Transcript New Oral Anticoagulants
Gli anticoagulanti di ultima generazione
Ida Martinelli Centro Emofilia e Trombosi A. Bianchi Bonomi Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico Milano
THE BURDEN OF THE DISEASE
Venous thromboembolism (VTE) is the 3 rd 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
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
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)
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)
TFPI (tifacogin) NAPc2 Oral – DIRECT Dabigatran
New anticoagulants
X Fibrinogen TTP889 TF/VIIa IX APC (drotrecogin alfa) sTM (ART-123) VIIIa IXa Va Xa II IIa Fibrin Oral - DIRECT Rivaroxaban Apixaban Edoxaban Betrixaban YM150 Parenteral - INDIRECT Fondaparinux Idraparinux Biotinylated idraparinux ULMWH adapted from Bates Br J Haematol 2006
New Oral Anticoagulants: pharmacologic properties
STEPS OF CLINICAL EVALUATION OF NEW ORAL ANTICOAGULANTS
First
Second
Third prevention of VTE in major orthopedic surgery treatment of VTE atrial fibrillation, acute coronary syndromes
Phase III Randomized Controlled Trials of New Anticoagulants for VTE Prevention
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
REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE Lassen et al, N Engl J Med 2008:358; 2776 Efficacy: Total VTE (primary endpoint) RECORD 1 Rivaroxaban 10 mg RECORD 2 RECORD 3 Enoxaparin 40 mg
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
Phase 3 Clinical Trials of New Oral Anticoagulants (
vs.
Enoxaparin) in Total Hip Replacement (THR) and Total Knee Replacement (TKR) RECORD-1 RECORD-2 RECORD-3 RECORD-4 Rivaroxaban
(Xa inhibitor)
RE-NOVATE
(220 mg)
RE-NOVATE
(150 mg)
RE-MODEL
(220 mg)
RE-MODEL
(150 mg)
Dabigatran
(thrombin inhibitor)
ADVANCE-1 ADVANCE-2 - 15 - 10 - 5 0 5 Absolute risk difference
(%)
10 Apixaban
(Xa inhibitor)
15
Phase III Randomized Controlled Trials of New Anticoagulants for Indications Other Than VTE Prevention
RE-COVER N Engl J Med 2009
RE-COVER, N Engl J Med 2009
EINSTEIN N Engl J Med 2010
EINSTEIN, N Engl J Med 2010
EINSTEIN-PE, N Engl J Med 2012
Dosi validate in studi di fase III (mg/die)
Profilassi TEV
(chirurgia e medicina)
FA Terapia del TEV Dabigatran (Pradaxa)
150 x 1
Oppure
220 x 1 110 x 2
Oppure
150 x 2 150 x 2
Rivaroxaban (Xarelto)
10 x 1 20 x 1 15 x 2 (prime 3 sett)
poi
20 x 1
Apixaban (Eliquis)
2,5 x 2 5 x 2
In corso
New Oral Anticoagulants ADVANTAGES
New Oral Anticoagulants CONCERNS
Unproven compliance in daily clinical practice More expensive than warfarin Unknown safety after years of administration
New Oral Anticoagulants CONCERNS
Contraindicated if renal or liver insufficiency Difficult to be detected in patients plasma in case of emergency No antidote Caution when combined with ASA
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)