Reducing Premature Coronary Artery Disease in Malaysia by early identification of Familial Hypercholesterolaemia

Coronary artery disease (CAD) is the leading cause of illness and death in most countries, including Malaysia, with up to 15% of young Malaysians affected. Identifying the causes for and reducing the incidence of premature CAD is a key national priority in Malaysia.

Familial Hypercholesterolemia (FH) has been identified as an important cause of premature CAD. This is one of the most common inherited conditions and has a high chance of being passed from one generation to another. Individuals with FH have high levels of Low Density Lipoprotein Cholesterol (LDL-C) from birth, known as "bad cholesterol". Left untreated, they are 22 times more likely to have premature CAD than individuals without FH. Early detection and treatment of FH through "statin" cholesterol-lowering drugs can effectively prevent heart attacks. Globally, between 1 in 200 and 1 in 500 people have the more common form of FH (heterozygous FH). Recent reports state as many as 1 in 100 Malaysians maybe affected. However, most of these individuals remain undiagnosed, resulting in lost opportunities to prevent premature CAD.

Improving identification of FH, particularly in primary care, enables early treatment of these individuals. As a result of reducing the risk of premature CAD, this will save lives, improve life expectancy and reduce long-term health expenditure. International guidelines recommend FH case finding using established diagnostic criteria developed from specialist care, specifically Simon-Broome (SB) and Dutch Lipid Clinic Criteria (DLCC). The UK team has demonstrated that using the SB criteria in English primary care setting has a low FH detection (6% of patients fulfilling criteria). To improve FH identification in primary care, the UK team has developed and validated the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT). On assessment of over 3.7 million British patients with cholesterol measurements in primary care, FAMCAT was between 15 and 20% better at identifying FH than DLCC or SB criteria.

To evaluate how this will perform in Malaysian primary care, we have developed a web-based tool to collect key information to identify individuals with suspected FH using FAMCAT, DLCC or SB criteria. To compare these criteria, when patients attend clinic, they will be invited to provide this information. Using these criteria, patients with suspected FH will be offered genetic testing and examined for features of the condition. Based on the findings of the UK FAMCAT studies, we predict this criteria will perform better by detecting a greater proportion of patients with FH. Having confirmed the best approach to identify suspected FH, the web tool will be refined to be used in primary care clinics. To improve the uptake of this new FH case identification tool, doctors and nurses will be interviewed as they use the tool with dummy patient information. By introducing genetic testing, we will, firstly, be able to show the type of FH causing genetic mutation found in the Malaysian primary care population. Secondly, we can explore the perception, attitude and experience of individuals who are offered genetic testing and seen in specialist care.

Hence, this project will indicate an acceptable and effective approach to identify FH in Malaysian primary care and a clearer picture of FH-causing genetic mutations that are found in the Malaysian population leading to better tailored genetic tests. Also, through interviews with patients with suspected FH, primary care doctors and nurses will be able to provide advice to the Ministry of Health and policymakers on how to introduce FH identification in primary care and clinical pathway once tested. This includes advising on guidelines, the training need of health professionals and public health campaigns. Further, this will benefit Malaysian society through reduction in premature CAD, especially in those from the low and middle income groups, and globally enhance the profile of Malaysian

BACKGROUND: Premature coronary artery disease is increasing rapidly in Malaysia and Familial Hypercholesterolemia (FH) is an important cause. Most FH cases remain undiagnosed. The UK team has developed a new primary care approach (FAMCAT) that is upto 20% better at identifying FH than the established Simon-Broome (SB) and Dutch Lipid Clinic (DLCC) diagnostic criteria. But FAMCAT's performance needs to be validated in Malaysia. Combined with eliciting patients and primary care practitioners' opinions of the approach, the study aims to improve identification of FH in Malaysian primary care

STUDY OBJECTIVES:
1. To compare detection rate of FH in Malaysian primary care population between FAMCAT and established clinical diagnostic criteria (SB and DLCC): Workstream (WS)1
2. To identify FH genetic profile in individuals with suspected FH in the Malaysian primary care population: WS2
3. To explore the experience, concerns and expectations of individuals with suspected FH who are referred for genetic testing: WS3
4. To evaluate clinical utility of a new FH case identification tool in Malaysian primary care: WS3

DESIGN AND SETTING: Through an observational study, WS1 will identify individuals with suspected FH in the Malaysian primary care using FAMCAT, SB or DLCC, who will be offered genetic testing. WS 2 will use targeted next generation sequencing to identify FH-causing genetic mutations. WS 3 will use qualitative interview methods to explore the experience of patients with suspected FH and primary care practitioners' opinions on usability of FH case identification tool

POPULATION:6800 patients complete 10 minutes assessment in 12 primary care clinics to identify 310 patients with suspected FH (WS1 &WS2). Up to 25 patients referred for genetic testing and 40 primary care practitioners (WS 3)

OUTPUT: Primary care FH case identification tool, genetic testing regime and clinical pathway that is acceptable to patients, doctors and policymakers.

The expected direct OUTPUTS from this study include:
1. Identification of the most appropriate primary care FH case identification tool to opportunistically identify suspected FH patients.
2. Genetic mutation profile of individuals with suspected FH in the general population.
3. Identification of new variant mutations in the 7 FH candidate genes to support development of genetic mutation testing for FH that is relevant to the Malaysian population.
4. An insight into patients and practitioners opinions of the intervention through qualitative research.

The expected FURTHER BENEFITS include:
1. Development of multidisciplinary integrated clinical care pathways between primary and specialist care to ensure early diagnosis and, through the resulting early management, reduction in premature CAD.
2. Development of FH Training Module for primary care doctors and nurses to identify and manage FH in primary care.
3. Development of national clinical guideline on FH identification and management in collaboration with the Health Technology Assessment (HTA) Division, Ministry of Health (MOH) Malaysia and the Malaysia Society of Atherosclerosis (MSA).
4. Development of policy on most appropriate route to identify FH in Malaysia, in collaboration with the MOH.
5. Public health campaigns to improve public awareness of how cardiovascular risk is associated with raised cholesterol level and how their doctors can use this information to identify FH. The campaigns could include printed brochures, posters, newspaper articles, mass media, social media and exhibitions, in collaboration with the Public Health Division, MOH.
6. Formation of an international consortium of experts from various specialties, particularly in the UK and Malaysia, to advance cutting-edge research on FH.

SPECIFIC STAKEHOLDERS:
1. Individuals with suspected FH in the Malaysian primary care population
a) Short term benefits:
(i) Early identification of suspected FH for further clinical assessment and genetic profiling
(ii) Access to multidisciplinary specialist care and management strategies to prevent premature CAD and other complications
(iii) Awareness of the conditions and understanding the ways to prevent complications
(iv) Early identification of affected family members of genetically-confirmed FH cases through cascade screening and access to early interventions
b) Long term benefits:
Reduction of CAD, through early identification and effective management of FH patients and their affected family members

2. Health care providers - primary care doctors:
(i) Improve engagement of practitioners through utilisation of FH identification tools that will assist them to identify FH cases
(ii) Increase awareness of FH among practitioners
(iii) Improve management of FH patients

3. Ministry of Health, Malaysia:
(i) Utilisation of new FH identification tools in the MOH public primary care clinics
(ii) Development of clinical practice guidelines by Health Technology Assessment (HTA) Division, MOH Malaysia to improve detection and early management of FH cases in collaboration with Malaysia Society of Atherosclerosis (MSA)
(iii) Public health campaigns by Public Health Division, MOH, Malaysia to improve public awareness on FH e.g. through printed brochures, posters, newspaper articles, mass media, social media and exhibitions

4. Regional/ international collaborative research groups such as FH-10 Countries, FH Registry for Asia Pacific:
(i) Research evidence to instigate the further advancement of FH research regionally and internationally
(ii) Research collaboration with the FH-10 countries to conduct similar collaborative studies in member countries

5. General public: Increase FH awareness among the general population, leading to early detection and treatment

6. Private sectors/industry - potential commercialisation of Web-based FH identification tools, with the tool open source to low and middle income countries