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
2.1% vs. 3.0% P<0.0001 (non-‐inferiority)
0.8% vs 1.2%
2.4% vs. 2.1% P<0.001 (non-‐inferiority)
1.1% vs. 1.7%
* Presented at XXIII ISTH Congress 2011, yet unpublished
2.1% vs. 1.8% P<0.003 (non-‐inferiority)
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
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
Agnelli G et al N Engl J Med 2013;368:699-‐708
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
Agnelli G et al N Engl J Med 2013;368:699-‐708
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