1. Gli anticoagulanti di ultima generazione
Ida Martinelli
Centro Emofilia e Trombosi A. Bianchi Bonomi
Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico Milano

2. THE BURDEN OF THE DISEASE
Venous thromboembolism (VTE) is the 3rd most common type of cardiovascular disease
VTE causes over deaths in Europe and 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

3. 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

4. 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)

5. 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)

6. New anticoagulants TF/VIIa IX X IXa VIIIa Va Xa II IIa Fibrinogen
TTP889
TF/VIIa
TFPI (tifacogin)
NAPc2 IX X
APC (drotrecogin alfa)
sTM (ART-123)
IXa
VIIIa Va
Oral - DIRECT
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
YM150
Parenteral - INDIRECT
Fondaparinux
Idraparinux
Biotinylated idraparinux
ULMWH Xa
Oral – DIRECT
Dabigatran II
Reference
Bates S, Weitz J. The status of new anticoagulants. Br J Haematol 2006;134(1):3-19
This is a very well known scheme of some of the anticoagulants in development. You see there are different targets (direct FIXa, XIa inhibitors, VIIIA inhibitors, VIIa/TF inhibitors, Va inhibitors, dual thrombin/Xa inhibitors), but the main targets are factor IIA (thrombin) and factor Xa. They can be administered orally or by parenteral route, subcutaneous or intravenous injections, and act directly binding thrombin or factor Xa (the oral compounds) or indirectly, binding antithrombin, for parenteral anti Xa inhibitors.
IIa
Fibrinogen
Fibrin
adapted from Bates Br J Haematol 2006 6

7. New Oral Anticoagulants: pharmacologic properties

8. 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

9. Phase III Randomized Controlled Trials of New Anticoagulants for VTE Prevention

10. 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

11. Efficacy: Total VTE (primary endpoint) RECORD 1 RECORD 2 RECORD 3
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
RECORD 2
RECORD 3
Rivaroxaban 10 mg Enoxaparin 40 mg

12. POOLED ANALYSIS OF RIVAROBAXAN IN VTE PROPHYLAXIS
More than patients studied in 4 randomized trials
56% reduction in symptomatic VTE and mortality
No increased risk of bleeding

13. in Total Hip Replacement (THR) and Total Knee Replacement (TKR)
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
(Xa inhibitor)
RECORD-3
RECORD-4
RE-NOVATE (220 mg)
RE-NOVATE (150 mg)
Dabigatran
(thrombin inhibitor)
RE-MODEL (220 mg)
RE-MODEL (150 mg)
ADVANCE-1
Apixaban
(Xa inhibitor)
ADVANCE-2
- 15
- 10
- 5 5 10 15
Absolute risk difference (%)

14. Phase III Randomized Controlled Trials of New Anticoagulants for Indications Other Than VTE Prevention

15. RE-COVER
N Engl J Med 2009

16. RE-COVER, N Engl J Med 2009

17. EINSTEIN
N Engl J Med 2010

18. EINSTEIN, N Engl J Med 2010

19. EINSTEIN-PE, N Engl J Med 2012

20. Dosi validate in studi di fase III (mg/die)
Dabigatran
(Pradaxa)
Rivaroxaban
(Xarelto)
Apixaban
(Eliquis)
Profilassi TEV
(chirurgia e medicina)
150 x 1
Oppure
220 x 1
10 x 1
2,5 x 2 FA
110 x 2
150 x 2
20 x 1
5 x 2
Terapia del TEV
15 x 2 (prime 3 sett) poi 20 x 1
In corso

21. New Oral Anticoagulants - ADVANTAGES

22. New Oral Anticoagulants - CONCERNS
Unproven compliance in daily clinical practice
More expensive than warfarin
Unknown safety after years of administration

23. 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

24. 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)