DROGAS ANTITROMBÓTICAS

DROGAS ANTITROMBÓTICAS

CONGRESO PARAGUAYO DE HEMATOLOGÍA 2011

Dra. Ana María Otero

HEPARINA

1916 HOWEL Y MACFARLAIN 1935 TRATAMIENTO DE LA ETV SALVÓ MUCHAS VIDAS PROVOCÓ MUCHAS MUERTES HASTA HOY SE EMPLEA Y ES ACEPTADA POR

ORGANISMOS INTERNACIONALES

WARFARINA

1945 ANTICOAGULANTE COMPLEJO SALVÓ MUCHAS VIDAS PROVOCÓ MUCHAS MUERTES AÚN HOY SE USA POR ESTUDIOS DE

EVIDENCIA COMO EFECTIVA PREVENCIÓN SECUNDARIA DE LA ETV PREVENCIÓN DE LA EMBOLIA SISTÉMICA

HBPM

1972 ESTUDIO DE KAKKAR SEPARACIÓN ACTIVIDAD ANTI Xa DE LA

ANTI TROMBINA (IIa) 1980 DESARROLLO DE LAS DIFERENTES

HBPM

NUMEROSOS ESTUDIOS DE EVIDENCIA EFECTIVA SEGURA EN LA PREVENCIÓN Y

EL TRATAMIENTO

•Lancet 1972; 2: 101-106.

HBPM

HAN CAMBIADO LOS TRATAMIENTOS ANTITROMBÓTICOS

HAN DESARROLLADO LA PREVENCIÓN PRIMARIA DE LA ETE

SON MUY SEGURAS, SON EFECTIVAS LLEVAN MAS DE 20 AÑOS DE USO MASIVO A

NIVEL MUNDIAL

EPÍDEMIOLOGÍA

TROMBOSIS PRIMERA CAUSA DE MUERTE E INCAPACIDAD

REPERCUSIÓN PERSONALREPERCUSIÓN FAMILARREPERCUSIÓN SOCIAL

PREVENCIÓN DE LA TROMBOSIS

SE PUEDE SE DEBE NO SIEMPRE SE HACE SITUACIONES DE RIESGO MAYOR RIESGO

CIRUGÍA ORTOPÉDICA MAYOR EMBOLIA POR FA ETV EN PACIENTE MEDICOS HOSPITALIZADOS CIRUGÍA MAYOR ASOCIACIÓN DE FACTORES

DROGA ANTITROMBOTICA IDEAL

EFECTIVA SEGURA NO REQUIERA CONTROLES VIA ORAL NO INTERFERENCIAS BAJO COSTO SIN EFECTOS SECUNDARIOS POSEA ANTÍDOTO PARA CASO DE

SANGRADO

DROGA ANTITROMBOTICA IDEAL

NO EXISTE

NUEVAS DROGAS

SINTÉTICASVIA ORALACCIÓN ESPECÍFICA SOBRE UN

FACTOR DE LA COAGULACIÓNRELACIÓN DIRECTA DOSIS EFECTONO NECESIDAD DE CONTROL

BIOLÓGICO ….(?)

NUEVAS DROGAS LAS MAS ESTUDIADADAS (2011)

ETEXILATO DE DABIGATRANRIVAROXABANAPIXABANOTRAS DROGAS VIENEN LLEGANDO

12

WARFARINA ETEXILATO DABIGATRAN RIVAROXABAN

APIXABAN

INHIBEVITAMINA K

E-REDUCTASA TROMBINA FACTOR X FACTOR X

ABSORCIÓN ORAL

99% 67% 60-80% 80%

T (max) 72-96 h 2 h 2.5-4 h 3 h

VIDA MEDIA 40 h 14-17 h5-9 h SANOS, 9-13 h VIEJOS

8-15 h

MONITOREO INR- NO NECESITA? NO NECESITA? NO NECESITA?

ADMINIST. 1/D 1/D o 2 /D 1/D o 2 /D 2/D

MET/ELIMIN.CYTOCHOMO

P45080% RENAL 20% BILIAR

66% RENAL 33% BILIAR

25% RENAL 75% BILIAR

ANTÍDOTO O TRAT.SANGRADO

VIT. K PLASMA

CONSIDERAR PCC O rVIIa



LABORAT. PT/INRECARIN CLOTTING

TIMEANTI FACTOR Xa

ANTI-FACTOR XA

INTERACCIÓN CON DROGAS

CYP 2C9, 1A2, and 3A4

Potent P-gp inhibiDORs/inducers; PPIs decrease

absorción

Potent P-gp inhibitors/inducer

s; CYP3A4 inhibitors

Potent P-gp inhibitors/induc

ers; CYP3A4 inhibitors

COMPARACION DE LA WARFARINA CON LOS NUEVOS ANTICOAGULANTES ORALES

ESTUDIOS CLÍNICOS

DROGA

PREVEN.

STROKE FA

ETV y PREV TRATAMIENTO

PROFILAXIS CIRUGIA ORTOPÉDICA MAYOR

DABIGATRAN

I. DE LA TROMB

RELY RECOVER

REMEDY

RE-MOBILIZE

RE-MODEL

RE-NOVATE

RIVAROXABAN

INHIBIDOR FXa

ROCKET AF EINSTEIN PE

EINSTEIN DVT

EINSTEIN-EXT

MAGELLAN

RECORD 1

RECORD 2

RECORD 3

RECORD 4

APIXABAN

INHIBIDOR FACTOR Xa

AVERROES (ASA)

ARISTOTLE (W)

AMPLIFY

AMPLIFY-EXT

ADVANCE 1

ADVANCE 2

ADVANCE 3

0.1 0.2 0.5 1 2 5 10

Wolowacz et al. Thromb Haemost 2009.

Favours Enoxaparin

Favours Dabigatran

RE-MOBILIZE 188/604 163/643 30mg BIDRE-MODEL 183/503 193/512 40mg QDRE-NOVATE 53/880 60/897 40mg QD

Study or sub-category

Dabigatran etexilate220 mg QD

n/N

Enoxaparin

n/N dose

RR [95% CI]

1.23 [1.03, 1.47]0.97 [0.82, 1.13]0.90 [0.63, 1.29]

Random Effects AnalysisTotal (95% CI) 1987 2052Test for overall effect: Z = 0.47 (P = 0.64)

1.05 [0.87, 1.26]

RR

Analysis is based on the 220 mg QD dose of dabigatran etexilate.

Dabigatran in Orthopedics

Dabigatran approved for VTE prophylaxis post TJR in Canada June 2008y en Europa

EndpointRivaroxaban

(%)

Enoxaparin

(%)HR or RR(95% CI)

Total VTE (DVT, PE, death)

4.26 9.43 RR 0.46

(0.39, 0.54)

Major VTE (proximal DVT, PE, VTE death)

0.68 2.74 RR 0.25

(0.17, 0.37)

Symptomatic VTE or death

0.57 1.32 HR 0.42

(0.29, 0.63)

Major bleeding event 0.39 0.21HR 1.84

(0.94, 3.62)

Major or CRNM bleeding event

3.19 2.55HR 1.25

(1.01, 1.54)

Major bleeding combined with surgical-site bleeding events

1.80 1.37HR 1.31

(0.99, 1.73)

Levitan et al. ASH 2009.

Rivaroxaban in OrthopedicsRECORD 1 - 4

Rivaroxaban approved for VTE prophylaxis post TJR in Canada 2008 y en Europa

KNEE REPLACEMENT1

APIXABAN 2.5 MG PO BID FOR 10 – 14 DAYS

VS ENOXAPARIN 30 MG SC BID STARTING POST-OP

FOR 10 - 14 DAYSFOLLOW-UP: 60 DAYS

N=3195

KNEE REPLACEMENT2


VS ENOXAPARIN 40 MG SC QD FOR 10–14 DAYS

FOLLOW-UP: 60 DAYS N=3057

~10,000 patients randomized

1. Lassen, et al. N Engl J Med. 2009.2. Lassen et al. Lancet 2010. 3. Lassen et al. Intl Congress on Thrombosis 2010.

ADVANCE 1 ADVANCE 2HIP REPLACEMENT3


VS ENOXAPARIN 40 MG SC

QD FOR 35 DAYS

FOLLOW-UP: 60 DAYS

N=3866

ADVANCE 3

Apixaban in OrthopedicsADVANCE 1 – 3

All VTE/Death

Major VTE Major Bleed

Apix Enox Apix Enox Apix Enox

ADVANCE 1 (TKR)

9.0% 8.9% 2.1% 1.6% 0.7% 1.4%

ADVANCE 2 (TKR)

15.1% 24.4% 1.1% 2.2% 0.6% 0.9%

ADVANCE 3 (THR)

1.4% 3.9% 0. 5% 1.1% 0.8% 0.7%

Apixaban in OrthopedicsADVANCE 1 – 3

• Did not meet prespecified criterion for noninferiority vs enoxaparin 30 mg BID in TKR (ADVANCE 1)

• Superior to enoxaparin 40 mg once daily in THR and TKR (ADVANCE 2 & 3)

1. Lassen, et al. N Engl J Med. 2009. 2. Lassen et al. Lancet 2010. 3. Lassen et al. Intl Congress on Thrombosis 2010.

Enoxaparin Abs. Risk Diff.Outcome- n/N (%) Apixaban 40 mg QD (95% CI)

Major VTE 23/3394 51/3394 -0.76 (0.7) (1.5) (-1.23 to -0.30)

VTE Death 2/4236 0/4228 0.05 (0.05) (0) (-0.02 to 0.11)

Non-Fatal PE 5/4236 5/4228 0.0 (0.12) (0.12) (-0.15 to 0.15)

Sx Proximal DVT 2/4236 5/4228 -0.07 (0.05) (0.12) (-0.19 to 0.05)

Asx Proximal DVT 14/3386 41/3385 -0.62 (0.41) (1.21) (-1.00 to -0.24)

Sx Distal DVT Only 2/4236 7/4228 -0.12 (0.05) (0.17) (-0.26 to 0.02)

Favors Enox

Favors Apixa

-1.5 0 0.5-0.5-1.0

Apixaban in OrthopedicsADVANCE 2 & 3

Raskob et al. ASH 2010 Abstract #192.

Apixaban Enoxaparin AbsoluteOutcome- N (%) (n=4,174) (n=4,167) Diff (95% CI)

MAJOR BLEED 31 (0.74) 32 (0.77) -0.02 (-0.40 to 0.35)

Non-Surgical Site 5 (0.12) 5 (0.12)

Surgical Site 26 (0.62) 27 (0.65) -0.02 (-0.37 to 0.32)

Before 1st Post-Op Dose 17 (0.41) 11 (0.26)

After 1st Post-Op Dose 9 (0.22) 16 (0.38) -0.17 (-0.40 to 0.07)

MAJOR BLEED OR CRNM 182 (4.36) 206 (4.94) -0.58 (-1.49 to 0.32)

Non-Surgical Site 47 (1.13) 51 (1.22)

Surgical Site 135 (3.23) 155 (3.72) -0.49 (-1.27 to 0.30)

Before 1st Post-Op Dose 42 (1.01) 33 (0.79)

After 1st Post-Op Dose 93 (2.23) 122 (2.93) -0.70 (-1.38 to -0.02)

Apixaban in OrthopedicsADVANCE 2 & 3

Raskob et al. ASH 2010 Abstract #192.

PROFILAXIS EN CIRUGÍA ORTOPEDICA MAYOR. CONCLUSI0NES

Los nuevos anticoagulantes orales son similares a la enoxaparina en eficacia y en riesgo de sangrado en prevención de la ETV en cirugía de cadera y rodilla. Dabigatran 220 mg once daily

Rivaroxaban 10 mg once daily

Apixaban 2.5 mg twice daily

Ninguno fue aprobado en EEUU por la FDA pero SI están aprobados por la EMEA y en Canadá.

ESTUDIOS CLÍNICOS

DROGA

PREVEN.

STROKE FA



DABIGATRAN

I. DE LA TROMB

RELY RECOVER

REMEDY

RE-MOBILIZE

RE-MODEL

RE-NOVATE

RIVAROXABAN

INHIBIDOR FXa


EINSTEIN DVT

EINSTEIN-EXT

MAGELLAN

RECORD 1

RECORD 2

RECORD 3

RECORD 4

APIXABAN

INHIBIDOR FACTOR Xa

AVERROES (ASA)

ARISTOTLE (W)

AMPLIFY

AMPLIFY-EXT

ADVANCE 1

ADVANCE 2

ADVANCE 3

NUEVOS ANTICOAGULANTES EN LA PREVENCIÓN DEL

STROKE

Fibrilación Auricular NO valvular

ESTUDIOS CLÍNICOS

DROGA

PREVEN.

STROKE FA



DABIGATRAN

I. DE LA TROMB

RELY RECOVER

REMEDY

RE-MOBILIZE

RE-MODEL

RE-NOVATE

RIVAROXABAN

INHIBIDOR FXa


EINSTEIN DVT

EINSTEIN-EXT

MAGELLAN

RECORD 1

RECORD 2

RECORD 3

RECORD 4

APIXABAN

INHIBIDOR FACTOR Xa

AVERROES (ASA)

ARISTOTLE (W)

AMPLIFY

AMPLIFY-EXT

ADVANCE 1

ADVANCE 2

ADVANCE 3

DABIGATRAN (RELY) 150 mg dos veces por día es tan eficáz como la warfarina pero,

al precio de un mayor riesgo de sangrado-. 110 mg dos veces al día es comparable la eficacia pero menor

riesgo de sangrado Menos HC que con la warfarina

RIVAROXABAN (ROCKET AF) 20 mg una vez al día, es comparable a la warfarina sin

necesidad de monitoreo. Menos riesgo de HC comparado a la wafarina.

APIXABAN (ABERROES ARISTÓTELES) Aberroes: 5 mg dos veces por dia es más eficáz que la aspirina

en pacientes que no toleran la warfarina. Aristoteles: Comparación con la warfarina está pendiente

stroke

Connolly et al. NEJM 2009. Mahaffey et al AHA 2010. Connolly et al ESC 2010.

DABIGATRAN (APROVADO POR LA FDA) 150 mg dos veces por día es tan eficáz como la

warfarina pero, al precio de un mayor riesgo de sangrado-.

110 mg dos veces al día es comparable pero menor riesgo de sangrado. Menos HC

RIVAROXABAN 20 mg una vez al día es comparable a la warfarina sin

necesidad de monitoreo

Menos riesgo de HC comparado a la wafarina

APIXABAN 5 mg dos veces por dia es más eficáz que la aspirina

en pacientes que no toleran la warfarina. Aristotle: August 28 at the European Society of Cardiology 2011

meeting in Paris, France.

FA y Stroke Co

nnol

ly e

t al.

NEJ

M 2

009.

Mah

affey

et a

l AH

A 20

10. C

onno

lly e

t al E

SC 2

010.

FDA APPROVES DABIGATRAN FOR AF

Indication Prevention of stroke and systemic embolism in patients

with nonvalvular atrial fibrillation

Dosing 150 mg BID for all patients except in renal impairment 75 mg BID if Cr Cl 15 – 30 mL/min No adjustment for hepatic impairment

Guidelines Take with or without meals Do not chew, break or open capsules

TRATAMIENTO DE LA ENFERMEDAD

TROMBOEMBÓLICA VENOSA

NUEVAS DROGAS

ESTUDIOS CLÍNICOS

DROGA

PREVEN.

STROKE FA



DABIGATRAN

I. DE LA TROMB

RELY RECOVER

REMEDY

RE-MOBILIZE

RE-MODEL

RE-NOVATE

RIVAROXABAN

INHIBIDOR FXa


EINSTEIN DVT

EINSTEIN-EXT

MAGELLAN

RECORD 1

RECORD 2

RECORD 3

RECORD 4

APIXABAN

INHIBIDOR FACTOR Xa

AVERROES (ASA)

ARISTOTLE (W)

AMPLIFY

AMPLIFY-EXT

ADVANCE 1

ADVANCE 2

ADVANCE 3

Routine therapy with UFH or

LMWH

Warfarin INR 2.0 – 3.0 x 6 months

Dabigatran 150 mg BID x 6 months

Routine therapy with UFH or

LMWH

Follow-up 1

month

Follow-up 1

month

Double blind

Primary Efficacy: Recurrent, symptomatic VTEPrimary Safety: Major bleeding

• 2539 patients with acute DVTor PE treated initially with UFH/LMWH for a mean of 10 days

• Randomized to dabigatran 150 mg BID vs warfarin x 6 months• Non-inferiority study

RECOVERDabigatran in VTE Treatment

Schulman et al. New Engl J Med 2009.

Dx of VTE

Dabigatran is non-inferior to warfarin for prevention ofrecurrent or fatal VTE with comparable major bleeding risk (1.6% vs 1.9%)

Schulman et al. New Engl J Med 2009.

Dabigatran in VTE TreatmentRECOVER

INR in range 60%above range 19%below range 21%

P<0.001 for noninferiority

ESTUDIOS CLÍNICOS

DROGA

PREVEN.

STROKE FA



DABIGATRAN

I. DE LA TROMB

RELY RECOVER

REMEDY

RE-MOBILIZE

RE-MODEL

RE-NOVATE

RIVAROXABAN

INHIBIDOR FXa


EINSTEIN DVT

EINSTEIN-EXT

MAGELLAN

RECORD 1

RECORD 2

RECORD 3

RECORD 4

APIXABAN

INHIBIDOR FACTOR Xa

AVERROES (ASA)

ARISTOTLE (W)

AMPLIFY

AMPLIFY-EXT

ADVANCE 1

ADVANCE 2

ADVANCE 3

Dx of DVT

Enoxaparin 1 mg/kd BID > 5 d, then warfarin with INR 2 – 3 x 3, 6 or 12 months (1,718)

Rivaroxaban, 15 mg BID x 21 days then 20 mg QD x 3, 6 or 12 months (1,731)


• 3,449 patients with acute DVT• Randomized to rivaroxaban or enoxaparin/warfarin for 3 to 12 months• Non-inferiority study

Rivaroxaban in DVT TreatmentEINSTEIN

OpenLabel

Buller et al. ASH 2010 Abstract #187. New Engl J Med 2010.

Cum

ulati

ve e

vent

rate

(%)

0 30 60 90 120 150 180 210 240 270 300 330 3600

1.0

2.0

3.0

Rivaroxaban (2.1%; 36/1,731)

Enoxaparin/VKA (3.0%; 51/1,718)4.0

Time to event (days)

Rivaroxaban in DVT TreatmentEINSTEIN


INR in range 58%above range 16% below range 24%

Rivaroxaban is non-inferior to warfarin for prevention ofrecurrent or fatal VTE with comparable major bleeding risk (0.8% vs 1.2%)

P<0.001 for noninferiority

ESTUDIOS CLÍNICOS

DROGA

PREVEN.

STROKE FA



DABIGATRAN

I. DE LA TROMB

RELY RECOVER

REMEDY

RE-MOBILIZE

RE-MODEL

RE-NOVATE

RIVAROXABAN

INHIBIDOR FXa


EINSTEIN DVT

EINSTEIN-EXT

MAGELLAN

RECORD 1

RECORD 2

RECORD 3

RECORD 4

APIXABAN

INHIBIDOR FACTOR Xa

AVERROES (ASA)

ARISTOTLE (W)

AMPLIFY

AMPLIFY-EXT

ADVANCE 1

ADVANCE 2

ADVANCE 3

Dx of VTE and treatment for 6 – 12 months(routine Rx or rivaroxaban)

Placebo x 6 – 12 months(mean duration 190 d)

Rivaroxaban 20 mg QD x 6 – 12 months (mean duration 190 d)


• 1197 patients with acute DVT treated for 6 – 12 months with standard Rx or rivaroxaban

• Randomized to rivaroxaban 20 mg QD vs placebo x 6 – 12 months• Superiority Study

Rivaroxaban in Extended TreatmentEINSTEIN EXT


Double blind

1110

5

21

Cum

ulati

ve e

vent

rate

(%)

34

9

13

678

12

00 30 60 90 120 150 180 210 240 270 300 330 360

Time to event (days)

Number needed to treat to prevent 1 primary efficacy outcome: 15

HR=0.18; p<0.0001

Placebo (7.1%; 42/594)

Rivaroxaban (1.3%; 8/602)

Rivaroxaban in Extended TreatmentEINSTEIN EXT


Rivaroxaban is superior to placebo for prevention ofrecurrent or fatal VTE with comparable bleeding risk (0.7% vs 0%)

Dabigatran Can replace warfarin for treatment of acute PE/DVT

without need for monitoring Does not eliminate the need for initial UFH/LMWH Comparable to warfarin in major bleeding risk

Rivaroxaban Can replace heparin/warfarin for treatment of acute

DVT without need for monitoring Effective in reducing recurrent VTE up to 1 yr Comparable to warfarin in major bleeding risk

Studies of other agents are pending None of the new agents have received regulatory

approval for this indication to date

Treatment of Acute VTE Summary

ESTUDIOS CLÍNICOS

DROGA

PREVEN.

STROKE FA



DABIGATRAN

I. DE LA TROMB

RELY RECOVER

REMEDY

RE-MOBILIZE

RE-MODEL

RE-NOVATE

RIVAROXABAN

INHIBIDOR FXa


EINSTEIN DVT

EINSTEIN-EXT

MAGELLAN

RECORD 1

RECORD 2

RECORD 3

RECORD 4

APIXABAN

INHIBIDOR FACTOR Xa

AVERROES (ASA)

ARISTOTLE (W)

AMPLIFY

AMPLIFY-EXT

ADVANCE 1

ADVANCE 2

ADVANCE 3

ESTUDIO MAGELLAN

OutcomeRivaroxaban, n=3997

Enoxaparin, n=4001 (%)

(%)

Clinically relevant bleeding* 2.8 1.2

Major bleeding 0.6 0.3

Fall in hemoglobin >2g/dL 0.4 0.2

Transfusions >2 units blood 0.4 0.1

Critical site bleeding 0.1 0.1

Fatal bleeding 0.1 <0.1

MAGELLAN

HR=2.3; p<0.0001

Bleeding Results at Days 1–10

Outcome Rivaroxaban, n=2967 (%)


Composite efficacy outcome*

4.4 5.7

Asymptomatic proximal DVT

3.5 4.4

Symptomatic lower extremity DVT

0.4 0.5

Symptomatic nonfatal PE

0.3 0.5

VTE-related death 0.6 1

HR=0.77 (95% CI 0.62–0.96); p=0.02

Primary Efficacy Outcome at Day 35 MAGELLAN


Enoxaparin, 2993 (%)

Composite efficacy outcome*

2.7 2.7

Asymptomatic proximal DVT

2.4 2.4

Symptomatic lower extremity DVT

0.2 0.2

Symptomatic nonfatal PE

0.2 0.1

VTE-related death 0.1 0.2

Primary Efficacy Outcome at Day 10

*p for noninferiority=0.0025

MAGELLAN



Clinically relevant bleeding*

1.4 0.5

Major bleeding 0.5 0.1

Fall in hemoglobin >2g/dL

0.4 <0.1

Transfusions >2 units blood

0.2 <0.1

Critical site bleeding 0.1 <0.1

Fatal bleeding <0.1 0

Bleeding Results at Days 11–35 MAGELLAN

HR=3.0; p<0.0001

RESULTADOS ESTUDIO MAGELLAN(prevencion de le etv en pacientes internados por cuadros médicos agudos)

Rivaroxaban, No inferior a la Enoxaparina a los 10 días de internación.

Superior al placebo a los 35 días.Nivel de sangrado superior a la

enoxaparina no aceptable.

Dr Alexander Cohen (King's College, London, UK) American College of Cardiology 2011 Scientific Sessions,

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