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Heparin-Induced Thrombocytopenia (HIT). Treatment with danaparoid (Orgaran ). 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 - PowerPoint PPT Presentation
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Heparin-Induced Thrombocytopenia (HIT)
Treatment with danaparoid (Orgaran)
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:
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 109/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
Management of HIT – treatment
• Danaparoid 1B
• 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*
Heparin-Induced Thrombocytopenia (HIT)
Rationale for initiating or continuing
antithrombotic therapy after
discontinuing heparin
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
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
00 2 4 6 10 12 14 168 18 22 26 28 302420
N = 62
14-year retrospective study
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 deficiency 14.4
• Antithrombin deficiency 24.1
• HIT 20-40
Warkentin TE. Can J Cardiol 1995;11(Suppl C):29C-34CWarkentin TE. Thromb Res 2003;110:73-82
Heparin-Induced Thrombocytopenia (HIT)
Rationale for using danaparoid – Orgaranas the antithrombotic therapy of choice
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
Danaparoid cross-reactivity withthe 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
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
00 2 4 6 8 10 12 14 16 18 30
Frequency of platelet count
recovery (≥ 150 x 109/L)
Days to platelet count recovery during danaparoid treatment
Unpublished data by Warkentin TE - used with permission
Danaparoid cross-reactivity withthe 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
Clinical Experience with Danaparoid in the Management of HIT
Typical course of a patient with HITtreated with danaparoid
Platelets 109/L
Adapted with permission from Greinacher A, Drost W, Michels I, et al. Ann Haematol. 1992;64:40–42.
5 101214 17 22
Danaparoid
= On Respirator= Dialysis= Thromboembolus
DanaparoidDalteparinHeparin
200
100
300
500Heparin
Days
Clinical Experience with Danaparoid
in the Management of HIT
Comparative Clinical Studies
Danaparoid vs. Dextran
• All patients with strong clinical evidence of HIT - platelet count < 100 X 109/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
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 studyChong BH et al. Thrombos Haemost 2001;81:1170-1175.
Exclusion Criteria:
* This represents the only randomized controlled trial performed on patients with HIT
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:
Danaparoid vs. Dextran
End point frequency (%)
Study end pointDanaparoid
(n = 25)
Dextran
(n = 17)
Resolution of thrombocytopenia
92 88
Clinical recovery from thrombosis
56* 14*
Overall clinical effectiveness
88† 47†
Major bleed 0 0
Deaths 1 3
*Odds Ratio 10.53, 95% Confidence Interval 1.6-71.4; p = 0.02† p = 0.01
Danaparoid vs. Lepirudin
A retrospective cohort (danaparoid) versus a prospective cohort (lepirudin) studyFarner B et al. Thromb Haemost 2001;85:950-957.
LepirudinPatients 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
DanaparoidHIT 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
Danaparoid vs. Lepirudin
Active HIT• Clinical criteria
• Platelet Count 50% or <100 x 109/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
Danaparoid vs. Lepirudin
Study characteristicsDanaparoid
(n = 53)
Lepirudin
(n = 114)
Mean age (yrs) 63 57
Treatment duration Days (median)
7 (1-115) 10 (Unknown)
Treatment schedule High dose Low dose High 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% >95%
† PCR = platelet count reduction *Dose reduced in patients given thrombolytic therapy
Danaparoid vs. Lepirudin
End point frequency (%)
Study end pointDanaparoid
(n = 53)
Lepirudin
(n = 114)
New thrombus 9.4* 7.9*
Major bleed 2.5† 10.4†
Deaths 6.6† 6.9†
* Patients on full anticoagulant dosage schedule (p = 0.913)† Included patients on low dose schedules
Danaparoid: less risk of major bleeding vs DTI
Farner B et al. Thromb Haemost 2001;85:950-957
P=0.0123
danaparoid1 122 107 87 58 41 28 18 13 11lepirudin1 173 159 152 118 47 25 14 8 3
Danaparoid
Lepirudin
0 7 14 21 28 35 42 49 56
days after start of treatment
0%
5%
10%
15%
20%
cumulative incidence
Danaparoid vs. Lepirudin
Characteristics Danaparoid Lepirudin
Mode of action Anti-Xa >> anti-IIa Anti-IIa
Half-life 25 hr (anti-Xa) >1.3 hr.
Route of administration i.v. or s.c. i.v.
Dose adjustment (bolus) <60 or >75 kg body wt mg/kg body wt
Monitoring recommended or body wt; renal
failureRoutine
Activated protein C generated
No Yes
Antibody development7% HIT cross-reactive (clinical significance?)
40% anti-lepirudin antibodies
Anaphylaxis No Yes
Major bleeding <10% 40%
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
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:
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
Use of danaparoidin cardiopulmonary bypass (CPB)
• Not generally recommended for anticoagulation during CPB
• Is an option for
• Post-CPB anticoagulation
• “Off-pump” cardiac surgery
Danaparoid is:
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
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
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
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
Heparin-Induced Thrombocytopenia (HIT)
Treatment with danaparoid (Orgaran)