide sequence
Long chains capture other factors as thrombin
thrombin
HeparinsHeparins
trombina
factor Xa
FondaparinuxFondaparinux
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
EPHESUSN = 1817
PENTATHLON 2000N = 1584
PENTHIFRAN = 1250
PENTAMAKSN = 724
Overall odds reduction
% odds reduction
Fondaparinux meglio Enoxaparina meglio
-100 -80 -60 -40 -20 200 40 60 80 100
58.5%
28.1%
61.6%
63.1%
55.3%
[72.9; 37.5]
[52.2; 7.6]
[73.4; 45.0]
[75.5; 44.8]
[63.2; 45.8]
Exact 95% CI
P = 10 P = 10 --1717
Anca
Anca
Frattura
Ginocchio
ChirurgiaChirurgia
OrtopedicaOrtopedica
MaggioreMaggiore
AncaAnca
PENTATHLON 2000 (N.A.)PENTATHLON 2000 (N.A.)GinocchioGinocchio
PENTAMAKS (N.A.)PENTAMAKS (N.A.)AncaAnca
EPHESUS (EU)EPHESUS (EU)FratturaFrattura
PENTHIFRA (EU)PENTHIFRA (EU)
Il Fondaparinux nella Il Fondaparinux nella prevenzione del TEV in prevenzione del TEV in chirurgia ortopedicachirurgia ortopedica Studi di fase III Studi di fase III -- efficaciaefficacia
LineeLinee guidaguida ACCPACCP
•
Ai pazienti
sottoposti
ad artroprotesi
elettiva
d’anca
o di
ginocchio dovrebbe
essere
prescritta
una
delle
seguenti
profilassi:
— LMWH (grado 1A)—— FondaparinuxFondaparinux ((gradogrado 1A)1A)— AVK con target INR = 2.5 (grado 1A)
•
Patients undergoing hip fracture surgery should receive either:
—— FondaparinuxFondaparinux ((gradogrado 1A)1A)— LMWH (grado 1C+)— AVK con target INR = 2.5 (grado 2B)— Eparina NF a basse dosi (grado 1B)
••
ProfilassiProfilassi
antitromboticaantitrombotica
per per almenoalmeno
10 10 giornigiorni
((gradogrado
1A), 1A), estesaestesa
a a 2828--35 35 giornigiorni
per per protesiprotesi
dd’’ancaanca
e e chirurgiachirurgia
per per fratturafrattura
dd’’ancaanca
Chest Chest 2004; 126 (3 2004; 126 (3 SupplSuppl): 163S): 163S--696S696S
Seventh ACCP Conference on Antithrombotic Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapyand Thrombolytic Therapy
GliGli StudiStudi MatisseMatisse
Outcome Outcome PrimarioPrimario didi EfficaciaEfficacia
Fondaparinux
(n=1,098) LMWH (n=1,107)MATISSE DVT2
EP fatale 5 (0.5%) 5 (0.5%) EP non fatale o TVP 38 (3.5%) 40 (3.6%)Recidive
di
TEV totali
sintomatiche
43 (3.9%) 45 (4.1%)
-0.15% Δ=3.5%0 1.5%-1.8%
Fondaparinux
-
LMWH (95% CI)
Fondaparinux
(n=1,103) UFH (n=1,110)
Fondaparinux
-
UFH (95% CI)
MATISSE PE1
-1.2% Δ=3.5%0 0.5%-3.0%
EP fatale 16 (1.5%) 15 (1.4%) EP non fatale o TVP 26 (2.4%) 41 (3.6%)Recidive
di
TEV totali
sintomatiche
42 (3.8%) 56 (5.0%)
1. The Matisse Investigators. N Engl J Med, 2003.2. The Matisse Investigators. Ann Intern Med, 2004
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
MATISSEMATISSE
DVTDVT22
FondaparinuxFondaparinux
LMWHLMWH 1.2%1.2%
1.1%1.1%
3.0%3.0%
2.6%2.6%
0% 2% 4% 6% 8%
3.7%3.7%
Outcome Outcome PrimarioPrimario didi SicurezzaSicurezza:: TrattamentoTrattamento InizialeIniziale
EmorrEmorr. . maggioremaggiore
EmorrEmorr. non. non--maggioremaggiore, , clinicamenteclinicamente
rilevanterilevante
FondaparinuxFondaparinux
UFHUFH
MATISSEMATISSE
PEPE11
1.1%1.1%
1.3%1.3%
5.2%5.2%
3.2%3.2%
0% 2% 4% 6% 8%
4.5 %4.5 %
6.3 %6.3 %
1. The Matisse Investigators. 1. The Matisse Investigators. N N EnglEngl J Med, J Med, 200320032. The Matisse Investigators. 2. The Matisse Investigators. Ann Intern Med, Ann Intern Med, 20042004
4.2%4.2%
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
Vitamin K antagonist (INR 2.0 Vitamin K antagonist (INR 2.0 --
3.0)3.0)
>
3 months
LMWH or LMWH or FondaparinuxFondaparinux
or UFH or UFH
5 to 7 daysInitial treatment
Long-term therapy
Treatment of VTETreatment of VTE
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
DecoususDecousus H, H, PrandoniPrandoni P, P, MismettiMismetti P, et al.P, et al.
FondaparinuxFondaparinux for the treatment of for the treatment of Superficial Vein ThrombosisSuperficial Vein Thrombosis
N N EnglEngl J J MedMed 2010; 363: 12222010; 363: 1222--32 32
Study Design
Randomization
Day 45±2
Fondaparinux 2.5 mg od
n=1501
Placebon=1501
Day 75±2
Double-blind
treatment during
45 days
Primary Efficacy Outcome: Symptomatic Thromboembolic
Complications/Death
Elastic stockings,topical NSAIDs and pain killers allowed
Follow-up
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
Primary Efficacy Outcome (Day 47)
0
1
2
3
4
5
6
7
Fondaparinux
2.5 mg Placebo
Sym
ptom
atic
Thr
ombo
embo
licC
ompl
icat
ions/
Dea
th (%
)
0.9% n=13
5.9% n=88
RRR 85.2%(95% CI= 73.7 to 91.7)
p<0.001
Primary efficacy outcome: Symptomatic PE, DVT, Extension of the initial SVT, Recurrent SVT, All-cause death
Conclusion
•
Once-daily fondaparinux
2.5 mg for 45 days is effective, well tolerated and widely applicable for the treatment of patients with symptomatic lower-limb SVT without concomitant DVT/PE at inclusion
•
The benefit of fondaparinux
persists beyond the end of treatment
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
POTENTIAL VTE MANAGEMENT LANDSCAPEPOTENTIAL VTE MANAGEMENT LANDSCAPE
Agent Half life (hrs)
Bioavailability Elimination Dosing/Class Prodrug Antidote
IDRA(biota)PARINUX 80-130 100% renal once weeklys.c. indirect aXa
No Yes
DABIGATRAN 14-17 5% 80% renal q.d. oraldirect T.I.
Yes No
RIVAROXABAN 5-13 >80% 1/3 renal2/3 hepatic
b.i.d./q.d. oraldirect aXa
No No
APIXABAN 8-15 50%-85%(in canine)
25% renal70% hepatic
b.i.d. oraldirect aXa
No No
EDOXABAN 7-14 NA 1/3 renal2/3 hepatic
q.d. oraldirect aXa
No No
New drugs. New regimens. Why?New drugs. New regimens. Why?
••
Warfarin is the most commonly used oral anticoagulant, but Warfarin is the most commonly used oral anticoagulant, but problems with both low and high international normalized ratios problems with both low and high international normalized ratios ((INRsINRs) and issues with adherence have been reported.) and issues with adherence have been reported.
••
Warfarin is the Warfarin is the second most common drug, after insulin, second most common drug, after insulin, implicated in adverse events (AE) treated in emergency implicated in adverse events (AE) treated in emergency departmentsdepartments, representing an estimated 6.2% of annual AE , representing an estimated 6.2% of annual AE cases, insulin representing 8cases, insulin representing 8%.%.
BudnitzBudnitz DS, DS, etet al.al. J Am Med Assoc 2006; 296: 1858J Am Med Assoc 2006; 296: 1858––1866.1866.
••
In addition, the Food and Drug Administration (FDA) has In addition, the Food and Drug Administration (FDA) has recently requested a label update to upgrade the warning of the recently requested a label update to upgrade the warning of the risk of major or fatal bleeding in patients receiving warfarin, risk of major or fatal bleeding in patients receiving warfarin, to a to a blackblack--box box warningwarning
U.S. Food and Drug Administration. 2006 Safety alerts for drugs,U.S. Food and Drug Administration. 2006 Safety alerts for drugs, biologics, medical devices, and dietary biologics, medical devices, and dietary supplementssupplements. . OctoberOctober 6, 2006. 6, 2006. AvailableAvailable at: http://www.fda.gov/at: http://www.fda.gov/medwatchmedwatch//safetysafety/2006/safety06./2006/safety06.
New drugs. New regimens. Why?New drugs. New regimens. Why?
•
The anticoagulant effect of warfarin appears to be affected by interactions with at least 120 foods and drugs
Holbrook AM, et al. Arch Intern MedHolbrook AM, et al. Arch Intern Med2005; 165: 10 952005; 165: 10 95––1106.1106.
••
A number of new anticoagulant agents are A number of new anticoagulant agents are under investigation or have recently been under investigation or have recently been approved, some of which reduce the problems approved, some of which reduce the problems with outwith out--ofof--range range INRsINRs, and may also offer , and may also offer improved improved pharmacodynamicpharmacodynamic propertiesproperties..
The ideal anticoagulant The ideal anticoagulant
IDEAL
No accumulation
if renal
impairment
No thrombo-
cytopenia
Nofood/druginteractions
No routine
coagulation monitoring
Predictable
response
Rapid
onset/
offset
Fixed dosing
Oral
Fondaparinux
Warfarin
Heparin
LMWH
...versus currently available agents...versus currently available agents
Anticoagulants in DevelopmentAnticoagulants in Development
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
Adapted from Bates Br J Haematol 2006
TTP889
TFPI (tifacogin)NAPc2
OralRivaroxabanApixabanEdoxabanBetrixabanYM150
ParenteralFondaparinuxIdraparinuxBiotinylated
idraparinux
OralDabigatran
APC (drotrecogin
alfa)sTM
(ART-123)
DABIGATRAN ETEXILATE (DABIGATRAN ETEXILATE (PradaxaPradaxa®®))
Dabigatran
etexilate
is an oral direct thrombin inhibitor exhibiting:
Predictable anticoagulant effect1-3
Fixed dose:-
No adjustment to body weight etc.
Acts on clot bound and free thrombinFast onset and offset
1. Eriksson BI et al. Journal of Thrombosis and Haemostasis 2004; 2: 1573–1580 2. Eriksson BI et al. Journal of Thrombosis and Haemostasis 2005; 3: 103–111
3. Wallentin
L et
al. European Heart Journal 2005; 26(suppl): 482. 4. Stassen JM et al. 28th Congress of the International Society on Thrombosis and Haemostasis; Paris July 6-12, 2001 5. Hauel
NH et al. J Med Chem2002; 45:1757-66
Dabigatran
etexilate
is the pro-drug of the active compound dabigatran, which binds directly to thrombin with a high affinity and specificity4-5
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
RERE--VOLUTION VOLUTION -- Trial Program OverviewTrial Program Overview
More than 36,000 patients involvedMore than 36,000 patients involvedMalattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
DabigatranDabigatran Clinical Program: REVOLUTIONClinical Program: REVOLUTION Phase III Studies in VTE Prophylaxis After THR/TKRPhase III Studies in VTE Prophylaxis After THR/TKR
Start evening before surgery* or12-24 hours post-operatively#
Start 1-4 hours* or6-12 hours# post-operatively
Enoxaparin40 mg QD* OR 30 mg BID #
Dabigatran etexilate75 / 150 mg QD
VenographyWithin 12 hours of last dose
Follow-up12–14 weeks
*RE-MODEL and RE-NOVATE #RE-MOBILIZE
Design:
Non-Inferiority in Modified Intention-To-Treat Population
R
Dabigatran etexilate110 / 220 mg QD
StudyTherapy Duration
Enoxaparin
Dose (mg)
RE-MODEL KneeKnee 6-10 days 40 QD
RE-NOVATE HipHip 28-35 days 40 QD
RE-MOBILIZE KneeKnee 12-15 days 30 BID
Eriksson Eriksson et al J et al J ThrombThromb HaemostHaemost 2007; Eriksson 2007; Eriksson et al Lancetet al Lancet 2007; 2007; Ginsberg Ginsberg et al J et al J ArthroplastArthroplast.. 2008 2008
Eriksson BI, Dahl OE, Eriksson BI, Dahl OE, RosencherRosencher
N, N, KurthKurth
AA, van AA, van DijkDijk
CN, CN, FrostickFrostick
SP, SP, PrinsPrins
MH, MH, HettiarachchiHettiarachchi
R, R, HantelHantel
S, S, SchneeSchnee
J, J, BBüüllerller
HR; REHR; RE--NOVATE Study GroupNOVATE Study Group
Lancet 2007; 370:949Lancet 2007; 370:949--56.56.
DabigatranDabigatran
etexilateetexilate
versus versus enoxaparinenoxaparin
for prevention of for prevention of venous venous thromboembolismthromboembolism
after after total hip replacementtotal hip replacement::
a randomised, doublea randomised, double--blind, nonblind, non--inferiority trial.inferiority trial.
Primary Efficacy OutcomePrimary Efficacy Outcome
EndpointDabigatran etexilate
EnoxaparinN=897
220 mgN= 880
150 mgN=874
Total VTE and all cause mortality - % 6.0 8.6 6.7
Absolute Difference versus Enoxaparin - % (95% CI) -0.7 (-2.9, 1.6) 1.9 (-1.6, 4.4) -
P-value for non-inferiority <0.05 <0.05
Eriksson BI et al. Lancet 2007;370:949-56
Bleeding OutcomesBleeding Outcomes
End pointDabigatran etexilate
Enoxaparin N=1122220 mg
N= 1116150 mgN=1123
Major Bleeding (%) 2.0 1.3 1.6
Major Bleeding Plus Clinically Relevant Bleeding (%) 6.2 6.0 5.0
Any Bleeding (%) 12.3 12.2 11.4
Eriksson BI et al. Lancet 2007;370:949-56
Eriksson BI, Dahl OE, Eriksson BI, Dahl OE, RosencherRosencher
N, N, KurthKurth
AA, van AA, van DijkDijk
CN, CN, FrostickFrostick
SP, SP, KKäälebolebo
P, P, Christiansen AV, Christiansen AV, HantelHantel
S, S, HettiarachchiHettiarachchi
R, R, SchneeSchnee
J, J, BBüüllerller
HR; REHR; RE--MODEL Study Group. MODEL Study Group.
J J ThrombThromb
HaemostHaemost. 2007; 5:2175. 2007; 5:2175--77
Oral Oral dabigatrandabigatran
etexilateetexilate
vs. subcutaneous vs. subcutaneous enoxaparinenoxaparin for the prevention for the prevention ofvenousofvenous
thromboembolismthromboembolism
after after total total
knee replacementknee replacement: the RE: the RE--MODEL randomized trial.MODEL randomized trial.
Primary Efficacy OutcomePrimary Efficacy Outcome
Dabigatran etexilate
EnoxaparinN=512
220 mgN= 503
150 mgN=526
Total VTE and all cause mortality - % 36.4 40.5 37.7
Absolute Difference versus Enoxaparin - % (95% CI) -1.3 (-7.3, 4.6) 2.8 (-3.1, 8.7) -
P-value for non-inferiority <0.05 <0.05
Eriksson BI et al. J Thromb
Haemost
2007; 5:2175-7
Bleeding OutcomesBleeding Outcomes
*No fatal bleeding, one critical organ bleed in each of the dabigatran
dose groups
End pointDabigatran etexilate (%)
Enoxaparin (%)N=694220 mg
N= 679150 mgN=703
Major Bleeding* 1.5 1.3 1.3
Major Bleeding Plus Clinically Relevant Bleeding 7.4 7.1 6.6
Any Bleeding 16.2 16.5 16.6
Eriksson BI et al. J Thromb
Haemost
2007; 5:2175-7
Conclusions Conclusions
•
Both doses of dabigatran
proved efficacious and comparable to enoxaparin
for the prevention of major VTE
in orthopedic surgery.
•
Showed a low rate of bleeding, comparable with enoxaparin
•
Showed no difference in ACS events or liver enzyme changes in either of the dabigatran
etexilate
doses
compared to enoxaparin
•
Offered fixed oral dosing without coagulation monitoring
Results of RE-NOVATE and RERE--MODELMODEL:
Schulman
S, Kearon
C, Kakkar
AK et
al N Engl
J Med. 2009; 361: 2342-52
Efficacy
Endpoints
2.4%30/1274 2.1%
27/1265
0
2
4
6
8
10
VTE
DabigatranWarfarin
DabigatranDabigatran versus Warfarin in the Treatment versus Warfarin in the Treatment ofof Acute Acute VenousVenous ThromboembolismThromboembolism
The Re-Cover Study
DabigatranDabigatran versus Warfarin in the Treatment versus Warfarin in the Treatment ofof Acute Acute VenousVenous ThromboembolismThromboembolism
1.6%(20/1274)
1.9%(24/1265)
16.1%(205/1274)
21.9%(277/1274)
0
5
10
15
20
25
Majorbleedings
Any
bleeding
DabigatranWarfarin
Schulman
S, Kearon
C, Kakkar
AK et
al. N Engl
J Med. 2009; 361: 2342-52
Safety
Endpoints
The Re-Cover Study
RivaroxabanRivaroxaban ((XareltoXarelto®®))
••
OralOral••
Direct, specific, competitive Direct, specific, competitive FXaFXa
inhibitor inhibitor
••
Inhibits free and fibrinInhibits free and fibrin-- bound bound FXaFXa
activity, and activity, and
prothrombinaseprothrombinase
activityactivity••
Effective anticoagulant Effective anticoagulant
••
Inhibits thrombin generation Inhibits thrombin generation ––
acts earlier in the acts earlier in the
coagulation cascadecoagulation cascade••
No direct effect on platelet No direct effect on platelet aggregation aggregation
••
Effects can potentially be Effects can potentially be reversed by recombinant reversed by recombinant Factor Factor VIIaVIIa, if required, if required
N N ONH
O
SCl
O
O
O RivaroxabanN N O
NH
O
SCl
O
O
O RivaroxabanN N O
NH
O
SCl
O
O
O Rivaroxaban
PerzbornPerzborn
et al., et al., J J ThrombThromb HaemostHaemost 2005; 2005; PathophysiolPathophysiol HaemostHaemost ThrombThromb 2004; 2004; DepasseDepasse
et alet al., ., J J ThrombThromb HameostHameost 2005;2005;KubitzaKubitza
et alet al.,.,
ClinClin PharmacolPharmacol TherTher 2005;2005;
Br J Br J ClinClin PharmacolPharmacol 2007;2007;
EurEur J J ClinClin PharmacolPharmacol 2005; Graff 2005; Graff et al.et al., , J J ClinClin PharmacolPharmacol 2007; 2007; FareedFareed
et al.et al., , J J ThrombThromb HaemostHaemost 2005; 2005; TinelTinel
et al.et al., , BloodBlood 20062006
Clinical programme overview: Clinical programme overview: 50,000 patients to be enrolled50,000 patients to be enrolled
Phase II Phase III VTE prevention after major orthopaedic surgery
•
ODIXa-HIP1 •
ODIXa-HIP2•
ODIXa-KNEE•
ODIXa-OD-HIP•
RECORD1 •
RECORD2•
RECORD3 •
RECORD4VTE prevention in hospitalized medically ill patientsVTE treatment •
ODIXa-DVT•
EINSTEIN-DVT •
EINSTEIN-DVT •
EINSTEIN-PE•
EINSTEIN-EXTStroke prevention in atrial
fibrillation Japanese Phase III study Secondary prevention of acute coronary syndromes
Enoxaparin
Rivaroxaban
10 mg QD
RECORD: RECORD: RivaroxabanRivaroxaban Phase III Studies in Phase III Studies in VTE Prophylaxis After THR/TKRVTE Prophylaxis After THR/TKR
Study
Therapy Duration (weeks) Enoxaparin
Dose (mg)Rivaroxaban Enoxaparin
RECORD1 Hip 5 5 40 QD
RECORD2 Hip 5 2‡ 40 QD
RECORD3 Knee 2 2 40 QD
RECORD4 Knee 2 2 30 BID
Mandatorybilateral
venographyR
SURGERY
FOLLOWUP
6–8 hours post-surgery
Day 1 Last dose, day before venography
*RECORD1, 2 and 3 #RECORD4 12–24 hours post-surgery‡followed by oral placebo for 3 weeks
Evening before surgery*Or 12–24 hours post-surgery#
Eriksson et al. New Engl J Med 2008; Kakkar
et al. Lancet 2008; Lassen
et al. New Engl J Med 2008; Turpie
EFORT
2008
DESIGN:
RECORD 1, 3, and 4
Non-Inferiority in per-protocol populationSuperiority in modified intention-to-treat population
RECORD 2
Superiority in modified intention-to-treat population
RECORD3 RECORD4 RECORD1
Primary Efficacy Outcome: Total VTE or AllPrimary Efficacy Outcome: Total VTE or All-- Cause MortalityCause Mortality
(Hip)(Knee)
RRR = 49%ARD = –9.2% (–12.4, –5.9)
p<0.001
RivaroxabanEnoxaparin
RRR = 31%ARD = –3.19% (–5.67, –0.71)
p<0.012
RRR = 78%ARD = –7.3% (–9.4, –5.2)
p<0.0001
Relative Risk Reduction (RRR) based on raw incidencesAbsolute Risk Difference (ARD) (95% CI)
Lassen
et al. New Engl J Med 2008; Turpie
EFORT
2008Kakkar
et al. Lancet 2008; Eriksson et al. New Engl J Med 2008
RECORD2
RRR = 70%ARD = –2.6% (–3.7, –1.5)
p<0.001
RivaroxabanRivaroxaban for the treatment of for the treatment of venous venous thromboembolismthromboembolism
58
EINSTEIN DVT: study designEINSTEIN DVT: study design
EINSTEIN DVT trial ID: NCT00440193
Randomized, open-label, event-driven, non-inferiority study Up to 48 hours’ heparins/fondaparinux treatment permitted before study entry88 primary efficacy outcomes needed
15 mg bidConfirmed
symptomatic DVT without symptomatic
PE
N=3,449Rivaroxaban
Day 1 Day 21
Enoxaparin 1.0 mg/kg bid ≥5 days, followed by
VKA INR range 2–3
Treatment period: 3, 6 or 12 months
20 mg od
Rivaroxaban
R
30-d
ay o
bser
vatio
n
pe
riod
Study outcomes Study outcomes
Primary efficacy outcome*•
Symptomatic recurrent VTE: composite of recurrent DVT, non-fatal PE or fatal PE
Principal safety outcome*•
Combination of major and clinically relevant non-major bleeding
Secondary and other outcomes* including:•
Net clinical benefit: primary efficacy outcome + major bleeding
•
Total mortality•
Cardiovascular events
Central laboratory•
Monthly ALT and bilirubin testing
*Adjudicated by the central independent and blinded adjudication
committee
Primary efficacy outcome analysisPrimary efficacy outcome analysis
ITT population; *non-inferiority
margin
required
for
standalone
non-inferiority
Rivaroxaban Rivaroxaban (n=1,731)(n=1,731)
Enoxaparin/VKAEnoxaparin/VKA (n=1,718)(n=1,718)
nn (%)(%) nn (%)(%)First symptomatic recurrent VTEFirst symptomatic recurrent VTE 3636 (2.1)(2.1) 5151 (3.0)(3.0)
Recurrent DVTRecurrent DVT 1414 (0.8)(0.8) 2828 (1.6)(1.6)Recurrent DVT + PERecurrent DVT + PE 11 (<0.1)(<0.1) 00 (0)(0)NonNon--fatal PEfatal PE 2020 (1.2)(1.2) 1818 (1.0)(1.0)Fatal PE/unexplained death whereFatal PE/unexplained death where
PE cannot be ruled outPE cannot be ruled out44 (0.2)(0.2) 66 (0.3)(0.3)
1.75*1 0
0.44 1.040.68
Hazard ratio
Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferiorp=0.076 for superiority (two-sided) p<0.0001
for non-inferiority
(one-sided)
Primary efficacy outcome: time to first eventPrimary efficacy outcome: time to first eventC
umul
ativ
e ev
ent r
ate
(%)
0 30 60 90 120 150 180 210 240 270 300 330 3600
1.0
2.0
3.0
Number of subjects at riskRivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1,220 400 369 363 345 309 266
Enox/VKA 1,718 1,616 1,581 1,553 1,368 1,358 1,186 380 362 337 325 297 264
Rivaroxaban (n=1,731)
Enoxaparin/VKA (n=1,718)4.0
Time to event (days)
RivaroxabanRivaroxaban (n=1,718)(n=1,718)
Enox/VKA Enox/VKA (n=1,711)(n=1,711) HR (95% CI)HR (95% CI)
nn (%)(%) nn (%)(%) pp valuevalueFirst major or clinically relevant First major or clinically relevant nonnon--major bleedingmajor bleeding
139139 (8.1)(8.1) 138138 (8.1)(8.1) 0.97 (0.760.97 (0.76––1.22) 1.22) pp=0.77=0.77
Major bleedingMajor bleeding 1414 ((0.80.8)) 2020 (1.2)(1.2)
Contributing to deathContributing to death 11 (<0.1)(<0.1) 55 (0.3)(0.3)
In a critical siteIn a critical site 33 (0.2)(0.2) 33 (0.2)(0.2)
Associated with fall in Hb Associated with fall in Hb ≥≥2 g/dl 2 g/dl and/or transfusion of and/or transfusion of ≥≥2 units2 units 1010 (0.6)(0.6) 1212 (0.7)(0.7)
Clinically relevant nonClinically relevant non--major bleedingmajor bleeding 129129 (7.5)(7.5) 122122 (7.1)(7.1)
Principal safety outcome analysisPrincipal safety outcome analysis
Safety population
RERE--LYLY –– study designstudy design
Atrial
fibrillation with ≥
1 risk factorAbsence of contraindications
R
Warfarin1 mg, 3 mg, 5 mg
(INR 2.0-3.0)N=6000
Dabigatran
etexilate110 mg bid
N=6000
Dabigatran
etexilate150 mg bid
N=6000
Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin
Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
RR 0.66 (95% CI: 0.53–0.82)p<0.001 (sup)
1,53
1,11
1,69
0
0,3
0,6
0,9
1,2
1,5
1,8
D110 mg BID D150 mg BID Warfarin
RR 0.91 (95% CI: 0.74–1.11)p<0.001 (NI)
% p
er y
ear
182 / 6,015 134 / 6,076 199 / 6,022
RRR34%
Stroke or systemic embolism (SSE)Stroke or systemic embolism (SSE)
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
Major bleeding ratesMajor bleeding rates
RR 0.93 (95% CI: 0.81–1.07)p=0.31 (NI)
2,71
3,113,36
0,00
0,50
1,00
1,50
2,00
2,50
3,00
3,50
D110 mg BID D150 mg BID Warfarin
RR 0.80 (95% CI: 0.69–0.93)p=0.003 (sup)
322 / 6,015 375 / 6,076 397 / 6,022
RRR20%
% p
er y
ear
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
RR 0.26 (95% CI: 0.14–0.49)p<0.001 (sup)
Hemorrhagic strokeHemorrhagic stroke
RR 0.31 (95% CI: 0.17–0.56)p<0.001 (sup)
Num
ber o
f eve
nts
6,015 6,076 6,022
14 12
45
0
10
20
30
40
50
D110 mg BID D150 mg BID Warfarin
0.10%0.10%
0.38%0.38%RRR69%
RRR74%
0.12%0.12%
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
ConclusionsConclusions
•
Dabigatran etexilate has shown to concurrently reduce both thrombotic and hemorrhagic events
•
Both doses of dabigatran provide different and complementary advantages over warfarin
•
150 mg BID has superior efficacy with similar bleeding
•
110 mg BID has significantly less bleedings with similar efficacy
•
Similar net clinical benefit was seen between the two dabigatran doses
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
Stroke Prevention Using the Oral Direct Factor Xa Stroke Prevention Using the Oral Direct Factor Xa inhibitor Rivaroxaban Compared with Warfarin in inhibitor Rivaroxaban Compared with Warfarin in Patients with Nonvalvular Atrial Fibrillation Patients with Nonvalvular Atrial Fibrillation (ROCKET AF) (ROCKET AF)
AHA Chicago, November 15, 2010 AHA Chicago, November 15, 2010
p<0.015 (sup)
1,70
2,15
0
0,3
0,6
0,9
1,2
1,5
1,8
2,1
2,4
Riva 20 mg Warfarin
% p
er y
ear
Rocket Study Rocket Study –– Per ProtocolPer Protocol PopulationPopulationStroke or systemic embolism (SSE)Stroke or systemic embolism (SSE)
AHA Chicago, November 15, 2010 AHA Chicago, November 15, 2010
p<0.001 (non inf)
2,12
2,42
0
0,3
0,6
0,9
1,2
1,5
1,8
2,1
2,4
Riva 20 mg Warfarin
% p
er y
ear
Rocket Study Rocket Study –– Intention To TreatIntention To Treat PopulationPopulationStroke or systemic embolism (SSE)Stroke or systemic embolism (SSE)
AHA Chicago, November 15, 2010 AHA Chicago, November 15, 2010
Primary efficacy endpointPrimary efficacy endpoint
Per Protocol PopulationPer Protocol Population
•• Rivaroxaban was superior to warfarin, delivering Rivaroxaban was superior to warfarin, delivering a 21% relative risk reduction in stroke and nona 21% relative risk reduction in stroke and non-- CNS systemic embolism in the preCNS systemic embolism in the pre--specified on specified on treatment populationtreatment population
Intention To Treat PopulationIntention To Treat Population
••
This result indicates that the treatment benefits This result indicates that the treatment benefits compared to warfarin were sustained as long as the compared to warfarin were sustained as long as the patients received rivaroxaban.patients received rivaroxaban.
Rocket StudyRocket Study
AHA Chicago, November 15, 2010 AHA Chicago, November 15, 2010
14,91 14,52
0,00
2,00
4,00
6,00
8,00
10,00
12,00
14,00
16,00
Riva 20 mg Warfarin
p=0.442
% p
er y
ear
Rocket Study Rocket Study ––Major and nonMajor and non--Major Bleeding RatesMajor Bleeding Rates
AHA Chicago, November 15, 2010 AHA Chicago, November 15, 2010
0,49
0,74
0,00
0,50
1,00
Riva 20 mg Warfarin
p=0.019
% p
er y
ear
Rocket Study Rocket Study Intracranial HemorrhagesIntracranial Hemorrhages
AHA Chicago, November 15, 2010 AHA Chicago, November 15, 2010
•• In addition, significantly fewer cases of In addition, significantly fewer cases of hemorrhagic stroke, one of the most severe types hemorrhagic stroke, one of the most severe types of stroke, were observed in patients on of stroke, were observed in patients on rivaroxaban (0.26% vs. 0.44% p=0.024). rivaroxaban (0.26% vs. 0.44% p=0.024).
•• Compared to warfarin, rivaroxaban also showed Compared to warfarin, rivaroxaban also showed numerically fewer cases of myocardial infarction numerically fewer cases of myocardial infarction (0.91% vs. 1.12%, p=0.121), and an observed (0.91% vs. 1.12%, p=0.121), and an observed reduction in rates of allreduction in rates of all--cause mortality (1.87% vs. cause mortality (1.87% vs. 2.21%, p=0.073). 2.21%, p=0.073).
Rocket StudyRocket Study
AHA Chicago, November 15, 2010 AHA Chicago, November 15, 2010
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
STRATIFICAZIONE DEL RISCHIO E STRATIFICAZIONE DEL RISCHIO E PROFILASSI CONSIGLIABILE PROFILASSI CONSIGLIABILE Fondazione IRCCS Policlinico di PaviaFondazione IRCCS Policlinico di Pavia
Livelli di Rischio
Senza Profilassi
Profilassi Raccomandata
Basso Rischio Chirurgia minore in pazienti mobiliPazienti internistici allettati <10%
Nessuna profilassi specifica ma deambulazione precoce e “aggressiva”
Rischio Intermedioo Moderato
Maggior parte dei pazienti sottoposti a procedure di chirurgia generale, urologica, ginecologica.
Se rischio moderato associato ad elevato rischio emorragico
15%-40%
Eparina a Basso Peso Molecolare (EBPM) alle dosi raccomandate (vedi tabella 4)Eparina Calcica b.i.d. oppure t.i.d.Fondaparinux
Profilassi meccanica**
Alto Rischio
Protesi elettiva d’anca o di ginocchio,frattura d’anca
Trauma maggiore, trauma spinale
Se alto rischio associato ad elevato rischio emorragico
40%-80%
Eparina a Basso Peso Molecolare (EBPM) alle dosi raccomandate (vedi tabella 4)Fondaparinux
Dabigatran (solo per chirurgia protesica d’anca o di ginocchio)
Rivaroxaban (solo per chirurgia protesica d’anca o di ginocchio)
Eparina a Basso Peso Molecolare (EBPM) alle dosi raccomandate (vedi tabella 4)
Profilassi meccanica**
Schema di dosaggio per la profilassi antitromboticaSchema di dosaggio per la profilassi antitromboticautilizzando i farmaci disponibili nella Fondazione IRCCS Policlutilizzando i farmaci disponibili nella Fondazione IRCCS Policlinico San Matteoinico San Matteo
SCORE RISCHIO PROVVEDIMENTO
≤
1 Basso Calze elastiche a compressione graduataMobilizzazione precoce
1.5 –
2.5 Moderato
Enoxaparina –
0.2 ml, 2000 UI aXa/dieNadroparina –
0.3 ml, 2850 UI aXa/die, a dose variabile secondo il peso (vedi scheda tecnica del farmaco)Eparina Calcica –
0.2 ml, 5.000 U.I. x 3 vv. al dìIniziare 12 ore prima dell’intervento o entro le 12 ore successive
≥
3 Alto
Fondaparinux 2,5 mg/die, iniziando 6-8 ore dopo l’interventoEnoxaparina –
0.4 ml, 4000 UI aXa/die Nadroparina 0.4 ml–
3750 UI aXa/die, modificando la dose con giornata post-operatoria (vedi scheda tecnica) Iniziare 12 ore prima dell’intervento o entro le 12 ore successive
Solo per chirurgia ortopedica protesica d’anca o di ginocchio Alto
Fondaparinux 2,5 mg/die, iniziando 6-8 ore dopo l’intervento
Enoxaparina –
0.4 ml, 4000 UI aXa/die oppure Nadroparina 0.4 ml–
3750 UI aXa/die, modificando la dose con giornata post-operatoria (vedi scheda tecnica). Iniziare 12 ore prima dell’intervento o entro le 12 ore successive
Dabigatran 150 o 220 mg/die, iniziando 4 ore dopo l’intervento (vedi raccomand. specifiche per prima dose)
Rivaroxaban 10,0 mg, iniziando 6-1\0 ore dopo l’intervento (vedi raccomandazioni specifiche)
2008 ACCP Recommendation 2008 ACCP Recommendation for Medical Conditionsfor Medical Conditions
••
For acutely ill medical patients admitted to hospital with For acutely ill medical patients admitted to hospital with congestive heart failure congestive heart failure oror
severe respiratory diseasesevere respiratory disease, or who , or who
are are confined to bed and have one or more additional risk confined to bed and have one or more additional risk factors, factors, includingincluding
active cancer, previous VTE, sepsis, acute active cancer, previous VTE, sepsis, acute
neurologic disease, neurologic disease, or or inflammatory bowel diseaseinflammatory bowel disease, we , we recommend thromboprophylaxis with LMWH (Grade 1A), recommend thromboprophylaxis with LMWH (Grade 1A), LDUH (Grade 1A), or fondaparinux (Grade 1A).LDUH (Grade 1A), or fondaparinux (Grade 1A).
••
For medical patients with risk factors for VTE, and for For medical patients with risk factors for VTE, and for whom there is a contraindication to anticoagulant whom there is a contraindication to anticoagulant thromboprophylaxis, we recommend the optimal use of thromboprophylaxis, we recommend the optimal use of mechanical thromboprophylaxismechanical thromboprophylaxiswith GCS or IPC (Grade 1A).with GCS or IPC (Grade 1A).
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
PE Kills 3 Times More Medical PE Kills 3 Times More Medical Patients Than Surgical PatientsPatients Than Surgical Patients
Sandler DA, et al. J R Soc Med. 1989;82:203Sandler DA, et al. J R Soc Med. 1989;82:203--5.5.
75%75%
25%25%
Medical patientsMedical patientsSurgical patientsSurgical patients
0
2
4
6
8
10
12
14
16
All VTE Proximal DVT PE
Placebo
Enoxaparin 20 mg
Enoxaparin 40 mg
Summary of venous thromboembolic Summary of venous thromboembolic events during the treatment periodevents during the treatment period
P P = 0.037= 0.037
PP = 0.0002= 0.0002
NSNS
(%)(%)
NS = not significantNS = not significant
RRR = RRR = --63%63%
RRR = RRR = --65%65%
Malattie Tromboemboliche Malattie Tromboemboliche --
PaviaPavia
ARTEMISARTEMIS
ARARixtraixtra®®
for for TThrombohromboEEmbolism prevention in a mbolism prevention in a
MMedical edical IIndications ndications SStudytudy
AT Cohen, B Davidson, A Gallus, MR Lassen, AT Cohen, B Davidson, A Gallus, MR Lassen,
W Tomkowski and AGG TurpieW Tomkowski and AGG Turpie
On behalf of the ARTEMIS InvestigatorsOn behalf of the ARTEMIS Investigators
Odds Reduction = Odds Reduction = 49.5%49.5%
(95%CI: 72.1; 8.6)(95%CI: 72.1; 8.6)
p = 0.029p = 0.029
PlaceboPlaceboFondaparinuxFondaparinux
5.6%5.6%18/32118/321
10.5%10.5%34/32334/323
00
22
44
66
88
1010
1212
% o
f VTE
% o
f VTE
Primary Efficacy OutcomePrimary Efficacy Outcome VTE Up to Day 15 VTE Up to Day 15
EXCLAIM: Study designEXCLAIM: Study design
Multicenter, Prospective, Randomized, DoubleMulticenter, Prospective, Randomized, Double--blind, Placeboblind, Placebo--controlled study to controlled study to demonstrate superiority of enoxaparin 40 mg sc qd for 28 days demonstrate superiority of enoxaparin 40 mg sc qd for 28 days ++ 4 days compared 4 days compared
with placebo both following 10 with placebo both following 10 ++ 4 days of initial treatment with enoxaparin 40 4 days of initial treatment with enoxaparin 40 mg sc qd mg sc qd
1010 ++ 44Mandatory ultrasonographyMandatory ultrasonography
00
RR
Enoxaparin 40 mg sc odEnoxaparin 40 mg sc od
PlaceboPlacebo
3838±± 44DaDa yy
FollowFollow--up up
EnoxaparinEnoxaparin40 mg sc od40 mg sc od
OpenOpen--labellabel DoubleDouble--blindblind
180180±± 1010qd = once a day, SC = subcutaneousqd = once a day, SC = subcutaneous
Hull RD Ann Intern Med 2010Hull RD Ann Intern Med 2010
EXCLAIM Efficacy EXCLAIM Efficacy all VTE until Day 90all VTE until Day 90
Day 38Day 38 Day 90Day 90
Inci
denc
e (%
)In
cide
nce
(%)
4.94.9
2.82.8
5.25.2
3.03.0
p = 0.0011p = 0.0011 p = 0.0115p = 0.0115
-- 44%44%
RRRRRR -- 42%42%
RRRRRR
PlaceboPlacebo
EnoxaparinEnoxaparin
Hull RD Ann Intern Med 2010Hull RD Ann Intern Med 2010
RivaroxabanRivaroxaban compared with compared with enoxaparinenoxaparin for the prevention of venous for the prevention of venous thromboembolismthromboembolism in acutely ill medical in acutely ill medical patientspatients
MAGELLAN Investigators
Patients Patients ≥≥4040
years years
hospitalized for hospitalized for acute medical acute medical illness with illness with decreased level decreased level of mobility of mobility
Oral Oral rivaroxabanrivaroxaban
10 mg 10 mg odod
3535±±4 days4 days
s.cs.c. . enoxaparinenoxaparin
40 mg 40 mg odod
1010±±4 days4 days
Day 35Day 35
(31(31––39)39)
Oral placebo Oral placebo 3535±±4 days4 days
FollowFollow--up up periodperiod
to Day 90to Day 90
s.cs.c. placebo . placebo 1010±±4 days4 days
UltrasonographyUltrasonography
on day 10on day 10±±44UltrasonographyUltrasonography
on day 35on day 35±±4 4
Primary efficacy outcome Primary efficacy outcome Day 10 (nonDay 10 (non--inferiority)inferiority)
Primary efficacy outcome Primary efficacy outcome Day 35* (superiority)Day 35* (superiority)
Day 10Day 10
(6(6––14)14)8,101 patients 8,101 patients
randomizedrandomized
MAGELLAN: clinical trial designMAGELLAN: clinical trial design
RR
Day 90Day 90
(83(83––97)97)
Cohen Cohen et alet al, 2011, 2011*Includes *Includes eevents frovents from Day 1 to Day 35m Day 1 to Day 35
Primary efficacy outcome: Day 10*Primary efficacy outcome: Day 10*
Rivaroxaban
(n=2,939)Enoxaparin
(n=2,993)n (%) n (%)
Primary efficacy outcome 78 (2.7) 82 (2.7)Asymptomatic proximal DVT 71 (2.4) 71 (2.4)Symptomatic lower extremity DVT 7 (0.2) 6 (0.2)Symptomatic non-fatal PE 6 (0.2) 2 (<0.1)VTE-related death‡ 3 (0.1) 6 (0.2)
*P*PPP
population, events up to Day 10+5 days; population, events up to Day 10+5 days; ‡‡includes cases where PE cannot be ruled outincludes cases where PE cannot be ruled out
Relative risk ratioRelative risk ratiopp=0.0025 for non=0.0025 for non--inferiority inferiority (one(one--sided) sided)
1.00 1.00 00
0.710.71 1.311.310.970.97
1.50 1.50
InferiorInferiorSuperiorSuperior NonNon--
inferiorinferior
Primary efficacy outcome: Day 35*Primary efficacy outcome: Day 35*
Rivaroxaban
(n=2,967)
Enoxaparin/
placebo
(n=3,057)n (%) n (%)
Primary efficacy outcome 131 (4.4) 175 (5.7)Asymptomatic proximal DVT 103 (3.5) 133 (4.4)Symptomatic lower extremity DVT 13 (0.4) 15 (0.5)Symptomatic non-fatal PE 10 (0.3) 14 (0.5)VTE-related death‡ 19 (0.6) 30 (1.0)
**mITTmITT
population, events up to Day 35+6 days; population, events up to Day 35+6 days; ‡‡4 confirmed fatal 4 confirmed fatal PEsPEs
includes cases where PE includes cases where PE cannot be ruled outcannot be ruled out
0.620.62 0.960.960.770.77
pp=0.0211 for superiority =0.0211 for superiority (two(two--sided)sided)
ARD: 1.3% ARD: 1.3% RRR: 22.9%RRR: 22.9%
1.00 1.00 00Relative risk ratioRelative risk ratio
InferiorInferiorSuperiorSuperior NonNon--
inferiorinferior
Safety outcomesSafety outcomes
Rivaroxaban
(n=3,997)
Enoxaparin/
placebo
(n=4,001)
RR p value
n (%) n (%)
Day 1 to 10 (principal safety outcome)
Clinically relevant bleeding* 111 (2.8) 49 (1.2) 2.3 <0.0001
Major bleeding 24 (0.6) 11 (0.3) 2.2 0.0318
Day 1 to 35 (principal safety outcome)
Clinically relevant bleeding* 164 (4.1) 67 (1.7) 2.5 <0.0001
Major bleeding 43 (1.1) 15 (0.4) 2.9 0.0004
Day 11 to 35
Clinically relevant bleeding* 56 (1.4) 19 (0.5) 3.0 <0.0001
Major bleeding 19 (0.5) 4 (0.1) 4.8 0.0045
**Major plus nonMajor plus non--major clinically relevant bleedingmajor clinically relevant bleeding
Safety population; Safety population; treatmenttreatment--emergent bleedingemergent bleeding
Components of major bleedingComponents of major bleeding
Day 1 to 10
Rivaroxaban
(n=3,997)
Enoxaparin/
placebo
(n=4,001)
n (%) n (%)Major bleeding* 24 (0.6) 11 (0.3)
Fall in hemoglobin
≥2g/dl 17 (0.4) 7 (0.2)Transfusions ≥2 units of blood 15 (0.4) 5 (0.1)Critical site† 5 (0.1) 3 (0.1)Fatal 5 (0.1) 1 (<0.1)
Day 11 to 35Major bleeding* 19 (0.5) 4 (0.1)
Fall in hemoglobin
≥2g/dl 14 (0.4) 3 (<0.1)Transfusions ≥2 units of blood 9 (0.2) 3 (<0.1)Critical site† 4 (0.1) 1 (<0.1)Fatal 2 (<0.1) 0
**Patients could have a bleeding event in more than one subcategorPatients could have a bleeding event in more than one subcategory; y; ††defined as defined as intracranial, intracranial, intraspinalintraspinal, intraocular, retroperitoneal, intra, intraocular, retroperitoneal, intra--articulararticular, pericardial or intramuscular with , pericardial or intramuscular with compartment syndrome compartment syndrome
““In the final analysis, the In the final analysis, the therapeutic efficacy of any drug therapeutic efficacy of any drug can only be demonstrated by can only be demonstrated by clinical trials in manclinical trials in man””
Annotation, Annotation, British Journal of British Journal of HaematologyHaematology 19841984