Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

Patricia M Fortin; Sheila A Fisher; Karen V Madgwick; Marialena Trivella; Sally Hopewell; Carolyn Doree; Lise J Estcourt

doi:10.1002/14651858.CD012349.pub2

Cochrane Database of Systematic Reviews

Intervenciones para mejorar la adherencia al tratamiento de quelación del hierro en pacientes con anemia de células falciformes o talasemia

Información

DOI:

https://doi.org/10.1002/14651858.CD012349.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

08 mayo 2018see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Fibrosis quística y enfermedades genéticas

Copyright:

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Patricia M Fortin

Sechelt, Canada
Sheila A Fisher

Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK
Karen V Madgwick

Department of Pathology, North Middlesex University Hospital NHS Trust, London, UK
Marialena Trivella

Centre for Statistics in Medicine, University of Oxford, Oxford, UK
Sally Hopewell

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK
Carolyn Doree

Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK
Lise J Estcourt

Correspondencia a: Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK

[email protected]

[email protected]

Contributions of authors

Lise Estcourt: searching; selection of trials; eligibility assessment; content expert, and review content development
Patricia Fortin: searching; selection of trials; eligibility assessment; data extraction, risk of bias assessment, and review content development.
Karen Madgwick: selection of trials; eligibility assessment; data extraction, risk of bias assessment, content expert.
Sally Hopewell: methodological expert and review development.
Marialena Trivella: statistical and methodological expert and review development
Sheila Fisher: data extraction, risk of bias assessment, review content development.

Sources of support

Internal sources

NHS Blood and Transplant, Research and Development, UK.

To fund the work of the Systematic Review Initiative (SRI)

External sources

National Institute for Health Research (NIHR) Cochrane Programme Grant, UK.

To provide funding for systematic reviewers and methodological support from the Centre for Statistics in Medicine, Oxford

Declarations of interest

Lise Estcourt: partly funded by the NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Patricia Fortin: funded by the NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Karen Madgwick: none to declare.

Sally Hopewell: partly funded by the NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Marialena Trivella: partly funded by the NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Sheila Fisher: partly funded by the NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Acknowledgements

We thank the National Institute for Health Research for supporting this project, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

This review is part of a series of reviews that have been partly funded by the NIHR Cochrane Programme Grant ‐ Safe and Appropriate Use of Blood Components.

Version history

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Version

2023 Mar 06

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

Review

Louise J Geneen, Carolyn Dorée, Lise J Estcourt

https://doi.org/10.1002/14651858.CD012349.pub3

2018 May 08

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

Review

Patricia M Fortin, Sheila A Fisher, Karen V Madgwick, Marialena Trivella, Sally Hopewell, Carolyn Doree, Lise J Estcourt

https://doi.org/10.1002/14651858.CD012349.pub2

2016 Sep 11

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

Protocol

Patricia M Fortin, Karen V Madgwick, Marialena Trivella, Sally Hopewell, Carolyn Doree, Lise J Estcourt

https://doi.org/10.1002/14651858.CD012349

Differences between protocol and review

See Fortin 2016.

Confidence intervals

In most studies we were unable to report total adverse events due to participants having one or more of the listed adverse events. We therefore use the 99% CI to report estimates of effects in subgroups of adverse events.

Assessment of reporting biases

We could not assess reporting bias as there were fewer than 10 trials for each comparison

Subgroup analysis

Due to insufficient data we could not undertake subgroup analyses as planned in the protocol (see below). From the outset, we also reported separately on the SCD trial.

Age of participant (child (one to 12 years), adolescent (13 to 17 years) adult (18+ years))
Type of disease (SCD or thalassaemia)
Route of administration of iron chelating agents (oral, intravenous or subcutaneous)

Sensitivity analysis

We could not undertake sensitivity analyses due to a lack of data.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Child; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 DFP versus DFO, Outcome 1 Adherence to iron chelation therapy (%, SD).

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Analysis 1.2

Comparison 1 DFP versus DFO, Outcome 2 SAEs (from therapy, disease, non‐adherence).

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Analysis 1.3

Comparison 1 DFP versus DFO, Outcome 3 All‐cause mortality.

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Analysis 1.4

Comparison 1 DFP versus DFO, Outcome 4 Iron overload: defined as proportion of participants with serum ferritin ≥ 800 (µg/L).

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Analysis 1.5

Comparison 1 DFP versus DFO, Outcome 5 Organ damage.

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Analysis 1.6

Comparison 1 DFP versus DFO, Outcome 6 Other AEs related to iron chelation.

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Analysis 2.1

Comparison 2 DFX versus DFO, Outcome 1 Adherence to iron chelation therapy (%, SD).

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Analysis 2.2

Comparison 2 DFX versus DFO, Outcome 2 SAEs.

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Analysis 2.3

Comparison 2 DFX versus DFO, Outcome 3 All‐cause mortality (thalassaemia).

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Analysis 2.4

Comparison 2 DFX versus DFO, Outcome 4 Proportion of participants with iron overload (thalassaemia).

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Analysis 2.5

Comparison 2 DFX versus DFO, Outcome 5 Other AEs related to iron chelation ‐ (thalassaemia).

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Analysis 2.6

Comparison 2 DFX versus DFO, Outcome 6 Total AEs (thalassaemia).

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Analysis 2.7

Comparison 2 DFX versus DFO, Outcome 7 Other AEs related to iron chelation (SCD).

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Analysis 3.1

Comparison 3 DFX film‐coated tablet versus DFX dispersible tablet, Outcome 1 Adherence to iron chelation therapy.

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Analysis 3.2

Comparison 3 DFX film‐coated tablet versus DFX dispersible tablet, Outcome 2 Incidence of SAEs.

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Analysis 3.3

Comparison 3 DFX film‐coated tablet versus DFX dispersible tablet, Outcome 3 All‐cause mortality.

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Analysis 3.4

Comparison 3 DFX film‐coated tablet versus DFX dispersible tablet, Outcome 4 Incidence of organ damage (renal event).

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Analysis 3.5

Comparison 3 DFX film‐coated tablet versus DFX dispersible tablet, Outcome 5 Other AEs related to iron chelation.

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Analysis 4.1

Comparison 4 DFP and DFO versus DFP, Outcome 1 Incidence of SAEs.

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Analysis 4.2

Comparison 4 DFP and DFO versus DFP, Outcome 2 All‐cause mortality.

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Analysis 4.3

Comparison 4 DFP and DFO versus DFP, Outcome 3 Incidence of chelation therapy‐related AEs.

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Analysis 5.1

Comparison 5 DFP and DFO versus DFO, Outcome 1 Other AEs related to iron chelation.

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Analysis 6.1

Comparison 6 DFP/DFX versus DFP/DFO, Outcome 1 Adherence to iron chelation therapy rates.

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Analysis 6.2

Comparison 6 DFP/DFX versus DFP/DFO, Outcome 2 Incidence of SAE.

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Analysis 6.3

Comparison 6 DFP/DFX versus DFP/DFO, Outcome 3 All‐cause mortality.

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Analysis 6.4

Comparison 6 DFP/DFX versus DFP/DFO, Outcome 4 Organ damage (serum creatinine (≥33%) above baseline in 2 consecutive occasions).

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Analysis 6.5

Comparison 6 DFP/DFX versus DFP/DFO, Outcome 5 Other AEs related to iron chelation.

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Summary of findings for the main comparison. DFP compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

DFP compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Patient or population: improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia Setting: outpatients Intervention: DFP Comparison: DFO
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with DFO	Risk with DFP
Adherence to iron chelation therapy (per cent, SD)			‐	242 (4 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2}	We found considerable heterogeneity and identified age as possible cause: 1 trial in children 10 years or older and 1 conducted in participants 18 or older
SAEs (from therapy, disease, non‐adherence) Agranulocytosis**	Study population		RR 7.88 (99% CI 0.18 to 352.39)	88 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{3 4}	No SAEs were reported in the second trial reporting this outcome
	15 per 1000	118 per 1,000 (7 to 1000)
All‐cause mortality	Study population		RR 0.44 (95% CI 0.12 to 1.63)	88 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{3 4}	No deaths occurred in the second trial reporting this outcome
	146 per 1000	64 per 1000 (18 to 239)
Sustained adherence ‐ not measured	‐	‐	‐	‐	‐	Sustained adherence is reported as adherence as all trials were longer than 6 months and only end of trial adherence numbers were provided
Quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DFO: deferoxamine; DFP: deferiprone; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence by 1 for risk of bias due to high or uncertain risk of bias due to lack of blinding of participants and personnel in all four RCTs, as well as selection bias (Olivieri 1997), attrition bias (El Beshlawy 2008; Olivieri 1997), reporting bias (El Beshlawy 2008; Pennell 2006), and other bias (Pennell 2006). ² We downgraded the quality of evidence by 2 for inconsistency due to considerable heterogeneity in comparison. ³ We downgraded the quality of evidence by 2 for imprecision due to very wide CIs that included clinically important benefits and harms. ⁴ We downgraded the quality of evidence by 1 for indirectness as the trial was conducted in participants with thalassaemia intermedia only; a milder form of thalassaemia ** Risk estimate based on: Tricta F, Uetrecht J, Galanello R, et al. Deferiprone‐induced agranulocytosis: 20 years of clinical observations. American Journal of Hematology. 2016;91(10):1026‐1031. doi:10.1002/ajh.24479.

Summary of findings for the main comparison. DFP compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

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Summary of findings 2. DFX compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

DFX compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Patient or population: improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia Setting: outpatients Intervention: DFX Comparison: DFO
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with DFO	Risk with DFX
Adherence to iron chelation therapy (per cent, SD)	The mean adherence to iron chelation therapy (per cent, SD) was 0	MD 1.4 lower (3.66 lower to 0.86 higher)	‐	197 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	Narrative report of adherence for 2 trials as either no or incompatible data to enable comparisons
SAEs ‐ thalassaemia‐related SAEs	Study population		‐	247 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2}	There were no SAEs to report in one trial so no estimate of effect
	see comment	see comment
SAEs ‐ SCD‐related SAEs	Study population		RR 1.08 (95% CI 0.77 to 1.51)	195 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	429 per 1000	463 per 1000 (330 to 647)
Incidence of SCD‐related SAEs ‐pain crisis	Study population		RR 1.05 (95% CI 0.68 to 1.62)	195 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	317 per 1000	333 per 1000 (216 to 514)
All‐cause mortality (thalassaemia)	Study population		RR 0.96 (95%CI 0.06 to 15.06)	240 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	8 per 1000	8 per 1000 (1 to 128)
Sustained adherence ‐ not measured	‐	‐	‐	‐	‐	Sustained adherence is reported as adherence as all trials were longer than 6 months and only end of trial adherence reported
Quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DFO: deferoxamine; DFX: deferasirox; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence by 2 due to high or uncertain risk of bias in several domains ² We downgraded the quality of evidence by 1 due to imprecision as CIs are wide and only 1 trial with data in comparison

Summary of findings 2. DFX compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

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Summary of findings 3. DFX film‐coated tablet compared to DFX dispersible tablet for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

DFX film‐coated tablet compared to DFX dispersible tablet for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Patient or population: improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia Setting: outpatients Intervention: DFX film‐coated tablet Comparison: DFX dispersible tablet
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with DFX dispersible tablet	Risk with DFX film‐coated tablet
Adherence to iron chelation therapy (n, N)	Study population		RR 1.10 (95% CI 0.99 to 1.22)	173 (1 RCT)	⊕⊕⊝⊝ LOW ¹
	849 per 1000	934 per 1000 (840 to 1000)
Incidence of SAEs	Study population		RR 1.22 (95% CI 0.62 to 2.37)	173 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	151 per 1,000	184 per 1000 (94 to 358)
All‐cause mortality	Study population		RR 2.97 (95% CI 0.12 to 71.81)	173 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}
	0 per 1000	0 per 1000 (0 to 0)
Sustained adherence ‐ not measured	‐	‐	‐	‐	‐	Reported as adherence as trial was 6 months in duration and end of trial adherence reported
Quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DFX: deferasirox; RCT: randomised controlled trial; RR: risk ratio; SAEs: serious adverse events
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence by 2 for risk of bias due to high or unclear risk of bias in all domains ² We downgraded the quality of evidence by 1 for imprecision due to wide CIs

Summary of findings 3. DFX film‐coated tablet compared to DFX dispersible tablet for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

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Summary of findings 4. DFP and DFO compared to DFP for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

DFP and DFO compared to DFP for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Patient or population: improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia Setting: outpatients Intervention: DFP and DFO Comparison: DFP
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with DFP	Risk with DFP and DFO
Adherence to iron chelation therapy (per cent, SD)	see comment	see comment	‐	289 (3 RCTs)	⊕⊝⊝⊝ VERY LOW ^{1 2}	Reported as narrative as no comparisons possible
Incidence of SAEs	Study population		RR 0.15 (95% CI 0.01 to 2.81)	213 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}
	28 per 1,000	4 per 1,000 (0 to 78)
All‐cause mortality	Study population		RR 0.77 (95% CI 0.18 to 3.35)	237 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{3 4}
	33 per 1,000	26 per 1,000 (6 to 112)
Sustained adherence ‐ not measured	‐	‐	‐	‐	‐	Sustained adherence is reported as adherence as trial duration longer than 6 months and reports adherence for length of trial
Quality of life ‐ not reported	‐	‐	‐	‐	‐	Quality of life was either not reported or no validated instruments were used
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DFO: deferoxamine DFP: deferiprone; RCT: randomised controlled trial; RR: risk ratio; SAEs: serious adverse events; SD: standard deviation.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence by 2 for risk of bias as there was high or uncertain risk of bias in most domains in 3 out of 4 trials ² We downgraded the quality of evidence by 1 due to high or unclear risk of bias in 3 domains ³ We downgraded the quality of evidence by 1 for imprecision due to wide CIs ⁴ We downgraded the quality of evidence by 2 for risk of bias as there was high or uncertain risk of bias in 1 of the trials in the comparison

Summary of findings 4. DFP and DFO compared to DFP for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

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Summary of findings 5. DFP and DFO compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

DFP and DFO compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Patient or population: improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia Setting: outpatients Intervention: DFP and DFO Comparison: DFO
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with DFO	Risk with DFP and DFO
Adherence to iron chelation therapy (per cent, SD)	see comment	see comment	‐	205 (4 RCTs)	⊕⊕⊝⊝ LOW ¹	Reported as narrative only as adherence in combined group not reported for combination therapy
Incidence of SAEs	Study population		‐	205 (4 RCTs)	⊕⊕⊝⊝ LOW ¹	3 trials report no SAEs; SAES are not reported in one trial
	see comment	see comment
All‐cause mortality	Study population		‐	205 (4 RCTs)	⊕⊕⊝⊝ LOW ¹	no deaths reported
	see comment	see comment
Sustained adherence ‐ not measured	‐	‐	‐	‐	‐	Sustained adherence reported as adherence as trial duration was longer than 6 months and adherence reported at end of trial
Quality of life ‐ not reported	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). DFO: deferoxamine; DFP: deferiprone; SAEs: serious adverse events.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence by 2 for risk of bias as high or unclear risk of bias in all domains

Summary of findings 5. DFP and DFO compared to DFO for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

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Summary of findings 6. DFP and DFO compared to DFP and DFX for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

DFP/DFO compared to DFP/DFX for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Patient or population: improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia Setting: outpatients Intervention: DFP/DFO Comparison: DFP/DFX
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with DFP/DFX	Risk with DFP/DFO
Adherence to iron chelation therapy rates (n,N) ‐ 1 year	Study population		RR 0.84 (95% CI 0.72 to 0.99)	96 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}
	938 per 1000	788 per 1000 (675 to 928)
Incidence of SAE	Study population		RR 1.00 (95% CI 0.06 to 15.53)	96 (1 RCT)	⊕⊝⊝⊝ VERY LOW^{1 2 3}
	21 per 1,000	21 per 1000 (1 to 324)
All‐cause mortality ‐ at 1 year ‐ trial end	Study population		Not estimable	96 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	No deaths were reported
	0 per 1000	0 per 1000 (0 to 0)
Sustained adherence ‐ not measured	‐	‐	‐	‐	‐	Sustained adherence is reported as adherence as trial was 1 year in duration and end of trial adherence reported
Quality of life see comment	‐	‐	‐	‐	‐	The study uses SF36 to measure quality of life, the results are presented as a graph. Quality of life increased in both trial arms with no significant difference between trial arms P = 0.860
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence by 1 for risk of bias as there was high or unclear risk of bias in 3 domains ² We downgraded the quality of evidence by 1 for indirectness as the trial included children 10 ‐ 18 with severe iron overload ³ We downgraded the quality of evidence by 1 for imprecision as the comparison has wide CIs

Summary of findings 6. DFP and DFO compared to DFP and DFX for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

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Summary of findings 7. Medication management compared to standard care for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

Medication management compared to standard care for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia
Patient or population: improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia Setting: outpatient Intervention: medication management Comparison: standard care
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with standard care	Risk with medication management	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Adherence to iron chelation therapy ‐ not reported			‐	‐	‐	Adherence was only reported in the intervention group and therefore no comparative data
SAEs ‐ not reported	‐	‐	‐	‐	‐
Mortality ‐ not reported	‐	‐	‐	‐	‐
Sustained adherence	‐	‐	‐	‐	‐	Adherence was only reported in the intervention group and therefore no comparative data
Quality of life assessed with: PedsQLTM HRQoL total score			‐	48 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	Medication management: 63.51 (51.75 – 84.54); standard care: 49.84 (41.9 – 60.81)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). RCT: randomised controlled trial; SAEs: serious adverse events.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ We downgraded the quality of evidence for indirectness by 2 because most outcomes were only reported in the medication management group ² We downgraded the quality of evidence by 2 for risk of bias due to high or uncertain risk of bias in all domains

Summary of findings 7. Medication management compared to standard care for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia

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Table 1. Adherence Measurement and Results Table

STUDY

HOW ADHERENCE MEASURED

RESULTS

Aydinok 2007

Drug accounting at each visit (by counting the returned empty blisters of DFP and used vials of DFO)
Trial‐specific designed questionnaire completed by the participants or their legal representative/guardian (or both) at quarterly intervals

Compliance was generally excellent during the entire trial period
1 participant in the DFP treatment arm who missed more than 1 chelation dose per week because of problems with swallowing

Badawy 2010

Questionnaire on chelation therapy, reasons for non‐compliance, side effects, life activities, transfusion regimen

Group II and group I were more compliant to chelation therapy but difference was statistically non significant
Non‐compliant participants (compliance less than 50%) showed increase in their SF levels in all studied groups
In non‐compliant participants the reduction in SF levels was higher in group I and III than in group II but difference was statistically non significant

Bahnasawy 2017

Clinical pharmacist analysed data to detect unnecessary drug therapy, need for additional drug therapy, ineffective drug product, dosage too low, adverse drug reaction, dosage too high, non‐compliance

All 24 participants in intervention group had non‐adherence at baseline and 3 where non‐adherent at end of trial
No data on control group

Calvaruso 2015

Counting the number of DFP pills in each returned bag
Assessing the number of infusions of DFO registered on the electronic pump

DFP compliance rate: 85%
DFO compliance rate: 76%

El Beshlawy 2008

Counting the returned empty blisters of DFP
Counting used vials of DFO

4 participants with DFO‐based regimen excluded from the trial due to lack of compliance
Compliance was otherwise excellent during the entire trial period
Majority of participants had no problems with the intake and swallowing of the DFP tablets
80% of participants in the combination arm and 76% of participants in the DFO monotherapy arm complained about difficulties in the parenteral use of DFO or problems to insert a needle

Elalfy 2015

Counting of returned tablets for the oral chelators
Counting vials for DFO
The percentage of actual dose that patient had taken in relation to the total prescribed dose was calculated

DFP/DFX: 95%
DFP/DFO: 80%

Galanello 2006

DFP assessed by pill counts, diary cards and an electronic cap that recorded the time and date of each opening of the tablet container
DFO assessed by diary cards, weekly physical examination of infusion sites, and by the Crono™ infusion pump that recorded the number of completed infusions

DFP/DFO: DFO: 96.1 ±5.0 (29 participants)
DFP compliance was not reported
DFO: 95.7 ± 5.7 (30 participants)

Hassan 2016

Records of all trial medications that were dispensed and returned
Parents were instructed to contact the investigator if the participant were unable to take the trial drug as prescribed

All participants compliant with prescribed doses
No discontinuation of drugs or dropout of follow‐up occurred

Maggio 2009

Counting the pills in each returned bag of DFP
Assessing the number of infusions of DFO registered on the electronic pump

DFP–DFO group: DFP: 92.7% (SD ± 15.2%; range 37–100%): DFO: 70.6% (SD ± 24.1%; range 25–100%)
DFP alone participants: 93.6% (SD ± 9.7%; range 56–100%)

Mourad 2003

Number of vials of DFX used
Number of tablets of DFO used

DFO/DFX group: compliance was excellent (arbitrarily defined as taking > 90% of the recommended doses) in 10 participants and good (75% to 90% of recommended doses) in 1 participant
DFX alone group: compliance was considered to be excellent in 11 patients and good in 3 participants

Olivieri 1997

Per cent of doses administered: number of doses of the iron chelator taken, out of number prescribed
DFP measured with computerised bottles
DFO measured using ambulatory pumps
Measured for a minimum of 3 months

DFP: 94.9% ± 1.1%
DFO: 71.6% ± 3.7%

Pennell 2006

DFP: measured using the Medication Event Monitoring System device calculated as the percent of openings with an interval longer than 4 hours recorded, divided by number of doses prescribed
DFO: calculated as the percentage of completed infusions, as determined by the Crono pumps, divided by the number of infusions prescribed

DFP: 94% ± 5.3%
DFO: 93% ± 9.7%

Pennell 2014

Not stated how adherence was measured

DFX: 99.0% ± 3.5%
DFO: 100.4% ± 10.9%

Taher 2017

Assessed by relative consumed tablet count

DT: 85.3% (95% CI: 81.1, 89.5)
FCT: 92.9% (95% CI: 88.8, 97.0)

Tanner 2007

DFO: calculated as the percentage of completed infusions, as determined by the Crono pumps, divided by the number of infusions prescribed
DFP/placebo: pill counting at the bimonthly visits

DFO/placebo: DFO: 91.4 ± 2.7%; placebo: 89.8 ± 7.2%;
DFO/DFP: DFO: 92.6 ± 2.7%; DFP: 82.4 ± 18.1%

Vichinsky 2007

DFX: counting the number of tablets returned in bottles at each visit
DFO: counting the numbers of vials returned at each visit

Ratios of the administered to intended doses of therapy were high (1.16 for DFX and 0.97 for DFO), indicating high adherence to the prescribed treatment regimens

DFO: deferoxamine
DFP: deferiprone
DFX: deferasirox
DT: dispersible tablet
FCT: film‐coated tablet
SD: standard deviation
SF: serum ferritin

Table 1. Adherence Measurement and Results Table

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Comparison 1. DFP versus DFO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adherence to iron chelation therapy (%, SD) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

2 SAEs (from therapy, disease, non‐adherence) Show forest plot	1		Risk Ratio (M‐H, Random, 99% CI)	Totals not selected

2.1 Agranulocytosis	1		Risk Ratio (M‐H, Random, 99% CI)	0.0 [0.0, 0.0]
3 All‐cause mortality Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

4 Iron overload: defined as proportion of participants with serum ferritin ≥ 800 (µg/L) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Organ damage Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Liver damage	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Other AEs related to iron chelation Show forest plot	3		Risk Ratio (IV, Random, 99% CI)	Subtotals only

6.1 Risk of leukopenia, neutropenia and/or agranulocytosis	3	192	Risk Ratio (IV, Random, 99% CI)	3.94 [0.44, 35.50]
6.2 Risk of pain or swelling in joints	3	192	Risk Ratio (IV, Random, 99% CI)	3.38 [0.54, 21.31]
6.3 Risk of nausea/vomiting	2	132	Risk Ratio (IV, Random, 99% CI)	13.68 [0.99, 188.88]
6.4 Risk of increased liver transaminase	1	44	Risk Ratio (IV, Random, 99% CI)	1.10 [0.03, 38.47]
6.5 Local reactions at infusion site	1	88	Risk Ratio (IV, Random, 99% CI)	0.17 [0.00, 9.12]

Comparison 1. DFP versus DFO

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Comparison 2. DFX versus DFO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adherence to iron chelation therapy (%, SD) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

2 SAEs Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Thalassaemia‐related SAEs	2		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 SCD‐related SAE ‐ painful crisis	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 SCD‐related SAEs ‐ other SCD‐related SAEs	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 All‐cause mortality (thalassaemia) Show forest plot	2	240	Risk Ratio (IV, Random, 95% CI)	0.96 [0.06, 15.06]

4 Proportion of participants with iron overload (thalassaemia) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Iron overload defined by ferritin 1500 (µg/l) or higher (Thalassaemia)	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.63, 2.20]
4.2 Proportion with severe iron overload (LIC at least 15 mg/Fe/g dw)	1	172	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.83, 1.20]
4.3 Myocardial T2* < 10ms	1	172	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.72, 1.70]
5 Other AEs related to iron chelation ‐ (thalassaemia) Show forest plot	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only

5.1 Total chelation‐related AE	1	187	Risk Ratio (IV, Random, 95% CI)	1.15 [0.76, 1.73]
5.2 Gastrointestinal upset	1	60	Risk Ratio (IV, Random, 95% CI)	3.0 [0.66, 13.69]
5.3 Rash	2	247	Risk Ratio (IV, Random, 95% CI)	3.05 [0.98, 9.47]
5.4 Risk of increased blood creatinine	1	187	Risk Ratio (IV, Random, 95% CI)	3.79 [0.83, 17.38]
5.5 Risk of proteinuria	1	187	Risk Ratio (IV, Random, 95% CI)	2.21 [0.59, 8.29]
5.6 Risk of increased ALT	1	187	Risk Ratio (IV, Random, 95% CI)	5.69 [0.70, 46.33]
5.7 Risk of increased AST	1	187	Risk Ratio (IV, Random, 95% CI)	5.69 [0.70, 46.33]
5.8 Risk of diarrhoea	1	187	Risk Ratio (IV, Random, 95% CI)	5.69 [0.70, 46.33]
5.9 Risk of vomiting	1	187	Risk Ratio (IV, Random, 95% CI)	6.64 [0.35, 126.78]
6 Total AEs (thalassaemia) Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

7 Other AEs related to iron chelation (SCD) Show forest plot	1		Risk Ratio (M‐H, Random, 99% CI)	Subtotals only

7.1 Risk of increased ALT	1	195	Risk Ratio (M‐H, Random, 99% CI)	5.29 [0.12, 232.98]
7.2 incidence of abdominal pain	1	195	Risk Ratio (M‐H, Random, 99% CI)	1.91 [0.80, 4.58]
7.3 Risk of pain or swelling in joints	1	195	Risk Ratio (M‐H, Random, 99% CI)	1.06 [0.41, 2.76]
7.4 Risk of diarrhoea	1	195	Risk Ratio (M‐H, Random, 99% CI)	4.14 [0.90, 18.92]
7.5 Nausea/vomiting	1	195	Risk Ratio (M‐H, Random, 99% CI)	1.63 [0.90, 2.94]

Comparison 2. DFX versus DFO

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Comparison 3. DFX film‐coated tablet versus DFX dispersible tablet

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adherence to iron chelation therapy Show forest plot	1	173	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.99, 1.22]

2 Incidence of SAEs Show forest plot	1	173	Risk Ratio (IV, Random, 95% CI)	1.22 [0.62, 2.37]

3 All‐cause mortality Show forest plot	1	173	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 71.81]

4 Incidence of organ damage (renal event) Show forest plot	1	173	Risk Ratio (IV, Random, 95% CI)	1.25 [0.83, 1.91]

5 Other AEs related to iron chelation Show forest plot	1		Risk Ratio (IV, Random, 99% CI)	Subtotals only

5.1 Total chelation‐related AEs	1	173	Risk Ratio (IV, Random, 99% CI)	0.75 [0.52, 1.08]
5.2 Risk of diarrhoea	1	173	Risk Ratio (IV, Random, 99% CI)	0.70 [0.29, 1.70]
5.3 Increased urine protein/urine creatinine ratio	1	173	Risk Ratio (IV, Random, 99% CI)	1.65 [0.60, 4.54]
5.4 incidence of abdominal pain	1	173	Risk Ratio (IV, Random, 99% CI)	0.49 [0.16, 1.52]
5.5 Incidence of nausea	1	173	Risk Ratio (IV, Random, 99% CI)	0.72 [0.23, 2.23]
5.6 Incidence of vomiting	1	173	Risk Ratio (IV, Random, 99% CI)	0.28 [0.07, 1.15]

Comparison 3. DFX film‐coated tablet versus DFX dispersible tablet

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Comparison 4. DFP and DFO versus DFP

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of SAEs Show forest plot	1	213	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.01, 2.81]

2 All‐cause mortality Show forest plot	2	237	Risk Ratio (IV, Random, 95% CI)	0.77 [0.18, 3.35]

3 Incidence of chelation therapy‐related AEs Show forest plot	3		Risk Ratio (IV, Random, 99% CI)	Subtotals only

3.1 Risk of leukopenia, neutropenia and/or agranulocytosis	3	280	Risk Ratio (IV, Random, 99% CI)	1.15 [0.50, 2.62]
3.2 Risk of pain or swelling in joints	2	256	Risk Ratio (IV, Random, 99% CI)	0.76 [0.31, 1.91]
3.3 Risk of gastrointestinal disturbances	1	213	Risk Ratio (IV, Random, 99% CI)	0.45 [0.15, 1.37]
3.4 Risk of increased liver transaminase	2	256	Risk Ratio (IV, Random, 99% CI)	1.02 [0.52, 1.98]
3.5 Nausea/vomiting	1	43	Risk Ratio (IV, Random, 99% CI)	0.55 [0.13, 2.23]

Comparison 4. DFP and DFO versus DFP

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Comparison 5. DFP and DFO versus DFO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Other AEs related to iron chelation Show forest plot	4		Risk Ratio (IV, Random, 99% CI)	Subtotals only

1.1 Risk of leukopenia, neutropenia and/or agranulocytosis	3	169	Risk Ratio (IV, Random, 99% CI)	1.18 [0.09, 15.37]
1.2 Risk of pain or swelling in joints	3	135	Risk Ratio (IV, Random, 99% CI)	2.39 [0.18, 32.31]
1.3 Risk of increased liver transaminase	2	104	Risk Ratio (IV, Random, 99% CI)	3.46 [0.45, 26.62]
1.4 Nausea/vomiting	4	194	Risk Ratio (IV, Random, 99% CI)	3.81 [0.84, 17.36]
1.5 Local reactions at infusion site	2	90	Risk Ratio (IV, Random, 99% CI)	0.18 [0.01, 3.56]

Comparison 5. DFP and DFO versus DFO

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Comparison 6. DFP/DFX versus DFP/DFO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adherence to iron chelation therapy rates Show forest plot	1	96	Risk Ratio (IV, Random, 95% CI)	0.84 [0.72, 0.99]

2 Incidence of SAE Show forest plot	1	96	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.06, 15.53]

3 All‐cause mortality Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

4 Organ damage (serum creatinine (≥33%) above baseline in 2 consecutive occasions) Show forest plot	1	96	Risk Ratio (M‐H, Random, 99% CI)	3.0 [0.16, 56.04]

5 Other AEs related to iron chelation Show forest plot	1		Risk Ratio (IV, Random, 99% CI)	Subtotals only

5.1 one year (study end)	1	96	Risk Ratio (IV, Random, 99% CI)	1.08 [0.68, 1.71]
5.2 Risk of leukopenia, neutropenia and/or agranulocytosis	1	96	Risk Ratio (IV, Random, 99% CI)	1.67 [0.27, 10.14]
5.3 Risk of pain or swelling in joints	1	96	Risk Ratio (IV, Random, 99% CI)	0.89 [0.29, 2.77]
5.4 Gastrointestinal problems	1	96	Risk Ratio (IV, Random, 99% CI)	0.6 [0.18, 2.04]
5.5 ALT (increase ≥3 folds)	1	96	Risk Ratio (IV, Random, 99% CI)	1.33 [0.20, 8.88]
5.6 Skin rash	1	96	Risk Ratio (IV, Random, 99% CI)	5.0 [0.10, 261.34]

Comparison 6. DFP/DFX versus DFP/DFO

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