CARDIOVASCULAR RESEARCH CENTER INSTITUTE FOR CARDIOVASCULAR SCIENCES HIGH COUNCIL FOR SCIENTIFIC RESEARCH HOSPITAL DE LA SANTA CREU I SANT PAU BARCELONA SPAIN
ANTICOAGULACION 2.0: A LAS PUERTAS DE UNA NUEVA ERA AVANCES EN LA ANTICOAGULACION Lina Badimon SEC – 2010 - VALENCIA
THROMBOSIS AND VIRCHOW’S TRIAD Flow: fast or slow- stasis
AF
Arterial or venous ?
Lack of efficacy of platelet inhibition in patients with AF or stroke
Arterial Thrombosis Endothelial damage
Hypercoagulability
THROMBOSIS fibrin deposition depends on shear rate
PLATELETS: RED FIBRIN: GREEN (200X)
artery
artery
L
L
1700/S
Badimon L. et al 2009
212/S
PLATELETS & FIBRIN JACC 1994, Circulation 1997, Circulation 1999, Circulation 2004, Cardiovasc Res 2005
THROMBOSIS Fibrinogen
STASIS
Tissue Factor
a Pl
et l te
Fibrin
Fibrin-rich Thrombus
Platelet
HIGH THROMBOEMBOLIC RISK
Thrombus formation: Platelets subendothelial matrix
Collagen
vWF
GPVI-FcR2
ADP
P2Y1 P2Y12
GPIb-IX-V PAR1 PAR4
SYK/PLC? PI 3-K G/R h
o/ P
Epinephrine
α2-ADRENERGIC Rc
G/Rho/PLCβ
LC β
GRANULES
Thrombin
G/AC
INSIDE OUT OUTSIDE IN SIGNALING
G/AC
ATP
5-HT
5-HT Rc
Fibrinogen P2X1
A.ac
αIIbβ3
TP-Rc
TXA2
Platelet agonists Platelet receptors
↑[Ca]
Thrombus formation: Platelets subendothelial matrix
Collagen
vWF
GPVI-FcR2
ADP
P2Y1 P2Y12
GPIb-IX-V PAR1 PAR4
SYK/PLC? PI 3-K G/R h
o/ P
Epinephrine
α2-ADRENERGIC Rc
G/Rho/PLCβ
LC β
GRANULES
Thrombin
G/AC
INSIDE OUT OUTSIDE IN SIGNALING
G/AC
ATP
5-HT
5-HT Rc
Fibrinogen P2X1
A.ac
αIIbβ3
TP-Rc
TXA2
Platelet agonists Platelet receptors
↑[Ca]
Coagulation cascade Extrinsic Pathway TF + VII
Intrinsic Pathway
TF:VIIa XIa IXa VIIIa X
XI
IX
VIII
Xa V
Va
Prothrombin (II) VIII
Ca2+
Thrombin (IIa)
VIIIa Fibrinogen
FIBRIN
COAGULATION PATHWAY
XI
Fragment E
Tissue Lesion
Surface Contact HMWK Prekallikrein XII XIIa
FIBRINOLYSIS
TF
Fragment D
VII
Fragment Y
TF VIIa Phospholipids Ca 2+
TFPI
α-2- ANTIPLASMIN
(FDP) Fragment X
TAFI
Plasmin
XIa Ca 2+ Phospholipis
IX
Prothrombinase Complex
Insoluble Fibrin
IXa
XIIIa Ca 2+
VIIIa *
Phospholipids Xa Va * Ca 2+
X
Prothrombin
F1+2
t-PA Fibrinogen Monomers FPA FPB
ANTITHROMBIN XIII
* V -VIII
Fibrinogen
Plasminogen
PROTEIN S Va -VIIIa
u-PA
Fibrinogen Polymers
Thrombin
XIIIa
D-Dimer
PROTEIN C Thrombomodulin
PAI-1
UN-INHIBITED COAGULATION PATHWAY Tissue Lesion
Surface Contact HMWK Prekallikrein XII XIIa XI
TF
VII
TF VIIa Phospholipids Ca 2+
TFPI XIa Ca 2+ Phospholipis
IX
Prothrombinase Complex
IXa
XIIIa Ca 2+
VIIIa *
Phospholipids Xa Va * Ca 2+
X
Prothrombin
F1+2
Fibrinogen Polymers
Fibrinogen Monomers
Thrombin
FPA FPB
ANTITHROMBIN XIII
* V -VIII
Fibrinogen PROTEIN S
XIIIa
Va -VIIIa
PROTEIN C Thrombomodulin
Evolución de los Anticoagulantes EVOLUTION OF ANTITHROMBOTIC TREATMENT
Class Target Regime
1930s
1940s
1980s
Heparins
VKAs
LMWH
ATIII + Xa + Iia II, VII, IX, X ATIII + Xa + Iia (1:1 ratio) (Proteina C,S) (Xa > IIa) Parenteral
Oral
Parenteral
1990s
2000s
DIRECT THROMBIN INHIBITORS
ANTI Xa
Anti IIa / Xa
Thrombin
ATIII + Xa
Anti IIa / Xa
Parenteral
Parenteral
Evolution of anticoagulant drugs
Oral
Evolución de los Anticoagulantes EVOLUTION OF ANTITHROMBOTIC TREATMENT
Class Target Regime
1930s
1940s
1980s
Heparins
VKAs
LMWH
ATIII + Xa + Iia II, VII, IX, X ATIII + Xa + Iia (1:1 ratio) (Proteina C,S) (Xa > IIa) Parenteral
Oral
Parenteral
1990s
2000s
DIRECT THROMBIN INHIBITORS
ANTI Xa
Anti IIa / Xa
Thrombin
ATIII + Xa
Anti IIa / Xa
Parenteral
Parenteral
Evolution of anticoagulant drugs
Evolution of antiplatelet drugs and strategies
Oral
Targets for ANTITHROMBOTICS Anticoagulants TF/FVIIi
Antiplatelets
Tissue factor
Collagen Aspirin
Plasma clotting cascade
ADP Thromboxane A2
LMWH Heparin AT-III Bivalirudin Hirudin Dabigatran
Clopidogrel
Prothrombin
Prasugrel
Factor Xa
AZD 6140 Conformational activation of GPIIb/IIIa
Direct Xa inhib
inhibitors
Thrombin Fibrinogen
GPIIb/IIIa
Platelet aggregation Fibrin
Thrombus
New anticoagulants TF/VIIa X
IX VIIIa
IXa
Va Xa
II IIa Fibrinogen
Fibrin
New anticoagulants ORAL
PARENTERAL TF/VIIa
TTP889
TFPI (tifacogin)
X Rivaroxaban Apixaban LY517717 YM150 DU-176b Betrixaban PRT-054021
IX VIIIa
Va Xa
APC (drotrecogin alfa) sTM (ART-123)
IXa AT
II
Ximelagatran Dabigatran
DX-9065a Otamixaban
IIa Fibrinogen
Fondaparinux Idraparinux
Fibrin
Direct Factor Xa Inhibitors
Oral Factor Xa inhibitors Clinical Development Rivaroxaban (JNJ/Bayer) Apixaban (BMS) YM150 (Astellas)
Phase III
Phase III Phase IIb
Edoxaban (DU-176b/Daiichi) Phase III LY517717 (Lilly)
Phase IIb
813893 (GSK)
Phase I/II
Betrixaban (Portola) TAK – 442 (Takeda)
Phase II Phase II
Direct Factor Xa inhibition Tissue factor
XIIa XIa IXa
× Xa
Factor II (prothrombin)
Fibrinogen
Fibrin clot
VIIa Rivaroxaban Apixaban DU-176b YM150 LY517717 PRT-054021
Direct Factor Xa Inhibitors FXa
Direct FXa inhibitors FXa in the prothrombinase complex • Direct Factor Xa inhibitors can inhibit Factor Xa within the prothrombinase complex
Rivaroxaban Fase II Prevención de TVP en cirugía ortopédica
♦ ODIXa-HIP1 ♦ ODIXa-HIP2 ♦ ODIXa-KNEE ♦ ODIXa-OD-HIP
Fase III
Completed (12.383)
♦ RECORD1 ♦ RECORD2 ♦ RECORD3 ♦ RECORD4
Prevención de TVP en pacientes médicos hospitalizados Tratamiento de TVP
♦ ODIXa-DVT ♦ EINSTEIN-DVT
♦ EINSTEIN-DVT Completo ♦ EINSTEIN-PE ♦ EINSTEIN-EXT Japanese Phase III study
Prevención de ictus en la FA no reumática Prevención secundaria en SCA
♦ ATLAS ACS-II TIMI 51 ~8,000
>42,000
Apixaban: Fase II APROPOS – Cirugía ortopédica BOTTICELLI – Tratamiento ADAPT – Cáncer avanzado APPRAISE 1 – ACS
Apixaban: Fase III ADVANCE 1,2,3 - Cirugía ortopédica ADOPT - Enfermedades médicas AVERROES - Fibrilación auricular ARISTOTLE - Fibrilación auricular APPRAISE 2 - ACS
Direct Thrombin Inhibitors
Direct Thrombin Inhibitors
• Dabigatran etexilato (Boehringer Ingelheim) Phase III • AZD0837 (Astra Zeneca) Phase II • MCC 977 (Mitsubishi Pharma Phase II
RE-VOLUTION™ programa clínico con Dabigatrán
Prevención primaria de TVP
Tratamiento agudo de TVE
Prevención secundaria en SCA
Prevencion secundaria de TVE
Incluyendo >38,000 pacientes en el mundo
Prevención de Ictus en fibrilación auricular
Direct Thrombin Inhibitors (DTIs) Specific for thrombin •
Block thrombin’s effects upon its substrates
•
Block both free and clot-bound thrombin
Direct Thrombin Inhibitors (DTIs) Block all procoagulant effects of thrombin: – Thrombin’s conversion of fibrinogen to fibrin – Thrombin’s platelet activation – Thrombin’s activation of clotting factors V, VIII, and XI
Direct Thrombin Inhibitors (DTIs) Features:
– Highly effective in the prevention of arterial and venous thrombus formation – Produce a predictable anticoagulant response – Do not require dose titration or anticoagulant monitoring
Direct Thrombin Inhibitors (DTIs) Oral DTIs – Predictable and consistent antithrombotic effect – Highly specific for thrombin – Inhibit free and clot-bound thrombin – Unlike parenteral DTIs, can be used both in the hospital and out-patient setting
Dabigatran Etexilate
Direct Oral Thrombin Inhibitor Dabigatran etexilate is an oral direct thrombin inhibitor, exhibiting: Predictable anticoagulant effect1-3 Fixed dose No need for monitoring1-3
It is the pro-drug of the active compound dabigatran (rapidly converted by serum estereses), which binds directly to thrombin with a high affinity and specificity4-5
1. Eriksson BI et al. Journal of Thrombosis and Haemostasis 2004; 2: 1573–1580 2. Eriksson BI et al. Journal of Thrombosis and Haemostasis 2005; 3: 103–111 3. Wallentin L et al. European Heart Journal 2005; 26(suppl): 482. 4. Stassen JM et al. 28th Congress of the International Society on Thrombosis and Haemostasis; Paris July 6-12, 2001 5. Hauel NH et al. J Med Chem 2002; 45:1757-66
6,5% bioavailability 80% kidney excretion Half life 14-17 hours Robust data on venous thrombosis (TKR, HR) No hepatic effects
Connolly S et al. N Engl J Med 2009;10.1056/NEJMoa0905561
IDEAL OAC Predictable effect Fixed oral dose No need of monitoring No interactions with drugs, foods or nutrients No toxicity Fast onset and end of action
Vitamin K Antagonists Vitamin K dependent • Factor II • Factor VII • Factor IX • Factor X Vitamin K is required for binding • Protein C to phospholipid membranes • Protein S
Vitamin K Antagonists Half-life of Vitamin K-dependent clotting factors
●
Factor VII - 4 to 6 hours
●
Factor IX - 24 hours
●
Factor X - 48 to 72 hours
●
Factor II - 60 hours
●
Protein C - 8 hours
●
Protein S - 30 hours
• Vitamin K antagonism results in the inability of clotting factors to attach to phospholipid membranes • No effect upon existing factors • Onset of action determined by half-life
NARROW THERAPEUTIC WINDOW – NEEDS MONITORING
80 Events / 1000 patient years
Ischemic stroke
Target INR (2.0-3.0)
Intracranial haemorrhage
The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range
60
40
20
0 <1.5
1.5–1.9
2.0–2.5
2.6–3.0
3.1–3.5
3.6-4.0
4.1-4.5
>4.5
International Normalised Ratio (INR)
Hylek EM, et al. N Eng J Med 2003; 349:1019-1026.
FDA approves dabigatran for stroke prevention, embolism, in AF patients OCTOBER 19, 2010 US FDA announced it has approved dabigatran (Pradaxa, Boehringer Ingelheim) for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug will be available in two doses: 75 mg and 150 mg. An advisory panel in September voted 9 to 0 to recommend that the oral antithrombin be approved. The cardiology community has expressed few major reservations about the randomized trial on which the drug's approval application is primarily based, the 18 000-patient Randomized Evaluation of LongTerm Anticoagulant Therapy (RE-LY).
FDA approves dabigatran for stroke prevention, embolism, in AF patients OCTOBER 19, 2010
•
•
•
And for a generation, it has longed for an oral antithrombin that's at least as safe and effective as warfarin but is more consistent in its effects and doesn't require cumbersome anticoagulation monitoring. As with other approved anticlotting drugs, bleeds, both lifethreatening and fatal, were among the most common adverse reactions reported by patients treated with dabigatran in studies. Other side effects, including gastrointestinal symptoms, dyspepsia, stomach pain, nausea, heartburn, and bloating also were reported. Dabigatran was approved with a Medication Guide that details the risk of serious bleeding for patients.
VIII i
+
Fibrin + FPs
Fibrin polimers
Fg
+
II XI IIa XI
VIIIa VIII X ase
Platelet PAR 1
THROMBIN
PTase
Signalling Aggregation Recruitment
V Va VI tPA + Thrombomodulin
+ -
Endothelial cell
Prot C
Proliferation VSMC V, VIII
+
-
+
Prevention of Thromboembolism Anticoagulants
VKAs
Novel anticoagulants
Antiplatelet agents
Aspirin ± Clopidogrel
Warfarin Direct thrombin Non-warfarin VKAs • Tecarfarin
inhibitors
Factor X inhibitors • Apixaban
• Ximelagatran
• Betrixaban
• Dabigatran
• Edoxaban
• AZD 0837
• Idraparinux • Rivaroxaban • YM150
Non-antithrombotic drugs
AntiHTN Statins
Antiarrhythmic
Atrial Fibrillation Phase 3 Estimated Study Timelines Dabigatran RE–LY Complete
2009
ROCKET–AF Estimated completion June 2010
2010
Rivaroxaban
2011
ARISTOTLE AVERROES completion 2010
Estimated completion November 2010
Apixaban
2012
ENGAGE–AF TIMI 48 Estimated completion March 2011
Edoxaban
G. ARDERIU L. CASANI J. CUBEDO R. FERRER M. G.-ARGUINZONIS R. HERNANDEZ-VERA O. JUAN V. LLORENTE-CORTES R. LUGANO B. MOLINS B. OÑATE T. PADRO E. PEÑA E. SEGALES R. SUADES M. TOUS G. VILAHUR
BARCELONA CARDIOVASCULAR RESEARCH CENTER CSIC-ICCC HOSPITAL DE LA SANTA CREU I SANT PAU