Heparin-Induced Thrombocytopenia (HIT)

1
Heparin-Induced Thrombocytopenia (HIT)

• Treatment with danaparoid (Orgaran?)

2
Management of HIT treatment
When HIT is strongly-suspected

• 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

3
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
4
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
5
Heparin-Induced Thrombocytopenia (HIT)

• Rationale for initiating or continuing
• antithrombotic therapy after
• discontinuing heparin

6
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, 2040)

7
Occurrence of symptomatic thrombosis after
stopping heparin in patients confirmed to have
isolated HIT
14-year retrospective study
Cumulative thrombotic event-rate ()
N 62
52.8
Days after isolated HIT recognized
Adapted from Warkentin TE, Kelton JG. Am J Med.
1996101502507.
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 deficiency 14.4
• Antithrombin deficiency 24.1

• HIT 20-40

Warkentin TE. Can J Cardiol 199511(Suppl
C)29C-34C Warkentin TE. Thromb Res 200311073-82
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 (lt5) of HIT patients treated with
  danaparoid has clinically-evident
  cross-reactivity been implicated, most often
  because of platelet count fall

11
Danaparoid cross-reactivity withthe HIT antibody
In vitro cross-reactivity determined by platelet
activation assays
Mean Range Danaparoid
7 (0-20) Unfractionated heparin
100 Low-molecular-weight heparin 80
(23-100)
Note Cross-reactivity of HIT antibodies for
danaparoid depends on the assay used
12
Cross-reactivity and platelet count recovery
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
13
Danaparoid cross-reactivity withthe HIT antibody
Potential in vivo cross-reactivity (rare) is not
predictable by in vitro testingthus,
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 ??109/L
Adapted with permission from Greinacher A, Drost
W, Michels I, et al. Ann Haematol. 1992644042.
16
Clinical Experience with Danaparoidin the
Management of HIT
Comparative Clinical Studies
17
Danaparoid vs. Dextran
Randomized, open-label study Chong BH et al.
Thromb Haemost 2001811170-1175.
Inclusion Criteria

• All patients with strong clinical evidence of HIT
  - ? platelet count lt 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
18
Danaparoid vs. Dextran
Randomized, open-label study Chong BH et al.
Thrombos Haemost 2001811170-1175.
Exclusion Criteria

• Alternative explanation for ? platelet count
• Initiation of VKA therapy and in the target
  therapeutic range (INR gt2.0) 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
19
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 gt2)

20
Danaparoid vs. Dextran
End point frequency () 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
21
Danaparoid vs. Lepirudin
A retrospective cohort (danaparoid) versus a
prospective cohort (lepirudin) study Farner B et
al. Thromb Haemost 200185950-957.
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
Inclusion Criteria

• Active HIT
• Clinical criteria
• Platelet Count ? ? 50 or lt100 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

23
Danaparoid vs. Lepirudin
Study characteristics Danaparoid (n 53) Danaparoid (n 53) Lepirudin (n 114) Lepirudin (n 114)
Mean age (yrs) 63 63 57 57
Treatment duration Days (median) 7 (1-115) 7 (1-115) 10 (Unknown) 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 gt95 gt95 gt95 gt95
PCR platelet count reduction Dose reduced
in patients given thrombolytic therapy
24
Danaparoid vs. Lepirudin
End point frequency () 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
25
Danaparoid less risk of major bleeding vs DTI
cumulative incidence
20
Lepirudin
15
P0.0123
10
Danaparoid
5
0
0
7
14
21
28
35
42
49
56
days after start of treatment
danaparoid1 122 107 87 58 41 28 18 13 11 lepi
rudin1 173 159 152 118 47 25 14 8 3
Farner B et al. Thromb Haemost 200185950-957
26
Danaparoid vs. Lepirudin
Characteristics Danaparoid Lepirudin
Mode of action Anti-Xa gtgt anti-IIa Anti-IIa
Half-life 25 hr (anti-Xa) gt1.3 hr.
Route of administration i.v. or s.c. i.v.
Dose adjustment (bolus) lt60 or gt75 kg body wt mg/kg body wt
Monitoring recommended ? or ? body wt renal failure Routine
? Activated protein C generated No Yes
Antibody development 7 HIT cross-reactive (clinical significance?) 40 anti-lepirudin antibodies
Anaphylaxis No Yes
Major bleeding lt10 40
27
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 lt60 kg, give
1500 U bolus if 75-90 kg, give 3000 U bolus
if gt90 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
28
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
• Maintenance 0.5-0.8 U/ml

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 danaparoidin cardiopulmonary bypass (CPB)
Danaparoid is

• Not generally recommended for anticoagulation
  during CPB
• Is an option for
• Post-CPB anticoagulation
• Off-pump cardiac surgery

31
Heparin-Induced ThrombocytopeniaRecognition,
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.
• Danaparoid is not secreted into the breast milk
  and can used in nursing mothers

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
The use of Danaparoid in the management of HIT
Summary Conclusions

1. Unlike the DTIs (especially argatroban),
   danaparoid does not prolong the INR, thus
   simplifying overlapping VKA therapy
2. It demonstrates a favorable anti-thrombotic
   efficacysafety ratio
3. Cross-reactivity of danaparoid with HIT
   antibodies is uncommon and of doubtful clinical
   significance

34
The use of Danaparoid in the management of HIT
Summary Conclusions

• Apart from evidence of prior in vivo
  cross-reactivity, there are no known
  contraindications for its use in HIT patients
• Danaparoid-induced HIT has not been reported
• Similar efficacy as lepirudin but has better
  safety profile with regard to
• Major bleeding
• Accumulation during renal failure
• Immunization and allergy/anaphylaxis

35
Heparin-Induced Thrombocytopenia (HIT)

• Treatment with danaparoid (Orgaran?)