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

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 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)

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 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

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)

- 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

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)

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

New Oral Anticoagulants - ADVANTAGES

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

New Oral Anticoagulants - CONCERNS

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)