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I NUOVI ANTICOAGULANTI ORALI MECCANISMO D’AZIONE E
FARMACOLOGIA SOPHIE TESTA
CENTRO EMOSTASI E TROMBOSI LABORATORIO ANALISI CHIMICO-CLINICHE E MICROBIOLOGICHE
Istituti Ospitalieri di Cremona
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FARMACI ANTICOAGULANTI
J.W. Eikelboom, Circulation 2010
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ANTICOAGULANTI ORALI
VAO Vecchi Anticoagulanti Orali
AVK
Anti Vitamina K
NOA Nuovi Anticoagulanti Orali
AOD Anticoagulanti Orali Diretti
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DOA: MECCANISMO D’AZIONE
XIIa XIa
IXa
Xa
IIa
VIIa
Fibrinogeno Fibrina
VIIIa
Va
inibitori FXa inibitori FIIa
warfarin
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CARATTERISTICHE DEI FARMACI ANTICOAGULANTI AD AZIONE
DIRETTA
ORIGINE SINTETICA
RAPIDO INIZIO
SELETTIVITA’ D’AZIONE
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CONFEZIONE ORIGINALE DEL WARFARIN
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Warfarin
sintesi di fattori emostatici NON
FUNZIONANTI
Antagonism of
Vitamin K
TAO: MECCANISMO D’AZIONE
Vitamin K
VII IX X II
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Daily Dose Daily Dose
Maintenance Dose Only
Loading Dose then Maintenance Dose
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ORAL ANTICOAGULANT TARGET
SITES
Antithrombin
Fibrinogen
Factor II (Prothrombin)
Fibrin
Factor IIa (Thrombin)
Factor X
Factor IX Factor VII
Anti-FXa drugs • Apixaban • Betrixaban • Edoxaban • Rivaroxaban • LY 517717 • TAK 442 • YM 150
Anti-FIIa drugs • Dabigatran
• Ximelagatran • AZD 0837
Factor Xa
VKA drugs • Tecarfarin
• Warfarin
FVIIa
FIXa
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FARMACOCINETICA E FARMACODINAMICA
• FARMACOCINETICA: assorbimento, distribuzione, metabolismo, escrezione
• FARMACODINAMICA: effetti biochimici e funzionali del farmaco e il meccanismo d’azione
1) siti d’azione del farmaco 2) relazione tra dose del farmaco e risposta
funzionale
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AVK- DOA
Poulsen BK et al, Drugs 2011
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DABIGATRAN: CLINICAL DEVELOPMENT
Postsurgical prophylaxis of
DVT DVT Treatment Stroke Prevention
in AF ACS
RE-MODEL RE-COVER RE-LY RE-DEEM
RE-MOBILIZE RE-MEDY
RE-NOVATE RE-SONATE
RE-NOVATE 2
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RIVAROXABAN: CLINICAL DEVELOPMENT
Postsurgical prophylaxis of
DVT DVT Treatment Stroke
Prevention in AF ACS
ODIXa-KNEE EINSTEIN-DVT ROCKET-AF ATLAS ACS-TIMI 46
ODIXa-HIP EINSTEIN-EXT ROCKET-J ATLAS ACS-TIMI 51
RECORD-1 EINSTEIN-PE RECORD-2 RECORD-3
RECORD-4
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APIXABAN: CLINICAL DEVELOPMENT
Postsurgical prophylaxis of
DVT DVT Treatment Stroke
Prevention in AF ACS
APROPOS Botticelli DVT ARISTOTLE APPRAISE-1
ADVANCE-1 AMPLIFY AVERROES APPRAISE-2 (study terminated because of
bleeding)
ADVANCE-2 AMPLIFY-EXT APPRAISE Japan
ADVANCE-3
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EDOXABAN: CLINICAL DEVELOPMENT
Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF
Oral direct FXa inhibition with E for thrombophylaxis after elective THR: a randomized double-blind dose-response study
The Edoxaban Hokusai-VTE Study
Randomized, parallel-group, multicenter, multinational Phase II study comparing E, an oral factor Xa inhibitor, with warfarin for SPAF
STARS J-1 ENGAGE AF-TIMI 48 STARS J-2 Safety of edoxaban, an oral factor Xa
inhibitor, in Asian patients with NVAF
STARS E-3
STARS J-4
STARS J-5
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DOA
Somministrati a dosi fisse in relazione a : -breve emivita - piu’ ampia finestra terapeutica rispetto a
warfarin -minori interazioni rispetto a warfarin
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FDA ANALYSIS OF RE-LY
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FDA ANALYSIS OF RE-LY
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FDA ANALYSIS OF ROCKET
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PT AND RISK OF BLEEDING IN MAJOR ORTHOPEDIC SURGERY
(RIVAROXABAN 10mg/die)
Douxfils J et al, Thromb Res 2012
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PT AND RISK OF BLEEDING IN ATRIAL FIBRILLATION
(RIVAROXABAN 20mg/die)
Douxfils J et al, Thromb Res 2012
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INTERAZIONI FARMACOLOGICHE
Interactions should be properly evaluated. Whenever a concomitant therapy is ongoing with a drug likely to interfere with NAO, a lab control should be performed (Pengo, 2011).
Many of these drugs interact with warfarin, but INR levels allows dose adjustment, which mitigates the risk of concomitant treatment (Schulman S et al, 2012)
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Stangier et al. Clin Pharmacokinet 2010
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Stangier et al. Clin Pharmacokinet 2010
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INFLUENCE OF RENAL IMPAIRMENT ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL DABIGATRAN ETEXILATE:
AN OPEN-LABEL, PARALLEL-GROUP, SINGLE- CENTRE STUDY
• Exposure to dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction • A decrease in the dose and/or an increase in the administration interval in these patients may be appropriate • In patients with end-stage renal disease (ESRD) dabigatran can be partly removed from the plasma by haemodialysis • AUC data was about two-fold greater in elderly men (> 65 years) than in young subjects after twice-daily dosing, presumably due to the 20-30% lower creatinine clearance
Stangier et al. Clin Pharmacokinet 2010
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Kreutz R, Fundamental Clin Pharmacol 2011
Renal disease
Hepatic disease
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DOA: LIVER AND RENAL FUNCTION
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LIVER AND RENAL FUNCTION
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POSSIAMO MISURARE LA CONCENTRAZIONE DEI DOA?
SI
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DOA
Pengo V et al, T&H 2011; Tripodi A. et al, 2012; Douxfils J et al, T&H 2012, Baglin T et al, BJH 2012, Douxfils J et al, ASH 2013 (abst)
FARMACO CONTROLLO
Dabigatran (ng/ml) dTT aIIa
Rivaroxaban (ng/ml) aXa PT R*
Apixaban (ng/ml) aXa
* Diversa sensibilita’ dei reagenti
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CONCLUSIONI • In tempi brevissimi saranno disponibili numerosi farmaci
anticoagulanti orali che presentano caratteristiche differenti
• Hanno un meccanismo d’azione selettivo e diretto contro 1 singolo fattore della coagulazione.
• Presentano una finestra terapeutica piu’ ampia rispetto ai farmaci dicumarolici e questo favorisce la somministrazione a dosi fisse giornaliere
• Alcune condizioni modificano la farmacocinetica e la farmacodinamica dei DOA: insuff epatica, renale, pazienti anziani, interazioni farmacologiche….