1. How Have Clinical Trials Altered Treatment of Stroke Due to Sickle Cell Disease?
E. Steve Roach, M. D.
Robert & Edgar Wolfe Foundation
Chair in Child Neurology
Ohio State University College of Medicine
Nationwide Children’s Hospital
Columbus, Ohio

2. STROKE & SICKLE CELL DISEASE
No conflicts of interest
No off label clinical uses except in the context of research
This presentation is fully HIPPA compliant

3. TODAY’S CONSIDERATIONS
What is the stroke risk from SCD?
Mechanisms of stroke due to SCD?
Have clinical trials altered treatment?

4. Milestones in Sickle Cell Disease
African literature “ogbanjes” -“children who come and go”
James B. Herrick (1910) first published
- Intern Ernest Edward Irons ( )
- Chicago Presbyterian Hospital
- Walter C. Noel – Grenadian dental student
Vernon Mason (1922) coined “sickle cell anemia”
Linus Pauling (1949) - abnormal hemoglobin
– First genetic disease to specific protein
Robert Adams et al (1998) – publication of STOP trial
Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 6: , 1910

5. SICKLE CELL DISEASE Autosomal recessive trait
Gene: 11p.15.5 (Hgb Beta)
Mutation: A-to-T in sixth codon
Heterozygous: 1:10 African Americans
Homozygous: 1:400 African Americans
Carrier & prenatal detection possible

6. SICKLE CELL STROKE RISK
Medical center: 40%
Cohort studies: 5 -15%
Abnormal TCD: 10% /year
Based on MRI: 25-50%
After 1st stroke: > 65%

7. SCD: OVERLAPPING STROKE PHENOTYPES
Small vessel occlusion
Large vessel ischemic stroke
Watershed (“border zone”) infarction
Brain and subarachnoid hemorrhage
Roach, Lo, Heyer. Pediatric Stroke and Cerebrovascular Disorders, New York, 2011

8. Small Vessel Occlusion
Obstruction by sickled cells?
No increased stroke risk during crises
Most are asymptomatic (“silent”)
Cumulative effects?
Roach, Lo, Heyer. Pediatric Stroke and Cerebrovascular Disorders, New York, 2011

9. SCD: Large Vessel Occlusion
Progressive endothelial proliferation
Artery to artery embolism
Border zone (“watershed”) infarctions
Roach, Lo, Heyer. Pediatric Stroke and Cerebrovascular Disorders, New York, 2011

10. Hemorrhage & Hemorrhagic Infarction
Hemorrhage much less than infarction
SCD responsible for 4-5% of spontaneous brain hemorrhages (3 of 68 in one report)

11. SICKLE TRAIT & STROKE? Mostly case reports of SCT & stroke
Younger patients, no other risk factors
Consider the odds:
- If a city population is 1 million
- And 20% are African-American
- Then about 20K have SCT
Need better data

12. RISK FROM SICKLE TRAIT? Symptoms in high altitudes*
Death among US military recruits**
> All recruits: 0.7 /
> Black recruits: 1.0 per 100,000
> With SCT: 32.2 per 100,000
Stroke risk from SCT is still very low
*Lane et al. JAMA, 253:2251-4, 1985
**Kark et al. NEJM 317:781-7, 1987

13. Research: Challenges & Opportunities
Challenges for stroke research in children
Heterogeneous stroke pathophysiology
Stroke still relatively uncommon
Unique opportunities with SCD
SCD more common than other risk factors
Diagnosis (& thus risk) known in advance
Transfusions prevent recurrent stroke
Development of TCD

14. SCD: Transcranial Doppler
TCD & infarction risk
Time averaged mean velocity, not peak
10%/ year infarction risk if TAM >200cm/sec
Predicts large vessel
Adams et al. N Eng J Med, 326:605-10, 1992

15. Stroke Prevention Trial in Sickle Cell Anemia (“STOP”)
Age: 2-16 years
TCD TAM velocity > 200 cm/sec
TCD abnormal x 2
TCD confirmed by central interpreter
Standardized neurological exam
Periodic MRI and MRA
Transfusion versus standard care
Adams et al. N Eng J Med 1998, 339:5-11

16. STOP RESULTS 1934 children screened in 14 centers
2941 TCDs in 21 months
206 patients with 2 TCDs > 200 cm/sec
130 patients randomized
Transfusions
N =63
Standard care
N =67
11 strokes
1 stroke
Adams et al. N Eng J Med 1998, 339:5-11

17. STOP RESULTS Trial halted at interim analysis
All patients offered transfusion
# with stroke

18. TOO MUCH OF A GOOD THING: AN ELEMENTAL IRONY
Transfusions work!
Iron overload > Liver & heart failure
Chelation helps
Is it possible to lessen intensity of transfusions?
- Transfusion duration
- Transfusion frequency

19. STOP II: Duration of Transfusion
Re-randomization of STOP I patients
Continued transfusion or standard care
STOP II also halted
- 2 ischemic strokes with standard care
- 14 TCDs reverted to high risk
Adams et al. N Eng J Med 2005; 353:

20. STOP2: TRANSFUSION WITHDRAWAL Adams et al
STOP2: TRANSFUSION WITHDRAWAL Adams et al. N Eng J Med 2005; 353:
Children transfused > 30 months
With normal TCD x 2 (n=79)
Continued versus halt transfusions
No transfusions
(n =41)
Transfusions
(n =38)
2 strokes
14 Doppler conversions
0 Strokes
0 Doppler conversions

21. Stroke With Transfusions Changing to Hydroxyurea (SWITCH)
Transfusions & chelation
versus
Hydroxyurea & phlebotomy
Age 5-18 years
Documented stroke after age 1
> 8 months transfusions & iron overload
Non-inferiority trial

22. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH)
SCD, stroke, iron overload
Transfusions > 18 months (n = 133)
Also no improvement in iron toxicity in drug arm.
Ware et al. Blood. 119: , 2012
Transfusions
& chelation
Stroke in 0/66
Hydroxyurea &
Phlebotomy
Stroke in 7/67 (10%)

23. Silent Infarction Transfusion Trial (SITT)
MRI with one or more infarction
No clinical stroke or focal lesions
Transfusion vs no transfusion
Periodic transfusions lower risk of new infarctions (6% vs 14%)
DeBaun MR, et al. N Engl J Med 2014; 371:

24. Silent Infarct Transfusion Trial (SITT)
Recurrent headaches in 317 of 872 (36.4%)
132 of 872 (15.1%) met criteria for migraine
Multivariable logistic regression analysis:
- No association with silent infarction
- Lower steady state Hgb (p = < 0.001)
- More pain episodes (p = < 0.001)
Only 6/317 (1.9%) on headache prophylaxis
Dowling MM, et al. J. Pediatr 2014; 164:

25. AHSA Guidelines for SCD
Class I Recommendations
Optimize hydration, oxygenation & blood pressure
Periodic RBC transfusions for abnormal TCD
Periodic RBC transfusions after confirmed infarct
Reduce SS Hgb to < 30% before catheter angiogram
Roach et al. Stroke. 39: 2644, 2008

26. AHSA Guidelines for SCD
Class II Recommendations
Evaluate SCD for causes of hemorrhage
Annual TCD if normal; if abnormal, q 3-6 months
Hydroxyurea if transfusion not feasible
Revascularization for symptomatic large vessel stenosis
Roach et al. Stroke. 39: 2644, 2008

27. FEWER STROKES DUE TO SCD?
California:
= 0.88 strokes/100 person-years
1999 = strokes/100 person-years
2000 = 0.17 strokes/100 person-years
KIDS Analysis:
: 0.51/ 100 patient years
: 0.28/ 100 patient years (p = 0.008)
McCavit et al. Pediatr Blood Cancer 2013; 60:823

28. SCD: Future Directions
Altered RBC function or structure
- L-glutamine – lessen RBC deformity?
- MP4CO – sickling occurs at lower PaO2
- Zinc sulphate – minimizes RCB dehydration
Increase % fetal HgB
- Hydroxyurea
- Valproic acid?
Hematopoietic stem cell transplantation – works
Gene therapy – starting to see initial reports
Ribeil, et al. N Engl J Med, 2017; 376: