I’NUOVI’ANTICOAGULANTI’ORALI’ - SIMI · Principali(limi (degli(anDcoagulanDin usoper(...

Convegno regionale SIMI Lombardia 2013 Milano 6 aprile 2013

I NUOVI ANTICOAGULANTI ORALI

Terapia del Tromboembolismo Venoso

Cimminiello C. – Vimercate (MB)

Terapia farmacologica del TEV

Le LG ACCP 2012

TraBamento iniziale con terapia anDcoagulante parenterale EBPM (2B), Fondaparinux, ENF endovena (2C)

0-‐7 giorni

7 giorni – 3 mesi TraBamento a lungo temine con anD Vit K, EBPM, rivaroxaban, dabigatran

3 mesi -‐ indefinitamente

Stabilizzazione del trombo e prevenzione delle recidive

Prevenzione delle recidive

ImpaFo della terapia standard del TEV sulla storia naturale della malaIa

TEV acuto 1° mese)

TEV acuto (2-‐3° mese)

TEV ricorrente

Rischio di re

cidiva

40

30

20

10

0

50 RRR: 80%

Kearon C et al NEJM 1997; 336:: 1507-‐11

Il traFamento del TEV: la sicurezza

EFFICACIA

SICUREZZA

Sanguinamento Maggiore 2.4%

EFFICACIA

SICUREZZA

Sanguinamento Maggiore > 6.5%

Principali limiD degli anDcoagulanD in uso per il traBamento del TEV

(in aggiunta ed oltre al sanguinamento) Eparina Non frazionata

-‐ Somministrazione parenterale -‐  HIT (Heparin induced thrombocytopenia, alto rischio) -‐  Incapacità di ina]vare la trombina legata alla fibrina ed il faBore Xa legato alle piastrine -‐ Biodisponibilità del tuBo variabile -‐  Origine animale -‐  Richiesto monitoraggio di laboratorio

Fondaparinux -‐ Somministrazione parenterale -‐  Rischio emorragico nei pazienD con Insuff. Renale

EBPM -‐ Somministrazione parenterale -‐  HIT (Heparin induced thrombocytopenia, basso rischio) -‐  Incapacità di ina]vare la trombina legata alla fibrina ed il faBore Xa legato alle piastrine -‐  Rischio emorragico nei pazienD con Insuff. Renale -‐ Origine animale

Dicumarolici -‐ Inizio e termine di effeBo lenD -‐ StreBa finestra terapeuDca -‐ Richiesto MONITORAGGIO di laboratorio -‐  Numerose interazioni con cibo e farmaci -‐  In grado di ridurre I livelli degli anDcoagulanD naturali, Proteina C ed S

Nuovi anDcoagulanD e terapia del TEV

Trattamento della fase iniziale del

TEV

Prevenzione secondaria a lungo

termine del TEV

Dabigatran Rivaroxaban Apixaban Edoxaban Completato In corso Completato In corso Completato

RECOVER RECOVER 2

REMEDY RESONATE

EINSTEIN DVT EINSTEIN PE

EINSTEIN Ext

AMPLIFY*

AMPLIFY ext

HOKUSAI

* I risultaD saranno presentaD al prossimo meeDng ESC 2013

In corso

Studies on iniDal treatment of VTE with novel anDcoagulants

Dabigratan vs. warfarin Drug

Study Design

Dosing schedule

Treament Period

Pa]ent Number

Recurrent VTE

Major Bleeding

RE-‐COVER RE-‐COVER II * EINSTEIN DVT EINSTEIN PE

Double blind

Parenteral anDcoagulaDon followed by Dabigatran 150 mg bid

6 months

2564 2559

2.4% vs. 2.1% P<0.001 (non-‐inferiority)

1.6% vs. 1.9%

Rivaroxaban vs. VKA Rivaroxaban vs. VKA

Open label Open label

Rivaroxaban 15 mg bid for 3 weeks followed by

20 mg od

Rivaroxaban 15 mg bid for 3 weeks followed

by 20 mg od

3-‐6 -‐12 months 3-‐6 -‐12 months

3449 4832


0.8% vs 1.2%


1.1% vs. 1.7%

* Presented at XXIII ISTH Congress 2011, yet unpublished


1.1% vs. 2.2% (P=0.003)

IniDal treatment of VTE with novel anDcoagulants: the safety issue Major and clinically relevant non major bleeding

10

8

6

4

2

% 8.8

5.6

P= 0.002

RECOVER

8.1 8.2

EINSTEIN DVT

11.4

10.3

EINSTEIN PE

Standard therapy Dabigatran

Rivaroxaban

La terapia anDcoagulante prolungata (la prevenzione secondaria)

  Dopo i primi tre mesi di traBamento anDcoagulante dovrebbe essere riconsiderato il rapporto tra rischio di recidiva e rischio emorragico

  Si riDene ragionevole considerare un traBamento anDcoagulante prolungato quando la frequenza aBesa di recidive supera il 5%

Le LG ACCP 2012

Frequenza aBesa di recidiva/anno in varie categorie di pazienD con TEV (traBaD)

20

16

12

8

4

%

TEV Post-‐chirurgia

8.8

TEV e faBori non chirurgici

15

TEV idiopaDco

TEV in oncologia

27 TVP distale vs

prossimale

EP vs TVP

Sesso e progredire dell’età

Trombofilie

Eleva] valori di D-‐Dimero

Residuo trombo]co

Risk Assessment of Recurrence in Pa]ents With Unprovoked Deep Vein Thrombosis or Pulmonary Embolism : The Vienna

Predic]on Model

Eichinger S et al CirculaDon 2010; 121: 1610

DASH predicDon score

ToseBo A et al JTH 2012

Assessing the risk of bleeding

Risk Factor Score Recent major bleeding

2

CreaDnine levels >1.2 mg/dL

1.5

Anemia 1.5 Cancer 1

Clinically overt PE 1 Age >75 years 1

Maximum Score 8

RIETE Risk Score

Low risk: 0; Intermediate risk: 1-‐4; High risk :>4

Age . 65 y Age . 75 y Previous bleeding Cancer MetastaDc cancer Renal failure Liver failure Thrombocytopenia Previous stroke Diabetes Anemia AnDplatelet therapy Poor anDcoagulant control Comorbidity and reduced funcDonal capacity Recent surgery Frequent falls Alcohol abuse

ACCP Risk Score

Low risk: 0 RF; moderate risk: 1 RF; High risk :>1 RF

Studies on extended treatment of VTE with novel anDcoagulants

Dabigratan vs warfarin Dabigatran vs placebo

Drug

Study Design

Dosing schedule

Treament Period

Pa]ent Number

Unprovoked VTE

RE MEDY RE SONATE EINSTEIN EXTENSION AMPLIFY EXTENSION

Double blind

Dabigatran 150 mg bid

6 -‐36 months 18 months

2866 1353

NR*

3 to 12 months 6 to 18 months

Rivaroxaban vs. placebo Apixaban vs placebo

Double blind Double blind

Rivaroxaban 20 mg od Apixaban 5 mg bid Apixaban 2.5 mg bid

6 -‐12 months 12 months

6-‐12 months

92%

* At increased risk for recurrent venous thromboembolism on the basis of the site invesDgator’s assessment

NR 74%

1196 2482

Completed An]coagula]on Period

6-‐12 months

RESONATE

Outcome

Dabigatran (n=681), n (%)

Placebo (n=662), n (%)

HR

p

Recurrent VTE

23(0.4)

37(5.6)

0.08

<0.0001

Major bleeds

2

0

NS

Any bleeding

36/684 (5.3%) 12/659 (1.8%)

2.92

=0.0013

1343 paDents with VTE who received 6 to 18 months of anDcoagulaDon randomized, to dabigatran 150 mg twice daily or placebo for an addiDonal six months.

Schulman S et al N Engl J Med 2013;368:709-‐18

RE MEDY

Outcome

Dabigatran (n=1430), n (%)

Warfarin (n=1426), n (%)

HR

p

Recurrent VTE

26 (1.8)

18 (1.3)

1.44

0.03 *

Deaths

17

19

0.90

NS

Major bleeds

13 (0.9)

25 (1.8)

0.52

0.058

Any bleeding

277 (19)

373 (26)

0.71

<0.0001

ACS

13 (0.9)

3 (0.2)

0.02

2856 paDents with VTE who received three to 12 months of anDcoagulaDon randomized, to dabigatran 150 mg twice daily or warfarin for an addiDonal six to 36

months.

* non-‐inferiority Schulman S et al N Engl J Med 2013;368:709-‐18

EINSTEIN Extension: primary efficacy outcome and individual components

Rivaroxaban (n=602)

Placebo (n=594)

n (%) n (%)

Symptoma]c recurrent VTE* 8 (1.3)# 42 (7.1)

Recurrent DVT 5 (0.8) 31 (5.2)

Non-‐fatal PE 2 (0.3) 13 (2.2)

Fatal PE 0 1 (0.2)

Unexplained death (where PE cannot be excluded) 1 (0.2) 0

ITT populaDon; *Some paDents experienced more than one event; #p<0.001

The EINSTEIN InvesDgators. N Engl J Med 2010;363:2499–2510

EINSTEIN Extension: major bleeding

Rivaroxaban (n=598)

Placebo (n=590)

n (%) n (%)

Major bleeding 4 (0.7)* 0

Bleeding contribuDng to death 0 0

Bleeding in a criDcal site 0 0

Associated with fall in haemoglobin ≥2 g/dl and/or transfusion of ≥2 units 4 0

GastrointesDnal bleeding 3 (0.5) 0

Menorrhagia 1 (0.2) 0

Safety populaDon; *p=0.11 The EINSTEIN InvesDgators. N Engl J Med 2010;363:2499–2510

EINSTEIN Extension: non-‐major clinically relevant bleeding

Rivaroxaban (n=598)

Placebo (n=590)

n (%) n (%)

Non-‐major clinically relevant bleeding 32 (5.4) 7 (1.2) Urogenital/uterus 12 (2.0) 2 (0.3) Nasal 8 (1.3) 1 (0.2) Rectal/anal 6 (1.0) 2 (0.3) Skin 4 (0.7) 2 (0.3) Ear 1 (0.2) 0 GastrointesDnal 1 (0.2) 0 Surgical site 1 (0.2) 0

Safety populaDon; some paDents experienced more than one event The EINSTEIN InvesDgators. N Engl J Med 2010;363:2499–2510

AMPLIFY-‐EXT

Clinical diagnosis of DVT or PE, an]coagula]on treatment 6-‐12 months,

completed with no recurrence N= 2482

Apixaban 2,5 mg BID 12 months

Apixaban 5 mg BID 12 months

Placebo 12 months

Primary end point: Venous Thromboembolic recurrence or death Secondary outcome measures: Bleeding

Agnelli G et al N Engl J Med 2013;368:699-‐708

AMPLIFY-‐EXT: efficacy


End point

Apixaban 2.5 mg N=840

Apixaban 5 mg N=813

Placebo

N=820

Apixaban 2.5 mg vs placebo

Apixaban 5 mg vs placebo

2.5 mg vs

5 mg

RR (95% CI)

Recurrent VTE or VTE-‐related death (%)

1.7 1.7 8.8 0.19 0.20 0.77

(0.11-‐0.33) (0.11-‐0.34) (0.21-‐2.88)

Recurrent VTE or death From any cause (%)

3.8 4.2 11.6 0.33 0.36 NA

(0.22-‐0.48) (0.25-‐0.53)

Non VTE-‐related CV death, MI, or stroke (%)

0.5 0.6 1.3 0.36 0.47 0.77 (0.11-‐1.12) (0.16-‐1.33) (0.21-‐2.88)

Recurrent VTE, VTE-‐related death, MI, stroke, or CVD-‐related death (%)

2.1 2.3 10 0.21 0.23 0.92

(0.13-‐0.35) (0.14-‐0.38) (0.48-‐1.74)

AMPLIFY-‐EXT: safety


End point

Apixaban 2.5 mg N=840

Apixaban 5 mg N=813

Placebo

N=820

Apixaban 2.5 mg vs placebo

Apixaban 5 mg vs placebo

2.5 mg vs

5 mg

RR (95% CI)

CRNM (%) 3.0 4.2 2.3 1.29 1.82 0.71

(0.72-‐2.33) (1.05-‐3.18) (0.43-‐1.18)

Major bleeding(%) 0.2 0.1 0.5 0.49 0.25 1.93

Major or CRNM bleeding (%)

3.2 4.3 2.7 1.20 1.62 0.74

(0.69-‐2.10) (0.96-‐2.73) (0.46-‐1.22)

(0.09-‐2.64) (0.03-‐2.24) (0.18-‐21.25)

ASPIRIN and prevenDon of VTE ASPIRE and WARFASA trial design

First unprovoked proximal DVT or PE

AnDcoagulant Therapy 6-‐18 months WARFASA 6-‐24 months ASPIRE

RAND

Aspirin 100 mg daily

Placebo once daily

Double blind treatment for 23.9 months (median, WARFASA)

Double blind treatment for 37.2 months (median, ASPIRE)

Recurrent SymptomaDc confirmed

VTE

BecaBni C et al NEJM 2012 Brighton TA et al NEJM 2012

ASPIRIN HR

WARFASA N= 402 6.6% 11.2 0,58 .02

ASPIRE N= 822 4.8% 6.5 0,74 .09

Recurrent VTE Aspirin Placebo (95% CI) p

Pooled 0,68 .007

(0,36-‐0.93)

(0,52-‐1.05)

(0,51-‐0.90)

WARFASA 0,67

.06

ASPIRE 0,66 .01

Pooled 0,66

.002

(0,43-‐0103)

(0,48-‐0.92)

(0,51-‐0.86)

Major vascular Events (VTE, MI, Stroke, CV death)

HR (95% CI)

BecaBni C et al NEJM 2012 Brighton TA et al NEJM 2012

I nuovi anDcoagulanD orali per il traBamento del tromboembolismo venoso: pro e contro

CONTRO -‐ vasDssima esperienza di impiego di

warfarin

-‐ costo/beneficio (rispeBo a warfarin)

-‐ assenza di anDdoto

-‐ difficile valutazione della compliance

-‐ Assenza di confronD dire] tra le varie

molecole

-‐Limitata aderenza alle due

somministrazioni /die

PRO -‐ no necessità monitoraggio di laboratorio

-‐ pari efficacia rispeBo a warfarin

-‐ possibile minore impaBo sul rischio

emorragico complessivo

-‐possibile unico traBamento per la fase

iniziale del TEV e per quella successiva

(rivaroxaban e apixaban)

-‐ Possibile nuovo standard di sicurezza

(emorragie) per I traBamenD prolungaD

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