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.
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
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).
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).
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.