Gli anticoagulanti di ultima generazione
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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

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Gli anticoagulanti di ultima generazione

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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

TTP889

TF/VIIa

TFPI (tifacogin)

NAPc2

IX

X

APC (drotrecogin alfa)

sTM (ART-123)

IXa

VIIIa

  • Oral - DIRECT

    • Rivaroxaban

    • Apixaban

    • Edoxaban

    • Betrixaban

    • YM150

  • Parenteral - INDIRECT

    • Fondaparinux

    • Idraparinux

    • Biotinylated idraparinux

    • ULMWH

Va

Xa

  • Oral – DIRECT

    • Dabigatran

II

IIa

Fibrinogen

Fibrin

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

  • Thirdatrial fibrillation, acute coronary syndromes


Phase III Randomized Controlled Trials of New Anticoagulants for VTE Prevention


CUMULATIVE RESULTS OF PHASE 3 TRIALS IN VTE PREVENTIONIN 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

Efficacy: Total VTE (primary endpoint)

RECORD 2

RECORD 3

RECORD 1

Rivaroxaban 10 mgEnoxaparin 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

(Xa inhibitor)

RECORD-3

RECORD-4

RE-NOVATE (220 mg)

RE-NOVATE (150 mg)

Dabigatran

(thrombininhibitor)

RE-MODEL (220 mg)

RE-MODEL (150 mg)

ADVANCE-1

Apixaban

(Xa inhibitor)

ADVANCE-2

- 15

- 10

- 5

0

5

10

15

Absolute risk difference (%)


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)


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)


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