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