stroke in sickle cell disease– - anpain children with sickle cell anemia: stop 2 trial design time...

Stroke in Sickle Cell Disease–some good news, some bad newsStroke in Sickle Cell Disease–some good news, some bad news

Robert J Adams MS MDProfessor of NeuroscienceUniversity Eminent Scholar

Director South Carolina Center of Economic Excellence

Director MUSC Stroke Center

Robert J Adams MS MDProfessor of NeuroscienceUniversity Eminent Scholar

Director South Carolina Center of Economic Excellence

Director MUSC Stroke Center

Brain Matters in Adults with SCD Brain Matters in Adults with SCD

* Goals of Neurological Intervention

• Brain Protection: Free of stroke (motor, sensory and behavioral syndromes due to vascular occlusion or rupture)

• Vascular Protection: Free of vascular damage (e.g. moyamoya, aneurysms) leading to late failure causing stroke or death

• Protection of Cognitive Brain Function: Free from disabling executive, memory, language, visual-perceptiive or social interaction deficits

• Ultimately reaching the “Ronald Reagan Endpoint”

* Goals of Neurological Intervention

• Brain Protection: Free of stroke (motor, sensory and behavioral syndromes due to vascular occlusion or rupture)

• Vascular Protection: Free of vascular damage (e.g. moyamoya, aneurysms) leading to late failure causing stroke or death

• Protection of Cognitive Brain Function: Free from disabling executive, memory, language, visual-perceptiive or social interaction deficits

• Ultimately reaching the “Ronald Reagan Endpoint”

The “Ronald Reagan Endpoint”The “Ronald Reagan Endpoint”

• Use of Doppler ultrasound to measure blood flow velocity rested on two observations1) Cerebral blood flow and flow velocity increase

with anemia2) Flow velocity increases as arterial diameter

decreases (Bernoulli effect)

• Use of Doppler ultrasound to measure blood flow velocity rested on two observations1) Cerebral blood flow and flow velocity increase

with anemia2) Flow velocity increases as arterial diameter

decreases (Bernoulli effect)

Big Strokes in Small PersonsBig Strokes in Small Persons

Use of TCD in Sickle Cell DiseaseUse of TCD in Sickle Cell Disease

• Changed the landscape of stroke in SCD– Dramatically reduced first stroke in children– Reduced hospitalizations for stroke in SCD kids– Cut the disparity in death from ischemic stroke

between black and white children by 74% – Increased the number of children on transfusion – Made the problem of stroke in SCD adults worse

• Changed the landscape of stroke in SCD– Dramatically reduced first stroke in children– Reduced hospitalizations for stroke in SCD kids– Cut the disparity in death from ischemic stroke

between black and white children by 74% – Increased the number of children on transfusion – Made the problem of stroke in SCD adults worse

Stroke in Sickle Cell DiseaseStroke in Sickle Cell Disease

• Large artery ischemic stroke in children and adults

• Small vessel disease also in both• Hemorrhages due to various forms of

cerebrovascular disease• Cognitive problems in adults not adequately

explained by the MRI appearance of brain

• Large artery ischemic stroke in children and adults

• Small vessel disease also in both• Hemorrhages due to various forms of

cerebrovascular disease• Cognitive problems in adults not adequately

explained by the MRI appearance of brain


• Key points:– Children with SS disease should be screened with

Transcranial Doppler from early age till 18– This is now standard of care in several countries– Regular blood transfusion for high risk TCD has

dropped the stroke rate in children markedly– No established role for any other treatment as yet

to prevent stroke

• Key points:– Children with SS disease should be screened with

Transcranial Doppler from early age till 18– This is now standard of care in several countries– Regular blood transfusion for high risk TCD has

dropped the stroke rate in children markedly– No established role for any other treatment as yet

to prevent stroke


• Key points: there is no such proven strategy for adults with sickle cell disease

• Rates of stroke are increasing as survival improves and these persons come into traditional risk factors such as hypertension

• Best advice is to lower the risk factors and use prophylactic aspirin (unproven in SS disease

• Key points: there is no such proven strategy for adults with sickle cell disease

• Rates of stroke are increasing as survival improves and these persons come into traditional risk factors such as hypertension

• Best advice is to lower the risk factors and use prophylactic aspirin (unproven in SS disease

Narrowed (arrow) vs NormalNarrowed (arrow) vs Normal

• the MCG TCD Risk Model*– study of 315 children studied with TCD before

onset of symptoms – age 3-18 years at first TCD– mean follow up 64 + 23 months– 17 developed stroke– stroke increased with velocity ( p<0.001)

* NEJM 1992

• the MCG TCD Risk Model*– study of 315 children studied with TCD before

onset of symptoms – age 3-18 years at first TCD– mean follow up 64 + 23 months– 17 developed stroke– stroke increased with velocity ( p<0.001)

* NEJM 1992


Time (months)

Prob

abili

ty o

f Rem

aini

ng S

trok

e-Fr

ee

0 5 10 15 20 25 30 35 400.5

0.6

0.7

0.8

0.9

1.0

< 170 cm/s170-199 cm/s> 200 cm/s

KM of time to stroke as function of TCD

• 1994 NHLBI funded STOP– first randomized controlled trial (RCT) of

regular transfusion in SCD– first RCT based on TCD– first RCT for stroke prevention in children

• 1994 NHLBI funded STOP– first randomized controlled trial (RCT) of

regular transfusion in SCD– first RCT based on TCD– first RCT for stroke prevention in children


S T O P :S T O P :S t ro k e P re v e n tio n T rial in S ic k le C e ll A n e m iaS t ro k e P re v e n tio n T rial in S ic k le C e ll A n e m ia

S c r e en C h i ld re nA g e 2- 1 6 W /T C D

S c r e e n C h i ld re nS c r e e n C h i ld re nA g e 2 -1 6 W / T C DA g e 2 -1 6 W / T C D

R e c ru i t/R a n d o m i ze A f te r 2 T C D ’s 2 0 0 C m / S e cR e c ru i t/ R a n d o m ize A fte r 2 R e c ru i t/ R a n d o m ize A fte r 2 T C D ’s T C D ’s 2 0 0 C m /S e c 2 0 0 C m /S e c

P e r io d i c T ra n s f u s i o nto H b S 3 0 %

P e r i o d ic T ra n s f u s io n P e r i o d ic T ra n s f u s io nto to H b SH b S 3 0 % 3 0 %

N o rm a l C a re (I n c lu d e s O c c a s i o n a l T ra n s f u s io n )N o rm a l C a re (In c lu d e s N o rm a l C a re (In c lu d e s

O c c a s io n a l T ra n s f u s i o n )O c c a s io n a l T ra n s f u s i o n )

Stroke Prevention Trial in Sickle Cell Anemia: STOP Trial DesignStroke Prevention Trial in Sickle Cell Anemia: STOP Trial Design

STOP Trial ResultsSTOP Trial Results

STOP IISTOP II

• Acceptance of STOP strategy limited by concerns about the indefinite duration of transfusion and need for chelation

• Purpose of STOP II was to determine if a substantial fraction of children could be safely removed from transfusion after 30 or more months

• Thereby optimizing use of transfusion to children with a continued need for treatment

• Acceptance of STOP strategy limited by concerns about the indefinite duration of transfusion and need for chelation

• Purpose of STOP II was to determine if a substantial fraction of children could be safely removed from transfusion after 30 or more months

• Thereby optimizing use of transfusion to children with a continued need for treatment

Optimizing Primary Stroke Preventionin Children With Sickle Cell Anemia:STOP 2 Trial Design

Optimizing Primary Stroke Preventionin Children With Sickle Cell Anemia:STOP 2 Trial Design

Time (In Months) Since Last Pre-Randomization Transfusion

Pro

babi

lity

of R

emai

ning

Eve

nt F

ree

0 5 10 15 20 25 30 35 40 45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

KM Of Event Risk

Treatment Arm 1Treatment Arm 2

p-value=0.0000091

KM time to Endpoint KM time to Endpoint

STOP 2 Trial ResultsSTOP 2 Trial Results

Summary of STOP andSTOP 2 TrialsSummary of STOP andSTOP 2 Trials


• After STOP II another approach was needed• SWITCH was a randomized controlled trial of

Hydroxyurea (HU) vs transfusion in children with SCD on transfusion for prior stroke

• HU had been shown to reduce pain crises in adults with SCD by raising fetal hemoglobin while reducing Hb S

• After STOP II another approach was needed• SWITCH was a randomized controlled trial of

Hydroxyurea (HU) vs transfusion in children with SCD on transfusion for prior stroke

• HU had been shown to reduce pain crises in adults with SCD by raising fetal hemoglobin while reducing Hb S

SWITCH: K-M stroke SWITCH: K-M stroke


• SWITCH halted by DSMB in 2010 when liver iron endpoint was not sufficiently better to balance the stroke risk in HU arm (10% on HU vs 0% with continuation of transfusion)

• TCD was used at baseline for correlation to MRA but otherwise played no role in SWITCH

• SWITCH halted by DSMB in 2010 when liver iron endpoint was not sufficiently better to balance the stroke risk in HU arm (10% on HU vs 0% with continuation of transfusion)

• TCD was used at baseline for correlation to MRA but otherwise played no role in SWITCH

TWITCHTWITCH

– After SWITCH comes TWITCH– Phase 3 study similar to SWITCH except that only

patients on transfusion for high TCD (primary prevention) are being enrolled

– Children with severe vasculopathy are being excluded by MRA in this trial

– Second Phase 3 RCT (after STOP II) to use TCD as the primary endpoint

– After SWITCH comes TWITCH– Phase 3 study similar to SWITCH except that only

patients on transfusion for high TCD (primary prevention) are being enrolled

– Children with severe vasculopathy are being excluded by MRA in this trial

– Second Phase 3 RCT (after STOP II) to use TCD as the primary endpoint

TWITCH DesignTWITCH Design

• Alternative treatment (hydroxyurea) non-inferior to the standard if the hydroxyurea-treated group has a mean TCD velocity similar to that observed with transfusion prophylaxis (margin of 15 cm/sec TAMM) after 24 months

• Alternative treatment (hydroxyurea) non-inferior to the standard if the hydroxyurea-treated group has a mean TCD velocity similar to that observed with transfusion prophylaxis (margin of 15 cm/sec TAMM) after 24 months

Impact of STOPImpact of STOP

• Fullerton et al examined temporal trends in first stroke in California before and after STOP reported in 1998

• Rates declined markedly in 1999 and 2000 (.17 and .50/100 person years) compared to 91-98 rate of .88 (p< .005 for trend)– Blood 2004 Jul 2004;104:336-339

• Fullerton et al examined temporal trends in first stroke in California before and after STOP reported in 1998

• Rates declined markedly in 1999 and 2000 (.17 and .50/100 person years) compared to 91-98 rate of .88 (p< .005 for trend)– Blood 2004 Jul 2004;104:336-339

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Year

Firs

t-str

oke

inci

denc

e(p

er 1

00 p

erso

n-ye

ars)

0

50

100

150

200

250

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Year

Oth

er S

CD

adm

issi

ons

per 1

00 p

erso

n-ye

ars


• Reduction in stroke in children has now been documented in two Phase 4 studies


Pre-TCD Post-TCDNumber 475 530

Person-years of follow-up 3,137 3,578

Overt stroke 21 2

- Ischemic 19 2

- Hemorrhagic 2 0

Other neuro event 3 6

Indeterminate 2 1Incidence rate - overt stroke (per

100 pt yr) 0.67 0.06*

* p value < 0.001

Incidence of Stroke

St Jude’s ExperienceSt Jude’s Experience



• Reduction in impact of stroke in children with SCD is being documented in national data sets specifically the National Inpatient Sample (hospitalized patients) and the National Center for Health Statistics (death)


• Reduction in impact of stroke in children with SCD is being documented in national data sets specifically the National Inpatient Sample (hospitalized patients) and the National Center for Health Statistics (death)


Ovbiagele and Adams (2011) examined data from hospitalized stroke –National Inpatient Sample—between 1997 and 2006 looking at time trends related to stroke and sickle cell disease

Ovbiagele and Adams (2011) examined data from hospitalized stroke –National Inpatient Sample—between 1997 and 2006 looking at time trends related to stroke and sickle cell disease

Brain Matters in Adults with SCDBrain Matters in Adults with SCD

• Pediatric strokes with co morbid SCD represented 8.7% of the 1997 sample but only 4.8% in 2006 (p=0.04)

• Adults stroke patients with SCD were 0.3% in 1997 vs .5% in 2006 (p-0.01)

• Pediatric drop was in the fraction with ischemic stroke (72% vs 56%) and was likely due to widening application of STOP protocol use

• Pediatric strokes with co morbid SCD represented 8.7% of the 1997 sample but only 4.8% in 2006 (p=0.04)

• Adults stroke patients with SCD were 0.3% in 1997 vs .5% in 2006 (p-0.01)

• Pediatric drop was in the fraction with ischemic stroke (72% vs 56%) and was likely due to widening application of STOP protocol use


• Strouse et al examined data from California hospital discharges 1997-2007

• Estimated rates of stroke using SCD prevalence estimates from birth and adjustment for early mortality

• Rates in children and young adults (18-34) were similar

• Strouse et al examined data from California hospital discharges 1997-2007

• Estimated rates of stroke using SCD prevalence estimates from birth and adjustment for early mortality

• Rates in children and young adults (18-34) were similar


• But rates in older adults were much higher• Stroke was associated with hypertension in

children but with hypertension, DM, hyperlipidemia, atrial fib, and renal disease in adults with Sickle Cell Disease

• As predicted, aging with SCD is associated with very high stroke rates due to intersection of SCD with other risk factors

• But rates in older adults were much higher• Stroke was associated with hypertension in

children but with hypertension, DM, hyperlipidemia, atrial fib, and renal disease in adults with Sickle Cell Disease

• As predicted, aging with SCD is associated with very high stroke rates due to intersection of SCD with other risk factors

George et al 2011George et al 2011


• Most of you are physicians to adults– Dilemma: is adult SCD vascular disease the older

version of what we see in children or should it be approached as “stroke in the young adult”?

– Recommend that a full workup be undertaken for other causes of ischemic stroke or hemorrhage

• Homocysteine• Lipids• Dissections and so on…

• Most of you are physicians to adults– Dilemma: is adult SCD vascular disease the older

version of what we see in children or should it be approached as “stroke in the young adult”?

– Recommend that a full workup be undertaken for other causes of ischemic stroke or hemorrhage

• Homocysteine• Lipids• Dissections and so on…


• Critical need for more information and a strategy to help preserve brain

• Strategy in children has evolved from brain protection to include “vascular” protection to avoid moyamoya and late stage vascular disease

• Most tertiary centers do not have well organized care pathways for adults with SCD

• Critical need for more information and a strategy to help preserve brain

• Strategy in children has evolved from brain protection to include “vascular” protection to avoid moyamoya and late stage vascular disease

• Most tertiary centers do not have well organized care pathways for adults with SCD


Point # 5.• Important brain issues exist across the

spectrum of adults with SCD• Even “neurologically intact” adults will not

score on tests as well as their peers without SCD and will have more “silent” brain lesions

Point # 5.• Important brain issues exist across the

spectrum of adults with SCD• Even “neurologically intact” adults will not

score on tests as well as their peers without SCD and will have more “silent” brain lesions


• Hb SC—less severe anemia, probably a small increase in stroke risk; also retinal problems

• Hb AS--- not clearly linked with stroke but in the news due to sudden death in athletes and military trainees

• S beta 0 thal---probably as severe as SS and we included them in the STOP trials

• Hb SC—less severe anemia, probably a small increase in stroke risk; also retinal problems

• Hb AS--- not clearly linked with stroke but in the news due to sudden death in athletes and military trainees

• S beta 0 thal---probably as severe as SS and we included them in the STOP trials

Thank-youThank-you

Medical University of South Carolina

stroke in sickle cell disease– - anpain children with sickle cell anemia: stop 2 trial design time...

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