Stroke With Transfusions Changing to Hydroxyurea (SWiTCH)

Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload.     

Long-term results using hydroxyurea/phlebotomy for reducing secondary stroke risk in children with sickle cell anemia and iron overload

Children with sickle cell anemia (SCA) and a primary overt stroke are at high risk of recurrent (secondary) stroke. Chronic transfusion therapy dramatically reduces but does not eliminate this high risk, and inevitably results in transfusion-related hemosiderosis. We previously reported the use of hydroxyurea/phlebotomy as an alternative to transfusions to reduce the risk of secondary stroke and improve management of iron overload in 35 children with SCA. To report long-term results, we retrospectively reviewed clinical and laboratory data through October 2008. With a median of 5.6 years and total of 219 patient-years of follow-up, 10 of 35 patients (29%) had recurrent stroke after switching to hydroxyurea; seven were previously reported and three new strokes occurred during extended follow-up. The overall secondary stroke event rate was 4.6 per 100 patient-years. Children on hydroxyurea received serial phlebotomy and had lower mean serum ferritin values than children on transfusions (591 ng/mL vs. 3410 ng/mL, P = 0.02). In this cohort, long-term hydroxyurea treatment reduced but did not eliminate the risk of stroke recurrence and, uniquely, allowed phlebotomy to reduce iron overload. Long-term assessments of this therapy should evaluate risk factors for secondary stroke and assessments of hemosiderosis, neurocognitive outcome, and health-related quality of life.     

Children with sickle cell anemia with normal transcranial Doppler ultrasounds and without silent infarcts have a low incidence of new strokes

In a prospective cohort study, we tested the hypothesis that children with sickle cell anemia (SCA) with normal transcranial Doppler ultrasound (TCD) velocities and without silent cerebral infarcts (SCIs) would have a lower incidence rate of new neurological events (strokes, seizures or transient ischemic attacks) compared to children with normal TCD measurements and SCIs, not receiving regular blood transfusions. Nonrandomized participants from the silent cerebral infarct transfusion (SIT) Trial who had screening magnetic resonance imaging (MRI) of the brain and normal TCD measurements were included. Follow‐up ended at the time of first neurological event (stroke, seizure or transient ischemic attack), start of regular blood transfusion, or loss to follow‐up, whichever came first. The primary endpoint was a new neurological event. Of 421 participants included, 68 had suspected SCIs. Mean follow‐up was 3.6 years. Incidence rates of new neurological events in nontransfused participants with normal TCD values with SCIs and without SCIs were 1.71 and 0.47 neurological events per 100 patient‐years, respectively, P = .065. The absence of SCI(s) at baseline was associated with a decreased risk of a new neurological event (hazard ratio 0.231, 95% CI 0.062‐0.858; P = .029). Local pediatric neurologists examined 67 of 68 participants with suspected SCIs and identified 2 with overt strokes classified as SCIs by local hematologists; subsequently one had a seizure and the other an ischemic stroke. Children with SCA, without SCIs, and normal TCD measurements have a significantly lower rate of new neurological events when compared to those with SCIs and normal TCD measurements. Pediatric neurology assessment may assist risk stratification.     

Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease.

Children with sickle cell disease (SCD) and stroke receive chronic transfusions to prevent stroke recurrence. Transfusion risks including infection, erythrocyte allosensitization, and iron overload suggest a need for alternative therapies. We previously used hydroxyurea (HU) and phlebotomy in two young adults with SCD and stroke as an alternative to transfusions. We have now prospectively discontinued transfusions in 16 pediatric patients with SCD and stroke. Reasons to discontinue transfusions included erythrocyte alloantibodies or autoantibodies, recurrent stroke on transfusions, iron overload, noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d based on hematologic toxicity. Patients with iron overload underwent phlebotomy. The children have been off transfusions 22 months, (range, 3 to 52 months). Their average HU dose is 24.9 +/- 4.2 mg/kg/d, hemoglobin concentration is 9.4 +/- 1.3 g/dL, and mean corpuscular volume (MCV) is 112 +/- 9 fL. Maximum percentage fetal hemoglobin (%HbF) is 20.6% +/- 8.0% and percentage HbF-containing erythrocytes (%F cells) is 79.3% +/- 14.7%. Fourteen patients underwent phlebotomy with an average of 8,993 mL (267 mL/kg) removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4 children have normal ferritin values. Three patients (19%) had neurological events considered recurrent stroke, each 3 to 4 months after discontinuing transfusions, but before maximal HU effects. These preliminary data suggest some children with SCD and stroke may discontinue chronic transfusions and use HU therapy to prevent stroke recurrence. Phlebotomy is well-tolerated and significantly reduces iron overload. Modifications in HU therapy to raise HbF more rapidly might increase protection against stroke recurrence.     

Microarray analysis of liver gene expression in iron overloaded patients with sickle cell anemia and beta‐thalassemia

Chronic transfusion therapy is used clinically to supply healthy erythrocytes for patients with sickle cell anemia (SCA) or beta‐thalassemia major (TM). Despite the benefits of red blood cell transfusions, chronic transfusions lead to iron accumulation in key tissues such as the heart, liver, and endocrine glands. Transfusion‐acquired iron overload is recognized as a cause of morbidity and mortality among patients receiving chronic transfusions. At present, there is little understanding of molecular events that occur during transfusional iron loading and the reasons for the large inter‐individual variation observed clinically in transfusion‐acquired iron accumulation. To address these issues, we examined whether any liver‐expressed genes in SCA or TM patients with transfusional iron overload were associated with the degree of iron accumulation. Specifically, we performed microarray analysis on liver biopsy specimens comparing SCA patients with mild or severe iron overload and also compared SCA with TM patients. Fifteen candidate genes were identified with significantly differential expression between the high and low liver iron concentrations. SCA patients and 20 candidate genes were detected between the SCA and TM patient comparison. Subsequent quantitative PCR experiments validated 12 candidate genes; with GSTM1, eIF5a, SULF2, NTS, and HO‐1 being particularly good prospects as genes that might affect the degree of iron accumulation. Future work will determine the baseline expression of these genes prior to transfusional iron overload and elucidate the full impact of these genes on the inter‐individual variation observed clinically in transfusion‐acquired iron accumulation. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

Chronic transfusion practice for children with sickle cell anaemia and stroke

Chronic transfusions to maintain haemoglobin S (HbS) ≤30% are the mainstay of treatment for children with sickle cell anaemia (SCA) and previous stroke. This HbS target is often hard to maintain, however, and values achieved in current practice are unknown. In preparation for the Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, we collected data on 295 children with SCA and stroke who received transfusions at 23 institutions. The overall average pre-transfusion %HbS was 35 ± 11% (institutional range 22–51%). Receiving scheduled transfusions on time was the most predictive variable for maintaining HbS at the ≤30% goal.     

Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open‐label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r² = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin‐creatinine ratios. Extra‐hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.     

Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload

Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (?8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well‐tolerated, with net iron removal in most children who completed 30 months of protocol‐directed treatment.     

Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170–199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute‐funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ⁰‐thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7–9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention‐to‐treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0–35%) in the hydroxyurea arm and 47% (95% CI = 6–81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (?15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. Am. J. Hematol. 90:1099–1105, 2015. © 2015 Wiley Periodicals, Inc.     

To SWiTCH or not to SWiTCH?

In this issue of Blood, Ware and Helms report results from the Stroke With Transfusions Changing To Hydroxyurea (SWiTCH) study designed to determine whether hydroxyurea is as effective as transfusions in preventing recurrent strokes in children with sickle cell anemia. The finding of strokes in 7 of 67 children receiving hydroxyurea but none in 66 children who received transfusions led the authors to conclude that hydroxyurea is not effective in mitigating strokes.1     

Hydroxyurea effectiveness in children and adolescents with sickle cell anemia: A large retrospective,population‐based cohort

The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre‐post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sβ⁰thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009‐2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2‐year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009–2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (P = 0.0001) and 43% (P < 0.0001), respectively. Average hemoglobin levels increased by 0.7 g/dl (P < 0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Am. J. Hematol. 92:77–81, 2017. © 2016 Wiley Periodicals, Inc.     

Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial)

The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence‐based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non‐imaging TCD measurements (≥200 cm/s) received moderate fixed‐dose hydroxyurea therapy (～20 mg/kg/day). A comparison group of children with TCD measurements <200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient‐years, respectively (P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.     

Treating iron overload in patients with non‐transfusion‐dependent thalassemia

Despite receiving no or only occasional blood transfusions, patients with non‐transfusion‐dependent thalassemia (NTDT) have increased intestinal iron absorption and can accumulate iron to levels comparable with transfusion‐dependent patients. This iron accumulation occurs more slowly in NTDT patients compared to transfusion‐dependent thalassemia patients, and complications do not arise until later in life. It remains crucial for these patients' health to monitor and appropriately treat their iron burden. Based on recent data, including a randomized clinical trial on iron chelation in NTDT, a simple iron chelation treatment algorithm is presented to assist physicians with monitoring iron burden and initiating chelation therapy in this group of patients. Am. J. Hematol. 88:409–415, 2013. © 2013 Wiley Periodicals, Inc.     

Hydroxyurea (HU) for prevention of recurrent stroke in sickle cell anemia (SCA)

Cerebrovascular accident (CVA) is a major cause of morbidity and death in sickle cell anemia (SCA). Transfusion of packed erythrocytes is widely used to prevent this complication. However, chronic transfusion may lead to iron overload, alloimmunization, or infections. Cost and compliance may compromise transfusion therapy. A possible alternative, the prophylactic use of hydroxyurea (HU), has not been tried to determine whether it may prevent recurrent stroke. We used HU in five children with SCA who had suffered stroke, in three of them after a first episode and in the other two after a second CVA. Four had infarctive stroke and one a transient ischemic attack (TIA). Four patients took HU at a dose of 40 mg/kg/d, one patient at 30 mg/kg/d. None of the patients had recurrent stroke during 42-112 months of observation. None experienced pain crises. In all, HbF increased significantly and was maintained above 14.7% during treatment. The total Hb concentration increased 19.5 g/L (median) above the value before treatment. HU was well tolerated. None of the five children had leukopenia or thrombocytopenia during therapy. HU appears to prevent recurrence of stroke in SCA without risk of major toxicity.     

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub‐Saharan Africa

Despite its well‐described safety and efficacy in the treatment of sickle cell anemia (SCA) in high‐income settings, hydroxyurea remains largely unavailable in sub‐Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open‐label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub‐Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30‐month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso‐occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α‐thalassemia (58.4% with at least a single α‐globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR β‐globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high‐quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa.     

Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion‐dependent thalassemia: A randomized controlled trial

Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion‐dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ≤6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to “early start deferiprone” (.ES‐DFP) at a low dose (50 mg/kg/day) or to “delay chelation” (DC), and remained in the study until their serum ferritin (SF) level reached ≥1000 μg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 µg/L and TSAT > 70% compared with none in the ES‐DFP group. LPI level > 0.6 µM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 µg/L was delayed by 6 months in the ES‐DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES‐DFP group.     

Feasibility and efficacy of chronic transfusion for stroke prevention in children with sickle cell disease

Objectives: In children with sickle cell disease (SCD), chronic transfusion to maintain haemoglobin S (HbS) below 30% markedly decreases both the risk of a first stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow velocities and the risk of recurrent stroke. Maintaining HbS below 30% may be difficult, especially in countries where blood donors and recipients belong to different ethnic groups and where the availability of closely matched blood products is limited. We assessed the feasibility and efficacy of chronic transfusion with an HbS target of 30% in children with SCD living in the Paris area. Methods: We retrospectively studied 29 children aged 6.8 ± 3.0 yr (3–15 yr) at inclusion who received chronic transfusion either because of abnormal TCD findings (primary prevention group, PPG, n = 17) or because of a previous cerebrovascular event (secondary prevention group, SPG, n = 12 including nine with a history of stroke and three of transient ischaemic attacks). Results: Mean follow‐up was 3.5 ± 3.0 yr (0.5–12 yr). No cases of stroke occurred in the PPG. In the SPG, one patient with a history of stroke and severe cerebrovascular disease had a recurrence after 11 yr of chronic transfusion, when the HbS level was 20%. The stroke recurrence rate (SPG group) was 1.6/100 patient‐years. Mean HbS levels before and after transfusion were 30 ± 10% and 20.6 ± 7%, respectively. Two patients acquired red‐cell alloantibodies. Of the 29 patients, 22 required iron chelation. Conclusions: Regular transfusion maintaining HbS below 30% is feasible and safe in children with SCD in France and protects from overt stroke.     

The effect of iron chelation therapy on overall survival in sickle cell disease and β‐thalassemia: A systematic review

Red blood cell transfusions have become standard of care for the prevention of life‐threatening anemia in patients with β‐thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event‐free survival in patients with β‐thalassemia and SCD. Eighteen articles discussing survival in β‐thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second‐generation oral agents, appears to be associated with improved overall and event‐free survival in transfusion‐dependent patients with β‐thalassemia and patients with SCD.     

How I manage sickle cell patients with high transcranial doppler results

Stroke is one of the most severe complications to affect children with sickle cell anaemia (SCA). Transcranial doppler (TCD) is an accurate and non‐invasive method to determine stroke risk. Randomised controlled trials have demonstrated the efficacy of chronic transfusion therapy in stroke prevention based on risk stratification determined by TCD velocities. This has led to the regular use of TCD monitoring for children with SCA in order to determine stroke risk. Significant resource allocation is necessary to facilitate training, quality assurance and failsafe arrangements for non‐attenders. In a subgroup of patients, chronic transfusions for primary stroke prevention can be replaced by hydroxycarbamide therapy, provided careful monitoring is undertaken; including repeat TCD studies at frequent intervals. The authors propose an evidence‐based algorithm for the management of abnormal TCD velocities and discuss the role of this test in other clinical contexts, such as in Haemoglobin SC disease.     

Outcome of overt stroke in sickle cell anaemia,a single institution's experience

Stroke is a traumatic complication in sickle cell anaemia (SCA) that is associated with significant morbidity and a risk of recurrent overt stroke of 2·2–6·4 events per 100 patient‐years. A retrospective study was performed on all paediatric SCA patients diagnosed with a history of overt stroke between 1997 and 2010. A total of 31 children with SCA had new onset overt stroke. The mean age of the active patients (n = 27) was 17·9 years (range 6·8–27·6 years) with a total period of observation of 305 patient‐years. Twenty‐two of 27 (81%) were receiving long term red blood cell transfusions and 16 (59%) were taking the anti‐platelet agent, aspirin, since diagnosis of the stroke. Two of 27 (7%) patients had a second overt stroke with an overall risk of recurrent stroke of 0·66/100 patient‐years (one stroke was ischaemic and the other haemorrhagic). In patients taking aspirin with 180 patient‐years of follow up, the recurrence rate of haemorrhagic stroke was 0·58/100 patient‐years. We have an excellent outcome for overt stroke in paediatric SCA patients with a low rate of recurrent stroke. Further studies are needed to determine the risk‐benefit ratio of aspirin therapy in the prevention of recurrent stroke in paediatric SCA.