HIBOR. 1st Prophilaxis. Acute phase treatment. Pentasaccharide. Long-term 2ª ACOs UFH LMWH LMWH LMWH. Competitors

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1 HIBOR Competitors 1st Prophilaxis LMWH Pentasaccharide Long-term Profilaxis treatment 2ª ACOs LMWH Acute phase treatment UFH LMWH

2 Unfractionated heparin (UFH) Discovered by J. Mc Lean in Later named heparin by Howell. In 1951 Rovi develops and markets sodium heparin. In 1971, low doses of UFH as VTE prophylaxis (Kakkar( Kakkar) In 1971 Rovi develops and markets calcium heparin. In 1976 Johnson elaborates a LMWH. In 1976 Rovi incorporates the pre-filled syringe In 1998 Rovi markets Bemiparina (HIBOR)

3 UFH STRUCTURE It belongs to the family of sulphated glycosaminoglicanes with a strong negative charge. CHEMICAL COMPOSITION Combination of uronic acids (glucuronic & iduronic) ) with acetilglucosamine A monosaccharide chain is formed

4 UFH SOURCE Bovine Pulmonary Mucosa Porcine Intestinal Mucosa (mastocites) MOLECULAR WEIGHT FROM 2000 to daltons (average daltons)

5 UFH ACTION MECHANISM The anticoagulant action is exerted by the binding of heparin to the AT-III III,, physiological inhibitor of several activated factors of coagulation (FIIa, FXa, FIXa, FXIa, FXIIa)

6 Plasmatic coagulation system INTRINSIC ROUTE TFPI EXTRINSIC ROUTE FXII, FXI, FIX, FVIII Ca ++ FXIIa, FXIa, FIXa, FVIIIa FX FXa FT (FIII), (FVII) to (FVIIa( FVIIa) PROTHROMBIN (FII) to to THROMBIN (FIIa( FIIa) UFH AT-III AT (FXIII) a (FXIIIa( FXIIIa) FIBRINOGEN (FI) to to FIBRIN (FIa( FIa) INSOLUBLE FIBRIN

7 UFH The presence of a critical pentasaccharide is essential (binding site to AT-III) in heparin chains 33% of such chains present this pentasaccharide

8 UFH The inhibition of the coagulation factors FIIa, FIXa, FXIa and FXIIa requires a heparinic chain length of more that 18 monosaccarides (long chain) The inhibition of FXa only requires a Heparin chain length of less than 18 monosaccharides (short chain) ) but containing the pentasaccharide

9 UFH AT-III Xa Inhibition of factor Xa ANTITHROMBOTIC AT-III IIa Inhibition of factor IIa HAEMORRAGIC EFFECT

10 HBPM AT-III Xa Inhibition of factor Xa ANTITHROMBOTIC EFFECT AT-III IIa Inhibition of factor IIa NO MINIMUM HAEMORRAGIC EFFECT

11 LMWH Advantages in comparison with UFH A single daily sc injection Longer half-life life Longer bioavailability Fixed dose Monitoring unrequired Lab controls Greater safety Lower haemorragic tendency Lower thrombocitopaenia frequency Lower bone demineralisation

12 Unfractionated heparins 5000 UI, 1 & 100 viales UI, 1 & 100 viales 5000 & 7500 UI, 4 & 100 viales UI & UI, 2 & 100 viales

13 DISADVANTAGES OF ETEV TREATMENT WITH UFH ETEV Recurrence Haemorrhagic complications Thrombopoenia Need of hopital administration Need of lab control

14 LMWH Low Molecular Weight Heparins Bemiparin HIBOR (Rovi) Enoxaparin Dalteparin Nadroparin Tinzaparin

15 RESULTS OF ETEV TREATMENT WITH LMWH Efficacy criteria -Reduction of the risk of progression of the thrombus -Reduction of the risk of ETEV recurrence -Reduction of mortality Safety criteria -Reduction of the risk of major haemorrhages Other advantages -No need of lab biological control -Ease of administration (a single daily dose) -Possibility of ambulatory treatment

16 Pentasaccaride Fondaparinux ARIXTRA (Sanofi-Synthelabo)

17 Oral anticoagulants SINTROM (Acenocumarol, Novartis) 1 mg,, 60 comp. 4 mg,, 20 and 500 comp. ALDOCUMAR (Warfarin,, Aldo Unión) 10 mg, 25 and 500 comp.

18 INR Value that doctors need in order to estimate the degree of anticoagulation of the patient, in relation to a normal situation. INR (International Normalized Ratio) quotient between the plasma thromboplastin time of the patient and the normal thromboplastin time, Elevated to the International Sensitivity Index (ISI)

19 TAO SINTROM dose The SINTROM dose must be established individually and adjusted according to INR values INR *8 to 12 mg the first day *4 to 8 mg the second day *Continuity from 1 to 8 mg/days, depending on INR values on INR

20 INR Recommended therapeutic ranges MILD RISK INR = 2-3 *Prophylaxis orthopaedic surgery *Prevention of venous thromboembolism in myocardial infarction *Auricular fibrilation *Biological valvular cardiac prostheses *Treatment of DVT and PE HIGH RISK INR = *Recurrent DVT *Mechanical valvular cardiac prostheses

21 TAO Dose control If the INR is lower than the pre-established established range for this patient, an increase of the anticoagulant dose is necessary If the INR is higher than the pre-established established range for this patient, a decrease of the anticoagulant dose is necessary

22 TAO Duration First episode 3 months First recurrence 1 year Subsequent recurrences Chronic

23 RISK OF HAEMORRHAGIC COMPLICATIONS ASSOCIATED WITH TAO Type of haemorrhage Fatal Annual occurrence Major Minor

24 RISK OF MAJOR HAEMORRHAGE ASSOCIATED WITH TAO IN RELATION TO AGE Age