Francesco Marongiu Università di Cagliari, Policlinico di Monserrato, Medicina Interna [email protected]Pavia, 21-22 giugno 2012 Pavia Spring Meeting on Thrombosis Aspetti Clinici e di Laboratorio del Tromboembolismo Venoso ed Arterioso alla luce delle Linee Guida ACCP 2012 Farmaci anticoagulanti vecchi e nuovi
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Francesco MarongiuUniversità di Cagliari, Policlinico di Monserrato, Medicina Interna
Pavia Spring Meeting on ThrombosisAspetti Clinici e di Laboratorio del Tromboembolismo Venoso ed Arterioso
alla luce delle Linee Guida ACCP 2012
Farmaci anticoagulanti vecchi e nuovi
Professor Diakonov nel suo articolo del 1809,Changes ofhuman blood in the leechnel 1809, scrisse che “lack of bloodcoagulation and dissolution of red blood corpuscles in the leech’s intestinal duct testifies that some dissolving agent exists there”
IRUDINA
Historical Article: Hirudo medicinalis: ancient origins of, and trends in the use of medicinal leeches throughout history. Br J Oral and Maxillofacial Surg 2004;42: 133-7
McLean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41: 250-7McLean J. The discovery of heparin. Circulation 1959; 19: 75-8.
Jay McLean
M W 15,000 (range: 3.000 to 30.000 d)Only one third of heparin molecules contain the high-affinity
pentasaccharide (AT) required for anticoagulant activity
UFH
Heparin doses Half-life min
25 U/Kg (1750 U) 30
100 U/Kg (7000 U) 45-60
400 U/Kg (28000 U) 46-150
Chest 2008;133;141-159
Highly sulphated mucopolysaccharide
Heparin binds to plasma proteins, endothelial cells, macrophages and AT.
Plasma proteins
Endothelial cells
Antithrombin
Macrophages
Chest 2008;133;141-159
LMWH Molecular WeightRatio
anti-Xa/anti-IIa
Enoxaparin 4500 3.9
Dalteparin 6000 2.5
Tinzaparin 6500 1.6
Nadroparin 4300 3.2
Certoparin 5400 2.4
Bemiparin 3600 9.7
Reviparin 4400 4.2
Thromb Haemost 2008; 99: 807–818
Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism
Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No.:
Control group: Heparin (60 IU/kg IV bolus followed by an infusion of 12 IU/kg/h) + eptifibatide (180 mg/kg IV bolus followed by an infusion of 1.0-2.0 mg/kg/min).
Pegmusirudin (PEG-hirudin; SPP200; LU87981)DTI con lunga emivita (fino a 36 h)
Antidoto: no
Emodialisi
Studio di fase II su 127 pazientiPEG-Hirudin: 0.052 o 0.065 mg/kg
Occlusione accesso vascolarePEG-hirudin 11 % versus Heparin 40 %
Sanguinamento maggiorePEG-Hirudin 8.4 % versus Heparin 5.4 %
Sanguinamento minore: 57.8 versus 32.4 %
J Am Soc Nephrol 17: F-PO769
Pentasaccaride + DTI +
biotina
Neutralizzato da avidina
EP217609: aggiunge soprattutto l’attività verso la trombina legata alla fibrina
Antidote
The REG1 anticoagulation system is composed of the drug RB006 and the oligonucleotide antidote to RB006 (RB007), which binds to RB006 via Watson-Crick base pairing and thereby neutralizes its pharmacological effect.
Anti-IX
Aptamer
Eur Heart J 2011;32:2412-9
Pegnivacogin results in near complete FIX inhibition in acute coronary syndrome patients: RADAR pharmacokinetic and
pharmacodynamic substudy.
The REG1 system (Regado Biosciences, Basking Ridge, NJ) consists of pegnivacogin (RB006), an RNA aptamer that directly inhibits factor IXa, and anivamersen (RB007), its complementary control agent.
RADAR is a Phase 2b study investigating the use of pegnivacogin in patients (n = 800) with ACS undergoing planned early cardiac catheterization.
Pegnivacogin 1 mg/kg rapidly achieved a high pegnivacogin plasmaconcentration (26.1 ± 4.6 µg/mL), prolonged the aPTT (mean aPTT 93.0 ±9.5 s), and approached near complete factor IX inhibition.
Anticoagulant Hours to
[C] maxHalf-life
hours
Renal
elimination
Dabigatran 2 12-14 80 %
Rivaroxaban 2-4 9-13 33 (66) %
Apixaban 1-3 8-15 25 %
Ericksson BI, Clin Phatmacokinet 2009
Ruff CR, Am Heart J 2010
General characteristics of NOA
Study name Statistics for each study Risk ratio and 95% CI
Risk Lower Upper ratio limit limit Z-Value p-Value
Apixaban AF 0,797 0,667 0,952 -2,501 0,012
Re-ly 150 0,667 0,538 0,828 -3,668 0,000
Re-ly 110 0,916 0,751 1,116 -0,873 0,383
ROCKET AF 0,880 0,750 1,033 -1,559 0,119
0,822 0,749 0,901 -4,167 0,000
0,5 1 2
Favours NOA Favours Warfarin
NOA versus Warfarin
Meta Analysis
Stroke
Hazard ratios and 95% confidence intervals of the primary safety
outcome (major bleeding) in the 3 pivotal trials comparing new oral
anticoagulants with warfarin in nonvalvular atrial fibrillation.
JACC 2012; 59:1413–25
Anticoagulant CHADS2
score
Heart failure
%
Dabigatran 2.10 32
Rivaroxaban 3.48 63
Apixaban 2.10 35
Complexity of patients
Anticoagulant M. B. % y ICH % y
Dabigatran 150 mg
Dabigatran 110 mg
Warfarin 2.0-3.0 INR
3.11
2.71
3.36
0.10
0.12
0.38
Rivaroxaban 20 mg*
Warfarin 2.0-3.0 INR
3.60
3.40
0.50
0.70
Apixaban 5 mg
Warfarin 2.0-3.0 INR
2.13
3.09
0.24
0.47
* Once daily
NOA and Atrial Fibrillation:
Major bleeding with warfarin: 3.09-3.36 %y
an unrealistic result
Anticoagulant Gastrointestinal
bleeding
Rivaroxaban 20 mg 224 (3.15 %)
Warfarin 2.0-3.0 INR 154 (2.16 %)
p<0.001
More gastroenteric bleeding with
Rivaroxaban
Anticoagulant Gastrointestinal
bleeding
Dabigatran 150 mg 182 (1.51 % y)
Warfarin 2.0-3.0 INR 120 (1.02 % y)
RR: 1.50 (1.19-1.89) p<0.001
More gastroenteric bleeding with
Dabigatran 150 mg (t.d.))
Anticoagulant Dispepsia
Dabigatran 150 mg 688 (11.3 %) *
Dabigatran 110 mg 707 (11.8 %) *
Warfarin 2.0-3.0 348 (5.8 %)
More dyspepsia with Dabigatran)
* p<0.001
unreliable result
(never seen)
Questions and answers on the use of dabigatran and
perpectives on the use of other new oral anticoagulants
in patients with atrial fibrillation
A consensus document of the Italian Federation of
Thrombosis Centers (FCSA)
Vittorio Pengo; Luciano Crippa; Anna Falanga; Guido
Finazzi; Francesco Marongiu; Gualtiero Palareti; Daniela
Poli; Sophie Testa; Eros Tiraferri; Alberto Tosetto;