Alternative cascade-testing protocols for identifying and managing patients with familial hypercholesterolaemia: systematic reviews, qualitative study and cost-effectiveness analysis.

IF 3.5 2区 医学 Q1 HEALTH CARE SCIENCES & SERVICES Health technology assessment Pub Date : 2023-10-01 DOI:10.3310/CTMD0148
Nadeem Qureshi, Bethan Woods, Rita Neves de Faria, Pedro Saramago Goncalves, Edward Cox, Jo Leonardi Bee, Laura Condon, Stephen Weng, Ralph K Akyea, Barbara Iyen, Paul Roderick, Steve E Humphries, William Rowlands, Melanie Watson, Kate Haralambos, Ryan Kenny, Dev Datta, Zosia Miedzybrodzka, Christopher Byrne, Joe Kai
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The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective.</p><p><strong>Objectives: </strong>The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers.</p><p><strong>Design and methods: </strong>This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals.</p><p><strong>Result: </strong>Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (<i>p</i> < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable.</p><p><strong>Limitations: </strong>Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. 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Abstract

Background: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective.

Objectives: The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers.

Design and methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals.

Result: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p < 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable.

Limitations: Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants.

Conclusions: Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families.

Future work: Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives.

Study registration: This study is registered as PROSPERO CRD42018117445 and CRD42019125775.

Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.

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识别和管理家族性高胆固醇血症患者的替代级联试验方案:系统综述、定性研究和成本效益分析。
背景:对家族性高胆固醇血症患者亲属进行级联检测是识别家族性高脂血症的有效方法。级联测试方案首先确定一名家族性高胆固醇血症的指标患者,然后选择三种联系其他亲属的方法之一:间接方法,指标患者联系其亲属;专家联系亲属的直接方法;或者直接和间接方法的组合。然而,目前尚不清楚哪种方案可能最有效。目的:目的是确定家族性高胆固醇血症患者不同级联测试方案、治疗模式和短期和长期结果的病例数;评估家族性高胆固醇血症级联试验替代方案的成本效益;并定性评估不同级联检测方案对家族性高胆固醇血症患者和家庭以及医疗保健提供者的可接受性。设计和方法:本研究包括对三个数据集的系统回顾和分析:PASS(PASS Software,Rijswijk,the Netherlands)医院家族性高胆固醇血症数据库、临床实践研究数据链(CPRD)-医院发作统计(HES)链接的一级-二级护理数据集和专家家族性高脂血症登记册。进行了成本效益建模,结合了先前的分析。在与病人、亲属和保健专业人员的访谈中检验了可接受性。结果:方案的系统回顾:根据24项研究中的4项研究的数据,与直接方法(33%,95%CI 28%至39%)或单独间接方法(34%,95%CI 30%至37%)相比,联合方法导致测试亲属的产率略高[40%,95%置信区间(CI)37%-42%]。PASS数据库表明,那些直接联系的人更有可能完成级联测试(p局限性:经济分析中没有使用系统评价,因为相关研究缺乏或质量较差。由于只有一部分初级保健编码的家族性高胆固醇血症患者可能实际患有家族性高脂血症,CPRD分析可能低估了真实效果。成本效益分析需要与长期心血管疾病风险、治疗对胆固醇的影响以及数据集估计的可推广性。面试招募仅限于讲英语的白人参与者。结论:基于有限的证据,最具成本效益的级联检测方案,诊断大多数亲属,通过基因检测选择指标病例,服务直接联系亲属,即使一级亲属没有接受检测,也要联系二级亲属。联系亲属的综合方法可能更适合一些家庭。未来的工作:建立一个长期的家族性高胆固醇血症队列,测量胆固醇水平、治疗和心血管结果。进行一项随机研究,比较联系亲属的不同方法。研究注册:该研究注册为PROSPERO CRD42018117445和CRD42019125775。资助:该项目由国家卫生与保健研究所(NIHR)卫生技术评估计划资助,并将在《卫生技术评估》上全文发表;第27卷第16期。有关更多项目信息,请访问NIHR期刊图书馆网站。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Health technology assessment
Health technology assessment 医学-卫生保健
CiteScore
6.90
自引率
0.00%
发文量
94
审稿时长
>12 weeks
期刊介绍: Health Technology Assessment (HTA) publishes research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS.
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