Intervenciones para mejorar la adherencia al tratamiento de quelación del hierro en personas con anemia drepanocítica o talasemia
Information
- DOI:
- https://doi.org/10.1002/14651858.CD012349.pub3Copy DOI
- Database:
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- Cochrane Database of Systematic Reviews
- Version published:
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- 06 March 2023see what's new
- Type:
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- Intervention
- Stage:
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- Review
- Cochrane Editorial Group:
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Cochrane Cystic Fibrosis and Genetic Disorders Group
- Copyright:
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- Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Cited by:
Authors
Contributions of authors
The author contributions for the 2022 update were as listed below.
Lise Estcourt: selection of trials; eligibility assessment; content expert, and review content development.
Carolyn Doree: development of search strategies; all searches and de‐duplication.
Louise Geneen: selection of trials; eligibility assessment; data extraction, risk of bias assessment and review content development; update of review text, tables and figures.
Sources of support
Internal sources
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NHS Blood and Transplant, Research and Development, UK
To fund the work of the Systematic Review Initiative (SRI)
External sources
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National Institute for Health Research, UK
This systematic review was supported by the National Institute for Health and Care Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.
Declarations of interest
Louise Geneen: none to declare.
Carolyn Doree: none to declare.
Lise Estcourt: declares her employment as a healthcare professional by NHS Blood and Transplant.
Acknowledgements
We thank the National Institute for Health and Care Research (NIHR) 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.
We would like to thank Patricia Fortin, Sheila Fisher, Sally Hopewell, Karen Madgwick and Marialena Trivella for their contributions to the original review (Fortin 2018).
Version history
| Published | Title | Stage | Authors | 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 | |
| 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 | |
| 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 | |
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
Where trial protocols had been published, or registered, we were able to assess reporting bias, comparing planned outcome reporting and analyses to those published by the triallists.
We could not assess publication 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:
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Age of participant (child (one to 12 years), adolescent (13 to 17 years) adult (18+ years))
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Type of disease (SCD or thalassaemia)
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Route of administration of iron chelating agents (oral, intravenous or subcutaneous)
Where different populations have been assessed, we have not pooled the data, and have instead presented as subgroups or single study data.
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;
PICOs
CFGD trials register: Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: DFP versus DFO, Outcome 1: Adherence to iron chelation therapy (%, SD)
Comparison 1: DFP versus DFO, Outcome 2: Total SAEs (from therapy, disease, non‐adherence)
Comparison 1: DFP versus DFO, Outcome 3: Other SAEs (from therapy, disease, non‐adherence)
Comparison 1: DFP versus DFO, Outcome 4: All‐cause mortality
Comparison 1: DFP versus DFO, Outcome 5: Iron overload: defined as proportion of participants with serum ferritin ≥ 800 (µg/L)
Comparison 1: DFP versus DFO, Outcome 6: Organ damage
Comparison 1: DFP versus DFO, Outcome 7: AEs related to iron chelation
Comparison 2: DFX versus DFO, Outcome 1: Adherence to iron chelation therapy (%, SD)
Comparison 2: DFX versus DFO, Outcome 2: SAEs (thalassaemia)
Comparison 2: DFX versus DFO, Outcome 3: SAEs (sickle cell disease)
Comparison 2: DFX versus DFO, Outcome 4: All‐cause mortality (thalassaemia)
Comparison 2: DFX versus DFO, Outcome 5: Proportion of participants with iron overload (thalassaemia)
Comparison 2: DFX versus DFO, Outcome 6: Total AEs related to iron chelation ‐ (thalassaemia)
Comparison 2: DFX versus DFO, Outcome 7: Other AEs related to iron chelation ‐ (thalassaemia)
Comparison 2: DFX versus DFO, Outcome 8: Total AEs (thalassaemia)
Comparison 2: DFX versus DFO, Outcome 9: Other AEs related to iron chelation (SCD)
Comparison 3: DFP versus DFX, Outcome 1: Adherence to iron chelation (%, SD)
Comparison 3: DFP versus DFX, Outcome 2: Total SAEs
Comparison 3: DFP versus DFX, Outcome 3: SAE (chelation‐related) (n/N)
Comparison 3: DFP versus DFX, Outcome 4: All‐cause mortality (n/N)
Comparison 4: DFX film‐coated tablet versus DFX dispersible tablet, Outcome 1: Adherence to iron chelation therapy (n/N)
Comparison 4: DFX film‐coated tablet versus DFX dispersible tablet, Outcome 2: Adherence to iron chelation therapy (%, SD)
Comparison 4: DFX film‐coated tablet versus DFX dispersible tablet, Outcome 3: Incidence of SAEs
Comparison 4: DFX film‐coated tablet versus DFX dispersible tablet, Outcome 4: All‐cause mortality
Comparison 4: DFX film‐coated tablet versus DFX dispersible tablet, Outcome 5: Incidence of organ damage
Comparison 4: DFX film‐coated tablet versus DFX dispersible tablet, Outcome 6: Total AEs related to iron chelation
Comparison 4: DFX film‐coated tablet versus DFX dispersible tablet, Outcome 7: Other AEs related to iron chelation
Comparison 5: DFP and DFO versus DFP, Outcome 1: Incidence of SAEs
Comparison 5: DFP and DFO versus DFP, Outcome 2: All‐cause mortality
Comparison 5: DFP and DFO versus DFP, Outcome 3: Incidence of chelation therapy‐related AEs
Comparison 6: DFP and DFO versus DFO, Outcome 1: Other AEs related to iron chelation
Comparison 7: DFP and DFX versus DFP and DFO, Outcome 1: Adherence to iron chelation therapy rates
Comparison 7: DFP and DFX versus DFP and DFO, Outcome 2: Incidence of SAE
Comparison 7: DFP and DFX versus DFP and DFO, Outcome 3: All‐cause mortality
Comparison 7: DFP and DFX versus DFP and DFO, Outcome 4: Organ damage (serum creatinine (≥ 33%) above baseline on 2 consecutive occasions)
Comparison 7: DFP and DFX versus DFP and DFO, Outcome 5: Total AEs related to iron chelation
Comparison 7: DFP and DFX versus DFP and DFO, Outcome 6: Other AEs related to iron chelation
| Intervention: DFP Comparison: DFO | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with DFO | Risk with DFP | |||||
| Adherence to iron chelation therapy (%, SD) | See comments. | — | 612 | ⨁◯◯◯ | 2 trials (unpooled) provided analysable data (%, SD); the remaining trials reported only as % (or narratively), with no error (SD, or otherwise) and have been presented in Table 1 separately to the analyses. | |
| Total reported SAEs (from therapy, disease, non‐adherence) | 184 per 1000 | 263 per 1000 | RR 1.43 | 228 | ⨁◯◯◯ | — |
| All‐cause mortality | 75 per 1000 | 35 per 1000 | RR 0.47 | 376 | ⨁◯◯◯ | In a fourth trial, no events occurred in either arm (Pennell 2006). |
| Sustained adherence | See comments. | — | — | — | Sustained adherence is reported as adherence since all trials were longer than 6 months and only provided end of study adherence numbers. | |
| QoL | See comments. | — | (1 RCT) | ⨁◯◯◯ | Data presented in additional tables from a single trial (Kwiatkowski 2021). No significant between‐group change over time. Major bias due to missing data (over half) for outcomes (DFP: CHQ‐50 n = 60/152 and SF‐36 n = 35/152; DFO: CHQ‐50 n = 23/76 and SF‐36 n = 19/76). | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aWe downgraded the certainty of evidence once for risk of bias due to high or uncertain risk of bias in one or more domains. bWe downgraded the certainty of evidence twice for inconsistency due to considerable heterogeneity in the comparison. cWe downgraded the certainty of evidence twice for imprecision due to wide CIs and small sample size (not reaching the optimal information size). dDowngraded twice due to high risk of bias in multiple domains, including blinding (detection bias), incomplete outcome data (attrition bias), and unclear risk of bias for selection bias and other (early termination). eWe downgraded the certainty of evidence once for indirectness as one trial was conducted in participants with thalassaemia intermedia only, a milder form of thalassaemia. fDowngraded twice for imprecision due to small sample size (below optimal information size for this outcome). | ||||||
| Study | How adherence was 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/week because of problems with swallowing |
| Badawy 2010 | Questionnaire on chelation therapy, reasons for non‐compliance, side effects, life activities, transfusion regimen | Combined therapy, and DFP only groups were more compliant (than DFO only) 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 were non‐adherent at end of trial
No data on control group |
| Calvaruso 2014 | 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: 89%
DFO compliance rate: 75%
No information regarding N or time point measured |
| 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%
No information regarding N or time point measured |
| 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 the participant 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) |
| Gharaati 2019 | Questionnaire developed by researchers in 4 sections:
| "phone‐mediated education managed to improve the use of chelation drugs in the intervention group and regulate patients’ visits to hospital for blood injection"
However, baseline difference may have biased this |
| Hassan 2016 | Records of all trial medications that were dispensed and returned
Parents were instructed to contact the investigator if the participants 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 |
| Kwiatkowsi 2021 | Treatment compliance was measured monthly by counting the number of tablets or measuring the volume of oral solution returned for participants on deferiprone, and by checking the infusion pump electronic record for participants on deferoxamine
In addition, participants were asked to record their medication usage in a diary
Participants who took 80% to 120% of the prescribed dose were considered to be compliant | Treatment compliance throughout the study was similar between the groups (P = 0.12)
DFP: 68.9%
DFO: 78.9% |
| 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, mean (SD; range): DFP 92.7% (15.2%; 37% to 100%); DFO 70.6% (24.1%; 25% to 100%)
DFP alone group, mean (SD; range): 93.6% (9.7%; 56% to 100%) |
| Maggio 2020 | Compliance was appropriate if the proportion of prescribed therapy taken was at least 80%
Compliance was estimated from electronic case report form data and the proportion of the prescribed doses taken | Appropriate compliance: DFP, proportion, mean (SD), median (IQR): 183/193 (95%) participants, mean 92% (17.35), 93% (13.6) DFX, proportion, mean (SD), median (IQR): 192/197 (97%) participants, 95% (18.56), 97% (11.1) |
| 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 participants and good in 3 participants |
| Olivieri 1997 | % 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, mean (SD): 94.9% (1.1%)
DFO, mean (SD): 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, mean (SD): 94% (5.3%)
DFO, mean (SD): 93% (9.7%)
|
| Pennell 2014 | Not stated how adherence was measured | DFX, mean (SD): 99.0% (3.5%)
DFO, mean (SD): 100.4% (10.9%) |
| Taher 2017 | Assessed by relative consumed tablet count
| DT: 85.3% (95% CI 81.1 to 89.5) FCT: 92.9% (95% CI 88.8 to 97.0)
Also reported as n/N, unrelated to % (SD) reported above: DT: 73/86 (84.9%) FCT: 81/87 (93.1%) FCT vs DT: RR 1.10 (95%CI 0.99, 1.22) |
| 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 bi‐monthly visits | DFO/placebo, mean (SD): DFO 91.4% (2.7%); placebo 89.8 (7.2%)
DFO/DFP, mean (SD): 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; IQR: interquartile range; RR: risk ratio; SD: standard deviation; SF: serum ferritin | ||
| Intervention: DFX Comparison: DFO | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with DFO | Risk with DFX | |||||
| Adherence to iron chelation therapy (%, SD) | See comments. | 452 | ⨁◯◯◯ | 3 RCTs (n = 452) reported adherence, although 2 of these could not be analysed (Hassan 2016, n = 60; and Vichinsky 2007, n = 195). All 3 RCTs reported no significant difference between groups. | ||
| SAEs Thalassaemia‐related SAEs | DFO: 83 per 1000 DFX: 79 per 1000 (34 to 179)
| RR 0.95 (0.41 to 2.17) | 247 | ⨁◯◯◯ | Zero cases reported in one RCT (n = 60, Hassan 2016), so data are based on a single trial (n = 187, Pennell 2014). | |
| SAEs SCD‐related SAEs | 1 RCT (n = 195) reported SCD‐related AEs as "pain crisis" and "other", so no overall estimate of effect (subtotals calculated using 99% CI)
| — | 195 | ⨁◯◯◯ | Data for sub‐outcome "pain crisis", and sub‐outcome "other", are presented in the main text, but we are unable to combine these data as there may be double‐counting; we have therefore not presented the summary statistic in the SoF table. Sub‐outcomes are presented using 99% CI instead of 95% CI. | |
| All‐cause mortality | 8 per 1000 | 8 per 1000 | POR 0.96 | 240 | ⨁◯◯◯ | Both RCTs reporting this outcome were in people with thalassaemia only; zero cases in 1 RCT. |
| Sustained adherence | See comments. | — | — | Sustained adherence is reported as adherence since all studies were longer than 6 months and only reported end of study adherence. | ||
| QoL | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aWe downgraded the certainty of evidence twice due to high or uncertain risk of bias in several domains. bWe downgraded the certainty of evidence once due to imprecision as the CIs are wide and there is only one study with data in the comparison. | ||||||
| Intervention: DFP Comparison: DFX | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with DFX | Risk with DFP | |||||
| Adherence to iron chelation (%, SD) | The mean adherence to iron chelation (%, SD) was 95.00%. | MD 3.00 % lower | — | 390 | ⨁⨁◯◯ | 95% adherence in DFX group as reported by Maggio 2020. |
| SAE (chelation‐related) (n/N) | 20 per 1000 | 31 per 1000 | POR 1.54 | 390 | ⨁◯◯◯ | — |
| Total SAEs | 71 per 1000 | 68 per 1000 | RR 0.95 | 390 | ⨁◯◯◯ | — |
| All‐cause mortality (n/N) | 0 per 1000 | 0 per 1000 | RD 0.00 | 390 | ⨁⨁◯◯ | No deaths occurred during the study period, though the sample size was below the optimal information size to make any assessment of risk. |
| Sustained adherence | See comments. | — | — | Sustained adherence is reported as adherence as the study was 1 year in duration and end of trial adherence reported. | ||
| QoL | Outcome 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aDowngraded twice for high risk of bias for blinding: may impact adherence, clinical decision‐making or reporting of AEs (no impact on mortality). bDowngraded twice for imprecision due to wide CIs. cDowngraded twice for imprecision due to zero events in both arms. Below optimal information size. | ||||||
| Intervention: DFX film‐coated tablet Comparison: DFX dispersible tablet | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with DFX dispersible tablet | Risk with DFX film‐coated tablet | |||||
| Adherence to iron chelation therapy (%, SD) | The mean adherence to iron chelation therapy (%, SD) was 84.3%. | MD 5.00% higher | — | 91 | ⨁◯◯◯ | Mean 84.3% (95% CI 81.1 to 89.5) as reported by Taher 2017 in control (DFX dispersible tablet). |
| Sustained adherence to iron chelation therapy (%, SD) | The mean sustained adherence to iron chelation therapy (%, SD) was 82.9%. | MD 7.00% higher | — | 54 | ⨁◯◯◯ | Mean 82.9% as reported in control group (dispersible tablet). |
| Incidence of SAEs | 151 per 1000 | 184 per 1000 | RR 1.22 | 173 | ⨁◯◯◯ | — |
| All‐cause mortality | 0 per 1000 | 0 per 1000 | POR 7.30 (0.14 to 368.15) | 173 | ⨁◯◯◯ | — |
| QoL | Outcome 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aWe downgraded the certainty of evidence twice for risk of bias due to high or unclear risk of bias in all domains. bDowngraded twice for imprecision due to very wide confidence intervals and small study size (smaller than optimal information size). cWe downgraded the certainty of evidence once for imprecision due to wide CIs. | ||||||
| Intervention: DFP plus DFO Comparison: DFP | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with DFP | Risk with DFP plus DFO | |||||
| Adherence to iron chelation therapy (%, SD) | See comments. | 369 | ⨁⨁◯◯ | 4 RCTs reported adherence: 1 did not report by group, but stated compliance was similar (Badawy 2010, n = 100); 2 reported compliance as "excellent compliance" (Aydinok 2007, n = 20 and El Beshlawy 2008, n = 36); and 1 as % (SD) with no difference between groups (Maggio 2009, n = 213). | ||
| Incidence of SAEs | 28 per 1000 | 4 per 1000 | RR 0.15 | 213 | ⨁⨁◯◯ | — |
| All‐cause mortality | 33 per 1000 | 26 per 1000 | POR 0.77 | 237 | ⨁◯◯◯ | — |
| Sustained adherence | Outcome not reported. | — | — | Sustained adherence is reported as adherence since trial duration was longer than 6 months and trials report adherence for the whole length of trial. | ||
| QoL | See comments. | — | — | QoL was either not reported or no validated instruments were used. | ||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aWe downgraded the certainty of evidence twice for risk of bias as there was high or uncertain risk of bias in most domains in three out of four trials. bWe downgraded the certainty of evidence once due to high or unclear risk of bias in three domains. cWe downgraded the certainty of evidence once for imprecision due to wide CIs. dWe downgraded the certainty of evidence twice for risk of bias as there was high or uncertain risk of bias in one trial in this comparison. | ||||||
| Intervention: DFP plus DFO Comparison: DFO | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with DFO | Risk with DFP plus DFO | |||||
| Adherence to iron chelation therapy (%, SD) | See comments. | 281 | ⨁⨁◯◯ | 5 RCTs reported adherence/compliance at approx 1 year: 2 RCTs did not report by group, simply stating "no statistical difference" (Badawy 2010, n = 100) and "excellent" (El Beshlawy 2008, n = 38); 1 RCT only reported compliance for the combined group (Galanello 2006a, n = 60); 1 RCT reported "excellent or good in all 11 (combined) and 14 (DFX only) participants" that were analysed (Mourad 2003, n = 25); and 1 RCT reported by group as "no significant difference" (Tanner 2007, n = 58). | ||
| Incidence of SAEs | See comments. | 180 | ⨁⨁◯◯ | 3 RCTs report zero SAEs; 1 RCT did not report SAEs. Badawy 2010 is not included in quantitative analysis | ||
| All‐cause mortality | See comments. | — | — | No included trials reported death as an outcome. As AEs/SAEs were reported, we suspect no deaths occurred. | ||
| Sustained adherence | See comments. | — | — | Sustained adherence reported above as adherence since study duration was longer than 6 months and adherence reported at end of trial. | ||
| QoL | Outcome 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aWe downgraded the certainty of evidence twice for risk of bias as high or unclear risk of bias in all domains. | ||||||
| Intervention: DFP plus DFO Comparison: DFP plus DFX | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with DFP plus DFX | Risk with DFP plus DFO | |||||
| Adherence to iron chelation therapy rates (n, N) Follow‐up 1 year | 938 per 1000 | 788 per 1000 | RR 0.84 | 96 | ⨁⨁◯◯ | — |
| Incidence of SAEs | 21 per 1000 | 21 per 1000 | POR 1.00 | 96 | ⨁◯◯◯ | — |
| All‐cause mortality ‐ at 1 year ‐ trial end | 0 per 1000 | 0 per 1000 | RD 0.00 | 96 | ⨁◯◯◯ | No deaths occurred during the trial period, though the sample size was significantly below the optimal information size to make any assessment of risk. |
| Sustained adherence | See comments. | — | — | Sustained adherence is reported as adherence since the trial was 1 year in duration and end of trial adherence data were reported. | ||
| QoL | See comments. | 96 | — | 1 RCT used SF‐36 to measure QoL; the results are presented as a bar graph only, with mean and SD not reported in extractable form (Elalfy 2015). Stated no difference between groups. | ||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aWe downgraded the certainty of evidence once for risk of bias as there was high or unclear risk of bias in three domains. bWe downgraded the certainty of evidence once for indirectness as the trial included children aged 10 to 18 years with severe iron overload. cWe downgraded the certainty of evidence once for imprecision as the comparison has wide CIs. dDowngraded twice for imprecision due to the small sample size, far below the optimal information size for mortality. | ||||||
| Intervention: medication management Comparison: standard care | ||||||
|---|---|---|---|---|---|---|
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with standard care | Risk with medication management | |||||
| Adherence to iron chelation | See comments. | — | — | — | This outcome was not reported in the control group and therefore there are no comparative data. | |
| SAEs | Outcome not reported. | — | — | — | ||
| Mortality | Outcome not reported. | — | — | — | ||
| Sustained adherence | Outcome not reported. | — | — | — | ||
| QoL PedsQLTM total score Follow‐up: 6 months | See comments. | — | 48 | ⨁◯◯◯ | 1 RCT reported medians and IQRs. Medication management: 63.51 (51.75 to 84.54), n = 24; standard care: 49.84 (41.9 to 60.81), n = 24. | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Explanations aWe downgraded the certainty of evidence twice for risk of bias due to high or uncertain risk of bias in all domains. bWe downgraded the certainty of evidence twice for indirectness because most outcomes were only reported in the medication management group. | ||||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Egypt | Age > 8 years β‐thalassaemia (100%) | DFP 75 mg/kg/day, daily n = 50 | DFO 40 mg/kg/day, 5 days/week n = 50 | Adherence AEs |
| Italy | Age > 13 years SCD (100%) | DFP 75 mg/kg/day, divided into 3 oral daily doses (daily) n = 30 | DFO SC infusion (8 to 10 hours) at 50 mg/kg/day for 5 days/week n = 30 | Compliance Mortality (5 years) AEs (not SAEs) |
| Italy | Age > 13 years Thalassaemia intermedia (100%) | DFP 75 mg/kg/day, divided into 3 oral daily doses (daily) n = 47 | DFO SC infusion (8 to 10 hours) at 50 mg/kg/day for 5 days/week n = 41 | Adherence Compliance Mortality (5 years) |
| Egypt | Age > 4 years β‐thalassaemia (100%) | DFP 60 to 83 mg/kg/day (daily) n = 18 | DFO 23 to 50 mg kg/day for 5 days/week n = 20 | Adherence Compliance AEs Iron overload |
| USA
Note: terminated early | Age > 2 years SCD or other iron overload (excluded thalassaemia or MDS) | DFP 75 mg/kg (25 mg/kg per dose); 3/day, 8 hours apart to 99 mg/kg for more severe n = 152 | DFO SC infusion (8 to 12 hours) 20 to 40 mg/kg/day for 5 to 7 days/week n = 76 | 12 months: Adherence Mortality HRQoL SAEs (chelation associated) All SAEs Other AEs related to chelation |
| Canada | Age > 10 years β‐thalassaemia major (100%) | DFP 75 mg/kg/day in 3 divided doses n = 19 | DFO 50 mg/kg/night, 4 to 7 nights/week n = 18 | Adherence (3 months) |
| Italy and Greece | Age > 18 years β‐thalassaemia major (100%) | DFP 75 mg/kg/day increasing to 100 mg/kg/day. Mean actual dose: 92 mg/kg/day n = 29 | DFO SC injection 50 mg/kg for 5 or more days/week n = 32 | Adherence AEs |
| *Badawy 2010 did not report any outcomes by intervention group and did not include counts of events (i.e. AEs) and so was not included in the quantitative analysis. Badawy 2010 and El Beshlawy 2008 are 3‐arm trials (DFP, DFO vs DFP vs DFO) and so are listed in more than one comparison. AE: adverse events; DFO: deferoxamine; DFP: deferiprone; MDS: myelodysplastic syndromes; SAE: serious adverse events; SC: subcutaneous; SCD: sickle cell disease; SF: serum ferritin | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Egypt | Age > 6 years β‐thalassaemia major | DFX 20 to 40 mg/kg/day on an empty stomach n = 30 | DFO 20 to 50 mg/kg/day via SC infusion over 8 to 10 hours, 5 days/week n = 30 | Adherence Drug safety |
| CORDELIA (multi‐national: 11 countries) | Age > 10 years β‐thalassaemia (100%) | DFX 20 mg/kg per day for 2 weeks, then 30 mg/kg/day for 1 week, then 40 mg/kg/day n = 98 | DFO 50 to 60 mg/kg/day via SC infusion over 8 to 12 hours, 5 to 7 days/week n = 99 | 1 year: Adherence LIC SF
|
| (Multi‐national: 5 countries) | Age > 2 years SCD | DFX 10 to 30 mg/kg according to baseline LIC (daily) n = 132 | DFO 50 to 70 mg/kg slow SC infusion over 8 to 12 hours, 5 to 7 days/week n = 63 | 52 weeks: Adherence Safety LIC SF
|
| DFO: deferoxamine; DFX: deferasirox; LIC: liver iron content; SC: subcutaneous; SCD: sickle cell disease, SF: serum ferritin | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| DEEP‐2 (multi‐national) | Age 1 month to 18 years Any hereditary haemoglobinopathy: including thalassaemia and SCD | DFP 75 to 100 mg/kg/day, orally, daily n = 193 | DFX (dispersible tablets) 20 to 40 mg/kg/day n = 197 | 12 months: Compliance |
| DFP: deferiprone; DFX: deferasirox; SCD: sickle cell disease | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| ECLIPSE (multi‐national) | Age > 10 years Thalassaemia and iron overload Thalassaemia major (81%) | DFX film‐coated tablet as 90 mg, 180 mg and 360 mg for oral use n = 87 | DFX dispersible tablet as 125 mg, 250 mg and 500 mg for oral use n = 86 | 13 and 24 weeks: Adherence Compliance Safety AEs |
| AEs: adverse events; DFX: deferasirox; SCD: sickle cell disease | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Turkey | Age > 4 years β‐thalassaemia (100%) | DFP + DFO (combined) DFO (50 mg/kg/day SC twice‐weekly) combined with DFP (75 mg/kg/day, daily) n = 12 (8 analysed) | DFP 75 mg/kg/day, daily n = 12 | 12 months: Adherence LIC SF QoL |
| Egypt
| Age > 8 years β‐thalassaemia (100%) | DFP, DFO Twice‐weekly DFO (40 mg/kg/day) DFP (75 mg/kg/day) n = 50 | DFP 75 mg/kg/day, daily n = 50 | Adherence AEs |
| Egypt | Age > 4 years β‐thalassaemia (100%) | DFP + DFO DFP 60 to 83 mg/kg/day (daily) and DFO 23 to 50 mg/kg per dose (8 hours, 2 days/week) n = 18 | DFP 60 to 83 mg/kg/day (daily) n = 18 | Adherence Compliance Adverse events Iron overload |
| Italy | Age > 13 years Thalassaemia major (100%) | DFP‐DFO (sequential treatment) DFP 75 mg/kg, divided into 3 oral daily doses, for 4 days/week DFO SC infusion (8 to 12 hours) at 50 mg/kg/day for the remaining 3 days/week n = 105 | DFP 75 mg/kg divided into 3 oral daily doses, daily n = 108 | 5 years: Adherence Survival LIC & SF AEs
|
| *Badawy 2010 did not report any outcomes by intervention group and did not include counts of events (i.e. AEs) and so was not included in the quantitative analysis. Badawy 2010 and El Beshlawy 2008 are 3‐arm trials (DFP, DFO vs DFP vs DFO) and so are listed in more than one comparison. AE: adverse events; DFO: deferoxamine; DFP: deferiprone; LIC: liver iron content; QoL: quality of life; SC: subcutaneous; SF: serum ferritin | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Egypt | Age > 8 years β‐thalassaemia (100%) | DFP, DFO Twice‐weekly DFO (40 mg/kg/day) DFP (75 mg/kg/day) n = 50 | DFO 40 mg/kg/day; 5 days/week n = 50 | Adherence SF |
| Egypt | Age > 4 years β‐thalassaemia (100%) | DFP + DFO DFP 60 to 83 mg/kg/day (daily) and DFO 23 to 50 mg/kg per dose (8 hours, 2 days/week) n = 18 | DFO 23 to 50 mg kg/day for 5 days/week n = 20 | 54 weeks: Adherence/compliance Adverse events (chelation‐related SAEs) Iron overload Other AEs SAEs not reported |
| Italy and Greece | Age > 10 years β‐thalassaemia major (100%) | DFP + DFO DFO 20 to 60 mg/kg/day SC on 2 days a week with DFP 25 mg/kg/ body weight 3 x daily for 5 days/week n = 29 | DFO 20 to 60 mg/kg/day subcutaneously on 5 to 7 days/week n = 30 | 12 months: Compliance LIC and SF AEs |
| Lebanon | Age 12 to 40 years β‐thalassaemia | DFP + DFO DFP 75 mg/kg/day orally in 3 divided doses, 7 days/week, DFO by SC injection, daily dose of 2 g over 8 to 12 hours, 2 days/week n = 11 | DFO SC injection, 40 to 50 mg/kg 8 to 12 hours a day, 5 to 7 days/week n = 14 | 1 year: Compliance Liver and renal function AEs (side effects)
|
| Sardinia | Age > 18 years β‐thalassaemia | DFP + DFO DFO 40 to 50 mg/kg SC for 5 days/week with DFP 75 mg/kg daily for 7 days/ week n = 28 | DFO 40 to 50 mg/kg SC for 5 days/week with an oral placebo n = 30 | 1 year: compliance LIC and SF AEs |
| *Badawy 2010 did not report any outcomes by intervention group and did not include counts of events (i.e. AEs) and so was not included in the quantitative analysis. Badawy 2010 and El Beshlawy 2008 are 3‐arm trials (DFP, DFO vs DFP vs DFO) and so are listed in more than one comparison. AE: adverse events; DFO: deferoxamine; DFP: deferiprone; LIC: liver iron content; QoL: quality of life; SAE: serious adverse events; SC: subcutaneous; SF: serum ferritin | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Egypt and Oman | Age 10 to 18 years β‐thalassaemia major | DFP/DFO DFP 75 mg/kg/day divided into 2 doses taken orally for 7 days (with 6‐ to 8‐hour interval between the 2 doses) with DFO 40 mg/kg/day by SC infusion over 10 hours starting at 10 p.m. for 6 days/week n = 48 | DFP/DFX DFP 75 mg/kg/day, divided into 2 doses taken orally with DFX 30 mg/kg/day taken orally at 10 p.m. for 7 days/week n = 48 | 1 year: Adherence LIC and SF SAEs and AEs Compliance Satisfaction QoL
|
| AE: adverse events; DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox; LIC: liver iron content; QoL: quality of life; SAE: serious adverse events; SC: subcutaneous; SF: serum ferritin | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Egypt | Age 8 to 18 years β‐thalassaemia major (100%) | Medication management n = 24 | Standard care n = 24 | 6 months: Adherence SF QoL |
| QoL: quality of life; SF: serum ferritin | ||||
| Study | Participants | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Iran | Age > 13 years Thalassaemia major | Education 6 x 15‐ to 18‐minute calls within a month n = 46 | Standard care n = 45 | 1 month: Use of chelation therapy |
| *Gharaati 2019 was not included in the quantitative analysis due to significant baseline imbalance (assessed using ROBINS‐I for non RCTs). | ||||
| Study | Reason for classification | Participants (inclusion criteria) | Intervention | Comparator | Outcomes |
|---|---|---|---|---|---|
| Medication interventions – RCTs only | |||||
| RCT; N = 32; India Expected start date: 1 Sept 2017 Expected end date: NR (6 month duration) | Full publication available: mentions greater compliance in IV group in discussion, but no data provided Randomised but severe baseline imbalance in serum ferritin Unclear trial design: significant differences between trial registration and publication (study design randomised or observational, and focus on adherence or not); contacted authors for further information | 3 to 18 years Thalassaemia patients on regular DFX | DFX, oral 15 to 40 mg/kg/day | DFO, injection, 20 to 40 mg/kg monthly |
|
| RCT; N = 45; India Start date: 30 July 2020 End date: 10 August 2021 | Unclear trial design (not designed to measure adherence?) No publications or data | 10 to 18 years Beta thalassaemia patients taking DFX | Combined DFP (75 mg/kg/day) + DFX (30 mg/kg/day), oral | DFX (30 mg/kg/day), oral |
|
| (NL6659, PPI Shine Again) RCT (cross‐over); N = 30; The Netherlands End date: 12 April 2021
| Completed, some results available (May 2022), but results presented without subgrouping, and so cannot extract only SCD and thalassaemia data – awaiting publication of further results and contacted authors for further information | 18+ years Hereditary anaemia (non‐transfusion dependent); secondary haemochromatosis | PPI: esomeprazole (oral capsule) | Placebo |
|
| RCT; N = 50; Iran Start date: 22 September 2016 End date: 22 May 2017
| Full publication available: mentions compliance with chelators was “acceptable”, but no data provided Unclear trial design: significant differences between trial registration and publication (trial design randomised or observational); contacted authors for further information Would be a new comparison if included: DFO + DFX vs DFX | 5 to 18 years Thalassaemia major | Combined DFO (Desferal ampoule) 50 mg/kg subcutaneously with Desferal pump, and DFX (Exjade) 30 mg/kg/day | DFX (Exjade) 30 mg/kg/day |
|
| RCT; N = 54; Iran Expected start date: 21 January 2018 Expected end date: 21 September 2018 | Unclear trial design (not designed to measure adherence?) No publications or data
| 12+ years People with β‐thalassaemia receiving DFO plus DFP | DFX plus DFP (n = 27) | DFO plus DFP (n = 27) |
|
| RCT; N = 107; Iran Start date: 19 February 2018 End date: 21 December 2018 | Unclear trial design (not designed to measure adherence?) No publications or data | 10+ years Transfusion‐dependent β‐thalassaemia | DFX (20 to 40 mg/kg daily) plus DFP (15 mg/kg/dose) | DFO (20 to 50 mg/kg daily with a pump) plus DFP (15 mg/kg/dose) |
|
| Start date: December 1998 End date: November 2002
| Unclear trial design (not designed to measure adherence?) No publications or data | 7+ years Iron overload and thalassaemia | Various combinations of experimental iron chelating drugs | Standard care |
|
| Non‐medication interventions – RCTs, NRSIs, CBA, ITS, repeated measures | |||||
| NRSI; N = 86; Turkey Intervention from February to June 2009; follow‐up to one year Abstract only | No information on inclusion/exclusion criteria No publications or data
| People using DFX (unclear diagnoses)
| Education (n = 45) | Standard care (n = 41) |
|
| Feasibility study; N = 18; USA Abstract only | Unclear trial design (single arm); part of larger study of self‐management interventions No publications or data
| 13 to 21 years SCD | Electronic monitoring bottles | Unclear |
|
| RCT; N = 70; Iran Start date: 20 June 2013 Expected end date: 21 September 2013 | Unclear trial design (not designed to measure adherence?) No publications or data
| 15 to 25 years Thalassaemia major | Education | Standard care |
|
| RCT; N = 60; Iran Expected start date: 11 September 2019 Expected end date (recruitment): 11 December 2019 | Unclear if relevant intervention No publications or data
| 14 ‐ 18 years β‐thalassaemia major
| Hope Therapy programme | Standard care |
|
| Pre/post‐test or NRSI; N = 47; Iran Start date: 25 September 2019 End date: 21 January 2020 | Unclear trial design (not designed to study adherence?) No publications or data
| 8 ‐ 18 years Thalassaemia major | Psycho‐educational group sessions (n = 25) | Standard care (pre‐test only) |
|
| RCT; N = 34; Iran Expected start date: 20 December 2020 Expected end date: 17 February 2021 | Unclear trial design (not designed to assess adherence?) No publications or data
| 15 to 20 years Thalassaemia major | Religious education | No intervention |
|
| CBA: controlled before‐after studies; DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox; ITS: interrupted time series; IV: intravenous; NR: not reported; NRSI: non‐randomised studies of interventions; PPI: proton pump inhibitor; QoL: quality of life; RCT: randomised controlled trial; SCD: sickle cell disease; SF: serum ferritin | |||||
| Study | Participants (inclusion criteria) | Intervention | Comparator | Outcomes |
|---|---|---|---|---|
| Medication interventions ‐ RCTs only | ||||
| CALYPSO NCT02435212 Multi‐country RCT; N =2 24 Expected start: 21 October 2015 Expected end: 19 December 2023 | 2 to 18 years Any transfusion‐dependent anaemia | DFX granule formulation; 14 mg/kg/day; 48 weeks | DFX DT formulation; 20 mg/kg/day; 48 weeks |
|
| IRCT2015101218603N2 Country: Iran RCT; N = 100 Expected start: 22 December 2015 Expected end: NR | 2+ years Transfusion‐dependent beta‐thalassaemia | DFX (new formulation Jadenu) 14 to 28 mg/kg/day orally | DFX (Exjade) 20 to 40 mg/kg/day orally |
|
| Non‐medication interventions – RCTs, NRSIs, CBA, ITS, repeated measures | ||||
| Madderom 2016 (TEAM) NTR4750 (NL42182.000.12) Country: The Netherlands RCT; N = 100 Expected start: January 2013 Expected end: NR | All ages Homozygous or compound heterozygous sickle cell disease | Group medical appointments | Individual appointments (standard care) |
|
| NCT04877054 Country: USA RCT; N = 16 Expected start: 30 December 2021 Expected end: 1 August 2022 | 13 to 22 years Sickle cell disease | Telehealth (inc psycho‐medical education and motivational interviewing) 1/week for 4 sessions | Education only (single session) |
|
| CBA: controlled before‐and‐after study; DFO: deferoxamine; DFP: deferiprone; DFX: deferasirox; DT: dispersible tablet; GI: gastrointestinal; ITS: interrupted time series; NRSI: non‐randomised studies of interventions; QoL: quality of life; RCT: randomised controlled trial; SF: serum ferritin | ||||
|
| DFP | DFO | ||
|---|---|---|---|---|
| n | Mean (SD) | n | Mean (SD) | |
| CHQ‐50 physical (12‐month change) | 60 | 29.3 (13.94) | 23 | 30.5 (11.51) |
| CHQ‐50 psychosocial (12‐month change) | 60 | 42.5 (11.62) | 23 | 41.3 (10.07) |
| SF‐36 physical (12‐month change) | 35 | 43.1 (10.65) | 19 | 43.0 (8.72) |
| SF‐36 mental (12‐month change) | 35 | 44.7 (15.97) | 19 | 40.9 (12.64) |
| CHQ‐50: Child Health Questionnaire ‐ 50 items; DFO: deferoxamine; DFP: deferiprone; HRQoL: health‐related quality of life; SD: standard deviation; SE: standard error; SF‐36: 36‐item Short Form Survey No significant between‐group differences. Major bias due to missing data (over half) for outcomes (DFP 152 at baseline; DFO 76 at baseline). Data presented as mean (SE) in publication, converted to SD here. | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Adherence to iron chelation therapy (%, SD) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.2 Total SAEs (from therapy, disease, non‐adherence) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.2.1 Total reported SAEs | 1 | 228 | Risk Ratio (M‐H, Random, 95% CI) | 1.43 [0.83, 2.46] |
| 1.3 Other SAEs (from therapy, disease, non‐adherence) Show forest plot | 2 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 1.3.1 Agranulocytosis | 1 | 88 | Risk Ratio (M‐H, Random, 99% CI) | 7.88 [0.18, 352.39] |
| 1.3.2 Pain crisis | 1 | 228 | Risk Ratio (M‐H, Random, 99% CI) | 1.30 [0.54, 3.16] |
| 1.3.3 Acute chest syndrome | 1 | 228 | Risk Ratio (M‐H, Random, 99% CI) | 3.52 [0.07, 170.19] |
| 1.3.4 Hepatic sequestration | 1 | 228 | Risk Ratio (M‐H, Random, 99% CI) | 1.51 [0.02, 99.77] |
| 1.3.5 Chelation therapy‐related SAEs | 1 | 228 | Risk Ratio (M‐H, Random, 99% CI) | 1.50 [0.28, 8.04] |
| 1.4 All‐cause mortality Show forest plot | 3 | 376 | Risk Ratio (M‐H, Random, 95% CI) | 0.47 [0.18, 1.21] |
| 1.4.1 Sickle cell disease | 2 | 288 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.12, 2.02] |
| 1.4.2 Thalassaemia intermedia | 1 | 88 | Risk Ratio (M‐H, Random, 95% CI) | 0.44 [0.12, 1.63] |
| 1.5 Iron overload: defined as proportion of participants with serum ferritin ≥ 800 (µg/L) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.6 Organ damage Show forest plot | 2 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 1.6.1 Liver damage | 2 | 148 | Risk Ratio (M‐H, Random, 99% CI) | 5.13 [0.54, 48.40] |
| 1.7 AEs related to iron chelation Show forest plot | 4 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 1.7.1 Risk of leukopenia, neutropenia and/or agranulocytosis | 3 | 192 | Risk Ratio (M‐H, Random, 99% CI) | 3.95 [0.37, 41.87] |
| 1.7.2 Risk of pain or swelling in joints | 3 | 192 | Risk Ratio (M‐H, Random, 99% CI) | 3.55 [0.49, 25.81] |
| 1.7.3 Risk of nausea/vomiting | 2 | 132 | Risk Ratio (M‐H, Random, 99% CI) | 13.68 [0.99, 188.88] |
| 1.7.4 Risk of increased liver transaminase | 1 | 44 | Risk Ratio (M‐H, Random, 99% CI) | 1.10 [0.03, 38.47] |
| 1.7.5 Local reactions at infusion site | 1 | 88 | Risk Ratio (M‐H, Random, 99% CI) | 0.17 [0.00, 9.12] |
| 1.7.6 Other AEs related to iron chelation | 1 | 228 | Risk Ratio (M‐H, Random, 99% CI) | 1.28 [0.81, 2.02] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Adherence to iron chelation therapy (%, SD) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.2 SAEs (thalassaemia) Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.2.1 Total thalassaemia‐related SAEs | 2 | 247 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.41, 2.17] |
| 2.3 SAEs (sickle cell disease) Show forest plot | 1 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 2.3.1 Painful crisis | 1 | 195 | Risk Ratio (M‐H, Random, 99% CI) | 1.05 [0.59, 1.86] |
| 2.3.2 Other sickle cell disease‐related SAEs | 1 | 195 | Risk Ratio (M‐H, Random, 99% CI) | 1.08 [0.69, 1.68] |
| 2.4 All‐cause mortality (thalassaemia) Show forest plot | 2 | 240 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.96 [0.06, 15.42] |
| 2.5 Proportion of participants with iron overload (thalassaemia) Show forest plot | 2 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 2.5.1 Iron overload defined by ferritin 1500 (µg/l) or higher (thalassaemia) | 1 | 60 | Risk Ratio (M‐H, Random, 99% CI) | 1.18 [0.52, 2.68] |
| 2.5.2 Proportion with severe iron overload (liver iron concentration at least 15 mg/Fe/g dry weight) | 1 | 172 | Risk Ratio (M‐H, Random, 99% CI) | 1.00 [0.78, 1.27] |
| 2.5.3 Myocardial T2* < 10 ms | 1 | 172 | Risk Ratio (M‐H, Random, 99% CI) | 1.10 [0.62, 1.95] |
| 2.6 Total AEs related to iron chelation ‐ (thalassaemia) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.6.1 Total chelation‐related AEs | 1 | 187 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.76, 1.73] |
| 2.7 Other AEs related to iron chelation ‐ (thalassaemia) Show forest plot | 2 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 2.7.1 Gastrointestinal upset | 1 | 60 | Risk Ratio (M‐H, Random, 99% CI) | 3.00 [0.41, 22.06] |
| 2.7.2 Rash | 2 | 247 | Risk Ratio (M‐H, Random, 99% CI) | 3.05 [0.69, 13.51] |
| 2.7.3 Risk of increased blood creatinine | 1 | 187 | Risk Ratio (M‐H, Random, 99% CI) | 3.79 [0.51, 28.05] |
| 2.7.4 Risk of proteinuria | 1 | 187 | Risk Ratio (M‐H, Random, 99% CI) | 2.21 [0.39, 12.56] |
| 2.7.5 Risk of increased ALT | 1 | 187 | Risk Ratio (M‐H, Random, 99% CI) | 5.69 [0.36, 89.55] |
| 2.7.6 Risk of increased AST | 1 | 187 | Risk Ratio (M‐H, Random, 99% CI) | 5.69 [0.36, 89.55] |
| 2.7.7 Risk of diarrhoea | 1 | 187 | Risk Ratio (M‐H, Random, 99% CI) | 5.69 [0.36, 89.55] |
| 2.7.8 Risk of vomiting | 1 | 187 | Risk Ratio (M‐H, Random, 99% CI) | 6.64 [0.14, 320.28] |
| 2.8 Total AEs (thalassaemia) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.9 Other AEs related to iron chelation (SCD) Show forest plot | 1 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 2.9.1 Risk of increased ALT | 1 | 195 | Risk Ratio (M‐H, Random, 99% CI) | 5.29 [0.12, 232.98] |
| 2.9.2 incidence of abdominal pain | 1 | 195 | Risk Ratio (M‐H, Random, 99% CI) | 1.91 [0.80, 4.58] |
| 2.9.3 Risk of pain or swelling in joints | 1 | 195 | Risk Ratio (M‐H, Random, 99% CI) | 1.06 [0.41, 2.76] |
| 2.9.4 Risk of diarrhoea | 1 | 195 | Risk Ratio (M‐H, Random, 99% CI) | 4.14 [0.90, 18.92] |
| 2.9.5 Nausea/vomiting | 1 | 195 | Risk Ratio (M‐H, Random, 99% CI) | 1.63 [0.90, 2.94] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Adherence to iron chelation (%, SD) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 3.2 Total SAEs Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.2.1 12 months | 1 | 390 | Risk Ratio (M‐H, Random, 95% CI) | 0.95 [0.46, 1.96] |
| 3.3 SAE (chelation‐related) (n/N) Show forest plot | 1 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 3.3.1 12 months | 1 | 390 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.54 [0.44, 5.39] |
| 3.4 All‐cause mortality (n/N) Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 3.4.1 12 months | 1 | 390 | Risk Difference (M‐H, Random, 95% CI) | 0.00 [‐0.01, 0.01] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Adherence to iron chelation therapy (n/N) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.2 Adherence to iron chelation therapy (%, SD) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.2.1 13 weeks | 1 | 91 | Mean Difference (IV, Random, 95% CI) | 5.00 [‐6.75, 16.75] |
| 4.2.2 24 weeks | 1 | 54 | Mean Difference (IV, Random, 95% CI) | 7.00 [‐8.94, 22.94] |
| 4.3 Incidence of SAEs Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.4 All‐cause mortality Show forest plot | 1 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 4.5 Incidence of organ damage Show forest plot | 1 | 173 | Risk Ratio (M‐H, Random, 99% CI) | 1.25 [0.72, 2.18] |
| 4.5.1 Renal events | 1 | 173 | Risk Ratio (M‐H, Random, 99% CI) | 1.25 [0.72, 2.18] |
| 4.6 Total AEs related to iron chelation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.6.1 Total chelation‐related AEs | 1 | 173 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.57, 0.99] |
| 4.7 Other AEs related to iron chelation Show forest plot | 1 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 4.7.1 Risk of diarrhoea | 1 | 173 | Risk Ratio (M‐H, Random, 99% CI) | 0.70 [0.29, 1.70] |
| 4.7.2 Increased urine protein/urine creatinine ratio | 1 | 173 | Risk Ratio (M‐H, Random, 99% CI) | 1.65 [0.60, 4.54] |
| 4.7.3 incidence of abdominal pain | 1 | 173 | Risk Ratio (M‐H, Random, 99% CI) | 0.49 [0.16, 1.52] |
| 4.7.4 Incidence of nausea | 1 | 173 | Risk Ratio (M‐H, Random, 99% CI) | 0.72 [0.23, 2.23] |
| 4.7.5 Incidence of vomiting | 1 | 173 | Risk Ratio (M‐H, Random, 99% CI) | 0.28 [0.07, 1.15] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Incidence of SAEs Show forest plot | 1 | 213 | Risk Ratio (M‐H, Random, 95% CI) | 0.15 [0.01, 2.81] |
| 5.2 All‐cause mortality Show forest plot | 2 | 237 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.77 [0.17, 3.42] |
| 5.3 Incidence of chelation therapy‐related AEs Show forest plot | 3 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 5.3.1 Risk of leukopenia, neutropenia and/or agranulocytosis | 3 | 280 | Risk Ratio (M‐H, Random, 99% CI) | 1.15 [0.50, 2.62] |
| 5.3.2 Risk of pain or swelling in joints | 2 | 256 | Risk Ratio (M‐H, Random, 99% CI) | 0.76 [0.31, 1.91] |
| 5.3.3 Risk of gastrointestinal disturbances | 1 | 213 | Risk Ratio (M‐H, Random, 99% CI) | 0.45 [0.15, 1.37] |
| 5.3.4 Risk of increased liver transaminase | 2 | 256 | Risk Ratio (M‐H, Random, 99% CI) | 1.02 [0.52, 1.98] |
| 5.3.5 Nausea/vomiting | 1 | 43 | Risk Ratio (M‐H, Random, 99% CI) | 0.55 [0.13, 2.23] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Other AEs related to iron chelation Show forest plot | 4 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 6.1.1 Risk of leukopenia, neutropenia and/or agranulocytosis | 3 | 169 | Risk Ratio (M‐H, Random, 99% CI) | 1.18 [0.09, 15.45] |
| 6.1.2 Risk of pain or swelling in joints | 3 | 135 | Risk Ratio (M‐H, Random, 99% CI) | 2.41 [0.17, 34.31] |
| 6.1.3 Risk of increased liver transaminase | 2 | 104 | Risk Ratio (M‐H, Random, 99% CI) | 3.46 [0.45, 26.62] |
| 6.1.4 Nausea/vomiting | 4 | 194 | Risk Ratio (M‐H, Random, 99% CI) | 4.34 [0.77, 24.44] |
| 6.1.5 Local reactions at infusion site | 2 | 90 | Risk Ratio (M‐H, Random, 99% CI) | 0.18 [0.01, 4.43] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Adherence to iron chelation therapy rates Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 7.2 Incidence of SAE Show forest plot | 1 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 7.3 All‐cause mortality Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
| 7.4 Organ damage (serum creatinine (≥ 33%) above baseline on 2 consecutive occasions) Show forest plot | 1 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 7.5 Total AEs related to iron chelation Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 7.5.1 one year (study end) | 1 | 96 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.76, 1.53] |
| 7.6 Other AEs related to iron chelation Show forest plot | 1 | Risk Ratio (M‐H, Random, 99% CI) | Subtotals only | |
| 7.6.1 Risk of leukopenia, neutropenia and/or agranulocytosis | 1 | 96 | Risk Ratio (M‐H, Random, 99% CI) | 1.67 [0.27, 10.14] |
| 7.6.2 Risk of pain or swelling in joints | 1 | 96 | Risk Ratio (M‐H, Random, 99% CI) | 0.89 [0.29, 2.77] |
| 7.6.3 Gastrointestinal problems | 1 | 96 | Risk Ratio (M‐H, Random, 99% CI) | 0.60 [0.18, 2.04] |
| 7.6.4 ALT (increase ≥ 3‐fold) | 1 | 96 | Risk Ratio (M‐H, Random, 99% CI) | 1.33 [0.20, 8.88] |
| 7.6.5 Skin rash | 1 | 96 | Risk Ratio (M‐H, Random, 99% CI) | 5.00 [0.10, 261.34] |
