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

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

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

Milestones in Sickle Cell Disease African literature “ogbanjes” -“children who come and go” James B. Herrick (1910) first published - Intern Ernest Edward Irons (1877-1959) - 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: 517-521, 1910

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

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

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

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

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

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

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

RISK FROM SICKLE TRAIT? Symptoms in high altitudes* Death among US military recruits** > All recruits: 0.7 /100 000 > 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

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

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

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

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

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

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

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; 353:2769-2778

STOP2: TRANSFUSION WITHDRAWAL Adams et al STOP2: TRANSFUSION WITHDRAWAL Adams et al. N Eng J Med 2005; 353:2769-2778 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

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

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. 119:3925-32, 2012 Transfusions & chelation Stroke in 0/66 Hydroxyurea & Phlebotomy Stroke in 7/67 (10%)

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; 371:699-710

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: 1175-1180

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

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

FEWER STROKES DUE TO SCD? California: 1991-1998 = 0.88 strokes/100 person-years 1999 = 0.05 strokes/100 person-years 2000 = 0.17 strokes/100 person-years KIDS Analysis: 1993-1998: 0.51/ 100 patient years 1999-2009: 0.28/ 100 patient years (p = 0.008) McCavit et al. Pediatr Blood Cancer 2013; 60:823

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; 376:848-855