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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.
2
Xa faktor i trombin imaju središnju ulogu u proces u koagulacije1,2
“ Zahvaljujući jedinstvenoj ulozi trombina u koagulacijskoj kaskadi, njegova inhibicija je ključna u uspješnoj antikoagulacijskoj
farmakoterapiji.”2
Inaktivirani Xa
InaktivranitrombinProtrombin
Fibrinogen Fibrin
Trombin(IIa)
XaX
AntitrombinIntrinzični(kontakt)
Ekstrinzičnii(tkivni faktor)
AntitrombinHeparin kofaktor II
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.
3
In 1951 the failed attempted suicide of a navy In 1951 the failed attempted suicide of a navy recruit who had taken a large dose of rat poison recruit who had taken a large dose of rat poison led clinicians to discard dicumarol in favor of led clinicians to discard dicumarol in favor of warfarin.warfarin.
The first clinical study with warfarinThe first clinical study with warfarin was reported in 1955. In the same year, President was reported in 1955. In the same year, President Eisenhower was treated with warfarin following a Eisenhower was treated with warfarin following a heart attackheart attack
WarfarinWarfarin
Scully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdfScully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdf
• Warfarin was launched as the ideal rat poison Warfarin was launched as the ideal rat poison in 1948. Although it was thought at first to be in 1948. Although it was thought at first to be too toxic for human usetoo toxic for human use
4
Warfarin vs. no Treatment or PlaceboWarfarin vs. no Treatment or Placebo
Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005
5
Therapeuticrange
1International normalized ratio
Odds
rati
o
2
15
8
10
5
01
3 4 5 6 7
20
5
ANTAGONISTI VITAMINA K IMAJU UZAK TERAPIJSKI PROZOR
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354& Eur Heart J 2006;27:1979–2030
Stroke
Intracranial bleed
VKAs = vitamin K antagonists
Gra
ph
rep
rod
uce
d w
ith
perm
issi
on
: ©
20
10
Am
eri
can
Colle
ge o
f C
hest
Ph
ysi
cian
s
6
Major Hemorrhage in First Yearof Warfarin Therapy
Hylek EM, et al. Circulation. 2007;115:2689-2696.
9 intracranial bleeds3 fatal8/9 age > 75
0 100 200 300 Days on Warfarin
Age > 80Age < 80
Pre
vale
nc
e o
f M
ajo
r H
em
orr
ha
ge
0.00
0.02
0.04
0.06
0.08
0.10
7
Intracerebralno krvarenje: najopasnija komplikacija antitrombotske terapije
>10% of intracerebral haemorrhages occur in patients on antithrombotic therapy
Intracerebral haemorrhages during anticoagulation can belife-threatening
Compared with placebo, antithrombotic therapy increases the riskof intracerebral haemorrhage:
~40% with Aspirin
~200% with warfarin (INR 2.0–3.0; increases to 0.3–0.6%/year)
7Hart RG et al. Stroke 2005;36:1588–93INR = international normalized ratio
8
terapija heparinom prekid th
24 h
4-5 dana
Varfarin(STAR 50 GODINA) INR 2.0
5-10 mg
oralni antikoagulans Haemostasis 1998
9
ZAŠTO SU POTREBNEPROMJENE ?
• NEZADOVOLJSTVO POSTOJEĆIM
• NOVA SAZNANJA
• ISKUSTVO
10
RADI TOGA POTREBNI SU NOVI LIJEKOVI
11
Key Steps in Coagulation Pathway
Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin2
Intrinsic pathway Extrinsic pathway
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.
Intrinsic pathway
1
50
Xa X
II
FibrinFibrinogen
Clot
Xa
Va
PL
Ca2+
IIa
VIIIa
Ca2+
PL
IXa
12
II a
13
New anticoagulant therapy
TFPI (tifacogin)
FondaparinuxIdraparinux
RivaroxabanApixabanLY517717YM150EdoxabanBetrixabanTAK 442
Dabigatran
ORAL PARENTERAL
DX-9065a
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
AT
APC (drotrecogin alfa)sTM (ART-123)
Adapted from Weitz & Bates, J Thromb Haemost 2007
TTP889
1414 14
Search for NewAnti-Coagulants
Intrinsic Limb
Contact activation
Tissue factor released by damaged cells
X Xa
Thrombin
Fibrinogen Fibrin Cross-linked fibrin
XIII
XIIIa
VIIVIIa
Va V
Prothrombin (II)
Fibrin Degradation
Extrinsic Limb
FXa Inhibitors X
DTIsX
Edoxaban
Rivaroxaban
Apixaban
Edoxaban
Rivaroxaban
Apixaban
ENGAGE AF-TIMI 48
ROCKET
ARISTOTLE
ENGAGE AF-TIMI 48
ROCKET
ARISTOTLE
FXa InhibitorsFXa Inhibitors
Dabigatran RE-LY
Dabigatran RE-LY
DTIDTI
1515
CONFIDENTIAL 15
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 3 h 2 h 2 h
CYP Metabolism 32%3 15%10 none < 4%
Bioavailability > 40%2 43 – 46%10 4-5%12 > 45%
Transporters P-gp/BCRP3 P-gp P-gp12 P-gp
Protein binding 92-95%3,4 87%9 34-35%12 54%
Half life 5-9 h1,2 9-15 h6 14-17 h12 8-10 h
Renal Elimination
Total 66%Unchanged: 36%3,5
Total: 25 - 29%Unchanged:24%10
Total: 85%Majority unchanged12
Total: 35%Unchanged: 24%
Linear PK no yes unknown yes
1Kubitza 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. 5Weinz C et al. Drug Metab Dispos. 2009;37:1056-64. 6Frost C et al. J ThrombHemostas. 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 ClinPharmacol. 2008;48:Abstract 142. 9He K et al. Blood. 2006;108: Abstract 910. 10Raghavan et al. Drug Metab Dispos. 200911
Gross & Weitz, CPT, 2009 12 CHMP Pradaxa Review15
16
Antikoagulacijsko liječenje bez određivanja INR
APIXABAN
DABIGRATRAN
EDOXABAN
RIVAROXABAN
17
Apixaban
Oral, direct, selective factor Xa inhibitor
Produces concentration-dependent anticoagulation
No formation of reactive intermediates
No organ toxicity or LFT abnormalities in chronic toxicology studies
Low likelihood of drug interactions or QTc prolongation
Good oral bioavailability
No food effect
Balanced elimination (~25% renal)
Half-life ~12 hrs
He et al., ASH, 2006, Lassen, et al ASH, 2006
N
N
NO
N O
NH2
O
O
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
20
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 6.7 8.6 p<0.0001*
6.0p<0.0001*
RE-MOBILIZE 25.3 33.7p=0.0009†
31.1p=0.02†
RE-MODEL 37.7 40.5p=0.0005*
36.4p=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
21
R E L Y ®: Randomised Evaluation of Long term anticoagulant therapy
18,113 2 randomiziranih bolesnika kroz godine12 / 2005 – 03 / 2009964 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
- – RE LY opće informacije
22
- – RE LY dizajn studije
Atrijska fibrilacija sa ≥ 1 rizičnim faktorom Odsutnost kontraindikacija
R
Warfarin1 mg, 3 mg, 5 mg
(INR 2.0-3.0)N=6000
Dabigatran eteksilat 110 mg (2 )x dnevno
N=6000
Dabigatran eteksilat 150 mg (2 )x dnevno
N=6000
23
- – RE LY rezultati studije
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
Dabigatran 110 mg v .s 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
24
- – 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 – mg34%)Značajno manje krvarenja – uključujući po život opasno i
intrakranijsko krvarenje (110 – 21%)mgZnačajno 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. “
25
Rivaroxaban: oral direct Factor Xa inhibitor
Predictable pharmacology
High bioavailability
Low risk of drug–drug interactions
Fixed dose
No requirement for monitoring
Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005
Rivaroxaban® – rivaroxaban
N NO
NH
O
SCl
O
O
O
26
RIVAROXABAN Clinical programme overview: 50,000 patients to be enrolled
VTE prevention in hospitalized medically ill patients
Secondary prevention of acute coronary syndromes
Japanese Phase III study
Stroke prevention in atrial fibrillation
EINSTEIN-DVT
EINSTEIN-PE
EINSTEIN-EXT
ODIXa-DVT
EINSTEIN-DVT
VTE treatment
RECORD1
RECORD2
RECORD3
RECORD4
ODIXa-HIP1
ODIXa-HIP2
ODIXa-KNEE
ODIXa-OD-HIP
VTE prevention after major orthopaedic surgery
Phase III Phase II
>42,000~8,000
Oral rivaroxaban compared with subcutaneous enoxaparin for extended
thromboprophylaxis after total hip arthroplasty
28
RECORD1: summaryIn
cide
nce
(%)
Total VTE
Major bleeding
Enoxaparin 40 mg once daily
Rivaroxaban 10 mg once daily
0
1
2
3
4
5
0.5% 0.3% 0.1% 0.3%
Symptomatic VTE
RRR 70%
2.0% 0.2%
Major VTE
RRR 88%
1.1%3.7%
Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis
with low molecular weight heparin after total hip arthroplasty
30
RECORD2: summary
Total VTE
Major bleeding
Major VTE
Inci
denc
e (%
)
0
2
4
6
10
8
9.3%
RRR 78.9%
2.0% 5.1% 0.1% 0.1%0.6%
RRR 87.8%RRR 80.1%
1.2% 0.2%
Symptomatic VTE
Enoxaparin 40 mg once daily
Rivaroxaban 10 mg once daily
Rivaroxaban – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in total knee arthroplasty surgery
32
RECORD3: summary
Total VTE
Major bleeding
20
Inci
den
ce (
%)
0
Major VTE
5
10
15
NS
RRR 49%
RRR 62%
Symptomatic VTE
Rivaroxaban 10 mg od
Enoxaparin 40 mg od
RRR 65%
0.5% 0.6%18.9% 9.6% 2.6% 1.0% 2.0% 0.7%
33
Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients
Alexander T Cohen
On behalf of the MAGELLAN Steering Committee and Investigators
3434
Patients ≥40 years hospitalized for acute medical illness with decreased level of mobility
Oral rivaroxaban 10 mg od 35±4 days
s.c. enoxaparin40 mg od 10±4 days
Day 35(31–39)
Oral placebo 35±4 days
Follow-up period
to Day 90
s.c. placebo 10±4 days
Ultrasonography on day 10±4
Ultrasonography on day 35±4
Primary efficacy outcome (non-inferiority)
Primary efficacy outcome (superiority)
Day 10(6–14)
8,101 patients randomized
MAGELLAN: clinical trial design
R
Day 90(83–97)
Cohen et al, 2011
3535
Primary efficacy outcome: Day 10*
* PP population, events up to Day 10 + 5 days; ‡includes cases where PE cannot be ruled out
Rivaroxaban (n=2,939)
Enoxaparin(n=2,993)
n % n %Primary efficacy outcome 78 2.7 82 2.7
Asymptomatic proximal DVT 71 2.4 71 2.4Symptomatic lower extremity DVT 7 0.2 6 0.2
Symptomatic non-fatal PE 6 0.2 2 <0.1 VTE-related death‡ 3 0.1 6 0.2
0.713 1.3340.968
Relative risk ratio
Superior Non-inferior
Inferior
p=0.0025 for non-inferiority (one-sided)
1.00 0 1.50
3636
Primary efficacy outcome: Day 35*
*mITT population, events up to Day 35 + 6 days; †4 confirmed fatal PEs
Rivaroxaban (n=2,967)
Enoxaparin/placebo(n=3,057)
n % n %Primary efficacy outcome 131 4.4 175 5.7
Asymptomatic proximal DVT 103 3.5 133 4.4Symptomatic lower extremity DVT 13 0.4 15 0.5 Symptomatic non-fatal PE 10 0.3 14 0.5 VTE-related death† 19 0.6 30 1.0
1.00 0
0.618 0.9620.771
Relative risk ratio
p=0.0211 for superiority (two-sided)
ARR 1.3%, RRR 22.9%
Superior Non-inferior
Inferior
3737
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
38
Rivaroxaban-Clinical Studies
- VTE Treatnent
- Atrial Fibrillation
ACS treatment
39
Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB
on behalf of the ROCKET AF Investigators
Rivaroxaban Once-daily oral direct factor Xa inhibition Compared
with vitamin K antagonism for prevention of stroke and Embolism
Trial in Atrial Fibrillation
40
Rivaroxaban Warfarin
Primary Endpoint: Stroke or non-CNS Systemic Embolism
INR target - 2.5 (2.0-3.0 inclusive)
20 mg daily15 mg for Cr Cl 30-49 ml/min
Atrial Fibrillation
RandomizeDouble Blind / Double Dummy
(n ~ 14,000)
Monthly MonitoringAdherence to standard of care guidelines
Study Design
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or Systemic embolus
At least 2 or 3 required*
41
Primary Efficacy OutcomeStroke and non-CNS Embolism
Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population
No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655
Warfarin
HR (95% CI): 0.79 (0.66, 0.96)
P-value Non-Inferiority: <0.001
Days from Randomization
Cu
mu
lati
ve e
ven
t ra
te (
%)
Rivaroxaban
Rivaroxaban Warfarin
Event Rate
1.71 2.16
42
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.
4343
Steering and Investigator Meeting Orlando, Florida
November 15, 2009
The Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation
ENGAGE AF-TIMI 48
EDOXABAN
44
DA LI SE MEĐU OVIM LIJEKOVIMA NALAZI
IDEALAN ANTIKOAGULACIJSKI LIJEK ?
II a
45
Najveći problem inhibitora Xa faktora i oralnih antitrombina:
NE POSTOJI ANTIDOT
potreban u slučaju komplikacija krvarenja!