Knowledge Gaps in the Management of Familial Hypercholesterolaemia - A UK based survey

Jonathan Schofield1, 2, See Kwok1, 3, Michael France1, Nigel Capps4, Ruth Eatough1, Rahul Yadav2, Kausik Ray5and Handrean Soran1, 2

1Cardiovascular Trials Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

2Cardiovascular Research Group, Core Technologies Facility, University of Manchester, Manchester, UK

3Barlow Medical Centre, Manchester, UK.

4Department of Clinical Biochemistry, Shrewsbury & Telford Hospital NHS Trust, Telford, UK.

5Cardiovascular Sciences Research Centre, St George’s Hospital NHS Trust, London, UK

Corresponding author:

Dr Handrean Soran MSc, MD, FRCP

Consultant Physician & Endocrinologist and Lead Cardiovascular Trials Unit, University Department of Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, M13 9WL, UK.

E-mail: ;

Tel: 0044 (0) 161 276 4066/4348, Fax: 0044 (0) 161 276 3630.

Abstract

Background and Aims. Untreated individuals with Familial Hypercholesterolaemia (FH) are at increased risk of developing premature cardiovascular disease (CVD). Early diagnosis and treatment can result in a normal life expectancy.A recent survey commissioned by the European Atherosclerosis Society (EAS) reported a lack of awareness of FH in the general population. We conducted a survey to assess knowledge among healthcare professionals involved in the assessment and management of cardiovascular risk and disease in the United Kingdom.

Methods. A survey designed to assess knowledge of diagnostic criteria, risk assessment, the role of cascade screening, and management options for patients with FH was distributed to 1000 healthcare professionals (response rate 44.3%). The same survey was redistributed following attendance at an educational session on FH.

Results. 151 respondents (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH, but just 61.4% recognized that cardiovascular risk estimation tools cannot be applied in FH, and only 22.3% understood the relative risk of premature CVD compared to the general population. Similarly, just 65.9% were aware of recommendations regarding cascade screening.

Conclusions. The prevalence and associated risk of FH continue to be underestimated, and knowledge of diagnostic criteria and treatment options is suboptimal. These results support the recent Consensus Statement of the EAS and production of quality standards by the National Institute for Health and Care Excellence. Further work is required to formulate interventions to improve FH awareness and knowledge, and to determine the effect these interventions have on patient outcomes.

Keywords

FH, Familial Hypercholesterolaemia, Survey, Knowledge, Education, CVD, LDL-C

Introduction

The life-threatening effects of Familial Hypercholesterolaemia (FH) are the result of abnormally high circulating concentrations of atherogenic low-density lipoprotein cholesterol(LDL-C), present from birth due to an inherited defect in low-density lipoprotein clearance[1].FH is under-diagnosed and often diagnosed late [2]. Lipid-modifying drug treatment reduces LDL-C levels and attenuates the development of cardiovascular disease (CVD) butfewer than one in six patients may be treated, with many of these being undertreated[3,4].Importantly, the overall mortality in treated Heterozygous FH is similar to that in the general population [5].

Patients with a history of premature CVDare not consistently screened for FH [6,7], and hence even Coronary Care Unit admissions thought to relate to FH may be overlooked[1]. Individuals with CVD secondary to FH may also be missed in primary care where other risk factors for CVD are more common [1,8]. Whilst the U.S. National Lipid Association recently highlighted the limited training available to practitioners to facilitate the screening and appropriate management of patients with FH[9], there has been little discussion of this in Europe beyond a recent survey commissioned by the European Atherosclerosis Society (EAS) that reported a lack of awareness among the general population [10]. We therefore carried out a survey of healthcare professionals working in primary and secondary care in the United Kingdom (UK) to assess current knowledge of FH, and explore whether targeted education could improve this.

Method

A structured surveywith questions based on expert recommendations and published guidelines (Figure 1) was distributed to healthcare professionals involved in the assessment and management of cardiovascular risk and disease at local and national educational meetings, and electronicallyby e-mail with an embedded single-use URL. The survey was introduced to potential participants with an explanation of the aims of the project including planned dissemination of the results to meet the requirements of informed consent. Due care was taken to protect confidentiality.

Demographic data were sought for job title and region within the UK.Participants were asked about their familiarity with FH, knowledge of its prevalence, inheritance, associated risks, awareness of diagnostic criteria and guidelines for management. Questions were also included on current and future treatment options. Participants were asked to choose the most correct statement, or to select one or more answers from a list; the only open questions related to previous experience of FH and suggestions to improve the care of patients with FH.

A second survey was distributed to healthcare professionals following attendance at an educational session on FH. Participants were asked to answer the same questions four weeks after this session.

Data were collected and analyses performed using SurveyMonkey and Microsoft Excel. Statistical tests (student’s t-test) to determine occupational and geographical differences in FH knowledge, practices and opinions used position and previous experience as categorical variables. Paired t-tests were used to determine the effect of education. Knowledge scores were calculated from answers submitted for questions on the pathogenesis of FH, and its management.

Results

The paper questionnaire distributed at educational meetings was completed by 81 of 100 healthcare professionals (81%). The response rate toelectronic distribution of the questionnaire was 40.2% (362 of 900) giving a cumulative response rate of 44.3% (443 of 1000). 35 of 50 (70%) completed a second survey assessing the effect of education (31 of 40 paper questionnaires, 4 of 10 electronic invitations).

Of 443 participants the majority (94.5%) were based in England, with 13 respondents (3%) from Scotland, 9 from Wales (2%), and 2 working in Northern Ireland (0.5%). The professional roles of respondents are shown in Table 1.

80 respondents (20.8%) were currently seeing patients in a specialty lipid clinic while a further 36 (9.4%) had done previously but not at the time of survey completion. 151 participants (40.5%) reported having patients under their care who would meet the diagnostic criteria for FH. Participants currently seeing patients in a specialty lipid clinic scored significantly better on the knowledge-based elements of the survey compared with those who had seen patients previously and those who had never seen patients in a specialty lipid clinic (82.5% vs. 62.3% vs. 46.1% (p<0.001 and p<0.05)). The mean knowledge score according to professional role is shown in Figure 2. The mean score post-education was 86.7%.

Guidelines and Diagnostic Criteria

59.1% selected the most appropriate description of FH, with66.2% (76.6% of General Practitioners [GPs]) correctly identifying total cholesterol greater than 7.5mmol/l as being consistent with a possible diagnosis ofHeterozygous Familial Hypercholesterolaemia (HeFH).61.9% were aware of National Institute for Health and Care Excellence (NICE) Guidelines for the diagnosis and management of FH and 43.5% of respondents were aware of the Simon Broome diagnostic criteria although 32.6% thought a diagnosis of definite FH could only be made by genetic testing. Awareness of diagnostic criteria and guidelines was similar across primary and secondary care.

Risk Assessment

54.5% of participants appreciated that LDL-C is raised from birth and 61.4% that cardiovascular risk estimation tools cannot be applied to people with FH[1]. The relative risk of premature CVD was significantly underestimated, with22.3% estimatingit correctly.

Prevalence, Inheritance and Cascade Screening

The prevalence of HeFH was underestimated by 23.7% of participants, with a further 25.5% unsure. 50.5% recognized its pattern of inheritance, with 65.9% aware that family cascade screening is recommended by NICE. 29.5% reported having detected FH in the first-degree relative of a patient already diagnosed with FH, and 15.7% had received a request from a lipid clinic or colleague to trace relatives of a patient with FH.

Treatment Options and Improving Care

91.4% were aware of ezetimibe as a treatment option, with 85.7% and75.2% aware of fibrates and bile acid sequestrants as additional treatment options respectively. A further 23.4% were aware of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as a potential future therapeutic option and 43.4% were aware of the existence of lipoprotein apheresis. 68.8% felt that better access to lipid clinics would improve the care of patients with FH. 8.4% reported that their region managed FH well. 73.4% felt that more education for GPs would improve the care of FH patients, while 34.4% thought patient forums might help.

Effect of Education

Education significantly improved all aspects of FH knowledge. Participants were more likely to identify the cholesterol level above which the diagnosis should be considered (91.4% vs. 66.2% (p<0.001)). Following education more healthcare providers recognized that there were patients under their care who would satisfy the diagnostic criteria (48.4% vs. 40.5% (p<0.05)), and participants were significantly more likely to recognize that treatment should not be guided by cardiovascular risk estimation (85.3% vs. 61.4% (p<0.001)), as LDL-C is raised from birth (85.3% vs. 54.5% (p<0.001)), resulting in a 20-fold increased risk of premature CVD (71.4% vs. 22.3% (p<0.001)). Education also improved understanding of the prevalence of FH (77.1% vs. 46.3% (p<0.001)) and of the importance of cascade screening (94.3% vs. 65.9% (p<0.001)).

Discussion

Worldwide there are between 14 and 34 million people with FH, of whom less than 1% are diagnosed and 200,000 die prematurely each year[1,11]. Fifteen years ago the Simon Broome registry reported under- and late diagnosis of FH in the UK[12], and there is limitedevidence to suggest that practice has significantly improved. It should also be noted that reported detection rates are based on an estimated prevalence of 1 in 500, but more recent data suggest the prevalence of FH to be between 1 in 200 and 1 in 250 [13]. Although guidelines for the diagnosis and management of FH are widely available [11], perceived under-diagnosis and treatment were the drivers for the recent production of a NICE quality standard [14] and EAS Consensus Statement [1]. The results of this survey suggest that lack of knowledge may be at least partially responsible for under-diagnosis and treatment in the UK.

Early diagnosis, before complications develop, is paramount to the successful treatment of FH[9]. The diagnostic hallmarks of FH are easily missed during routine physical examination[9], andthe failure of over 40% of respondents to select the most appropriate definition of FH also suggests that accurate diagnosis might require review by a physician with an interest in lipid disorders[15].

The key role of primary care in the diagnosis and identification of individuals with FH has long been recognized, with GPs requesting 92% of lipid profiles [11,16]. The EAS has suggested that a family history of premature CVD or hypercholesterolaemia might be used to address under-diagnosis and under-treatment through opportunistic or targeted systematic screening[1].Whilst awareness of relevant guidelines was higher in this UK cohort than that observed iIn a recent review of FH knowledge and practice in Western Australia [17], further education is clearly warranted. This survey suggests that 1 in 5 primary care practitioners are unable to identify cholesterol concentrations consistent with a possible diagnosis ofFH. Laboratories therefore continue to have an important role alerting physicians to the possibility of FH [16].

If opportunities for early diagnosis are not taken, patients with FH may first present to a cardiologist[18]. A 2011 survey of selected American College of Cardiology members also reported limited knowledge of FH among cardiologists [19]. The current focus on acute event management and patient discharge in secondary care may also result in missed opportunities to detect individuals with FH [20]. This survey confirms that FH is universally under-recognized.

It is important to emphasise that the introduction of lipid-lowering therapy is not the only reason to correctly identify individuals with FH. As a relatively common, but treatable, disorder, FH fulfils all the World Health Organization (WHO) criteria for disease screening[21]. Cascade screening of first-degree relatives of index cases is undoubtedly the most cost-effective means of finding previously undiagnosed individuals with FH [22]. However just 50.5% of healthcare professionals recognize the pattern of inheritance of FH, a similar level of awareness to that recently reported among physicians in Asia [23], which perhaps partially explains under-appreciation of the role of cascade screening [6].NICE has recommended cascade screening based on genetic testing but this has not yet been widely adopted in England, due to lack of funding, although there are established programmes in Wales, Scotland and Northern Ireland [24]. Accordingly just 8.6% reported having unrestricted access to genetic testing, with a further 17.5% reporting restricted access for selected patients. The 2013 NICE Quality Standard has supported the commissioning of services that offer genetic testing to people with a clinical diagnosis of FH as part of a specialist assessment [14]. It is to be hoped that access to genetic testing will continue to improve, but important that clinicians do not forget that the vascular consequences of FH are driven by LDL-C levels, and not by genotype.

Attainment of LDL-C targets is imperative to reduce cumulative lifetime CVD risk[25],but under-treatment of FH remains a major issue[8]. A review of the Netherlands genetic cascade screening program found that even after a diagnosis of FH, patients were undertreated, with a minority reachingagreed treatment goals [26]. The National Lipid Association concluded that provider education must emphasise not only the importance of screening, but also the need for aggressive therapy[9]. The Copenhagen General Population Study found that only 48% of patients with FH received statins, and that those not receiving them had a 13-fold increased risk of CVD[13]. Unfortunately, monotherapy with high doses of even the most potent statins will not achieve treatment targets in many patients [1]. GPs are central to improving adherence to lipid lowering therapies[27], and knowledge of potential therapeutic options is crucial to appropriate treatment. LDL apheresis is a treatment option for individuals refractory to conventional lipid-lowering therapy[11]; knowledge of apheresis and novel agentsmust be improved if patients who might benefit from these interventions are to be recognized. FH has attracted renewed focus with the development of novel therapies that are highly effective in lowering LDL-C [8], illustrated by increased awareness of PCSK9 inhibitors.

Diagnosing and managing FH in an individual and their relatives can be complex, and is best achieved when there is access to specialist services. 68.8% felt that better access to lipid clinics would improve the care of patients with FH. Our survey supports previous suggestions that FH care might be improved throughtargeted education[1]. The potential for service improvement is underlined by just 8.4% reporting that their region manages FH well.

The authors of previous studies have recommended the formulation of interventions to improve GP knowledge and awareness in collaboration with primary care and specialists in lipidology and preventative cardiology[17]. We have demonstrated that targeted education has the potential to significantly improve care. Importantly, following education, more participants recognized that there were patients under their care who would satisfy the diagnostic criteria for FH.

Limitations of this work

Study participants were invited to complete the survey at educational meetings and through e-mail invitation of healthcare professionals involved in the assessment and management of CVD. This opportunistic selection represents an inherent limitation of these findings as knowledge might reasonably be expected to be lower among those who chose not to participate.

Conclusion

When patients with FH present with CHD, they are more likely to be inappropriately managed if seen by physicians unfamiliar with the condition. An understanding of the prevalence of FH and its associated risk is central to promoting early diagnosis and more effective treatment, but this study suggests that these continue to be underestimated, and knowledge of diagnostic criteria and treatment options is suboptimal. FH is not uncommon in the general population, and it should always be considered when a family or personal history of premature CHD is encountered. It is to be hoped that the production of quality standards by NICE and the EAS FH Studies Collaboration will raise awareness to improve the detection and management of FH.

Healthcare economic modelling hasdemonstrated that the identification and appropriate management of individuals with FH offers considerable overall savings[28]. Urgent action isneeded to improve education and the diagnosis of FH [4]. Although we have demonstrated that knowledge of FH can easily be improved through targeted education, further work is required to determine the effect such interventions might have on actual case detection and management[17]. Clearly such work would be aligned to the aims and objectives of the EAS FH Studies Collaboration’s recent call to arms [29].

Disclosures

This project is part of the European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) United Kingdom team’s activity. HS is the FHSC UK national coordinator and member of the steering committee. KR is the chair of the FHSC steering committee.

Author Contributions

All authors contributed to the conception and design of this study. JS, NC and HS were responsible for the distribution of questionnaires and acquisition of results. JS, SK, MF, NC and HS analysed the data. JS, SK, MF, KR and HS drafted the work. Critical revisions were made by all authors. All authors have given their final approval of the submitted version, and agree to be accountable for all aspects of the work.

Acknowledgement

We acknowledge support from the National Institute for Health Research/Wellcome Trust Clinical Research Facility at Central Manchester University Hospitals NHS Foundation Trust, Greater Manchester Comprehensive Local Research Network and Lipid Disease Fund.

We would like to thank HEART UK for help and support for this project, and the healthcare professionals who participated in the survey.

References

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2. Civeira F (2004) Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 173: 55-68.

3. Marks D, et al. (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168: 1-14.

4. Versmissen J, et al. (2008) Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337: a2423.

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