Hokusai-VTE: study rationale

LA TERAPIA DEL TROMBOEMBOLISMO
VENOSO
Pavia 13 giugno 2014
Domenico Prisco
SOD Patologia Medica
AOU Careggi, Firenze
DMSC, Università di Firenze
VTE TREATMENT
• Pharmacological
- UFH
- LMWHs
- Fondaparinux
- VKAs
- Aspirin
- New anticoagulants (dabigatran, rivaroxaban, apixaban,
edoxaban)
- Thrombolysis
• Non
pharmacological
- Surgery (embolectomy, thrombectomy)
- Interventional radiology (mechanical fragmentation,
thrombosuction)
- IVCFs
Imberti, Th Res, 2012
Treatment of VTE (DVT & PE): current practice
Thrombolysis
LMWH
Fondaparinux
Unfractionated heparin
Initial treatment
vitamin K antagonists
INR 2.0-3.0
2.0-3.0 or 1.5-1.9
Long term-treatment
Extended* treatment
≥ 5 days
at least 3 months
indefinite*
* With re-assessment of the individual risk-benefit at periodic intervals
Agnelli & Becattini, N Engl J Med 2010
Treatment for pulmonary embolism
Adam Torbicki
Arnaud Perrier
S Konstantinides
Giancarlo Agnelli
Nazareno Galié
Piotr Pruszczyk
Embolia polmonare: scelta del trombolitico
 Nessun agente o regime di trattamento ha
mostrato superiorità in termini di efficacia
 Alteplasi è comunque l’unico agente
trombolitico approvato dalla Food and Drug
Adminstration per il trattamento
dell’embolia polmonare massiva.
Alteplasi ed embolia polmonare
emodinamicamente instabile
 Al momento della decisione di intraprendere la terapia sospendere la
somministrazione di eparina ed ottenere aPTT di base.
 Intraprendere infusione continua di Alteplasi (100 mg in 2 ore).
 La somministrazione di boli non ha mostrato vantaggi rispetto al regime di infusione
continua (Sors H et al; Chest 1994).
 Al termine infusione misurare di nuovo aPTT
aPTT < 80 secondi: riprendere infusione di eparina senza bolo.
aPTT > 80 secondi: effettuare nuovo controllo in 4 ore.
 La somministrazione loco-regionale mediante catetere in arteria polmonare non ha
mostrato vantaggi rispetto a quella sistemica in accordo ai risultati idi un singolo
trial (Verstraete et al; Circ. 1988)
Controindicazioni alla terapia
fibrinolitica
Controindicazioni assolute:
•Stroke emorragico o di origine sconosciuta
•Stroke ischemico nei precedenti 6 mesi
•Danno o neoplasia del sistema nervoso centrale
•Recente trauma maggiore/ chirurgia maggiore/ trauma cranico (nelle
precedenti 3 settimane)
•Sanguinamento gastrointestinale nell’ultimo mese
•Sanguinamento noto
Le controindicazioni considerate assolute possono diventare relative in un
paziente con alto rischio di EP con indicazione al trattamento immediato
Risk stratification-driven clinical management
Clinical features
Shock or
sustained hypotension:
- systolic BP<90mmHg
- pressure drop of ≥40 mmHg >15 minutes
Hemodynamically unstable
Hemodynamically stable
Stratify for adverse outcome
Proceed to thrombolysis
or surgery or catheter
embolectomy
All Absent
Continue anticoagulation
and consider early discharge
or home treatment
Markers of RV
Dysfunction
Echocardiography
MDCT
BNP levels
Dysfunction or injury
Continue
anticoagulation
Medical ward admission
Injury
Troponin
Dysfunction & Injury present
Consider ICU admission
and/or thrombolysis in
patients at low bleeding risk
International, multicenter study aimed at assessing the
efficacy and safety of TNK versus placebo in patients with
acute pulmonary embolism, normal blood pressure
and right ventricle overload
PEITHO study
FASI E SCOPI DEL TRATTAMENTO DELLA
TVP PROSSIMALE
Antithrombotic Therapy for VTE Disease.
Kearon C et al, Chest 2012; 141(2)(Suppl):e419S–e494S
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines
• Fase iniziale:
prevenire estensione trombosi ed embolia
• Lungo termine:
prevenire recidive precoci
• Estesa:
prevenire recidive tardive/non correlate all'evento iniziale
TERAPIA INIZIALE DELLA TVP PROSSIMALE:
QUALE FARMACO E COME ?
6 opzioni:
• con monitoraggio:
Eparina non frazionata (ENF) EV o SC (fino agli anni ‘90)
•
senza monitoraggio:
ENF SC
Eparine a basso peso molecolare (EBPM) SC
Fondaparinux SC (dagli anni 2000)
Rivaroxaban per OS: senza monitoraggio (2010)
TERAPIA INIZIALE DELLA TVP PROSSIMALE:
DOVE?
•
•
Tipo di farmaco, via di somministrazione, necessità di
monitoraggio può condizionare scelta tra
ricovero ospedaliero vs. gestione a domicilio
Initial and long term treatment of VTE
5-7 days
UFH
LMWH UFH Monitor APTT (1.5-2.0 x control)
Fondaparinux
4-5 days
Warfarin
Monitor INR (2.0-3.0)
start
Monitor INR
(2.0-3.0)
3-6 months
Kearon, Chest, 2008
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
TERAPIA INIZIALE DELLA TVP PROSSIMALE:
Antithrombotic Therapy for VTE Disease.
Kearon C et al, Chest 2012; 141(2)(Suppl):e419S–e494S
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines
NB: se edema e dolore severi, può essere necessario ritardare deambulazione
TERAPIA INIZIALE DELLA TVP PROSSIMALE:
Antithrombotic Therapy for VTE Disease.
Kearon C et al, Chest 2012; 141(2)(Suppl):e419S–e494S
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Compression stockings with ankle pressure of 30 to 40 mm Hg and a lower
pressure higher up the leg (ie, graduated pressure) should be started as
soon as feasible after starting anticoagulant therapy (within 2 weeks).
Venous thromboembolic diseases: the management of
venous thromboembolic diseases and the role of
thrombophilia testing.
National Clinical Guideline Centre - June 2012
National Institute of Clinical Excellence
Contraindications:
Blood. 2012;119:1561-1565
CES-related side effects (ie, itching, erythema, or
allergic reaction) developed in 55 (40.7%) of the 135 patien
allocated to the thigh-length CES and in 36 (27.3%) of thos
randomized to the below-knee group (P = .017), and led to
premature discontinuation of their use in 29 (21.5%)
and 18 (13.6% patients, respectively (P =0.11).
Vitamin K antagonists – major drawbacks
Slow onset/offset
of action
Unpredictable response
Narrow therapeutic
window
(INR range 2-3)
Routine coagulation
monitoring
Frequent dose
adjustments
Warfarin
therapy has
several
limitations
that make it
difficult to
use in
practice
Numerous food-drug
interactions
Numerous drug-drug
interactions
Risk of Bleeding
Complications
Features of novel oral anticoagulants
Dabigatran1
Rivaroxaban1,2
Apixaban1,3
Edoxaban4-6
IIa (thrombin)
Xa
Xa
Xa
Hours to Cmax
1.25-3
2-4
3-4
1-2
CYP metabolism
None
32%
Minimal
<4%
6%
80%
60%
62%
Transporters
P-gp
P-gp/BCRP
P-gp/ BCRP
P-gp
Protein binding
35%
93%
87%
50%
14-17 h (BD)
7-11 h (QD/BD)
8-15 h (BD)
8-10 h (QD)
80%*
33%#
25%#
35%#
Target
Bioavailability
Half-life
Renal elimination
BCRP, breast cancer resistance protein
CYP, cytochrome P450; P-gp, P-glycoprotein
NR, not reported
*Of
absorbed substance
#Of
ingested substance
1. Eriksson et al. Clin Pharmacokinet 2009;48:1-22; 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.;
2011; 3. ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK; 4. Ruff et al. Hot Topics
in Cardiology 2009;18:1-32; 5. Matsushima et al. Am Assoc Pharm Sci 2011; abstract; 6. Ogata et al. J Clin Pharmacol
2010;50:743-53
Treatment of acute VTE with new
anticoagulants: possible options
Start with standard parenteral drugs (i.e. LMWHs) for the
initial therapy before the new compound
Start therapy with an intensive regimen of the new
compound for the first weeks (“single drug approach”)
Acute VTE treatment
Phase III Clinical Program Overview
THRIVE
 Ximelagatran
VAN GOGH
 Idraparinux
CASSIOPEA *
 Idrabiotaparinux
RECOVER, *
 Dabigatran
RECOVER II *
AMPLIFY
 Apixaban
HOKUSAI *
 Edoxaban
EINSTEIN PE
 Rivaroxaban
EINSTEIN DVT
* INITIAL PARENTERAL TREATMENT
Acute VTE treatment
Phase III Clinical Program Overview
THRIVE *
 Ximelagatran
VAN GOGH *
 Idraparinux
CASSIOPEA
 Idrabiotaparinux
RECOVER,
 Dabigatran
RECOVER II
AMPLIFY *
 Apixaban
HOKUSAI
 Edoxaban
EINSTEIN PE *
 Rivaroxaban
EINSTEIN DVT *
* “SINGLE DRUG APPROACH”
Rationale for intensified initial treatment in
phase III VTE treatment studies
Evidence of early recurrent VTE in
THRIVE study with ximelagatran1
Evidence of early recurrent VTE in the
van Gogh PE study with idraparinux2
5
4
3
Ximelagatran 36 mg bid
2
Enoxaparin 1 mg/kg bid 5–20 days/
warfarin (INR 2.0–3.0)
1
0
0

30
60
90
120
Time after randomization (days)
150
180
Cumulative
incidence (%)
Estimated
cumulative risk (%)
5
4
Idraparinux 2.5 mg
once weekly
3
2
Standard therapy*
1
0
0
60
120
180
Days
Early separation of the curves indicates the need for intensified anticoagulant
treatment in the acute phase
*Heparin followed by an adjusted-dose VKA for either 3 or 6 months
1. Fiessinger J-N et al. JAMA 2005
2. The van Gogh Investigators. N Engl J Med 2007
NOAC VTE: study designs
RE-COVER I1
RE-COVER II2
EINSTEIN-DVT3
EINSTEIN-PE4
AMPLIFY5
Hokusai-VTE6
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Double-blind
Open-label
Double-blind
Double-blind
NR
<48 hrs
<36 hrs
<48 hrs
At least 5 days
None
None
At least 5 days
150 mg BID
15 mg BID x 3 wk
then 20 mg QD
10 mg BID x 7 d
then 5 mg BID
60 mg QD
30 mg QD†
Dose reduction
NONE
NONE
NONE
18%
Randomized
population
2,5641
2,5682
3,4493
4,8334
5,400
8,292
6 months
Pre-specified
3, 6, 12 months
6 months
Flexible
3 to 12 months
Study drug
Study design*
Pre-randomization
heparin
Heparin lead-in
Dose
Treatment
duration
*Comparator was warfarin in each case
†Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding by predefined criteria
NR=not reported
1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. Schulman et al. Blood 2011;118:Abstract 205
3. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 4. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297
5. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 6. The Hokusai-VTE Investigators. N Engl J Med 2013
NOAC VTE trials:
Baseline characteristics
RE-COVER1#
(Dabigatran)
Patients, N
EINSTEIN
DVT2
(Rivaroxaban)
EINSTEIN PE3 AMPLIFY4
(Rivaroxaban) (Apixaban)
HokusaiVTE5
(Edoxaban)
2539
3449
4832
5395
8292
Age (yrs)
55
56
58
57
56
Female (%)
42
43
47
41
43
Creatinine
clearance
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
<50 mL/min (%)
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
NOAC VTE trials:
Baseline characteristics
RE-COVER I1
EINSTEIN-DVT2
EINSTEIN-PE3
AMPLIFY4
Hokusai-VTE5-7
Dabigatran
Rivaroxaban
Rivaroxaban
Apixaban
Edoxaban
100
-
12
63
25
5
58
37
100
-
12
26
61
40†
Mean treatment
duration, days
<180
NR
215
<180
249
≥1 dose heparin prior to
randomization (%)
100
72
92
86
100
Adherence to therapy
>80% (%)
98
NR
94
96
99
Drug
Treatment duration (%)
3 months
6 months*
6-12 months
12 months
*For
Hokusai-VTE duration was 3 to 6 months
of patients in Hokusai-VTE reaching 12 months is included within 61% of patients reaching 6-12 months
NR= Not Reported
†40%
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. doi:10.1056/NEJMoa.1302507
5. The Hokusai-VTE Investigators. N Engl J Med 2013; 6. Raskob et al. J Thromb Haemost 2013;11:1287-1294; 7. Daiichi Sankyo, data on file.
Phase III VTE trials – recurrent VTE
†
3.5%
Patients (%)
**
*
3.0%
*
**
2.4%
3.2%
2.7%
#
2.3%
2.1%
2.1%
All NOACs were
non-inferior to
warfarin
2.1%
1.9%
1.8%
1.6%
Overall
Follow up period:
*6 months
**3, 6 or 12 months
†12 months regardless
of treatment duration
#3 to 12 months (ontreatment analysis)
On-treatment
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; e-pub ahead of print
Phase III VTE trials – safety
Major or clinically relevant non-major bleeding
NOAC
Warfarin
11.4%
10.3%
P<0.001
10.3%
9.7%
P=0.002
8.8%
8.5%
8.1% 8.1%
Patients (%)
P=0.004
5.6%
4.3%
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; e-pub ahead of print
Phase III VTE trials – safety
Major bleeding
NOAC
Warfarin
P=0.003
2.2%
P<0.001
1.9%
1.8%
Patients (%)
1.6%
1.6%
1.4%
1.2%
1.1%
0.8%
0.6%
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; e-pub ahead of print
Effectiveness and safety of NOACs as compared with VKAs in the
treatment of acute symptomatic VTE: a systematic review and metaanalysis
Efficacy outcomes
Van Der Tulle, J Thromb Haemost, 2014
Effectiveness and safety of NOACs as compared with VKAs in the treatment of acute
symptomatic VTE: a systematic review and meta-analysis
Safety outcomes
NNH for Major Bleeding
149
Van Der Tulle, J Thromb Haemost, 2014
ACCP 2012 Treatment of VTE
2012
Cumulative incidence
of recurrent DVT and/or
PE
Recurrence rates in
patients with
unprovoked vs
secondary VTE
Prandoni et al, Haematologica 2007
Annualized recurrence rates after a
first episode of venous
thromboembolism
• Transient risk factor: 3.3% per patient-year
– 0.7% with a surgical risk factor (95% CI 0-1.5%)
– 4.2% with a non-surgical risk factor (95% CI 2.85.6%)
• Unprovoked VTE: 7.4% per patient-year
(95% CI 6.5-8.2%)
Iorio et al Arch Intern Med 2010
Possible strategies in pts with a
previous unprovoked VTE
• Prolonged OAT in all
(many pts treated unnecessarily; complications)
• Prolonged, low intensity OAT in all pts
(less effective, complications non completely avoided)
• Prolonged treatment with new, low risk drugs
(for the future?)
• Identify those pts who are at higher/lower risk
Thrombophilia
Persistence of residual vein thrombosis
D-dimer test
Risk of Recurrence
(> 500)
n=222
(< 500; n=377)
Palareti et al, Circulation 2003
(Palareti et al., NEJM 2006;335:1780-9)
Systematic review: D-dimer to predict recurrent disease after stopping
anticoagulant therapy for unprovoked venous thromboembolism
Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T, Poli D, Lim W.
positive D-dimer post-anticoagulation Vs negative D-dimer post-anticoagulation
Author,
reference
Patients, Recurrent
n
VTE
Annualized
risk (95%CI)
Patients, n
Recurrent
VTE
N (%)
Annualized
risk
(95%CI)
Palareti,
2003
139
23
7.3
(4.3,10.3)
143
10
2.8
(1.0,4.5)
Eichinger,
2003
401
63
4.5
(3.4,5.6)
209
16
3.0
(1.5,4.4)
Palareti,
2006
120
18
10.9
(5.9,15.9)
30
24
4.4
(2.6,6.1)
Shrivastava,
2006
15
3
11.3
(0.0,24.1)
30
2
3.7
(0.0,8.7)
Tait, 2007
71
18
14.4
(7.7, 21.1)
58
4
3.8
(0.1,7.6)
Baglin, 2008
91
23
8.8
(5.2,12.2)
51
8
4.8
(1.5,8.1)
Poli, 2008
70
17
10.8
(5.6,15.9)
105
10
3.8
(1.4,6.1)
Pooled
907
165
8.9
(5.8,11.9)*
981
74
3.5
(2.7,4.3)**
Ann Intern Med 2008
Cumulative hazard of recurrence combining
Ddimer with sex and hormone therapy
Douketis et al, Ann Int Med 2010
Gli algoritmi
Clinical decision rule to identify patients at low risk(*) of recurrent venous
thromboembolism after 5–7 months of oral anticoagulant therapy
Men
always long-term anticoagulation
Women
Predictive values
score
•Post-thrombotic signs (hyperpigmentation,
edema or redness in either leg)
1
•D-Dimer level ≥ 250 μg/L
1
• Body mass index ≥ 30 kg/m2
1
• Age ≥ 65 yr
1
(*)Low-risk ≤1
Rodger M et al. CMAJ, 2008
Predictive values
sex
Localization
VTE
males
females
of distal
Proximal DVT
PE
D-dimer levels
continous
Points (according to nomogram)
60
0
0
70
90
0-100
Low-risk ≤180 points (according to nomogram) 4.4% (95% CI 2.7%-6.2%)
Circulation, 2010
Predictive values
score
Elevated D-dimer levels 1 months
after stopping VKA
2
Age < 50 years
1
Male sex
1
Women assuming oral contraceptives
-2
The DASH score varies between -2 to 4, identifying patients at low risk of recurrence when the score is ≤ 1.
Tosetto A et al. JTH, 2012
Gli studi di management
PERCORSO DIAGNOSTICO-TERAPEUTICO DEI SOGGETTI
ARRUOLATI: VALUTAZIONE SU BASE CLINICASTRUMENTALE (CUS E/O ECOCARDIOGRAMMA)
• Tutti i pazienti inclusi (con TVP e/o EP)
• CUS bilaterale degli arti inferiori
• (V. femorale comune all’inguine, la femorale superficiale a metà coscia
e la poplitea nel cavo popliteo fino alla triforcazione)
• Se in almeno uno dei punti suddetti dell’arto sintomatico
permane un residuo trombotico (> 4 mm): proseguire TAO
per un totale di almeno 12 mesi
• Al termine di almeno 12 mesi di TAO CUS ripetuta;
qualsiasi siano i risultati i paz avviati alla fase successiva
Prevalence of first-time ever D-dimer above the predefined cut-off levels
after VKA withdrawal
Blood, in press
Total screened patients
n = 2458
Excluded for pre-specified
criteria
n = 442
DD neg 52,3%
DD pos reassume VKA 36,9%
DD pos refuse VKA 10,8%
Candidate to extended
VKA treatment
n = 606
Candidate to short
VKA treatment
n = 353
Eligible for the study
n = 1057
Excluded for various
reasons #
n = 47
Patients included in the
analysis
n = 1010
Patients with positive DD
Patients with always negative
DD (no VKAs)
n = 528 (52.3%)
(VTE idiopathic = 377)
(Associated with WRF = 151)
- resumed VKAs
n = 373 (36.9%)
(VTE idiopathic = 311)
(Associated with WRF = 62)
- refused VKAs
n = 109 (10.8%)
(VTE idiopathic = 83)
(Associated with WRF = 26)
Blood, in press
Kaplan–Meier Cumulative Event Rates for recurrent VTE in patients with
persistently negative D-dimer results in whom anticoagulation was definitively
stopped (dotted line) and in those with positive D-dimer results who refused to
resume anticoagulation (continuous line)
Blood, in press
Primary outcomes and major bleeding events
in the DULCIS study
Normal DD,
no
anticoagulation
(n. 506; 821 yr)
Outcomes no. (%; CI)
Incidence % pt/yr %
(CI)
Major bleeding no.
(%;CI)
Incidence % pt/yr %
(CI)
Altered DD,
anticoagulation
refused
(n. 109; 171 yr)
Altered DD,
anticoagulation
resumed
(n. 373; 601 yr)
23 (4.5%; 2.9-6.7) 15 (13.8%; 7.9-21.7) 4 (1.1%; 0.3-2.7)
2.8% (1.8-4.2)
8.8% (5.0-14.1)
0.7% (0.2-1.7)
0
0
14* (3.7%; 2.16.2)
2.3% (1.3-3.9)
(* = 1 fatal)
Blood in pressi
Extended treatment of VTE
Three studies comparing ODIs with placebo in
patients who stopped anticoagulant treatment
– RE-SONATE (150 mg bid as in RECOVER)
– EINSTEIN EXTENSION (20 mg od as in EINSTEIN)
– AMPLIFY EXTENSION (5 mg bid or 2.5 mg bid)
One study comparing ODI with warfarin
– REMEDY (150 mg bid as in RECOVER)
Phase III VTE_Ext trials – recurrent VTE
HR 0.19
NNT 14
HR 0.61
HR 0.20
NNT 14
HR 0.08
HR 1.44*
*= 95%CI: 0.78-2.64
1. Einstein Investigators N Engl J Med 2010 Dec 23;363(26):2499-510 ; 2. Agnelli et al. N Engl J Med c2012. DOI:
10.1056/NEJMoa1207541; 3. Schulman et al. N Engl J Med 2013;368:709-18.
Phase III VTE_Ext trials – Major bleeding
HR 0.52***
RR 0.49*
RR 0.25**
P=1.0
95%CI
* 0.09-2.64
** 0.03-2.24
*** 0.27-1.02: P=0.06
1. Einstein Investigators N Engl J Med 2010 Dec 23;363(26):2499-510 ; 2. Agnelli et al. N Engl J Med c2012. DOI:
10.1056/NEJMoa1207541; 3. Schulman et al. N Engl J Med 2013;368:709-18.
Phase III VTE_Ext trials – CRNMBs
HR 0.54
RR 1.29**
NNH 200***
RR 1.82
NNH 63***
HR 2.92
*one major bleeding
** 95%CI: 0.72-2.33
*** one major bleeding or CRNMB
1. Einstein Investigators N Engl J Med 2010 Dec 23;363(26):2499-510 ; 2. Agnelli et al. N Engl J Med c2012. DOI:
10.1056/NEJMoa1207541; 3. Schulman et al. N Engl J Med 2013;368:709-18.
Einstein, Amplify, Remedy, Resonate:
EXTENSION
Study
Indication
Patient Drug
s (n°)
Recurrent
VTE#
Major
bleeding#
EINSTEIN
EXTENSION
Extension VTE
1196
Rivaroxaban 20 mg o.d.
1.3 vs 7.1
P<0.001**
0.7 vs 0
P=0.11*
AMPLIFY
EXTENSION
Extension VTE
2486
Apixaban 2.5 mg b.d. or
5 mg b.d.
3.8 vs 4.2 vs
11.6 P<0.001
0.2 vs 0.1 vs
0.5
REMEDY
Extension VTE
2856
Dabigatran 150 mg b.d.
Vs warfarin
1.8 vs 1.3
P=0.03*
0.9 vs 1.8
P=0.058*
RRR -31%
RESONATE
Extension VTE
1343
Dabigatran 150 mg b.d.
0.4 vs 5.6
P<0.0001**
0.3 vs 0
P=0.996*
# drugs vs comparator (%)
* for non inferiority, ** for superiority
≠ major and clinical relevant non major bleeding
Imberti, Clinical Appl Thromb, 2013
Clinical management of venous thromboembolism before
(conventional management) and after (future management)
the availability of new oral anticoagulants in this indication
Agnelli G, Best Pract & Res Clin Haemat 2013
Main conclusions
 All four NOAs are effective and safe enough to qualify as ideal oral
anticoagulants for treatment of patients with acute VTE, including those with
clinically stable PE
 Rivaroxaban and apixaban do not require an initial parenteral treatment, but
require a more intensive treatment regimen in the first weeks (3 and 1,
respectively)
 Rivaroxaban (after the first 3 weeks) and edoxaban can be given in once daily
administration
 Low-dose apixaban is promising for the long-term treatment of VTE
 All of them have limitations for the treatment of patients with severe renal
failure and lack an antidote
 All of them require further investigation in cancer patients and in pregnant
women with VTE

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