gli anticoagulanti di ultima generazione ida martinelli centro emofilia e trombosi a. bianchi bonomi...
TRANSCRIPT
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Gli anticoagulanti di ultima generazione
Ida Martinelli
Centro Emofilia e Trombosi A. Bianchi Bonomi
Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico Milano
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THE BURDEN OF THE DISEASE
Venous thromboembolism (VTE) is the 3rd most common type of cardiovascular disease
VTE causes over 500.000 deaths in Europe and 300.000 deaths in the United States each year
Annual deaths attributable to VTE are estimated to exceed the combined number of deaths from breast and prostate cancers, AIDS, and traffic accidents
Total estimated cost for VTE-associated care = EUR 3.1 billion per year
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ACHIEVEMENTS WITH TRADITIONAL ANTITHROMBOTIC AGENTS
Heparins (UFH and LMWH) reduce by about 60% the incidence of venous thromboembolism (VTE) after high-risk surgery
Vitamin K antagonists reduce by more than 90% VTE recurrence
Vitamin K antagonists reduce by about 60% the rate of stroke in patients with atrial fibrillation or artificial valves
Aspirin and clopidogrel reduce by about 50% the rate of stent thrombosis
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LIMITS OF TRADITIONAL ANTICOAGULANTS
Slow onset of action (warfarin) need for bridging
Need for laboratory monitoring (unfractionated heparin, warfarin)
Need for parenteral administration (heparins)
Non-hemorragic adverse effects, such as heparin induced thrombocytopenia, osteoporosis (heparins)
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LIMITS OF TRADITIONAL ANTICOAGULANTS
Interindividual variability in dosing requirements (warfarin)
Food and drug interactions (warfarin)
Reduced synthesis of all vitamin-K dependent proteins (risk of skin necrosis in protein C or S deficiency) (warfarin)
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New anticoagulants New anticoagulants
Xa
IIa
TF/VIIa
X IX
IXaVIIIa
Va
II
FibrinFibrinogen
adapted from Bates adapted from Bates Br J HaematolBr J Haematol 2006 2006
TTP889
TFPI (tifacogin)NAPc2
Oral - DIRECTRivaroxabanApixabanEdoxabanBetrixabanYM150
Parenteral - INDIRECTFondaparinuxIdraparinuxBiotinylated idraparinuxULMWH
Oral – DIRECTDabigatran
APC (drotrecogin alfa)sTM (ART-123)
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New Oral Anticoagulants:pharmacologic properties
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STEPS OF CLINICAL EVALUATION OF NEW ORAL ANTICOAGULANTS
First prevention of VTE in major orthopedic surgery
Second treatment of VTE
Third atrial fibrillation, acute coronary syndromes
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Phase III Randomized Controlled Trials of New Anticoagulants for VTE Prevention
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CUMULATIVE RESULTS OF PHASE 3 TRIALS IN VTE PREVENTION
IN HIGH-RISK ORTHOPEDIC SURGERY
Oral dabigatran, rivaroxaban and apixaban, given once daily starting after surgery, are at least as effective or more effective than subcutaneous enoxaparin in patients undergoing high-risk orthopedic surgery
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REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PELassen et al, N Engl J Med 2008:358; 2776
RECORD 1 RECORD 2 RECORD 3
Efficacy: Total VTE (primary endpoint)
Rivaroxaban 10 mg Enoxaparin 40 mg
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POOLED ANALYSIS OF RIVAROBAXAN IN VTE PROPHYLAXIS
More than 10.000 patients studied in 4 randomized trials
56% reduction in symptomatic VTE and mortality
No increased risk of bleeding
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Phase 3 Clinical Trials of New Oral Anticoagulants (vs. Enoxaparin)in Total Hip Replacement (THR) and Total Knee Replacement (TKR)
- 15 - 10 - 5 0 5 10 15
Absolute risk difference (%)
RECORD-1
RECORD-2
RECORD-3
RECORD-4
RE-NOVATE (220 mg)
RE-NOVATE (150 mg)
RE-MODEL (220 mg)
RE-MODEL (150 mg)
ADVANCE-1
Rivaroxaban(Xa inhibitor)
Dabigatran(thrombin inhibitor)
Apixaban(Xa inhibitor)ADVANCE-2
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Phase III Randomized Controlled Trials of New Anticoagulants for Indications Other Than VTE
Prevention
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RE-COVER
N Engl J Med 2009
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RE-COVER, N Engl J Med 2009
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EINSTEIN
N Engl J Med 2010
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EINSTEIN, N Engl J Med 2010
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EINSTEIN-PE, N Engl J Med 2012
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Dosi validate in studi di fase III (mg/die)
Dabigatran (Pradaxa)
Rivaroxaban(Xarelto)
Apixaban(Eliquis)
Profilassi TEV(chirurgia e medicina)
150 x 1Oppure220 x 1
10 x 1 2,5 x 2
FA110 x 2Oppure150 x 2
20 x 1 5 x 2
Terapia del TEV 150 x 2 15 x 2 (prime 3 sett) poi 20 x 1
In corso
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New Oral Anticoagulants - ADVANTAGES
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Unproven compliance in daily clinical practice
More expensive than warfarin
Unknown safety after years of administration
New Oral Anticoagulants - CONCERNS
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Contraindicated if renal or liver insufficiency
Difficult to be detected in patients plasma in case of emergency
No antidote
Caution when combined with ASA
New Oral Anticoagulants - CONCERNS
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Personal opinion
“Fixed” doses are not always better for any patient
Phase IV independent clinical trials are needed (risks and benefits in daily clinical practice and in patients excluded from phase III trials)