We wanted to determine if there are any interventions (medication, psychological or educational) that would help people adhere to their iron chelation therapy.
People with sickle cell disease or thalassaemia, who receive regular transfusions, are exposed to iron overload that can result in toxicity to organs and death. Iron chelation therapy is used to prevent or treat iron overload, but it can be a demanding regimen, and have unwanted side effects. There are three types of iron chelators being used to treat iron overload: deferoxamine given subcutaneously (by injecting a drug into the tissue layer between the skin and the muscle), and two agents that are taken orally, deferiprone and deferasirox.
The evidence is current to 1 August 2022.
We searched the literature for both randomised and non-randomised trials, and found 19 randomised trials and one non-randomised trial, totalling 1525 participants, published between 1997 and 2021.
A total of 18 trials looked at drug interventions, one trial looked at a medication management intervention, and one assessed an education intervention (a non-randomised trial).
We were uncertain if single agents or combined agents made any difference in adherence rates, serious adverse events or mortality. Quality of life, measured using validated questionnaires, was only reported in three trials, but not enough data were reported to determine any differences between treatments.
There was no evidence on intervention strategies for different age groups.
We found that there was an unusually high adherence rate to all drugs and combinations of drugs in all the trials. This may be because participants may have been selected based on their ability to stick to medication regimens. Also, adherence may increase in trial participants when there is a higher level of clinician involvement in care.
We concluded that real-world randomised and non-randomised trials, run in both the community and in clinics, are needed to examine a variety of proven and unproven strategies that may be useful for increasing adherence to iron chelation therapy.
Two trials assessed non-medication interventions: one six-month trial of medication management reported very little usable data, and we cannot be certain of the impact of the intervention. The other trial assessing an education intervention was unbalanced, and the data did not allow a good comparison, therefore we were unable to use it.
Quality (certainty) of the evidence
We rated the certainty of the evidence as low to very low across all the outcomes in this review. This was due to trials being at serious or very serious risk of bias, and the outcome estimates being imprecise (wide confidence intervals) and not widely applicable (some trials were conducted only in children of a specific age and meeting specific criteria).
The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis.
Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation.
Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy.
Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence.
To identify and assess the effectiveness of different types of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) and interventions specific to different age groups, to improve adherence to iron chelation therapy compared to another listed intervention, or standard care in people with SCD or thalassaemia.
We searched CENTRAL (Cochrane Library), MEDLINE, PubMed, Embase, CINAHL, PsycINFO, ProQuest Dissertations & Global Theses, Web of Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (13 December 2021). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (1 August 2022).
For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion.
For studies including psychological and psychosocial interventions, educational interventions, or multi-component interventions, non-randomised studies of interventions (NRSIs), controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion.
For this update, two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE.
We included 19 RCTs and one NRSI published between 1997 and 2021. One trial assessed medication management, one assessed an education intervention (NRSI) and 18 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral chelating agents, deferiprone and deferasirox.
We rated the certainty of evidence as very low to low across all outcomes identified in this review.
Four trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL.
We identified nine comparisons of interest.
1. Deferiprone versus deferoxamine
We are uncertain whether or not deferiprone affects adherence to iron chelation therapy (four RCTs, unpooled, very low-certainty evidence), all-cause mortality (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.18 to 1.21; 3 RCTs, 376 participants; very low-certainty evidence), or serious adverse events (SAEs) (RR 1.43, 95% CI 0.83 to 2.46; 1 RCT, 228 participants; very low-certainty evidence).
Adherence was reported as "good", "high" or "excellent" by all seven trials, though the data could not be analysed formally: adherence ranged from 69% to 95% (deferiprone, mean 86.6%), and 71% to 93% (deferoxamine, mean 78.8%), based on five trials (474 participants) only.
2. Deferasirox versus deferoxamine
We are uncertain whether or not deferasirox affects adherence to iron chelation therapy (three RCTs, unpooled, very low-certainty evidence), although medication adherence was high in all trials.
We are uncertain whether or not there is any difference between the drug therapies in serious adverse events (SAEs) (SCD or thalassaemia) or all-cause mortality (thalassaemia).
3. Deferiprone versus deferasirox
We are uncertain if there is a difference between oral deferiprone and deferasirox based on a single trial in children (average age 9 to 10 years) with any hereditary haemoglobinopathy in adherence, SAEs and all-cause mortality.
4. Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT)
One RCT compared deferasirox in different tablet forms. There may be a preference for FCTs, shown through a trend for greater adherence (RR 1.10, 95% CI 0.99 to 1.22; 1 RCT, 88 participants), although medication adherence was high in both groups (FCT 92.9%; DT 85.3%). We are uncertain if there is a benefit in chelation-related AEs with FCTs.
We are uncertain if there is a difference in the incidence of SAEs, all-cause mortality or sustained adherence.
5. Deferiprone and deferoxamine combined versus deferiprone alone
We are uncertain if there is a difference in adherence, though reporting was usually narrative as triallists report it was "excellent" in both groups (three RCTs, unpooled).
We are uncertain if there is a difference in the incidence of SAEs and all-cause mortality.
6. Deferiprone and deferoxamine combined versus deferoxamine alone
We are uncertain if there is a difference in adherence (four RCTs), SAEs (none reported in the trial period) and all-cause mortality (no deaths reported in the trial period). There was high adherence in all trials.
7. Deferiprone and deferoxamine combined versus deferiprone and deferasirox combined
There may be a difference in favour of deferiprone and deferasirox (combined) in rates of adherence (RR 0.84, 95% CI 0.72 to 0.99) (one RCT), although it was high (> 80%) in both groups.
We are uncertain if there is a difference in SAEs, and no deaths were reported in the trial, so we cannot draw conclusions based on these data (one RCT).
8. Medication management versus standard care
We are uncertain if there is a difference in QoL (one RCT), and we could not assess adherence due to a lack of reporting in the control group.
9. Education versus standard care
One quasi-experimental (NRSI) study could not be analysed due to the severe baseline confounding.