Journal of Clinical Lipidology (2019) 13, 989–996 Long-term effect of 2 intensive statin regimens on treatment and incidence of cardiovascular events in familial hypercholesterolemia: The SAFEHEART study Leopoldo Perez de Isla, MD, PhD**, Raquel Arroyo-Olivares, RD, Ovidio Mun ~iz-Grijalvo, MD, PhD, Jose Luis Diaz-Dıaz, MD, PhD, Daniel Zambo n, MD, PhD, Francisco Fuentes, MD, PhD, Juan F. Sanchez Mun ~oz-Torrero, MD, PhD, Juan Diego Mediavilla, MD, PhD, Aurora Gonzalez-Estrada, MD, PhD, Jose Pablo Miramontes-Gonzalez, MD, PhD, Raimundo de Andr es, MD, PhD, Marta Mauri, MD, PhD, Daniel Mosquera, MD, PhD, Jose M. Cepeda, MD, PhD, Lorena Suarez, MD, PhD,  Miguel Angel Barba-Romero, MD, PhD, Rosa Argu €eso, MD, PhD,  Pilar Alvarez-Ban~os, MD, PhD, Alfredo Michan, MD, PhD, Manuel J. Romero-Jim enez, MD, PhD, Jesus Garcıa-Cruces, MD, PhD, Teresa Padro, MD, PhD, Rodrigo Alonso, MD, PhD, Pedro Mata, MD, PhD* Cardiology Department, Hospital Clınico San Carlos, IDISSC, Facultad de Medicina, Universidad Complutense, Madrid, Spain (Dr Perez de Isla); Fundacion Hipercolesterolemia Familiar, Madrid, Spain (Drs Perez de Isla, Arroyo-Olivares, and Mata); Department of Internal Medicine, Hospital Virgen del Rocıo, Sevilla, Spain (Drs Mu~niz-Grijalvo and Gonzalez-Estrada); Department of Internal Medicine, Hospital Abente y Lago, A Coru~na, Spain (Dr Diaz-Dıaz); Department of Endocrinology, Hospital Clinic, Barcelona, Spain (Dr Zambon); Lipids and Atherosclerosis Unit, IMIBIC/ Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain (Dr Fuentes); Department of Internal Medicine, Hospital San Pedro de Alc antara, C aceres, Spain (Dr Sanchez Mu~noz-Torrero); Department of Internal Medicine, Hospital Virgen de las Nieves, Granada, Spain (Dr Mediavilla); Department of Internal Medicine, Hospital Clınico For the SAFEHEART investigators (Complete list accessible at: https:// boards and received research grants from Amgen and Sanofi. Dr Ovidio www.colesterolfamiliar.org/en/safeheart-study/lipid-clinics-participating- Mu~niz-Grijalvo has received honoraria for consulting, speaker, or in-the-study/). researcher activities from Merck, Sharp and Dohme, Amgen, and Sanofi. ClinicalTrials.gov number NCT02693548. Dr Jose Luis Dıaz-Dıaz has received honoraria for consulting, speaker or Funding: This study was supported by Fundacion Hipercolesterolemia researcher activities from Merck, Sharp and Dohme, Amgen, and Sanofi. Familiar; Grant G03/181 and FIS PI12/01289 from Instituto de Salud Car- * Corresponding author. Fundacion Hipercolesterolemia Familiar, C/ los III (ISCIII), Grant 08-2008 Centro Nacional de Investigacion Cardio-  General Alvarez de Castro 14, 28010 Madrid, Spain. vascular (CNIC). ** Corresponding author. Hospital Clınico San Carlos, Unidad de Imagen Conflict of interest: Dr Perez de Isla has received honoraria for consul- Cardiovascular, C/ Profesor Martın Lagos s/n, 28040 Madrid, Spain. ting, speaker or researcher activities from Merck, Sharp and Dohme, Astra E-mail addresses: leopisla@hotmail.com; Zeneca, Esteve, Amgen, and Sanofi. Dr Alonso reports personal fees from pmata@colesterolfamiliar.org Amgen, Aegerion, and Ionis. Dr Mata received honoraria for advisory Submitted July 11, 2019. Accepted for publication October 3, 2019. 1933-2874/Ó 2019 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.jacl.2019.10.005 990 Journal of Clinical Lipidology, Vol 13, No 6, December 2019 Universitario, Valladolid, Spain (Dr Miramontes-Gonzalez); Department of Internal Medicine, Fundacion Jimenez Dıaz, Madrid, Spain (Dr de Andres); Department of Internal Medicine, Hospital de Terrassa, Barcelona, Spain (Dr Mauri); Department of Internal Medicine, Hospital San Pedro, Logro~no, Spain (Dr Mosquera); Department of Internal Medicine, Hospital Vega Baja, Orihuela, Alicante, Spain (Dr Cepeda); Department of Endocrinology, Hospital Central de Asturias, Oviedo, Spain (Dr Su arez); Department of Internal Medicine, Complejo Hospitalario Universitario, Albacete, Spain (Dr Barba-Romero); Department of Endocrinology, Hospital de Lugo, Lugo, Spain (Dr Arg€ueso); Department of  Endocrinology, Hospital Universitario de Burgos, Burgos, Spain (Dr Alvarez-Ba~ nos); Department of Internal Medicine, Hospital del SAS Jerez de la Frontera, Cadiz, Spain (Dr Michan); Department of Internal Medicine, Hospital Infanta Elena, Huelva, Spain (Dr Romero-Jimenez); Department of Preventive Medicine, Hospital Universitario Rıo Hortega, Valladolid, Spain (Dr Garcıa-Cruces); Programa–ICCC Cardiovascular, Institut de Recerca del Hospital Santa Creu i Sant Pau, IIB Santa Pau, Barcelona, Spain (Dr Padr o); and Department of Nutrition, Clınica las Condes, Santiago de Chile, Chile (Dr Alonso) KEYWORDS: BACKGROUND: Maximal doses of potent statins are the basement of treatment of familial hyper- Familial cholesterolemia (FH). Little is known about the use of different statin regimens in FH. hypercholesterolemia; OBJECTIVES: The objectives of the study were to describe the treatment changes and low-density Atorvastatin; lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the Rosuvastatin; SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events Long-term prognosis (ACVEs) and changes in the cardiovascular risk. METHODS: SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs. RESULTS: A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5–10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67–3.39) and 1.22 (0.54–2.93) at enrollment for ATV and RV, respectively (P , .001). There were no significant differ- ences at the follow-up: 1.29 (0.54–2.82) and 1.22 (0.54–2.76) in the ATV and RV groups, respectively (P 5 .51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C ,100 mg/dL and 4% in secondary prevention with ATV and 5% with RV achieved an LDL-C ,70 mg/dL. The use of ezetimibe was marginally greater in the RV group. One hundred sixty ACVEs occurred during follow-up, being its incidence rate 1.1 events/100 patient-years in the ATV group and 1.2 in the RV group (P 5 .58). CONCLUSION: ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated. Ó 2019 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction health planning policies.5,6 The SAFEHEART study (Span- ish Familial Hypercholesterolemia Cohort Study), a na- Heterozygous familial hypercholesterolemia (FH) is a tional registry of patients with FH was designed to codominant autosomal disorder with a prevalence around improve the knowledge of this disease in Spain.7,8 1:250 cases worldwide, making it by far the most common The objective of this study was to describe the changes genetic condition causing premature morbidity and mor- in the treatment and achievement of LDL-C goals with tality from atherosclerotic cardiovascular disease.1 potent statins such as atorvastatin (ATV) and rosuvastatin Although lipid-lowering therapy (LLT) has shown a reduc- (RV) used alone or in combination with Ezetimibe in the tion in coronary and total mortality in patients with FH and SAFEHEART cohort from inclusion until the last follow- LLT has improved in recent years, most patients with FH up, as well as to analyze the incidence of cardiovascular do not reach an optimal therapeutic level of low-density li- events and changes in the estimated risk in the FH poprotein cholesterol (LDL-C) and, therefore, continue to population treated with 2 intensive statin regimens. have a high risk of premature atherosclerotic cardiovascular events (ACVEs).2–4 Little is known about the use of different statins and the Methods achievement of LDL-C goals in patients with FH. National registries are a valuable source to provide this key infor- Design and population mation, necessary to improve models of health care, family cascade screening, the education of physicians and patients, SAFEHEART is a prospective nationwide cohort study, and to help define priorities in therapeutic guidelines and open, multicentric with long-term protocolized follow-up in Perez de Isla et al Atorvastatin versus rosuvastatin in FH 991 a molecularly defined FH population with participation Comparisons of proportions between the qualitative vari- from primary and specialized care.7 The recruitment of ables were carried out using the chi square test and the families with FH began in 2004 and the end date for report- binomial test to compare the proportion observed in each ing events was January 2019. This study was approved by treatment group with the value of the total population. The the ethics committee of the Fundaci on Jimenez Dıaz Hos- mean comparisons of the quantitative variables were pital in Madrid and all the subjects gave their written analyzed with the Student’s t-test for independent data, informed consent. The objectives of treatment were defined and the medians comparisons were analyzed with the according to the hyperlipidemia guidelines.9 These guide- Mann-Whitney U-test for independent data. The incidence lines were used to inform, educate, and train participating rate of cardiovascular events was calculated as the quotient physicians and include patients and families in this registry. in which the numerator is the number of observed events The coordinating center of the SAFEHEART study and the denominator is the time at risk for the event. The managed the follow-up of the patients. The patients were time at risk was the sum of the follow-up time of patients contacted on a yearly basis by using a standardized who do not have an event plus the sum of the time until telephone survey to obtain relevant changes in life habits, the event appears in the patients in which the event occurs. medication, and the appearance of cardiovascular events. The incidence rate was expressed as the number of events The definitions of previous and incident ACVEs have been per 100 patient-years. A value of P , .05 was considered previously reported.10 statistically significant. Variables Results In addition to the aforementioned demographic and clinical variables, age, classic cardiovascular risk factors, A total of 4870 subjects were enrolled, 3601 with physical examination, and LLT were included. The lipid genetic diagnosis of FH and 1269 nonaffected relatives. profiles were determined in venous blood samples in a The analysis in this study was made with 1939 patients with centralized laboratory.7 The serum concentration of LDL-C FH, after excluding homozygous subjects, younger than was calculated using the Friedewald formula. The DNA 18 years, without complete follow-up, those who did not was isolated from whole blood using standard methods, receive LLT at the last follow-up, took a statin different and the genetic diagnosis of FH was performed as previ- from ATV or RV, or were in treatment with inhibitors of ously described.11 Cardiovascular risk was defined by the proprotein convertase subtilisin/kexin type 9 (PCSK9) SAFEHEART risk equation (SAFEHEART-RE).10 The (Fig. 1). The median follow-up time was 6.6 years (5– classification of LLT was defined as previously reported4: 10 years). Three hundred patients changed during the maximal statin dose as ATV 40 to 80 mg/d or RV 20 to follow-up from ATV to RV and 46 patients from RV to 40 mg/d which was considered high-intensity statin doses; ATV. All of them were treated with the last drug until the maximal combined therapy as maximal statin dose plus last contact and always, continuously, for more than half ezetimibe 10 mg/d; and maximal LLT as any LLT expected of the follow-up. to produce at least a 50% reduction in LDL-C baseline The main characteristics of the cohort are described in levels. The classification of LLT intensity, in terms of po- Table 1. It is interesting to point out that only statistically tency, has been previously reported.12,13 significant differences were found between the ATV group Incident ACVEs during follow-up was defined as the and the RV group in the following variables: use of statins occurrence after enrollment of the first one of the at maximum dose (71% and 81% in the ATV and RV following: fatal or nonfatal myocardial infarction, fatal or groups, respectively, P , .001), use of added ezetimibe nonfatal ischemic stroke, coronary revascularization, pe- (65% and 77% in the ATV and RV groups, respectively, ripheral artery revascularization, and cardiovascular death P , .001), use of maximum combined treatment (53% (any death related to cardiovascular disease or derived of and 66% in the ATV and RV groups, respectively, cardiovascular therapeutic procedures not described in the P , .001), and maximum LLT (88% and 81% in the previous definitions). ATV and RV groups, respectively, P , .001). Likewise, 505 patients in the ATV group (47%) and 252 in the RV Statistical analysis group (29%) were managed in primary care (P , .001). Regarding the lipid parameters, statistically significant dif- The statistical analysis was carried out with the STATA ferences were found in LDL-C levels [128 mg/dL (107– program, version 12.0 (Stata Corporation, College Station, 152) and 123 mg/dL (104–146) in the ATV and RV groups, TX). A descriptive analysis was carried out to report the respectively; P , .005] and TG levels [82 mg/dL (64–116) number of cases and percentages for the qualitative vari- and 93 mg/dL (70–129) in the ATV and RV groups, respec- ables, the mean, and the standard deviation for the tively; P , .001]. quantitative variables that followed a normal distribution Figure 2 shows the evolution between the time of enroll- and the median and interquartile range for the quantitative ment in the SAFEHEART study and the time of the last variables that did not follow a normal distribution. follow-up in the ATV or RV treatment in the studied cohort. 992 Journal of Clinical Lipidology, Vol 13, No 6, December 2019 It is important to highlight the considerable change that all potency increased during the follow-up, going from monotherapies and combined therapies have undergone, 6.7 6 1.6 to 7.1 6 1.4 in the ATV group (P , .001) and highlighting the very important numerical increase of pa- from 6.9 6 1.4 to 7.5 6 1.2 in the RV group (P , .001). tients treated with coadministration of RV and ezetimibe: Regarding the risk of developing a cardiovascular event 200 patients at the time of enrollment (10%) and 675 pa- estimated by the SAFEHEART-RE, Table 3 shows how in tients at the time of the last follow-up (35%) (P , .001). the inclusion, the estimated 10-year risk was 1.61 (0.67– Table 2 shows the potency of lipid-lowering treatment 3.39) and 1.22 (0.54–2.93) in the groups ATV and RV, used at inclusion and at the time of the last follow-up in respectively (P , .001), meaning there were no significant the ATV and RV groups expressed in potency terms. differences between the 2 groups at the time of the last Although the potency of the treatment in this population follow-up: 1.29 (0.54–2.82) and 1.22 (0.54–2.76) in the did not strictly follow a normal distribution and, therefore, ATV and RV groups, respectively (P 5 .51). was expressed as a median, values are given here as means Regarding the achievement of LDL-C goals, 16% of because it may be more informative. In both groups, the patients in primary prevention in the ATV group and 18% Figure 1 Flow diagram showing the recruitment of cases in the SAFEHEART registry. ATV, atorvastatin; RV, rosuvastatin; LLT, lipid- lowering therapy; PCSK9, proprotein convertase subtilisin/kexin type 9; FH, familial hypercholesterolemia; HeFH, heterozygous familiar hypercholesterolaemia; HoFH, homozygous familiar hypercholesterolaemia. Perez de Isla et al Atorvastatin versus rosuvastatin in FH 993 Table 1 Characteristics of the SAFEHEART population treated with ATV or RV in the last follow-up Qualitative variables; n (%) Total ATV RV P n 1939 1065 874 ,.001 Gender (male) 890 508 (48) 382 (44) .08 ACVEs at enrollment 232 134 (13) 98 (11) .35 Nonfatal ACVEs in follow-up 128 61 (6) 67 (8) .09 Fatal ACVEs in follow-up 42 28 (3) 14 (2) .12 Fatal or nonfatal ACVEs in follow-up 160 83 (8) 77 (9) .42 ACVEs at enrollment or during follow-up 311 168 (16) 143 (16) .73 Diabetes mellitus 160 93 (9) 67 (8) .39 Hypertension 432 237 (22) 195 (22) .97 Active smoking 291 160 (15) 131 (15) .98 Maximal statin dose 1460 755 (71) 705 (81) ,.001 Ezetimibe 1367 692 (65) 675 (77) ,.001 Maximal combined therapy 1135 561 (53) 574 (66) ,.001 Maximum lipid-lowering therapy 1647 942 (88) 705 (81) ,.001 Patients in primary prevention 1628 897 (84) 731 (84) .7 Patients in secondary prevention 281 148 (14) 133 (15) .5 LDL-C,100 mg/dL in patients in primary prevention 274 140 (16) 134 (18) .14 LDL-C,70 mg/dL in patients in secondary prevention 13 6 (4) 7 (5) .56 Patients managed in primary care 757 505 (47) 252 (29) ,.001 Quantitative variables; median (IQR) Age (y) 54 (42–65) 54 (42–66) 54 (43–65) .70 BMI Kg/m2 25.8 (23–29) 25.7 (23–28) 26.1 (23–29) .07 Total cholesterol mg/dL 198 (176–225) 200 (177–227) 197 (176–222) .12 LDL-C mg/dL 125 (106–148) 128 (107–152) 123 (104–146) ,.005 HDL-C mg/dL 51 (43–61) 51 (43–61) 51 (44–60) .95 TG mg/dL 86 (67–121) 82 (64–116) 93 (70–129) ,.001 Years on statin treatment 18 (13–26) 18 (13–26) 18 (13–26) .71 Years on Ezetimibe treatment* 4.7 (0–11) 5.7 (0–12) 3.8 (0–11) .08 ATV, atorvastatin; RV, rosuvastatin; ACVEs, atherosclerotic cardiovascular events; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; IQR, interquartile range. * Only patients on ezetimibe treatment. in the RV group achieved an LDL-C ,100 mg/dL and 4% the achievement of objectives in LDL-C. Nevertheless, in secondary prevention in the ATV group and 5% in the there was an increase during follow-up in the percentage RV group achieved an LDL-C ,70 mg/dL. Figure 3 shows of subjects without ACVEs who reached an LDL-C under 115 and 130 mg/dL, respectively, and the increase was sig- nificant in the RV group compared with the ATV group (P , .05). During follow-up, a total of 160 fatal or nonfatal first incident ACVEs were recorded; 128 first nonfatal events and 42 deadly events (Table 1). The overall incidence rate of cardiovascular events was 1.15 events/100 patient-years; 1.1 in the ATV group and 1.2 in the RV group (P 5 .58). Figure 4 shows the survival curves in both treatment groups for incident ACVEs. Discussion This study is the first, to our knowledge, to compare the use in real clinical practice of 2 high-potency statins in patients with FH. It is a prospective long-term follow-up Figure 2 Changes in the treatment with ATV or RV in the study analyzing the incidence of fatal and nonfatal SAFEHEART registry. ATV, atorvastatin; EZ, ezetimibe; RV, ro- cardiovascular events. It is well known that lipid-lowering suvastatin; Tot, total. treatment with high-potency statins in FH lowers LDL-C 994 Journal of Clinical Lipidology, Vol 13, No 6, December 2019 to their lipid-lowering potency, have several effects inde- Table 2 Classification of lipid-lowering treatment by potency* (mean 6 SD) pendent of their lipid-lowering effect, the so-called pleio- tropic effects.21 One of these pleiotropic effects is its Potency Total ATV RV P ability to stabilize atherosclerosis plaques, thus preventing Potency at 6.8 6 1.5 6.7 6 1.6 7.1 6 1.4 ,.001 its rupture and the appearance of subsequent cardiovascular enrollment events. Most acute coronary syndromes are secondary to Potency at 7.2 6 1.4 6.9 6 1.4 7.5 6 1.2 ,.001 the rupture of vulnerable atherosclerotic plaques. After follow-up the instabilization of an atherosclerotic plaque, a process ATV, atorvastatin group; RV, rosuvastatin group. of healing or stabilization arises. However, until this study, * Lipid-lowering therapy potency has been calculated according the it was not known if there are statins that favor more than method described in the study by Penning-van Beest et al12 modified others this stabilization of the atherosclerotic plaque. by Masana et al.13 As a reference point, the potency of atorvastatin It is important to emphasize that although more than 40 mg is 6. 80% patients analyzed in our study were on maximum LLT, the majority did not achieve the recommended LDL-C goals. These findings show the difficulty in reducing the levels, a fact that is associated with a reduction in the LDL-C in patients with FH as they usually have high incidence of cardiovascular events.14 A strong recommen- baseline LDL-C levels.16,22 However, although the targets dation for the use of high-intensity statins15 and combined are not fully achieved in many patients, we can affirm therapy with ezetimibe should be established in patients that their control has improved with respect to previous with FH,16 with the use of ezetimibe now being well sup- data from the same cohort.4 These results depict that a ported by IMPROVE-IT.17 As the results of the present considerable number of patients with FH may be candidates study show, although the reduction in LDL-C levels is to receive new medications, such as PCSK9 inhibitors. greater in the group treated with RV than in the group With reference to this aspect, we have recently shown treated with ATV, the incidence of fatal and nonfatal car- that the application of SAFEHEART-RE can help make a diovascular events is similar in both groups. better selection of patients with FH for the use of PCSK9 In parallel with the findings of a study comparing the inhibitors to improve the cost-effectiveness of its use.23 efficacy of both statins to reduce the progression of Effective lipid-lowering therapies with statins and coronary atherosclerosis18 and in which no significant dif- ezetimibe are now available as generic medications. A ferences were found between the 2 drugs, no differences point of special consideration is that RV was marketed in were found in the present study when the incidence rate September 2009 (ATV in October 1997) in Spain and of cardiovascular events was analyzed. It is well known therefore takes longer to be available as generic. Despite that the burden of coronary atherosclerosis is directly and this delay in its availability, we can observe that the use of proportionately related to the incidence of cardiovascular RV has increased considerably in patients with FH, events, including coronary events.19 This parallelism be- especially in those who are managed in the specialized tween the burden of atherosclerosis and cardiovascular health care system. Furthermore, a recent study concerning events reinforces the plausibility of the findings of our cost-effectiveness of LLT in patients with FH involved in a study, which align with the findings of the aforementioned national detection program has shown that the use of ATV study. However, another recent study shows that although and RV with or without ezetimibe is cost-effective.24 RV and ATV at doses of 10 and 20 mg, respectively, ob- When applying the SAFEHEART-RE equation to the tained similar reductions in LDL-C levels, RV showed patients analyzed at the time of their enrollment in the that it was able to improve earlier and more robustly than SAFEHEART registry and at the time of the last follow-up, ATV the image parameters related to the stability of the no significant differences were found in the estimated risk atherosclerosis plaques. Nevertheless, both statins signifi- reduction between these 2 moments between the group that cantly reduced the atheroma volume.20 Statins, in addition used ATV and the group that used RV. Table 3 Ten-year cardiovascular risk in the SAFEHEART cohort with ATV/RV Risk Total ATV RV P Ten-year SAFEHEART- 1.54 (0.64–3.39) 1.61 (0.67–3.39) 1.22 (0.54–2.93) ,.001 RE risk at enrollment Ten-year SAFEHEART- 1.27 (0.54–2.76) 1.29 (0.54–2.82) 1.22 (0.54–2.76) .51 RE risk at follow-up ATV, atorvastatin group; RV, rosuvastatin group; SAFEHEART-RE, SAFEHEART risk equation; IQR, interquartile range. Median (IQR). Perez de Isla et al Atorvastatin versus rosuvastatin in FH 995 Figure 3 Goal achievement for different LDL cholesterol thresholds in FH patients with and without atherosclerotic cardiovascular dis- ease in the atorvastatin and rosuvastatin groups. CVD (1): Patient who had a history of atherosclerotic cardiovascular disease; CVD (2): patient without history of atherosclerotic cardiovascular disease. LDL-C, low-density lipoprotein cholesterol; FH, familial hypercholester- olemia; CVD, cardiovascular disease. The strengths and limitations of our study merit to be be at higher risk. This fact could be reflected in the greater taken into account. The SAFEHEART study is a nation- use of RV in referral practice as compared to primary care. wide, long-term prospective contemporary cohort of a Another major limitation is the very small differences in molecularly defined FH population. This fact makes these LDL-C level and in risk of ACVEs between the ATV and results as a reference because of the lack of other cohorts of RV groups that raise the possibility that unaccounted similar characteristics and similar follow-up around the confounders and limited statistical power could explain world. Nevertheless, the 2 groups considered for this study the lack of differences in ACVEs. were not randomly assigned. Furthermore, RV was the newer drug pointed out and, although known risk factors were matched, an important limitation is that RV might Conclusion have been favored for patients perceived by physicians to ATV and RV are 2 high-potency statins widely used for patients with FH. The results of the present study show that although the reduction in LDL-C levels was greater in the group treated with RV than in the group treated with ATV, the superiority of RV for reducing ACVEs was not demonstrated. Acknowledgments The authors thank Ms Teresa Pariente for her hard work managing the familial cascade screening from the begin- ning of the SAFEHEART registry and all the Spanish Familial Hypercholesterolemia Foundation for assistance in the recruitment and follow-up of participants and to the FH families for their valuable contribution and willingness to participate. Authors’ contributions: All authors have approved the final article. L.P.d.I., R.A-O., O.M-G., J.L.D-D., T.P., R.A., Figure 4 Survival curves for incident ACVEs in both treatment and P.M. contributed to patients’ enrollment and follow-up, groups. ACVEs, atherosclerotic cardiovascular events. research development, statistical analysis, manuscript 996 Journal of Clinical Lipidology, Vol 13, No 6, December 2019 writing, and manuscript review. D.Z., F.F., J.F.S.M-T, 12. Penning-van Beest FJA, Termorshuizen F, Goettsch WG, Klungel OH, J.D.M., A.G.E., J.P.M-G., R.d.A., M.M., D.M., J.M.C., Kastelein JJP, Herings RMC. Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial L.S., M.A.B-R., R.A., P.A.B., A.M., M.J.R.J., and J.G-C. infarction by 40%: a cohort study. Eur Heart J. 2007;28(2):154–159. contributed to patients’ enrollment and follow-up, research 13. Masana L, Ibarretxe D, Plana N. Maximum low-density lipoprotein development, manuscript writing, and manuscript review. cholesterol lowering capacity achievable with drug combinations. When 50 plus 20 equals 60. Rev Esp Cardiol (Engl Ed). 2016;69(3): 342–343. References 14. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hyper- 1. Gidding SS, Champagne MA, de Ferranti SD, et al. The Agenda for cholesterolaemia is underdiagnosed and undertreated in the general Familial Hypercholesterolemia: a scientific statement from the Amer- population: guidance for clinicians to prevent coronary heart disease: ican Heart Association. Circulation. 2015;132(22):2167–2192. consensus statement of the European Atherosclerosis Society. Eur 2. Humphries SE, Cooper JA, Seed M, et al. Coronary heart disease mor- Heart J. 2013;34(45):3478–3490. tality in treated familial hypercholesterolaemia: update of the UK 15. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACV- Simon Broome FH register. Atherosclerosis. 2018;274:41–46. PR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guide- 3. Saltijeral A, Perez de Isla L, Alonso R, et al. Attainment of LDL line on the management of blood cholesterol. J Am Coll Cardiol. cholesterol treatment goals in children and adolescents with familial 2019;73:e285–e350. hypercholesterolemia. The SAFEHEART follow-up registry. Rev 16. Santos RD, Gidding SS, Hegele RA, et al. Defining severe familial hy- Esp Cardiol (Engl Ed). 2017;70(6):444–450. percholesterolaemia and the implications for clinical management: a 4. Perez De Isla L, Alonso R, Watts GF, et al. Attainment of LDL- consensus statement from the International Atherosclerosis Society cholesterol treatment goals in patients with familial hypercholesterole- Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endo- mia: 5-year SAFEHEART registry follow-up. J Am Coll Cardiol. crinol. 2016;4(10):850–861. 2016;67(11):1278–1285. 17. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to 5. Kindt I, Mata P, Knowles JW. The role of registries and genetic data- statin therapy after acute coronary syndromes. N Engl J Med. 2015; bases in familial hypercholesterolemia. Curr Opin Lipidol. 2017; 372(25):2387–2397. 28(2):152–160. 18. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive 6. Mata P, Alonso R, Perez de Isla L. Atherosclerotic cardiovascular dis- statin regimens on progression of coronary disease. N Engl J Med. ease risk assessment in familial hypercholesterolemia. Curr Opin Lip- 2011;365(22):2078–2087. idol. 2018;29(6):445–452. 19. Nicholls SJ, Hsu A, Wolski K, et al. Intravascular ultrasound-derived 7. Mata N, Alonso R, Badimon L, et al. Clinical characteristics and eval- measures of coronary atherosclerotic plaque burden and clinical uation of LDL-cholesterol treatment of the Spanish Familial Hyper- outcome. J Am Coll Cardiol. 2010;55(21):2399–2407. cholesterolemia Longitudinal Cohort Study (SAFEHEART). Lipids 20. Thondapu V, Kurihara O, Yonetsu T, et al. Comparison of rosuvastatin Health Dis. 2011;10(1):94. versus atorvastatin for coronary plaque stabilization. Am J Cardiol. 8. Ellis KL, Perez de Isla L, Alonso R, Fuentes F, Watts GF, Mata P. 2019;123(10):1565–1571. Value of measuring lipoprotein(a) during cascade testing for familial 21. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. hypercholesterolemia. J Am Coll Cardiol. 2019;73(9):1029–1039. Circulation. 2004;109(23_suppl_1):III39–III43.  Klabnık A, et al. Treatment pattern of familial 22. Vohnout B, Fabryova L, 9. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guide- lines for the management of dyslipidaemias. Eur Heart J. 2016; hypercholesterolemia in Slovakia: Targets, treatment and obstacles in 37(39):2999–3058. common practice. Atherosclerosis. 2018;277:323–326. 10. Perez de Isla L, Alonso R, Mata N, et al. Predicting cardiovascular 23. Perez de Isla L, Ray KK, Watts GF, et al. Potential utility of the SAFE- events in familial hypercholesterolemia: the SAFEHEART registry HEART risk equation for rationalising the use of PCSK9 monoclonal (Spanish Familial Hypercholesterolemia Cohort Study). Circulation. antibodies in adults with heterozygous familial hypercholesterolemia. 2017;135(22):2133–2144. Atherosclerosis. 2019;286:40–45. 11. Bourbon M, Alves AC, Alonso R, et al. Mutational analysis and 24. Lazaro P, Perez de Isla L, Watts GF, et al. Cost-effectiveness of a genotype-phenotype relation in familial hypercholesterolemia: the cascade screening program for the early detection of familial hyper- SAFEHEART registry. Atherosclerosis. 2017;262:8–13. cholesterolemia. J Clin Lipidol. 2017;11(1):260–271.