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Meta-Analysis
. 2020 Apr 6;4(4):CD012389.
doi: 10.1002/14651858.CD012389.pub3.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease

Lise J Estcourt  1 , Catherine Kimber  2 , Sally Hopewell  3 , Marialena Trivella  4 , Carolyn Doree  5 , Miguel R Abboud  6
Affiliations
Meta-Analysis

Interventions for preventing silent cerebral infarcts in people with sickle cell disease

Lise J Estcourt et al. Cochrane Database Syst Rev. .

Abstract

Background: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient.

Objectives: To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD.

Search methods: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 14 November 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 07 October 2019.

Selection criteria: Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status.

Data collection and analysis: We used standard Cochrane methodological procedures.

Main results: We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention. Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents). The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence). No deaths were reported in either trial. Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence). Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial) Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence). We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence). The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence). Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence). Neither trial reported on quality of life or cognitive function.

Authors' conclusions: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions. Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention. All other evidence in this review is of very low-quality.

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Conflict of interest statement

  1. Lise Estcourt: none known

  2. Catherine Kimber: none known

  3. Sally Hopewell: none known

  4. Marialena Trivella: none known

  5. Miguel Abboud: is a board member for several companies, has received research funding, consultancy and travel expenses (Global Research Therapeutics (GBT), Novartis, Crispr Therapeutics and Vertex Pharma, Modus Pharmaceutical, Roche, Novo, Astra Zeneca (personal and institution)). These activities had no relationship to the management of neurologic complications in sickle cell disease.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Red blood cell transfusions vs standard care, Outcome 1 Proportion of participants developing new or progressive SCI lesions.
1.2
1.2. Analysis
Comparison 1 Red blood cell transfusions vs standard care, Outcome 2 SCD ‐ related serious adverse events ‐ acute chest syndrome.
1.3
1.3. Analysis
Comparison 1 Red blood cell transfusions vs standard care, Outcome 3 SCD‐related serious adverse events ‐ pain crisis.
1.4
1.4. Analysis
Comparison 1 Red blood cell transfusions vs standard care, Outcome 4 Clinical stroke.
1.5
1.5. Analysis
Comparison 1 Red blood cell transfusions vs standard care, Outcome 5 Any transfusion‐related adverse events ‐ antibody development.
1.6
1.6. Analysis
Comparison 1 Red blood cell transfusions vs standard care, Outcome 6 Any transfusion‐related adverse events ‐ transfusion reactions.
2.1
2.1. Analysis
Comparison 2 Transfusions continued vs transfusions halted, Outcome 1 Proportion of participants developing new or progressive SCI lesions.
2.2
2.2. Analysis
Comparison 2 Transfusions continued vs transfusions halted, Outcome 2 All‐cause mortality.
2.3
2.3. Analysis
Comparison 2 Transfusions continued vs transfusions halted, Outcome 3 Clinical stroke.
3.1
3.1. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 1 Proportion of participants developing new or progressive SCI lesions ‐ secondary prevention.
3.2
3.2. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 2 All‐cause mortality ‐ secondary prevention.
3.3
3.3. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 3 SCD‐related SAEs ‐ Acute chest syndrome ‐ primary prevention.
3.4
3.4. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 4 SCD‐related SAEs ‐ Acute chest syndrome ‐ secondary prevention.
3.5
3.5. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 5 SCD‐related SAEs ‐ Pain crisis ‐ primary prevention.
3.6
3.6. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 6 SCD‐related SAEs ‐ Pain crisis ‐ secondary prevention.
3.7
3.7. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 7 Total SCD‐related SAEs ‐ primary prevention.
3.8
3.8. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 8 Total SCD‐related SAEs ‐ secondary prevention.
3.9
3.9. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 9 Clinical stroke ‐ secondary prevention.
3.10
3.10. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 10 Transfusion‐related complications ‐ serum ferritin ‐ primary prevention.
3.11
3.11. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 11 Transfusion‐related complications ‐ liver iron concentration ‐ primary prevention.
3.12
3.12. Analysis
Comparison 3 Hydroxyurea vs red blood cell transfusions, Outcome 12 Any SCD‐related adverse events ‐ secondary prevention.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

SIT 2014 {published data only}
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    1. Bhatnagar P, Casella EB, Arking DE, Casella JF. Genome‐wide association for silent cerebral infarction (SCI) in sickle cell disease: the silent infarct transfusion trial (SIT) cohort. Blood 2009;114(22):2563. [CFGD Register: SC184v]
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STOP 1998 {published data only}
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    1. Adamkiewicz T, Abboud M, Barredo J, Cavalier ME, Peterson J, Rackoff B, et al. Serum ferritin in children with SCD on chronic transfusion: correlation with serum alanine aminotransferase and liver iron (STOP/STOP II liver iron ancillary study). 35th Anniversary Convention of the National Sickle Cell Disease Program and the Sickle Cell Disease Association of America; 2007 Sep 17‐22; Washington DC. 2007:316.
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STOP 2 2005 {published data only}
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SWiTCH 2012 {published data only}
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    1. Aygun B, Mortier NA, Kesler K, Schultz WH, Alvarez OA, Rogers ZR, et al. Therapeutic phlebotomy in children with sickle cell anemia, stroke, and iron overload: the SWiTCH experience. 53rd Ash Annual Meeting and Exposition; 2011 Dec 10‐13; San Diego, California.. 2011. [Abstract no: 1044]
    1. Helton KJ, Adams RJ, Kesler KL, Lockhart A, Aygun B, Driscoll C, et al. Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial. Blood 2014;124(6):891‐8. - PMC - PubMed
    1. NCT00122980. Stroke with transfusions changing to hydroxyurea (SWiTCH). clinicaltrials.gov/ct2/show/NCT00122980 Date first received: 20 July 2005.
    1. National Institutes of Health. Stroke prevention study in children with sickle cell anemia, iron overload stopped early. www.nih.gov/news/health/jun2010/nhlbi‐03.htm (accessed prior to 09 February 2017).
TWITCH 2016 {published data only}
    1. Aygun B, Mortier N, Rogers ZR, Owen W, Fuh B, George A, et al. Iron unloading by therapeutic phlebotomy in previously transfused children with sickle cell anemia: the twitch experience. Blood 2016;128(22):1018. [DOI: 10.1182/blood.V128.22.1018.1018] - DOI
    1. Aygun B, Wruck LM, Schultz WH, Mueller BU, Brown C, Luchtman‐Jones L, et al. Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities. American Journal of Hematology 2012;87(4):428‐30. - PubMed
    1. Helton K, Roberts D, Schultz WH, Davis BR, Kalfa TA, Pressel SL, et al. Effects of Chronic Transfusion Therapy on MRI and MRA in Children with Sickle Cell Anemia at Risk for Primary Stroke: Baseline Imaging from theTwitch Trial. Blood 2014;124(21):4052.
    1. Imran H, Aygun B, Davis BR, Pressel SL, Schultz WH, Jackson S, et al. Effects of chronic transfusion therapy on transcranial doppler ultrasonography velocities in children with sickle cell anemia at risk for primary stroke: Baseline findings from the Twitch trial. Blood 2014;124(21):87.
    1. NCT01425307. Transcranial doppler (TCD) with transfusions changing to hydroxyurea [TCD with transfusions changing to hydroxyurea (TWiTCH): a phase III randomized trial to compare standard therapy (erythrocyte transfusions) with alternative therapy (hydroxyurea) for the maintenance of lowered TCD velocities in pediatric subjects with sickle cell anemia and abnormal pre‐treatment TCD velocities]. clinicaltrials.gov/ct2/show/NCT01425307 Date first received: 19 August 2011.

References to studies excluded from this review

Adams 1999 {published data only}
    1. Adams RJ, Carl EM, McKie VC, Odo NA, Kutlar A, Phillips M, Brambilla D. A pilot trial of hydroxyurea to prevent strokes in children with sickle cell anemia. National Sickle Cell Disease Program Annual Meeting Conference Proceedings; 1999 Mar. 1999:53.
BABY HUG 2011 {published data only}
    1. Adams RJ, Luden J, Miller S, Wang W, Rees R, Li D, et al. TCD in infants: a report from the Baby Hug study. 28th Annual Meeting of the National Sickle Cell Disease Program; 2005 Apr 9‐13; Cincinnati, Ohio.. 2005:105.
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DREPAGREFFE 2019 {published data only}
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Howard 2018 {published data only}
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Kawadler 2016 {published data only}
    1. Kawadler JM, Clayden JD, Clark CA, Kirkham FJ. Intelligence quotient in paediatric sickle cell disease: a systematic review and meta‐analysis. Developmental Medicine & Child Neurology 2016;58(7):672‐9. - PubMed
Kwiatkowski 2019 {published data only}
    1. Kanter J, Kwiatkowski J, Voeks J, Fullerton H, Debenham E, Adams R. Results of transcranial doppler ultrasound screening from the post‐stop study. Haematologica 2016;Supplement 1:167.
    1. Kwiatkowski JL, Voeks JH, Kanter J, Fullerton HJ, Debenham E, Brown L, et al. Ischemic stroke in children and young adults with sickle cell disease in the post‐STOP era. American Journal of Hematology 2019;94(12):1335‐43. - PubMed
Manwani 2012 {published data only}
    1. Manwani D. Hydroxycarbamide for very young children with sickle cell anaemia: No effect on the primary outcomes of spleen or kidney function, but evidence for decreased pain and dactylitis, with minimal toxicity. Evidence‐Based Medicine 2012;17(2):37‐8. [CFGD Register: SC334] - PubMed
Misra 2017 {published data only}
    1. Misra H, Bainbridge J, Berryman J, Abuchowski A, Galvez KM, Uribe LF, et al. A Phase Ib open label, randomized, safety study of SANGUINATETM in patients with sickle cell anemia. Revista Brasileira de Hematologia e Hemoterapia 2017;39(1):20‐7. - PMC - PubMed
NCT00004485 {published data only}
    1. NCT00004485. Bone marrow transplantation in treating children with sickle cell disease [Phase I/II study of induction of stable mixed chimerism after bone marrow transplantation from HLA‐identical donors in children with sickle cell disease]. clinicaltrials.gov/ct2/show/NCT00004485 Date first received: 18 October 1999.
NCT00402480 {published data only}
    1. NCT00402480. Hydroxyurea to prevent stroke in children with sickle cell anemia and elevated TCD flow velocity [Effects of hydroxyurea on the prevention of primary stroke in children with sickle cell anemia and elevated transcranial doppler (TCD) flow velocity]. clinicaltrials.gov/ct2/show/NCT00402480 Date first received: 21 November 2006.
NCT01801423 {published data only}
    1. NCT01801423. Sickle cell disease ‐ stroke prevention in Nigeria trial (SPIN) [Primary prevention of strokes in Nigerian children with sickle cell disease affiliated titles: sickle cell disease ‐ stroke prevention in Nigeria (SPIN) trial]. clinicaltrials.gov/ct2/show/NCT01801423 Date first received: 26 February 2013.
NCT01987908 {published data only}
    1. EUCTR2013‐001534‐18‐GB. A study to investigate the effects aes‐103 in patients with sickle cell disease [A phase 2, exploratory, placebo‐controlled, multicenter, double‐blind evaluation of the safety, pharmacokinetics, pharmacodynamics, and clinical effects of five dose regimens of aes‐103 given for 28 days to subjects with stable sickle cell disease]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2013‐001534‐18‐GB 2013. [CENTRAL: CN‐01864959; CFGD Register: SC368; CRS: 10764747]
    1. NCT01987908. Evaluation of different dose regimens of Aes‐103 given for 28 days to subjects with stable sickle cell disease. https://clinicaltrials.gov/ct2/show/NCT01987908 First submitted on: 29 October 2013.
NCT02114203 {published data only}
    1. NCT02114203. Safety, tolerability, pharmacokinetics, and pharmacodynamics study of PF‐04447943, co‐administered with and without hydroxyurea, in subjects with stable sickle cell disease. clinicaltrials.gov/ct2/show/NCT02114203 First submitted on: 7 April 2014.
NCT02560935 {published data only}
    1. NCT02560935. Primary prevention of stroke in children with SCD in Sub‐Saharan Africa II (SPRING). clinicaltrials.gov/ct2/show/NCT02560935 Date first received: 2 September 2015.
NCT02675790 {published data only}
    1. NCT02675790. Low dose hydroxyurea for secondary stroke prevention in children with sickle cell disease in Sub‐Saharan Africa (SPRINT). clinicaltrials.gov/ct2/show/NCT02675790 Date first received: 8 January 2016.
NCT02813850 {published data only}
    1. NCT02813850. Oxygen therapy and pregnancy in sickle cell disease (DRO2G). clinicaltrials.gov/ct2/show/NCT02813850 First submitted on: 23 June 2016.
NCT03128515 {published data only}
    1. NCT03128515. Optimizing hydroxyurea therapy in children with SCA in malaria endemic areas (NOHARM‐MTD). clinicaltrials.gov/ct2/show/NCT03128515 First submitted on: 22 March 2017.
NCT03401112 {published data only}
    1. NCT03401112. A study of IMR‐687 in adult patients With sickle cell anaemia (homozygous HbSS or sickle‐β0 thalassemia). clinicaltrials.gov/ct2/show/NCT03401112 First submitted on: 2 January 2018.
NCT03666806 {published data only}
    1. NCT03666806. Preventing stroke triggers in children with sickle cell anaemia in Mulago Hospital, Kampala (PREST ): a randomized control trial. https://clinicaltrials.gov/ct2/show/NCT03666806 First submitted on: 10 September 2018.
NCT03975894 {published data only}
    1. NCT03975894. TAPS2 Transfusion Antenatally in Pregnant Women With SCD (TAPS2). clinicaltrials.gov/ct2/show/NCT03975894 Date first received: 17 May 2019.
NCT03976180 {published data only}
    1. NCT03976180. High‐flow oxygen for vaso‐occlusive pain crisis (OSONE). https://clinicaltrials.gov/ct2/show/NCT03976180 First submitted on: 24 May 2019.
NCT04084080 {published data only}
    1. NCT04084080. Sickle cell disease and cardiovascular risk ‐ red cell exchange trial (SCD‐CARRE). clinicaltrials.gov/ct2/show/NCT04084080 Date first received: August 26 2019.
Steinberg 2010 {published data only}
    1. Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD, Smith W, et al. The risks and benefits of long‐term use of hydroxyurea in sickle cell anemia: A 17.5 year follow‐up. American Journal of Hematology 2010;85(6):403‐8. - PMC - PubMed
Washington 2018 {published data only}
    1. EUCTR2017‐000903‐26. A phase 3, randomized, double‐blind, placebo controlled study of voxelotor (GBT440) in pediatric participants with sickle cell disease and an open‐label study in infants with sickle cell disease (HOPE Kids 2). clinicaltrialsregister.eu/ctr‐search/trial/2017‐000903‐26/GB First submitted on:22 June 2018.
    1. Washington CB, Goldstein B, Dixon S, Hoppe C, Ware RE, Lehrer J. Voxelotor dose extrapolation in a phase 3, randomized, double‐blind, placebo‐controlled study in pediatric patients with sickle cell disease (GBT440‐032, hope kids 2). HemaSphere 2018;2(Supplement 2):666.

References to studies awaiting assessment

Vichinsky 2010 {published data only}
    1. NCT00850018. Examining cognitive function and brain abnormalities in adults with sickle cell disease ‐ pilot intervention study [Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell disease ‐ a pilot intervention study]. clinicaltrials.gov/ct2/show/NCT00850018 Date first received: 20 February 2009.
    1. Vichinsky E, Neumay L, Gold JI, Weiner MW, Kasten J, Truran D, et al. A Randomized trial of the safety and benefit of transfusion vs. standard care in the prevention of sickle cell‐related complications in adults: a preliminary report from the phase I NHLBI comprehensive sickle cell centers (cscc) study of neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adult patients with sickle cell disease. Blood 2010;116(21):1321.
    1. Vichinsky E, Neumayr L, Gold JI, Weiner MW, Kasten J, Truran D. A randomised trial of the safety and benefit of transfusion vs. standard care in the prevention of sickle cell‐related complications in adults: a preliminary report from the phase II NHLBI comprehensive sickle cell centers (CSCC) study of neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adult patients with sickle cell disease. 52nd Ash Annual Meeting and Exposition; 2010 Dec 4‐7; Orlando, Florida.. 2010. [Abstract no: 3221]

References to ongoing studies

NCT01389024 {published data only}
    1. NCT01389024. Hydroxyurea to prevent brain injury in sickle cell disease (HUPrevent) [Hydroxyurea to prevent central nervous system (CNS) complications of sickle cell disease in children]. clinicaltrials.gov/ct2/show/NCT01389024 Date first received: 30 June 2011.

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References to other published versions of this review

Estcourt 2016
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