noac workshop radionica
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RADIONICA – KAKO prevazići strah od nepoznatog UPOZNATI SE SA NOACs
Mr sci med Dragana Šarenac spec.interne medicine – kardiologIKVB DEDINJE
* PREPOZNATI ZNAČAJ Afib
* PROCENITI RIZIK od CVI primenom postojećih skorova
* INDIVIDUALIZOVATI PRISTUP bolesniku - PREPORUKAMA
PREPOZNATI ZNAČAJ Afib
A Fib. porast sa godinama
ATRIA: Porast AF sa godinama
<55 55-59 60-64 65-69 70-74 75-79 80-84 ≥85
Pre
vale
nce
(%)
Age (years)
Men (n = 10,173) Women (n = 7801)
0
2
4
6
8
10
12
Go AS et al. JAMA. 2001;285:2370-5.AF = atrial fibrillation
Gaziano TA. Circ 2005.
High income
Low and middle income
KVB – globalna epidemija
Atrial Fibrillation in CAD: Prevalence in the REACH Registry
37,724 stable outpatients with CAD
AF, atrial fibrillation.Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
3,00
0,93
3,38 2,99
3,44
1,26
0,44
1,56 1,57 1,96
0,0
1,0
2,0
3,0
4,0
Total Risk FactorsOnly
CAD CVD PAD
Ann
ual E
vent
Rat
e (%
)
AF Patients Non-AF Patients
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
ATRIA: Prevalenca AF kod polivaskularnih bolesnika
Veća incidenca AF kod vaskularnih bolesnika u odnosu na one koji imaju pojedinačne faktore rizika
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
KV dogadjaji (%) kod AF i non-AF pts
Patients with a history of AF
Combined event of CV death and/or nonfatal MI and/or nonfatal strokeE
vent
rate
of C
V
deat
h/M
I/Stro
ke (%
)
Time (months)
AF Non-AF
0
5
10
0 6 122 4 108
Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.
AF i bubržna insuficijencija
Etiologija ...?
Etiopatogeneza ...?
Patofiziologija
ŠTA možemo poboljšati u lečenju
Venska tromboza• Prevencija
– In-hospital– Out-of-hospital
• Lečenje – Initial – Long term
Arterijska tromboza• Lečenje
– ACS • Prevencija
– Stroke (AF, CHF, prosthestic heart valves)
– Post MI– PCI / HD
ŠTA možemo poboljšati u lečenju
ŠTA možemo poboljšati u lečenju
CHA2DS2-VAScRisk of Stroke in Patients With AF
ŠTA možemo poboljšati u lečenju
Primer
ŠTA možemo poboljšati u lečenju
Procena rizika za CVI od strane doktora vs korišćenjem
ŠTA možemo poboljšati u lečenju
Fuster V. Circulation 2012; epubl April 18
ŠTA je novo u lečenju AFib
AF PIE:FUTURE
AF PIE:PAST
Kombinovanje CHADS2 i HEMORR2HAGES skorova u cilju antitrombotske profilakse kod AF kod stariji od 80g.
‘The clinical usefulness of using the two scores seems poor since they indicated that two-thirds of the patients had a similar risk of hemorrhagic and ischemic events.’
One year stroke risk for 100 patients without anticoagulation according to CHADS2Major hemorrhage risk for 100 patients with anticoagulation according to HEMORRH2AGES
N=83
Mean age 89.2+/-4.9 god
Somme et al Aging Clin Exp Res. 2009 as DOI: 10.3275/6709
Klinička korist kod gerijatrijskih pts
Score
Eve
nts/
year
(%)
0 1 2 3 4 5
25
20
15
10
5
0
Comprehensive Meta-Analysis Comparing the Efficacy and Safety of NOACs with
Warfarin in AF
An Analysis Including 71,683 Patients from Four Large Randomized Clinical Trials
ŠTA možemo poboljšati u lečenju
25
Pivotal Warfarin-Controlled TrialsStroke Prevention in AF
6 Trial of Warfarin vs. Placebo1989-1993
RE-LY(Dabigatran)
2009
ROCKET AF (Rivaroxaban)
2010
ARISTOTLE (Apixaban)
2011
ENGAGE AF-TIMI 48 (Edoxaban)
2013
Warfarin vs. Placebo2,900 Patients
NOACs vs. Warfarin71,683 Patients
100% 50% 0% -50% -100%
AFASAK-1 (671) SPAF (421)BAATAF (420)
CAFA (378)
SPINAF (571)
EAFT (439)
All Trials (n=6)
Warfarin Better Warfarin Worse
64%
Stroke Prevention in AF Warfarin vs. Placebo
Hart RG, et al. Ann Intern Med 2007;146:857-867.26
ACTIVE W: Benefit OAC prema TTR ( Time in Therapeutic Range- Vreme u terapijskom
opsegu)
Connolly et al. Circulation. 2008;118:2029.
Stroke
No. at RiskC + ASA 1598 1527 1156 439OAC 1600 1525 1152 417
1737 1625 1233 4881771 1697 1306 507
1598 1533 1164 4411600 1531 1156 419
1737 1635 1255 5001771 1702 1311 511
0
2
4
6
8
10
12
0 0,5 1,0 1,50
2
4
6
8
10
12
0 0,5 1,0 1,5
OAC
OAC
C + ASA
C + ASA OAC
C + ASA
OAC
Eve
nt ra
te (%
)
TTR <65% TTR ≥65% TTR <65%
Eve
nt ra
te (%
)
Years Years
RR = 0.93 (0.70-1.24)P=0.61
RR = 2.14 (1.61-2.85)P<0.0001
RR = 1.22 (0.75-1.97)P=0.42
0
1
2
3
4
0 0,5 1,0 1,50
1
2
3
4
0 0,5 1,0 1,5
C + ASA
TTR ≥65%
RR = 2.25 (1.45-3.49)P=0.0003
Years Years
Stroke, MI, Non-CNS Systemic Embolism, Vascular Death Stroke
TTR ≥ 65%TTR < 65%TTR ≥ 65%TTR < 65%
0.0
0.01
0.02
0.03
0.04
0.05
0.0 0.5 1.0 1.5
OAC
C+A
0.0
0.01
0.02
0.03
0.04
0.05
0.0 0.5 1.0 1.5
OAC
C+A
Connolly SJ, et al. Circulation 2008;118:2029-203728
ACTIVE-W: Velika Krvarenja
Years Years
Eve
nt R
ate
(%)
P-interaction = 0.0006
RR = 1.55P = 0.027
RR = 0.68P = 0.08
TTR ≥ 65% TTR < 65%
Uzan terapijski prozor & Mnogo interakcija
Dug polu-život Spor početak delovanja
Varfarin ( VKA ) ima ograničenja
Doziranje Warfarina je kompleksno * mnogobrojni faktori utiču *
• Starosna dob, pol• BMI ili težina • Amiodaron • Drugi lekovi (eg, acetaminophen)• Rasa• Nivo vit. K u plazmi • Dekompenzovana HF • Aktivan malignitet • Genetika
CHF = congestive heart failure; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; VKORC1 = vitamin K epoxide reductase complex subunit 1
Drugi faktori(do 40%)
God. Pol, Težina
(10–20%)
CYP2C9( do 15%)
VKORC1(do 25%)
Pridržavanje prepisane terapije ( adherentnost za VKA)
Idealni Oralni Antikoagulans
Bez monitoringa
Min. interakcija sa hranom i drugim lekovima
Dobar sigurnosni profil – smanjena krvarenja
Slična efikasnost sa varfarinom + smanjenje TEtro
Visoka konc. u plazmi brzo postignuta
Koagulaciona kaskada
Initiation Vlla/TF
Propagation
Fibrin Formation
Fibrinogen Fibrin
IXX
IXa VllIa
XaVa
IIa (Thrombin)
II
Traditionalna Paradigma Factor Xa i Trombin
Mackman. ATVB 2008;28:698-704
Factor Xa – Pluripotenti Efektor Enzim
VIIa
XaIXa
XIaXIIa
Direct Factor Xa inhibitionTissue factor
Fibrinogen Fibrin clot
Factor II(prothrombin)
RivaroxabanApixabanDU-176b
YM150LY517717
PRT-054021
×
Direktni Factor Xa Inhibitori
FXa u prothrombinaza
complexu
FXa
DirectFXa inhibitors
• Direktni Faktor Xa inhibitori mogu inhibisati Factor Xa • unutar protrombinaza compleksa
Farmakološki Profili OAK
Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011Weinz et al. Drug Dispos Metab 2009;37:1056–1064 . ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK Matsushima et al. Am Assoc Pharm Sci 2011; Ogata, et al. J Clin Pharmacol 2010;50:743–753. Mendell, et al. Am J Cardiovasc Drugs 2013;13:331–342Bathala, et al. Drug Metab Dispos 2012;40:2250–2255
RE-LY(Dabigatran)
ROCKET-AF(Rivaroxaban)
ARISTOTLE(Apixaban)
ENGAGE AF(Edoxaban)
# Randomized 18,113 14,264 18,201 21,105Age, years 72 ± 9 73 [65-78] 70 [63-76] 72 [64-78]
Female, % 37 40 35 38Paroxysmal AF 32 18 15 25VKA naive 50 38 43 41
Aspirin Use 40 36 31 29
39
Osnovne karakteristike
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel MR, et al. N Engl J Med 2011;365:883-891Granger CB, et al. N Engl J Med 2011;365:981-992Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
32
35
33 13
87
4753
34
36
30CHADS2
23-6
0-1
40
Trial Metrics
RE-LY(Dabigatran)
ROCKET-AF(Rivaroxaban)
ARISTOTLE(Apixaban)
ENGAGE AF(Edoxaban)
Median Follow-Up, years 2.0 1.9 1.8 2.8Median TTR 66 58 66 68
Lost to Follow-Up, N 20 32 90 1
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151Patel MR, et al. N Engl J Med 2011;365:883-891Granger CB, et al. N Engl J Med 2011;365:981-992Giugliano RP, et al. N Engl J Med 2013; e-pub ahead of print DOI:10.1056/NEJMoa1310907
*TTR, time in therapeutic range
Smanjenje doze NOAC kod HBI
Kako izračunati crCl
KONTRAINDIKACIJE
ENGAGE AF-TIMI 48
ARISTOTLE
ROCKET AF
RE-LY
Combined
Favors NOAC Favors Warfarin
0.88 (0.75 - 1.02)
0.80 (0.67 - 0.95)
0.88 (0.75 - 1.03)
0.66 (0.53 - 0.82)
0.81 (0.73 - 0.91)
Risk Ratio (95% CI)
p=<0.0001
0.5 1 2
All NOACS: Stroke or SEE
[Random Effects Model]
N=58,541
Heterogeneity p=0.13
[60 mg]
[150 mg]
Ruff CT, et al. Lancet 2013 [in-press] 45
All-Cause Mortality
MI
Hemorrhagic Stroke
Ischemic Stroke
0.90 (0.85 - 0.95)
0.97 (0.78 - 1.20)
0.49 (0.38 - 0.64)
0.92 (0.83 - 1.02)
Risk Ratio (95% CI)
p=0.0003
p=0.77
p<0.0001
p=0.10
Favors NOAC Favors Warfarin
0.2 0.5 1 2
Secondary Efficacy Outcomes
46
Heterogeneity p=NS for all outcomes
Ruff CT, et al. Lancet 2013 [in-press]
GI Bleeding 0.89 (0.57 - 1.37)
ICH 0.31 (0.24 - 0.41)
Major Bleeding 0.65 (0.43 - 1.00)
All-Cause Mortality 0.89 (0.83 - 0.96)
MI 1.25 (1.04 - 1.50)
Hemorrhagic Stroke 0.33 (0.23 - 0.46)
Ischemic Stroke 1.28 (1.02 - 1.60)
Stroke or SEE 1.03 (0.84 - 1.27)
Risk Ratio (95% CI)
p=0.58
p<0.0001
p=0.05
p=0.003
p=0.019
p<0.0001
p=0.045
p=0.74
Favors Low Dose NOAC Favors Warfarin0.2 0.5 1 2
Low Dose RegimensEfficacy & Safety Outcomes
47
N=26,107
Dabigatran 110 mg & Edoxaban 30 mg
Heterogeneity P=NS for outcomes except: Major Bleeding, p=<0.001GI Bleeding, p=0.01 Ruff CT, et al. Lancet 2013 [in-press]
ARISTOTLE
ROCKET AF
Combined
Favors NOAC Favors Warfarin
Risk Ratio (95% CI)
0.80 (0.71 - 0.90)
0.71 (0.61 - 0.81)
1.03 (0.90 - 1.18)
0.94 (0.82 - 1.07)
0.86 (0.73 - 1.00)
0.5 1 2
All NOACS: Major Bleeding
48
[Random Effects Model]
N=58,498p=0.06
Heterogeneity p=0.001
RE-LY[150 mg]
ENGAGE AF-TIMI 48[60 mg]
Ruff CT, et al. Lancet 2013 [in-press]
GI Bleeding
ICH
1.25 (1.01 - 1.55)
0.48 (0.39 - 0.59)
Risk Ratio (95% CI)
p=0.043
p<0.0001
Favors NOAC Favors Warfarin
0.2 0.5 1 2
Secondary Safety Outcomes
49
Heterogeneity ICH, p=0.22GI Bleeding, p=0.009
Ruff CT, et al. Lancet 2013 [in-press]
50
NOACs značajno smanjuju nastanak moždanog udara (19%)− Prvenstveno zbog smanjenja hemoragičnog insulta (51%)
NOACs značajno smanjenje mortaliteta (10%)
Trend prema manjem krvarenju - Osnovno je smanjenje ICH (52%)
− Increased GI bleeding (25%)
Zaključci
Recommendations for Prevention of TE in NVAF:
NOACs
Anti-Xa or Anti-IIa?
Anti-IIa Anti-Xa
HirudinBivalirudinArgatroban
XimelagatranDabigatran Etexilate
FondaparinuxIdraparinuxRivaroxaban
Apixaban
UnfractionatedHeparin
DalteparinEnoxaparinNadroparinReviparin
Factor Xa AF Trial Designs: Apixaban
Randomizovane kliničke studije ( RCT )vs stvarni podaci iz prakse ( Real world Data )
Real-World NOACs DatabaseStvarni podaci iz prakse ( Real world Data )
Podaci iz Registra
ESC preporuke –lečenje krvarenja kod pacijenata koji uzimaju
NOAK
1. With dabigatran.Adapted from Camm et al. Eur Heart J 2012; e-published August 2012, doi: 10.1093/eurheartj/ehs253.
Pacijenti na terapiji NOAK koji su imali krvarenje
proveriti hemodinamski status, osnovne testove koagulacije za procenu antikoagulacionog efekta (npr., aPTT za dabigatran, PT ili anti Xa aktivnost), funkciju bubrega itd)
Malo
Umereno-teško
Vrlo teško
► Simptomatska / suportivna terapija► Mehanička kompresija► Nadoknada tečnosti► Transfuzija krvi► Oralno dat aktivni ugalj ukoliko je nedavno uzet lek1
► PCC iili razmotriti rFVIIa ► Filtracija aktvinim ugljem1 / hemodializa1
► Odložiti sledeću dozu ili prekinuti lečenje
Reversal Strategies
Preston et al. British Journal of Haematology 2002. 116: 619–624
Baseline 20 min 60 min 120 min13
13
11
9
7
5
3
1
25 u/kg (m=20)35 u/kg (n=12)50 u/kg (n=10)
4-factor prothrombin complex concentrate
administered
Nelečena AF udružena je sa porastom mortaliteta i CVI
* Povećava se procenat pts kod kojih se AF leči radi prevencije CVI
* Raste poverenje u NOACs korištenje
Umesto zaključka
Zašto Apixaban ( Eliquis)
ARISTOTLE Efikasnost: Apixaban
Granger CB, et al. NEJM 2011; 365:981-992
HR 0.79 (0.66–0.95)
P (non-inferiority) < 0.001
21% RRR
(1.27 %/yr )
(1.60 %/yr)
P (superiority) = 0.011
ARISTOTLE krvarenja: Apixaban
Započinjanje i praćenje pts na NOAC
Započinjanje i kako se odlučiti za NOAC (Apixaban)
Započinjanje - KOME prepisati NOAC (Apixaban)
Neregulisan INR
Novootkrivena Afib.Prethodna ICH
HBI
Neregulisana HTA
Započinjanje i praćenje pts na NOAC
- Indikacija- edukacija- Izbor
NOAC- IPP da li- Hgb,
bubrežni retenti, funkcija jetre
- OAC kartica
- Praćenje
- Redovno uzimanje (preostale tabl.)
- Tromboembolisjki dogadjaji
- Krvarenja- Ostali
neželjeni efekti
- Ko-medikacija sa lekovima i OTC
- Merenje anti Xa
- Ispunjavati karticu
- Ugovoriti TAČAN termin sledeće posete
- Zavisi od pts
DOBRO je imati mogućnost IZBORA
VIT K ANTAGONISTI (NOAC) Direktni anti Xa/anti IIa INHIBITORI
Umetnost je postići BALANS izmedju PREVENCIJE CVI i KRVARENJA
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