Transcript danaparoid international slide kit_HIT_Treatment

Heparin-Induced Thrombocytopenia
(HIT)
Treatment with danaparoid (Orgaran)
Management of HIT – treatment
When HIT is strongly-suspected:
• Stop all heparin (both unfractionated and lowmolecular-weight heparin)
• Initiate alternative non-heparin anticoagulant
because of high risk of symptomatic thrombosis
• Test for HIT antibodies
• Duplex ultrasonography to exclude DVT
Management of HIT – treatment
When the diagnosis of HIT is confirmed:
• 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
* 7th. ACCP Conference 2004 Chest, 126, 311S-337S
Management of HIT – treatment
Alternative non-heparin antithrombotic therapies include:
Grade of recommendation*
• Danaparoid
1B
• Direct thrombin inhibitors
 Lepirudin
1C+
 Argatroban
1C
 Bivalirudin
2C
*Grading as per 7th American College of Chest Physicians Conference.
Chest 2004, 126: 311S-337S
Heparin-Induced Thrombocytopenia
(HIT)
Rationale for initiating or continuing
antithrombotic therapy after
discontinuing heparin
Initiating or continuing antithrombotic therapy
Rationale for initiating or continuing antithrombotic
therapy after stopping heparin because of HIT
• Patient typically has pre-existing indication for
prophylactic or therapeutic anticoagulation
• HIT greatly increases baseline risk of thrombosis
(odds ratio, 20—40)
Occurrence of symptomatic thrombosis after stopping
heparin in patients confirmed to have isolated HIT
14-year retrospective study
Cumulative thrombotic event-rate (%)
100
90
80
70
60
50
40
30
20
10
0
N = 62
52.8%
0
2
4
6
8
10
12 14 16
18 20
22
24
26 28
30
Days after isolated HIT recognized
Adapted from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.
Odds ratios for risk of thrombosis
•
•
•
•
•
•
•
Prothrombin anomaly
Lupus anticoagulant
Factor V Leiden
Protein S deficiency
Dysfibrinogenemia
Protein C deficiency
Antithrombin deficiency
• HIT
2.0
5.4
6.6
10.9
11.3
14.4
24.1
20-40
Warkentin TE. Can J Cardiol 1995;11(Suppl C):29C-34C
Warkentin TE. Thromb Res 2003;110:73-82
Heparin-Induced Thrombocytopenia
(HIT)
Rationale for using danaparoid – Orgaran
as 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 with
the HIT antibody
In vitro cross-reactivity determined by
platelet activation assays
Mean
Danaparoid
7% *
Unfractionated heparin
~100%
Low-molecular-weight heparin
~80%
Range
(0-20%)
(23-100%)
*Note:
Cross-reactivity of HIT antibodies for danaparoid depends on the
assay used
Cross-reactivity and
platelet count recovery
Frequency of platelet count
recovery (≥ 150 x 109/L)
1.0
0.9
0.8
0.7
0.6
0.5
No cross-reactivity (N=16)
Cross-reactivity (N=13)
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
18
30
Days to platelet count recovery during danaparoid treatment
Unpublished data by Warkentin TE - used with permission
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
Clinical Experience with Danaparoid
in the Management of HIT
Typical course of a patient with HIT
treated with danaparoid
Platelets 109/L
500
Heparin
Heparin
Dalteparin Danaparoid
Danaparoid



300
200
= On Respirator
= Dialysis
 = Thromboembolus
100
5
101214 17
22
Days
Adapted with permission from Greinacher A, Drost W, Michels I, et al. Ann Haematol. 1992;64:40–42.
Clinical Experience with
Danaparoid
in the Management of HIT
Comparative Clinical Studies
Danaparoid vs. Dextran
Randomized, open-label study*
Chong BH et al. Thromb Haemost 2001;81:1170-1175.
Inclusion Criteria:
• 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
* This represents the only randomized controlled trial performed on patients with HIT
Danaparoid vs. Dextran
Randomized, open-label study
Chong BH et al. Thrombos Haemost 2001;81:1170-1175.
Exclusion Criteria:
• 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
* This represents the only randomized controlled trial performed on patients with HIT
Danaparoid vs. Dextran
Treatment regimens:
• 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)
Danaparoid vs. Dextran
End point frequency (%)
Study end point
Danaparoid
(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) 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
Danaparoid vs. Lepirudin
Inclusion Criteria
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
Exclusion Criteria
• Renal impairment
• Pregnancy
• Overt or enhanced bleeding risk
• Need for cardiopulmonary bypass surgery
Danaparoid vs. Lepirudin
Study characteristics
Danaparoid
(n = 53)
Lepirudin
(n = 114)
Mean age (yrs)
63
57
Treatment duration
Days (median)
7 (1-115)
10 (Unknown)
Treatment schedule
High dose
2250U i.v. bolus
400U/h – 4hrs
300U/h – 4hrs
200U/h
PCR† at entry
>95%
Low dose
High dose*
Low dose
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.
>95%
† PCR = platelet count reduction
*Dose reduced in patients given thrombolytic therapy
Danaparoid vs. Lepirudin
End point frequency (%)
Study end point
Danaparoid
(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
cumulative incidence
20%
Lepirudin
15%
P=0.0123
10%
Danaparoid
5%
0%
0
7
14
21
28
35
42
49
56
18
14
13
8
11
3
days after start of treatment
danaparoid1
lepirudin1
122
173
107
159
87
152
58
118
41
47
28
25
Farner B et al. Thromb Haemost 2001;85:950-957
Danaparoid vs. Lepirudin
Characteristics
Danaparoid
Lepirudin
Mode of action
Anti-Xa >> anti-IIa
Anti-IIa
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
 or  body wt; renal
failure
Routine
 Activated protein C
generated
No
Yes
Antibody development
7% HIT cross-reactive
(clinical significance?)
40% anti-lepirudin
antibodies
No
Yes
<10%
40%
Half-life
Monitoring recommended
Anaphylaxis
Major bleeding
Danaparoid HIT Dosing Regimen
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 †
* 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
7th. American College of Chest Physicians Conference Chest 2004, 126: 311S-337S
Danaparoid HIT Monitoring Recommendations
The anti-Xa levels (U/ml) achieved should be:
•
Post-bolus:
0.5-0.7 U/ml
• Adjustment phase:
 1.0 U/ml
•
0.5-0.8 U/ml
Maintenance:
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 danaparoid
in cardiopulmonary bypass (CPB)
Danaparoid is:
• Not generally recommended for
anticoagulation during CPB
• Is an option for
• Post-CPB anticoagulation
• “Off-pump” cardiac surgery
Heparin-Induced Thrombocytopenia:
Recognition, Treatment & Prevention
Theodore E. Warkentin & Andreas Greinacher
‘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.’
7th. American College of Chest Physicians Conference Chest 2004, 126: 311S-337S
Danaparoid is not secreted into the breast milk and can used in
nursing mothers
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
The use of Danaparoid in the management of HIT
Summary & Conclusions
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
Heparin-Induced Thrombocytopenia
(HIT)
Treatment with danaparoid (Orgaran)