1

Introduction

Heterozygous familial hypercholesterolemia (FH) is an autosomal dominant condition with reduced low-density lipoprotein (LDL) receptor (LDL-R) activity, resulting in an approximate doubling of plasma LDL-cholesterol (LDL-C) levels from the first year of life. If untreated, the risk of premature atherosclerotic cardiovascular disease (ASCVD) and death is substantially increased . Children with FH have increased inflammation and carotid intima-media thickness (cIMT) already from 8 years of age [ , ]. Guidelines therefore recommend lipid lowering therapy (LLT) to be initiated from around 10 years of age, with statins as the first drug of choice . Early initiation of statin treatment reduces cIMT and inflammation in these children [ , , ]. At the time of this study, the treatment goal for adults with FH without other major risk factors was LDL-C level < 2.5 mmol/L, or < 1.8 mmol/L if presence of concomitant ASCVD or other major risk factors . Recently, in the updated 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Guidelines for the management of dyslipidemias, these treatment goals have been further lowered to LDL-C level < 1.8 mmol/l and < 1.4 mmol/L, respectively . For children below the age of 18 years the treatment goal is LDL-C level < 3.5 mmol/L and this has not been changed in the updated ESC/EAS guidelines . Ideally, when initiated, lipid-lowering therapy (LLT) in FH patients is lifelong, except for periods of pregnancy and breastfeeding, but the treatment may be interrupted for other reasons, i.e. side effects, motivational issues or drug supply. It is well known that not only the LDL-C level, but also the duration of the LDL-C elevation (the cholesterol burden) has an impact on the atherosclerotic process . Patients starting treatment later in life are at significantly higher risk than those having initiated treatment at a younger age, and adherence to the lifelong treatment is considered to be of great importance for preventing premature ASCVD . There are some reports on treatment adherence in children and young adults with hypercholesterolemia or FH [ , , ]. However, more knowledge is needed about the long-term adherence to LLT and the reasons for poor adherence in young individuals with FH. The aim of the present study was to assess the adherence to LLT, reasons for poor adherence and achievement of LDL-C treatment goals in a large cohort of children and young adults with FH, followed at a specialized lipid clinic. Further, we aimed to investigate associations of adherence with demographics, lipid profile, smoking habits, diet, family history, and number of visits to the lipid clinic.

2

Methods

We retrospectively reviewed the medical records of 438 children and young adults with heterozygous FH treated and followed-up at the lipid clinic, Oslo University Hospital between 1990 and 2010. Available follow-up data was collected until July 2019. Patients were included if they had at least two visits with available laboratory data. All patients were ≤18 years at the first visit to the lipid clinic, however age at first visit where cholesterol measurements were available in the medical records was above 18 years in some individuals ( n = 9, all <23 years). We excluded those not initiated on statins, and those who were pregnant or lactating at their latest follow-up visit ( Fig. 1 , Study flowchart). Differences in characteristics between the excluded 67 patients and the 371 patients included in the data analysis are shown in Supplementary Table 1.

Study flow-chart.

Information on adherence to LLT was collected from the latest visit, using the physicians’ assessment of how patients had used their LLT during at least the last month. Due to the fact that information was collected retrospectively there was no formal standardization of the information recorded, but review of the lipid profile and adherence to treatment are issues of special interest at every consultation. Patients were assigned to one of two groups, designated “good adherence” and “poor adherence”. The “good adherence” group was selected if there were no or minor remarks in the medical records about the regular use of LLT, and “poor adherence” was selected if there were remarks about major irregular or no use of LLT. Information about poor adherence was first collected by one of the main authors (AKJ) as quotes from the text in the medical notes. These quotes were then reviewed by the two main authors together (AKJ and GL). Reasons for poor adherence were categorized as: “lack of motivation” (including forgetfulness, carelessness and skepticism about using drugs), “ran out of drugs”, or “side effects”. All poorly-adherent patients were classified according to these three main categories. If there was evidence of more than one reason, the patient was classified according to what was considered to be the main reason. The “poor adherence” group was subdivided in two groups designated “irregular user”, if the LLT had been taken irregularly, and “non-user”, if LLT had not been taken at all.

Demographic and diagnostic data, lipid levels and other relevant blood chemistry data were also collected. The standard procedure in our clinic is that blood samples are taken at the General Practitioner and shipped to the Department of Medical Biochemistry, Oslo University Hospital, for routine analysis. From 2001, this laboratory has measured LDL-C by the direct enzymatic method. A small number of blood samples were analyzed by independent or local hospital laboratories. In most cases, the laboratory results had been analyzed in the last weeks before the visit and were available at the visit.

Diet was assessed by the validated questionnaire Smart Diet, which gives a score as a measure of the heart-healthiness of the diet, with a maximum score of 41 points [ , ]. A low score; < 27 points, indicates a non-heart-healthy diet, a middle score; 28–35 points, indicates a diet with opportunities for improvement, and a high score; ≥ 36 points, indicates a heart-healthy diet. All patients received dietary advice by a registered clinical nutritionist or a medical doctor at every visit.

In Norway, prescription medication is free of charge for children below 16 years of age, or at a fraction of the retail price when the person is above 16 years of age, through the universal public health services.

The study was approved by the Regional Committee for Medical Health Research Ethics, South East region of Norway, with permission to perform the study with passive consent. Thus, patients were given an opportunity to withdraw consent.

Continuous variables were normally distributed and are presented as means and standard deviations (SD). Categorical variables are presented as frequencies and percentages. For both continuous and dichotomous variables, a 95% confidence interval (CI) was estimated. Comparisons between groups were performed using the chi-square test or Fisher’s exact test for categorical variables, depending on the expected cell frequencies. For continuous variables, comparisons between two groups and three groups were performed using the Student’s t -test, and the one-way analysis of variance (ANOVA) with post hoc tests, respectively. When more than two groups were compared, a Bonferroni correction to the alpha level was applied to control for type 1 errors. Statistical analyses were conducted in SPSS (version 26) and STATA (version 16). All tests were two-sided. A 5% level of significance was used.

3

Results

Three hundred and seventy-one children and young adults were included; 57 patients not yet started on statin treatment before their latest visit and 10 patients who were pregnant or lactating were excluded from the analyses ( Fig. 1 , Study flowchart). Mean age (SD) at first and latest visit was 11.0 (4.0) years and 24.0 (7.1) years, respectively. Mean follow-up time was 12.9 (6.7) years, and 200 (53.9%) of the patients were male ( Table 1 ). Mean age at initiation of LLT was 15.6 (3.5) years, reflecting that this cohort dates back to year 1990 when guidelines were different with respect to age for treatment initiation in children. All children, except one, had a confirmed pathogenic mutation in the LDL-R gene or the R3500Q mutation in the apolipoprotein B gene. No one had mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene. One child without a confirmed mutation had elevated LDL-C (>8 mmol/L) and a first-degree relative with an FH-mutation.

Among the 57 patients that had not yet been started on LLT before their latest visit, 29 were initiated on statins at the latest visit. Among the remaining 28 patients, 12 were below 15 years of age and three attained the LDL-C goal without initiation of statin treatment. The remaining 13 patients above 15 years of age were still not started on statins despite not attaining the LDL-C treatment goal.

Almost all (370 of 371) patients on LLT were treated with statins. One patient was on monotherapy with a PCSK9-inhibitor due to statin intolerance ( Table 2 ). In addition, 117 (32%) patients were treated with ezetimibe in combination with a statin. No patients used ezetimibe in monotherapy. Atorvastatin was prescribed in 210 (57%) patients, rosuvastatin in 126 (34%) patients, and simvastatin in 34 (9%) patients. Low or moderate-dose statin (atorvastatin 5, 10 and 20 mg, rosuvastatin 5 and 10 mg, simvastatin 10, 20 and 40 mg) was prescribed in 208 (56%) patients, and high-dose statin (atorvastatin 40 and 80 mg, rosuvastatin 20 and 40 mg, simvastatin 80 mg) in 162 (44%) patients.

At the latest visit, 260 patients (70%, CI: 65–74%) had good adherence and 111 patients (30%, CI: 25–35%) had poor adherence to the prescribed LLT ( Table 3 ). Among the 111 patients with poor adherence 70 were “non-users” (19% of all; 63% of the poorly-adherent) and 41 were “irregular users” (11% of all; 37% of the poorly-adherent).

Table 3

Adherence to statins at latest visit.

	n		95% CI
Adherence to statins, n (%)	371
Good adherence		260 (70.1)	65.2–74.5
Poor adherence		111 (29.9)	25.5–34.8
Reasons for poor adherence, n (%)	111
Lack of motivation		85 (76.6)	67.9–83.5
Ran out of drugs		10 (9.0)	5.0–15.8
Side effects		16 (14.4)	9.1–22.1

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. The Johns Hopkins Ciccarone Center’s expanded ‘ABC’s approach to highlight 2020 updates in cardiovascular disease prevention
2. The landscape of preventive cardiology in Turkey: Challenges and successes
3. Prevalence of cardiovascular risk factors in a nationally representative adult population with inflammatory bowel disease without atherosclerotic cardiovascular disease
4. Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective

Stay updated, free articles. Join our Telegram channel

Join