Dalya Marks

A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia

BACKGROUND Familial hypercholesterolaemia (FH) affects approximately 1 in 500 people (10 million world-wide) and the elevated serum cholesterol concentrations lead to a more than 50% risk of fatal or non-fatal coronary heart disease by age 50 years in men and at least 30% in women aged 60 years. Based on a systematic literature search, we review the natural history of FH, describe the diagnostic criteria, and consider the effectiveness of treatment. METHODS A comprehensive review was conducted of the literature on the diagnosis of FH, the morbidity and mortality related to treated and untreated FH, and the evidence on the effectiveness of treatment of FH in adults and children. Treatment options have changed since statin treatment became available, and we have not considered pre-statin therapy studies of treatment effectiveness. FINDINGS AND DISCUSSION A clinical diagnosis of FH is widely used, but a definitive diagnosis can be made by genetic screening, although mutations are currently only detected in 30-50% of patients with a clinical diagnosis. Under-diagnosis of FH has been reported world-wide ranging from less than 1% to 44%. The relative risk of death of FH patients not treated with statins is between three and fourfold but treatment is effective, and delays or prevents the onset of coronary heart disease. Early detection and treatment is important. Aggressive LDL therapy is more effective in the regression of the carotid intima media thickness than conventional LDL therapy. Diagnosis at birth is problematic, and should be delayed until at least 2 years of age. Statins are not generally recommended for the treatment of children up to adolescence. Resins may be used but poor adherence is a problem. Technical advances in mutation detection, and the identification of other genes that cause FH, are likely to have important implications for the cost effectiveness of genetic diagnosis of FH.

Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia

Abstract Objectives: To assess the cost effectiveness of strategies to screen for and treat familial hypercholesterolaemia. Design: Cost effectiveness analysis. A care pathway for each patient was delineated and the associated probabilities, benefits, and costs were calculated. Participants: Simulated population aged 16-54 years in England and Wales. Interventions: Identification and treatment of patients with familial hypercholesterolaemia by universal screening, opportunistic screening in primary care, screening of people admitted to hospital with premature myocardial infarction, or tracing family members of affected patients. Main outcome measure: Cost effectiveness calculated as cost per life year gained (extension of life expectancy resulting from intervention) including estimated costs of screening and treatment. Results: Tracing of family members was the most cost effective strategy (£3097 (€5066,

Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies

4479) per life year gained) as 2.6 individuals need to be screened to identify one case at a cost of £133 per case detected. If the genetic mutation was known within the family then the cost per life year gained (£4914) was only slightly increased by genetic confirmation of the diagnosis. Universal population screening was least cost effective (£13 029 per life year gained) as 1365 individuals need to be screened at a cost of £9754 per case detected. For each strategy it was more cost effective to screen younger people and women. Targeted strategies were more expensive per person screened, but the cost per case detected was lower. Population screening of 16 year olds only was as cost effective as family tracing (£2777 with a clinical confirmation). Conclusions: Screening family members of people with familial hypercholesterolaemia is the most cost effective option for detecting cases across the whole population.

Cascade screening for familial hypercholesterolaemia: implications of a pilot study for national screening programmes:

Objective To estimate the probabilistic cost-effectiveness of cascade screening methods in familial hypercholesterolaemia (FH) from the UK NHS perspective. Design Economic evaluation (cost utility analysis) comparing four cascade screening strategies for FH: Using low-density lipoprotein (LDL) cholesterol measurements to diagnose affected relatives (cholesterol method); cascading only in patients with a causative mutation identified and using DNA tests to diagnose relatives (DNA method); DNA testing combined with LDL-cholesterol testing in families with no mutation identified, only in patients with clinically defined ‘definite’ FH (DNA+DFH method); DNA testing combined with LDL-cholesterol testing in no-mutation families of both ‘definite’ and ‘probable’ FH patients (DNA+DFH+PFH). A probabilistic model was constructed to estimate the treatment benefit from statins, with all diagnosed individuals receiving high-intensity statin treatment. Population A cohort of 1000 people suspected of having FH aged 50 years for index cases and 30 years for relatives, followed for a lifetime. Main outcomes Costs, quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER). Results The DNA+DFH+PFH method was the most cost-effective cascade screening strategy. The ICER was estimated at £3666/QALY. Using this strategy, of the tested relatives 30.6% will be true positives, 6.3% false positives, 61.9% true negatives and 1.1% false negatives. Probabilistic sensitivity analysis showed that this approach is 100% cost-effective using the conventional benchmark for cost-effective treatments in the NHS of between £20 000 and £30 000 per QALY gained. Conclusion Cascade testing of relatives of patients with DFH and PFH is cost-effective when using a combination of DNA testing for known family mutations and LDL-cholesterol levels in the remaining families. The approach is more cost-effective than current primary prevention screening strategies.

Family tracing to identify patients with Familial Hypercholesterolaemia: the second Audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing Project

Objectives: To determine what proportion of cases of heterozygous familial hypercholesterolaemia would be identified by cascade screening conducted by a specialist hospital clinic, and by how much this would increase the prevalence of diagnosed cases. Setting: Hospital clinic serving a population of 605,900 in Oxfordshire, UK Methods: A specialist nurse obtained details of living first-degree relatives from 227 adult patients with heterozygous familial hypercholesterolaemia currently or previously attending Oxford lipid clinic after excluding 79 adults without relatives living in Oxfordshire and 48 children. Index cases were asked to invite relatives resident in Oxfordshire for testing. Results: A total of 227 index cases had 1075 first-degree relatives, including 442 adults and 117 children aged < 18 years resident in Oxfordshire. We excluded 171 previously screened adults and 46 for other reasons. Among 225 eligible adult relatives, 28 responders (12%) planned to consult their general practitioner and 52 (23%) attended the clinic for testing. Parents of 113 children (97%) wanted them tested. The positive diagnostic rate was 29% (15/52) in adults and 32% (36/113) in children. Screening increased prevalence by 14.4%, from 0.58/1000 (95% confidence intervals [CI] 0.52–0.65) to 0.67/1000 (95% CI 0.60–0.73), representing 33.5% of predicted cases. Conclusions: Cascade screening conducted by a specialist hospital clinic within its population catchment area did not substantially increase the prevalence of diagnosed familial hypercholesterolaemia. To maximize response rates, clinic staff need to approach relatives directly. Validated age, sex and country-specific diagnostic criteria should be defined, possibly with access to DNA-based tests, to help resolve diagnostic uncertainty.

Injecting drug use and unstable housing: Scope for structural interventions in harm reduction

Background Family tracing is a method recognized to find new patients with familial hypercholesterolaemia (FH). We have implemented family tracing led by FH Nurses and have determined acceptability to patients, feasibility and costs. Methods Nurses were located at five National Health Service (NHS) Trusts; they identified FH patients and offered them family tracing. Responses and test results were recorded on a database and summarized on a family pedigree. Results The majority (∼70%) of index cases participated; the proportion was lower when patients had been discharged from the clinics and in metropolitan areas. On average, 34% (range 13–50%) of relatives lived outside the catchment area of the clinics and could not attend the nurse-led FH clinics. Of the previously untested relatives, 76% who lived in the catchment area of the clinic came forward to be tested. One-third of the relatives who came forward for testing were children ≤16 y of age. The proportion of relatives diagnosed as likely to have FH was lower than would be predicted (30% vs. 50%). This was mainly due to the uncertainty of a diagnosis based on lipid measurements. The average cost to identify and test one relative was approximately £500 but was higher in the metropolitan areas. Conclusion Cascade testing for FH in the UK is feasible, acceptable and likely to be cost-effective if it is a routine aspect of clinical care. However, national implementation would require an integrated infrastructure, so that all individuals have access to testing, and specialist services for the management of young people.

Consequences of removing cheap, super-strength beer and cider: a qualitative study of a UK local alcohol availability intervention

Evidence links unstable housing, and especially homelessness, with elevated health harm among drug users, including riskier drug injecting practices. We undertook 45 qualitative interviews with injecting drug users (IDUs) in Bristol and London in 2006, the majority of whom had recently experienced homelessness. IDUs were recruited through drug user networks and drug agencies. We undertook thematic analyses of drug injector accounts concentrating on risk linked to drug injecting in a context of unstable housing. Findings show that temporary accommodation and hostels for the homeless may provide a ‘safe haven’ from street-based drug use and public injecting environments, and are characterized as a retreat from the ‘chaos’ of the street. But hostels may also constitute ‘risk environments’, facilitating drug using and risk networks and transitions to new patterns of use, including increased frequency of injecting. For some, homelessness was positioned as ‘safer’ than temporary housing with regards to managing drug use. Stable housing emerges as a key structural factor in creating enabling environments for health. We emphasize that temporary accommodation hostels have potential for harm-reduction interventions, but may also be associated with the production of risk related to drug use and injecting.

The views of genitourinary medicine (GUM) clinic users on unlinked anonymous testing for HIV: evidence from a pilot study of clinics in two English cities

Objectives Increasingly, English local authorities have encouraged the implementation of an intervention called ‘Reducing the Strength’ (RtS) whereby off-licences voluntarily stop selling inexpensive ‘super-strength’ (≥6.5% alcohol by volume (ABV)) beers and ciders. We conceptualised RtS as an event within a complex system in order to identify pathways by which the intervention may lead to intended and unintended consequences. Design A qualitative study including a focus group and semistructured interviews. Setting An inner-London local authority characterised by a high degree of residential mobility, high levels of social inequality and a large homeless population. Intervention piloted in three areas known for street drinking with a high alcohol outlet density. Participants Alcohol service professionals, homeless hostel employees, street-based services managers and hostel dwelling homeless alcohol consumers (n=30). Results Participants describe a range of potential substitution behaviours to circumvent alcohol availability restrictions including consuming different drinks, finding alternative shops, using drugs or committing crimes to purchase more expensive drinks. Service providers suggested the intervention delivered in this local authority missed opportunities to encourage engagement between the council, alcohol services, homeless hostels and off-licence stores. Some participants believed small-scale interventions such as RtS may facilitate new forms of engagement between public and private sector interests and contribute to long-term cultural changes around drinking, although they may also entrench the view that ‘problem drinking’ only occurs in certain population groups. Conclusions RtS may have limited individual-level health impacts if the target populations remain willing and able to consume alternative means of intoxication as a substitute for super-strength products. However, RtS may also lead to wider system changes not directly related to the consumption of super-strengths and their assumed harms.

Universal screening at age 1–2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: A cost-utility analysis

A study was undertaken of the views of users of two genitourinary medicine (GUM) clinics in England on unlinked anonymous testing (UAT) for HIV. The UAT programme measures the prevalence of HIV in the population, including undiagnosed prevalence, by testing residual blood (from samples taken for clinical purposes) which is anonymised and irreversibly unlinked from the source. 424 clinic users completed an anonymous questionnaire about their knowledge of, and attitudes towards, UAT. Only 1/7 (14%) were aware that blood left over from clinical testing may be tested anonymously for HIV. A large majority (89%) said they would agree to their blood being tested, although 74% wanted the opportunity to consent. These findings indicate broad support for UAT of blood in a group of patients whose samples are included in the HIV surveillance programme. The findings suggest the need for greater attention to be given to the provision of information and, if replicated in a larger survey, may justify a reappraisal of UK policy on UAT.

A Mixed-Methods Evaluation of a Community-Based Glaucoma Check Service in Hackney, London, UK.

BACKGROUND AND AIMS Familial hypercholesterolaemia (FH) is widely underdiagnosed. Cascade testing (CT) of relatives has been shown to be feasible, acceptable and cost-effective in the UK, but requires a supply of index cases. Feasibility of universal screening (US) at age 1-2 years was recently demonstrated. We examined whether this would be a cost-effective adjunct to CT in the UK, given the current and plausible future undiagnosed FH prevalence. METHODS Seven cholesterol and/or mutation-based US ± reverse cascade testing (RCT) alternatives were compared with no US in an incremental analysis with a healthcare perspective. A decision model was used to estimate costs and outcomes for cohorts exposed to the US component of each strategy. RCT case ascertainment was modelled using recent UK CT data, and probabilistic Markov models estimated lifetime costs and health outcomes for the cohorts screened under each alternative. 1000 Monte Carlo simulations were run for each model, and average outcomes reported. Further uncertainty was explored deterministically. Threshold analysis investigated the association between undiagnosed FH prevalence and cost-effectiveness. RESULTS A strategy involving cholesterol screening followed by diagnostic genetic testing and RCT was the most cost-effective modelled (incremental cost-effectiveness ratio (ICER) versus no US £12,480/quality adjusted life year (QALY); probability of cost-effectiveness 96·8% at £20,000/QALY threshold). Cost-effectiveness was robust to both deterministic sensitivity analyses and threshold analyses that modelled ongoing case ascertainment at theoretical maximum levels. CONCLUSIONS These findings support implementation of universal cholesterol screening followed by diagnostic genetic testing and RCT for FH, under a UK conventional willingness-to-pay threshold.