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)