Transcript thrombocytopenia - Clinical Trial Results

Thrombocytopenia with
GP IIb/IIIa Inhibitors
Robert P. Giugliano, MD, SM
TIMI Study Chairman’s Office
Cardiovascular Division
Brigham and Women’s Hospital
Harvard Medical School
1
Historical Review
• Hypersensitivity to drug, foodstuffs, chemicals,
vaccines, and insect bites known to cause
thrombocytopenia since early 1900’s
• Drug-induced thrombocytopenia:
– Quinine purpura first reported in 1928
– Sedermoid purpura, first detailed study (1949-55) by
Ackroyd -> Agglutination of normal human platelets
with serum of pts with plts due to sedermoid
2
Diagnosis of Drug-Induced
Thrombocytopenia
1. Onset temporally related to drug initiation
2. No alternative explanation
3. Platelet count returns to normal once drug is
discontinued
4. Confirmation of diagnosis by either:
» in vitro testing
» rechallenge
3
Diagnosis is More Challenging Today
Pre-1960’s
Today
No automated plt count
Bleeding, plt <10-20K
Pts younger, less ill
Few medications/pt
Established relationships
Automated plt counts
Variable plt cts, Sx
Older, more ill
Multiple meds
Unknown risks of new meds
4
Antiplatelet Antibody Testing
1. “Modified indirect antiglobulin test”
Drug + pt serum (plasma) + nl donor plts
Look for deposition of Ig’s or
complement on normal donor plts
2. Platelet functional tests - altered results
- plt activation
- release of dense granule contents
- release of cytoplasmic contents
- stimulation of plt procoagulant activity
5
Drug-dependent Ab:
Five Potential Mechanisms
(1) Ab binds to drug in plasma to
form circulating immune-complexes.
Change in IgG conformation then
recognized by platelet Fc receptor
Y
(2) Ab binds directly to drug which
is concentrated on plt surface (relative
to drug concentration in the plasma)
y
Adapted from McCrae KR and Cines DB, Ch 29, Thrombosis and Hemorrhage
6
Drug-dependent Ab:
Five Potential Mechanisms
(3) When drug binds the platelet,
the drug changes conformation
and is then recognized by the Ab
y
(4) Drug binding causes a change
in the plt conformation, which
the Ab then recognizes
7
Drug-dependent Ab:
Five Potential Mechanisms
(5) The Ab recognizes one or more neoepitopes comprised
of both platelet-derived and drug-derived determinants
Y
Y
8
Other Drugs:
What Have We Learned
•
Plt counts for any one drug may (?often) have
multiple mechanisms (e.g. EtOH)
• Contribution of suppressed plt production may
be underestimated
– Megakaryocytes in marrow = normal plt production
– Difficult to study megakaryocytopoiesis in vitro
• Drug-dependent anti-plt Ab in early stages or
non-existent for most drug (?sens, ?? specificity)
9
Thiazide-induced Thrombocytopenia
GP IIb/IIIa associated plts shares features with
the historical description for thiazides:
–
–
–
–
–
–
cardiac patients appear at higher risk
incidence may be 1-2%, but little prospective data
generally mild-mod (30-100K), occasionally severe
smear shows only reduced # plts
counts recover in 5-14 days
mechanism(s): likely multiple, immune-destruction
most frequent
10
Quinidine / Quinine Purpura
• Incidence estimated at 1/1000 [though probably
higher in cardiac pts]
• Drug-dependent Abs bind to epitopes within
either the GP Ib/IX or GP IIb/IIIa complexes
• Bernard-Soulier Syndrome (GP Ib complex
proteins deficient) may have “no” receptor for
quinidine/quinine induced Ab (controversial)
• Hypothesis: Drug induces changes in plt GP that
are then recognized by Ab (mechanism 4 or 5)
11
Sulfa Compounds
• Typically occurs 1-2 wks after initiation
• Severe cases not uncommon
• Ab have been found against metabolite as well
as drug (both components for TMP-SX)
• Some donor plts serve as targets, other do not,
? Polymorphic determinants (?? PlA2)
12
Valproic Acid
•
•
•
•
Plt counts usually < 2 wks, as late as 4 mths
Spectrum of plt counts seen (severe - mild)
Mechanism(s) unclear, ? dose related
Plt counts may return to normal despite
continued therapy => implications for
mechanism(s)
13
Heparin
• At least two mechanisms (?spectrum of disease)
• Incidence varies (0-30%) among series:
–
–
–
–
bovine vs porcine, LMWH, heparinoids
dose may be important
clinical factors (cardiac disease, surgery)
method of diagnosis
• Ubiquitous use in hospital, esp cardiology may
confound analysis of other drugs
14
Mechanism of HIT
• Type 1: mild, early onset, may resolve despite
continued heparin, no thrombosis.
– plt agglutination due to (-) charge of heparin
• Type 2: mild-severe (subtypes?), onset 7-14 d, may
be associated with fatal arterial/venous thrombosis
– Ab reacts with heparin and/or PF4 -> immune complex
which then is recognized by Fc receptor on the plt
Y
U
U
Y
15
Thrombocytopenia with GP
IIb/IIIa inhibitors:
A Meta-analysis
Robert P. Giugliano, M.D., S.M.
Raymond R. Hyatt, Jr., S.M.
Brigham and Women’s Hospital
Harvard Medical School
16
Background
• Hemorrhage and thrombocytopenia ( plt)
are major safety concerns with GP IIb/IIIa
• Comprehensive review of plt lacking
• Challenges in evaluating plt:
–
–
–
–
Infrequent events
Varying definitions
Confounding
Limited # publications
17
Objectives
Use metanalysis to estimate the risk of
plt due to GP IIb/IIIa inhibitors in:
1. All trials
2. Subgroups stratified by:
- specific agent
- pt population
- heparin use
- trial design
18
Methods I
• Abstract and manuscripts thru AUG 1997
(Medline, ACC/AHA, references)
• Inclusion: Phase II/III clinical trials, results
publicly presented
• Exclusion: No placebo control, > 2 GP IIb/IIIa
inhibitors, secondary reports
• PARAGON treated as 2 separate trials
• Outcome measurement: Odds ratio of plt
(defined as plt ct < 100K [if available])
19
Methods II
• Subgroup analyses:
–
–
–
–
By drug: 4 most widely studied agents
Heparin required vs. not required
Pt population: interventional, lytic, other
Trial design: dose-ranging vs. fixed dose (<2)
• DerSimonian and Laird random effects
model to estimate combined OR (95%CI)
• 1/6th added if zero cell
• Sensitivity analyses: Fail-safe N, publication
bias, excluding trials
20
Results - Trial Identification
140 papers/abstracts reviewed
38 phase II/III trials
6 no placebo control
3 follow-up/subgroup
1 multiple IIb/IIIa inhibitors
28 trials included
1159 cases of plt in 33,234 pts (3.49%)
21
Simple Combined Results
4%
3%
2%
OR = 1.22
1%
0%
3.76%
GP IIb/IIIa
No. pts :
19,250
(1.07, 1.36)
P = 0.002
3.11%
Placebo
13,984
22
Heterogeneity of Data
• 28 trials range in size 24 - 10,000+ pts
• Absolute rates of plt vary widely:
– GP IIb/IIIa: 0 - 12%
– Odds ratio: 0.02 - 9.5
Placebo: 0 - 10%
• 7 different types of GP IIb/IIIa studied
• Varying patient populations, concomitant
medications, #doses studied
• Def of plt: <50K to <100K or 50% decline
23
Odds of Thrombocytopenia in 28 Trials
OR with 95% CI
100
10
1
0.1
0.01
1
3
5
7
9
11
13
15
17
19
21
23
25
27
Odds Ratio
upper 95%
lower 95%
Individual Trials from smallest to largest
24
10
Odds of Thrombocytopenia by Drug
OR with 95% CI
3.16
3.57
1.89
2.01
1.36
1
0.1
4.03
Lamifiban
0.89
Abciximab
1.13
Tirofiban
0.58
#trials 4
# pts 3758
Odds Ratio
upper 95%
lower 95%
1.69
1.12
Eptifibatide
1.91
1.48
1.14
All Trials
0.75
4
6272
6
7159
6
15,486
28
33,234
25
OR with 95% CI
10.00
No Evidence for Confounding
by Required Heparin
Odds Ratio
upper 95%
lower 95%
3.68
1.80
1.00
0.88
Heparin not
required
#trials 10
# pts 6038
0.10
1.89
1.44
1.09
Heparin
required
18
27,196
1.91
1.48
1.14
All Trials
28
33,234
26
Effect of Patient Population
OR with 95% CI
10
Odds Ratio
upper 95%
lower 95%
4.00
1.50
1
0.1
Lytic
0.56
#trials 3
# pts 603
2.16
1.49
1.03
Interventional
12
12,792
2.15
1.46
0.99
1.91
1.48
1.14
Other *
All Trials
13
19,839
28
33,234
*Other includes acute and stable coronary syndromes
27
Effect of Trial Design
OR with 95% CI
10
Odds Ratio
upper 95%
lower 95%
2.70
1
1.12
Dose ranging
Fixed dose
1.91
1.48
1.14
All Trials
0.47
#trials 11
# pts 1661
0.1
1.99
1.52
1.16
17
31,573
28
33,234
28
Sensitivity Analyses
• Over >100,000 pts per arm, 0% plt with
IIb/IIIa inhibitor => negate overall result
• Fail-safe N: 3 trials of 10,000 pts, 0% plt with
IIb/IIIa inhibitor
• Excluding trials
– <1000 pts (18)
1.56 (1.14, 2.12 )
– No plt observed (13) 1.51 (1.16, 1.96)
– Our model
1.48 (1.14, 1.91)
• Add 1/2 to zero cells
1.40 (1.09, 1.80)
29
Conclusions
• GP IIb/IIIa inhibitors associated with an approx
50% in plt compared to placebo (or an extra 1-2
cases per 100 pts treated with GP inhibitor)
• Heterogeneity marked esp. in small trials
• Odds of plt similar in 4 most widely studied drugs
• No strong evidence for confounding by heparin,
patient population, or trial design
• Sensitivity analyses => main finding is robust
30
Platelet Count < 50,000
(Preliminary Results)
•
•
•
•
•
•
23 trials with data on platelet counts < 50K
11 trials had no cases in either treatment group
Only 7 trials had cases in both treatment groups
GP IIb/IIIa: 101 cases in 17330 pts (0.58%)
Placebo:
40 cases in 12280 pts (0.33%)
OR (metanalysis): 1.30 (0.84, 2.03)
31
10
100,000 vs. 50,000 Threshold (preliminary)
OR with 95% CI
4.03
1
0.1
Odds Ratio
upper 95%
lower 95%
8.36
3.25
3.57
2.01 2.21
1.89
1.43
2.08
1.69
1.48
1.12 1.15
0.89
0.75
1.91 2.03
1.14
1.30
0.84
0.62
0.59
0.63
Abciximab
Tirofiban
Eptifibatide
All trials
100K 50K
100K 50K
100K 50K
100K 50K
32
Required Heparin - 100K vs 50K (preliminary)
OR with 95% CI
10.00
1.00
25
Odds Ratio
upper 95%
lower 95%
3.68
1.80
2.20
1.89
2.01
1.44 1.28
1.09
0.88
0.81
Heparin not
required
Heparin required
1.91
2.03
1.48 1.30
1.14
0.84
All Trials
0.19
0.10
33
Patient Population - 100K vs 50K
OR with 95% CI
10
Odds Ratio
upper 95%
lower 95%
4.00 3.60
1.50
1
0.83
2.97
2.16 2.37
2.15
1.91 2.03
1.49
1.46 1.51
1.48
1.03
1.25
0.99
0.65
0.56
Lytic trials
1.14
Intervention
0.84
0.77
Other*
1.30
All trials
0.19
*Other includes acute and stable coronary syndromes
0.1
34
Effect of Trial Design
OR with 95% CI
10.00
1.00
Odds Ratio
upper 95%
lower 95%
2.70
2.57
1.99
2.28
1.52 1.42
1.16
1.12
0.73
0.88
1.91
2.03
1.48 1.30
1.14
0.84
0.47
0.21
Dose ranging
0.10
Fixed-dose
All trials
35
Is Thrombocytopenia Dose-related?
(Preliminary Results)
• 14 trials with > 2 doses of IIb/IIIa inhibitor
that reported plt by dose
• Highest dose compared to lowest dose
• High dose: 389 cases in 7737 pts (5.0%)
• Low dose: 215 cases in 4511 pts (4.8%)
• 3 largest trials: More cases in low dose group
• Metanalytic OR [high:low] = 0.73 (0.51, 1.04)
• High-degree of heterogeneity of trials
36
ReoPro Readministration Registry (R3)
(Tcheng JE, JACC ‘98;31(Suppl A):55A)
• 256 pts readministered Abciximab
• 27% developed human anti-chimeric
antibodies (HACA)
• No anaphylaxis observed
• Rate of thrombocytopenia is approx 3x in pts
that are HACA + (7.2% vs 2.3%, p =.06)
37
Complex Interaction with Heparin?
(Kereiakes DJ, JACC 98;31(Suppl A):55A)
10%
5.6%
5%
% decrease plt count
5.2%
% with plt ct < 100K
2.6%
2.5%
Capture EPIC Ab Epilog
Ab
Ab+SD
-5%
Epilog
Ab+LD
1.5%
0%
Epilog
P+SD
% Drop
-8.4%
-10%
-15%
-12.9%
-11.7%
38
Multivariate Predictors of
Plts in Abciximab Trials
Age > 65
Wt < 90 kg
Baseline plt count < 150K
Use of Abciximab
------------------------------------In MVA, heparin dose had p = 0.19
Kereiakes DJ, JACC 98;31(Suppl A):55A
39
TIMI Treatment Guidelines
• Acute (days 1-3) or delayed (days 4+)
• Platelet count
– < 10,000
– 10,000 - 50,000
– > 50,000
• Is there bleeding?
– None
– Minor to moderate (include mucosal bleeding)
– Severe
40
Acute Thrombocytopenia (1)
Platelets
Acute <10K
Bleeding?
No bleeding
Recommendations
1. Transfuse plts
2. Reverse heparin
Minor-mod
As above
Severe
1. Critical care
2. Transfuse plts
3. Reverse heparin
4. Transfuse RBCs
41
Acute Thrombocytopenia (2)
Platelets
Acute 10-50K
Bleeding?
No bleeding
Recommendations
1. Careful obs.
2. Stop heparin
3. Consider plt tx
Minor-mod
1. Transfuse plts
2. Reverse heparin
Severe
1. Critical care
2. Transfuse plts
3. Reverse heparin
4. Transfuse RBCs
42
Acute Thrombocytopenia (3)
Platelets
Bleeding?
Acute <50-100K Yes or no
Recommendations
1. Careful obs
2. ?stop heparin
43
Delayed Thrombocytopenia (1)
Platelets
<10,000
Bleeding?
None
Recommendations
1. Transfuse plts
2. Reverse heparin
3. Consider IV steroids
and/or IgG
Minor-mod
As above
Severe
1. Critical care
2. Transfuse plts
3. Reverse heparin
4. Transfuse RBCs
5. IV steroids/IgG
44
Delayed Thrombocytopenia (2)
Platelets
10,000-50,000
Bleeding?
No bleeding
Recommendations
1. Careful obs.
2. Stop heparin
3. Consider plt tx
4. Consider IV steroids
and/or IgG
Minor-mod
As above
Severe
1. Critical care
2. Transfuse plts
3. Reverse heparin
4. Transfuse RBCs
5. Give steroids/IgG
45
Delayed Thrombocytopenia (3)
Platelets
50-100K
Bleeding?
Yes or no
Recommendations
1. Careful obs
2. ?stop heparin
46
Life-threatening Cases
If no response to above measures, consider:
– emergent hemodialysis
– plasmapheresis
(neither of proven benefit)
47