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 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
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)
New anticoagulants
TFPI (tifacogin)
NAPc2
TTP889
TF/VIIa
IX
X
VIIIa
IXa
Oral - DIRECT
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
YM150
Va
Xa
Oral – DIRECT
Dabigatran
II
IIa
Fibrinogen
APC (drotrecogin alfa)
sTM (ART-123)
Fibrin
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
prevention of VTE in major
orthopedic surgery
 Second
treatment of VTE
 Third
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
Rivaroxaban
RECORD-3
(Xa inhibitor)
RECORD-4
RE-NOVATE (220 mg)
RE-NOVATE (150 mg)
Dabigatran
RE-MODEL (220 mg)
(thrombin inhibitor)
RE-MODEL (150 mg)
ADVANCE-1
Apixaban
ADVANCE-2
(Xa inhibitor)
- 15
- 10
-5
0
5
Absolute risk difference (%)
10
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)
Dabigatran
(Pradaxa)
Profilassi TEV
(chirurgia e medicina)
Rivaroxaban
(Xarelto)
Apixaban
(Eliquis)
10 x 1
2,5 x 2
20 x 1
5x2
15 x 2 (prime 3 sett) poi
20 x 1
In corso
150 x 1
Oppure
220 x 1
110 x 2
FA
Oppure
150 x 2
Terapia del TEV
150 x 2
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)