Heterozygous familial hypercholesterolemia (HeFH) is an autosomal codominant disorder with a prevalence of approximately 1 case per 300 people in the general population.1 It is the most common genetic disorder linked to premature atherosclerotic cardiovascular disease (ASCVD). Although lipid-lowering treatment has been shown to reduce coronary heart disease and overall mortality in patients with HeFH2—and has improved in recent years—most patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels3,4 and therefore continue to be at increased risk of premature ASCVD. Not all patients with HeFH, however, have the same CV risk. We recently published an equation for estimating individual CV risk in patients with HeFH based on 8 simple variables,5 including lipoprotein(a), which has proven to be an effective predictor of incident ASCVD in this setting.6

The latest European Society of Cardiology/European Atherosclerosis Society Guidelines for the Management of Dyslipidemias7 (ESC/EAS Guidelines) consider patients with HeFH to be at high or very high CV risk and recommend a target LDL-C level of less than 100mg/dL for patients without a history of CV disease and less than 70mg/dL for those with a history. They also recommend reducing baseline LDL-C levels by at least 50% in both cases. Little, however, is known about the use of lipid-lowering treatment or the attainment of LDL-C goals in Spain. National registries serve as an invaluable source of such data, which are essential for improving current health care models, educating physicians and patients, and setting priorities in treatment guidelines and health care policies.8 The SAFEHEART Spanish Familial Hypercholesterolemia Cohort Study was designed to collect nationwide data on FH in order to improve knowledge of this disease in Spain.

The aim of this study was to analyze data from the SAFEHEART registry to determine the incidence of CV events in patients with HeFH in Spain, estimate their risk of experiencing a cardiovascular event using the SAFEHEART Risk Equation (SAFEHEART-RE), assess changes to this risk, and analyze the use of lipid-lowering treatments and attainment of treatment goals on inclusion in the registry and at the most recent follow-up.

A total of 4870 individuals were recruited: 3601 with a genetic diagnosis of HeFH and 1269 unaffected relatives. After exclusion of patients without a complete follow-up and patients not receiving lipid-lowering treatment at the time of the most recent evaluation (last follow-up), 2648 patients with HeFH were included in the analysis (figure 1). Median follow-up time was 6.6 years (IQR, 4.8–9.7 years). The main characteristics of the cohort at entry in the registry and at the last follow-up are summarized in table 1 and table 2. The distribution of patients according to region of residence is shown in table 1 of the supplementary data. The sample included patients from all regions except the autonomous communities of Cantabria, Murcia, and Navarre and the autonomous cities of Ceuta and Melilla.

Figure 1.

Flow diagram showing inclusion of cases in the SAFEHEART Registry. HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia.

(0.29MB).

A total of 251 first fatal or nonfatal ASCVD events were recorded during follow-up; there were 202 nonfatal events and 62 fatal events. The nonfatal events were nonfatal acute coronary syndrome (83 patients, 3.1%), coronary revascularization (64 patients, 2.4%), nonfatal stroke (23 patients, 0.9%), peripheral revascularization (15 patients, 0.6%), and aortic valve replacement (17 patients, 0.6%). The fatal events were fatal acute coronary syndrome (16 patients, 0.6%), fatal stroke (8 patients, 0.3%), and other CV death, including sudden death (38 patients, 1.4%). Thirteen (21%) of the 62 patients with a fatal event had had a previous CV event during follow-up. All patients who experienced an event (and/or their relatives) were contacted. Of the 251 patients who experienced a fatal or nonfatal event during follow-up, 114 (45.4%) had had a CV event before inclusion in the registry. The overall incidence of CV events was 1.3 events per 100 patient-years. The breakdown by region is shown in figure 2. The proportion of patients on maximal lipid-lowering treatment increased from 58.8% at entry to 80.8% at the last follow-up (P<.001), while that of patients on PCSK9 inhibitors increased from 0.4% to 11.6% (P<.001). In the group of patients excluded because they were not on lipid-lowering treatment at the last follow-up (n=253), there were 5 first nonfatal events and 6 first fatal events (preceded by a nonfatal event in 2 cases). In the group of patients excluded because of nonavailability of LDL-C results at the last follow-up (n=391), there were 10 first nonfatal events and 12 first fatal events, 1 of which was preceded by a nonfatal event.

Figure 2.

Incidence of cardiovascular events according to place of residence. AND, Andalusia; ARA, Aragon; AST, Asturias; BAL, Balearic Islands; BC, Basque Country; CAN, Canaries; CAT, Catalonia; CL, Castilla-León; CLM, Castilla-La Mancha; EXT, Extremadura; GAL, Galicia; MAD, Madrid; RIO, La Rioja; VAL, Valencia.

(0.09MB).

At entry, 4.0% of patients in primary prevention and 2.1% of those in secondary prevention met their respective LDL-C goals of less than 100mg/dL and less than 70mg/dL. The corresponding rates for patients meeting their goals at the last follow-up were 20.6% and 22.2% (P<0.001). The proportion of active smokers fell from 24.8% at entry to 14.7% at the last follow-up (P <.001). There were no significant changes in body mass index (BMI) during this period.

Mean changes in CV risk from entry to last follow-up according to the SAFEHEART-RE and stratified by place of residence are shown in figure 3 together with the corresponding 95% confidence intervals. The results for the other variables stratified by place of residence are shown in table 2 of the supplementary data andtable 3 of the supplementary data. In total, 37.5% of the patients were treated in primary care.

Figure 3.

Mean changes in estimated risk with corresponding confidence intervals in different Spanish regions. 95%CI, 95% confidence interval.

(0.09MB).

We have described, for the first time, the incidence of CV events in patients with HeFH in Spain and have provided additional data on CV risk, use of lipid-lowering treatment, and attainment of treatment goals at a country and regional level. The overall incidence rate detected for CV events was 1.3 events per 100 patient-years.

Our findings show that intensification of lipid-lowering treatment in patients with HeFH improved LDL-C levels over the follow-up period of 6 years. During this time, the proportion of patients on maximal lipid-lowering treatment rose from 58.8% to 80.8%. Although 80.8% of patients were on maximal lipid-lowering treatment and 11.6% were on PCSK9 inhibitors at the last follow-up evaluation, just 20.6% of patients in primary prevention and 22.2% of those in secondary prevention had optimal LDL-C levels (<100mg/dL and <70mg/dL, respectively. A number of points should be made regarding LDL-C goals: a) the proportion of patients with optimal LDL-C levels has doubled since the last analysis of patients from the SAFEHEART registry3; b) attainment of goals was more common in secondary than in primary prevention patients, probably because of the recent incorporation of PCSK9 inhibitors for patients at increased risk; and c) the proportion of patients failing to meet their LDL-C goals remains high, possibly in part because patients with FH have very high initial LDL-C levels; this highlights the importance of recommending potent statins and combination therapy with ezetimibe and PCSK9 inhibitors in patients with HeFH.11 The findings of this study show the persistence of a considerable gap between treatment goals and practice, confirming that there is still much room for improvement. They also, however, show just how difficult it is for patients with HeFH to achieve optimal LDL-C levels, despite treatment with the best lipid-lowering treatments available. It should be noted that the statistical power for comparing results across the different regions of Spain was limited by the characteristics of the registry. A recent study on the incidence of CVD in patients with FH in Catalonia reported a similar incidence rate to that observed in the SAFEHEART registry, despite using a different methodology.12

The improvement in CV risk observed over the follow-up period is probably due to the significant reduction in LDL-C levels. Although the prevalence of clinical CVD and hypertension has increased, there has been a significant reduction in tobacco use among patients with HeFH. Mean BMI was 26.1, which is lower than the BMI for the average Spanish adult: 26.7 (27.2 for men and 26.1 for women). In addition, mean BMI did not change during follow-up, contrasting with the situation for Spanish adults in general, who tend to have increasing BMI as they age.13 In part, patients with HeFH probably maintain a better BMI because they are more aware of the importance of CVD prevention and healthy lifestyle habits.14

Before the emergence of new tools for assessing CV risk in patients with FH, baseline LDL-C levels (levels before initiation of lipid-lowering treatment) were used to identify severe phenotypes.15,16 The SAFEHEART-RE, which is based on prospective data, provides a more accurate tool for defining risk and guiding decisions on the most appropriate treatment strategies for patients with HeFH.5

A final note of interest is that 37.5% of patients with HeFH are treated in primary care, although rates varied considerably across regions. One example is Castile-León, which has a regional FH detection program that involves the participation of primary care physicians.17

We are aware of the strengths and limitations of the present study. This is the largest longitudinal study to analyze real-life treatment practices at different levels of the health care system in patients with molecularly defined HeFH. Although SAFEHEART is a national registry, it does not include patients from all the autonomous communities in Spain. Our results show the need for a prospective registry to evaluate trends in CV healthcare provision in the setting of HeFH.

This study is the first to show the incidence of CV events in a large population of patients with HeFH and to analyze associated risk and changes in risk, attainment of treatment goals, and treatment strategies employed in this population. Although the risk is high, adequate treatment considerably reduces the likelihood of a CV event. Efforts should thus focus on achieving adequate LDL-C control and improving risk factors in patients with HeFH.

We would like to thank the staff at Fundación Hipercolesterolemia Familiar for their invaluable help with the recruitment and follow-up of patients in the registry. We are also very grateful to all the families who collaborated in this study.

This study was funded by the Fundación Hipercolesterolemia Familiar; grant G03/181 and FIS PI12/01289 of the Instituto de Salud Carlos III (ISCIII) and grant 08-2008 from the Centro Nacional de Investigación Cardiovascular (CNIC).

The authors declare that they have no conflicts of interest.