The Treatment Pattern and Economic Burden of Homozygous Familial Hypercholesterolemia in China: A Study based on a Patient-Survey

yan yang Shanghai Health Development Research Center https://orcid.org/0000-0002-3469-0463 Lvya Wang Beijing Institute of Heart Lung and Blood Vessel Diseases Ya Yang Beijing An Zhen Hospital Wenhui Wen Beijing An Zhen Hospital Mi Tang Shanghai Health Development Research Center Jiangjiang He Shanghai Health Development Research Center Shanlian Hu (  hushanlian@hotmail.com ) Fudan University https://orcid.org/0000-0002-6240-695X


Introduction
Homozygous familial hypercholesterolemia (HoFH) is an autosomal dominant genetic rare disease, characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) concentration levels (>13 mmol/L) [1]. It is caused by the occurrence of mutations in genes such as the low-density lipoprotein receptor (LDLR), apolipoprotein B (apoB), proprotein convertase subtilisin/kexin type 9 (PCSK9), which all impair LDL-C levels ultimately [2]. HoFH has been recognized as a cause of premature atherosclerotic cardiovascular disease (ASCVD), which may lead to myocardial infarction or premature death [3] [4]. There is a lack of epidemiology study on HoFH. The prevalence of HoFH is generally considered as 1/1,000,000, which could be higher among speci c populations such as French Canadians and Transvaal Afrikaners [5][6]. However, there is currently no epidemiological data of the patients with HoFH in China.
A combination of dieting management, lipid-lowering therapy (LLT), LDL apheresis and liver transplantation are available alternatives to treat HoFH [7]. However, a considerable part of patients still has di culty in achieving the target level for plasma LDL-C [1]. The curative effect of the conventional pharmacotherapy such as high-dose statins (with or without ezetimibe) is very limited. In recent years, innovative pharmaceuticals, such as Lomitapide (an oral inhibitor of the microsomal triglyceride transport protein (MTP)), mipomersen (a second generation antisense oligonucleotide) and Evolocumab(monoclonal antibody therapies targeting PCSK9), have been developed approved by different authorities [7].
In 2018, HoFH was included in the included in the rst batch of Nation Rare Diseases List in China (NRDL) [8].
A series of policies have been issued to improve the accessibility of drugs for rare diseases in China [9]. After that, the Chinse government has published a series of policies to improve comprehensive healthcare security of rare diseases, including constructing the diagnosis and treatment network, registering rare disease patients, publishing guidelines for diagnosis and treatment, improving the accessibility, reducing the import tax, accelerating the market authorization process of drugs for rare diseases, and bring the drugs for rare diseases into the National Drug Reimbursement List. Meanwhile, Evolocumab has been approved by the China National Medical Products Administration (NMPA) in 2018. However, the utilization of different pharmaceuticals for HoFH remains unknown in China.
The study aimed to investigate the treatment pattern of patients with HoFH in China and further measure the cost-of-illness and the incidence of catastrophic health expenditure of the patients. Thus, policy recommendation could be provided to policy-makers to improve the healthcare security of the patients.

Study design
The study of economic burden of disease is also called study of cost-of-illness, it is a partial economic evaluation approach which measures the economic burden or total costs attributable to a particular disease and can help improve the accessibility of diagnosis and treatment for patients, put forward policy recommendations of enhancing the relevant healthcare systems of the disease, and effectively alleviate the economic burden suffered by patients [10] [11].
The study surveyed patients with HoFH who were diagnosed and treated in Beijing Anzhen Hospital from September 2017 to December 2019. All patients or their family members completed a self-made questionnaire survey designed according to the family health questionnaire of the fth National Health Services Survey (NHSS) in China [12]. Respondents answered questions on their own demographics, clinicopathological characteristics, household healthcare expenditures and medical insurance status.

Cost calculation
Three types of costs are included in this study: direct costs, indirect costs and intangible costs. Depending on the different expenditures, direct costs included direct medical costs and direct non-medical costs [13]. Indirect costs re ected to e ciency or productivity losses of working caused by premature death or disability related to the disease, as well as the lost working time of the relatives due to the care of the patient.
Intangible costs refer to the anxiety, sadness, pain and other mental losses of patients and their families caused by diseases. Currently, no certain approach is quanti ed due to high subjectivity and measurement di culties of the indicator, thus no calculations of intangible costs were performed in this study [14].

Individual economic burden of Patients with HoFH
The evaluation indicators of individual economic burden include annual direct medical costs, annual direct non-medical costs, and annual indirect costs.

Catastrophic health expenditure
Household catastrophic health expenditure (CHE) is de ned as the proportion of out-of-pocket (OOP) payments for healthcare exceeds a certain level of household capacity to pay, which poses a catastrophic threat to the family. Generally, the global threshold is 40% as a threshold [15].

Statistical Methods
Means and standard deviations (SD) were used for continuous variables, and percentages and frequencies were used for categorical variables as descriptive statistics. Comparison of two age groups were performed using chi-square test and Fisher's exact test. EpiData 3.1 was used for double data entry, and SPSS was used to perform the analyses. Estimates with P-values < 0.05 were considered statistically signi cant.

Ethical statements
Informed consents were attained by all the participants before the formal survey started. The participants' privacy, including any individual information they provided in the survey, would be protected. This study was approved by the ethics committee of Beijing An'zhen Hospital (Approval No.2017035).

Demographic and characteristics
A total of 120 patients were included in the study, and a maximum of 17 patients came from Hebei Province.
Most of the other patients were from East China, with more than 10 patients coming from Anhui, Jiangsu, Shandong, and Zhejiang, respectively (Figure1).
Among the patients, 59 were males and 61 were females. There were 66 children (age<18) and 54 adults (age≥18), accounted for 55% and 45%, respectively. The mean age of children was 8.13 years old, and the mean age of adults were 31.06 years old(  Discussion This is the rst study to reveal the economic burden of patients with HoFH in China and is a key step to provide evidence for policy-makers. A total of 120 patients were surveyed and the following characteristics are mainly presented: Firstly, the number of children patients with HoFH is more than that of adults. One of the possible reasons may be that most patients with severe ASCVD complications, which is highly lethal, resulting in the low tendency of young patients to be investigated. In fact, more than 80% of rare diseases are caused by genetic defects [16], and there are common problems that need to be solved such as low diagnosis rate, lack of effective treatment methods, and drugs have not been included in the medical insurance system, which can easily cause disability or premature death of patients. Secondly, current treatments are lack of effectiveness based on our research. According to previous studies, elevated LDL-C levels has been identi ed as an important risk factor for ASCVD, so decreasing LDL-C levels becomes particularly important in the treatment of HoFH. As our survey showed, one of the mostly used treatment methods was dietary management combined with lipid-lowering drugs, while serum LDL-C level of only 6 non-adult patients (5%) achieved the targets in this study, indicating the lack of effectiveness in current situation. The European Atherosclerosis Society (EAS) pointed out that lifestyle intervention and maximum tolerated dose of statin therapy are the main treatments for HoFH, adjuvant lipoprotein apheresis can be performed before 8 years old as well due to LDL-C targets are seldom achieved. The study by Hartgers et al.
showed that LDL-C activity was reduced in patients treated with Alirocumab and has clinical signi cance.
Despite Evolocumab has been approved by NMPA in China [17], it was not included in the National Drug Reimbursement List and thus had never been used among the patients investigated when maximum tolerated dosage statin were still not effective enough. There is a lack of speci c treatment drugs for HoFH in China, and it is recommended to speed up the introduction of corresponding drugs and inclusion in the medical insurance.
The third is that the patient has a heavy burden of disease, with a CHE rate of more than 26%, and the main It is also reported that early detection, early diagnosis, and early treatment play an important role in improving the prognosis of the disease, preventing the occurrence of related complications, reducing medical costs, and reducing the burden on patients. Clinicians should raise awareness of familial hypercholesterolemia and improve the ability in the eld of diagnosis and treatment. It is also suggested that the introduction of advanced medications and effective therapeutic drugs should be accelerated, and a multi-channel fee payment mechanism should be established to reduce the burden on patients, delay the progression of atherosclerosis, and prolong the life cycle.
Our study also has some limitations. Firstly, the patients were only recruited from Beijing Anzhen hospital, which may cause selection bias. Secondly, intangible costs were omitted, as it is di cult to calculate precisely.
Further research is needed in this eld.

Conclusion
In summary, as a rare disease, the economic burden of HoFH is heavy in China, and it is very easy to cause premature death of patients due to ASCVD, more attention is needed in this eld.

Declarations
Ethics approval and consent to participate This study was approved by the ethics committee of Beijing An'zhen Hospital (Approval No.2017035).

Figure 1
Province of HoFH patients in China