Transcript Dia 1

Nieuwe inzichten in anti-stolling
Dr. Dimitri Breems, internist-hematoloog
Ziekenhuis Netwerk Antwerpen, Campus Stuivenberg
Antitrombotica
Anti-aggregantia
Acetylsalicylzuur
Thiënopyridines (clopidogrel, ticlopidine)
Dipyridamol
Glycoproteïne IIb/IIIa-receptor antagonisten
Anticoagulantia
Trombolytica
Anticoagulantia (klassiek)
Heparines
Niet-gefractioneerd
Laag moleculair gewicht
Vitamine K-antagonisten (coumarines)
Marcoumar (fenprocoumon)
Marevan (warfarine)
Sintrom (acenocoumarol)
Verschillen tussen vitamine K
antagonisten
acenocoumarol: Sintrom
4 mg
1 mg (mitis)
T ½ 8 uur
warfarin: Marevan
5 mg
T ½ 32 – 48 uur
phenprocoumon: Marcoumar
3 mg
T ½ 100 – 150 uur
Behandelindicaties (anticoagulantia)
Behandeling en preventie van:
Veneuze trombo-embolie
Longembool
Diepe veneuze trombose
Arteriële trombo-embolie
Acute ischemische accidenten
Hartkleplijden
Hartklepprothesen
Voorkamerfibrillatie
Stollingschema
Werkingsmechanisme vitamine K
antagonisten (coumarines)
Vitamin K
VII
6h T1/2
IX
18-24h
X
40-50h
II
48-60h
PS
Warfarine
PC
48h
6-8h
Stollingschema
Stollingschema
Proteine C
Proteine S
Thrombomoduline
Tissue Factor
Pathway Inhibitor
Anti-trombine
Vitamine K-antagonisten monitoring
Protrombinetijd (PT)
Seconden
%
International normalized ratio (INR)
INR =
(
Patiënts PT in Seconden
Normale PT in Seconden
)
Vitamine K-antagonisten monitoring
Stollingschema
Direct thrombin
inhibitor
Anticoagulantia (nieuw)
Trombine-inhibitoren
Lepirudine (Refludan), intraveneus
Bivalirudine (Angiox), intraveneus
Dabigatran (Pradaxa), oraal
LEPIRUDINE (Refludan)
Direct thrombin inhibitor (recombinant)
Saliva of Hirudo medicinalis
Treatment of trombo-embolism and
heparin-induced trombocytopenia
65
1
BIVALIRUDINE (Angiox)
Zeer specifieke directe trombine inhibitor
Synthetisch peptide 20 aminozuren
Alternatief voor heparine bij coronaire interventies
Active site
binding
(Gly)4
Exosite binding
DABIGATRAN (Pradaxa)
Oral direct thrombin inhibitor
Predictable anticoagulant effect
Fixed dose
No need for monitoring
No antidote
Half life 12-17 hours
Prevention of DVT after orthopedic surgery
Dabigatran for prevention of VTE after
major orthopaedic surgery
Enoxaparin
Dabigatran
(150 mg)
Dabigatran
(220 mg)
RE-NOVATE
6.7
8.6
p<0.0001*
6.0
p<0.0001*
RE-MODEL
37.7
40.5
p=0.0005*
36.4
p=0.0345*
RE-NOVATE
1.6
1.3
2.0
RE-MODEL
1.3
1.3
1.5
DVT, PE and all-cause mortality
(%)
Major bleeding (%)
*Non-inferior to enoxaparin;
Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J
Thromb Haemost 2007
RE-COVER trial design
Single-dummy
period
Warfarin
placebo
Double-dummy period
Dabigatran etexilate 150 mg bid
Warfarin placebo
30 days
follow up
Dabigatran etexilate placebo bid
72 h
Objective
confirmation
of VTE
Warfarin
Warfarin
(INR 2.0–3.0)
Initial parenteral
therapy
E
E= enrolment
R= randomization
19
R
Until INR 2.0 at
two consecutive
measurements
(8-11 days)
6 months
End of treatment
Cumulative risk of recurrent VTE
and related death
Dabigatran
Warfarin
Months Since Randomization
No. at risk
Dabigatran was non-inferior to warfarin for prevention of recurrent or fatal VTE
(P<0.001 for both hazard ratio and risk difference criteria).
Cumulative risk of first event of
major bleeding and of any bleeding
Warfarin, any bleeding
Dabigatran, any bleeding
Warfarin, MBE
Dabigatran, MBE
Warfarin and any bleeding
29% RRR
Dabigatran and
any bleeding
Dabigatran and
major bleeding
Warfarin and
major bleeding
Months since First Intake of Study Drug
The hazard ratio for any bleeding at 6 months is 0.71 (95% CI, 0.59–0.85) in favor of dabigatran (P=0.0002).
Stollingschema
Factor Xa
inhibitor
Anticoagulantia (nieuwer)
Factor Xa-inhibitoren
Fondaparinux (Arixtra), subcutaan
Rivaroxaban (Xarelto), oraal
Fondaparinux:
Indirect, AT-mediated FXa inhibition
Intrinsic
pathway
Extrinsic
pathway
Antithrombin
AT
AT
Fondaparinux
AT
Xa
Xa
II
IIa
Fibrinogen
Turpie AGG et al. N Engl J Med. 2001;344:619.
Fibrin clot
Clinical Development of Fondaparinux
Prevention
of VTE
2.5 mg
Major Orthopaedic Surgery
PENTATHLON
PENTATHLON 2000
PENTAMAKS
EPHESUS
PENTHIFRA
PENTHIFRA PLUS
Medical Patients
ARTEMIS
Abdominal Surgery
PEGASUS
APOLLO
Treatment
of VTE
7.5 mg
REMBRANDT
MATISSE DVT
MATISSE PE
Treatment
of ACS
2.5 mg
PENTALYSE
PENTUA
ASPIRE
OASIS 5
OASIS 6
Rivaroxaban:
Eerste directe FXa inhibitor
High oral bioavailability
Rapid onset of action
Half-life: 7–11 hours
Dual mode of elimination:
1/3 of drug excreted unchanged by the kidneys
2/3 of drug metabolized by the liver: half excreted
renally; half excreted via the faecal route
Rivaroxaban clinical program overview
Phase II
VTE prevention after major
orthopaedic surgery
Phase III
 ODIXa-HIP1
 ODIXa-HIP2
 ODIXa-KNEE
 ODIXa-OD-HIP
 RECORD1
10 mg OD
 RECORD2
 RECORD3
 RECORD4
VTE prevention in hospitalized
medically ill patients
VTE treatment
 ODIXa-DVT
 EINSTEIN-DVT
 EINSTEIN-DVT
 EINSTEIN-PE
 EINSTEIN-EXT
Stroke prevention in atrial
fibrillation
Secondary prevention of acute
coronary syndromes
3 Japanese dose-finding
studies
RECORD3: Rivaroxaban vs Enoxaparin
35 dagen na THP
20
RRR 49%
Enoxaparin 40 mg o.d.
18.9%
Rivaroxaban 10 mg o.d.
Incidence (%)
15
10
9.6%
RRR 61%
5
RRR 66%
NS
2.6%
1.0%
2.0%
0.7%
0.6%
0.5%
0
Total VTE
Major VTE
p < 0.001
Data from Lassen MR et al. N Engl J Med 2008;358:2776–86.
p = 0.010
Symptomatic VTE
p = 0.005
Major bleeding
p = 0.77
EINSTEIN DVT
Randomized, open-label, event-driven, non-inferiority study
Rivaroxaban
N=3,449
Confirmed symptomatic
DVT without
symptomatic PE
15 mg bid
20 mg od
R
Enoxaparin 1.0 mg/kg bid ≥5 days, followed by VKA INR range 2–3
Day 1
30-day observation
Rivaroxaban
period
Treatment period: 3, 6 or 12 months
Day 21
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EINSTEIN DVT trial ID: NCT00440193
Primary efficacy outcome:
time to first event
4.0
Cumulative event rate (%)
Enoxaparin/VKA (n=1,718)
3.0
Rivaroxaban (n=1,731)
2.0
1.0
0
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to event (days)
Number of
subjects at risk
Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1,220 400
369
363
345
309
266
Enox/VKA
362
337
325
297
264
1,718 1,616 1,581 1,553 1,368 1,358 1,186 380
Primary efficacy outcome analysis
Rivaroxaban
(n=1,731)
First symptomatic recurrent VTE
Recurrent DVT
Recurrent DVT + PE
Non-fatal PE
Fatal PE/unexplained death where
PE cannot be ruled out
Enoxaparin/VKA
(n=1,718)
n (%)
36 (2.1)
n (%)
51 (3.0)
14 (0.8)
28 (1.6)
1 (<0.1)
0 (0)
20 (1.2)
18 (1.0)
4 (0.2)
6 (0.3)
p<0.0001 for non-inferiority (one-sided)
p=0.076 for superiority (two-sided)
ITT population
31
Principal safety outcome:
time to first event
14
Enoxaparin/VKA (n=1,711)
Cumulative event rate (%)
12
10
Rivaroxaban (n=1,718)
8
6
4
2
0
0
Number of
subjects at risk
30
60
90
120
150
180
210
240
270
300
330
360
Time to event (days)
Rivaroxaban 1,718 1,585 1,538 1,382 1,317 1,297 715
355
338
304
278
265
140
Enox/VKA
338
321
287
268
249
118
1,711 1,554 1,503 1,340 1,263 1,238 619
Principal safety outcome analysis
Rivaroxaban
(n=1,718)
Enox/VKA
(n=1,711)
HR (95% CI)
n (%)
p value
139 (8.1)
138 (8.1)
0.97 (0.76–1.22)
p=0.77
14 (0.8)
20 (1.2)
n
First major or clinically relevant
non-major bleeding
Major bleeding
(%)
Contributing to death
1 (<0.1)
5 (0.3)
In a critical site
3 (0.2)
3 (0.2)
10 (0.6)
12 (0.7)
129 (7.5)
122 (7.1)
Associated with fall in Hb 2 g/dl
and/or transfusion of ≥2 units
Clinically relevant non-major bleeding
Safety population
Anticoagulantia (nieuwst)
Conclusies anticoagulantia
Nieuwe anticoagulantia
Trombine-inhibitoren
Factor Xa inhibitoren
Voordelen
Meestal geen monitoring nodig
Betere of gelijkwaardige trombose preventie
Minder of gelijkwaardige bloedingscomplicaties
Nadelen
Geen antidote
Hoge kost (beperkte terugbetaling)
Nieuwe middelen, dus nog beperkte gegevens over
veiligheid op langere termijn (ximelagatran)