Advanced method for the identification of patients with inherited hypercholesterolemia.

Familial hypercholesterolemia (FH) has a prevalence of 1 in 500 in Western society and predisposes for premature cardiovascular disease. Lipid-lowering treatment of affected individuals is widely advocated. Maximum health benefit can be obtained in FH if treatment is started as early as possible, as the World Health Organization has recently recommended. In 1994 we initiated an active case-finding program for individuals with FH, based on family investigation and DNA-testing. In an initial pilot study we established that active family screening supported by DNA diagnostics resulted in the identification of substantial numbers of FH heterozygotes and determined that diagnosis by DNA analysis was superior to conventional cholesterol measurement. Since its initiation, the program has led to the identification of more than 6000 individuals with FH, of whom the greatest part was not adequately treated at the time of identification. Our findings indicate not only that this case-finding approach is effective in identifying FH patients who otherwise would not have been identified but also that the vast majority of these patients seek treatment and are successfully started on cholesterol-lowering therapy to reduce their risk of premature cardiovascular disease. Here we describe an effective model to identify and bring under treatment large numbers of individuals affected by FH.

Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.

Familial hypercholesterolemia (FH) is associated with pronounced atherosclerosis leading to premature cardiovascular disease and untimely death. Despite the availability of effective preventative drug treatments, many affected individuals remain undiagnosed and untreated until they become symptomatic with cardiovascular disease. To assess the cost-effectiveness of systematic genetic screening of family members of persons diagnosed with FH, an analysis was conducted using data from a nationwide screening program for the identification of individuals with FH, instituted in The Netherlands in 1994, and from other sources. There was DNA testing of families with a known genetic defect to identify new cases of FH in the presymptomatic stage of the disease. After identification, most newly identified patients were started on cholesterol-lowering statin treatment. On average, new cases diagnosed by the screening program gained 3.3 years of life each. Twenty-six myocardial infarctions would be avoided for every 100 persons treated with statins between the ages of 18 and 60 years. The average total lifetime incremental costs, over all age ranges and both sexes, including costs for screening and testing, lifetime drug treatment, and treatment of cardiovascular events, was US dollars 7500 per new case identified. Cost per life-year gained was US dollars 8700. Therefore, systematic genetic screening of family members of persons diagnosed with FH is cost-effective in The Netherlands and should be considered for other settings.

Long-term compliance with lipid-lowering medication after genetic screening for familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia is a common lipid disorder that predisposes to premature cardiovascular disease. Lipid-lowering treatment of affected individuals is widely advocated, and maximum benefit can be obtained if medication is started early. A screening program for familial hypercholesterolemia is ongoing in the Netherlands since 1994. To assess the extent of treatment and therapy compliance, patients were followed up for 2 years after the diagnosis was established. METHODS: Data were obtained by questionnaire. The 747 patients with familial hypercholesterolemia participating in the study were from the general community, and 62.4% were not receiving cholesterol-lowering medication. RESULTS: The overall percentage of treated patients had risen from 37.6% at screening to 92.5% 1 year later and then decreased to 85.9% 2 years after screening. During follow-up, 6.4% of patients discontinued their medication and 12.0% of untreated patients never started medication for various reasons, but in the majority of cases as advised by their own physicians. The mean reduction in low-density lipoprotein cholesterol levels in previously untreated patients was 30.1% (from 219 to 153 mg/dL [5.7 to 4.0 mmol/L]). For those already receiving treatment, an additional reduction of 10.3% (from 195 to 175 mg/dL [5.0 to 4.5 mmol/L]) was obtained. CONCLUSIONS: Most patients were receiving treatment 2 years after identification and had a positive attitude toward the screening program. However, the reduction of cholesterol levels still did not meet the internationally accepted goals of treatment. This underscores the fact that additional education is required to improve the treatment of individuals with familial hypercholesterolemia.

Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population.

BACKGROUND: A large cohort of patients with familial hypercholesterolemia (FH), free from selection for cardiovascular disease (CVD), and their unaffected relatives was collected by genetic cascade screening and examined for the influence of different mutations of the LDL receptor gene on lipoprotein levels and the risk of CVD. Multivariate analyses with adjustment for age, sex, and specific family ties were performed. METHODS AND RESULTS: Significant variation of LDL levels was observed among 399 patients with FH with different mutations. Null alleles were associated with more severely elevated LDL cholesterol, whereas the frequent N543H/2393del9 mutation led to less elevated LDL cholesterol. The type of mutation did not influence HDL cholesterol levels. Patients with FH had CVD 8.5 times more often compared with their unaffected relatives (RR, 8.54; 95% CI, 5.29 to 13.80). The N543H/2393del9 mutation was associated with a smaller increase of risk compared with other mutations (P<0.0001). After exclusion of families with the N543H/2393del9 mutation, null alleles and other allele mutations no longer differed with regard to LDL cholesterol levels and CVD risk. CONCLUSIONS: LDL receptor mutations only partly contributed to the variation of LDL cholesterol levels and cardiovascular burden in FH. Additional, so far unidentified, familial risk factors must underlie the differences of CVD risk, most likely independent of lipids and lipoproteins.