Long-Term Statin Treatment in Children with Familial Hypercholesterolemia: More Insight into Tolerability and Adherence

Familial hypercholesterolemia (FH), a common dominantly inherited disorder of lipoprotein metabolism, is characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth onwards that predispose to premature atherosclerosis and subsequent cardiovascular disease (CVD) [1, 2]. In order to protect FH children from premature CVD, statins are currently the preferred pharmacological therapy and are recommended from the age of 8 years onwards [3, 4]. The efficacy of statins in this patient group was recently underlined by the results of a 10-year follow-up study in young adults with FH that showed that long-term statin treatment was associated with normalization of progression of the carotid intima media thickness (cIMT), a marker of early atherosclerosis [5]. However, LDL-C levels of the majority of patients in this study did not meet current treatment standards.

Studies among middle-aged hypercholesterolemic patients reported that a significant number do not achieve LDL-C goals, mainly due to poor adherence to statin therapy [6‐8]. It could be hypothesized that young FH patients might be even less adherent since several studies among individuals with other chronic disorders reported poor adherence during adolescence, a stage of life in which both development and social context change simultaneously [9‐11]. Furthermore, in FH individuals, young patients are asymptomatic and less likely to perceive themselves at risk for CVD, which could lead to poor adherence. Lastly, statin intolerance, or the inability to use statins because of side effects, might cause poor adherence or even discontinuation of treatment.

Little is known about tolerability and adherence in young FH patients and we therefore set out to study these characteristics in a cohort of young adult FH patients after 10 years of statin therapy that was initiated in childhood. Furthermore, we also examined the association between patient characteristics and adherence. Here, we present our results.

The current study is the first study that assessed tolerability and adherence of young adult FH patients after long-term statin therapy that was initiated in childhood. Our findings indicated that statin therapy was well tolerated; only a small minority (1.5 %) discontinued therapy because of side effects and reported side effects were in fact mild. The vast majority of patients (82.4 %) continued lipid-lowering therapy, with a high self-reported adherence rate of 78.7 %. None of the patient characteristics were significantly associated with adherence.

The use of statin treatment for the prevention of CVD in patients with FH is supported by extensive clinical evidence, and the data highlight the safety and tolerability of statins [18]. Our present study is the longest follow-up study of patients treated with statins. A follow-up rate as high as 95.8 % was achieved and patient characteristics of the non-participants (n = 9) did not differ significantly from those of the 205 participants at the start of the randomized trial period. No major side effects like elevation of liver enzymes or rhabdomyolysis had occurred. Analyses by the FDA have reported a rate of fatal rhabdomyolysis of 0.15 per one million statin prescriptions; therefore, our present sample size is too small to draw conclusions on the occurrence of rhabdmyolysis or other serious adverse events [19].

The most frequently discussed side effects of statin therapy are muscle-related complaints. In our study, we found 9.3 % of the FH patients have reported to have ever experienced muscle complaints. Studies on myopathy related to long-term statin therapy in young adult FH patients have not been previously reported. Our results are, however, in line with a large observational study of 7,924 hyperlipidemic patients on high-dose statins in general practice, aged 18–75 years (PRIMO study). This study reported an incidence of 10.5 % of mild muscular symptoms in the first months after statin therapy was initiated. These patients were using high doses of statins which increase the risk of muscular complaints [20]. Two reviews of more than 35 published clinical trials on patients taking different kinds of statins reported lower incidences of myalgia of 1–5 %, which was not significantly different from the incidence in their placebo group [19, 21]. Inclusion criteria in these statin studies are quite stringent and patients with a medical history of statin-related side effects might have been excluded from participation resulting in a low incidence of myalgia. Mean duration of follow-up varied extensively between these studies and no consistent and uniformly applied definition was used; therefore, these results on muscle-related side effects are difficult to compare with our study. Furthermore, we used questionnaires to get insight into muscle-related side effects due to statin treatment. Also, the average age of our patient cohort is relatively young compared with most other studies and therefore the patients in our study might be more active and practising sports and subsequently experience more muscle complaints.

Adherence to and persistence with statin therapy is crucial in the management of patients at risk for CVD, since good adherence and longer duration of persistence are associated with increasing clinical benefits [22‐24]. In general, persistence rates among patients with chronic conditions such as FH are quite low, decreasing mainly in the first 6 months of therapy [25‐27]. In our study, 10 years after the start of statin treatment, we found a remarkably high adherence rate of 78.7 %, defined as those for whom 80 % or more of days in the last month were covered by statin therapy. This was further supported by a high median score of 24 (range 5–25) on MARS statements, indicating that only very few patients showed non-adherent behavior. Other long-term follow-up studies evaluating adherence to statin therapy in primary prevention indicated adherence rates as low as 39 % after 3 years of treatment. These trials have been conducted in elderly non-FH patients, who initiated treatment at the mean age of 56 years and older [26, 27]. These results are therefore difficult to compare with our young adult population using statins as primary prevention from childhood onwards. Our study subjects initiated statin therapy in childhood during a clinical trial, with regular visits (i.e., every 3 months) to our outpatient clinic. This early initiation of treatment and close monitoring might contribute to habitual use of statins and therefore better adherence to therapy. However, patients’ self-reported statin use was acquired to determine their adherence. This method might be susceptible to inaccurate patient recall or social desirability and might lead to an overestimation of adherence. However, adherent patients had significantly lower cholesterol levels than non-adherent patients, an effect that cannot be explained by a difference in untreated cholesterol levels.

As in all randomized controlled trials, stringent inclusion and exclusion criteria were applied, essentially excluding the sickest and frailest people, which could limit the generalizability of our results. However, FH children were enrolled in the trial between 1997 and 1999 and at that time the Academic Medical Center was the only clinic in The Netherlands and one of the very few clinics worldwide that treated these children. As a consequence, children with FH were referred from all over the country to our lipid clinic and from that point of view the children included in our study are a reasonable representative of the general population with this disorder.

The main reason for discontinuation of therapy in our study group was pregnancy, which is in accordance to current medical advice. Non-adherence in our cohort was accompanied by significantly higher LDL-C levels and a lower out-patient follow-up frequency. Reasons for non-adherence were unwillingness to take medication and forgetfulness. According to the literature, non-adherence is associated with younger age, female gender, lower socio-economic status and complex treatment regimen [6, 28, 29]. Although we did not have information on socio-economic status, our results did not reveal significant associations between these or any of the other factors and adherence to statin therapy.

Current practice in FH patients is to achieve LDL-C reduction of at least 50 % and preferably LDL-C levels below 2.5 mmol/L [30]. Neither of these treatment goals have been reached in our study group. Despite a good adherence rate of 78.7 % in our cohort, the mean LDL-C level of the adherent group was still 3.85 mmol/L, and only eight patients had LDL-C levels <2.50 mmol/L. Our results are in line with those of Pijlman et al. [31], who conducted a cross-sectional study among adult FH patients in the Netherlands and concluded that only 21 % of the 1,249 patients reached the treatment goal for LDL-C of <2.5 mmol/L. This raises serious concerns on the risk of future cardiovascular events and therefore treatment regimens for this patient group should be improved in the future.

In conclusion, this study demonstrates that patients with FH who started statin therapy in childhood, regardless whether this was before or after puberty, showed good adherence during 10 years of treatment. The fact that early initiation may contribute to habitual use of medication despite its preventive character, and the fact that none of the patients had suffered from cardiovascular disease are important clinical findings. Even more important, statin therapy was very well tolerated; only a very small minority discontinued therapy because of side effects, and reported side effects were mild. However, their treatment appeared to be suboptimal in terms of efficacy and this merits further attention.