1 Thrombocytopenia with GP IIb/IIIa Inhibitors Robert P. Giugliano, MD, SM TIMI Study Chairman’s...

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Thrombocytopenia withThrombocytopenia withGP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors

Thrombocytopenia withThrombocytopenia withGP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors

Robert P. Giugliano, MD, SMRobert P. Giugliano, MD, SM

TIMI Study Chairman’s OfficeTIMI Study Chairman’s Office

Cardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s Hospital

Harvard Medical SchoolHarvard Medical School

Robert P. Giugliano, MD, SMRobert P. Giugliano, MD, SM

TIMI Study Chairman’s OfficeTIMI Study Chairman’s Office

Cardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s Hospital

Harvard Medical SchoolHarvard Medical School

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Historical ReviewHistorical ReviewHistorical ReviewHistorical Review

• Hypersensitivity to drug, foodstuffs, chemicals, Hypersensitivity to drug, foodstuffs, chemicals, vaccines, and insect bites known to cause vaccines, and insect bites known to cause thrombocytopenia since early 1900’sthrombocytopenia since early 1900’s

• Drug-induced thrombocytopenia:Drug-induced thrombocytopenia:– Quinine purpura first reported in 1928Quinine purpura first reported in 1928– Sedermoid purpura, first detailed study (1949-55) by Sedermoid purpura, first detailed study (1949-55) by

Ackroyd -> Agglutination of normal human platelets Ackroyd -> Agglutination of normal human platelets with serum of pts with plts due to sedermoidwith serum of pts with plts due to sedermoid

• Hypersensitivity to drug, foodstuffs, chemicals, Hypersensitivity to drug, foodstuffs, chemicals, vaccines, and insect bites known to cause vaccines, and insect bites known to cause thrombocytopenia since early 1900’sthrombocytopenia since early 1900’s

• Drug-induced thrombocytopenia:Drug-induced thrombocytopenia:– Quinine purpura first reported in 1928Quinine purpura first reported in 1928– Sedermoid purpura, first detailed study (1949-55) by Sedermoid purpura, first detailed study (1949-55) by

Ackroyd -> Agglutination of normal human platelets Ackroyd -> Agglutination of normal human platelets with serum of pts with plts due to sedermoidwith serum of pts with plts due to sedermoid

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Diagnosis of Drug-Induced Diagnosis of Drug-Induced ThrombocytopeniaThrombocytopenia

Diagnosis of Drug-Induced Diagnosis of Drug-Induced ThrombocytopeniaThrombocytopenia

1. Onset temporally related to drug initiation1. Onset temporally related to drug initiation

2. No alternative explanation2. No alternative explanation

3. Platelet count returns to normal once drug is 3. Platelet count returns to normal once drug is discontinueddiscontinued

4. Confirmation of diagnosis by either:4. Confirmation of diagnosis by either:» in vitroin vitro testing testing» rechallengerechallenge

1. Onset temporally related to drug initiation1. Onset temporally related to drug initiation

2. No alternative explanation2. No alternative explanation

3. Platelet count returns to normal once drug is 3. Platelet count returns to normal once drug is discontinueddiscontinued

4. Confirmation of diagnosis by either:4. Confirmation of diagnosis by either:» in vitroin vitro testing testing» rechallengerechallenge

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Diagnosis is More Challenging TodayDiagnosis is More Challenging TodayDiagnosis is More Challenging TodayDiagnosis is More Challenging Today

Pre-1960’sPre-1960’s TodayToday

No automated plt countNo automated plt count Automated plt countsAutomated plt counts Bleeding, plt <10-20KBleeding, plt <10-20K Variable plt cts, SxVariable plt cts, Sx

Pts younger, less illPts younger, less ill Older, more illOlder, more ill

Few medications/ptFew medications/pt Multiple medsMultiple meds

Established relationshipsEstablished relationships Unknown risks of new medsUnknown risks of new meds

Pre-1960’sPre-1960’s TodayToday

No automated plt countNo automated plt count Automated plt countsAutomated plt counts Bleeding, plt <10-20KBleeding, plt <10-20K Variable plt cts, SxVariable plt cts, Sx

Pts younger, less illPts younger, less ill Older, more illOlder, more ill

Few medications/ptFew medications/pt Multiple medsMultiple meds

Established relationshipsEstablished relationships Unknown risks of new medsUnknown risks of new meds

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Antiplatelet Antibody TestingAntiplatelet Antibody TestingAntiplatelet Antibody TestingAntiplatelet Antibody Testing

1. “Modified indirect antiglobulin test”1. “Modified indirect antiglobulin test”Drug + pt serum (plasma) + nl donor pltsDrug + pt serum (plasma) + nl donor pltsLook for deposition of Ig’s or Look for deposition of Ig’s or complement on normal donor plts complement on normal donor plts

2. Platelet functional tests - altered results2. Platelet functional tests - altered results- plt activation- plt activation- release of dense granule contents- release of dense granule contents- release of cytoplasmic contents- release of cytoplasmic contents- stimulation of plt procoagulant activity- stimulation of plt procoagulant activity

1. “Modified indirect antiglobulin test”1. “Modified indirect antiglobulin test”Drug + pt serum (plasma) + nl donor pltsDrug + pt serum (plasma) + nl donor pltsLook for deposition of Ig’s or Look for deposition of Ig’s or complement on normal donor plts complement on normal donor plts

2. Platelet functional tests - altered results2. Platelet functional tests - altered results- plt activation- plt activation- release of dense granule contents- release of dense granule contents- release of cytoplasmic contents- release of cytoplasmic contents- stimulation of plt procoagulant activity- stimulation of plt procoagulant activity

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Drug-dependent Ab: Drug-dependent Ab: Five Potential MechanismsFive Potential Mechanisms


(1) Ab binds to drug in plasma to (1) Ab binds to drug in plasma to form circulating immune-complexes.form circulating immune-complexes.Change in IgG conformation then Change in IgG conformation then recognized by platelet Fc receptorrecognized by platelet Fc receptor

(1) Ab binds to drug in plasma to (1) Ab binds to drug in plasma to form circulating immune-complexes.form circulating immune-complexes.Change in IgG conformation then Change in IgG conformation then recognized by platelet Fc receptorrecognized by platelet Fc receptor

(2) Ab binds directly to drug which(2) Ab binds directly to drug whichis concentrated on plt surface (relativeis concentrated on plt surface (relativeto drug concentration in the plasma)to drug concentration in the plasma)

(2) Ab binds directly to drug which(2) Ab binds directly to drug whichis concentrated on plt surface (relativeis concentrated on plt surface (relativeto drug concentration in the plasma)to drug concentration in the plasma)

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Adapted from McCrae KR and Cines DB, Ch 29, Adapted from McCrae KR and Cines DB, Ch 29, Thrombosis and HemorrhageThrombosis and HemorrhageAdapted from McCrae KR and Cines DB, Ch 29, Adapted from McCrae KR and Cines DB, Ch 29, Thrombosis and HemorrhageThrombosis and Hemorrhage

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(3) When drug binds the platelet,(3) When drug binds the platelet,the drug changes conformation the drug changes conformation and is then recognized by the Aband is then recognized by the Ab

(3) When drug binds the platelet,(3) When drug binds the platelet,the drug changes conformation the drug changes conformation and is then recognized by the Aband is then recognized by the Ab

(4) Drug binding causes a change(4) Drug binding causes a changein the plt conformation, which in the plt conformation, which the Ab then recognizesthe Ab then recognizes

(4) Drug binding causes a change(4) Drug binding causes a changein the plt conformation, which in the plt conformation, which the Ab then recognizesthe Ab then recognizes

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(5) The Ab recognizes one or more neoepitopes comprised (5) The Ab recognizes one or more neoepitopes comprised of of bothboth platelet-derived and drug-derived determinants platelet-derived and drug-derived determinants(5) The Ab recognizes one or more neoepitopes comprised (5) The Ab recognizes one or more neoepitopes comprised of of bothboth platelet-derived and drug-derived determinants platelet-derived and drug-derived determinants

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Other Drugs: Other Drugs: What Have We LearnedWhat Have We Learned

Other Drugs: Other Drugs: What Have We LearnedWhat Have We Learned

• Plt counts for any one drug may (?often) have Plt counts for any one drug may (?often) have multiple mechanisms (e.g. EtOH)multiple mechanisms (e.g. EtOH)

• Contribution of suppressed plt production may Contribution of suppressed plt production may be underestimatedbe underestimated– Megakaryocytes in marrow = normal plt productionMegakaryocytes in marrow = normal plt production– Difficult to study megakaryocytopoiesis Difficult to study megakaryocytopoiesis in vitroin vitro

• Drug-dependent anti-plt Ab in early stages or Drug-dependent anti-plt Ab in early stages or non-existent for most drug (?sens, ?? specificity)non-existent for most drug (?sens, ?? specificity)

• Plt counts for any one drug may (?often) have Plt counts for any one drug may (?often) have multiple mechanisms (e.g. EtOH)multiple mechanisms (e.g. EtOH)

• Contribution of suppressed plt production may Contribution of suppressed plt production may be underestimatedbe underestimated– Megakaryocytes in marrow = normal plt productionMegakaryocytes in marrow = normal plt production– Difficult to study megakaryocytopoiesis Difficult to study megakaryocytopoiesis in vitroin vitro

• Drug-dependent anti-plt Ab in early stages or Drug-dependent anti-plt Ab in early stages or non-existent for most drug (?sens, ?? specificity)non-existent for most drug (?sens, ?? specificity)

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Thiazide-induced ThrombocytopeniaThiazide-induced ThrombocytopeniaThiazide-induced ThrombocytopeniaThiazide-induced Thrombocytopenia

GP IIb/IIIa associated plts shares features with the GP IIb/IIIa associated plts shares features with the historical description for thiazides:historical description for thiazides:– cardiac patients appear at higher riskcardiac patients appear at higher risk– incidence may be 1-2%, but little prospective dataincidence may be 1-2%, but little prospective data– generally mild-mod (30-100K), occasionally severegenerally mild-mod (30-100K), occasionally severe– smear shows only reduced # pltssmear shows only reduced # plts– counts recover in 5-14 dayscounts recover in 5-14 days– mechanism(s): likely multiple, immune-destruction mechanism(s): likely multiple, immune-destruction

most frequent most frequent

GP IIb/IIIa associated plts shares features with the GP IIb/IIIa associated plts shares features with the historical description for thiazides:historical description for thiazides:– cardiac patients appear at higher riskcardiac patients appear at higher risk– incidence may be 1-2%, but little prospective dataincidence may be 1-2%, but little prospective data– generally mild-mod (30-100K), occasionally severegenerally mild-mod (30-100K), occasionally severe– smear shows only reduced # pltssmear shows only reduced # plts– counts recover in 5-14 dayscounts recover in 5-14 days– mechanism(s): likely multiple, immune-destruction mechanism(s): likely multiple, immune-destruction

most frequent most frequent

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Quinidine / Quinine PurpuraQuinidine / Quinine PurpuraQuinidine / Quinine PurpuraQuinidine / Quinine Purpura

• Incidence estimated at 1/1000 [though probably higher Incidence estimated at 1/1000 [though probably higher in cardiac pts]in cardiac pts]

• Drug-dependent Abs bind to epitopes within either the Drug-dependent Abs bind to epitopes within either the GP Ib/IX or GP IIb/IIIa complexesGP Ib/IX or GP IIb/IIIa complexes

• Bernard-Soulier Syndrome (GP Ib complex proteins Bernard-Soulier Syndrome (GP Ib complex proteins deficient) may have “no” receptor for quinidine/quinine deficient) may have “no” receptor for quinidine/quinine induced Ab (controversial)induced Ab (controversial)

• Hypothesis: Drug induces changes in plt GP that are Hypothesis: Drug induces changes in plt GP that are then recognized by Ab (mechanism 4 or 5)then recognized by Ab (mechanism 4 or 5)

• Incidence estimated at 1/1000 [though probably higher Incidence estimated at 1/1000 [though probably higher in cardiac pts]in cardiac pts]

• Drug-dependent Abs bind to epitopes within either the Drug-dependent Abs bind to epitopes within either the GP Ib/IX or GP IIb/IIIa complexesGP Ib/IX or GP IIb/IIIa complexes

• Bernard-Soulier Syndrome (GP Ib complex proteins Bernard-Soulier Syndrome (GP Ib complex proteins deficient) may have “no” receptor for quinidine/quinine deficient) may have “no” receptor for quinidine/quinine induced Ab (controversial)induced Ab (controversial)

• Hypothesis: Drug induces changes in plt GP that are Hypothesis: Drug induces changes in plt GP that are then recognized by Ab (mechanism 4 or 5)then recognized by Ab (mechanism 4 or 5)

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Sulfa CompoundsSulfa CompoundsSulfa CompoundsSulfa Compounds

• Typically occurs 1-2 wks after initiationTypically occurs 1-2 wks after initiation

• Severe cases not uncommonSevere cases not uncommon

• Ab have been found against metabolite as well Ab have been found against metabolite as well as drug (both components for TMP-SX)as drug (both components for TMP-SX)

• Some donor plts serve as targets, other do Some donor plts serve as targets, other do not, ? Polymorphic determinants (?? Plnot, ? Polymorphic determinants (?? PlA2A2))

• Typically occurs 1-2 wks after initiationTypically occurs 1-2 wks after initiation

• Severe cases not uncommonSevere cases not uncommon

• Ab have been found against metabolite as well Ab have been found against metabolite as well as drug (both components for TMP-SX)as drug (both components for TMP-SX)

• Some donor plts serve as targets, other do Some donor plts serve as targets, other do not, ? Polymorphic determinants (?? Plnot, ? Polymorphic determinants (?? PlA2A2))

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Valproic AcidValproic AcidValproic AcidValproic Acid

• Plt counts usually Plt counts usually << 2 wks, as late as 4 mths 2 wks, as late as 4 mths

• Spectrum of plt counts seen (severe - mild)Spectrum of plt counts seen (severe - mild)

• Mechanism(s) unclear, ? dose relatedMechanism(s) unclear, ? dose related

• Plt counts may return to normal despite Plt counts may return to normal despite continued therapy => implications for continued therapy => implications for mechanism(s)mechanism(s)

• Plt counts usually Plt counts usually << 2 wks, as late as 4 mths 2 wks, as late as 4 mths

• Spectrum of plt counts seen (severe - mild)Spectrum of plt counts seen (severe - mild)

• Mechanism(s) unclear, ? dose relatedMechanism(s) unclear, ? dose related

• Plt counts may return to normal despite Plt counts may return to normal despite continued therapy => implications for continued therapy => implications for mechanism(s)mechanism(s)

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HeparinHeparinHeparinHeparin• At least two mechanisms (?spectrum of disease)At least two mechanisms (?spectrum of disease)

• Incidence varies (0-30%) among series: Incidence varies (0-30%) among series: – bovine vs porcine, LMWH, heparinoidsbovine vs porcine, LMWH, heparinoids– dose may be importantdose may be important– clinical factors (cardiac disease, surgery)clinical factors (cardiac disease, surgery)– method of diagnosismethod of diagnosis

• Ubiquitous use in hospital, esp cardiology may Ubiquitous use in hospital, esp cardiology may confound analysis of other drugsconfound analysis of other drugs

• At least two mechanisms (?spectrum of disease)At least two mechanisms (?spectrum of disease)

• Incidence varies (0-30%) among series: Incidence varies (0-30%) among series: – bovine vs porcine, LMWH, heparinoidsbovine vs porcine, LMWH, heparinoids– dose may be importantdose may be important– clinical factors (cardiac disease, surgery)clinical factors (cardiac disease, surgery)– method of diagnosismethod of diagnosis

• Ubiquitous use in hospital, esp cardiology may Ubiquitous use in hospital, esp cardiology may confound analysis of other drugsconfound analysis of other drugs

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Mechanism of HITMechanism of HITMechanism of HITMechanism of HIT

• Type 1: mild, early onset, may resolve despite Type 1: mild, early onset, may resolve despite continued heparin, no thrombosis.continued heparin, no thrombosis.– plt agglutination due to (-) charge of heparinplt agglutination due to (-) charge of heparin

• Type 2: mild-severe (subtypes?), onset 7-14 d, may Type 2: mild-severe (subtypes?), onset 7-14 d, may be associated with fatal arterial/venous thrombosisbe associated with fatal arterial/venous thrombosis– Ab reacts with heparin and/or PF4 -> immune complex Ab reacts with heparin and/or PF4 -> immune complex

which then is recognized by Fc receptor on the pltwhich then is recognized by Fc receptor on the plt

• Type 1: mild, early onset, may resolve despite Type 1: mild, early onset, may resolve despite continued heparin, no thrombosis.continued heparin, no thrombosis.– plt agglutination due to (-) charge of heparinplt agglutination due to (-) charge of heparin

• Type 2: mild-severe (subtypes?), onset 7-14 d, may Type 2: mild-severe (subtypes?), onset 7-14 d, may be associated with fatal arterial/venous thrombosisbe associated with fatal arterial/venous thrombosis– Ab reacts with heparin and/or PF4 -> immune complex Ab reacts with heparin and/or PF4 -> immune complex

which then is recognized by Fc receptor on the pltwhich then is recognized by Fc receptor on the plt

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Thrombocytopenia with GP Thrombocytopenia with GP IIb/IIIa inhibitors:IIb/IIIa inhibitors:

A Meta-analysisA Meta-analysis

Thrombocytopenia with GP Thrombocytopenia with GP IIb/IIIa inhibitors:IIb/IIIa inhibitors:

A Meta-analysisA Meta-analysis

Robert P. Giugliano, M.D., S.M.Raymond R. Hyatt, Jr., S.M.

Brigham and Women’s HospitalHarvard Medical School

Robert P. Giugliano, M.D., S.M.Raymond R. Hyatt, Jr., S.M.

Brigham and Women’s HospitalHarvard Medical School

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BackgroundBackgroundBackgroundBackground

• Hemorrhage and thrombocytopenia ( plt) Hemorrhage and thrombocytopenia ( plt) are major safety concerns with GP IIb/IIIa are major safety concerns with GP IIb/IIIa

• Comprehensive review of plt lackingComprehensive review of plt lacking

• Challenges in evaluating plt:Challenges in evaluating plt:– Infrequent events Infrequent events – Varying definitionsVarying definitions– Confounding Confounding – Limited # publicationsLimited # publications

• Hemorrhage and thrombocytopenia ( plt) Hemorrhage and thrombocytopenia ( plt) are major safety concerns with GP IIb/IIIa are major safety concerns with GP IIb/IIIa

• Comprehensive review of plt lackingComprehensive review of plt lacking

• Challenges in evaluating plt:Challenges in evaluating plt:– Infrequent events Infrequent events – Varying definitionsVarying definitions– Confounding Confounding – Limited # publicationsLimited # publications

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ObjectivesObjectivesObjectivesObjectives

Use metanalysis to estimate the risk of Use metanalysis to estimate the risk of

plt due to GP IIb/IIIa inhibitors in:plt due to GP IIb/IIIa inhibitors in:

1. All trials1. All trials

2. Subgroups stratified by:2. Subgroups stratified by:- specific agent- specific agent - heparin use- heparin use

- pt population- pt population - trial design- trial design

Use metanalysis to estimate the risk of Use metanalysis to estimate the risk of

plt due to GP IIb/IIIa inhibitors in:plt due to GP IIb/IIIa inhibitors in:

1. All trials1. All trials

2. Subgroups stratified by:2. Subgroups stratified by:- specific agent- specific agent - heparin use- heparin use

- pt population- pt population - trial design- trial design

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Methods IMethods IMethods IMethods I• Abstract and manuscripts thru AUG 1997 (Medline, Abstract and manuscripts thru AUG 1997 (Medline,

ACC/AHA, references)ACC/AHA, references)

• Inclusion: Phase II/III clinical trials, results publicly Inclusion: Phase II/III clinical trials, results publicly presentedpresented

• Exclusion: No placebo control, Exclusion: No placebo control, >> 2 GP IIb/IIIa inhibitors, 2 GP IIb/IIIa inhibitors, secondary reportssecondary reports

• PARAGON treated as 2 separate trialsPARAGON treated as 2 separate trials

• Outcome measurement: Odds ratio of plt (defined as plt Outcome measurement: Odds ratio of plt (defined as plt ct < 100K [if available])ct < 100K [if available])

• Abstract and manuscripts thru AUG 1997 (Medline, Abstract and manuscripts thru AUG 1997 (Medline, ACC/AHA, references)ACC/AHA, references)

• Inclusion: Phase II/III clinical trials, results publicly Inclusion: Phase II/III clinical trials, results publicly presentedpresented

• Exclusion: No placebo control, Exclusion: No placebo control, >> 2 GP IIb/IIIa inhibitors, 2 GP IIb/IIIa inhibitors, secondary reportssecondary reports

• PARAGON treated as 2 separate trialsPARAGON treated as 2 separate trials

• Outcome measurement: Odds ratio of plt (defined as plt Outcome measurement: Odds ratio of plt (defined as plt ct < 100K [if available])ct < 100K [if available])

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Methods IIMethods IIMethods IIMethods II• Subgroup analyses: Subgroup analyses:

– By drug: 4 most widely studied agentsBy drug: 4 most widely studied agents– Heparin required vs. not requiredHeparin required vs. not required– Pt population: interventional, lytic, otherPt population: interventional, lytic, other– Trial design: dose-ranging vs. fixed dose (Trial design: dose-ranging vs. fixed dose (<<2)2)

• DerSimonian and Laird random effects model to DerSimonian and Laird random effects model to estimate combined OR (95%CI)estimate combined OR (95%CI)

• 1/6th added if zero cell1/6th added if zero cell• Sensitivity analyses: Fail-safe N, publication bias, Sensitivity analyses: Fail-safe N, publication bias,

excluding trialsexcluding trials

• Subgroup analyses: Subgroup analyses: – By drug: 4 most widely studied agentsBy drug: 4 most widely studied agents– Heparin required vs. not requiredHeparin required vs. not required– Pt population: interventional, lytic, otherPt population: interventional, lytic, other– Trial design: dose-ranging vs. fixed dose (Trial design: dose-ranging vs. fixed dose (<<2)2)

• DerSimonian and Laird random effects model to DerSimonian and Laird random effects model to estimate combined OR (95%CI)estimate combined OR (95%CI)

• 1/6th added if zero cell1/6th added if zero cell• Sensitivity analyses: Fail-safe N, publication bias, Sensitivity analyses: Fail-safe N, publication bias,

excluding trialsexcluding trials

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Results - Trial IdentificationResults - Trial IdentificationResults - Trial IdentificationResults - Trial Identification140 papers/abstracts reviewed140 papers/abstracts reviewed

38 phase II/III trials38 phase II/III trials6 no placebo control6 no placebo control

3 follow-up/subgroup3 follow-up/subgroup

1 multiple IIb/IIIa inhibitors1 multiple IIb/IIIa inhibitors

28 trials included28 trials included 1159 cases of plt in 33,234 pts (3.49%)1159 cases of plt in 33,234 pts (3.49%)

140 papers/abstracts reviewed140 papers/abstracts reviewed

38 phase II/III trials38 phase II/III trials6 no placebo control6 no placebo control

3 follow-up/subgroup3 follow-up/subgroup

1 multiple IIb/IIIa inhibitors1 multiple IIb/IIIa inhibitors

28 trials included28 trials included 1159 cases of plt in 33,234 pts (3.49%)1159 cases of plt in 33,234 pts (3.49%)

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Simple Combined ResultsSimple Combined ResultsSimple Combined ResultsSimple Combined Results

0%

1%

2%

3%

4%

GP IIb/IIIa Placebo

0%

1%

2%

3%

4%

GP IIb/IIIa Placebo

No. pts : 19,250 13,984No. pts : 19,250 13,984

3.76% 3.11%

Th

rom

boc

ytop

enia

Th

rom

boc

ytop

enia

OR = 1.22OR = 1.22(1.07, 1.36)(1.07, 1.36) P = 0.002P = 0.002

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Heterogeneity of DataHeterogeneity of DataHeterogeneity of DataHeterogeneity of Data

• 28 trials range in size 24 - 10,000+ pts28 trials range in size 24 - 10,000+ pts

• Absolute rates of plt vary widely:Absolute rates of plt vary widely:– GP IIb/IIIa:GP IIb/IIIa: 0 - 12%0 - 12% Placebo: Placebo: 0 - 10%0 - 10%– Odds ratio: 0.02 - 9.5Odds ratio: 0.02 - 9.5

• 7 different types of GP IIb/IIIa studied7 different types of GP IIb/IIIa studied

• Varying patient populations, concomitant Varying patient populations, concomitant medications, #doses studiedmedications, #doses studied

• Def of plt: <50K to <100K or 50% declineDef of plt: <50K to <100K or 50% decline

• 28 trials range in size 24 - 10,000+ pts28 trials range in size 24 - 10,000+ pts

• Absolute rates of plt vary widely:Absolute rates of plt vary widely:– GP IIb/IIIa:GP IIb/IIIa: 0 - 12%0 - 12% Placebo: Placebo: 0 - 10%0 - 10%– Odds ratio: 0.02 - 9.5Odds ratio: 0.02 - 9.5

• 7 different types of GP IIb/IIIa studied7 different types of GP IIb/IIIa studied

• Varying patient populations, concomitant Varying patient populations, concomitant medications, #doses studiedmedications, #doses studied

• Def of plt: <50K to <100K or 50% declineDef of plt: <50K to <100K or 50% decline

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0.01

0.1

1

10

100

1 3 5 7 9 11 13 15 17 19 21 23 25 27

Odds Ratio

upper 95%

lower 95%0.01

0.1

1

10

100

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 largestIndividual Trials from smallest to largest

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

Odds of Thrombocytopenia in 28 TrialsOdds of Thrombocytopenia in 28 TrialsOdds of Thrombocytopenia in 28 TrialsOdds of Thrombocytopenia in 28 Trials

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1.361.89 2.01

1.121.48

3.164.03 3.57

1.69 1.91

0.58

0.891.13 1.14

0.1

1

10

Lamifiban Abciximab Tirofiban Eptifibatide All Trials

Odds Ratioupper 95%lower 95%

1.361.89 2.01

1.121.48

3.164.03 3.57

1.69 1.91

0.58

0.891.13 1.14

0.1

1

10

Lamifiban Abciximab Tirofiban Eptifibatide All Trials


OR

wit

h 95

% C

IO

R w

ith

95%

CI

Odds of Thrombocytopenia by DrugOdds of Thrombocytopenia by DrugOdds of Thrombocytopenia by DrugOdds of Thrombocytopenia by Drug

#trials 4 4 6 6 28# pts 3758 6272 7159 15,486 33,234

#trials 4 4 6 6 28# pts 3758 6272 7159 15,486 33,234

0.75

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1.801.44 1.48

3.68

1.89 1.91

0.881.09 1.14

0.10

1.00

10.00

Heparin notrequired

Heparinrequired

All Trials


1.801.44 1.48

3.68

1.89 1.91

0.881.09 1.14

0.10

1.00

10.00

Heparin notrequired

Heparinrequired

All Trials


OR

wit

h 9

5% C

IO

R w

ith

95%

CI

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

No Evidence for Confounding No Evidence for Confounding by Required Heparinby Required Heparin

No Evidence for Confounding No Evidence for Confounding by Required Heparinby Required Heparin

#trials 10 18 28#trials 10 18 28# pts 6038 27,196 33,234# pts 6038 27,196 33,234


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1.50 1.49 1.46 1.48

4.00

2.16 2.15 1.91

0.56

1.03 0.99 1.14

0.1

1

10

Lytic Interventional Other * All Trials


1.50 1.49 1.46 1.48

4.00

2.16 2.15 1.91

0.56

1.03 0.99 1.14

0.1

1

10

Lytic Interventional Other * All Trials


OR

wit

h 9

5% C

IO

R w

ith

95%

CI

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

Effect of Patient PopulationEffect of Patient PopulationEffect of Patient PopulationEffect of Patient Population

#trials 3 12 13 28#trials 3 12 13 28# pts 603 12,792 19,839 33,234# pts 603 12,792 19,839 33,234

*Other includes acute and stable coronary syndromes*Other includes acute and stable coronary syndromes

#trials 3 12 13 28#trials 3 12 13 28# pts 603 12,792 19,839 33,234# pts 603 12,792 19,839 33,234

*Other includes acute and stable coronary syndromes*Other includes acute and stable coronary syndromes

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1.121.52 1.48

2.701.99 1.91

0.47

1.16 1.14

0.1

1

10

Dose ranging Fixed dose All Trials


1.121.52 1.48

2.701.99 1.91

0.47

1.16 1.14

0.1

1

10

Dose ranging Fixed dose All Trials


OR

wit

h 9

5% C

IO

R w

ith

95%

CI

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

Effect of Trial DesignEffect of Trial DesignEffect of Trial DesignEffect of Trial Design



29

Sensitivity AnalysesSensitivity AnalysesSensitivity AnalysesSensitivity Analyses• Over >100,000 pts per arm, 0% plt with IIb/IIIa Over >100,000 pts per arm, 0% plt with IIb/IIIa

inhibitor => negate overall result inhibitor => negate overall result • Fail-safe N: 3 trials of 10,000 pts, 0% plt with IIb/IIIa Fail-safe N: 3 trials of 10,000 pts, 0% plt with IIb/IIIa

inhibitorinhibitor• Excluding trialsExcluding trials

– <1000 pts (18) <1000 pts (18) 1.56 (1.14, 2.12 )1.56 (1.14, 2.12 )– No plt observed (13)No plt observed (13) 1.51 (1.16, 1.96)1.51 (1.16, 1.96)– Our modelOur model 1.48 (1.14, 1.91)1.48 (1.14, 1.91)

• Add 1/2 to zero cellsAdd 1/2 to zero cells 1.40 (1.09, 1.80) 1.40 (1.09, 1.80)

• Over >100,000 pts per arm, 0% plt with IIb/IIIa Over >100,000 pts per arm, 0% plt with IIb/IIIa inhibitor => negate overall result inhibitor => negate overall result

• Fail-safe N: 3 trials of 10,000 pts, 0% plt with IIb/IIIa Fail-safe N: 3 trials of 10,000 pts, 0% plt with IIb/IIIa inhibitorinhibitor

• Excluding trialsExcluding trials– <1000 pts (18) <1000 pts (18) 1.56 (1.14, 2.12 )1.56 (1.14, 2.12 )– No plt observed (13)No plt observed (13) 1.51 (1.16, 1.96)1.51 (1.16, 1.96)– Our modelOur model 1.48 (1.14, 1.91)1.48 (1.14, 1.91)

• Add 1/2 to zero cellsAdd 1/2 to zero cells 1.40 (1.09, 1.80) 1.40 (1.09, 1.80)

30

ConclusionsConclusionsConclusionsConclusions

• GP IIb/IIIa inhibitors associated with an approx 50% in plt GP IIb/IIIa inhibitors associated with an approx 50% in plt compared to placebo (or an extra 1-2 cases per 100 pts treated compared to placebo (or an extra 1-2 cases per 100 pts treated with GP inhibitor)with GP inhibitor)

• Heterogeneity marked esp. in small trialsHeterogeneity marked esp. in small trials

• Odds of plt similar in 4 most widely studied drugsOdds of plt similar in 4 most widely studied drugs

• No strong evidence for confounding by heparin, patient No strong evidence for confounding by heparin, patient population, or trial design population, or trial design

• Sensitivity analyses => main finding is robustSensitivity analyses => main finding is robust

• GP IIb/IIIa inhibitors associated with an approx 50% in plt GP IIb/IIIa inhibitors associated with an approx 50% in plt compared to placebo (or an extra 1-2 cases per 100 pts treated compared to placebo (or an extra 1-2 cases per 100 pts treated with GP inhibitor)with GP inhibitor)

• Heterogeneity marked esp. in small trialsHeterogeneity marked esp. in small trials

• Odds of plt similar in 4 most widely studied drugsOdds of plt similar in 4 most widely studied drugs

• No strong evidence for confounding by heparin, patient No strong evidence for confounding by heparin, patient population, or trial design population, or trial design

• Sensitivity analyses => main finding is robustSensitivity analyses => main finding is robust

31

Platelet Count < 50,000Platelet Count < 50,000(Preliminary Results)(Preliminary Results)

Platelet Count < 50,000Platelet Count < 50,000(Preliminary Results)(Preliminary Results)

• 23 trials with data on platelet counts < 50K23 trials with data on platelet counts < 50K

• 11 trials had no cases in either treatment group11 trials had no cases in either treatment group

• Only 7 trials had cases in both treatment groupsOnly 7 trials had cases in both treatment groups

• GP IIb/IIIa: GP IIb/IIIa: 101 cases in 17330 pts (0.58%)101 cases in 17330 pts (0.58%)

• Placebo:Placebo: 40 cases in 12280 pts (0.33%) 40 cases in 12280 pts (0.33%)

• OR (metanalysis): 1.30 (0.84, 2.03)OR (metanalysis): 1.30 (0.84, 2.03)

• 23 trials with data on platelet counts < 50K23 trials with data on platelet counts < 50K

• 11 trials had no cases in either treatment group11 trials had no cases in either treatment group

• Only 7 trials had cases in both treatment groupsOnly 7 trials had cases in both treatment groups

• GP IIb/IIIa: GP IIb/IIIa: 101 cases in 17330 pts (0.58%)101 cases in 17330 pts (0.58%)

• Placebo:Placebo: 40 cases in 12280 pts (0.33%) 40 cases in 12280 pts (0.33%)

• OR (metanalysis): 1.30 (0.84, 2.03)OR (metanalysis): 1.30 (0.84, 2.03)

32

2.01 2.21

1.12 1.151.48 1.30

4.033.25 3.57

0.59

1.69

0.63

1.91 2.03

0.89

0.62

8.36

0.75

2.08

1.14

0.84

1.891.43

0.1

1

10Odds Ratioupper 95%lower 95%

2.01 2.21

1.12 1.151.48 1.30

4.033.25 3.57

0.59

1.69

0.63

1.91 2.03

0.89

0.62

8.36

0.75

2.08

1.14

0.84

1.891.43

0.1

1


OR

wit

h 9

5% C

IO

R w

ith

95%

CI

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

100,000 vs. 50,000 Threshold 100,000 vs. 50,000 Threshold (preliminary)(preliminary)100,000 vs. 50,000 Threshold 100,000 vs. 50,000 Threshold (preliminary)(preliminary)

Abciximab Tirofiban Eptifibatide All trialsAbciximab Tirofiban Eptifibatide All trials 100K 50K 100K 50K 100K 50K 100K 50K100K 50K 100K 50K 100K 50K 100K 50K

Abciximab Tirofiban Eptifibatide All trialsAbciximab Tirofiban Eptifibatide All trials 100K 50K 100K 50K 100K 50K 100K 50K100K 50K 100K 50K 100K 50K 100K 50K

33

1.802.20

1.28 1.48 1.30

3.68

25.17

1.89 2.01 1.91 2.03

0.88

0.19

1.090.81

1.140.84

1.44

0.10

1.00

10.00Odds Ratioupper 95%lower 95%

1.802.20

1.28 1.48 1.30

3.68

25.17

1.89 2.01 1.91 2.03

0.88

0.19

1.090.81

1.140.84

1.44

0.10

1.00

10.00Odds Ratioupper 95%lower 95%

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

Required Heparin - 100K vs 50KRequired Heparin - 100K vs 50K (preliminary)(preliminary) Required Heparin - 100K vs 50KRequired Heparin - 100K vs 50K (preliminary)(preliminary) 25

Heparin notHeparin not Heparin requiredHeparin required All Trials All Trials requiredrequiredHeparin notHeparin not Heparin requiredHeparin required All Trials All Trials requiredrequired

34

1.50

0.83

1.491.25

1.46 1.51 1.48 1.30

4.00 3.60

2.16 2.37 2.15

2.97

1.91 2.03

0.56

0.19

1.03

0.65

0.990.77

1.14

0.84

0.1

1


1.50

0.83

1.491.25

1.46 1.51 1.48 1.30

4.00 3.60

2.16 2.37 2.15

2.97

1.91 2.03

0.56

0.19

1.03

0.65

0.990.77

1.14

0.84

0.1

1


OR

wit

h 9

5% C

IO

R w

ith

95%

CI

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

Patient Population - 100K vs 50KPatient Population - 100K vs 50KPatient Population - 100K vs 50KPatient Population - 100K vs 50K

Lytic trials Intervention Other* All trials

*Other includes acute and stable coronary syndromes

Lytic trials Intervention Other* All trials

*Other includes acute and stable coronary syndromes

35

1.12

0.73

1.52 1.42 1.48 1.30

2.70 2.571.99

2.281.91 2.03

0.47

0.21

1.160.88

1.140.84

0.10

1.00

10.00


1.12

0.73

1.52 1.42 1.48 1.30

2.70 2.571.99

2.281.91 2.03

0.47

0.21

1.160.88

1.140.84

0.10

1.00

10.00


OR

wit

h 9

5% C

IO

R w

ith

95%

CI

OR

wit

h 9

5% C

IO

R w

ith

95%

CI

Effect of Trial DesignEffect of Trial DesignEffect of Trial DesignEffect of Trial Design

Dose ranging Fixed-dose All trialsDose ranging Fixed-dose All trialsDose ranging Fixed-dose All trialsDose ranging Fixed-dose All trials

36

Is Thrombocytopenia Dose-related?Is Thrombocytopenia Dose-related?(Preliminary Results)(Preliminary Results)

Is Thrombocytopenia Dose-related?Is Thrombocytopenia Dose-related?(Preliminary Results)(Preliminary Results)

• 14 trials with 14 trials with >> 2 doses of IIb/IIIa inhibitor that 2 doses of IIb/IIIa inhibitor that reported plt by dosereported plt by dose

• Highest dose compared to lowest doseHighest dose compared to lowest dose

• High dose: 389 cases in 7737 pts (5.0%)High dose: 389 cases in 7737 pts (5.0%)

• Low dose: 215 cases in 4511 pts (4.8%)Low dose: 215 cases in 4511 pts (4.8%)

• 3 largest trials: More cases in low dose group3 largest trials: More cases in low dose group

• Metanalytic OR [high:low] = 0.73 (0.51, 1.04)Metanalytic OR [high:low] = 0.73 (0.51, 1.04)

• High-degree of heterogeneity of trialsHigh-degree of heterogeneity of trials

• 14 trials with 14 trials with >> 2 doses of IIb/IIIa inhibitor that 2 doses of IIb/IIIa inhibitor that reported plt by dosereported plt by dose

• Highest dose compared to lowest doseHighest dose compared to lowest dose

• High dose: 389 cases in 7737 pts (5.0%)High dose: 389 cases in 7737 pts (5.0%)

• Low dose: 215 cases in 4511 pts (4.8%)Low dose: 215 cases in 4511 pts (4.8%)

• 3 largest trials: More cases in low dose group3 largest trials: More cases in low dose group

• Metanalytic OR [high:low] = 0.73 (0.51, 1.04)Metanalytic OR [high:low] = 0.73 (0.51, 1.04)

• High-degree of heterogeneity of trialsHigh-degree of heterogeneity of trials

37

ReoPro Readministration Registry (RReoPro Readministration Registry (R33))(Tcheng JE, JACC ‘98;31(Suppl A):55A)(Tcheng JE, JACC ‘98;31(Suppl A):55A)

ReoPro Readministration Registry (RReoPro Readministration Registry (R33))(Tcheng JE, JACC ‘98;31(Suppl A):55A)(Tcheng JE, JACC ‘98;31(Suppl A):55A)

• 256 pts readministered Abciximab256 pts readministered Abciximab

• 27% developed human anti-chimeric 27% developed human anti-chimeric antibodies (HACA)antibodies (HACA)

• No anaphylaxis observedNo anaphylaxis observed

• Rate of thrombocytopenia is approx 3x in pts Rate of thrombocytopenia is approx 3x in pts that are HACA + (7.2% vs 2.3%, p =.06) that are HACA + (7.2% vs 2.3%, p =.06)

• 256 pts readministered Abciximab256 pts readministered Abciximab

• 27% developed human anti-chimeric 27% developed human anti-chimeric antibodies (HACA)antibodies (HACA)

• No anaphylaxis observedNo anaphylaxis observed

• Rate of thrombocytopenia is approx 3x in pts Rate of thrombocytopenia is approx 3x in pts that are HACA + (7.2% vs 2.3%, p =.06) that are HACA + (7.2% vs 2.3%, p =.06)

38

Complex Interaction with Complex Interaction with Heparin?Heparin?

(Kereiakes DJ, JACC 98;31(Suppl A):55A)(Kereiakes DJ, JACC 98;31(Suppl A):55A)

Complex Interaction with Complex Interaction with Heparin?Heparin?

(Kereiakes DJ, JACC 98;31(Suppl A):55A)(Kereiakes DJ, JACC 98;31(Suppl A):55A)

1.5%2.5%2.6%

5.2%5.6%

-8.4%

-11.7%-12.9%

-15%

-10%

-5%

0%

5%

10%

CaptureAb

EPIC Ab EpilogAb+SD

EpilogAb+LD

EpilogP+SD

% decrease plt count

% with plt ct < 100K

% Pts% Pts

% Drop% Drop

39

Multivariate Predictors of Multivariate Predictors of Plts in Abciximab Trials Plts in Abciximab Trials

Multivariate Predictors of Multivariate Predictors of Plts in Abciximab Trials Plts in Abciximab Trials

Age > 65Age > 65

Wt < 90 kgWt < 90 kg

Baseline plt count < 150KBaseline plt count < 150K

Use of AbciximabUse of Abciximab

--------------------------------------------------------------------------

In MVA, heparin dose had p = 0.19In MVA, heparin dose had p = 0.19

Age > 65Age > 65

Wt < 90 kgWt < 90 kg

Baseline plt count < 150KBaseline plt count < 150K

Use of AbciximabUse of Abciximab

--------------------------------------------------------------------------

In MVA, heparin dose had p = 0.19In MVA, heparin dose had p = 0.19

Kereiakes DJ, JACC 98;31(Suppl A):55AKereiakes DJ, JACC 98;31(Suppl A):55AKereiakes DJ, JACC 98;31(Suppl A):55AKereiakes DJ, JACC 98;31(Suppl A):55A

40

TIMI Treatment GuidelinesTIMI Treatment GuidelinesTIMI Treatment GuidelinesTIMI Treatment Guidelines• Acute (days 1-3) or delayed (days 4+)Acute (days 1-3) or delayed (days 4+)

• Platelet countPlatelet count– < 10,000< 10,000– 10,000 - 50,00010,000 - 50,000– > 50,000> 50,000

• Is there bleeding?Is there bleeding?– NoneNone– Minor to moderate (include mucosal bleeding)Minor to moderate (include mucosal bleeding)– SevereSevere

• Acute (days 1-3) or delayed (days 4+)Acute (days 1-3) or delayed (days 4+)

• Platelet countPlatelet count– < 10,000< 10,000– 10,000 - 50,00010,000 - 50,000– > 50,000> 50,000

• Is there bleeding?Is there bleeding?– NoneNone– Minor to moderate (include mucosal bleeding)Minor to moderate (include mucosal bleeding)– SevereSevere

41

Acute Thrombocytopenia Acute Thrombocytopenia (1)(1)Acute Thrombocytopenia Acute Thrombocytopenia (1)(1)

PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendationsAcute <10KAcute <10K No bleedingNo bleeding 1. Transfuse plts1. Transfuse plts

2. Reverse heparin2. Reverse heparin

Minor-modMinor-mod As aboveAs above

SevereSevere 1. Critical care1. Critical care2. Transfuse plts2. Transfuse plts3. Reverse heparin3. Reverse heparin4. Transfuse RBCs4. Transfuse RBCs

PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendationsAcute <10KAcute <10K No bleedingNo bleeding 1. Transfuse plts1. Transfuse plts

2. Reverse heparin2. Reverse heparin



42

Acute Thrombocytopenia Acute Thrombocytopenia (2)(2)Acute Thrombocytopenia Acute Thrombocytopenia (2)(2)PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendationsAcute 10-50KAcute 10-50K No bleedingNo bleeding 1. Careful obs.1. Careful obs.

2. Stop heparin2. Stop heparin3. Consider plt tx3. Consider plt tx

Minor-modMinor-mod 1. Transfuse plts1. Transfuse plts2. Reverse heparin2. Reverse heparin


PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendationsAcute 10-50KAcute 10-50K No bleedingNo bleeding 1. Careful obs.1. Careful obs.

2. Stop heparin2. Stop heparin3. Consider plt tx3. Consider plt tx

Minor-modMinor-mod 1. Transfuse plts1. Transfuse plts2. Reverse heparin2. Reverse heparin


43

Acute Thrombocytopenia Acute Thrombocytopenia (3)(3)Acute Thrombocytopenia Acute Thrombocytopenia (3)(3)

PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendationsAcute <50-100KAcute <50-100K Yes or noYes or no 1. Careful obs1. Careful obs

2. ?stop heparin2. ?stop heparin

PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendationsAcute <50-100KAcute <50-100K Yes or noYes or no 1. Careful obs1. Careful obs


44

Delayed Thrombocytopenia Delayed Thrombocytopenia (1)(1)Delayed Thrombocytopenia Delayed Thrombocytopenia (1)(1)PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendations<10,000<10,000 NoneNone 1. Transfuse plts1. Transfuse plts

2. Reverse heparin2. Reverse heparin3. Consider IV steroids 3. Consider IV steroids

and/or IgGand/or IgG


SevereSevere 1. Critical care1. Critical care2. Transfuse plts2. Transfuse plts3. Reverse heparin3. Reverse heparin4. Transfuse RBCs4. Transfuse RBCs5. IV steroids/IgG5. IV steroids/IgG

PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendations<10,000<10,000 NoneNone 1. Transfuse plts1. Transfuse plts

2. Reverse heparin2. Reverse heparin3. Consider IV steroids 3. Consider IV steroids



SevereSevere 1. Critical care1. Critical care2. Transfuse plts2. Transfuse plts3. Reverse heparin3. Reverse heparin4. Transfuse RBCs4. Transfuse RBCs5. IV steroids/IgG5. IV steroids/IgG

45

Delayed Thrombocytopenia Delayed Thrombocytopenia (2)(2)Delayed Thrombocytopenia Delayed Thrombocytopenia (2)(2)PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendations10,000-50,00010,000-50,000 No bleedingNo bleeding 1. Careful obs.1. Careful obs.

2. Stop heparin2. Stop heparin3. Consider plt tx3. Consider plt tx4. Consider IV steroids4. Consider IV steroids



SevereSevere 1. Critical care1. Critical care2. Transfuse plts2. Transfuse plts3. Reverse heparin3. Reverse heparin4. Transfuse RBCs4. Transfuse RBCs5. Give steroids/IgG5. Give steroids/IgG

PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendations10,000-50,00010,000-50,000 No bleedingNo bleeding 1. Careful obs.1. Careful obs.

2. Stop heparin2. Stop heparin3. Consider plt tx3. Consider plt tx4. Consider IV steroids4. Consider IV steroids



SevereSevere 1. Critical care1. Critical care2. Transfuse plts2. Transfuse plts3. Reverse heparin3. Reverse heparin4. Transfuse RBCs4. Transfuse RBCs5. Give steroids/IgG5. Give steroids/IgG

46

Delayed Thrombocytopenia Delayed Thrombocytopenia (3)(3)Delayed Thrombocytopenia Delayed Thrombocytopenia (3)(3)

PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendations50-100K50-100K Yes or noYes or no 1. Careful obs1. Careful obs


PlateletsPlatelets Bleeding?Bleeding? RecommendationsRecommendations50-100K50-100K Yes or noYes or no 1. Careful obs1. Careful obs


47

Life-threatening CasesLife-threatening CasesLife-threatening CasesLife-threatening Cases

If no response to above measures, consider:If no response to above measures, consider:– emergent hemodialysisemergent hemodialysis– plasmapheresisplasmapheresis

(neither of proven benefit)(neither of proven benefit)

If no response to above measures, consider:If no response to above measures, consider:– emergent hemodialysisemergent hemodialysis– plasmapheresisplasmapheresis

(neither of proven benefit)(neither of proven benefit)

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