hemorrhagic stroke in hemorrhagic stroke asian patients · page 1 neurocritical care program uc sf...

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

ICH

SAH

ICH ICH -- EtiologiesEtiologies

•• PrimaryPrimary–– hypertensionhypertension (~70%)(~70%)–– vascular malformationvascular malformation

»» AVMAVM»» aneurysm aneurysm

–– amyloid angiopathyamyloid angiopathy–– coagulopathycoagulopathy–– sympathomimetic drugssympathomimetic drugs–– vasculitisvasculitis–– MoyaMoya--MoyaMoya

•• SecondarySecondary–– into infarctinto infarct

»» arterialarterial»» venousvenous

–– into tumorinto tumor

ICH ICH -- ManagementManagement

•• 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)

GCSGCS 0.69 (0.580.69 (0.58--0.82)0.82) <0.001<0.001

Age (Age (>> 80 y)80 y) 9.55 (2.409.55 (2.40--38.07)38.07) 0.0010.001

ICH VolumeICH Volume 1.40 (1.061.40 (1.06--1.84)1.84) 0.0170.017

Infratentorial only (n=30)Infratentorial only (n=30)

GCSGCS 0.64 (0.460.64 (0.46--0.88)0.88) 0.0070.007

IVHIVH 10.52 (0.8410.52 (0.84--131.19)131.19) 0.0670.067

All ICH Patients (n=152)All ICH Patients (n=152)

GCSGCS 0.69 (0.590.69 (0.59--0.80)0.80) <0.001<0.001

Age (Age (>> 80 y)80 y) 9.84 (2.589.84 (2.58--37.47)37.47) 0.0010.001

Infratentorial OriginInfratentorial Origin 4.24 (1.154.24 (1.15--15.65)15.65) 0.0300.030

IVHIVH 2.97 (0.992.97 (0.99--8.92)8.92) 0.0520.052

ICH VolumeICH Volume 1.31 (1.001.31 (1.00--1.71)1.71) 0.0470.047

Odds ratio is expressed per point on the GCS score and per 10 cc of ICH Volume

Hemphill, Stroke 2001

ICH VolumeICH Volume

A x B x C2

Select CT slice with largest ICHA = longest axis (cm)B = longest axis perpendicular to A (cm)C = # of slices x slice thickness (cm)

Estimated volume of spheroidCorrelates well w/ planimetric CT analysis

Kothari et al. Stroke 27:1304-1305, 1996

Issues in Acute ICH TreatmentIssues in Acute ICH Treatment

•• Surgical hematoma evacuationSurgical hematoma evacuation

•• Preventing hematoma enlargementPreventing hematoma enlargement–– Hemostatic agents (recombinant factor VIIa)Hemostatic agents (recombinant factor VIIa)

•• CoagulopathyCoagulopathy--related ICHrelated ICH

•• Blood Pressure ManagementBlood Pressure Management

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

AliveAlive 304 (64%)304 (64%) 316 (63%)316 (63%)

DeadDead 173 (36%)173 (36%) 189 (37%)189 (37%)

Primary OutcomePrimary Outcome(“Prognosis based” (“Prognosis based” functional outcome)functional outcome)

Early SurgeryEarly Surgery Initial Conservative txInitial Conservative tx

FavourableFavourable 112 (26%)112 (26%) 118 (24%)118 (24%)

UnfavourableUnfavourable 346 (74%)346 (74%) 351 (76%)351 (76%)

P=0.71

P=0.41

• 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

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

Initial CT 2’ 45” later

Images Courtesy of Jonathan Rosand, MD

NovoSeven ICH Trial

F7ICH-1371 Trial design:Multi-center, randomized, double-blind, parallel group, placebo-controlled trial

N = 400 patients randomized

Baseline CT scan

Placebo N = 100

rFVIIa 40 µg/kgN = 100



EfficacyPercent Change in ICH volume at 24 hours

Clinical outcome•Mortality•mRS• Barthel Index • E-GOS • NIHSS • GCS• Euro-QOL

24 hours 90 days≤60 mins<3 hours

CTs performed CTs performed atat baseline, 24 and 72 hours

Safety• Adverse events until discharge

• Serious adverse events until day 90

Mayer SA, NEJM 2005 NovoSeven ICH Trial

Conclusions

� Significantly reduces hematoma growth in a dose-dependent fashion� Reduces mortality and significantly

improves global functional outcome(mRS and BI) at 90 days� Is associated with a small increase in

the risk of acute thromboembolic events (2% v. 7%)

� rFVIIa for acute ICH

Mayer SA, NEJM 2005

FAST TrialFAST Trial

•• Phase III Trial of rFVIIa in acute ICHPhase III Trial of rFVIIa in acute ICH

•• FAST trial under way globally since May 2005; FAST trial under way globally since May 2005; completed in November 2006completed in November 2006

–– >120 global sites; ~70 US sites; > 10% of patients >120 global sites; ~70 US sites; > 10% of patients enrolled in Chinaenrolled in China

–– 841 patients randomized; 821 patients dosed841 patients randomized; 821 patients dosed

•• 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

Hematoma Growth Hematoma Growth at 24 hrsat 24 hrs PlaceboPlacebo 20 20 µµg/kgg/kg 80 80 µµg/kgg/kg PP

Mean % changeMean % change 26%26% 18%18% 11%11%0.0004 0.0004

(80 (80 µµg/kgg/kg vs vs placebo)placebo)

Absolute Absolute differencedifference 7.8 7.8 ++ 18.718.7 4.7 4.7 ++ 14.814.8 3.8 3.8 ++ 15.315.3

0.009 0.009 (20 (20 µµg/kgg/kg vs vs

placebo)placebo)


FAST: Primary ResultsFAST: Primary Results

•• Clinical outcome not affected by treatmentClinical outcome not affected by treatment–– Different than phase IIb studyDifferent than phase IIb study

Clinical Outcome Clinical Outcome at 90 daysat 90 days PlaceboPlacebo 20 20 µµg/kgg/kg 80 80 µµg/kgg/kg PP

Modified Rankin Modified Rankin Score Score >> 55 24%24% 26%26% 29%29% NSNS

MortalityMortality 19%19% 18%18% 21%21% NSNS


WarfarinWarfarin--related hemorrhagerelated hemorrhage

•• 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

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

•• INTERACT INTERACT –– Australia/NZ, China, probably USAustralia/NZ, China, probably US–– Randomized openRandomized open--label studylabel study–– Entry criteria Entry criteria

»» ≥ 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

Aneurysmal Subarachnoid Aneurysmal Subarachnoid HemorrhageHemorrhage

•• Risk factors for Risk factors for aneurysms/SAHaneurysms/SAH

–– FemaleFemale–– SmokingSmoking–– HypertensionHypertension–– EtOH consumption?EtOH consumption?

Figure 2: Neurologic Complications after SAH

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days

Hydrocephalus

Rebleeding

Vasospasm

Hyponatremia

Aneurysmal Subarachnoid HemorrhageAneurysmal Subarachnoid Hemorrhage Aneurysm TreatmentAneurysm Treatment

Aneurysm TreatmentAneurysm Treatment

•• “Preventive medicine”“Preventive medicine”•• Allows aggressive treatment for vasospasmAllows aggressive treatment for vasospasm

•• OptionsOptions–– “Clipping versus coiling”“Clipping versus coiling”–– ISAT ISAT –– International Subarachnoid Aneurysm TrialInternational Subarachnoid Aneurysm Trial

»» LancetLancet, 2002, 2002»» 2143 patients2143 patients»» OneOne--year dead/dependentyear dead/dependent

•• ClippingClipping 30.6%30.6%•• CoilingCoiling 23.7% (p=0.0019)23.7% (p=0.0019) 36 yo woman with L carotid-ophthalmic artery aneury sm, SAH, & vasospasm

SAH D8 Mild fluctuating right hemiparesis, no a phasia, on maximal HTN therapy

VasospasmVasospasm

VasospasmVasospasm

•• Classical ApproachesClassical Approaches–– NimodipineNimodipine-- prevents sequelae but not angiographic prevents sequelae but not angiographic

vasospasmvasospasm–– “triple“triple--H” therapyH” therapy * *

(hypertension, hypervolemia, hemodilution)(hypertension, hypervolemia, hemodilution)

•• New ApproachesNew Approaches–– AngioplastyAngioplasty–– Statins Statins –– decrease inflammatory response? Clinical trialsdecrease inflammatory response? Clinical trials–– Endothelin receptor antagonists Endothelin receptor antagonists –– clinical trialsclinical trials

*Kassell et al, Neurosurgery 11: 337-343, 1982.

Angioplasty for VasospasmAngioplasty for Vasospasm

Pre Post

Hemorrhagic StrokeHemorrhagic Stroke

•• Is hemorrhagic stroke different across Is hemorrhagic stroke different across different race/ethnicities?different race/ethnicities?

–– Incidence?Incidence?–– Etiology?Etiology?–– Outcome?Outcome?–– ICH or SAH or both?ICH or SAH or both?

Annual Incidence of First ICH (by Age, Sex, Race)

Adapted with permission from Kissela B, et al. Stroke. 2004;35:426-431.

Greater Cincinnati/Northern Kentucky Stroke Study: 1993-1994

0

0.5

1

1.5

2

2.5

0-34 35-44 45-54 55-64 65-74 75-84 ≥85

Age (years)

Per

100

0

White menWhite womenBlack menBlack women

Usually presented as evidence of health-care disparities and

generally attributed to access to health care and differential treatment of hypertension

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)

–– 128,934 persons 128,934 persons –– selfself--classified ethnicityclassified ethnicity»» 60% white, 27% black60% white, 27% black»» 5% Chinese, 1% Japanese, 0.5% Filipino, 0.5% South Asian, 0.7% 5% Chinese, 1% Japanese, 0.5% Filipino, 0.5% South Asian, 0.7%

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

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

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)

–– Asians 4.06 (2.47Asians 4.06 (2.47--6.65)6.65)–– Hispanics 2.06 (1.31Hispanics 2.06 (1.31--3.24)3.24)–– Blacks 2.04 (1.25Blacks 2.04 (1.25--3.35)3.35)

•• INR INR >> 3.5 at time of ICH in 32% of Asians 3.5 at time of ICH in 32% of Asians (c/w 11% of whites) (c/w 11% of whites)

Warfarin for Atrial FibrillationWarfarin for Atrial Fibrillation

•• Pooled analysis of 5 primary stroke trialsPooled analysis of 5 primary stroke trials–– Stroke rate (annual)Stroke rate (annual)

»» NonNon--warfarin warfarin 4.5%4.5%»» Warfarin Warfarin 1.4%1.4%

–– 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

•• Genotypes determine warfarin dose needsGenotypes determine warfarin dose needs–– Cytochrome P450 isoform Cytochrome P450 isoform CYP2CPCYP2CP–– Vitamin K epoxide reductase subunit 1 Vitamin K epoxide reductase subunit 1 VKORC1VKORC1

•• 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%

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

factorsfactors–– HypertensionHypertension–– AnticoagulationAnticoagulation

•• Reasonable approachReasonable approach–– Avoid fatalism Avoid fatalism –– treat risk factors aggressively!!treat risk factors aggressively!!–– WellWell--designed studies that account fordesigned studies that account for

»» Genetics v. selfGenetics v. self--descriptiondescription»» Include diverse cohortInclude diverse cohort

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