Understanding HeparinInduced Thrombocytopenia HIT: Historical and Clinical Perspectives - PowerPoint PPT Presentation

About This Presentation
Title:

Understanding HeparinInduced Thrombocytopenia HIT: Historical and Clinical Perspectives

Description:

Understanding HeparinInduced Thrombocytopenia HIT: Historical and Clinical Perspectives – PowerPoint PPT presentation

Number of Views:88
Avg rating:3.0/5.0
Slides: 59
Provided by: Ede67
Category:

less

Transcript and Presenter's Notes

Title: Understanding HeparinInduced Thrombocytopenia HIT: Historical and Clinical Perspectives


1
Understanding Heparin-Induced Thrombocytopenia
(HIT) Historical and Clinical Perspectives
2
Heparin-Induced Thrombocytopenia
  • Heparin is a widely used anticoagulant drug for
    the treatment and prevention of thromboembolic
    disorders
  • Heparin may cause immune thrombocytopenia (a
    reduction in platelet count), or HIT
  • HIT can cause life- or limb-threatening thromboses

3
Clinical Conditions/Causes of Thrombocytopenia
  • Increased platelet destruction
  • Non-immune
  • Septicemia/Inflammation
  • Disseminated intravascular coagulation
  • Thrombotic thrombocytopenic purpura
  • Immune
  • Autoimmune idiopathic or secondary immune
    thrombocytopenia
  • Alloimmune post-transfusion purpura
  • Drug-induced prothrombic (heparin),
    prohemorrhagic (quinine, quinidine, gold, sulfa
    antibiotics, rifampin, vancomycin, NSAIDs, many
    others)

4
Clinical Conditions/Causes of Thrombocytopenia
(cont.)
  • Decreased platelet production
  • Alcohol, cytotoxic drugs
  • Aplastic anemia
  • Leukemia, myelodysplasia
  • Metastatic invasion of marrow
  • Certain infections
  • Hypersplenism
  • Hemodilution (infusion of blood products,
    colloids, or crystalloids)

5
Terminology Relating to HIT
  • Heparin-induced thrombocytopenia (HIT)
  • Also known as HIT type II, white clot syndrome,
    and heparin-associated thrombocytopenia (HAT)
  • Denotes demonstrable role of heparin in
    inducing thrombocytopenia (ie,
    heparin-dependent antibodies are detectable)
  • Non-immune heparin-associated thrombocytopenia
    (non-immune HAT)
  • Also known as HIT type I, HAT
  • Denotes absence of heparin-dependent antibodies
    and the potential role for other factors in
    causing thrombocytopenia

6
Frequency of HIT
  • Related to heparin source
  • Bovine lung 1.9 to 30.8
  • Porcine intestine 1.3 to 8
  • Full-dose IV heparin 0 to 30
  • Prospective studies (P) and review of literature
    (R) for HIT
  • (R) Warkentin and Kelton, 1994 3.4
  • (P) Warkentin et al, 1995 2.7 (unfractionated
    lt1 LMW)
  • (R) Schmitt, 1993 Schulman, 1997 1.1 to 2.9
  • Some high rates are from studies that included
    patients with non-immune HAT.

7
Incidence of HIT and HIT Thrombosis Prospective
Studies of IV Therapeutic-Dose Heparin
No. of
Early (
4 days)
Late (
5 days)
?
?
Patients
Thrombosis
thrombo-
thrombo-
Arterial
Venous
cytopenia
cytopenia
Ansell, 1980
43
1
4
0
0
Ansell, 1985
104
5
5
0
0
Bailey, 1986
43
0
1
1
0
Ramirez-
Lassepas, 1984
211
2
9
2
1

Cipolle, 1983
Gallus, 1980
143
4
5
0
1
Green, 1984, 1986
89
0
2
1
1
Holm, 1980
90
0
1
0
0
Kakkasseril, 1985
142
--
9
2
2
Monreal, 1989
89
--
2
0
1
Nelson, 1978
37
6
3
0
0
Powers, 1979
120
2
2
1
1
Powers, 1984
131
2
3
0
0
Rao, 1989
94
3
3
0
0
Total
1,336
24 (1.8)
46 (3.4)
7
7
From Warkentin TE, Kelton JG. In Bounameaux H,
ed. Low-Molecular-Weight Heparins in Prophylaxis
and Therapy of Thromboembolic Diseases.
Fundamental and Clinical Cardiology. New York
Marcel Dekker, Inc 199475127. Some
information obtained by personal communication.
8
Differences Between HIT and Non-Immune HAT
Non-Immune HAT
HIT
Usually 514 days (may be
Onset
Within 4 days
sooner)
Platelet count
Typically 100,000150,000/
?
L
Typically 20,000150,000/
?
L
?

median nadir 50,000/
?
L in
most series rarely lt20,000/
?
L
?

sometimes falls gt30, but
remains gt150,000/
?
L
Complications
Thromboembolic lesions
None
530
1 at 1 week 3 at 2 weeks
Incidence
Recovery
13 days
57 days
Benign, tiny platelet
IgG-mediated strong platelet
Cause
aggregates
activation
9
Thromboembolic Disorders Associated With HIT
Consequences
  • Venous thrombosis DVT venous limb gangrene
    pulmonary embolism cerebral sinus thrombosis
  • Arterial thrombosis Limb gangrene
    cerebrovascular accident MI miscellaneous
    end-organ thromboses
  • Other complications Adrenal hemorrhagic
    infarction heparin-induced skin lesions (at
    injection sites) acute systemic reactions (post
    IV heparin bolus) disseminated intravascular
    coagulation

10
Skin Necrosis
  • Used with permission from Warkentin TE. Br J
    Haematol. 199692494497.

11
Acute Systemic Reactions Caused by IV Heparin
Bolus
  • The following can occur in patients sensitized to
    heparin within 530 minutes
  • Fever, chills
  • Tachycardia, hypertension
  • Flushing, headache
  • Chest pain, dyspnea
  • Nausea, vomiting, large-volume diarrhea
  • Sudden anaphylactoid death
  • Transient global amnesia

12
Molecular Structure of Heparin
  • Member of heterogeneous family of
    glycosaminoglycans MW3,00030,000 daltons

CH2OH
O
O
OH
OH
OH
OH
HO
O
O
NHAc
NHSO3
COO
COO
OH
O
OH
O
OH
COO OH
OH
HO
OSO3
HO
HO
OH
OH
(1)
(2)
(3)
(4)
(5)
Adapted with permission from Physicians Desk
Reference. Montvale, NJ Medical Economics,
19983044.
13
Action of Heparin
  • Primary action
  • Binds to antithrombin (cofactor)
  • After binding, increases antithrombins
    inhibition of thrombin (factor IIa) and factors
    IXa, Xa, XIa, XIIa, and kallikrein
  • Limited anticoagulant action
  • Prevents additional thrombus accretion
  • Unable to dissolve an existing thrombus directly

14
Pathophysiology of HIT and Thrombosis
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
15
Pathophysiology of HIT and Thrombosis (cont.)
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
16
Pathophysiology of HIT and Thrombosis (cont.)
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
17
Pathophysiology of HIT and Thrombosis (cont.)
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
18
Fourteen-Year Study of HIT
  • Study design Retrospective cohort study
  • Population 127 patients with serologically
    confirmed HIT in one medical community
  • Group I (n65) HIT diagnosed after appearance of
    new thrombosis
  • Group II (n62) Initial diagnosis of isolated
    HIT (ie, no new thrombosis at time of diagnosis)
  • Reason for hospitalizations
  • Surgical approximately 2/3 (mostly orthopedic)
  • Medical approximately 1/3 (DVT or PE)
  • Warkentin TE, Kelton JG. Am J Med.
    1996101502507.

19
Fourteen-Year Study of HITGroup II Results
After Heparin Discontinuation
100 90 80 70 60 50 40 30 20 10 0
52.8
Cumulative Thrombotic Event Rate ()
0
2
4
6
10
12
14
16
8
18
22
26
28
30
24
20
Days After Isolated HIT Recognized
Adapted with permission from Warkentin TE, Kelton
JG. Am J Med. 1996101502507.
20
Fourteen-Year Study of HIT Summary
  • Relatively conservative, conventional management
    of patients with isolated HIT (ie,
    discontinuation of heparin with or without
    substitution with warfarin)
  • Conservative treatment approaches can result in
    unacceptably high rates (50) of subsequent
    thrombosis
  • Additional clinical studies needed to show
    whether more aggressive treatments using
    alternative anticoagulants would be useful for
    this patient population
  • Warkentin TE, Kelton JG. Am J Med.
    1996101502507.

21
Diagnosis of HIT
  • Normal platelet count before commencement of
    heparin therapy
  • Onset of thrombocytopenia typically 514 days
    after initiation of heparin therapy but can occur
    earlier
  • Exclusion of other causes of thrombocytopenia
    (eg, sepsis)
  • Occurrence of thromboembolic complications during
    heparin therapy

22
Diagnosis Based on Time of Onset
15
First Exposureto Heparin
Subsequent Exposureto Heparin
10
Thrombocytopenia
Number of Patients
5
Thrombocytopenia
0
Thrombosis
Thrombosis
2
4
6
8
10
12
14
16
18
20
2
4
6
8
10
Day of Treatment
Day of Treatment
Adapted with permission from King DJ, Kelton JG.
Ann Intern Med. 1984100536540.
23
Diagnosis Platelet Aggregation Assay
  • Measures platelet aggregation of IgG in serum or
    plasma of a HIT patient treated with heparin
  • Donor platelets can be washed or suspended in
    citrated plasma
  • Advantages
  • Easily performed in most laboratories
  • Specificity greater than 90
  • Disadvantages
  • Low sensitivity 3581 sensitivity higher
    using washed platelets
  • Reactivity varies among donor platelets

24
Diagnosis Serotonin Release Assay
  • Measures the release of serotonin from aggregated
    platelets in serum of patient with HIT relies on
    platelet aggregation in the presence of heparin
  • Advantages
  • High specificity and sensitivity
  • Validated in blinded assessment of a clinical
    trial
  • Disadvantages
  • Technically demanding and time-consuming
  • Requires the use of radioactive materials
  • Not widely available

25
Relationship Between Release of 14C-Serotonin and
Final Concentration of Heparin in HIT Patients
100 80 60 40 20 0
1
2
3
4
14C-Serotonin Release
0.001
0.01
0.1
1
10
100
1000
0
Heparin Concentration (µ/mL)
Adapted with permission from Sheridan D, Carter
C, Kelton JG. Blood. 1986672730.
26
Diagnosis Heparin/PF4 ELISA
Relative Sensitivity in 12 Patients with HIT
Positive Reactions,
n
Assay
Undiluted
110
1100
1200
1500
Serotonin
12
12
2
Not
Not
Release
Tested
Tested
ELISA
12
12
12
12
9
Adapted with permission from Visentin GP, Aster
RH. Curr Opin Hematol. 19952351357.
27
Prevention of HIT
  • Obtain medical history regarding previous
    sensitization to heparin earlier monitoring may
    be required if patient previously received
    heparin
  • Limit heparin duration whenever possible to lt5
    days
  • Avoid heparin flushes
  • Use warfarin early to minimize the length of
    heparin administration in patients requiring
    longer-term anticoagulation, except when HIT is
    diagnosed
  • Routinely initiate oral anticoagulation at start
    of heparin therapy in patients who need
    longer-term oral anticoagulation
  • Use LMWH if possible

28
Prevention of Thrombotic Complications of HIT
  • When HIT is recognized, promptly discontinue use
    of heparin
  • Avoid warfarin unless there is adequate
    anticoagulant control with a drug such as
    danaparoid sodium or recombinant hirudin
  • Monitor platelet count throughout hospitalization
  • Use alternative antithrombotic therapy, such as
    danaparoid sodium or recombinant hirudin, for
    patients with HIT and thrombosis

29
Incidence of Complications and Mortality of HIT
No. of
Age (year
Complications
Mortality
Year
Patients
range or SD)
n
()
n
()
M
F
1983
62
34
28
19-93
38 (61.0)
14 (23.0)
1986
169
97
72
2-94
38 (22.5)
20 (12.0)
1996
127
60
67
67.0 /- 11.4
99 (78.0)
26 (20.5)

1996
62
33
29
66.7 /- 12.3
32 (51.6)
13 (21.0)
Includes patients initially presenting with
thrombosis Subgroup of the 127 patients
presenting with thrombosis From Laster J, Cikrit
D, Walker N, Silver D. Surgery. 1987102763-770
and Warkentin TE, Kelton JG. Am J Med.
1996101502507.
30
Treatment of Non-Immune HAT
  • Heparin should be continued if still indicated
  • Patients with non-immune HAT are asymptomatic
    platelet counts should return to normal during
    continuation of heparin therapy
  • No additional risk of thrombosis

Note It may sometimes be difficult to
distinguish between immune HIT and non-immune HAT
on clinical grounds alone
31
Treatment of Suspected HIT
  • Discontinue all heparin immediately, including
  • Heparin flushes
  • Heparin-coated pulmonary catheters
  • Heparinized dialysate and any other medications
    or devices containing heparin
  • Confirm diagnosis of HIT with the appropriate
    laboratory test
  • Consider alternative anticoagulation
  • Monitor carefully for thrombosis
  • Monitor platelet counts until recovery
  • Avoid prophylactic platelet transfusions

32
Conventional Strategies for HIT Variable Success
  • Cessation of heparin alone
  • Warfarin
  • LMWH
  • Danaparoid sodium
  • Ancrod
  • Prostacyclin analogues

33
Treatment of HIT Complicated by DVT Risk for
Warfarin-Induced Venous Limb Gangrene
  • Vitamin K antagonists such as warfarin may also
    be used for continuing anticoagulant therapy
  • Mechanism of action Inhibits vitamin K
    dependent coagulant factors
  • Disadvantages
  • Requires ?5 days to achieve full therapeutic
    effect
  • Warfarin has been associated with venous limb
    gangrene when used alone (especially at high
    doses) or with ancrod during acute HIT,
    particularly in patients with DVT

Note Venous limb gangrene arises from a
disturbance in procoagulant/anticoagulant
hemostatic balance (HIT-associated increase in
thrombin generation/warfarin-associated depletion
of the natural anticoagulant protein C)
34
Venous Limb Gangrene

Used with permission from Warkentin TE, Elavathil
LJ, Hayward CPM, Johnston MA, Russett JI, Kelton
JG. Ann Intern Med. 1997127804812.
35
Low-Molecular-Weight Heparins
  • Advantages
  • Binding to plasma proteins and endothelial cells
    not as strong compared with unfractionated
    heparin
  • Reduced binding associated with greater
    bioavailability and more predictable dose
    response than unfractionated heparin
  • Disadvantages
  • High in vitro cross-reactivity rates with
    heparin-dependent antibody (approaching 100
    using sensitive assays)
  • Potential cause of HIT, but less often than
    unfractionated heparin
  • Significant risk of recurrent or progressive
    thrombocytopenia and/or thrombosis

36
Danaparoid Sodium - a LMW Heparinoid
  • Mixture of anticoagulant glucosaminoglycans with
    a low degree of sulfation (50 fewer sulfate
    groups than heparin)
  • Favorable results in 90 of patients
  • Half-life of anti-factor Xa activity is 25
    hours a potential disadvantage for patients who
    may need surgical procedures
  • Cross-reactivity with heparin-dependent antibody
    in vitro is 10 to 20
  • Defined as increased platelet activation over
    background in presence of patient serum and
    danaparoid
  • Uncertain clinical significance of in vitro
    cross-reactivity

37
Typical Course of a Patient with HIT Treated with
Danaparoid Sodium
Heparin
500
Heparin
Dalteparin
Danaparoid
Danaparoid
300
Platelets ??109/L
200
Artificial respiration Dialysis
Thromboembolus
100
5
10
12
14
17
22
Days
Adapted with permission from Greinacher A, Drost
W, Michels I, et al. Ann Haematol. 1992644042.
38
Clinical Report of HIT Patients Treated with
Ancrod
Delay for
Nadir Platelet
Indication for
Platelet
Count
Increase gt150
Age
Anticoagulant
Bleeding
/L
(yr)
Therapy
Episode
Recurrence
76
DVT
425
N/A
No
No
History of HIT
74
DVT/PE
68
5
No
Yes

57
DVT/PE
74
10
No

Yes
54
Axillary DVT
47
4
No
No
65
DVT
26
7
No
No
64
DVT
38
6
No
No
76
PE
59
4
No
No
66
DVT
67
2
No
No

70
DVT
20
6
Yes
No
48
DVT
266
N/A
No
No
History of HIT
80
DVT/PE
52
7
No
No
DVT, deep venous thrombosis PE, pulmonary
embolism N/A not applicable. Extension of DVT,
10 days after stopping ancrod while receiving
adequate warfarin (INR between 2 and
3). Terminal carcinoma, phlegmasia cerulea
dolens 10 days after stopping ancrod
therapy. Increase in thigh volume and 16 g/L
decrease in hemoglobin concentration. Adapted
with permission from Demers C, Ginsberg JS,
Brill-Edwards P, et al. Blood. 19917821942197.
39
Prostacyclin Analogues
  • Act as natural vasodilators
  • Inhibit platelet aggregation
  • Advantages
  • Platelet activation blocked in patients with HIT
  • Short half-life (1530 minutes) permits ease of
    control
  • Disadvantage
  • Adverse reactions, such as hypotension, may limit
    usefulness

40
Alternative Treatments of HIT
  • IV immunoglobulin preparations of the IgG class
    success reported in a few cases
  • Platelet transfusions usually unnecessary (low
    bleeding risk in HIT) may increase risk of new
    thromboembolic lesions
  • Plasmapheresis anecdotal experience only

Note Consider alternative treatments only as
adjuncts to a major alternative anticoagulant
agent such as danaparoid sodium or recombinant
hirudin
41
Action of Thrombin
Releases from endothelium NO PGI2 t-PA
von Willebrand ADP
Factor V Va Factor VIII VIIIa
Prothrombin thrombin
Thrombin
Activation of platelets
Adapted with permission from Fuster V, Verstraete
M. In Braunwald E, ed. Heart Disease A Textbook
of Cardiovascular Medicine. Philadelphia WB
Saunders Company 199718091842.
42
Development of Lepirudin (rDNA) for Injection
(Refludan?)
Lepirudin (recombinant hirudin) approved for
anticoagulation in patients
1998 with heparin-induced
thrombocytopenia (HIT) and thromboembolic disease
in order to prevent further
thromboembolic complications



Lepirudin phase I-II trials (safety,
PK) 19901993
Potential indications






Clin-Pharm investigations of lepirudin
19871989




Lepirudin developed 19861987

Amino
acid sequence determined
19841985


LTYTDCTESGQNLCLCEGSNVCGQGNKCILGSDGEKNQCVTGEGTPKPQS
HNDGDFEEIPEEYLQ
Hirudin primary structure determined
1976


Hirudin defined as
thrombin inhibitor
19551957


Use of hirudin from H. medicinalis
19031904


Anticoagulant activity of
medicinal leech identified 1884
43
Hirudin Inhibition
Antithrombin
Endothelial Cells
Synthesis and release Prostacyclin EDRF,
t-PA Endothelin Tissue factor Activation Prote
in C ??PC a Thrombomodulin
Thrombin
HIRUDIN
Smooth Muscle
Contraction Mitogenesis
Adapted with permission from Markwardt F. Thromb
Res. 199474123.
44
Structure of Lepirudin
65
63
COO
10
Tyr
60
30
Cys
Cys
14
6
Cys
Cys
Leu
1
28
16
NH3
22
Cys
20
50
Cys
47
Val
39
Lys
40
45
Properties of Unfractionated Heparin, LMWH, and
Hirudin
Unfractionated Heparin
LMWH
Hirudin
Inhibits thrombin and factor Xa equally, less
for IXa, XIa, and XIIa
Some extent, mainly factor Xa
Specific and potent
Thrombin inhibition
Antithrombin-dependent
Yes
No
Yes
Yes, also by several plasma proteins, PF4, and
endothelium
Neutralized by heparinase
Yes, weak endothelium binding
No
Inactivates clot-bound thrombin and factor VII
Yes (clot-bound thrombin)
No
No
No, except prevents thrombin-induced aggregation
Affects platelet
Yes
Yes
function
Adapted with permission from Fuster V, Verstraete
M. In Braunwald E, ed. Heart Disease A Textbook
of Cardiovascular Medicine. Philadelphia WB
Saunders Co. 19971809-1842.
46
Properties of Unfractionated Heparin, LMWH, and
Hirudin (cont.)
Unfractionated Heparin
LMWH
Hirudin
Can cause immune
Yes
Yes
No
thrombocytopenia
Bioavailability after
30
gt90
85
SC injection
Dose effect response
Poor
Fair
Fair
Possible in 40
Immunogenicity
Yes (HIT)
Yes (HIT)
of patients
Transient increase
Transient increase
Liver toxicity
of liver enzymes
of liver enzymes
No
common
possible
Increases vascular
Yes
No
No
permeability
Adapted with permission from Fuster V, Verstraete
M. In Braunwald E, ed. Heart Disease A
Textbook of Cardiovascular Medicine.
Philadelphia WB Saunders Co. 19971809-1842.
47
Clinical Trials of Lepirudin HAT-1 and HAT-2
Studies on HIT
  • Design Prospective, historically controlled
    trials
  • Primary objective Demonstrate that treatment of
    HIT with lepirudin increases platelet counts or
    maintains normal baseline values while providing
    effective anticoagulation (prolongation of aPTT
    to 1.5 to 3 times baseline value)
  • Secondary objective Evaluate incidences of new
    arterial or venous thromboembolic complications,
    major bleeding complications, surgical
    interventions/limb amputations, and deaths

48
Baseline Characteristics of Patients Presenting
with Thromboembolic Complications in HAT-1 and
HAT-2
Historical Control
Lepirudin
HAT-1
HAT-2
(
n
91)
(
n
54)
(
n
59)
Males
27.8
44.1
35.2
Females
72.2
55.9
64.8
Age lt 65 years
63.0
67.8
44.0
Age gt 65 years
37.0
32.2
56.0
49
Lepirudin Treatment Regimens for HAT-1 and HAT-2
  • Treatment regimen A1
  • HIT patients with arterial or venous
    thromboembolism without thrombolytic therapy
  • initial IV bolus 0.4 mg/kg BW
  • continuous IV infusion 0.15 mg/kg BW/h, 210
    days
  • Treatment regimen A2
  • HIT patients with arterial or venous
    thromboembolism with concomitant thrombolytic
    therapy
  • initial IV bolus 0.2 mg/kg BW
  • continuous IV infusion 0.1 mg/kg BW/h, 210
    days

BW, body weight Not to exceed body weight of 110
kg Typically 210 days duration longer if
clinically warranted
50
Lepirudin Treatment Regimens for HAT-1 and HAT-2
(cont.)
  • Treatment regimen B
  • Prophylaxis of arterial or venous thromboembolism
  • continuous IV infusion 0.1 mg/kg BW/h, 210
    days
  • Treatment regimen C
  • Anticoagulation during cardiopulmonary bypass
  • priming of HLM 0.2 mg/kg BW
  • initial IV bolus 0.25 mg/kg BW
  • additional boluses 5 mg (to maintain ECT gt 40 s)

BW, body weight ECT, ecarin clotting time Not
to exceed body weight of 110 kg Typically 210
days duration longer if clinically warranted
51
Results of HAT-1 Platelet Count Recovery Profile
Platelets x 109/L
n 63 64 64 64 61 60 58
54 57 54 52 45 40
500- 400- 300- 200- 100- 0-
Nadir
Before heparin
Before lepirudin
2
4
5
6
7
3
8
9
10
11
Day
Day 1 Start of infusion of lepirudin
52
Results of HAT-2 Platelet Count Recovery Profile
Platelets x 109/L
n 60 63 62 60 57 60 54
57 58 51 51 51 37
500- 400- 300- 200- 100- 0-
Nadir
Before heparin
Before lepirudin
2
4
5
6
7
3
8
9
10
11
Day
Day 1 Start of infusion of lepirudin
53
Results of HAT-1 aPPT Prolongation
A1 n 63 62 60 60 55 54 53 50 45 43 36A2 n
4 4 3 3 3 3 3 3 3 3 3B n 40 41 37 36 32 30 2
8 24 21 20 18
??4.5
3.0
aPPT Ratio
1.5
Treatment regimen A1 A2 B
0.0
2
4
5
6
7
3
8
9
10
11
Before lepirudin
Day
Day 1 Start of infusion of lepirudin
54
Results of HAT-1 and HAT-2 Cumulative Risk of
Death, Limb Amputation, or Thromboembolic
Complications
Lepirudin
10255
9238
7628
2720
912
611
36
Historical control
80
70
60
P 0.004, log-rank test
50
Cumulative Risk ()
40
30
20
10
0
0
7
14
21
28
35
42
49
Days After Start of Treatment
Lepirudin (n 113, censored 88) Historical
control (n 75, censored 45)
Number at risk Censored observations
55
Adverse Events in HAT-1 and HAT-2
  • Study group 198 pts treated with lepirudin
    historical controls
  • Bleeding was most frequent adverse event
  • Bleeding events in 113 pts with thromboembolic
    complications compared with historical control
    group
  • Anemia or an isolated drop in hemoglobin pts,
    12.4 control, 1.1
  • Bleeding from puncture sites and wounds pts,
    10.6 control, 4.4
  • Other hematomas and unclassified bleeding pts,
    10.6 control, 4.4
  • No intracerebral or fatal bleeding seen in any pt
    receiving lepirudin major bleeding occurred only
    slightly more often (statistically
    non-significant) in study group
  • Fever, pneumonia, sepsis, and unspecified
    infections, taken as a whole, were most
    frequently reported nonhemorrhagic events in
    lepirudin pts

56
Development of Anti-Hirudin Antibodies in HAT-1
and HAT-2
  • Possible immunologic preselection as HIT patients
    already developed drug-induced antibodies
  • Positive anti-hirudin antibodies (IgG) developed
    in 40 of pts
  • No association of reduced hirudin plasma levels
    with formation of anti-hirudin antibodies
  • No association between antibody levels and
    clinical endpoints (death, limb amputation, new
    thromboembolic complications, major bleedings,
    and allergic reactions)
  • May increase anticoagulant effect of hirudin
    possibly due to delayed renal elimination of
    active lepirudin-antihirudin complex
  • Because anti-hirudin antibodies can increase the
    anticoagulant effect of lepirudin, strict ongoing
    monitoring of aPTT is necessary even during
    prolonged therapy

57
Conclusions from HAT-1 and HAT-2
  • Lepirudin is a safe and effective anticoagulant
    that allows rapid recovery of platelet counts in
    patients with HIT
  • Lepirudin does not cross-react with
    heparin-induced antibodies, as demonstrated by
    rapid and sustained platelet recovery
  • In comparison to a historical control group,
    lepirudin substantially reduced the risk of
    serious complications associated with HIT
  • Lepirudin is well-tolerated major bleeding was
    not significantly more common in the
    lepirudin-treated group

58
Conclusions
  • Heparin, although an important anticoagulant, has
    several drawbacks, most notably its ability to
    cause HIT
  • HIT can lead to severe and even life-threatening
    thromboembolic disorders
  • Treatment of HIT should be initiated before
    laboratory confirmation
  • A new generation of drugs such as the thrombin
    inhibitors, including the hirudins, may provide
    important new options for the treatment and
    possible prevention of HIT
Write a Comment
User Comments (0)
About PowerShow.com