Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease

  • Review
  • Intervention

Authors


Abstract

Background

In sickle cell disease, a common inherited haemoglobin disorder, abnormal haemoglobin distorts red blood cells, causing anaemia, vaso-occlusion and dysfunction in most body organs. Without intervention, stroke affects around 10% of children with sickle cell anaemia (HbSS) and recurrence is likely. Chronic blood transfusion dilutes the sickled red blood cells, reducing the risk of vaso-occlusion and stroke. However, side effects can be severe.

Objectives

To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease to prevent first stroke or recurrences.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings.

Date of the latest search of the Group's Haemoglobinopathies Trials Register: 28 January 2013.

Selection criteria

Randomised and quasi-randomised controlled trials comparing blood transfusion as prophylaxis for stroke in people with sickle cell disease to alternative or no treatment.

Data collection and analysis

Both authors independently assessed the risk of bias of the included trials and extracted data.

Main results

Searches identified three eligible randomised trials (n = 342). The first two trials addressed the use of chronic transfusion to prevent primary stroke; the third utilized the drug hydroxycarbamide (hydroxyurea) and phlebotomy to prevent both recurrent (secondary) stroke and iron overload in patients who had already experienced an initial stroke. In the first trial (STOP) a chronic transfusion regimen for maintaining sickle haemoglobin lower than 30% was compared with standard care in 130 children with sickle cell disease judged (through transcranial Doppler ultrasonography) as high-risk for first stroke. During the trial, 11 children in the standard care group suffered a stroke compared to one in the transfusion group, odds ratio 0.08 (95% confidence interval 0.01 to 0.66). This meant the trial was terminated early. The transfusion group had a high complications rate, including iron overload, alloimmunisation, and transfusion reactions. The second trial (STOP II) investigated risk of stroke when transfusion was stopped after at least 30 months in this population. The trial closed early due to a significant difference in risk of stroke between participants who stopped transfusion and those who continued as measured by reoccurrence of abnormal velocities on Doppler examination or the occurrence of overt stroke in the group that stopped transfusion. The third trial (SWiTCH) was a non-inferiority trial comparing transfusion and iron chelation (standard management) with hydroxyurea and phlebotomy (alternative treatment) with the combination endpoint of prevention of stroke recurrence and reduction of iron overload. This trial was stopped early after enrolment and follow up of 133 children because of analysis showing futility in reaching the composite primary endpoint. The stroke rate (seven strokes on hydroxyurea and phlebotomy, none on transfusion and chelation, odds ratio 16.49 (95% confidence interval 0.92 to 294.84)) was within the non-inferiority margin, but the liver iron content was not better in the alternative arm.

Authors' conclusions

The STOP trial demonstrated a significantly reduced risk of stroke in participants with abnormal transcranial Doppler ultrasonography velocities receiving regular blood transfusions. The follow-up trial (STOP 2) indicated that individuals may revert to former risk status if transfusion is discontinued. The degree of risk must be balanced against the burden of chronic transfusions. The combination of hydroxyurea and phlebotomy is not as effective as "standard" transfusion and chelation in preventing secondary stroke and iron overload. Ongoing multicentre trials are investigating the use of chronic transfusion to prevent silent infarcts, the use of hydroxyurea as an alternative to transfusion in children with abnormal transcranial Doppler ultrasonography velocities, and the use of hydroxyurea to prevent conversion of transcranial Doppler ultrasonography velocities from conditional (borderline) to abnormal values.

Résumé scientifique

Transfusion sanguine pour la prévention de l'AVC primaire et secondaire chez les patients atteints de drépanocytose

Contexte

Lors de drépanocytose, un trouble héréditaire d'hémoglobine courant, l'hémoglobine anormale déforme les globules rouges, entraînant une anémie, une vaso-occlusion et un dysfonctionnement dans la plupart des organes du corps. Sans intervention, un AVC touche environ 10% des enfants atteints d'anémie falciforme (HbSS) et la rechute est probable. La transfusion sanguine chronique dilue les globules rouges drépanocytaires, réduisant le risque de vaso-occlusion et d’AVC. Cependant, les effets secondaires peuvent être graves.

Objectifs

Évaluer les risques et les bénéfices des traitements par transfusions sanguines chronique chez les patients atteints de drépanocytose pour prévenir un premier AVC ou des rechutes.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais cliniques du groupe Cochrane sur la mucoviscidose et les autres maladies génétiques, comprenant des références identifiées par des recherches exhaustives dans des bases de données électroniques et des recherches manuelles de revues pertinentes et d’actes de conférence.

Date de la dernière recherche dans le registre des essais du groupe Cochrane sur les hémoglobinopathies : 28 janvier 2013.

Critères de sélection

Essais contrôlés randomisés et quasi-randomisés comparant la transfusion sanguine en prophylaxie pour traiter l'AVC chez les patients atteints de drépanocytose à d'autres alternatives ou à l'absence de traitement.

Recueil et analyse des données

Deux auteurs ont évalué les risques de biais des essais inclus et extrait les données de manière indépendante.

Résultats principaux

Les recherches ont identifié trois essais randomisés éligibles (n =342). Les deux premiers essais portaient sur l'utilisation de la transfusion sanguine pour prévenir l'AVC primaire; la troisième utilisait le médicament hydroxycarbamide (hydroxyurée) et la phlébotomie pour prévenir la rechute de l’AVC (secondaire) et la surcharge ferrique chez les patients qui avaient déjà subi un AVC. Dans le premier essai (STOP), un traitement de transfusion sanguine chronique pour maintenir l'hémoglobine falciforme inférieure à 30% a été comparé aux soins standards chez 130 enfants atteints de drépanocytose et jugés être à haut risque de premier AVC (au moyen de l'échographie transcrânienne Doppler). Durant l'essai, 11 enfants dans le groupe de soins standard ont subi un AVC par rapport à un dans le groupe de la transfusion, rapport des cotes de 0,08 (intervalle de confiance à 95% de 0,01 à 0,66). L'essai a donc été interrompu prématurément. Le groupe de la transfusion avait un taux élevé de complications, notamment une surcharge ferrique, une allo-immunisation et des réactions transfusionnelles. Le deuxième essai (STOP II) portait sur le risque d'AVC de cette population lors de l’arrêt de la transfusion après au moins 30 mois. L'essai a été arrêté prématurément en raison d'une différence significative en termes de risque d'AVC entre les participants ayant arrêté la transfusion et ceux qui continuaient, comme la réapparition de vélocité anormale mesurée par l'examen Doppler ou la survenue d’un AVC dans le groupe ayant arrêté la transfusion sanguine. Le troisième essai (SWiTCH) était un essai de non-infériorité comparant la transfusion et la chélation ferrique (prise en charge standard) avec l'hydroxyurée et la phlébotomie (traitement alternatif), avec comme critère de jugement, la prévention de la rechute d'AVC et la réduction de la surcharge ferrique. Cet essai a été arrêté prématurément après le recrutement et le suivi de 133 enfants en raison d'analyses montrant une futilité à atteindre le principal critère de jugement. Le taux d'AVC (sept AVC sur l'hydroxyurée et la phlébotomie, aucun sur la transfusion et la chélation, rapport des cotes 16,49 (intervalle de confiance à 95% de 0,92 à 294,84)) se situait dans les marges de non-infériorité, mais la concentration hépatique en fer n'était pas plus efficace dans le traitement alternatif.

Conclusions des auteurs

L’essai STOP a démontré une réduction significative du risque d'AVC chez les patients atteints de vélocités anormales, dépistés par l'échographie transcrânienne Doppler et recevant des transfusions régulières. L’essai suivant (STOP 2) indiquait que les patients pouvaient être de nouveau à risque en cas d’arrêt de transfusions. Le degré de risque doit être comparé avec le fardeau des transfusions chroniques. La combinaison de l'hydroxyurée et de la phlébotomie n'est pas aussi efficace que la transfusion «standard» et la chélation dans la prévention secondaire d'AVC et la prévention de la surcharge ferrique. Des essais multicentriques étudient actuellement l'utilisation de la transfusion chronique pour prévenir les AVC silencieux, l'utilisation d'hydroxyurée en tant qu’alternative à la transfusion chez les enfants atteints de vélocités anormales dépistées par l'échographie transcrânienne Doppler et l'utilisation d'hydroxyurée pour prévenir les vélocités conditionnelles (limitées) de devenir anormales, dépistées par l'échographie transcrânienne Doppler.

Plain language summary

Regular blood transfusions to prevent a stroke in people with sickle cell disease

In sickle cell disease there are fewer red blood cells. This means less oxygen is carried to tissues and there are problems throughout the body. Sickled red blood cells can block flow in blood vessels in the brain, leading to strokes. We aimed to compare long-term blood transfusion schedules to other transfusion schedules or other ways of preventing stroke. There are three trials in the review. The results of the STOP and STOP 2 trials showed that regular blood transfusions reduce the risk of stroke significantly in those at high risk (determined by ultrasound screening of blood flow in the brain), but that patients returned to having a high risk for stroke when transfusions were stopped. There are important side effects (iron overload, infection transmitted through blood and reactions to the transfusions). When using this treatment the burden of long-term transfusion should be weighed against the degree of risk of stroke. The third trial showed that there is no evidence of an advantage for the combination of hydroxyurea and phlebotomy (removing blood from the body) compared with standard transfusion and iron "chelation" treatment in preventing stroke and iron overload. Current research is evaluating the use of transfusion to prevent 'silent' strokes and hydroxyurea to replace transfusion in those with abnormal ultrasound examinations.

Résumé simplifié

Transfusions sanguines régulières pour prévenir un accident vasculaire cérébral (AVC) chez les patients atteints de drépanocytose

Le nombre de globules rouges est diminué lors de drépanocytose. Cela signifie un manque d’oxygénation des tissus et des problèmes occurrent à travers le corps. Les globules rouges drépanocytaires peuvent bloquer le débit dans les vaisseaux sanguins du cerveau, conduisant à des accidents vasculaires cérébraux. Nous avons cherché à comparer des traitements de transfusion de sang à long terme à d’autres traitements de transfusion ou à d'autres moyens pour prévenir l'AVC. La revue comporte trois essais. Les résultats des essais STOP et STOP 2 ont montré que des transfusions sanguines régulières réduisent significativement le risque d'AVC chez les patients présentant un risque élevé (déterminé par dépistage à ultrasons du débit sanguin dans le cerveau), mais que les patients présentaient à nouveau un risque élevé d'AVC lors de l’arrêt de transfusions sanguines. Il existe des effets secondaires importants (surcharge ferrique, infection transmise par le sang et réactions aux transfusions sanguines). Lors de l'utilisation de ce traitement, le fardeau des transfusions à long terme devrait être comparé avec le degré de risque d'AVC. Le troisième essai a montré qu’il n'existe aucun avantage pour la combinaison de l'hydroxyurée et de la phlébotomie (ablation de sang dans l'organisme) par rapport à un traitement de transfusion et de chélation ferrique standard dans la prévention de l'AVC et de la surcharge ferrique. La recherche courante évalue l'utilisation de la transfusion pour prévenir les AVC silencieux et l'hydroxyurée afin de remplacer la transfusion chez les patients dont l’examen échographique est anormal.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Minist�re Fran�ais des Affaires sociales et de la Sant�, Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Description of the condition

Sickle cell disease is a genetic haemoglobin disorder which can cause severe pain crises and dysfunction of virtually every organ system in the body, ultimately causing premature death. Populations originating from sub-Saharan Africa, India and parts of the Mediterranean are predominantly affected, but population movement has made this a worldwide problem. Approximately 89,000 Afro-Americans, 10,000 people in the UK and 1 in 60 people in West Africa now suffer from the disease (Brousseau 2010 ; Hickman 1999). Despite improved care and services for people with sickle cell disease in developed countries, the average life expectancies for men and women with homozygous disease (HbSS) from the 'Cooperative Study of Sickle Cell Disease Study' analysis was only 42 and 48 years respectively (Platt 1994), although more recent data have shown a trend toward increase in overall survival (Hassell 2010) as well as significant improvement in survival (to 94 to 99%) of children and adolescents with HbSS (Quinn 2010;Telfer 2007).

Normal adult haemoglobin (HbA) is made up of two alpha and two beta globin protein chains plus 4 haem entities. Homozygous sickle cell disease (HbSS) is caused by the inheritance from both parents of a mutated beta globin (ßS) gene, causing abnormal sickle haemoglobin (HbS) to be produced. Other forms of the disease arise when the sickle gene is inherited along with another abnormal β-globin gene; these combinations can have symptoms similar to those of HbSS. Sickle-ß0 thalassaemia and sickle-ß+ thalassaemia result from absent or reduced production, respectively, of beta globin by the thalassaemic gene, co-inherited with ßSglobin. The former is similar to homozygous sickle cell disease in severity. Sickle haemoglobin C disease (HbSC) is generally milder (Nagel 2003).

In sickle cell disease, under certain conditions in the absence of oxygen, the haemoglobin molecules within the red blood cells can associate as polymers, making the cells rigid and distorted into a variety of shapes, some resembling a sickle. The red blood cells have a shortened life span, resulting in anaemia. They also demonstrate increased adherence to endothelial cells lining the blood vessels, contributing to vaso-occlusion. In later life, chronic damage to poorly perfused organs becomes apparent (Steinberg 1999). Individual heterogeneity among persons with sickle cell disease make the symptoms highly variable in frequency and severity, but the most common clinical manifestation is the acute sickle pain crisis which occurs when small vessels are blocked, depriving the tissues of oxygen and causing ischaemic damage and pain. Vaso-occlusion can also occur in some large vessels, such as those in the brain, causing or contributing to stroke.

Stroke, usually ischaemic, occurs in up to 10% of children with sickle cell anaemia (HbSS) (Cohen 1996) and can cause weakness in the limbs, slurring of speech, seizures, coma and cognitive impairment. Recurrent (secondary) strokes occur in a half to two thirds of untreated individuals and are associated with increasing morbidity and mortality (Cohen 1996). 'Silent infarctions' often go unnoticed but can also cause significant neurological damage and cognitive disability and are present in a further 17% to 27% of children with sickle cell anaemia (Kinney 1999; Kwiatkowski 2009).

Description of the intervention

The focus in the past has largely been on secondary prevention with chronic transfusion, as risk factors for first stroke were not well established. However, with the technological breakthrough of the use of transcranial Doppler (TCD) cerebral blood flow velocity measurement, screening has become feasible and is currently the standard of care. Transcranial Doppler screening is a technique used to measure the velocity of blood flow in the distal internal carotid and proximal anterior and middle cerebral arteries. Abnormally high blood flow in one or more major arteries is associated with vascular narrowing and predicts an increased risk of stroke, allowing preventative treatment (i.e., chronic transfusion) prior to the first stroke (Adams 1998a). The fetal haemoglobin (HbF) stimulating drug hydroxyurea has been substituted successfully for chronic transfusion for the prevention of secondary stroke in a limited number of cases (Ware 2010). Serial phlebotomy may be highly effective in the reduction of iron overload if transfusions are no longer necessary (Ware 2004).

As well as the direct and indirect costs, chronic blood transfusions can have adverse side effects. Iron overload is a problem and requires daily oral iron chelation with deferasirox or deferiprone (or daily subcutaneous or intravenous infusions with desferrioxamine) to avoid the toxic effects of excess iron (Inati 2011). However, compliance with the chelation programmes is often poor, and therefore problems of iron overload are potentially serious. Alloimmunisation occurs when the individual develops antibodies to the foreign red cells (Smith-Whitley 2012), which is a major problem for future transfusion. Blood products can be contaminated with infective agents such as hepatitis C and HIV, and while this now occurs only rarely in developed countries, the risk is much higher in the developing countries where sickle cell disease is most prevalent. Other problems with transfusions include hyperviscosity of the blood due to over-transfusion, and haemolytic transfusion reactions, both potentially serious side effects. The regimen is often complex and time-consuming, requiring monthly transfusions to maintain the HbS at approximately 20% to 30%. In short, blood transfusion is a lengthy and costly process which is not without risks, and these must be balanced against the possible benefits prior to embarking on a chronic regimen.

How the intervention might work

Blood transfusions are undertaken in many people with sickle cell disease to dilute the circulating sickle cells, thus reducing the risk of vaso-occlusive episodes and anaemia (Serjeant 1992) and increasing tissue oxygen delivery. Transfusions can be given acutely, in emergency treatment of complications such as acute splenic sequestration, aplastic crisis, and acute chest syndrome, and are also frequently used in preparation for surgery. In addition, many persons with sickle cell disease receive chronic transfusion regimens in an attempt to prevent severe vaso-occlusion and stroke (Smith-Whitley 2012).

The mechanisms for the reduction in stroke risk from chronic transfusion are not known (DeBaun 2006). However, a reduction in cells containing high amounts of HbS or an increase in Hb level could have beneficial effects on cerebral blood vessels or interactions between red blood cells and endothelial cells (Adams 1998b). Transfusion does have an immediate haemodynamic effect measured by reduction of middle cerebral artery velocity (Venkatesubramanian 1994).

Hydroxyurea is currently the only approved therapeutic drug for the treatment of sickle cell anaemia (for adults with severe vaso-occlusive episodes of pain or acute chest syndrome) and its use has become widespread in both children and adults with this condition. In preliminary studies it was substituted successfully for chronic transfusion in the prevention of secondary strokes, leading to its consideration for use in the phase III SWiTCH trial (SWiTCH 2012).

For the past three decades the standard treatment for iron overload related to chronic transfusion has been the use of iron chelating agents, including desferrioxamine, deferiprone and deferasirox. Although serial phlebotomy has long been utilized for conditions such as polycythemia, it has recently been found to be highly effective in the reduction of iron overload from chronic red blood cell transfusion in patients who are no longer requiring that treatment (Ware 2004). Pilot information on the combination use of hydroxyurea and phlebotomy led to the development of the SWiTCH trial (SWiTCH 2012).

Why it is important to do this review

In the USA the National Institutes of Health (NIH) guidelines recommend a long-term blood transfusion programme for prevention of stroke in people with sickle cell disease who have had a prior stroke, or who have an abnormal TCD reading (blood flow velocity equal to or greater than 200 cm per second in the internal carotid artery or the middle cerebral artery). While many studies support the efficacy of this treatment (Adams 1998a; Bernaudin 2011), the optimum regimen and duration of treatment for primary stroke prophylaxis have not been widely agreed upon. This review aims to assess the relative risks and benefits of blood transfusion regimens for preventing primary stokes in people with sickle cell disease. Furthermore, older data indicated the need for indefinite continuation of chronic transfusion and iron removal in the prevention of secondary stroke and its treatment consequences (Wang 1991). The potential substitution of an oral drug (hydroxyurea) for chronic transfusion and of periodic phlebotomy for oral or subcutaneous iron chelation offered less demanding and potentially less expensive secondary stroke preventative management for patients and providers.

The publication is a minor update of a Cochrane review first published in 2002 (Hirst 2002).

Objectives

The aim of the review was to determine whether chronic blood transfusion regimens in people with sickle cell disease:

  1. reduce occurrence of stroke (primary prevention);

  2. reduce recurrence of stroke (secondary prevention);

  3. reduce mortality;

  4. reduce other complications of sickle cell disease including pain crises, acute chest syndrome and splenic sequestration;

  5. are associated with unacceptable adverse events or costs.

Methods

Criteria for considering studies for this review

Types of studies

Randomised trials were included. Trials in which quasi-randomised methods, such as alternation, are used will be included in future updates if there is sufficient evidence that the treatment and control groups are similar at baseline.

Types of participants

Persons with sickle cell disease (HbSS, SC, Sß+ and Sß0; proven by electrophoresis, with family studies or DNA tests as appropriate) of all ages and both sexes, whether or not they have a history of prior stroke or transient ischaemic attack.

Types of interventions

Chronic blood transfusion regimens compared to other transfusion regimens, no treatment or the use of hydroxyurea to reduce the incidence of stroke in persons with sickle cell disease.

Types of outcome measures

Primary outcomes
  1. Deaths from any cause in each treatment group

  2. Incidence of clinical diagnosis of any type of stroke (by clinical symptoms and signs, magnetic resonance imaging (MRI) scan, computed tomography imaging (CT) scan or autopsy)

  3. Transfusion-related complications, including alloimmunisation, infection from blood product, procedural complications, transfusion reactions, reduced immunocompetency, iron overload (measured by serum ferritin, liver iron or quantitative MRI)

Secondary outcomes
  1. Incidence of transient ischaemic attack or silent infarction

  2. Measures of neurological impairment, and measures of neuropsychiatric performance (e.g. full scale intelligence quotient (FSIQ))

  3. Incidence of other sickle cell complications (e.g. pain crises, acute chest syndrome, splenic sequestration)

  4. Quality of life, inpatient stay, immobility and disability

  5. Measures of organ damage (e.g. renal function, liver function, and lung function tests)

  6. Haemoglobin level and HbS percentage (mean, pre- and post-transfusion, and at time of event)

Outcome data, where appropriate, were grouped into those measured prior to transfusion regimen, one month, one year, five years and more than five years after initiation of transfusion, and one year, five years and more than five years after stopping transfusion.

Search methods for identification of studies

Electronic searches

Relevant trials were identified from the Group's Haemoglobinopathies Trials Register using the terms: sickle cell AND stroke AND blood transfusion.

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue) and quarterly searches of MEDLINE. Unpublished work is identified by searching the abstract books of four major conferences: the European Haematology Association conference; the American Society of Hematology conference; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group Module.

Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 28 January 2013.

Searching other resources

Trial registries will be searched in future updates of this review and experts in the area will be contacted.

Data collection and analysis

Selection of studies

Two authors independently selected the trials to be included in the review, first by screening titles and abstracts and then by accessing the full reports of trials thought to be eligible.

Data extraction and management

Two authors independently extracted data, if disagreements arose, we reached a consensus by discussion.

Assessment of risk of bias in included studies

Each author independently assessed the risk of bias of each trial. In particular, authors examined details of the randomisation method (sequence generation and allocation concealment), the degree of blinding in the trial, incomplete outcome data and selective reporting.

We categorised these domains as having either a low, unclear or high risk of bias.

Measures of treatment effect

We recorded dichotomous outcomes (e.g. life or death) as present or absent, while we recorded continuous data such as organ function tests as either mean change from baseline for each group or mean post-treatment values and standard deviation for each group. We aimed to calculate a pooled estimate of the treatment effect for each outcome across trials: for dichotomous outcomes an odds ratio (OR) and 95% confidence interval (CI) and for continuous data a mean difference (MD) and 95% CI.

Unit of analysis issues

Cross-over trials and cluster randomised trials were not eligible for inclusion in this review.

Dealing with missing data

We sought full reports from authors where trials had been published in abstract form, presented at meetings or reported to the co-authors. Where information was missing or unclear, we contacted the primary investigator.

In order to allow an intention-to-treat analysis, we collected data by allocated treatment groups, irrespective of later exclusion (regardless of cause) or loss to follow up.

Assessment of heterogeneity

Heterogeneity between trials was assessed by inspecting forest plots to detect overlapping confidence intervals and applying the chi-squared test (P < 0.1). The I2 statistic will be calculated, with values of 50% representing moderate heterogeneity.

Assessment of reporting biases

If sufficient trials (approximately 10) are identified in the future, we will construct a funnel plot, which will be assessed for asymmetry. Other reasons for funnel plot asymmetry, such as heterogeneity and selective outcome reporting, will also be considered.

Data synthesis

For future updates of the review, if more trials are included and combined in a meta-analysis, we will use a fixed-effect model unless moderate heterogeneity is identified and then a random-effects model will be used.

Subgroup analysis and investigation of heterogeneity

If, in future updates, we identify moderate heterogeneity between trials, we will examine subgroups to help explain the reasons for this.

We planned to analyse trials comparing transfusion therapy with no treatment or other treatments separately from those comparing different transfusion regimens. We would have performed subgroup analysis of transfusion regimens to prevent recurrent stroke if there were sufficient data. In addition, we would have performed subgroup analyses of ischaemic and haemorrhagic stroke if appropriate.

Sensitivity analysis

If more trials are included in future updates of this review we will perform a sensitivity analysis based on the risk of bias of the trials, including and excluding quasi-randomised trials.

Results

Description of studies

Results of the search

A total of 83 references have been identified: 75 references related to three included trials (STOP 1998; STOP 2 2005; SWiTCH 2012) and eight to three ongoing trials (SIT Trial; SCATE Trial; TWiTCH Trial).

Ongoing studies

The 'Silent Cerebral Infarct Multi-Center Trial' (SIT Trial). This study includes 204 children aged 6 to 13 years old, with silent infarcts on MRI of the brain (from approximately 1880 screened for neurological damage). It is hypothesized that prophylactic blood transfusion will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts. Participants are evenly randomised to receive blood transfusion or observation for prevention of stroke and further neurological damage (SIT Trial; Casella 2010). A risk-benefit analysis is planned, which will aim to determine whether the risks of blood transfusion therapy are outweighed by the benefits in terms of prevention of neurological damage, evaluated in part with serial neuropsychologic testing and neurologic examinations.

The TCD with 'Transfusions Changing to Hydroxyurea' (TWiTCH) trial (TWiTCH Trial). The primary goal of the phase III TWiTCH trial is to compare 24 months of alternative therapy (hydroxyurea) to standard therapy (transfusions) for children with sickle cell anaemia and abnormally high (greater than or equal to 200 cm/sec) TCD velocities, who currently receive chronic transfusions to reduce the risk of primary stroke. For the alternative treatment regimen (hydroxyurea) to be declared non-inferior to the standard treatment regimen (transfusions), after adjusting for baseline differences, the hydroxyurea-treated group must have a mean TCD velocity similar to that observed with transfusion prophylaxis.

The 'Sparing Conversion to Abnormal TCD (Transcranial Doppler) Elevation' (SCATE) trial (SCATE Trial). The primary goal of the phase III SCATE trial is to compare 30 months of alternative therapy (hydroxyurea) to standard care (observation) in children with sickle cell anaemia and conditional (170 to 199 cm/sec) TCD velocities. For the alternative regimen (hydroxyurea) to be declared superior to the standard treatment regimen (observation), the hydroxyurea-treated group must have a three-fold reduction in the incidence of conversion to abnormal TCD velocities (greater than or equal to 200 cm/sec), compared to the standard treatment arm.

Results from ongoing trials will be included in future updates of this review when they become available.

Included studies

The first randomised controlled trial included 130 children (60 boys) with sickle cell disease who underwent chronic blood transfusion or standard care to prevent first stroke at 14 centres in the USA (STOP 1998). The children were previously assessed to be at high-risk of a first stroke through TCD, and the efficacy of transfusions to prevent a first stroke was measured. Of the 1934 children aged 2 to 16 years of age, who were screened using TCD, 206 were found to have abnormal readings on at least two occasions. However, 76 were excluded before randomisation, including 14 due to ineligibility, 17 due to concerns over participant compliance and 35 due to individual reluctance. The 130 remaining children were then randomised to blood transfusion to maintain HbS at less than 30% (n = 63) or standard care (n = 67). Although the trial was planned to include 30 months of treatment and observation for all participants, it was stopped 16 months early by the data monitoring board when a 92% reduction in incidence of stroke in the transfused group was seen. At trial termination median follow up was 21.1 months.

The second included trial evaluated whether, in children in whom routine transfusions were indicated because of high stroke risk, the transfusions could be discontinued safely after 30 months of treatment without the children reverting to high risk of stroke, as judged by TCD (STOP 2 2005). The trial was conducted in 23 clinical centres in the USA and Canada. Seventy-nine children were randomised to continue transfusion or discontinue transfusion. Baseline characteristics of participants were broadly similar. The trial was terminated two years early due to significant findings (STOP 2 2005). At the close of the trial, 16 of the 41 participants in the no transfusion group had resumed transfusion due to the occurrence of a trial endpoint, and a further nine participants who had not experienced a trial endpoint had either resumed transfusion (n = 5) or started hydroxyurea treatment (n = 4). Of the 38 participants in the transfusion group, six were not receiving transfusions at the close of the trial (STOP 2 2005).

The third trial, the 'Stroke With Transfusion Changing to Hydroxyurea' (SWiTCH) trial was a multicentre phase III randomised trial comparing standard treatment (transfusions and chelation) to alternative treatment (hydroxyurea and phlebotomy) for children with SCA, stroke, and iron overload (SWiTCH 2012). SWiTCH was a non-inferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Participants on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Participants on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Participants on standard treatment maintained HbS levels of approximately 30% and tolerated deferasirox at 28.2 (6.0) mg/kg/d. Participants on alternative treatment initiated hydroxyurea and 60 (90%) reached MTD at 26.2 (4.9) mg/kg/d with 29.1% ± 6.7% HbF. The NIH Heart, Lung and Blood Institute (NHLBI) closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point.

Excluded studies

There were no excluded trials.

Risk of bias in included studies

See: the risk of bias tables in 'Characteristics of included studies'.

Allocation

Sequence generation

The STOP trial used computer-generated randomisation by permuted blocks (STOP 1998). The STOP 2 trial used computer-generated randomisation by permuted blocks, and participants were stratified according to the presence of ischaemic lesions on MRI (STOP 2 2005). The SWiTCH trial used computer-generated randomisation (SWiTCH 2012). Therefore, all trials were classified as having a low risk of bias.

Allocation concealment

It was not possible to conceal participants or investigators from the randomised treatment in the STOP trial (STOP 1998). Obviously, disguising the administration of chronic transfusion was not feasible, nor was there a suitable "control" procedure. Similarly, the STOP 2 trial could not conceal participants or investigators from the randomised treatment, since one arm involved chronic transfusion (STOP 2 2005). Therefore, these trials were at a high risk of bias.

Investigators were not aware of the treatment allocation process in the SWiTCH trial, therefore this trial was at a low risk of bias (SWiTCH 2012).

Blinding

In the STOP trial, it was not possible to blind the treating physicians, the centre co-ordinators or the participants (high risk of bias) (STOP 1998), although outcome assessors were blind to treatment allocation (low risk). In the STOP 2 trial, experts who adjudicated suspected strokes were blinded to treatment allocation (low risk) (STOP 2 2005). In the SWiTCH trial, a stroke adjudication process provided systematic evaluation of all new acute neurologic events by treatment-masked neurologists and neuroradiologists (SWiTCH 2012). Each group of three persons formed an independent decision with limited data; this was followed by a group consensus decision. In addition, the overall trial principal investigator was masked to all trial treatment data and local site investigators were masked to trial treatment results outside of their own centre. This was deemed as having a low risk of bias.

Incomplete outcome data

For the STOP trial, an intention-to-treat analysis was used; despite 12 participants crossing over between groups or withdrawing from the trial, reasons were provided (low risk of bias) (STOP 1998).

It was not stated whether intention-to-treat analysis was used in the STOP 2 trial and reasons were not provided for all patient withdrawals (high risk of bias) (STOP 2 2005).

For the SWiTCH trial, an intention-to-treat analysis was utilized (which consists of all participants who were randomised to a trial treatment and for whom outcome data were available) and details were provided for patient withdrawal (SWiTCH 2012); therefore, this trial was regarded as having a low risk of bias.

Selective reporting

There was a low risk of bias from selective reporting in the three trials (STOP 1998; STOP 2 2005; SWiTCH 2012) as all of this review's primary outcomes were fully reported (Table 1). Not all secondary outcomes were reported but they were not necessarily measured in these trials.

Table 1. Outcome Table
  1. TIA: transient ischaemic attack

TrialMortalityIncidence of clinical strokeTransfusion related complications (relating only to transfusion group)Incidence of TIA or silent infarctionMeasures of neurological impairmentIncidence of other sickle cell complicationsQuality of life, inpatient stay, immobility and disabilityMeasures of organ damageHaemoglobin level and haemoglobin S percentage
STOP 1998fully reportedfully reportedfully reportedfully reportedpartially reportedfully reportednot reportednot reportednot reported
STOP 2 2005fully reportedfully reportedfully reportednot reportednot reportedpartially reportednot reportednot reportedfully reported
SWiTCH 2012fully reportedfully reportedfully reportedfully reportednot reportednot reportednot reportednot reportedfully reported

Other potential sources of bias

There are no other potential sources of bias.

Effects of interventions

Blood transfusion versus standard care

The STOP trials (n = 209) evaluated different patient populations; since those in the former had not been transfused and those in the latter had already been treated with chronic transfusion for a minimum of 30 months, these trials were not combined in a meta-analysis (STOP 1998; STOP 2 2005).

Primary outcomes

1. Mortality

No participants died in the STOP trial (STOP 1998).

One participant, who was assigned to continue transfusion, died in the STOP 2 trial due to complications of acute chest syndrome, OR 3.32 (95% CI 0.13 to 84.01) (STOP 2 2005) (Analysis 1.1).

2. Incidence of clinical stroke

In the STOP trial, of a possible 29 suspected strokes, 12 were confirmed by the expert panel. There were 10 cerebral infarctions and one intracerebral hematoma in the standard care group, compared to one infarction in the transfusion group, OR 0.08 (95% CI 0.01 to 0.66) (STOP 1998) (Analysis 1.2). Since the trial was terminated early, the groups had different periods of follow-up, a total of 1229 months in the standard care group, and 1321 in the transfusion group. Rate of stroke per patient year of follow up was therefore 0.107 in the standard care group, and 0.009 in the transfusion group. There was a 90% relative risk reduction in the intervention group. Although in the transfusion group the target HbS percentage of 30% was occasionally not met, none of these participants had a stroke (STOP 1998).

In the STOP 2 trial, two participants had confirmed strokes, both of whom were in the group which discontinued transfusion, OR 0.21 (95% CI 0.01 to 4.41) (STOP 2 2005) (Analysis 1.2).

3. Transfusion related complications (relating only to transfusion group)

In the STOP trial, 10 participants in the transfusion group developed alloimmunisation, despite a more rigorous matching protocol than usual. There were 15 mild reactions to the procedure or the blood products, including hypertensive or circulatory overload (n = 5), febrile non-haemolytic reactions (n = 5), allergic reactions (n = 3) and haemolytic events (n = 2). No participants were known to have contracted infection from the transfused blood. Iron overload developed faster than anticipated in this group, with mean serum ferritin and standard deviation, rising from 164 (155) nanograms per millilitre (ng/ml) to 1804 (773) ng/ml at 12 months and 2509 (974) ng/ml at 24 months (Adams 1998b). This last outcome was not reported for the control group (STOP 1998).

In the STOP 2 trial, chelation therapy was being received by 93% (n = 35) of participants assigned to continue transfusion and 76% (n = 31) assigned to discontinue transfusion. One new case of alloimmunisation was reported in a participant continuing transfusion. There were no cases of hepatitis C. Serum ferritin levels in the transfused group rose from 3274 (1718) ng/dl at baseline to 3562 (1536) ng/ml after 12 months (STOP 2 2005).

Secondary outcomes

1. Incidence of transient ischaemic attack (TIA) or silent infarction

In the STOP trial, at baseline, 18 of the 56 children in the transfusion group and 29 of 71 in the standard care group had silent cerebral infarcts. During the trial, among those receiving transfusion, one child developed a new silent infarct, compared to 11 in the standard care group, OR 0.10 (95% CI 0.01 to 0.79) (Analysis 1.3). This was not an intention-to-treat analysis, and children in the transfusion group who had never received transfusion were analysed with the standard care group (Pegelow 2001).

This was not reported in the STOP 2 trial (STOP 2 2005).

2. Measures of neurological impairment

In the STOP trial, at the time of discharge, of the 11 children in the standard care group diagnosed with cerebral infarction, two had a major disability, five had mild to moderate disability, two had symptoms but no disability and one was asymptomatic. Measures of neurological impairment in other participants were not reported in this trial (STOP 1998).

Measures of neurological impairment were not reported in the STOP 2 trial (STOP 2 2005).

3. Incidence of other sickle cell complications

In the STOP trial, four children in the transfusion group had acute chest syndrome, compared to 14 in the standard care group, showing a significant reduction in those receiving blood transfusions, OR 0.25 (95% CI 0.08 to 0.81) (STOP 1998) (Analysis 1.4). Painful crises requiring hospitalisation were seen in 11 children in the transfusion group and 13 in the standard care group, OR 0.86 (95% CI 0.35 to 2.10) (Analysis 1.4). The difference between groups was not significant (Miller 2001). One child from the standard care group was excluded from these analyses due to a stroke on day 16 of the trial (STOP 1998).

In the STOP 2 trial, the authors state that there were significant reductions in the incidence of painful crises and acute chest syndrome in participants receiving transfusion. In the non-transfusion group, 18 of 41 participants had at least one episode of acute chest syndrome. Comparative numbers for the transfusion group were not reported, and numbers of painful crises were also not reported (STOP 2 2005).

4. Quality of life, inpatient stay, immobility and disability

These outcomes were not recorded in any of the trials. However, the STOP trial noted that after 24 months of transfusion, children receiving transfusion had significantly improved growth (height, weight and body mass index (BMI)) which approached normal, whereas there was no improvement in growth rate in the non-transfusion group (Wang 2005).

5. Measures of organ damage

No information was given for these trials.

6. Haemoglobin level and haemoglobin S percentage

This outcome was not reported at the end of the STOP trials.

In the STOP trial, at baseline mean (SD) haemoglobin per decilitre was significantly lower in the transfusion group, 7.2 g (0.8) compared to 7.6 g (0.7) in the standard care group. HbS% and white blood cell (WBC) haematologic variables were similar. Data were not reported which compared haematological variables at later time points (STOP 1998).

In the STOP 2 trial, at six months after randomisation, mean (SD) haemoglobin was 9.4 (0.9) g/dl in the transfusion group compared to 7.7 (0.8) g/dl in the non-transfusion group (STOP 2 2005). HbS% was 25.4 (10.9) in the transfusion group and 81.0 (13.6) in the non-transfusion group. These results were expected.

Transfusions and chelation versus hydroxyurea and phlebotomy

One trial was included in this comparison (n = 133) (SWiTCH 2012).

Primary outcomes

1. Mortality

There was one fatal hemorrhagic stroke in a patient in the hydroxyurea and phlebotomy arm and one death due to pulmonary embolism in the transfusion and chelation arm in the SWiTCH trial, OR 0.98 (95% CI 0.06 to 16.08) (SWiTCH 2012) (Analysis 2.1).

2. Incidence of clinical stroke

In the SWiTCH trial, seven participants (10%) on the alternative treatment (hydroxyurea and phlebotomy) arm had a stroke, compared with none on the standard treatment (transfusion/iron chelation) arm, OR 16.49 (95% CI 0.92 to 294.84) (SWiTCH 2012) (Analysis 2.2). One fatal hemorrhagic stroke occurred on the alternative arm. MRI/MRA findings have not been reported other than the fact that all seven of those who experienced a stroke had baseline MRA exams which showed severe vasculopathy, including two with moya-moya (SWiTCH 2012).

3. Transfusion related complications (relating only to transfusion group)

In the SWiTCH trial, there was no significant difference in the liver iron concentration (LIC) at the first interim analysis in the two groups (16.6 versus 15.7 mg/g dry weight liver in the standard and alternative arms, respectively), leading to closure of the trial because of futility in meeting the composite primary endpoint (SWiTCH 2012). At the final assessment, median LIC was 17.3 (interquartile range (IQR) 8.8 to 30.7) mg/g in the standard arm and 17.2 (IQR 10.0 to 30.6) mg/g in the alternative arm.

Secondary outcomes

1. Incidence of transient ischaemic attack (TIA) or silent infarction

In the SWiTCH trial, six participants on the alternative arm were judged to have TIAs compared with nine on the standard treatment arm, OR 0.62 (95% CI 0.21 to 1.86) (SWiTCH 2012) (Analysis 2.3).

2. Measures of neurological impairment

Measures of neurological function have not been reported from the SWiTCH trial (SWiTCH 2012).

3. Incidence of other sickle cell complications

The incidence of other sickle cell complications has not been reported from the SWiTCH trial at this time.

4. Quality of life, inpatient stay, immobility and disability

These outcomes were not recorded in this trial.

5. Measures of organ damage

No information was given for this trial.

6. Haemoglobin level and haemoglobin S percentage

In the SWiTCH trial, median Hb level was the same in the two groups at the end of the trial (9.0 g/dL) with interquartile ranges of 8.7 to 9.6 and 8.4 to 9.6 for the alternative arm and standard arm, respectively. As expected, median HbS was markedly lower in the transfused arm (32.3% versus 64.1%). Median HbF was also markedly lower in the transfused participants (1.3% versus 19.5%) (SWiTCH 2012).

Discussion

Stroke is a potentially devastating event which affects up to 10% of children with sickle cell anaemia. Recurrences are common after the first stroke, and result in progressively more severe neurological dysfunction. The use of TCD screening has made it possible to identify a subset of children who are at particular risk for primary stroke (Adams 1992). The optimal level of sensitivity and specificity for TCD screening remains unclear. In the STOP trial, which included high-risk children with abnormal TCD velocities, the rate of stroke in the standard care group was approximately 10% per year (STOP 1998). The number of participants needed to treat (NNT) was approximately 11 participants per year to prevent one stroke. In a lower risk group this NNT would be higher. However, if the specificity of the screening, or the 'cut-off point' for a high-risk classification, was increased, only the very highest risk children would be treated and children at risk of stroke may be missed. It must therefore be judged at what level of risk it is justifiable to enrol a child to a potentially life-long regimen of transfusion. (The TWiTCH Trial is currently addressing the possibility of substituting hydroxyurea for long-term transfusion for primary stroke prophylaxis.)

The STOP trial demonstrated that chronic transfusion was associated with a 92% reduction (OR 0.08, 95% CI 0.01 to 0.66) in the risk of stroke in children judged to be at high-risk by TCD screening. While this is a convincing statistic, the chances of having a stroke must be weighed carefully with the burden of regular blood transfusion (STOP 1998). Of the 192 children eligible to take part in the trial, 52 declined to undergo randomisation due to either reluctance of the child or their parents, or due to concern of the physician about compliance to the regimen. A further 10 children dropped out of the transfusion group after 2 to 23 months. These figures may illustrate a relatively poor level of acceptance of this therapy.

Cumulative alloimmunisation, iron overload and other transfusion-related adverse events, including the amount of time spent in hospital, are associated with high morbidity and reduced quality of life. In the trial, particular care was taken in matching blood types and monitoring iron levels. Despite this, 10 children developed alloantibodies, onset of iron overload was rapid, and there were 16 other transfusion-related reactions. In a true clinical setting we may expect these to be even worse. In addition, the financial cost of chronic transfusion regimens in the USA has been calculated to amount to between USD 9828 and USD 50,852 per patient per year (including chelation therapy where required) (Wayne 2000).

Iron overload is one of the most important adverse events associated with chronic transfusion and previously required daily eight-hour long subcutaneous infusions of desferrioxamine, the most established effective iron chelator. Compliance with this therapy was very poor, estimated to be 40% to 60% (Davies 1995). Erythrocytapheresis (automated red cell transfusion) has made exchange transfusions much easier and more time efficient where available, and reduces the problem of iron overload (Adams 1996). Although the equipment is relatively expensive and not available in many parts of the world, it may help in making chronic transfusion more acceptable in some cases. However, oral iron chelators have now replaced desferrioxamine in Europe and Asia (deferiprone) and in the USA (deferasirox), although they remain extremely expensive (Karnon 2008).

Despite these barriers, the routine use of TCD screening and appropriate prophylactic transfusion has greatly lowered the risk of stroke in patients who are managed in contemporary sickle cell programs (Enninful-Eghan 2010; Fullerton 2004; McCarville 2008; Telfer 2007). At present, the majority of transfusions provided by large sickle cell centres are for the provision of primary rather than secondary stroke prevention.

Developing countries often do not have the resources to support an extensive transfusion programme and TCD screening is less likely to be available. In addition, the potential risks associated with transfusion therapy are increased in such settings due to a lack of trained staff, modern equipment, sanitary conditions and clean, infection-free blood products (Ohene-Frempong 1999). Therefore, the risk-benefit ratio will be different in developing countries to those in the included trials, and the results discussed in this review are not be generalised to this setting.

This systematic review noted a lack of prospective randomised controlled trials of blood transfusion for prevention of secondary stroke (following an initial stroke) in sickle cell disease. However, the practice of long-term transfusion therapy is supported by evidence from several observational studies (Sarnaik 1979; Styles 1994). It was demonstrated in a small study of 15 participants that a target HbS level of 30% to 50% retains a high protective value against stroke, but reduces transfusion requirements and the associated risks (Cohen 1992). However, in a study which observed 60 persons with sickle cell disease for 192 patient years, HbS was greater than 30% in 7 of the 16 reported transient ischaemic events and five of six recurrent infarctions (Pegelow 1995). A recent survey has indicated that an acceptable "community standard" level of pre-transfusion HbS is less than 45% rather than less than 30% (Aygun 2009).

The STOP 2 trial attempted to determine a safe age, or period, for discontinuation of chronic transfusion therapy for primary stroke prevention (STOP 2 2005). However, because of the high proportion (39%) of participants who reverted to high stroke risk or had a stroke after transfusion was ceased, the trial was terminated two years early with the implication that transfusion therapy should be continued indefinitely in indicated participants. Although eight participants (20%) of those who discontinued transfusion had no abnormal TCD over 25 months of observation, there is currently no way of predicting which individuals will require continuance of transfusion and which will not. Extended follow-up analysis of the STOP trial also failed to identify predictors for lower-risk patient groups (Lee 2006).

Several observational studies have also attempted to define whether transfusion may be safely stopped. One review suggested that transfusion may be safely stopped at age 18 years (Powars 2000), and no recurrences occurred in a small series of seven adults with sickle cell disease followed up for three years to 18 years (Rana 1997). However, a study of 10 participants who discontinued transfusion after one to two years showed a 70% recurrence rate after only 11 months (Wilimas 1980). In a subsequent study, five out of 10 persons with sickle cell disease who had been receiving regular transfusions for five to 12 years experienced an ischaemic event in the 12-month period after transfusions were stopped (Wang 1991). These findings suggest that the risk of secondary stroke may be almost as high after discontinuing transfusion therapy 'prematurely' as before starting it. Evaluation of risk factors related to the initial stroke might be an important consideration in the design of any further studies. For example, in a retrospective analysis of 137 stroke patients, those who had an identified medical or concurrent event associated with their initial stroke did not have a recurrent stroke two or more years after the initial event (Scothorn 2002).

The SWiTCH trial, an alternative intervention to prevent stroke with the anti-sickling drug hydroxyurea coupled with the use of phlebotomy to reduce iron burden, was recently completed (SWiTCH 2012). This trial found that the use of hydroxyurea and phlebotomy was associated with a higher rate of stroke (10% versus 0%; OR 16.49, 95% CI 0.92 to 294.84) and had no advantage in iron removal compared with standard treatment.

The recently initiated TWiTCH trial is investigating the utility of hydroxyurea compared with standard transfusion in patients who are being transfused for primary stroke prevention based on abnormal TCD velocities (TWiTCH Trial). Given that hydroxyurea has been shown to lower TCD velocities in a number of single institution reports (Gulbis 2005; Kratovil 2006; Zimmerman 2007), there is a reasonable expectation that it may be substituted for chronic transfusion (after an initial 18 months of transfusion treatment) in this setting. Of additional interest is the SCATE trial, which has been initiated internationally, and which will explore the use of hydroxyurea (compared with placebo) in participants who have demonstrated conditional (borderline) velocities (which place them at higher risk for stroke than those with normal velocities) to prevent progression to an abnormal TCD velocity or overt stroke, or both (SCATE Trial).

Finally, the ongoing SIT trial is nearing completion (SIT Trial). In this trial, intervention with transfusion (compared with observation) is being evaluated in people found to have silent cerebral infarcts on MRI to determine if further silent (or overt) infarcts can be prevented. Importantly, serial evaluation of neurocognitive status in this trial should indicate if transfusion is of benefit in improving neuropsychological function as may be suggested by a trial in adults which has recently completed data collection (SIT Trial). Of note, a recent prospective study found that new silent cerebral infarcts still occur as frequently, despite regular blood transfusion used for secondary stroke prophylaxis (Hulbert 2011).

Summary of main results

The STOP and STOP 2 trials addressed the use of chronic transfusion for primary stroke prophylaxis in children with HbSS who were at high risk for ischaemic stroke indicated by abnormally increased TCD velocity measurements (STOP 1998; STOP 2 2005). These trials demonstrated conclusively that intervention with a chronic transfusion program greatly diminished the risk of occurrence of an acute stroke, but that discontinuation of chronic transfusion after a minimum of 30 months of treatment was unsafe because of the likelihood of reoccurrence of abnormal TCD velocities or actual overt stroke.

The SWiTCH trial addressed the combined use of hydroxyurea and phlebotomy to replace standard treatment using chronic transfusion and iron chelation in the prevention of secondary stroke in children at high risk for recurrent stroke because of having already had an initial cerebrovascular accident (CVA) (SWiTCH 2012). In the SWiTCH trial, the use of hydroxyurea was not as effective as chronic transfusion in stroke prophylaxis and the substitution of phlebotomy for iron chelation was not advantageous.

Overall completeness and applicability of evidence

Blood transfusion for preventing primary stroke: the STOP and STOP 2 trials were well executed prospective randomised trials that demonstrated the efficacy of chronic blood transfusion for prevention of stroke in SCA patients who were at high risk based on abnormal TCD examinations (STOP 1998; STOP 2 2005). The trials did not answer the question of how long chronic transfusion needed to be continued in this population (other than the conclusion that 30 months was not long enough), nor did they address the optimal schedule for screening with TCD. The trials also did not examine alternatives to chronic transfusion such as hydroxyurea, which is currently being investigated through the TWiTCH and SCATE trials in patients with abnormal and conditional TCD velocities, respectively. No prospective randomised trials have been performed based on other risk factors for primary stroke with the exception of the SIT trial, which is evaluating the efficacy of chronic transfusion in patients with silent cerebral infarcts (SCATE Trial; SIT Trial; TWiTCH Trial).

Blood transfusion for preventing secondary stroke: no randomised prospective trials were performed to establish the efficacy of chronic transfusion in the prevention of secondary stroke, but this approach has been the standard of care for at least three decades. Although complicated by the use of a composite endpoint, the SWiTCH trial demonstrated that hydroxyurea was not as effective as chronic transfusion in preventing secondary stroke and that recurrent phlebotomy was not more effective than standard iron chelation in reducing iron overload from transfusion (SWiTCH 2012). No prospective trials have addressed the length of time that chronic transfusion is needed, nor have other interventions (e.g. anticoagulation, anti-platelet function agents) been evaluated adequately for secondary stroke prophylaxis.

Therefore, at the present time, current practice for primary and secondary stroke prevention in sickle cell anaemia is highly dependent on chronic transfusion, with appropriate management of its complications, such as iron overload. The role of other interventions, particularly hydroxyurea, for primary stroke prevention may be elucidated by ongoing or future trials. The use of pharmacotherapeutic approaches may ultimately prove to be more feasible in limited resource settings, where chronic transfusion and iron chelation are not safe and available.

Quality of the evidence

In the three trials, the numbers of randomised participants were adequate based on predetermined endpoint calculations and their evaluations over the course of the trials were of low risk of bias with relatively few participants being lost to follow up or otherwise not able to be evaluated.

Out of necessity, the trials were not blinded because of the impossibility of masking chronic transfusion. Nevertheless, the determination of the occurrence of the primary endpoint of clinical stroke was made by blinded "stroke adjudication" panels in the trials. Overall, the trials were carefully monitored by 'Data and Safety Monitoring Boards' and predetermined "stopping rules" led to their being terminated earlier than originally planned when it was concluded that the primary endpoint questions had been answered.

Potential biases in the review process

The review was limited by the small number of randomised trials addressing the use of chronic transfusion in primary and secondary stroke management.

Agreements and disagreements with other studies or reviews

With regard to the conclusions of STOP and STOP II, multiple reports have supported the efficacy of chronic transfusion in preventing primary stroke in those at high risk based on abnormal TCD velocities (Enninful-Eghan 2010; Fullerton 2004; McCarville 2008); this has become standard of care practice in almost all sickle cell centres and has led to more subjects being transfused for primary than for secondary stroke prevention in those centres. The findings of the SWiTCH trial were somewhat unexpected because of previously published smaller single institution studies which suggested greater efficacy from phlebotomy in reducing iron overload and not as great a degree of protection from chronic transfusion in secondary stroke prophylaxis (SWiTCH 2012). However, the performance of the SWiTCH trial has generated the infrastructure and momentum for the ongoing TWiTCH trial, which should addresses the question of the possible role of hydroxycarbamide in primary stroke prevention (TWiTCH Trial).

Authors' conclusions

Implications for practice

The STOP trial demonstrated a 90% relative reduction in risk of first stroke in high-risk children receiving regular blood transfusions, over a median follow-up time of 21.1 months (STOP 1998). This must be balanced against the adverse effects and costs of a chronic transfusion regimen. The STOP 2 trial found that it is not safe to discontinue transfusion therapy, even after 30 months of treatment, in these high risk individuals (STOP 2 2005). Recently, the SWiTCH trial (SWiTCH 2012) demonstrated a greater risk of recurrent secondary stroke (10%) and only equivalent efficacy in iron removal in patients treated with the combination of hydroxyurea and phlebotomy compared with chronic transfusion and iron chelation. Therefore, chronic transfusion (with iron chelation when needed) is the appropriate management for patients at high risk for primary and secondary stroke.

Implications for research

Information from a well-designed, prospective, randomised controlled trial of chronic blood transfusion regimens in persons with sickle cell disease who have had a previous stroke is desirable in order to make recommendations for the optimal use of this therapy in secondary stroke prevention. Recent improvements in methods of detecting high-risk individuals are improving clinical outcome, but further research is ongoing to assess the relative risks and benefits of hydroxyurea in comparison with long-term transfusion therapy for primary prevention of cerebral infarcts.

Acknowledgements

We acknowledge the substantial contribution by Dr Ceri Hirst in undertaking the original version of this review (Hirst 2002).

Data and analyses

Download statistical data

Comparison 1. Blood transfusion versus standard care
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality2 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Clinical stroke2 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Other neurological events1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 New silent infarcts1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Other sickle cell related complications1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
4.1 Acute chest syndrome1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Painful crises1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Blood transfusion versus standard care, Outcome 1 Mortality.

Analysis 1.2.

Comparison 1 Blood transfusion versus standard care, Outcome 2 Clinical stroke.

Analysis 1.3.

Comparison 1 Blood transfusion versus standard care, Outcome 3 Other neurological events.

Analysis 1.4.

Comparison 1 Blood transfusion versus standard care, Outcome 4 Other sickle cell related complications.

Comparison 2. Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Clinical stroke1133Odds Ratio (M-H, Fixed, 95% CI)16.49 [0.92, 294.84]
3 Other neurological event1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Transient ischaemic attack1133Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.21, 1.86]
Analysis 2.1.

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 1 Mortality.

Analysis 2.2.

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 2 Clinical stroke.

Analysis 2.3.

Comparison 2 Hydroxyurea and phlebotomy versus standard treatment (transfusions/chelation), Outcome 3 Other neurological event.

What's new

DateEventDescription
6 November 2013New search has been performed

A Search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register identified six additional references to two already included trials (STOP 1998; STOP 2 2005) and 11 additional references to two trials previously listed in Ongoing studies (SIT Trial; SWiTCH 2012). The SWiTCH 2012 trial has now been listed as an included study. Two further studies have been included in the ongoing studies section of the review (SCATE Trial; TWiTCH Trial).

The title has been amended to include the terms 'primary and secondary'.

6 November 2013New citation required but conclusions have not changedThe inclusion of additional trials resulted in only minor amendments to the conclusion section of the review.

History

Protocol first published: Issue 3, 2001
Review first published: Issue 1, 2002

DateEventDescription
22 May 2009New search has been performedA search of the Group's Trials Register did not identify any new references which may have been eligible for inclusion in this review.
31 July 2008New search has been performedA search of the Group's Haemoglobinopathies Trials Register identified no new trials potentially eligible for inclusion in the review.
31 July 2008AmendedConverted to new review format.
1 August 2007New search has been performedA search of the Trials Register identified a total of 10 new references. Eight were of the STOP trials (two of which refer to both the STOP and STOP 2 trials and so appear in both lists (Adamkiewicz 2006; Kwiatkowski 2002)): six new references to the STOP trial (STOP 1998) as follows (Adamkiewicz 2006; Kwiatkowski 2002; Kwiatkowski 2006; Lee 2006; Lezcano 2006; Wang 2005).

The search also identified a further two abstracts (DeBaun 2005; Ware 2006) which have been listed in the 'Ongoing studies' section of the review.
1 February 2006New search has been performed

A search of the Trials Register identified seven new references to the included trial (STOP 1998) as follows: Abboud 2004; Adams 2004; Bulas 2000; Gates 2002; Hsu 2003; Kwiatkowski 2002; Kwiatkowski 2003.

It has also been reported that the STOP II trial has been terminated early, although published findings are not yet available.

31 August 2004New search has been performedA search of the trials register identified no new trials eligible for inclusion in the review.
31 August 2003New search has been performed

Additional references to the already included STOP 1998 study have been added. However, no new data have been found.

The references added to the STOP 1998 study ID were:
Adams 1998
Wang 1998
Adams 2002
Files 2002

30 September 2002New search has been performed

Additional references to the already included STOP 1998 study have been added. Therefore, further results are presented on the following outcomes -

1. Transfusion related complications
2. Incidence of transient ischaemic attack or silent infarction
3. Incidence of other sickle cell complications

The references added to the STOP 1998 study ID were:

Abbound 1999
Adams 1996
Adams 1997
Adams 1999 - two references
Adams 2001
Duncan 1997
Kutlar 2000
Lee 2002
Nichols 2001
Miller 2000 - two references
Miller 2001
Pegelow 1999
Pegelow 2001
Vichinsky 1999
Vichinsky 2001

Contributions of authors

The review was conceived by the Cochrane Cystic Fibrosis and Genetic Disorders Group and designed by Dr Hirst (née Riddington)

Dr Hirst and the Cochrane Cystic Fibrosis and Genetic Disorders Group conducted searches for relevant trials in previous versions of this review. In this current version WW and the Cochrane Cystic Fibrosis and Genetic Disorders Group conducted searches for relevant trials.

Drs Hirst and Wang screened, appraised and abstracted data for previous versions of this review and sought additional information from authors where necessary. Dr Hirst performed data entry and interpretation with advice from the Cochrane Cystic Fibrosis and Genetic Disorders Group for previous versions of this review. These tasks were performed by WW and Dr Kerry Dwan (KD) for this version.

WW acts as guarantor of the review.

Declarations of interest

WW was a PI on all included trials. KD has no known conflicts of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Department of Health - Research & Development, UK.

Differences between protocol and review

The title has been amended to include the terms 'primary and secondary'.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

STOP 1998

MethodsParallel RCT.
Participants

130 children with HbSS or HbSβ0Thal, at high risk of stroke as predicted by TCD.

Transfusion: 63

Standard care: 67

InterventionsTransfusion (HbS < 30%) or standard care.
OutcomesDeath, stroke (intracranial haemorrhage or cerebral infarction).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation by permuted blocks.
Allocation concealment (selection bias)High riskIt was not possible to conceal whether the patient was randomised to receive transfusion or not.
Blinding (performance bias and detection bias)
Suspected stroke
High riskIt was not possible to blind the treating physicians, the centre coordinators or the participants.
Blinding (performance bias and detection bias)
All other outcomes
Low riskA blinded panel of neurologist adjudicators made the decision of whether an event should be classified as a stroke (cerebral infarction or intracranial haemorrhage).
Incomplete outcome data (attrition bias)
All outcomes
Low riskAn intention-to-treat analysis was used, despite 12 participants crossing over between groups (2) or withdrawing from the trial (10). Reasons were provided. 10 participants from the transfusion group withdrew from the trial because of problems with compliance (n = 4), multiple alloantibodies (n = 1), ineligibility (n = 1) or other unspecified reasons (n = 4). 2 participants from the standard care group crossed over to the transfusion group, one on the second day due to diagnosis of subacute intracerebral hematoma and the other after 12 months for treatment of leg ulcers.
Selective reporting (reporting bias)Low riskAll review primary outcomes fully reported (see Table 1).

STOP 2 2005

MethodsParallel RCT.
Participants

79 children with HbSS or HbSβ0Thal at high risk of stroke, who had received regular blood transfusions for at least 30 months.

Transfusion continued: 38.

Tansfusion halted: 41.

InterventionsTransfusion or discontinuation of transfusion (standard care).
OutcomesDeath, stroke, high risk of stroke judged by abnormal TCD velocity.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation by permuted blocks. Participants were stratified according to the presence of ischaemic lesions on MRI.
Allocation concealment (selection bias)High riskIt was not possible to conceal whether the patient was randomised to receive transfusion or not.
Blinding (performance bias and detection bias)
Suspected stroke
Low riskExperts who adjudicated suspected strokes were blinded to treatment allocation.
Blinding (performance bias and detection bias)
All other outcomes
Unclear riskNo information provided.
Incomplete outcome data (attrition bias)
All outcomes
High riskIt was not stated whether intention-to-treat analysis was used. Some reasons were provided for the 25 that dropped out.
Selective reporting (reporting bias)Low riskAll review primary outcomes fully reported (see Table 1).

SWiTCH 2012

  1. a

    HbS: sickle haemoglobin
    HbSβ0Thal: sickle beta-zero thalassaemia
    HbSS: homozygous sickle cell disease
    MRI: magnetic resonance imaging
    RCT: randomised controlled trial
    TCD: transcranial Doppler ultrasonography

MethodsParallel RCT.
Participants133 children with HbSS and a history of stroke, chronic transfusion treatment and iron overload.
Interventions66 received transfusion and iron chelation; 67 received hydroxyurea and phlebotomy.
Outcomes

Composite primary endpoint of secondary stroke recurrence rate and quantitative liver iron concentration.

Secondary trial endpoints included non-stroke neurological events, non-neurological sickle cell clinical events, quality of life evaluation, and measures of organ function.

NotesClinicalTrials.gov NCT00122980.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation.
Allocation concealment (selection bias)Low riskInvestigators were unaware of allocation determination process.
Blinding (performance bias and detection bias)
Suspected stroke
Low riskSingle blind. The stroke adjudication panel was blinded to the patient's intervention.
Blinding (performance bias and detection bias)
All other outcomes
Low riskOther part of primary outcome (iron overload) based on quantitative measurement, so bias unlikely.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe SWiTCH trial states that they conducted an analysis in the "Intent to Treat Population, which consists of all participants who were randomised to a study treatment and for whom outcome data are available". Reasons were provided in each group for drop out.
Selective reporting (reporting bias)Low riskAll review primary outcomes fully reported (see Table 1).

Characteristics of ongoing studies [ordered by study ID]

SCATE Trial

Trial name or titleSparing Conversion to Abnormal TCD Elevation (SCATE Trial)
MethodsPhase III randomised trial comparing 30 months of alternative therapy (hydroxyurea) to standard care (observation)
ParticipantsApproximately 115 children with sickle cell anaemia, 2 - 10 years old, with conditional TCD velocities
InterventionsHydroxyurea x 30 months
OutcomesPrimary outcome: Conversion to abnormal TCD. Secondary outcomes: neurologic and non-neurologic events, TCD velocities, quality of life.
Starting dateMay 2012
Contact informationRussell E Ware
NotesClinicalTrials.gov identifier: NCT01531387

SIT Trial

Trial name or title'Silent Cerebral Infarct Multi-Center Trial' (SIT Trial)
Methods 
ParticipantsApproximately 3020 children with sickle cell disease, 6 - 13 years from 24 sites in USA will be screened (MRI), and approximately 204 who already have neurologic morbidity will be eligible for participation.
InterventionsProphylactic blood transfusion
OutcomesStroke, new cerebral infarcts, neurological damage and intellectual ability, risk benefit analysis of transfusion
Starting dateOngoing (36 month duration for individual patient follow up)
Contact informationMichael R DeBaun, Washington University School of Medicine
NotesClinicalTrials.gov identifier NCT00072761

TWiTCH Trial

  1. a

    MRI: magnetic resonance imaging
    TCD: transcranial Doppler ultrasonography

Trial name or titleTranscranial Doppler with Transfusions Changing to Hydroxyurea (TWiTCH Trial)
MethodsPhase III randomised trial comparing 24 months of alternative therapy (hydroxyurea) to standard care (chronic transfusion)
ParticipantsChildren with sickle cell disease and abnormal TCD velocity
InterventionsContinued prophylactic blood transfusion compared to hydroxyurea
OutcomesPrevention of recurrence of abnormal TCD velocity
Starting dateOngoing
Contact informationRussell E Ware
NotesClinicalTrials.gov identifier: NCT01425307

Ancillary