1. Heparin-Induced Thrombocytopenia (HIT) Treatment with danaparoid (Orgaran  )

2. Management of HIT – treatment Stop all heparin (both unfractionated and low- molecular-weight heparin) Initiate alternative non-heparin anticoagulant because of high risk of symptomatic thrombosis Test for HIT antibodies Duplex ultrasonography to exclude DVT When HIT is strongly-suspected:

3. Management of HIT – treatment Therapeutic doses of alternative non-heparin anticoagulants are usually required Postpone starting overlapping coumarin until the platelet count has recovered to at least 100 (and preferably) 150 x 10 9 /L If a sensitive test for HIT is negative, heparin therapy may be re-started with regular platelet count monitoring When the diagnosis of HIT is confirmed: * 7th. ACCP Conference 2004 Chest, 126, 311S-337S

4. Management of HIT – treatment Danaparoid1B Direct thrombin inhibitors  Lepirudin 1C+  Argatroban 1C  Bivalirudin 2C Alternative non-heparin antithrombotic therapies include: *Grading as per 7th American College of Chest Physicians Conference. Chest 2004, 126: 311S-337S Grade of recommendation*

5. Heparin-Induced Thrombocytopenia (HIT) Rationale for initiating or continuing antithrombotic therapy after discontinuing heparin

6. Initiating or continuing antithrombotic therapy Patient typically has pre-existing indication for prophylactic or therapeutic anticoagulation HIT greatly increases baseline risk of thrombosis (odds ratio, 20—40) Rationale for initiating or continuing antithrombotic therapy after stopping heparin because of HIT

7. Adapted from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507. Occurrence of symptomatic thrombosis after stopping heparin in patients confirmed to have isolated HIT Cumulative thrombotic event-rate (%) Days after isolated HIT recognized 52.8% 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 10121416 8 18222628302420 N = 62 14-year retrospective study

8. Odds ratios for risk of thrombosis Prothrombin anomaly 2.0 Lupus anticoagulant 5.4 Factor V Leiden 6.6 Protein S deficiency 10.9 Dysfibrinogenemia 11.3 Protein C deficiency14.4 Antithrombin deficiency24.1 HIT 20-40 Warkentin TE. Can J Cardiol 1995;11(Suppl C):29C-34C Warkentin TE. Thromb Res 2003;110:73-82

9. Heparin-Induced Thrombocytopenia (HIT) Rationale for using danaparoid – Orgaran  as the antithrombotic therapy of choice

10. Rationale for using Orgaran  –danaparoid as the antithrombotic therapy of choice Danaparoid is a nonheparin antithrombotic It has been shown to be an effective antithrombotic with a high benefit-to-risk ratio in the treatment of HIT in an open-label randomized controlled trial and in studies using historical controls In a minority (<5%) of HIT patients treated with danaparoid has clinically-evident cross-reactivity been implicated, most often because of platelet count fall

11. Danaparoid cross-reactivity with the HIT antibody Mean Range Danaparoid 7% * (0-20%) Unfractionated heparin ~100% Low-molecular-weight heparin ~80% (23-100%) In vitro cross-reactivity determined by platelet activation assays *Note: Cross-reactivity of HIT antibodies for danaparoid depends on the assay used

12. Cross-reactivity and platelet count recovery No cross-reactivity (N=16) Cross-reactivity (N=13) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 024681012141618 30 Frequency of platelet count recovery (≥ 150 x 10 9 /L) Days to platelet count recovery during danaparoid treatment Unpublished data by Warkentin TE - used with permission

13. Danaparoid cross-reactivity with the HIT antibody “Potential in vivo cross-reactivity (rare) is not predictable by in vitro testing; thus, cross-reactivity testing is not recommended prior to use [of danaparoid]” 7th. American College of Chest Physicians Conference Chest 2004, 126: 311S-337S

14. Clinical Experience with Danaparoid in the Management of HIT

15. Typical course of a patient with HIT treated with danaparoid Platelets  10 9 /L Adapted with permission from Greinacher A, Drost W, Michels I, et al. Ann Haematol. 1992;64:40–42.

16. Clinical Experience with Danaparoid in the Management of HIT Comparative Clinical Studies

17. Danaparoid vs. Dextran All patients with strong clinical evidence of HIT -  platelet count < 100 X 10 9 /L while on heparin with no other obvious cause for thrombocytopenia All patients were tested for HIT antibodies by platelet activation assay but negative patients were not excluded if there was strong clinical suspicion of HIT All had thrombosis: in 50% of patients in each treatment group, thrombosis was severe and progressive Randomized, open-label study* Chong BH et al. Thromb Haemost 2001;81:1170-1175. Inclusion Criteria: * This represents the only randomized controlled trial performed on patients with HIT

18. Danaparoid vs. Dextran Alternative explanation for  platelet count Initiation of VKA therapy and in the target therapeutic range (INR >2.0) prior to consideration for inclusion Patients with renal failure, heart failure, pregnancy or requiring surgery were excluded from the study Randomized, open-label study Chong BH et al. Thrombos Haemost 2001;81:1170-1175. Exclusion Criteria: * This represents the only randomized controlled trial performed on patients with HIT

19. Danaparoid vs. Dextran Comparison Therapies  Danaparoid i.v. bolus + infusion for 5 days  Control: Dextran 1,000 ml on Day 1 followed by 500 ml/day for 5 days. All received oral anticoagulant (VKA) therapy from Day 1 (Target INR >2) Treatment regimens:

20. Danaparoid vs. Dextran End point frequency (%) Study end point Danaparoid (n = 25) Dextran (n = 17) Resolution of thrombocytopenia 9288 Clinical recovery from thrombosis 56*14* Overall clinical effectiveness 88 † 47 † Major bleed00 Deaths13 *Odds Ratio 10.53, 95% Confidence Interval 1.6-71.4; p = 0.02 † p = 0.01

21. Danaparoid vs. Lepirudin A retrospective cohort (danaparoid) versus a prospective cohort (lepirudin) study Farner B et al. Thromb Haemost 2001;85:950-957. Lepirudin Patients satisfying the study inclusion/exclusion criteria were treated with aPTT-adjusted lepirudin i.v. either at therapeutic anticoagulation dose +/- thrombolysis or at thrombosis prophylaxis dose and followed prospectively Danaparoid HIT patients who otherwise fulfilled the same inclusion and exclusion criteria as in the prospective lepirudin study but who instead were treated with danaparoid (either in therapeutic or prophylactic doses i.v. or s.c.) were evaluated retrospectively and compared with lepirudin-treated patients

22. Danaparoid vs. Lepirudin Active HIT Clinical criteria Platelet Count   50% or <100 x 10 9 /L and/or thromboembolism during i.v. or s.c heparin treatment Skin inflammation at the heparin injection site Laboratory criteria Positive heparin-induced platelet aggregation (HIPA) test Inclusion Criteria Exclusion Criteria Renal impairment Pregnancy Overt or enhanced bleeding risk Need for cardiopulmonary bypass surgery

23. Danaparoid vs. Lepirudin Study characteristics Danaparoid (n = 53) Lepirudin (n = 114) Mean age (yrs)6357 Treatment duration Days (median) 7 (1-115)10 (Unknown) Treatment scheduleHigh doseLow doseHigh dose*Low dose 2250U i.v. bolus 400U/h – 4hrs 300U/h – 4hrs 200U/h 750U s.c. b.i.d or t.i.d. 0.4 mg/kg i.v. bolus 0.15 mg/kg/hr 0.10 mg/kg/hr i.v. PCR † at entry>95% † PCR = platelet count reduction *Dose reduced in patients given thrombolytic therapy

24. Danaparoid vs. Lepirudin End point frequency (%) Study end point Danaparoid (n = 53) Lepirudin (n = 114) New thrombus 9.4* 7.9* Major bleed2.5 † 10.4 † Deaths6.6 † 6.9 † * Patients on full anticoagulant dosage schedule (p = 0.913) † Included patients on low dose schedules

25. Danaparoid: less risk of major bleeding vs DTI Farner B et al. Thromb Haemost 2001;85:950-957 P=0.0123 danaparoid 1 122107 87584128181311 lepirudin 1 173159152118 472514 8 3 Danaparoid Lepirudin 0714212835424956 days after start of treatment 0% 5% 10% 15% 20% cumulative incidence

26. Danaparoid vs. Lepirudin CharacteristicsDanaparoidLepirudin Mode of actionAnti-Xa >> anti-IIaAnti-IIa Half-life25 hr (anti-Xa)>1.3 hr. Route of administrationi.v. or s.c.i.v. Dose adjustment (bolus) 75 kg body wtmg/kg body wt Monitoring recommended  or  body wt; renal failure Routine  Activated protein C generated NoYes Antibody development 7% HIT cross-reactive (clinical significance?) 40% anti-lepirudin antibodies AnaphylaxisNoYes Major bleeding<10%40%

27. Danaparoid HIT Dosing Regimen * for body weight of 60-75 kg (if <60 kg, give 1500 U bolus; if 75-90 kg, give 3000 U bolus; if >90 kg, give 3,750 U bolus) † Adjust by anti-Xa assay levels, if available The following dosing regimen is recommended for patients with HIT (with or without associated thromboembosis): Bolus: 2,250 u* Adjustment phase: 400 u/hr for 4 hrs 300 u/hr for 4 hrs Maintenance: 150-200 u/hr † 7th. American College of Chest Physicians Conference Chest 2004, 126: 311S-337S

28. Danaparoid HIT Monitoring Recommendations Post-bolus: 0.5-0.7 U/ml Adjustment phase:  1.0 U/ml Maintenance: 0.5-0.8 U/ml The anti-Xa levels (U/ml) achieved should be:

29. Danaparoid HIT Monitoring Recommendations Platelet counts should be determined daily for 1 week, then on alternate days for 2 weeks, then weekly to monthly thereafter (while on danaparoid) In vitro cross-reactivity testing should be performed if: Recovery in platelet count does not occur An existing thrombus extends or a new thromboembolic event occurs

30. Use of danaparoid in cardiopulmonary bypass (CPB) Not generally recommended for anticoagulation during CPB Is an option for Post-CPB anticoagulation “Off-pump” cardiac surgery Danaparoid is:

31. Heparin-Induced Thrombocytopenia: Recognition, Treatment & Prevention ‘Certain of the pharmacokinetic features of danaparoid, such as its long half-life, lack of effect on the INR, and its potential for SC administration make it an appropriate choice for an otherwise uncomplicated patient with venous thromboembolism in whom eventual overlap with oral anticoagulants is required. Danaparoid does not cross the placenta, and thus should be safe for management of pregnant patients with HIT.’ Danaparoid is not secreted into the breast milk and can used in nursing mothers Theodore E. Warkentin & Andreas Greinacher 7th. American College of Chest Physicians Conference Chest 2004, 126: 311S-337S

32. The use of Danaparoid in the management of HIT Summary & Conclusions 1.Danaparoid has been used in at least 100,000 treatment episodes in patients with HIT 2.Clinical studies in HIT suggest a 94% success rate (investigator-reported) 3.It can be given by both i.v. & s.c routes with 100% bioavailability

33. 4.Unlike the DTIs (especially argatroban), danaparoid does not prolong the INR, thus simplifying overlapping VKA therapy 5.It demonstrates a favorable anti-thrombotic efficacy:safety ratio 6.Cross-reactivity of danaparoid with HIT antibodies is uncommon and of doubtful clinical significance The use of Danaparoid in the management of HIT Summary & Conclusions

34. 7.Apart from evidence of prior in vivo cross-reactivity, there are no known contraindications for its use in HIT patients 8.Danaparoid-induced HIT has not been reported 9.Similar efficacy as lepirudin but has better safety profile with regard to: Major bleeding Accumulation during renal failure Immunization and allergy/anaphylaxis The use of Danaparoid in the management of HIT Summary & Conclusions

35. Heparin-Induced Thrombocytopenia (HIT) Treatment with danaparoid (Orgaran  )