Diapositiva 1

Nuovi anticoagulanti a confronto:
i risultati dei trials clinici
Walter Ageno
Dipartimento di Medicina Clinica e Sperimentale
Università dell’Insubria – Varese
ACCP 2012 Treatment of VTE
2012
Real-life treatment of acute VTE:
RIETE registry
Treatment
PE±DVT
(n=20,543)
Isolated DVT
(n=21,283)
p
Thrombolytics
0.9%
0.1%
<0.001
UFH
LMWH
Fondaparinux
12%
85%
1.3%
2.9%
95%
1.6%
<0.001
<0.001
0.036
VKA
73%
67%
<0.001
Lecumberri R et al Thromb Haemost 2013
Venous thromboembolism:
drugs and strategies
LMWH or
Fonda s.c.*
Current standard of care
VKA
Day 1
Day 5–11
At least 3 months
RE-COVER + RE-COVER II
DABIGATRAN (publ . 2009/2013)
HOKUSAI-VTE
LMWH s.c.
dabi bid / edo OD
EDOXABAN (publ. 2013)
Day 1
EINSTEIN-DVT + EINSTEINPE RIVAROXABAN (publ 2010/2012)
riva 15 mg BID 3 wk,
AMPLIFY
At least 3 months
Day 5–11
then 20 mg OD
api 10 BID 1 wk, then 5 mg BID
APIXABAN (publ. 2013)
Day 1
At least 3 months
*Or unfractionated heparin or fondaparinux
BID = twice daily; LMWH = low molecular weight heparin; OD = once daily; s.c. = subcutaneous; VKA = vitamin K
antagonist
VTE: optimal treatment for acute initial period
iv UFH / VKA versus VKA alone:
VTE recurrences at 3 months:
7%
20 %
Brandjes et al. N Engl J Med 1992;327:1485-9.
Ximelagatran alone
LMWH / VKA
Nunber of recurrences
8
Idraparinux ow alone
6
LMWH / VKA
4
HR = 2.09 [ 1.2 – 3.6 ]
2
0
D1-7
D7-14
D15-30
THRIVE II-V study. Fiessinger et al. JAMA 2005;293:681-9.
Van Gogh PE study. N Engl J Med 2007;357:1094-104.
Acute initial phase: period at risk requiring intensive parenteral treatments
Phase III VTE trials – Recurrent VTE
4
NOAC
Control
Patients (%)
3,5
3
2,5
2.7%
2.3%
2.2%
2.1%
2.3%
2.3%
1.9%
2
1.6%
1,5
1
0,5
0
RE-COVER
Dabigatran
* On Treatment
EINSTEIN
Rivaroxaban
AMPLIFY
Apixaban
*
Hokusai-VTE
Edoxaban
1. Schulman et al. N Engl J Med 2009;361:2342–2352
2. EINSTEIN Investigators. N Engl J Med 2010; 3. EINSTEIN–PE Investigators. N Engl J Med
4. Agnelli et al. N Engl J Med 2013; 5. The Hokusai-VTE Investigators. N Engl J Med 2013
Phase III VTE trials – Major Bleeding
4
NOAC
Control
Patients (%)
3,5
3
2,5
2.0%
2
1,5
1.8%
1.7%
1.4%
1.6%
1.4%
1.0%
1
0.6%
0,5
0
RE-COVER
Dabigatran
EINSTEIN
Rivaroxaban
AMPLIFY
Apixaban
Hokusai-VTE
Edoxaban
1. Schulman et al. N Engl J Med 2009;361:2342–2352
2. EINSTEIN Investigators. N Engl J Med 2010; 3. EINSTEIN–PE Investigators. N Engl J Med
4. Agnelli et al. N Engl J Med 2013; 5. The Hokusai-VTE Investigators. N Engl J Med 2013
NOAC VTE trials:
Baseline characteristics
REEINSTEIN
Hokusai3 AMPLIFY4
EINSTEIN
PE
COVER1#
DVT2
VTE5
(Rivaroxaban) (Apixaban)
(Dabigatran) (Rivaroxaban)
(Edoxaban)
Patients, N
2539
3449
4832
5395
8292
Age (yrs)
55
56
58
57
56
Female (%)
42
43
47
41
43
Creatinine
clearance
<50 mL/min (%)
NR
7
8
6
7
DVT (%)
69
99
-
65
59
PE±DVT (%)
31
0.6
100
35
40
Unprovoked (%)
NR
62
65
90
65
Cancer (%)
5
6
5
3
9†
Previous VTE
26
19
19
16
18
NR=not reported; #RECOVER II is still only available as an abstract and therefore is not included in the table
†Data from Hokusai-VTE are for history of cancer; active cancer was observed in 2.4% of patients overall
1. Schulman et al. N Engl J Med 2009;361:2342–2352
2. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 3. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297
4. Agnelli et al. N Engl J Med 2013;369:799–808; 5. The Hokusai-VTE Investigators. N Engl J Med 2013
EINSTEIN PE Primary efficacy outcome:
time to first event
Cumulative event rate (%)
3.0
2.5
Rivaroxaban
N=2419
50 (2.1%)
2.0
1.5
Enoxaparin/VKA
N=2413
44 (1.8%)
1.0
HR=1.12; p<0.0026 (non-inferiority)
0.5
0.0
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to event (days)
Number of patients at risk
Rivaroxaban
2419 2350
2321 2303
2180
2167 2063
837
794
785
757
725
672
Enoxaparin/VKA2413 2316
2296 2274
2157
2149 2053
837
789
774
748
724
677
ITT population
The EINSTEIN Investigators. N Engl J Med 2012
EINSTEIN PE Principal safety outcome:
Cumulative event rate (%)
major or non-major clinically relevant bleeding
Enoxaparin/VKA
N=2405
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
11.4% (Major 2.2%*)
Rivaroxaban
N=2412
10.3% (Major 1.1%*)
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to event (days)
Number of patients at risk
Rivaroxaban
2412 2183
Enoxaparin/VKA 2405 2184
Safety population
2133 2024
1953
1913 1211
696
671
632
600
588
313
2115
1923
1887 1092
687
660
620
589
574
251
1990
* 0.49 (0.31-0.79)
The EINSTEIN Investigators. N Engl J Med 2012
Hokusai study:
Subgroup analysis in PE patients with
NT-proBNP ≥500 pg/mL
HR=0.52 (95% CI, 0.28-0.98)
6.2%
3.3%
15/454
30/484
The Hokusai-VTE Investigators. N Engl J Med 2013
ACCP 2012 Treatment of VTE
2012
RE-MEDY™ study design
Screening/
baseline
Follow up
30 days
Treatment period
Dabigatran etexilate 150 mg bid
Warfarin placebo
Anticoagulant
therapy
3–12 months*
and “increased
risk of
recurrence” 0–7 days until
INR ≤2.3
Confirmed
VTE
S
R
Warfarin (INR 2.0–3.0)
Dabigatran placebo
Up to 36 months*
End of treatment
*Original protocol, 3–6 months of pre-treatment, then 18 months on study drug; amendment
allowed 3–12 months of pre-treatment, then up to 36 months on study drug.
S, screening; R, randomization.
Recurrent symptomatic VTE and VTErelated deaths
HR 1.44 (95% CI: 0.78–2.64)
Percentage
p = 0.027 (non-inferiority)
1.8%
1.3%
26/1430
Risk difference 0.38 (95% CI: -0.50–1.25); p < 0.0001 (non-inferiority).
18/1426
Major bleeding
3
HR 0.52 (95% CI: 0.27–1.02)
Percentage
2,5
p = 0.058
2
1,5
48%
RRR
1.8%
1
0.9%
0,5
0
Dabigatran 150 mg bid
13/1430
RRR, relative risk reduction.
On treatment
Warfarin
25/1426
Eleggibilità da piano terapeutico
per Xarelto
• Prevenzione della TVP recidivante e dell’EP
dopo TVP PROSSIMALE acuta nell’adulto
• Diagnosi confermata mediante ecografia
ARTI INFERIORI nelle 48 ore precedenti
• Oppure
• Terapia con EBPM o ENF o fondaparinux
Pazienti non candidabili ai nuovi
anticoagulanti orali
• Insufficienza grave (clearance creatinina < 30
mL/min-15 mL/min per alcuni farmaci?)
• Insufficienza epatica moderata-grave (Child-Pugh
B-C); epatite acuta
• Terapia con farmaci non associabili (es.
antiretrovirali)
• Gravidanza e allattamento
• Neoplasia attiva con indicazione a EBPM a lungo
termine
• Concomitante EP con instabilità emodinamica
I nuovi anticoagulanti nella terapia del
TEV: conclusioni
• Studi di fase III 27.100 pazienti con TVP ed EP
dimostrano efficacia comparabile al trattamento
standard e sicurezza complessivamente
superiore
• Non vi sono segnali di differenze nei vari
sottogruppi, soprattutto di pazienti più fragili
• I vantaggi pratici sono indiscutibili
• Siamo in attesa di dati da studi
osservazionali/fase IV (Xalia)
I nuovi anticoagulanti nella terapia del
TEV: conclusioni 2
• E’ fondamentale la selezione dei pazienti idonei
per ciascun trattamento
• E’ fondamentale un’adeguata istruzione dei
pazienti
• E’ fondamentale un adeguato follow-up
• Aree incerte:
•
•
•
Embolia polmonare con disfunzione ventricolare dx
Neoplasia attiva (vs EBPM)
Sedi inusuali