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Gli anticoagulanti di ultima generazione

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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  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 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

  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 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

  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 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

  11. 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

  12. 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

  13. 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 (%)

  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)

  21. New Oral Anticoagulants - ADVANTAGES

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

  23. 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

  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)

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