Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK.
Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK.
Cochrane Database Syst Rev. 2023 Mar 6;3(3):CD012349. doi: 10.1002/14651858.CD012349.pub3.
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.
AUTHORS' CONCLUSIONS: 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.
经常接受输血的镰状细胞病 (SCD) 和地中海贫血症患者有发生铁过载的风险。铁过载会导致心脏、肝脏和内分泌腺体等脆弱器官的铁毒性，可通过使用铁螯合剂进行预防和治疗。密集的治疗需求和不舒服的副作用会对日常生活和幸福感产生负面影响，这可能会影响治疗的依从性。
确定并评估不同类型的干预措施（心理和社会心理、教育、药物干预或多组分干预）以及针对不同年龄组的特定干预措施的有效性，与另一种列出的干预措施或 SCD 或地中海贫血症患者的标准护理相比，提高铁螯合治疗的依从性。
我们检索了 Cochrane 图书馆的 Cochrane 中心对照试验数据库（Cochrane Library）、MEDLINE、PubMed、Embase、CINAHL、PsycINFO、ProQuest 学位论文和全球专题论文集索引以及正在进行的试验数据库（2021 年 12 月 13 日）。我们检索了 Cochrane 囊性纤维化和遗传疾病组的血红蛋白病试验登记处（2022 年 8 月 1 日）。
对于比较药物或药物更改的试验，只有随机对照试验（RCT）才有资格入选。对于包括心理和社会心理干预、教育干预或多组分干预的研究，干预的非随机研究（NRSI）、对照前后研究和以依从性为主要结局的中断时间序列研究也有资格入选。
对于本次更新，两名作者独立评估了试验的纳入标准和偏倚风险，并提取了数据。我们使用 GRADE 评估了证据的确定性。
我们纳入了 19 项 RCT 和一项 2021 年发表的 NRSI。一项试验评估了药物管理，一项评估了教育干预（NRSI），18 项 RCT 评估了药物干预。评估的药物包括皮下去铁胺和两种口服螯合剂，去铁酮和地拉罗司。我们将所有在本综述中确定的结果的证据确定性评为极低至低。四项试验使用经过验证的工具测量了生活质量（QoL），但未提供可分析的数据，也未报告 QoL 存在差异。我们确定了九项感兴趣的比较。1. 去铁酮与去铁胺：我们不确定去铁酮是否会影响铁螯合治疗的依从性（四项 RCT，未合并，极低确定性证据）、全因死亡率（风险比（RR）0.47，95%置信区间（CI）0.18 至 1.21；3 项 RCT，376 名参与者；极低确定性证据）或严重不良事件（SAE）（RR 1.43，95%CI 0.83 至 2.46；1 项 RCT，228 名参与者；极低确定性证据）。七项试验均报告“良好”、“高”或“优秀”的依从性，但数据无法进行正式分析：依从性范围为 69%至 95%（去铁酮，平均 86.6%）和 71%至 93%（去铁胺，平均 78.8%），基于五项试验（474 名参与者）。2. 地拉罗司与去铁胺：我们不确定地拉罗司是否会影响铁螯合治疗的依从性（三项 RCT，未合并，极低确定性证据），尽管所有试验的药物依从性均较高。我们不确定药物治疗在严重不良事件（SCD 或地中海贫血症）或全因死亡率方面是否存在差异。3. 去铁酮与地拉罗司：我们不确定口服去铁酮和地拉罗司之间是否存在差异，基于一项针对任何遗传性血红蛋白病的儿童（平均年龄 9 至 10 岁）的单中心试验，在依从性、SAE 和全因死亡率方面。4. 地拉罗司薄膜包衣片（FCT）与地拉罗司分散片（DT）：一项 RCT 比较了不同形式的地拉罗司。可能对地拉罗司 FCT 有偏好，这表明依从性呈上升趋势（RR 1.10，95%CI 0.99 至 1.22；1 项 RCT，88 名参与者），尽管两组的药物依从性均较高（FCT 92.9%；DT 85.3%）。我们不确定 FCT 是否会降低与螯合相关的 AE。我们不确定 SAE、全因死亡率或持续依从性是否存在差异。5. 去铁酮和去铁胺联合与去铁酮单独：我们不确定依从性是否存在差异，尽管报告通常是叙述性的，因为三中心试验报告两组的依从性均为“优秀”（三项 RCT，未合并）。我们不确定 SAE 和全因死亡率的发生率是否存在差异。6. 去铁酮和去铁胺联合与去铁胺单独：我们不确定依从性（四项 RCT）、SAE（试验期间未报告）和全因死亡率（试验期间无死亡报告）是否存在差异。所有试验的依从性均较高。7. 去铁酮和去铁胺联合与去铁酮和地拉罗司联合：去铁酮和地拉罗司联合（组合）可能在依从率方面存在差异（RR 0.84，95%CI 0.72 至 0.99）（一项 RCT），尽管两组的依从性均较高（>80%）。我们不确定 SAE 是否存在差异，试验期间无死亡报告，因此我们无法根据这些数据得出结论（一项 RCT）。8. 药物管理与标准护理：我们不确定 QoL 是否存在差异（一项 RCT），并且由于对照组缺乏报告，我们无法评估依从性。9. 教育与标准护理：一项准实验（NRSI）研究由于基线严重混杂而无法进行分析。
本综述中包括的药物比较具有高于平均水平的依从率，这与药物管理或不良反应无关，但通常随访情况不佳（长期试验中脱落率较高），依从性基于方案分析。参与者可能是基于在试验药物治疗中的较高依从性而入选的。此外，在临床试验背景下，由于增加了对临床医生的关注和参与，因此较高的依从率可能是试验参与的一种人为现象。需要在社区和诊所环境中进行真实世界的、实用的试验，以检验可能增加铁螯合治疗依从性的已确认或未确认的依从性策略。由于缺乏证据，本综述无法对不同年龄组的干预策略发表评论。
