2021 年 28 巻 5 号 p. 417-434
Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.
Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.
Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.
Familial hypercholesterolemia (FH) is the most common autosomal co-dominantly inherited condition affecting humankind. Mutations of three main genes encoding for the low-density lipoprotein (LDL) receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9) cause FH. FH poses a major threat to public health because affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease (ASCVD) 1) . Untreated individuals with homozygous FH (HoFH) typically present with ASCVD before 20 years of age, and most do not survive beyond 30 years 2). Those with heterozygous FH (HeFH) are at significantly higher risk of developing premature coronary artery disease (CAD) compared with individuals without the condition. Despite a range of available interventions that can dramatically decrease LDL cholesterol levels, slow down the progression of ASCVD, reduce the incidence of cardiovascular events, and improve survival 3) , FH is widely underdiagnosed and undertreated throughout the world.
In 2017, the global population was 7.6 billion 4) , with 4.5 billion or 60% living in Asia. Accordingly, investigators from the “Ten Countries Study” estimated that more than half of individuals with FH reside in the Asia Pacific region 5) . Assuming a prevalence of one FH case per 250 individuals, 30 million individuals could be affected worldwide 6) , of whom at least 15 million cases would be in the World Health Organization-defined South-East Asian and Western Pacific regions.
This review aimed to provide an overview of ongoing efforts in the Asia Pacific region to improve the diagnosis and management of FH.
A literature review was undertaken to identify publications relating to FH from the following countries and regions: Australia, China, Hong Kong, India, Indonesia, Japan, Malaysia, New Zealand, Philippines, Singapore, South Korea, Sri Lanka, Taiwan, Thailand, and Vietnam. For each country or region, a search was undertaken of the PubMed database with the search term “Country/Region AND familial hypercholesterolemia.” All abstracts from 2010 to October 2019 were scrutinized. Those relating to the topics described above were assigned to a group within an EndNote library (Clarivate Analytics, Philadelphia), and full publications were sourced. To identify FH initiatives in the Asia Pacific region not described in peer-reviewed publications, internet searches were undertaken using the search term “Country/Region AND familial hypercholesterolemia.” A summary of the findings of the review follows.
Table 1 summarizes the published estimates of FH prevalence in 15 Asia Pacific countries and regions: Australia, China, Hong Kong, India, Indonesia, Japan, Malaysia, New Zealand, Philippines, Singapore, South Korea, Sri Lanka, Taiwan, Thailand, and Vietnam. In only four countries—Australia, China, India, and Japan—were the estimates based on locally conducted studies of FH prevalence.
In 2015, Watts et al described the prevalence and treatment of FH in Australian communities 7) . The first data set was obtained from the Australian Diabetes, Obesity and Lifestyle (AusDiab) study 8) , and the second data set was obtained from individuals who volunteered for a risk assessment for cardiovascular disease and clinical trials. Analysis of these two data sets enabled a comparison of FH prevalence in a randomly selected community population with a group undergoing cardiovascular risk evaluation 9) . The prevalence of definite/probable FH was 1 in 353 (0.28%, 95% confidence interval [CI]: 0.16%–0.41%) in the AusDiab group and 1 in 229 (0.44%, 95% CI: 0.26%–0.62%) in the risk assessment and clinical trial group.
In 2014, Shi et al described the prevalence, underdetection, and undertreatment of FH in a community population in China 10) . The prevalence of probable/definite FH was 0.28%, which equates to 1 per 357 in the general population. In 2019, Wang et al 11) determined FH prevalence among participants in the Henan Rural Cohort Study 12) . The prevalence of probable/definite FH was 0.35% (95% CI: 0.29%–0.41%), which equates to 1 per 286 in the general population.
In 2017, Gupta et al reviewed recent studies on the epidemiology of dyslipidemias in India 13) , which included the population-based India Heart Watch study 14) and another study conducted at a tertiary care hospital 15) . Severe hypercholesterolemia, defined as an LDL cholesterol level of ≥ 220 mg/dL, was considered as suspected FH. In the population-based study and hospital-based study, 1 per 357 participants and 1 in 209 participants had suspected FH, respectively.
In 2011, Mabuchi et al described the molecular genetic epidemiology of FH in the Hokuriku district of Japan 16) . The frequency of HeFH was 1 in 208 residents, and that of HoFH was 1 in 171,167.
All other estimates of FH prevalence provided in Table 1 were based on the application of an estimate of prevalence, ranging from 1 per 200 to 1 per 500, to national population data. Accordingly, there is a pressing need to characterize the actual prevalence of FH across the region.
The prevalence of FH among high-risk groups has been evaluated in several studies. Investigators from Beijing, China, determined the prevalence of FH among patients with premature myocardial infarction (PMI, defined by age at the first onset of myocardial infarction: male ≤ 55 years old and female ≤ 60 years old) 17) . The prevalence of FH diagnosed by genetic testing was 4.4% and definite/probable FH diagnosed by the modified Dutch Lipid Clinic Network (DLCN) criteria was 23.6%. Investigators from New Delhi, India, assessed individuals with premature CAD for FH using the DLCN criteria 18) . Four percent were diagnosed as definite and 11% as probable. In Japan, the prevalence of HeFH among patients admitted to hospital with ACS 19) was 5.7% overall, increasing to 7.8% among patients less than 60 years.
| Country or region | aFH Prevalence | References | |
|---|---|---|---|
| Rate | Cases ( n) | ||
| Australia | 1:229-353 a | - | 7) |
| China | 1:286-357 a | 4.6 million b | 10, 11, 20) |
| Hong Kong | 1:300 b | 24,000 b | 20) |
| India | 1:209-357 c | - | 13- 15) |
| Indonesia | - | - | - |
| Japan | 1:208 d | 608,900 e | 16) |
| Korea | - | - | - |
| Malaysia | 1:300 b | 107,000 b | 20) |
| New Zealand | 1:500 f | 10,500 f | 22) |
| Philippines | 1:300 b | 340,000 b | 20) |
| Singapore | - | 22,000 g | 23) |
| Sri Lanka | - | - | - |
| Taiwan | - | 100,000 h | 24) |
| Thailand | - | - | - |
| Vietnam | 1:300 i | 300,000 i | 7, 10, 25) |
a Definite/probable FH according to modified DLCN criteria.
b Estimate provided in 2019 “Ten Countries Study” publication based upon HeFH rate of 1:300 applied to population data for 2016.
c Suspected FH based on LDL cholesterol ≥ 220mg/dl.
d Calculated using the Hardy-Weinberg equilibrium.
e Based on application of a rate of 1:208 to the population of Japan in 2018 (126.5 million).
f Estimate provided in review of identification of FH in New Zealand based upon 1:500 rate for Western populations.
g Estimate provided in European Atherosclerosis Society FH Studies Collaboration review in ＞ 60 countries.
h Estimate provided in FH section of 2017 Taiwan lipid guidelines based upon prevalence of 1:200 for HeFH and 6 per million for HoFH.
i Estimate for Vietnam is informed by prevalence estimates from Australian and Chinese studies above.
In 2019, Chang and Su explored the relationship between perceived depression and FH among patients recruited to the “Ten Countries Study” in Taiwan 26) . The FH patients had a higher risk of perceived depression than patients with hypertriglyceridemia or controls with normal lipid levels, with an odds ratio of possible depression of 1.50 (95% CI: 1.07–2.11) and probable depression of 1.73 (95% CI: 1.10–2.75) after adjustment for relevant cardiovascular risk factors. Among patients with a family history of coronary heart disease, total Center for Epidemiological Studies Depression Scale scores were higher for FH patients than those for the non-FH group (17.30 vs. 13.08, p=0.022).
Notable differences exist between the genetics of people with FH in the Asia Pacific region and those of Western countries. Furthermore, some differences are apparent between different locales within the Asia Pacific region.
In 2016, Chiou and Charng reviewed the genetic diagnosis of FH in Han Chinese 27) . As illustrated in Fig. 1 , the total of 143 different mutations of the LDL receptor identified was low compared with European populations. Most of the mutations were reported in southeast China, Hong Kong, and Taiwan, with the five most common mutations being APOB 10579C＞T, LDLR 986G＞A, 1747C＞T, 1879G＞A, and 268G＞A.
Number of LDL receptor mutations in Han Chinese compared with European populations 27)
In 2019, Tomlinson et al summarized recent studies of mutations found in Chinese patients with FH, as shown in Table 2 28) . Many of the LDLR mutations were novel at the time of identification and some were relatively common.
| c.DNA change | Protein change | Number of index cases | Frequency (%) |
|---|---|---|---|
| 339 mutation-positive probands from China, Hong Kong, and Taiwan | |||
| APOB c.10579C＞ T | p.R3500W (Arg3527Trp) | 37 | 10.9 |
| LDLR c.986G＞ A | p.C308Y (Cys329Tyr) | 28 | 8.3 |
| LDLR c.1747C＞ T | p.H562Y (His583Tyr) | 21 | 6.2 |
| LDLR c.1879G＞ A | p.A606T (Ala627Thr) | 16 | 4.7 |
| LDLR c.268G＞ A | p.D69N (Asp90Asn) | 14 | 4.1 |
| 99 mutation-positive probands only from China | |||
| LDLR c.1879G＞ A | p.A606T (Ala627Thr) | 13 | 13.1 |
| LDLR c.1448G＞ A | p.W462X (Trp483X) | 10 | 10.1 |
| LDLR c.1864G＞ T | p.D601Y (Asp622Tyr) | 6 | 6.1 |
Reproduced with permission from Curr Opin Lipidol. 2019 Apr; 30(2): 94-100 courtesy of Wolters Kluwer Health, Inc
In 2017, Chiou and Charng established an FH assay panel for the Han population residing in Taiwan 29) . The performance of the assay was verified by comparison of results with Sanger DNA sequencing for 180 previously sequenced subjects. Among the 120 subjects with point mutations, only one discrepancy was found between the 2 techniques. A subsequent blinded study was conducted that involved 62 probands with mutations that were identified by both techniques. The detection sensitivity and specificity rates of the Agena iPLEX were 92.5% and 100%, respectively. The authors conclude that the Agena iPLEX assay has great potential to be included in FH screening in Taiwan on account of its low cost, rapidity, and flexibility.
In 2016, Zhou and Zhao reviewed studies of FH in Asian populations 30) . The authors found that reports of FH frequency were commonly based on different diagnostic criteria. Among 28 studies from 16 Asian countries or regions, 14 used self-defined FH criteria, and only one specific FH guideline was available from Japan. Six Asian countries or regions participated in the global Make Early Diagnosis Prevent Early Death (MEDPED) FH programme 31) . It was estimated that FH diagnosis rates for Hong Kong, Israel, Japan, and Singapore ranged from 3% to 10%.
In 2017, investigators from China sought to identify the prevalence of FH among a large group ( n=8,050) of patients who underwent coronary angiography 32) . Definite and probable FH were reported for 1.0% and 2.5% of patients, respectively. Only 5% of definite/probable FH patients received high-intensity lipid-lowering treatment, of whom none achieved an LDL cholesterol level of ＜100 mg/dL (2.59 mmol/L).
In 2017, Australian investigators studied the association between elevated LDL cholesterol levels in children and family history of hypercholesterolemia or documented premature cardiovascular disease 33) . Almost 21% of children with LDL cholesterol of ≥ 3.4 mmol/L (≥ 95 th percentile) had a positive family history, and among children with LDL cholesterol of ≥ 3.8 mmol/L (≥ 99 th percentile), the proportion was 20%. The authors concluded that an opportunity was missed for the identification of children with FH based on their family history.
In 2019, investigators from the “Ten Countries Study” invited key opinion leaders from 12 countries or regions to participate in a series of online questionnaires regarding various aspects of FH care 20) . Key findings included the following:
• Diagnosis rates were estimated to vary from ＜0.1% in China to 4% in Australia, compared with 10%–20% in the United Kingdom.
• Less than 5% of patients in China, Japan, Malaysia, and Vietnam were reported as achieving an LDL cholesterol treatment goal of ＜1.8 mmol/L.
• Registries had been established in Australia, Japan, Malaysia, and Vietnam.
• Educational initiatives were available in Australia, China, Japan, Taiwan, and Vietnam.
• Cost-effectiveness analysis of screening had been conducted in Australia, and cost-effectiveness analyses of treatment had been conducted in Australia and Japan.
The authors concluded that a combination of approaches was required to address current deficits in FH care across the Asia Pacific:
• government policy relating to FH with associated public funding;
• improvement of the efficiency of healthcare systems in the diagnosis and management of FH;
• empowering patients and communities to recognize the importance of managing cholesterol among families with a history of premature coronary disease.
In 2014, the International FH Foundation published comprehensive guidance that provided detailed recommendations for the following 9) :
1. Detection of Index Cases: Screening and Phenotypic Diagnosis;
2. Diagnosis and Assessment of Adults;
3. Diagnosis and Assessment of Children and Adolescents;
4. Cascade Screening: Testing and Risk Notification of Families;
5. Genetic Testing;
6. Management of Adults;
7. Management of Children and Adolescents;
8. Lipoprotein Apheresis and Related Treatments;
9. Organisation and Development of Care.
In the Asia Pacific region, specific FH guidelines have been published for Australia and New Zealand 34, 35) , China 36) , Hong Kong 37) , and Japan 38, 39) . Table 3 provides a summary of the key recommendations made in these guidelines regarding diagnosis, treatment, and cascade screening. General dyslipidemia guidelines that make recommendations on the management of FH have been published for India 40, 41) , Indonesia 42) , Malaysia 43) , Philippines 44) , South Korea 45) , Singapore 46) , Taiwan 24) , and Thailand 47) .
| Country or region | Diagnosis | Treatment | Cascade screening | References |
|---|---|---|---|---|
| Australia and New Zealand |
|
|
|
34, 35) |
| China |
3.6mmol/L and first-degree relatives have history of FH or premature ASCAD |
|
- Patients with xanthoma or gerontotoxon (＜45years) - Their first-degree relatives have the above three conditions |
36) |
| Hong Kong |
|
|
|
37) |
| Japan |
|
|
|
38, 39) |
In 2013, Australian investigators proposed that the development of a global network of inter-operable FH registries would provide a platform to 48)
1. address the current care gap,
2. support basic research,
3. enable equitable access to clinical trials, and
4. disseminate evidence for best practice and information for care services.
In 2015, the European Atherosclerosis Society FH Studies Collaboration was launched to establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide 6, 49) . As of August 2019, 61,223 cases globally had been entered into the registry 50) , and the collaboration had grown to encompass 87 lead investigators from 69 countries, including Australia, China, Hong Kong, India, Iran, Iraq, Japan, Kyrgyzstan, Malaysia, Pakistan, Philippines, Singapore, South Korea, Taiwan, Thailand, Turkey, Uzbekistan, and Vietnam.
To date, in the Asia Pacific region, FH registries have been established in Australia and New Zealand 51) , India 52) , Japan 53) , Malaysia 20) , Taiwan 54) , and Thailand 55) . In 2019, investigators from Beijing advocated for the establishment of a Chinese FH registry 56) .
A range of opportunities exist to systematically identify individuals with FH throughout the life cycle. These include FH screening in childhood, cascade screening, reverse screening, screening of individuals with ACS, and identification of FH in the primary care setting. Summaries of promising strategies from the Asia Pacific region and elsewhere follow.
FH Screening in ChildhoodIn 2011, the US National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents recommended universal screening for dyslipidemia by the age of 9–11 years and subsequently at age 17–21 years 57) . Slovenia started universal screening for hypercholesterolemia in 5-year-old children in 1995 58) . In 2015, Battelino et al conducted genetic testing for FH in 272 children identified by the screening program and reported that 57% carried disease-causing genetic variants 59) .
Cascade ScreeningTable 4 provides a summary of studies that have evaluated cascade screening in the Asia Pacific region.
| Country or region | Study subjects | Summary of findings | References |
|---|---|---|---|
| Hong Kong SAR, China |
|
→ 83% of these subjects were previously unaware of having HeFH |
60) |
| Hong Kong SAR, China |
|
→ 48 (39%) were newly diagnosed → 74 (61%) were aware of having hypercholesterolemia, although 53% of these relatives had never been treated or had stopped treatment |
61) |
| India |
|
→ 88 (66%) carried the family mutation → 15 (11%) had CAD → 63 (47%) were already taking lipid lowering therapy → 12 were children ＜18 years of age:
|
62) |
| Vietnam |
|
→ Of 89 who were genetically screened, an FH mutation was found in 47 including 3 homozygotes and 44 heterozygotes → Among the 47 mutation positive individuals, 18 were children aged ＜18 years → 9 additional relatives had “likely FH” based on the Starr et al criteria 63) → Only 5 (9%) of relatives with FH were subsequently treated due to:
|
25) |
In 2016, Wald et al described a child–parent FH screening program in primary care 64) . A positive screening result was assigned for children with elevated cholesterol and an FH mutation or elevated cholesterol on a repeat measurement taken 3 months later. Parents were deemed to have a positive screening result for FH if he or she had the same mutation as the child or, if no mutation was evident, had the higher cholesterol measurement of the two parents. The authors stated that the strategy was feasible, and for every 1,000 children screened, 4 children and 4 parents had positive screening results for FH.
In 2017, Lin et al evaluated reverse screening strategy in China 65) . Among 41 children with severe hypercholesterolemia, 12 were shown to have HoFH and 29 to have compound HeFH. Among 81 first-degree family members, all were genotypically diagnosed with FH. Among 37 second-degree relatives, 92% were diagnosed with FH. Accordingly, for every child with FH, 2.8 new cases were diagnosed among family members.
Screening of Individuals with ACSIn addition to the publications from China 17) , India 18) , and Japan 19) described in the epidemiology section of this review, Table 5 provides the summaries of additional efforts to screen ACS patients in the Asia Pacific region.
| Country | Study subjects | Summary of findings | References |
|---|---|---|---|
| Australia |
|
→ 26.3% of patients had elevated lipoprotein(a) (i.e. ≥ 0.5 g/L), which was more common among those with a premature coronary event (31.9% vs. 20.3%, p = 0.019) → 11.4% had phenotypic FH, which was almost twice as common among those with premature CAD, although not a statistically significant difference (14.8% vs 7.8%, p = 0.052) → 4.4% had both disorders, which was more common among those with premature CAD (6.2% vs. 2.6%, p = 0.033) |
66) |
| China |
|
→ Definite/probable FH (vs. unlikely FH, odds ratio, 5.05 [1.10–23.23]) → Possible FH (vs unlikely FH, odds ratio, 2.65 [1.22–5.77])
|
67) |
| China |
|
→ LDL cholesterol (3.58 mmol/L vs. 6.52 mmol/L, p＜0.001) → Lp(a)-adjusted LDL cholesterol (3.25 mmol/L vs. 6.16 mmol/L) → Gensini score (33.40 vs. 77.66, p = 0.009)
|
68) |
| Japan |
|
→ Patients with premature ACS (＜55 years in men and ＜65 years in women) than those without (4.7% [95% CI: 2.9-7.2] vs. 2.1% [95% CI: 1.4-3.0]) → Patients aged ＜40 years than those aged ≥ 40 years (8.3% [95% CI: 1.8-22.5] vs. 2.6% [95% CI: 1.9-3.4]) → Patients without prior use of statins than those with prior use (3.2% [95% CI: 2.3-4.2] vs. 1.3% [95% CI: 0.5-2.7] |
69) |
Several studies from Australia 71- 74) and the United Kingdom 75, 76) have evaluated the potential for identification of FH in the primary care setting. Key findings included the following:
• Community-based laboratories are well placed to opportunistically identify individuals with potential FH 71) .
• Electronic extraction tools can increase the detection of FH in general practice 74, 75) .
• A study using the UK Clinical Practice Research Datalink reported that the FAMCAT FH prediction model showed high discrimination for distinguishing cases from non-cases (area under receiver operating curve [AUC] 0.860, 95% CI 0.848–0.871) 76) .
In 2018, Brett et al advocated screening of FH in primary care 77) , noting that such a screening program would adhere to many of the principles of the classic Wilson and Jungner criteria as revised for the genomic age by Andermann et al in 2008 78) :
1. The screening program should respond to a recognized need.
2. The objectives of screening should be defined at the outset.
3. There should be a defined target population.
4. There should be scientific evidence of screening program effectiveness.
5. The program should integrate education, testing, clinical services, and program management.
6. There should be quality assurance, with mechanisms to minimize potential risks of screening.
7. The program should ensure informed choice, confidentiality, and respect for autonomy.
8. The program should promote equity and access to screening for the entire target population.
9. Program evaluation should be planned from the outset.
10. The overall benefits of screening should outweigh the harm.
Brett et al proposed that FH is best diagnosed in childhood or early adolescence, which should be followed by cascade testing of family members of young people diagnosed with the condition. Development of a shared care model would result in primary care managing relatively low-risk patients, with support from specialists as required for high-risk patients and those cases that prove difficult to manage. A succinct guide for general practice was published by the same authors 79) .
The summary of key recommendations of specific FH guidelines in the Asia Pacific region in Table 3 describes the role of statins, bile acid sequestrants, and cholesterol absorption inhibitors (e.g., plant sterols or ezetimibe) in the management of FH and highlights when lipoprotein apheresis may be required. Other therapies, including ezetimibe, fibrates, PCSK9 inhibitors, lomitapide, and mipomersen, may be required when statins that are administered at the highest tolerated dose in combination with other medications do not achieve target LDL cholesterol levels 80) . Pasta et al 81) and Raal et al 82) have recently published reviews on the role of PCSK9 inhibitors in the management of hypercholesterolemia. Table 6 provides a summary of findings from clinical trials and meta-analyses for PCSK9 inhibitors.
| PCSK9 Inhibitor | Study design and subjects | Summary of findings | References |
|---|---|---|---|
| Alirocumab |
|
→ Reduced LDL cholesterol by -52.6% (95% CI: -58.2 to -47.0%) versus placebo and by -29.9% (95% CI: -32.9 to -26.9%) versus ezetimibe → Increased high-density lipoprotein (HDL) cholesterol by 8.0% (95% CI: 4.2 to 11.7%) versus placebo |
83) |
| Alirocumab |
|
→ At week 144, the mean LDL cholesterol level was reduced by 48.7% compared to the mean level at baseline (3.65±1.9 mmol/L [standard deviation, SD]) → Injection site reactions reported for eight patients, with one treatment discontinuation → Treatment emergent anti-drug antibodies were identified in five patients but did not affect efficacy |
84) |
| Alirocumab |
→ Who had an ACS within the previous 12 months → With LDL cholesterol ≥ 70 mg/dL (1.8 mmol/L), non-HDL cholesterol level ≥ 100 mg/dL (2.6 mmol/L), or an apolipoprotein B level ≥ 80 mg/dL → Receiving high-intensity dose or maximum tolerated dose of statin |
→ Significantly reduced the risk of the primary efficacy end point a (903 patients [9.5%] vs. 1052 patients [11.1%]; HR, 0.85; 95% CI 0.78 to 0.93; p＜0.001) → Significantly reduced the risk of the major secondary efficacy end point b (1199 patients [12.7%] vs. 1349 patients [14.3%]; HR, 0.88; 95% CI 0.81-0.95; p = 0.001) |
85) |
| Evolocumab |
|
→ Reduced LDL cholesterol by -54.6% (95% CI: -58.7 to -50.5%) versus placebo and by -36.3% (95% CI: -38.8 to -33.9%) versus ezetimibe → Increased HDL cholesterol by 7.6% (95% CI: 5.7 to 9.5%) versus placebo |
83) |
| Evolocumab |
|
→ In HoFH patients, mean percentage changes (±SD) in LDL cholesterol relative to baseline were -21.2±25.0% at week 12 and -24.0±41.3% at week 216 → In HeFH, mean percentage changes (±SD) in LDL cholesterol relative to baseline were -54.9± 17.4% at week 12 and -47.2±27.9% at week 216 → Potential injection site reactions were reported for 14 and 22 patients with HoFH and HeFH, respectively → No neutralizing antievolocumab antibodies were detected |
86) |
| Evolocumab |
→ Had clinically evident ASCVD → With LDL cholesterol ≥ 70 mg/dL (1.8 mmol/L), non-HDL cholesterol level ≥ 100 mg/dL (2.6 mmol/L) → Taking an optimized regimen of lipid-lowering therapy |
→ Significantly reduced the risk of the primary efficacy end point c (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio [HR], 0.85; 95% CI: 0.79 to 0.92; p＜0.001) → Significantly reduced the risk of key secondary efficacy end point d (816 patients [5.9%] vs. 1013 patients [7.4%]; HR, 0.80; 95% CI, 0.73 to 0.88; p＜0.001) |
87) |
a. The composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalisation
b. Any coronary heart disease event defined as death from coronary heart disease, nonfatal myocardial infarction, unstable angina requiring hospitalisation, and an ischemia-driven coronary revascularization procedure
c. The composite of cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, or coronary revascularization
d. The composite of cardiovascular death, myocardial infarction, or stroke
As Table 7 shows, although PCSK9 inhibitors have been approved and are available in the majority of countries and regions considered in this review, these innovative drugs are reimbursed for use in only approximately one quarter of the listed countries and regions.
| Country or region | Approval of any PCSK9 inhibitor | Availability of any PSCK9 inhibitor | Reimbursement of any PCSK9 inhibitor |
|---|---|---|---|
| Australia | Yes | Yes | Yes (FH) |
| China | Yes | Yes | No |
| Hong Kong | Yes | Yes | No |
| India | Yes | Yes | No |
| Indonesia | No | No | No |
| Japan | Yes | Yes | Yes (FH) |
| Malaysia | Yes | Yes | No |
| New Zealand | Yes | Yes | No |
| Philippines | Yes | Yes | No |
| Singapore | Yes | Yes | No |
| South Korea | Yes | Yes | Yes (FH) |
| Sri Lanka | Not known | Not known | Not known |
| Taiwan | Yes | Yes | Yes |
| Thailand | Yes | Yes | No |
| Vietnam | No | No | No |
In advance of the United Nations High-level Meeting on Non-communicable Diseases in 2018, the World Heart Federation brought together “… a global coalition of international, regional, and national stakeholders in cardiovascular diseases (CVDs) to drive the urgent action needed to combat heart disease and stroke 89) .” At the national level, Kalra et al articulated the need for all clinical specialties of relevance to FH in India to collaborate to expedite improvements in all aspects of FH care 90) .
Although not focused upon FH, the Secondary Prevention Alliance in Australia could illustrate how healthcare professional organizations operating in the cardiovascular arena could collaborate to form national FH alliances 91) . The Secondary Prevention Alliance comprised a broad group of national healthcare, consumer, government, and non-government organizations. National FH alliances could be standing bodies or “virtual organizations” established based on a memorandum of understanding agreed between key stakeholder organizations, which could
• advocate for improved FH care to policymakers with a unified voice,
• encourage the development of consensus clinical guidelines and concise clinical standards for FH care,
• endorse and engage with global efforts to develop sustainable national FH registries,
• develop education programs that can help build the multidisciplinary workforce required to deliver the best clinical practice.
Analogous national alliances have been established to improve the care of a broad range of conditions in several countries, including arthritis 92) , dementia 93) , diabetes 94) , and fragility fractures 95) . Accordingly, the FH community has considerable generic experience to draw upon in terms of why such alliances were formed, how they function, and what specific activities they have undertaken and the progress that they have made.
With half of the world’s population of individuals who are living with FH residents in the Asia Pacific, the time has come to implement systematic and system-wide improvements in the management of this debilitating and life-threatening condition. The findings of this review simultaneously provide cause for concern and optimism.
Diagnosis rates are very low in most countries. Specific FH guidelines have only been published in 5 of the 15 countries and regions considered, although some degree of commentary on FH features in practically all national clinical guidelines for dyslipidemia. A similar picture is evident regarding FH registries, with established or nascent registries present in seven countries or regions. Furthermore, although approved and available in most countries and regions considered, innovative drugs such as PCSK9 inhibitors are reimbursed in only one quarter.
On a positive note, in terms of identifying relatives with FH, early experience with cascade screening has proved effective in Hong Kong, India, and Vietnam. However, engaging patients to initiate new treatment or restart previously discontinued treatment presents a challenge to healthcare professionals. A reverse screening strategy in China resulted in the diagnosis of 2.8 new cases among family members for every child with FH. Studies from Australia, China, India, and Japan have described screening of patients admitted to hospital with ACS and make a compelling case for this strategy to be routine, particularly among patients with premature cardiovascular events. Several approaches have been explored in the primary care setting to improve the identification of FH, and the case has been made for widespread screening programs to be delivered through primary care.
Finally, national quality improvement programs in the management of FH could be expedited by the formation of national FH alliances comprising all relevant healthcare professional organizations. Such alliances could provide a potent mechanism to influence policymakers with a unified voice, develop consensus clinical guidelines and quality standards where they are absent, establish sustainable national FH registries, and implement nationwide educational programs to build a highly capable clinical workforce.
There is an urgent need to improve the diagnosis and management of FH across the Asia Pacific region which can be achieved by:
1. Engaging healthcare professionals – both specialists and generalists – in educational programmes which will equip them to play their role in delivering optimal FH management
2. Developing public awareness campaigns that will demystify this genetic disease and destigmatize people who are living with FH
3. Establishing national FH alliances with representation from all relevant national learned societies that will:
i. Persuade policymakers of the pressing need for investment in a national strategy which aims to identify all individuals living with FH
ii. Secure funding – whether public and/or private – to support cascade screening programmes and national FH registries
iii. Work with government and insurers to identify novel funding streams to ensure that the full therapeutic armamentarium is reimbursed
The following list of links to organisations in the Asia Pacific region may be of interest to readers.
• Asian-Pacific Society of Atherosclerosis and Vascular Diseases. http://www.apsavd.org/.
• South Asian Society on Atherosclerosis and Thrombosis. http://www.sasat.org/.
• South Asian Federation of Endocrine Societies. http://www.safesendocrine.com/.
• Asian Pacific Society of Cardiology. http://www.apscardio.org/.
• ASEAN Federation of Cardiology. http://aseancardiology.org/.
• Asia-Pacific Heart Network. http://aphn.info/.
• Asia Pacific Alliance for Rare Diseases. See https://doi.org/10.1007/s40271-014-0103-y.
Australian Organisations• Australian Atherosclerosis Society. https://www.athero.org.au/.
• FH Australasia Network. https://www.athero.org.au/fh/.
• The Cardiac Society of Australia and New Zealand. http://www.csanz.edu.au/.
• Heart Foundation. https://www.heartfoundation.org.au/.
• Rare Voices Australia. https://www.rarevoices.org.au/.
• Steve Waugh Foundation. https://www.stevewaughfoundation.com.au/.
Chinese Organisations• The Chinese Society of Cardiology. http://csc.cma.org.cn/.
• China Heart Society. http://cvia-journal.org/establishment-china-heart-society-chs/.
• Rare Disease in China. http://www.hanjianbing.org/index!index.action.
Hong Kong Organisations• Hong Kong College of Cardiology. https://www.hkcchk.com/.
• Hong Kong Alliance for Rare Diseases. http://www.hkard.org/.
Indian Organisations• Indian Society for Atherosclerosis Research. http://www.isar.co.in/.
• Lipid Association of India. http://lipid.net.in/.
• Cardiological Society of India. http://www.csi.org.in/.
• Endocrine Society of India. http://endocrinesocietyindia.org/.
• Indian Association of Clinical Cardiologists. http://www.accindia.org/.
• Indian College of Cardiology. http://www.icc-india.com/.
• Heart Care Foundation of India. http://www.heartcarefoundation.org/.
• Heart Foundation and Research Institute. http://www.heartfoundationindia.org.in/.
• Indian Heart Association. http://indianheartassociation.org/.
• Organisation for Rare Diseases India. http://ordindia.org/.
• Rare Diseases India. http://www.rarediseasesindia.org/.
Indonesian Organisations• Indonesian Heart Association. http://www.inaheart.org/.
Japanese Organisations• Japan Atherosclerosis Society. http://www.j-athero.org/en/index.html.
• Japanese College of Cardiology. http://www.jcc.gr.jp/en/index.html.
• Japan Heart Foundation. http://www.jhf.or.jp/english/.
• Japan Patient Association (rare diseases). http://www.nanbyo.jp/.
Korean Organisations• Korean Society of Lipids and Atherosclerosis. http://www.lipid.or.kr/eng/.
• Korean Society of Cardiology. http://www.circulation.or.kr/eng/.
• Korea Heart Foundation. http://new.heart.or.kr/english/2012/index.php.
• Korean Organization for Rare Disorders. https://www.kord.or.kr:55308/index.php.
Malaysian Organisations• Malaysian Society of Atherosclerosis. https://www.malaysianheart.org/?p=msa.
• National Heart Association of Malaysia. https://www.malaysianheart.org/.
• Malaysian Rare Disorders Society. http://www.mrds.org.my/.
New Zealand Organisations• FH Australasia Network. https://www.athero.org.au/fh/.
• The Cardiac Society of Australia and New Zealand. http://www.csanz.edu.au/.
• Heart Foundation. https://www.heartfoundation.org.nz/.
• New Zealand Organisation for Rare Disorders. https://www.nzord.org.nz/.
Philippine Organisations• Philippine Lipid & Atherosclerosis Society. http://plas.org.ph/.
• Philippine Heart Association. https://www.philheart.org/.
• Philippine Society for Orphan Disorders. https://www.facebook.com/psod.org.ph/.
Singaporean Organisations• Singapore Cardiac Society. http://www.singaporecardiac.org/.
• Singapore Heart Foundation. http://www.myheart.org.sg/.
• Rare Disorders Society Singapore. http://www.rdss.org.sg/.
Sri Lankan Organisations• Sri Lanka Heart Association. http://www.slheart.org/.
• Sri Lanka College of Endocrinologists. http://endocrinesl.org/.
Taiwanese Organisations• Taiwan Society of Lipids & Atherosclerosis. http://www.tas.org.tw/.
• Taiwan Society of Cardiology. http://www.tsoc.org.tw/.
• Taiwan Foundation for Rare Disorders. http://www.tfrd.org.tw/tfrd/.
Thai Organisations• Thai Atherosclerosis Society. http://www.thaiathero.org/.
• Heart Association of Thailand. http://www.thaiheart.org/.
• Thai Rare Disease Foundation. http://www.thairdf.com/.
Vietnamese Organisations• Vietnam Heart Association. http://www.vnha.org.vn/.
Sanjay Kalra has received speaker fees from Amgen, Boehringer Ingelheim, Eli Lilly, NovoNordisk and Sanofi.
Zhenyue Chen has been a speaker for Pfizer, AstraZeneca, Bayer, Daiichi Sankyo, Sanofi, Amgen, Kowa and MSD.
Chaicharn Deerochanawong has been a speaker for Amgen, Pfizer and MSD.
Kou-Gi Shyu has been a speaker for Pfizer, AstraZeneca, Bayer, Daiichi Sankyo, Boehringer Ingelheim, Sanofi and Amgen.
Tan Ru San has been a speaker for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Johnson & Johnson, MSD, Novo Nordisk and Pfizer.
Brian Tomlinson has been a speaker for Amgen Inc, Kowa, and Merck Serono.
Hung-I Yeh has been a speaker for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Lilly, Mitsubishi Tanabe, Novartis, MSD, Orient Europharma, Pfizer and Sanofi.
The authors would like to thank Amgen Asia for funding medical writing support provided by Paul Mitchell of Synthesis Medical NZ Limited.
