Short summary

Background: Familial Hypercholesterolemia (FH) affects 1/217 leading to premature cardiovascular disease. The National FH Database monitors detection and treatment of FH, but covers only 50% of FH diagnosis in the National Patients Registry. The validity of the FH diagnosis in both registries is unknown. Aim: This study will validate the FH diagnosis in both registries. Method: 800 FH diagnosis will be validated against patient records describing the positive predicitive value of both registries

Rationale

Familial hypercholesterolemia (FH) is characterized by highly elevated low-density lipoprotein cholesterol (LDL-C). FH is the most common inherited cause of atherosclerotic cardiovascular disease (ASCVD) with a prevalence of 1/217. Only few of the estimated 30.000 patients in Denmark is diagnosed. Patients with FH may have a 22-fold higher risk of ASCVD compared to the background population.

However, FH is a disease that can be treated with lipid-lowering treatment, and early initiation of treatment may lower the risk of ASCVD to be comparable with individuals without FH. Therefore, early diagnosis, lifestyle modifying therapies and lipid-lowering treatment are paramount to lower the risk of ASCVD in FH patients. Unfortunately, FH remains under-diagnosed and suboptimal treated, resulting in premature ASCVD and death.

FH is typically diagnosed from clinical criteria with the Dutch Lipid Clinical Network (DLCN) and The Simon Broome being the most common. These criteria are based on LDL-C levels, history of cardiovascular disease, familial disposition, clinical signs of FH and genetic analysis. Treatment and investigation of FH is a specialist task and is handled in the Danish Lipid Clinics. The medical treatment of FH consist of dietary guidance and lipid lowering treatment with statins and ezetimibe, however not infrequently there is a need for more advanced lipid lowering treatment to achieve treatment goals.

Given that most FH patients' aren´t aware of their diagnosis, these patients has a significantly increased risk of premature cardiovascular disease and death. Prior studies have shown that if FH remains untreated 50% of men and 30% of women develop an acute myocardial infarction before the age of 50 years, however if primary prophylaxis is initiated early, the risk can be reduced to be comparable with the background population. However FH remains underdiagnosed and suboptimal treated. Thus, there is a need for a description of detection and treatment of FH in Denmark.

In 2017 the work began with establishing the Danish National FH Database under the auspices of The Regions Clinical Quality Development Program. The Database was implemented in October 2020, and the first report has recently been published. The purpose of the database is to monitor diagnostics, screening and treatment of FH patients in Denmark. Data is gathered in the database as a combination of registrations from lipid clinic personal and data capture from the Danish registries.

Detection of FH and assessment of investigation- and treatment quality is based on the registered FH diagnosis in the Danish National Patients Registry and persons fulfilling clinical criteria for FH in the Danish National FH Database. The first report from the database suggest that only 50% of the patients newly diagnosed with FH in The Danish National Patients Registry has been registered in the family tree system PROGENY and hereby in the Danish National FH Database. This degree of coverage lies far below the goal for The Danish National FH Database, which is that over 90% of the patients registered with a FH diagnosis in the Danish National Patients Registry, should be registered in the Danish National FH Database.

The validity of the FH diagnosis in the Danish National Patients Registry and the data registered in the Danish National FH Database is currently unknown. Valid data is a prerequisite for using and interpreting data in clinical databases and diagnosis registered in The Danish National Patients Registry. It is of significant societal interest to investigate the validity of this information. The Danish National FH database is expected to be a central part of the decision-making basis regarding political and medical prioritizing of detection, investigation and treatment of patients with FH in Denmark, with focus on preventing premature cardiovascular disease. The Danish National FH Database is furthermore expected to provide data for future research regarding FH in Denmark.

Aim: The primary aim of the study is to investigate the validity of FH diagnosis in the Danish National FH Database and the Danish National Patients Registry by comparing with data from patient records. This will ensure a valid database for future application.

The secondary objective is to investigate whether subgroup analysis and stratification can increase the validity of the registered diagnosis.

Description of the cohort

This study aim to identify a random sample of 800 persons registered with a FH diagnosis in the Danish National Patients Registry (ICD: DE780B, DE780B1, DE780B2), equaly distributed regarding geography. The study aims to validate these diagnosis against the current diagnostic criteria for FH by examination of patient records. An FH diagnosis is considered valid if the DLCN score is 6 point or above.

Hereafter we will identify persons, which are also registered in the Danish National FH Database, and validate the registered data against the current diagnostic criteria based on information from the patient record and calculate the degree of coverage of the Danish National FH Database.

We will request the Danish National FH Database for delivery of 800 randomly chosen personal identification numbers (CPR registry) from patients registered with a new diagnose of FH in the Danish National Patients Registry in the period 01.01.2020 - 01.06.2023.

Data and biological material

The study is a registry study examining ICD-10 codes in the National Patients Registry and data from the National FH Database compared with data from patient records regarding FH diagnostics.

Identification of persons with FH through Registries: Registered first time FH diagnosis in the National Patients Registry (DE780B Familial hypercholesterolemia. DE708B1 Familial Hypercholesterolemia, heterozygous. DE780B2 Familial Hypercholesterolemia, homozygous) with department code and type of diagnosis (A or B).

Persons registered with FH in the National Database for FH is identified hereafter.

CPR-number is registered for examining medical record, registration of gender and age, and to avoid double registration of patients.

Data from Medical record: Information for classification according to diagnostic criteria for FH, including DLCN and Simon Broome criteria. This information is listed below.

Family History: Premature cardiovascular disease in the family (men < 55 years and women < 60 years) in first or second-degree relatives. First and second-degree relatives with LDL-C > 95 percentile for age and gender. First and second-degree relatives with xanthelasmata, tendon xanthoms and/or corneal arcus before the age of 45 years. Children < 16 or 18 years (depending on criteria) with LDL-C > 95 percentile for age and gender.

Clinical history: Patient with premature coronary disease (men < 55 years and women < 60 years). Patient with premature ischemic stroke or peripheral arterial disease (men < 55 years and women < 60 years).

Objective examination, presence of: Xanthelasmata Tendon xanthoms Corneal arcus before the age of 45 years.

Biochemistry Total Cholesterol LDL-C HDL-C Non-HDL-C Triglycerides Lipoprotein(a) DNA analysis for FH including variants of uncertain significans

Current medication as noted in the Prescription Chart and medical records. Fish oil or cod liver oil. Statins (type and dose). Ezetimibe. Bile acid sequestrants. PCSK9-inhibitors. Nicotine acid analogs. Bembedoic acid Inclisaran (interfering small RNA therapy)

Non-pharmacological treatment. Referral to dietician.

Collaborating researchers and departments

Department of Cardiology, Aalborg University Hospital

• Phsysician, PhD Christian Sørensen Bork
• Professor, Phd. Erik Berg Schmidt
• Lipid Nurse, PhD. Berit Storgaard Hedegaard

Department of Cardiology, Rigshospitalet

• Professor, Consultant, Dr. med. Henning Bundgaard
• Consultant PhD. Lia Evi Bang