Novi oralni antikoagulansi u prevenciji trombembolijskog rizika

kod fibrilacije atrija Akademik Doc.dr Emir Fazlibegović, ESC, FESC

Mostar 04.04.2013.

Svjetski dan zdravlja, 7. april 2013. godineNaučni simpozijum

ATRIJALNA FIBRILACIJAUDRUŽENJE KARDIOLOGA BiHRadna grupa za aterosklerozuRadna grupa za naprasnu smrtRadna grupa za bazična istraživanjaUdruženje kardiologa HNK/Ž

Kratka istorija antikoagulanasa

1930s

1940s

1980s

1990s

2000s

Oral

Parenteral

Parenteral

Parenteral

Oral

Oral

Parenteral UFH: antitrombin zavisna inhibicija FXai thrombina u odnosu 1:1

VKAs: indirektni uticaj na sintezu brojnih od vitamina K-zavisnih faktora koagulacije

LMWH: antitrombin-zavisna inhibicija FXa >trombin

DTIs

Indirektni FXa inhibitori

DTIs

Direktni FXa inhibitori

Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990

Oralni warfarin je jedini antikoagulans za hroničnu upotrebuUFH, nefrakcionirani heparin; LMWH, niskomolekularni heparin; DTIs, direktni inhibitori trombina

Potencijali antikoagulansi i njihova ciljna mjesta

TFPI (tifacogin)

FondaparinuxIdraparinux

RivaroxabanApixabanLY517717YM150DU-176bBetrixaban

Dabigatran

ORALNI PARENTERALNI

DX-9065aOtamixaban

Xa

IIa

TF/VIIa

X IX

IXaVIIIaVa

II (trombin)

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz & Bates. J Thromb Haemost 2005

TTP889

APC, activated protein C; AT, antithrombin; sTM, soluble thrombomodulin; TF, tissue factor; TFPI, tissue factor pathway inhibitor

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

AVK

DabigatranHeparin(s)Fondaparinux

Apixaban, Rivaroxaban

Početno odmjeravanje dvije standarne opscije

Istraživanje novih oralnih antikoagulanasa

Jedan lijek u jednoj dozi u dugoroćnoj prevenciji

Velike studije sa novom generacijom antikoagulanasa

Dabigatran Rivaroxaban Apixaban

VTE prevencija

RE-MODELRE-NOVATERE-MOBILIZERE-SOLVE

RECORD 1-4MAGELLAN

ADVANCE I-IIIADOPT

VTE tretmanRE-COVERRE-MEDYRE-SONATE

EINSTEIN-DVTEINSTEIN-PEEINSTEIN-EXT

AMPLIFYAMPLIFY-EXT

RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

ROCKET AFRivaroxaban 20mg 1.7% per yearWarfarin 2.2% per year

ARISTOTLEApixaban 5 mg 1.27% per yearWarfarin 1.60% per year

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis

p<0.001

p<0.001 p<0.001

Non Inferiorityp vs warfarin

ITT Analysis

Modified ITT

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.

p<0.001ITT Analysis

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

HR = 0.79

HR = 0.79

HR = 0.91HR = 0.66

Hemorrhagic StrokeDabigatran 110 mg 0.12% / yr 0.31 <0.001Dabigatran 150 mg 0.10% / yr 0.26 <0.001

Warfarin 0.38% / yr

HRITT

P-value

Rivaroxaban 20 mg 0.26% / yr 0.59 0.012*

Warfarin 0.44% / yr

ROCKET

RELY

C. Michael Gibson, M.S., M.D.

*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.

Apixaban 5 mg 0.24% / yr 0.51 <0.001

Warfarin 0.47% / yr

ARISTOTLE

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 StrokeDabigatran 110 mg 1.34% / yr 1.20 0.35Dabigatran 150 mg 0.92% / yr 0.76 0.03

Warfarin 1.20% / yr

HRITT

P-value

Rivaroxaban 20 mg 1.62% / yr 0.99 0.92*

Warfarin 1.64% / yr

ROCKET

RELY

C. Michael Gibson, M.S., M.D.

*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

Apixaban 5 mg 0.97% / yr 0.92 0.42

Warfarin 1.05% / yr

ARISTOTLE

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

Dabigatran 110 mg 2.71% / yr 0.8 0.003Dabigatran 150 mg 3.11% / yr 0.93 0.31

Warfarin 3.36150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052

Major BleedingHR

ITTP-valueRE-LY

Rivaroxaban 20 mg 3.60% / yr 0.92 0.58*

Warfarin 3.45% / yr

ROCKET

C. Michael Gibson, M.S., M.D.

*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.

On TreatmentP-value

P-valueApixaban 5 mg 2.13% / yr 0.69 <0.001

Warfarin 3.09% / yr

ARISTOTLE

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

2 g drop in 24 hours

2 g drop

NB: Indirect comparison only. No head to head comparison available.

All Cause Mortality

Dabigatran 110 mg 3.75% / yr 0.91 0.35Dabigatran 150 mg 3.64% / yr 0.88 0.051

Warfarin 4.13% / yr

HRITT

p-value

Rivaroxaban 20 mg 4.52% / yr 0.92 0.152*

Warfarin 4.91% / yr

ROCKET

RELY

C. Michael Gibson, M.S., M.D.

*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.

Apixaban 5 mg 3.52% / yr 0.89 0.01

Warfarin 3.94% / yr

ARISTOTLE

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

95% CI 0.89 (0.80, 0.998)N=448 events planned, 480 in trial

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

ClinicalTrials.gov Identifier: NCT01477775

4000 PCI patientsStandard of carevsCustomized antiplatelet treatment according to platelet Function Testing and genotyping for CYP450 2C19*2 and ABCB1 C

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, BMS-

593214), FVa inhibitors (drotrecogin alpha activated, ART-123) Dual thrombin/FXa inhibitors (EP217609, tanogitran).

jednom dnevnoPredvidljive farmakokinetike i farmakodinamikeVisoka oralna bioraspoloživpostBrzo djelovanje Fiksna dozaNe zatijeva monitoring koagulacije

Rivaroxaban:novi oralni, direktni inhibitor Faktora Xa

Roehrig et al. 2005; Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007

Rivaroxaban se veže direktno za aktivno mjesto Faktora Xa (Ki 0.4 nM)

Rivaroxaban

N N ONH

O

SCl

O

O

O

STRATUM 2STRATUM 1

Rivaroxabanjednom /dan

3 doze*

Rivaroxabandvaput/dan

3 doze*Placebo

Rivaroxabanjednom/dan

3 doze*

Rivaroxabandvaput/dan

3 doze*

Tretman tokom 6 mjeseci

MD odluka za liječenje clopidogrelom

Pacijenti sa svježim akutnim koronarnim sy.Stabilizacija 1–7 dana od početka događaja

*Doze od5, 10 i 20 mg

N ~3,500

Aspirin 75–100 mg

DANE

Primarni cilj:TIMI značajno krvarenje

Placebo

Rivaroxaban

Warfarin

Primarni cilj: ICV ili ne-CNS sistemski embolizam

INR ciljni 2.5 (2.0–3.0 )

20 mg dnevno15 mg za CrCl 30–49

n ~14,000

Pacijenti sa AF +

≥2 riziko faktora: CHF, hipertension, ≥75 god., diabetes ili ICV, TIA ili sistemska embolija

TIA, tranzitorna ishemijska ataka;ICV:moždani udar;CHF:hronična srčana slabost CrCl, kreatinin klirens

Monthly monitoring and adherence to standard of care guidelinesMjesečni monitoring prema

prihvaćenim standardima liječenja

Sprovedena u 45 zemalja, 1178 centara, na 14 264 pacijenta

Primarni rezultati efikasnosti kod moždanog udara i ne-CNS embolije

Rezultat Rivaroxaban (n=7081)

Warfarin (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

ROCKET-AF: Primarni rezultat efikasnosti

Primarni rezultati - sigurnost

Rezultat Rivaroxaban (n=7081)

Warfarin (n=7090)

Hazard ratio (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

ROCKET-AF: Krvarenja

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 događanjaManje ICH i fatalnih krvarenja sa rivaroxabanom.

Zaključak:Rivaroxaban može biti alternativa warfarinu kod srednje do visokorizičnih pacijenata sa AF.

AFFIRM: CNS događanja kod pacijenata koji su prevedeni u SR

Ishemična73%Subdural /

Subarahnoidalna12%

PrimarnaICH15%

AFFIRM Investigators. New Engl J Med. 2002;347:1825-1833.

0

10

20

30

40

50

60

Na warfarinINR <2.0

n=17 (21%)

KontrolnaAF

n=25 (31%)

Nakon D/Cwarfarin

n=44 (55%)

% o

f Pat

ient

s w

ith Is

chem

ic S

trok

e

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 udarkontrola odgovora u miru <100/minkontrola ritma sa DC konverzijom ili antiaritmicimapraćenje 2 godinePrimarni 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 bolnicaWarfarin therapy

No warfarin therapy

53% 47%

*US population January–December 2002AF, atrial fibrillation

53% 47%

Waldo et al. J Am Coll Cardiol 2005

Optimlna doza warfarina u prevenciji ICV u AF

Prothrombin time ratio >2.0 (INR of 3.7 to 4.3) increases the risk of bleeding

Odds ratio of stroke by INR

Hylek & Singer. Ann Intern Med 1994; Hylek et al. N Engl J Med 1996

INR Odds ratio2.0 1.01.7 2.01.5 3.31.3 6.0

AF, atrial fibrillation; ICH, intracranial haemorrhage; INR, international normalized ratio

1.6

1.40 1.8 2 2.3 2.7Prothrombin time ratio

0

2

4

6

8

1018.211.2

Odd

s ra

tio fo

r IC

H

1.0 1.5 3.0 4.0 7.0

135

10

15

INR2.0

Odd

s ra

tio fo

r str

oke

Bleeding Stroke

0

Optimal intensity for warfarin for stroke prevention in AF

Fuster et al. Circulation 2006

5.0 6.0 8.01.0 2.0 3.0 4.0 7.0

5

15

10Ischaemic

strokeIntracranial

bleeding

1

20

Odd

s ra

tio

INR

AF, atrial fibrillation; INR, international normalized ratio

Age

Pro

babi

lity Stroke rate

Warfarin use

White et al. Am J Med 1999; Wolf et al. Arch Intern Med 1987

AF, atrial fibrillation

Tretman AF prema starosti

Antikoagulansi i rizik za ICV

Unmet need

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 dnevnoŠirok terapeutski prozor Fiksna dozaDa ne stupa u interakciju sa hranom i lijekovimaBrzo postizanje i brz prekid aktivnostiPredvidljiva farmakokinetika i farmakodinamikaBrzi 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

ZaključakRIVAROXABAN JE DOKAZANA ALTERNATIVA VARFARINU ZA SREDNJE ILI VISOKO RIZIČNE PACIJENTE SA ATRIJALNOM FIBRILACIJOM