noac workshop radionica

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


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


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

CHA2DS2-VAScRisk of Stroke in Patients With AF


Primer


Procena rizika za CVI od strane doktora vs korišćenjem

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


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


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


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]


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


0.2 0.5 1 2

Secondary Safety Outcomes

49

Heterogeneity ICH, p=0.22GI Bleeding, p=0.009


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

noac workshop radionica

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