Svjetski dan zdravlja, 7. april 2013. godine
Naučni simpozijum
ATRIJALNA FIBRILACIJA
UDRUŽENJE KARDIOLOGA BiH
Radna grupa za aterosklerozu
Radna grupa za naprasnu smrt
Radna grupa za bazična istraživanja
Udruženje kardiologa HNK/Ž
Novi oralni antikoagulansi u
prevenciji trombembolijskog rizika
kod fibrilacije atrija
Akademik Doc.dr Emir Fazlibegović, ESC, FESC
Mostar 04.04.2013.
Kratka istorija antikoagulanasa
UFH: antitrombin zavisna inhibicija FXa
i thrombina u odnosu 1:1
Parenteral
1930s
VKAs: indirektni uticaj na sintezu brojnih od
vitamina K-zavisnih faktora koagulacije
Oral
Parenteral
1940s
LMWH: antitrombin-zavisna inhibicija
FXa >trombin
Parenteral
DTIs
Parenteral
Indirektni FXa inhibitori
Oral
Oral
1980s
1990s
2000s
DTIs
Direktni FXa
inhibitori
 Oralni warfarin je jedini antikoagulans za hroničnu upotrebu
UFH, nefrakcionirani heparin; LMWH, niskomolekularni heparin; DTIs, direktni inhibitori trombina
Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990
Potencijali antikoagulansi
i njihova ciljna mjesta
ORALNI
PARENTERALNI
TFPI (tifacogin)
TF/VIIa
TTP8
89
X
IX
VIIIaIXa
Va
AT
Xa
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
II (trombin)
Betrixaban
IIa
Dabigat
ran
Fibrinogen
Fibrin
APC (drotrecogin alfa)
sTM (ART-123)
Fondaparinux
Idraparinux
DX-9065a
Otamixaban
APC, activated protein C; AT, antithrombin; sTM, soluble thrombomodulin; TF, tissue factor;
TFPI, tissue factor pathway inhibitor
Adapted from Weitz & Bates. J Thromb Haemost 2005
Faktori koji utiču na primjenu
antikoagulanasa
Starost od 80 i > godina
(biološka prema hronološkoj)
Procjena rizika od krvarenja
(absolutni prema relativni)
Mogućnost INR monitoringa
(prevoz, udaljenost, cijena)
Pacijentove želje
(razmotriti životni stil)
INR, international normalized ratio
Prosthetic Valves Thromboses
Rizik od krvarenja kod pacijenata sa
AIM tretiranih različitim
kombinacijama:aspirin, clopidogrel i
vitamin K antagonista
CHADS -2 / HAS - BLED
SCORE
Nove strategije sa novim
antikoagulansima
Heparin(s)
Fondaparinux
Početno odmjeravanje dvije standarne
opscije
AVK
Istraživanje novih oralnih antikoagulanasa
Heparin(s)
Fondaparinux
Dabigatran
Jedan lijek u jednoj dozi u dugoroćnoj prevenciji
Apixaban,
Rivaroxaban
Velike studije sa novom generacijom
antikoagulanasa
Dabigatran
Rivaroxaban
Apixaban
RE-MODEL
VTE
prevencija
RE-NOVATE
RECORD 1-4
ADVANCE I-III
RE-MOBILIZE
MAGELLAN
ADOPT
RE-SOLVE
RE-COVER
VTE tretman
EINSTEIN-DVT
RE-MEDY
EINSTEIN-PE
RE-SONATE
EINSTEIN-EXT
AMPLIFY
AMPLIFY-EXT
Primary Endpoint of Stroke or Systemic
Embolism: Non-inferiority Analysis
Non Inferiority
p vs warfarin
RE-LY
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
1.53% per year
1.11% per year
1.69% per year
ROCKET AF
Rivaroxaban 20mg
Warfarin
1.7% per year
2.2% per year
ARISTOTLE
Apixaban 5 mg
Warfarin
1.27% per year
1.60% per year
ITT Analysis
HR = 0.91
HR = 0.66
p<0.001
p<0.001
Modified ITT
HR = 0.79
p<0.001
ITT Analysis
HR = 0.79
p<0.001
ROCKET showed non-inferiority in ITT analysis.
An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous
patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis
for performing a per-protocol analysis in a non-inferiority assessment.
NB: Indirect comparison only. No head to head comparison available.
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
Hemorrhagic Stroke
RELY
Dabigatran 110 mg
Dabigatran 150 mg
0.12% / yr
0.10% / yr
Warfarin
0.38% / yr
ROCKET
Rivaroxaban 20 mg
0.26% / yr
Warfarin
ARISTOTLE
Apixaban 5 mg
Warfarin
HR
0.31
0.26
ITT
P-value
<0.001
<0.001
0.59
0.012*
0.51
<0.001
0.44% / yr
0.24% / yr
0.47% / yr
*In an on treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr
for warfarin, p=0.024. No on treatment analysis is available from RE-LY.
NB: Indirect comparison only. No head to head comparison shown.
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
Ischemic Stroke
HR
RELY
Dabigatran 110 mg
Dabigatran 150 mg
1.34% / yr
0.92% / yr
Warfarin
1.20% / yr
ROCKET
Rivaroxaban 20 mg
1.62% / yr
Warfarin
ARISTOTLE
Apixaban 5 mg
Warfarin
1.20
0.76
ITT
P-value
0.35
0.03
0.99
0.92*
0.92
0.42
1.64% / yr
0.97% / yr
1.05% / yr
*In an on treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and
1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY.
NB: Indirect comparison only. No head to head comparison available
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
RE-LY
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Major Bleeding
2.71% / yr
3.11% / yr
HR
0.8
0.93
ITT
P-value
0.003
0.31
0.92
On Treatment
P-value
0.58*
3.36
150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052
ROCKET
Rivaroxaban 20 mg
3.60% / yr
Warfarin
3.45% / yr
2 g drop
*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.
ARISTOTLE
Apixaban 5 mg
2.13% / yr
Warfarin
3.09% / yr
0.69
P-value
<0.001
2 g drop in 24 hours
NB: Indirect comparison only. No head to head comparison availa
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
All Cause Mortality
RELY
Dabigatran 110 mg
Dabigatran 150 mg
3.75% / yr
3.64% / yr
Warfarin
4.13% / yr
ROCKET
Rivaroxaban 20 mg
4.52% / yr
Warfarin
ARISTOTLE
Apixaban 5 mg
Warfarin
HR
0.91
0.88
ITT
p-value
0.35
0.051
0.92
0.152*
0.89
0.01
4.91% / yr
3.52% / yr
3.94% / yr
95% CI 0.89 (0.80, 0.998)
N=448 events planned, 480 in trial
*In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21%
/ yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY.
NB: Indirect comparison only. No head to head comparison available.
C. Michael Gibson, M.S., M.D.
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
VerifyNowTM
(Ultegra rapid platelet function assay)
• Turbidimetric based optical detection system –
to measure PLT induced aggregation as an increase
in light transmission
• Simple, rapid report, not require specialized technician
“Point-of-care system”
Impact of Platelet Reactivity on Clinical Outcomes After
PCI Failure Rate for Normal and High On-Treatment
Platelet Reactivity (P2Y12 reaction unit - PRU > 230)
Brar S J Am Coll Cardiol, 2011; 58:1945-1954
Gene-Matrix Trial
4000 PCI patients
Standard of care
vs
Customized antiplatelet treatment according to platelet
Function Testing and genotyping for CYP450 2C19*2 and ABCB1 C
ClinicalTrials.gov Identifier: NCT01477775
What is cooking behind the scene ?
 New regimens / applications
 Accoast
 Atlantic
 Pegasus
 Euromax (bivalirudin vs SOC STEMI)
 Brave 4 (prasugrel + bivalirudin vs SOC in STEMI)
 AAA (dabigatran in Afib & ACS)
 Re-Align (Dabigatran in mechanical heart valves)
 New antiplatelet agents
 Elinogrel / Cangrelor / Vorapaxar
 New anticoagulants (very many)
New Parenteral Anticoagulants
under Investigation
 Idrabiotaparinux,
 ultra-low-molecular-weight heparins, re-engineered UFH [M118]),
 Direct FIIa inhibitors , flovagatran sodium, pegmusirudin, NU172, HD1





22),
Direct FXIa inhibitors (BMS-262084, antisense oligonucleotides
targeting FXIa, clavatadine),
FIXa inhibitors (RB-006),
FVIIIa inhibitors (TB-402),
FVIIa/tissue factor inhibitors (tifacogin, NAPc2, PCI-27483, BMS593214),
FVa inhibitors (drotrecogin alpha activated, ART-123)
Dual thrombin/FXa inhibitors (EP217609, tanogitran).
Rivaroxaban:novi oralni, direktni
inhibitor Faktora Xa
jednom dnevno
Predvidljive farmakokinetike i
farmakodinamike
Visoka oralna bioraspoloživpost
Brzo djelovanje
Fiksna doza
Ne zatijeva monitoring koagulacije
O
O
N
N
O
O
Cl
S
H
N
O
Rivaroxaban
Rivaroxaban se veže direktno za aktivno
mjesto Faktora Xa (Ki 0.4 nM)
Roehrig et al. 2005; Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007
Pacijenti sa svježim akutnim koronarnim sy.
Stabilizacija 1–7 dana od početka događaja
N ~3,500
NE
MD odluka za liječenje clopidogrelom
DA
STRATUM 1
Placebo
Aspirin 75–100 mg
*Doze od
5, 10 i 20 mg
Rivaroxaban
jednom /dan
Rivaroxaban
dvaput/dan
3 doze*
3 doze*
Placebo
STRATUM 2
Rivaroxaban
jednom/dan
Rivaroxaban
dvaput/dan
3 doze*
3 doze*
Tretman tokom 6 mjeseci
Primarni cilj:
TIMI značajno krvarenje
Pacijenti sa AF
+
≥2 riziko faktora: CHF, hipertension, ≥75 god., diabetes
ili ICV, TIA ili sistemska embolija
n ~14,000
Rivaroxaban
20 mg dnevno
15 mg za CrCl 30–49
Warfarin
INR ciljni 2.5
(2.0–3.0 )
Monthly monitoring and adherence to standard of
Mjesečnicare
monitoring
prema
guidelines
prihvaćenim standardima liječenja
Primarni cilj: ICV ili ne-CNS sistemski embolizam
TIA, tranzitorna ishemijska ataka;ICV:moždani udar;CHF:hronična srčana slabost CrCl, kreatinin klirens
Sprovedena u 45 zemalja, 1178
centara, na 14 264 pacijenta
Primarni rezultati efikasnosti kod
moždanog udara i ne-CNS embolije
ROCKET-AF: Primarni rezultat efikasnosti
Rezultat
Rivaroxaban Warfarin
(n=7081)
(n=7090)
Hazard ratio
(95% CI)
p
Primarni cilj, značajan
1.71
2.16
0.79 (0.66-0.96)
<0.001
Primarni cilj, tretman
superiorniji
1.70
2.15
0.79 (0.65-0.95)
0.015
Primarni cilj, početak Th
superiorniji
2.12
2.42
0.88 (0.74-1.03)
0.117
Vaskularna smrtnost, ICV,
embolizam
3.11
3.63
0.86 90.74-0.99)
0.034
Hemoragični ICV
0.26
0.44
0.59 (0.37-0.93)
0.024
Ishemijski ICV
1.34
1.42
0.94 (0.75-1.17)
0.581
ICV nepoznatog uzroka
0.06
0.10
0.65 (0.25-1.67)
0.366
Primarni rezultati - sigurnost
ROCKET-AF: Krvarenja
Rezultat
Rivaroxaba Warfarin Hazard ratio
n (n=7081) (n=7090) (95% CI)
p
Velika i mala krvarenja
14.91
14.52
1.03 (0.96-1.11)
0.442
Velika krvarenja
3.60
3.45
1.04 (0.90-1.20)
0.576
>2 g/dL pad hemoglobina
2.77
2.26
1.22 (1.03-1.44)
0.019
Transfuzija
1.65
1.32
1.25 (1.01-1.55)
0.044
Krvarenja iz kritičnih
organa
0.82
1.18
0.69 (0.53-0.91)
0.007
Smrtna krvarenja
0.24
0.48
0.50 (0.31-0.79)
0.003
Intrakranijalna krvarenja
0.49
0.74
0.67 (0.47-0.94)
0.019
Ključni sekundarni rezultati
efikasnosti
Sumarni rezultati ROCKET AF studije
Rivaroxaban : Warfarin (Čikago,15.Nov 2010.)
Efikasnost:
Rivaroxaban nije bio slabiji od warfarina u prevenciji ICV i drugih
embolizama.
Rivaroxaban je bio bolji od warfarina kod pacijenata koji su uzeti u studiju sa
lijekom.
Na početku tretmana, rivaroxaban nije bio slabiji niti mnogo bolji od
warfarina
Sigurnost:
Sličnost u broju krvarenja i dodatnih događanja
Manje ICH i fatalnih krvarenja sa rivaroxabanom.
Zaključak:
Rivaroxaban može biti alternativa warfarinu kod srednje do visokorizičnih
pacijenata sa AF.
Primarna
ICH
15%
Subdural /
Subarahnoidalna
12%
Ishemična
73%
% of Patients with Ischemic Stroke
AFFIRM: CNS događanja kod
pacijenata koji su prevedeni u SR
60
50
40
30
20
10
0
Nakon D/C
warfarin
n=44 (55%)
AFFIRM Investigators. New Engl J Med. 2002;347:1825-1833.
Na warfarin
INR <2.0
n=17 (21%)
Kontrolna
AF
n=25 (31%)
Kontrola odgovora : DC Kardioverzija
kod Perzistentne AF u RACE Study
522 pacijenta sa perzistentnom AF/AFl 24 h
do 1 g randomizirano je prema kontrola odgovora/ritma
90%iz grupe sa kontrolom odgovora,a 91% sa kontrolom
ritma je imalo 1 ili više riziko faktora za moždani udar
kontrola odgovora u miru <100/min
kontrola ritma sa DC konverzijom ili antiaritmicima
praćenje 2 godine
Primarni rezultat: uzrok smrti zbog kardiovaskularnih i
drugih događanja, pacemaker implantacija i antiaritmici
Van Gelder et al. N Engl J Med. 2002;347:1834-1840.
Zanemarenost antikoagulantne
terapije u AF*
Oko polovine pacijenata sa AF uzima
warfarin
13 opštih bolnica
21 kliničkih bolnica
Warfarin therapy
No warfarin therapy
53%
47%
*US population January–December 2002
AF, atrial fibrillation
Waldo et al. J Am Coll Cardiol 2005
53%
47%
Optimlna doza warfarina
u prevenciji ICV u AF
Bleeding
11.2
Stroke
18.2
15
Odds ratio for stroke
Odds ratio for ICH
10
8
6
4
2
0
0
1.4
1.6
1.8
2
2.3
2.7
10
5
3
1
0
1.0
1.5
2.0
Prothrombin time ratio
Prothrombin time ratio >2.0
(INR of 3.7 to 4.3) increases
the risk of bleeding
3.0
4.0
INR
Odds ratio of stroke by INR
INR
2.0
1.7
1.5
1.3
Odds ratio
1.0
2.0
3.3
6.0
AF, atrial fibrillation; ICH, intracranial haemorrhage; INR, international normalized ratio
Hylek & Singer. Ann Intern Med 1994; Hylek et al. N Engl J Med 1996
7.0
Optimal intensity for warfarin for
stroke prevention in AF
20
Odds ratio
15
Ischaemic
stroke
10
Intracranial
bleeding
5
1
1.0
2.0
3.0
4.0
5.0
INR
AF, atrial fibrillation; INR, international normalized ratio
Fuster et al. Circulation 2006
6.0
7.0
8.0
Tretman AF prema starosti
Antikoagulansi i rizik za ICV
Unmet need
Age
AF, atrial fibrillation
White et al. Am J Med 1999; Wolf et al. Arch Intern Med 1987
Ograničenja za upotrebu
antagonista vitamina K (3)
Otpor u propisivanju antagonista vitamina K
•Posebno starijim pacijentima zbog visokog
pretpostavljenog rizika naspram mogućeg benefita
•Bojazan od intrakranijalnog krvarenja, najteže
komplikacije krvarenja
Karakteristike
‘idealnog’ antikoagulansa
Doziranje jednom dnevno
Širok terapeutski prozor
Fiksna doza
Da ne stupa u interakciju sa hranom i
lijekovima
Brzo postizanje i brz prekid aktivnosti
Predvidljiva farmakokinetika i
farmakodinamika
Brzi reverziblni efekt
Bez potrebnog monitoringa primjene
Rezultati ROCKET studije
 Efikasnost
• Rivaroxaban nije bio inferiorniji od varfarina u
prevenciji moždanog udara i ne-CNS embolije
 Sigurnost
• Sličan nivo pojave krvarenja i neželjenih efekata
• Manje intrakranijalnih krvarenja i smrtnih krvarenja sa
rivaroxabanom
 Zaključak
RIVAROXABAN JE DOKAZANA ALTERNATIVA
VARFARINU ZA SREDNJE ILI VISOKO RIZIČNE
PACIJENTE SA ATRIJALNOM FIBRILACIJOM