Vietata la copia non autorizzata: tutti i diritti del ... · INR 1.5-1.9 ≥ 5 giorni almeno ......

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

≥≥



Trattamento esteso


Scopo del trattamento anticoagulante a lungo termine

Stabilizzare il tromboPrevenire le recidive precoci

≥≥



Trattamento esteso


Scopo del trattamento anticoagulante esteso

Prevenire le recidive tardiveed i nuovi episodi non correlati all’evento iniziale

≥≥



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


IXaIXa VIIaVIIa

VIIIVIII VIIIaVIIIa

VV VaVa

EparinaEparina

IXIX VIIVII

XX

IIII






XIIXII XIIaXIIa

XIXI


IXIX VIIVII

VIIIVIII VIIIaVIIIa

XX

VV VaVa

IIII

EparinaEparina

Antagonisti della Antagonisti della Vitamina KVitamina K

IIaIIa

XaXa

XIaXIa

IXaIXa VIIaVIIa






XIIXII XIIaXIIa

XIXI


IXIX VIIVII

VIIIVIII VIIIaVIIIa

XX

VV VaVa

IIII

Eparine Eparine e LMWHe LMWH


IIaIIa

XaXa

XIaXIa

IXaIXa VIIaVIIa






IIaIIa

XIIXII XIIaXIIa

XIXI


IXIX VIIVII

VIIIVIII VIIIaVIIIa

XX

VV VaVa

IIII

Eparine e LMWHEparine e LMWH


Inibitori diretti della Inibitori diretti della trombinatrombina IIaIIa

XaXa

XIaXIa

IXaIXa VIIaVIIa

IIa






IIaIIa


XIIXII XIIaXIIa

XIXI


IXIX VIIVII

VIIIVIII VIIIaVIIIa


XX

VV VaVa

IIII


Eparine e LMWHEparine e LMWH


Inibitori diretti della Inibitori diretti della TrombinaTrombina

Inibitori del Fattore XaInibitori del Fattore Xa

(Trombina)(Trombina)IIaIIa

XaXa

XIaXIa

IXaIXa VIIaVIIa

IIa

Xa


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


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


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


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


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


PaviaPavia

MATISSEMATISSE

DVTDVT22


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


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%


PaviaPavia


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


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


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


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


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


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)


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


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


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


0.10%0.10%

0.38%0.38%RRR69%

RRR74%

0.12%0.12%


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


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)


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)


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


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


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


•• 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



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).


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%


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)


Major bleeding 43 (1.1) 15 (0.4) 2.9 0.0004

Day 11 to 35


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

Vietata la copia non autorizzata: tutti i diritti del ... · INR 1.5-1.9 ≥ 5 giorni almeno ......

Documents

Transcript of Vietata la copia non autorizzata: tutti i diritti del ... · INR 1.5-1.9 ≥ 5 giorni almeno ......