Transcript Document
Nove spoznaje o
antikoagulacijskoj terapiji
Prof. Mijo
Bergovec,FESC, FACC
Medicinski fakultet Sveučilišta u Zagrebu
XXVIII STRUČNI SASTANAK
UDRUŽENJA KARDIOLOGA BiH
Orašje 7. aprila 2012.
1
Xa faktor i trombin imaju središnju ulogu u procesu koagulacije1,2
Intrinzični Ekstrinzičnii
(kontakt)
Antitrombin
(tkivni faktor)
Xa
X
Inaktivirani Xa
Antitrombin
Heparin kofaktor II
Inaktivrani
trombin
Trombin
Protrombin
(IIa)
Fibrinogen
Fibrin
“Zahvaljujući jedinstvenoj ulozi trombina u koagulacijskoj kaskadi,
njegova inhibicija je ključna u uspješnoj antikoagulacijskoj
farmakoterapiji.”2
1. Di Nisio M et al. N Engl J Med 2005; 353:1028–1040. 2. Gurm HS et al. Am Heart J 2005; 149(Suppl):S43–S53.
3. van Ryn J et al. Abstract accepted. Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), Atlanta, GA, USA. May 2008.
2
Warfarin
• Warfarin was launched as the ideal rat poison in
1948. Although it was thought at first to be too toxic
for human use
In 1951 the failed attempted suicide of a navy
recruit who had taken a large dose of rat poison
led clinicians to discard dicumarol in favor of
warfarin.
The first clinical study with warfarin
was reported in 1955. In the same year, President
Eisenhower was treated with warfarin following a
heart attack
Scully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdf
3
Warfarin vs. no Treatment or Placebo
Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005
4
Therapeutic
range
Odds ratio
15
Stroke
10
Intracranial bleed
5
1
0
1
2
3
4
5
International normalized ratio
VKAs = vitamin K antagonists
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354
& Eur Heart J 2006;27:1979–2030
6
7
8
5
Graph reproduced with permission: ©2010 American College of Chest Physicians
20
ANTAGONISTI VITAMINA K IMAJU UZAK
TERAPIJSKI PROZOR
5
Prevalence of Major Hemorrhage
Major Hemorrhage in First Year
of Warfarin Therapy
Age > 80
Age < 80
0.10
0.08
9 intracranial bleeds
3 fatal
8/9 age > 75
0.06
0.04
0.02
0.00
0
100
Hylek EM, et al. Circulation. 2007;115:2689-2696.
200
Days on Warfarin
300
6
Intracerebralno krvarenje:
najopasnija komplikacija antitrombotske terapije
>10% of intracerebral haemorrhages occur in patients on
antithrombotic therapy
Intracerebral haemorrhages during anticoagulation can be
life-threatening
Compared with placebo, antithrombotic therapy increases the risk
of intracerebral haemorrhage:
~40% with Aspirin
~200% with warfarin (INR 2.0–3.0; increases to 0.3–0.6%/year)
INR = international normalized ratio
Hart RG et al. Stroke 2005;36:1588–93
7
7
terapija heparinom
prekid th
24 h
4-5 dana
Varfarin
(STAR 50 GODINA)
INR 2.0
5-10 mg
oralni antikoagulans
Haemostasis 1998
8
ZAŠTO SU POTREBNE
PROMJENE ?
• NEZADOVOLJSTVO POSTOJEĆIM
• NOVA SAZNANJA
• ISKUSTVO
9
RADI TOGA POTREBNI SU
NOVI LIJEKOVI
10
Key Steps in Coagulation Pathway
Intrinsic pathway
Extrinsic pathway
IXa
1
VIIIa
Xa
PL
Ca2+
X
Inhibition of one molecule
of factor Xa can inhibit the
generation of 50 molecules
of thrombin2
Xa
Va
Ca2+
II
PL
IIa
50
Fibrin
Fibrinogen
Clot
1. Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64.
2. Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8.
11
II a
12
New anticoagulant therapy
ORAL
PARENTERAL
TF/VIIa
TTP889
TFPI (tifacogin)
X
Rivaroxaban
Apixaban
LY517717
YM150
Edoxaban
Betrixaban
TAK 442
IX
VIIIa
Va
Xa
APC (drotrecogin alfa)
sTM (ART-123)
IXa
AT
II
Dabigatran
Fondaparinux
Idraparinux
DX-9065a
IIa
Fibrinogen
Adapted from Weitz & Bates, J Thromb Haemost 2007
Fibrin
13
Search for New
Anti-Coagulants
Extrinsic Limb
Intrinsic Limb
Tissue factor
released by damaged cells
Contact activation
FXa Inhibitors
Edoxaban
ENGAGE AF-TIMI 48
Rivaroxaban
ROCKET
Apixaban
ARISTOTLE
VIIa
X
Xa
FXa Inhibitors
X
Prothrombin (II)
Va
V
VII
XIII
Thrombin
X
Fibrinogen
DTIs
Fibrin
DTI
Dabigatran
RE-LY
XIIIa
Cross-linked fibrin
Fibrin Degradation
14
14
14
New Anticoagulants:
Summary of Profile
Name
Rivaroxaban
Apixaban
Dabigatran
Edoxaban
Company
Bayer/J&J
BMS/Pfizer
Boehringer
Daiichi Sankyo
Time to Cmax
2-3 h
3h
2h
2h
CYP Metabolism
32%3
15%10
none
< 4%
> 40%2
43 – 46%10
4-5%12
> 45%
P-gp/BCRP3
P-gp
P-gp12
P-gp
92-95%3,4
87%9
34-35%12
54%
5-9 h1,2
9-15 h6
14-17 h12
8-10 h
Total 66%
Unchanged: 36%3,5
Total: 25 - 29%
Unchanged:24%10
Total: 85%
Majority unchanged12
Total: 35%
Unchanged: 24%
no
yes
unknown
yes
Bioavailability
Transporters
Protein binding
Half life
Renal
Elimination
Linear PK
D et al. Eur J Clin Pharmacol. 2005;61:873-880. 2Kubitza D et al. Clin Pharmacol Therap. 2005;78:412-421. 3FDA
Briefing material. Available from URL: http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4417b1-01-FDA.pdf. 4Xarelto.
Summary of Product Characteristics - EU. 2008. 5WeinzCONFIDENTIAL
C et al. Drug Metab Dispos. 2009;37:1056-64. 6Frost C et al. J Thromb
15
Hemostas. 2007;5:suppl 2:P-M-664. 7Frost C et al. J Thromb Hemostas. 2007;5:suppl 2: P-M-665. 8Frost C et al. J Clin
15
Pharmacol. 2008;48:Abstract 142. 9He K et al. Blood. 2006;108: Abstract 910. 10Raghavan et al. Drug Metab Dispos. 200911
15
1Kubitza
15
Antikoagulacijsko liječenje
bez određivanja INR
APIXABAN
DABIGRATRAN
EDOXABAN
RIVAROXABAN
16
Apixaban
Oral, direct, selective factor Xa inhibitor
O
Produces concentration-dependent
anticoagulation
N
No formation of reactive intermediates
No organ toxicity or LFT abnormalities in
chronic toxicology studies
NH2
N
O
O
N
Low likelihood of drug interactions or QTc
prolongation
Good oral bioavailability
No food effect
N
O
Balanced elimination (~25% renal)
Half-life ~12 hrs
He et al., ASH, 2006, Lassen, et al ASH, 2006
17
Apixaban :Phase II
Apropos – orthopaedic surgery
Botticelli – treatment
Adapt – advanced cancer
Appraise 1 – ACS
Apixaban : Phase III
Advance 1,2,3 – orthopaedic surgery
Adopt – medically ill
Aristotle -atrial fibrillation
Appraise 2 - ACS
Dabigatran for prevention of VTE after major orthopaedic surgery:
results
Enoxaparin
Dabigatran
(150 mg)
Dabigatran
(220 mg)
DVT, PE and all-cause mortality (%)
RE-NOVATE
RE-MOBILIZE
6.7
25.3
8.6
6.0
p<0.0001*
p<0.0001*
33.7
31.1
p=0.0009
RE-MODEL
37.7
†
p=0.02†
40.5
36.4
p=0.0005*
p=0.0345*
Major bleeding (%)
RE-NOVATE
1.6
1.3
2.0
RE-MOBILIZE
1.4
0.6
0.6
RE-MODEL
1.3
1.3
1.5
*Non-inferior to enoxaparin; †inferior to enoxaparin
Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007
20
RE-LY – opće informacije
R E L Y ®: Randomised Evaluation of Long term
anticoagulant therapy
18,113 randomiziranih bolesnika kroz 2 godine
12 / 2005 – 03 / 2009
964 centra u 44 zemlje
Primarni cilj: utvrditi jednaku djelotvornost dabigatran eteksilata u
odnosu na warfarin
Rezultati su predstavljeni prvi puta na Kongresu Europskog društva
kardiologa te objavljeni online u New England Journal of Medicine
21
RE-LY – dizajn studije
Atrijska fibrilacija sa ≥ 1 rizičnim faktorom
Odsutnost kontraindikacija
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
Dabigatran eteksilat
110 mg (2x dnevno)
N=6000
Dabigatran eteksilat
150 mg (2x dnevno)
N=6000
22
RE-LY – rezultati studije
Dabigatran 110 mg vs. warfarin
Usporediva učestalost moždanih/sistemskih embolija
Statistički značajno smanjenje hemoragijskih moždanih udara
Statistički značajno smanjenje velikih krvarenja
Značajno smanjenje ukupnog broja krvarenja, po život opasnih krvarenja i
intrakranijalnog krvarenja
Dabigatran 150 mg vs. warfarin
Statistički značajno smanjenje moždanih/sistemskih embolija
Statistički značajno smanjenje hemoragijskih moždanih udara
Statistički značajno smanjenje krvožilnih uzroka smrti
Usporediva učestalost velikih krvarenja
Značajno smanjenje ukupnog broja krvarenja, po život opasnih krvarenja i
intrakranijalnog krvarenja
23
RE-LY – zaključci
U usporedbi s bolesnicima koji su dobro kontroliranim
varfarinom, dabigatran eteksilat je pokazao:
Značajno smanjenje rizika od moždanog udara i sistemske
embolije – uključujući hemoragijske moždane udare (150 mg –
34%)
Značajno manje krvarenja – uključujući po život opasno i
intrakranijsko krvarenje (110 mg – 21%)
Značajno smanjenje svih uzroka smrtnosti
“ ... dabigatran eteksilat u dozi od 150mg dva puta
dnevno može spriječiti oko 3.000 moždanih udara
dnevno širom svijeta u usporedbi s dobro kontroliranim
varfarinom. “
24
Rivaroxaban: oral direct Factor Xa inhibitor
Predictable pharmacology
High bioavailability
O
O
Low risk of drug–drug
interactions
N
O
N
O
Cl
S
H
N
O
Rivaroxaban® – rivaroxaban
Fixed dose
No requirement for monitoring
Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005
25
RIVAROXABAN
Clinical programme overview:
50,000 patients to be enrolled
Phase II
VTE prevention after major
orthopaedic surgery
Phase III
ODIXa-HIP1
ODIXa-HIP2
ODIXa-KNEE
ODIXa-OD-HIP
RECORD1
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
Japanese Phase III study
Secondary prevention of acute
coronary syndromes
~8,000
>42,000
26
Oral rivaroxaban compared with
subcutaneous enoxaparin for extended
thromboprophylaxis after total hip
arthroplasty
RECORD1: summary
5
Rivaroxaban 10 mg once daily
Enoxaparin 40 mg once daily
Total VTE
Incidence (%)
4
RRR 70%
3
Major VTE
RRR 88%
2
Symptomatic VTE
Major bleeding
1
3.7%
0
1.1%
2.0%
0.2%
0.5%
0.3%
0.1%
0.3%
28
Extended thromboprophylaxis with rivaroxaban
compared with short-term thromboprophylaxis
with low molecular weight heparin
after total hip arthroplasty
RECORD2: summary
10
Total VTE
Rivaroxaban 10 mg once daily
Enoxaparin 40 mg once daily
Incidence (%)
8
6
Major VTE
4
Symptomatic VTE
RRR 78.9%
2
Major bleeding
RRR 87.8%
9.3%
2.0%
RRR 80.1%
5.1%
0.6%
1.2%
0.2%
0.1%
0.1%
0
30
Rivaroxaban – an oral, direct Factor Xa inhibitor –
for the prevention of venous thromboembolism in
total knee arthroplasty surgery
RECORD3: summary
20
Total VTE
RRR 49%
Enoxaparin
40 mg od
Rivaroxaban 10 mg od
Incidence (%)
15
10
Major VTE
5
RRR 62%
18.9%
9.6%
2.6%
1.0%
Symptomatic VTE
Major bleeding
RRR 65%
2.0%
0.7%
NS
0.5%
0.6%
0
32
Alexander T Cohen
On behalf of the MAGELLAN Steering Committee
and Investigators
Rivaroxaban compared with
enoxaparin for the prevention
of venous thromboembolism
in acutely ill medical patients
33
MAGELLAN: clinical trial design
Day 10
(6–14)
8,101 patients
randomized
Day 35
(31–39)
Day 90
(83–97)
Oral rivaroxaban 10 mg od 35±4 days
Patients ≥40
years
hospitalized for
acute medical
illness with
decreased level
of mobility
s.c. placebo
10±4 days
R
Follow-up
period
to Day 90
Oral placebo
35±4 days
s.c. enoxaparin
40 mg od 10±4 days
Ultrasonography
on day 10±4
Primary efficacy outcome
(non-inferiority)
Cohen et al, 2011
Ultrasonography
on day 35±4
Primary efficacy outcome
(superiority)
34
34
Primary efficacy outcome: Day 10*
Primary efficacy outcome
Asymptomatic proximal DVT
Symptomatic lower extremity DVT
Rivaroxaban Enoxaparin
(n=2,939)
(n=2,993)
n %
n %
78 2.7
82 2.7
71 2.4
71 2.4
7 0.2
6 0.2
Symptomatic non-fatal PE
VTE-related death‡
0.713
0
6 0.2
3 0.1
0.968
1.334
1.00 1.50
Relative risk ratio
Superior
2 <0.1
6 0.2
Noninferior
p=0.0025 for non-inferiority
(one-sided)
Inferior
* PP population, events up to Day 10 + 5 days; ‡includes cases where PE cannot be ruled out
35
35
Primary efficacy outcome: Day 35*
Primary efficacy outcome
Asymptomatic proximal DVT
Symptomatic lower extremity DVT
Symptomatic non-fatal PE
VTE-related death†
0.618
0
0.771
Rivaroxaban
Enoxaparin/placebo
(n=2,967)
n %
131 4.4
103 3.5
13 0.4
10 0.3
19 0.6
(n=3,057)
n %
175 5.7
133 4.4
15 0.5
14 0.5
30 1.0
0.962
ARR 1.3%, RRR 22.9%
1.00
Relative risk ratio
Superior
Noninferior
*mITT population, events up to Day 35 + 6 days; †4 confirmed fatal PEs
p=0.0211 for superiority
(two-sided)
Inferior
36
36
Summary
MAGELLAN met its primary efficacy endpoints
Day 10: rivaroxaban was non-inferior to enoxaparin in reducing
the risk of VTE
Day 35: extended thromboprophylaxis rivaroxaban was superior
to enoxaparin followed by placebo in reducing the risk of VTE
Overall bleeding rates were low, but significantly higher in
the rivaroxaban arm across the entire study period
Rates of other adverse events, including liver and
cardiovascular events, were similar in both arms
37
37
Rivaroxaban-Clinical Studies
- VTE Treatnent
- Atrial Fibrillation
ACS treatment
38
Rivaroxaban Once-daily oral direct factor Xa inhibition Compared
with vitamin K antagonism for prevention of stroke and Embolism
Trial in Atrial Fibrillation
Kenneth W. Mahaffey, MD and Keith AA Fox,
MB ChB
on behalf of the ROCKET AF Investigators39
Risk Factors
• CHF
• Hypertension
At least 2 or
3 required*
• Age 75
• Diabetes
OR
• Stroke, TIA or
Systemic embolus
Study Design
Atrial Fibrillation
Rivaroxaban
20 mg daily
15 mg for Cr Cl 30-49 ml/min
Randomize
Double Blind /
Double Dummy
(n ~ 14,000)
Warfarin
INR target - 2.5
(2.0-3.0 inclusive)
Monthly Monitoring
Adherence to standard of care guidelines
Primary Endpoint: Stroke or non-CNS Systemic Embolism
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
40
Primary Efficacy Outcome
Stroke and non-CNS Embolism
Cumulative event rate (%)
6
5
4
3
Even
t
Rate
Rivaroxaban
Warfarin
1.71
2.16
Warfarin
Rivaroxaban
HR (95% CI): 0.79 (0.66, 0.96)
P-value Non-Inferiority: <0.001
2
1 No. at risk:
Rivaroxaban 6958
Warfarin
7004
0
Days from Randomization
6211
6327
5786
5911
5468
5542
Event Rates are per 100 patient-years
Based on Protocol Compliant on Treatment Population
0
120
240
360
4406
4461
480
3407
3478
600
2472
2539
1496
1538
720
634
655
840
41
960
Summary ROCKET AF
Efficacy:
Rivaroxaban was non-inferior to warfarin for prevention of
stroke and non-CNS embolism.
Rivaroxaban was superior to warfarin while patients were
taking study drug.
By intention-to-treat, rivaroxaban was non-inferior to warfarin
but did not achieve superiority.
Safety:
Similar rates of bleeding and adverse events.
Less ICH and fatal bleeding with rivaroxaban.
Conclusion:
Rivaroxaban is a proven alternative to warfarin for moderate or
high risk patients with AF.
42
The Effective Anticoagulation With Factor
Xa Next Generation in Atrial Fibrillation
ENGAGE AF-TIMI 48
EDOXABAN
Steering and Investigator Meeting
Orlando, Florida
November 15, 2009
43
43
DA LI SE MEĐU OVIM LIJEKOVIMA NALAZI
IDEALAN ANTIKOAGULACIJSKI LIJEK ?
II a
44
Najveći problem
inhibitora Xa faktora i oralnih antitrombina:
NE POSTOJI ANTIDOT
potreban u slučaju komplikacija krvarenja!
45