Page 1 NEUROCRITICAL CARE PROGRAM UC SF Hemorrhagic Stroke in Hemorrhagic Stroke in Asian Patients Asian Patients J. Claude Hemphill III, MD, MAS J. Claude Hemphill III, MD, MAS Associate Professor of Clinical Neurology and Associate Professor of Clinical Neurology and Neurological Surgery Neurological Surgery University of California, San Francisco University of California, San Francisco Director, Neurocritical Care Director, Neurocritical Care San Francisco General Hospital San Francisco General Hospital Selected slides courtesy of: Dr. David Mendelow, PI-STICH Dr. Stephan Mayer, PI-rVIIA phase IIa ICH study Disclosures Research Support: NIH/NINDS, Novo Nordisk Consulting: Astra Zeneca, Novo Nordisk, Innercool Therapies, Medivance Stock options: Cardium Therapeutics (Innercool Therapies) Hemorrhagic Stroke Hemorrhagic Stroke • General issues in General issues in – Etiology Etiology – Prevention Prevention – Treatment Treatment – Outcome Outcome • “Asian specific” issues “Asian specific” issues – Related to risk factors or something more? Related to risk factors or something more? – Etiology/prevention Etiology/prevention – Management/outcome Management/outcome Frequency of Stroke by Etiologic Subtype Frequency of Stroke by Etiologic Subtype Ischemic Hemorrhagic 84% 16% Thrombotic Embolic 53% 31% 10% 6% Intracerebral Subarachnoid Hemorrhagic Stroke Hemorrhagic Stroke – High Burden of Disease High Burden of Disease • High morbidity and mortality High morbidity and mortality – 35 35-52% 30 52% 30-day mortality day mortality – 20% of ICH patients independent at 6 mo 20% of ICH patients independent at 6 mo • 34% of years of potential life lost to stroke 34% of years of potential life lost to stroke • Lifetime cost per case ~ $124,000 Lifetime cost per case ~ $124,000 • Total lifetime cost for annual US cases >$4B Total lifetime cost for annual US cases >$4B Johnston et al. Neurology 50:1413-1418, 1998 Taylor et al. Stroke 26:1459-1466, 1996 • 5-10% of all strokes 10% of all strokes • Incidence: 6 Incidence: 6-16 per 100,000/ year 16 per 100,000/ year • Aggregate costs of $5 billion/ year Aggregate costs of $5 billion/ year • One One-third of potential years of life lost third of potential years of life lost before age 65 due to stroke before age 65 due to stroke ICH SAH
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NEUROCRITICAL CARE PROGRAM
UCSF
Hemorrhagic Stroke in Hemorrhagic Stroke in Asian PatientsAsian Patients
J. Claude Hemphill III, MD, MASJ. Claude Hemphill III, MD, MAS
Associate Professor of Clinical Neurology and Associate Professor of Clinical Neurology and Neurological SurgeryNeurological Surgery
University of California, San FranciscoUniversity of California, San FranciscoDirector, Neurocritical CareDirector, Neurocritical Care
San Francisco General HospitalSan Francisco General Hospital
Selected slides courtesy of:Dr. David Mendelow, PI-STICHDr. Stephan Mayer, PI-rVIIA phase IIa ICH study
Disclosures Research Support: NIH/NINDS, Novo NordiskConsulting: Astra Zeneca, Novo Nordisk, Innercool Therapies, MedivanceStock options: Cardium Therapeutics (Innercool Therapies)
Hemorrhagic StrokeHemorrhagic Stroke
•• General issues inGeneral issues in–– EtiologyEtiology–– PreventionPrevention–– TreatmentTreatment–– OutcomeOutcome
•• “Asian specific” issues“Asian specific” issues–– Related to risk factors or something more?Related to risk factors or something more?–– Etiology/preventionEtiology/prevention–– Management/outcomeManagement/outcome
Frequency of Stroke by Etiologic SubtypeFrequency of Stroke by Etiologic Subtype
Ischemic
Hemorrhagic
84%
16%
Thrombotic
Embolic
53%
31%
10%6%
Intracerebral
Subarachnoid
Hemorrhagic Stroke Hemorrhagic Stroke –– High Burden of DiseaseHigh Burden of Disease
•• High morbidity and mortalityHigh morbidity and mortality–– 3535--52% 3052% 30--day mortalityday mortality–– 20% of ICH patients independent at 6 mo20% of ICH patients independent at 6 mo
•• 34% of years of potential life lost to stroke34% of years of potential life lost to stroke•• Lifetime cost per case ~ $124,000Lifetime cost per case ~ $124,000•• Total lifetime cost for annual US cases >$4BTotal lifetime cost for annual US cases >$4B
Johnston et al. Neurology 50:1413-1418, 1998Taylor et al. Stroke 26:1459-1466, 1996
•• 55--10% of all strokes10% of all strokes•• Incidence: 6Incidence: 6--16 per 100,000/ year16 per 100,000/ year•• Aggregate costs of $5 billion/ yearAggregate costs of $5 billion/ year•• OneOne--third of potential years of life lost third of potential years of life lost
before age 65 due to strokebefore age 65 due to stroke
•• EvidencedEvidenced--based vs. “In My Experience”based vs. “In My Experience”•• No approved treatment (medical or surgical) No approved treatment (medical or surgical)
proven beneficial in improving outcome proven beneficial in improving outcome (mortality or function) in randomized, (mortality or function) in randomized, controlled trialcontrolled trial
•• Guidelines for the Management of Guidelines for the Management of Spontaneous Intracerebral Hemorrhage Spontaneous Intracerebral Hemorrhage –– AHA Stroke Council, 2007 (revised)AHA Stroke Council, 2007 (revised)
•• Primary and Secondary Brain InjuryPrimary and Secondary Brain Injury
ICH ICH –– Outcome PredictorsOutcome Predictors
Patient CharacteristicPatient Characteristic Odds Ratio (95% CI)Odds Ratio (95% CI) PP ValueValue
Supratentorial only (n=122)Supratentorial only (n=122)
Surgical Trial for ICH (STICH)Surgical Trial for ICH (STICH)
•• Completed in 2003Completed in 2003•• Largest study of surgery in ICH (>1000 pts)Largest study of surgery in ICH (>1000 pts)•• Does a policy of “Early Surgery” improve Does a policy of “Early Surgery” improve
outcome in patients with spontaneous outcome in patients with spontaneous supratentorial ICH compared with a policy of supratentorial ICH compared with a policy of “Initial Conservative Treatment”?“Initial Conservative Treatment”?–– Randomisation within 72 hours of ictusRandomisation within 72 hours of ictus–– Surgery within 24 hours of randomisationSurgery within 24 hours of randomisation–– Selection based on “uncertainty principle”Selection based on “uncertainty principle”
Mendelow Lancet , 2005
STICH Randomisation by Country
Argent inaAustralia
Aus triaBelgium
ChinaCzech Republic
GermanyGreece
HungaryIndiaI taly
JapanLatv ia
LithuaniaMacedonia
MalaysiaNetherlands
PolandRussia
SingaporeSouth Af rica
SpainSwedenTurkey
UKUkraine
USA
No. Patients
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
STICH STICH -- ResultsResults
MortalityMortality Early SurgeryEarly Surgery Initial Conservative txInitial Conservative tx
• No Difference•• 26% of patients randomised to Initial Conservative Treatment 26% of patients randomised to Initial Conservative Treatment
later had surgerylater had surgery•• Early surgery is not harmfulEarly surgery is not harmful•• There is no evidence favoring early surgery in supr atentorial ICHThere is no evidence favoring early surgery in supr atentorial ICH
Mendelow Lancet , 2005
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Hematoma Expansion in ICHHematoma Expansion in ICH
•• Previously suggested as Previously suggested as –– rarerare–– suggestive of underlying AVM, coagulopathysuggestive of underlying AVM, coagulopathy
•• Studies of early serial CT show as commonStudies of early serial CT show as common–– Fujii (1994) Fujii (1994) -- 60 of 419 pts (14%)60 of 419 pts (14%)–– Kazui (1996) Kazui (1996) –– 20% w/ enlargement by 13 cc or 40%20% w/ enlargement by 13 cc or 40%–– Brott (1997) Brott (1997) –– 38% of 103 pts in first 20 hours38% of 103 pts in first 20 hours
Fujii et al. J Neurosurg 80:51, 1994Kazui et al. Stroke 27:1783, 1996Brott et al. Stroke 28:1, 1997
Hematoma Expansion in ICHHematoma Expansion in ICH
•• Largest ICH medical trial ever conductedLargest ICH medical trial ever conducted•• Protocol similar to phase IIb trialProtocol similar to phase IIb trial•• rFVIIa 80 rFVIIa 80 µgµg/kg vs 20 /kg vs 20 µgµg/kg vs placebo/kg vs placebo
Mayer SA. Presented at the American Academy of Neurology 59th Annual Meeting; April 28-May 5, 2007; Boston, Massachusetts.
FAST: Primary ResultsFAST: Primary Results
•• Dramatic effect on reducing hematoma expansionDramatic effect on reducing hematoma expansion–– similar to phase IIb studysimilar to phase IIb study
•• 64 yo woman with atrial 64 yo woman with atrial fibrillation, fibrillation, hypertensionhypertension
–– On warfarin, INR 4.5On warfarin, INR 4.5
Initial CT 10 hours later
•• FFP ordered stat, FFP ordered stat, thawed and infusion thawed and infusion initiated, INR rechecked initiated, INR rechecked periodicallyperiodically
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Reversal of AnticoagulationReversal of Anticoagulation
•• Principle Principle –– any ICH in patient on warfarin (with IN R > 1.4) any ICH in patient on warfarin (with INR > 1.4) should be considered “lifeshould be considered “life--threatening”threatening”
•• Goal Goal –– normal INR ASAPnormal INR ASAP
•• Guidelines from US, UK, Australasia recommendGuidelines from US, UK, Australasia recommend–– Prothrombin complex concentrate (PCC)Prothrombin complex concentrate (PCC)–– Vitamin K (1 mg IV or 10 mg SQ)Vitamin K (1 mg IV or 10 mg SQ)–– Fresh frozen plasmaFresh frozen plasma
•• Less hematoma growth with PCC, with no difference w ith Less hematoma growth with PCC, with no difference w ith FFP if INR corrected w/in 2 hours (Huttner, FFP if INR corrected w/in 2 hours (Huttner, StrokeStroke 2006)2006)
•• However, PCC underutilized However, PCC underutilized –– lack of availabilitylack of availability•• Reports of recombinant factor VIIa usageReports of recombinant factor VIIa usage
Ansell et al. Managing oral anticoagulation. Chest 2001;119:22S-38SHanley. Warfarin reversal. J Clin Pathol 2004;57:1132-1139Baker et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian
Society of Thrombosis and Haemostasis. Med J Aust 2004;181-492-497
Ansell et al. Managing oral anticoagulation. Chest 2001;119:22S-38SHanley. Warfarin reversal. J Clin Pathol 2004;57:1132-1139Baker et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian
Society of Thrombosis and Haemostasis. Med J Aust 2004;181-492-497
BP in ICH BP in ICH -- Expert ConsensusExpert Consensus
•• Guidelines for the Management of Guidelines for the Management of Spontaneous Intracerebral Hemorrhage Spontaneous Intracerebral Hemorrhage –– AHA Stroke Council, 1999AHA Stroke Council, 1999
•• Blood PressureBlood Pressure–– Maintain MAP < 130 mm Hg (~180/110), Maintain MAP < 130 mm Hg (~180/110),
in patients with a h/o hypertensionin patients with a h/o hypertension–– CPP > 70 mmHg (if ICP monitoring done)CPP > 70 mmHg (if ICP monitoring done)–– MAP < 100 mmHg postMAP < 100 mmHg post--op (if surgical evacuation)op (if surgical evacuation)–– Keep SBP > 90 mmHgKeep SBP > 90 mmHg
Arbitrary expert opinion based on balancing concern sof rehemorrhage and perihematoma ischemia
BP Lowering Trials in ICHBP Lowering Trials in ICH
»» ≥ 2 SBP measurements ( ≥150 to ≤ 200 mm Hg) ≥ 2 SBP measurements ( ≥150 to ≤ 200 mm Hg) »» BPBP--lowering regimen < 6 h of onset lowering regimen < 6 h of onset
–– BP Rx goals BP Rx goals –– SBP < 180 v. SBP < 140SBP < 180 v. SBP < 140
–– Primary outcomePrimary outcome»» Mortality and mRS (> 2) at 3m Mortality and mRS (> 2) at 3m
–– 2º outcome2º outcome»» Neurological deterioration ≤ 72hNeurological deterioration ≤ 72h»» Hematoma expansion at 24h and 72hHematoma expansion at 24h and 72h
•• ATACH ATACH -- NIHNIH–– PI PI –– Adnan QureshiAdnan Qureshi–– “Dose“Dose--escalation” study of feasibility of achieving 3 successive BP escalation” study of feasibility of achieving 3 succ essive BP
goals for 24 hours after acute ICHgoals for 24 hours after acute ICH–– Safety evaluation by decline in GCS of 2 points or NIHSS of 4 pointsSafety evaluation by decline in GCS of 2 points or NIHSS of 4 points–– Total Total –– 60 patients60 patients
Usually presented as evidence of health-care disparities and
generally attributed to access to health care and differential treatment of hypertension
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Cerebrovascular Disease in AsiaCerebrovascular Disease in Asia
•• ChinaChina–– Stroke is more common cause of death than CADStroke is more common cause of death than CAD–– 1990 (death rate / 100,000 1990 (death rate / 100,000 –– males only)males only)
»» MIMI StrokeStroke»» ChinaChina 22.722.7 126.4126.4»» USUS 106.8106.8 46.846.8
–– Hemorrhagic stroke (principally ICH) accounts for ~ 30% of Hemorrhagic stroke (principally ICH) accounts for ~ 30% of strokesstrokes
•• JapanJapan–– Higher incidence of aneurysmal SAHHigher incidence of aneurysmal SAH
•• IndiaIndia–– single center registry, ~50% of hospital admitted s troke single center registry, ~50% of hospital admitted s troke
patients had ICH (Banerjee, J Indian Med Assoc. 200 5) patients had ICH (Banerjee, J Indian Med Assoc. 200 5)
Is this an “Asian Effect?”Is this an “Asian Effect?”
•• Klatsky et al. Risk of Hemorrhagic Stroke in Asian American Ethnic Klatsky et al. Risk of Hemorrhagic Stroke in Asian American Ethnic Groups. Groups. Neuroepidemiology Neuroepidemiology 2005 (Kaiser Permanente, Oakland)2005 (Kaiser Permanente, Oakland)
other Asian, 2.2% Mixed/Otherother Asian, 2.2% Mixed/Other–– 431 with ICH (69%) or SAH (31%)431 with ICH (69%) or SAH (31%)
•• Compared to whitesCompared to whites–– Increased relative risk (1.6) of hemorrhagic stroke in AsiansIncreased relative risk (1.6) of hemorrhagic stroke in Asians–– Due to increased Due to increased
»» SAH risk in Japanese (RR=3.9) and SAH risk in Japanese (RR=3.9) and »» ICH risk in Filipinos (RR=2.6)ICH risk in Filipinos (RR=2.6)
–– Adjusted for age, smoking, BPAdjusted for age, smoking, BP
Asians in America?Asians in America?
Fang et al. Cardiovascular Mortality of Chinese in New York City. J of Urban Health. March 1999
Asians in America?Asians in America?
Fang et al. Cardiovascular Mortality of Chinese in New York City. J of Urban Health. March 1999
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Defining Race/EthnicityDefining Race/Ethnicity
Ayala C et al. Racial/ethnic disparities in mortali ty by stroke subtype in the United States, 1995-1998
Definitions per US CensusRace – White, Black, American Indian, APIEthnicity – Hispanic or non-Hispanic
Defining Race/EthnicityDefining Race/Ethnicity
Ayala C et al. Racial/ethnic disparities in mortali ty by stroke subtype in the United States, 1995-1998
Definitions per US CensusRace – White, Black, American Indian, APIEthnicity – Hispanic or non-Hispanic
Does this help with understanding• Minority access to health care in US?• Genetic predisposition to disease?• Neither?• Does it Matter?
No Increased Risk in Hispanics?No Increased Risk in Hispanics?
•• Stroke subtype comparison between RMH (Buenos Stroke subtype comparison between RMH (Buenos Aires, Argentina) and BIMC (Boston)Aires, Argentina) and BIMC (Boston)
•• Hypertension present in 75% (RMH) and 65% (BIMC)Hypertension present in 75% (RMH) and 65% (BIMC)Saposnik. Stroke 2000
Genetic Predisposition to ICHGenetic Predisposition to ICH
•• Factor XIII AFactor XIII A--subunit gene (FXIII Val34Leu) is subunit gene (FXIII Val34Leu) is risk factor for primary ICHrisk factor for primary ICH
•• FXIII Val34Leu present inFXIII Val34Leu present in–– ~50% of Westerners~50% of Westerners–– 2.5% of Asians2.5% of Asians
•• Cho, Cho, J Korean Med SciJ Korean Med Sci 20022002–– CaseCase--control (58/48) studycontrol (58/48) study–– No mutations found No mutations found --> thus, no association w/ ICH> thus, no association w/ ICH
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Genetics and AneurysmsGenetics and Aneurysms
•• Multiple gene loci implicatedMultiple gene loci implicated–– Chromosome 19q13.3 as susceptibility locusChromosome 19q13.3 as susceptibility locus
•• High incidence in JapaneseHigh incidence in Japanese–– ~2~2--3% with cerebral aneurysms3% with cerebral aneurysms
•• Dutch MRI screening study (Dutch MRI screening study ( NEJMNEJM 2007)2007)–– 1.8% with incidental cerebral aneurysms1.8% with incidental cerebral aneurysms
MoyamoyaMoyamoya
•• Obliterative arteropathy Obliterative arteropathy with b/l distal intracranial with b/l distal intracranial ICA occlusions or highICA occlusions or high--grade stenosesgrade stenoses
•• Usually diagnosed Usually diagnosed angiographically (“vague or angiographically (“vague or hazy puff of smoke”)hazy puff of smoke”)
•• More common in AsiansMore common in Asians
•• NonNon--inflammatory with inflammatory with intimal thickening and intimal thickening and smooth muscle smooth muscle proliferationproliferation
RICALICA
LICA lenticulostriate “puff of smoke”
What About Risk Factors?What About Risk Factors?
•• 31% prevalence of hypertension (BP > 140/90)31% prevalence of hypertension (BP > 140/90)•• Risk ratio no different for stroke among Chinese th an Risk ratio no different for stroke among Chinese th an
Framingham & Honolulu for Framingham & Honolulu for cholesterolcholesterol , , smokingsmoking , , obesityobesity ..
•• Attributable risk for hypertension much higher than in Attributable risk for hypertension much higher than in whiteswhites
–– Ischemic stroke 31% v. 25%Ischemic stroke 31% v. 25%–– Hemorrhagic stroke 42% v. 34%Hemorrhagic stroke 42% v. 34%
•• Conclusion Conclusion –– hypertension is a greater risk factor for hypertension is a greater risk factor for stroke in Asians than whitesstroke in Asians than whites
–– Interaction between genetics and risk factor?Interaction between genetics and risk factor?
WarfarinWarfarin--related ICHrelated ICH
•• Shen et al. Racial/Ethnic differences in the Shen et al. Racial/Ethnic differences in the risk of intracranial hemorrhage among risk of intracranial hemorrhage among patients with atrial fibrillation. patients with atrial fibrillation. J Am Coll J Am Coll CardiolCardiol 2007.2007.
•• Kaiser NorCal cohortKaiser NorCal cohort•• 173 ICH events over 3.3 years173 ICH events over 3.3 years•• Hazard ratio for ICH (c/w whites)Hazard ratio for ICH (c/w whites)
–– 68% risk reduction with warfarin68% risk reduction with warfarin–– Absolute increase in major bleeding of 0.3%/yearAbsolute increase in major bleeding of 0.3%/year
•• Shen et al. Shen et al. –– Kaiser studyKaiser study–– Annual ICH rate for AsiansAnnual ICH rate for Asians
»» Not on warfarin Not on warfarin 0.12%0.12%»» On warfarinOn warfarin 1.75%1.75%
•• Bottom line Bottom line –– potential potential ↑ risk of ICH in Asians more ↑ risk of ICH in Asians more than offset by benefit of warfarinthan offset by benefit of warfarin
•• Attention to level of anticoagulation is extremely Attention to level of anticoagulation is extremely important important
Genetics of Warfarin DosingGenetics of Warfarin Dosing
•• CoumaCouma--Gen study (Gen study ( CirculationCirculation 2007)2007)–– Randomized trial of dosing based on genotypeRandomized trial of dosing based on genotype–– 206 subjects (95% white)206 subjects (95% white)–– No difference in “within range” INRsNo difference in “within range” INRs–– Proof of principleProof of principle
Study ChallengesStudy Challenges
•• Case ascertainment and quality of databases in larg e Case ascertainment and quality of databases in larg e countries with rural populationscountries with rural populations
•• Bias related to hospitalized patientsBias related to hospitalized patients
•• Definitions of race/ethnicityDefinitions of race/ethnicity–– Purpose driven v. science drivenPurpose driven v. science driven
•• Changing risk factors with immigrationChanging risk factors with immigration–– AcculturationAcculturation–– Changes in dietChanges in diet
•• Homogeneity of cohorts (White, Chinese, etc.)Homogeneity of cohorts (White, Chinese, etc.)
UCSF ICH CohortUCSF ICH Cohort
UCSF ICH Cohort (n=243)
American Indian or Alaskan Native 0.80%
Asian 44%
Black or African American 17.70%
Native Hawaiian or Pacific Islander 3.70%
White 33.70%
Hispanic (ethnicity) 5.80%
San Francisco CensusSan Francisco Census
American Indian and Alaska Native 0.4%
Asian 30.8%
Black or African American 7.8%
Native Hawaiian and Other Pacific Islander 0.5%
White persons 49.7%
Persons reporting some other race 6.5%
Persons reporting two or more races 4.3%
Persons of Hispanic or Latino origin 14.1%
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SummarySummary--Hemorrhagic Stroke in AsiansHemorrhagic Stroke in Asians
•• Stroke is a major cardiovascular issue in Asian pat ientsStroke is a major cardiovascular issue in Asian pat ients–– Hemorrhagic stroke accounts for a larger proportion of Hemorrhagic stroke accounts for a larger proportion of
strokesstrokes•• Primary genetic component is possible but unclear a t Primary genetic component is possible but unclear a t
presentpresent•• May have increased susceptibility to May have increased susceptibility to modifiablemodifiable risk risk