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Long-term effect of 2 intensive statin regimens on treatment and incidence of cardiovascular events in familial hypercholesterolemia: The SAFEHEART study

Open AccessPublished:October 11, 2019DOI:https://doi.org/10.1016/j.jacl.2019.10.005

      Highlights

      • This study analyzes event rates of 2 high-potency statins in FH.
      • LDL-C goal attainment and risk were similar in both groups.
      • LDL-C reduction was greater with rosuvastatin. Events were similar in both groups.
      • Event rate was 1.1/100 patient-years with atorvastatin and 1.2 with rosuvastatin.

      Background

      Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH.

      Objectives

      The objectives of the study were to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (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 differences 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 = .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 = .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.

      Keywords

      Introduction

      Heterozygous familial hypercholesterolemia (FH) is a codominant autosomal disorder with a prevalence around 1:250 cases worldwide, making it by far the most common genetic condition causing premature morbidity and mortality from atherosclerotic cardiovascular disease.
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • et al.
      The Agenda for Familial Hypercholesterolemia: a scientific statement from the American Heart Association.
      Although lipid-lowering therapy (LLT) has shown a reduction in coronary and total mortality in patients with FH and LLT has improved in recent years, most patients with FH do not reach an optimal therapeutic level of low-density lipoprotein cholesterol (LDL-C) and, therefore, continue to have a high risk of premature atherosclerotic cardiovascular events (ACVEs).
      • Humphries S.E.
      • Cooper J.A.
      • Seed M.
      • et al.
      Coronary heart disease mortality in treated familial hypercholesterolaemia: update of the UK Simon Broome FH register.
      • Saltijeral A.
      • Pérez de Isla L.
      • Alonso R.
      • et al.
      Attainment of LDL cholesterol treatment goals in children and adolescents with familial hypercholesterolemia. The SAFEHEART follow-up registry.
      • Perez De Isla L.
      • Alonso R.
      • Watts G.F.
      • et al.
      Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
      Little is known about the use of different statins and the achievement of LDL-C goals in patients with FH. National registries are a valuable source to provide this key information, necessary to improve models of health care, family cascade screening, the education of physicians and patients, and to help define priorities in therapeutic guidelines and health planning policies.
      • Kindt I.
      • Mata P.
      • Knowles J.W.
      The role of registries and genetic databases in familial hypercholesterolemia.
      ,
      • Mata P.
      • Alonso R.
      • Pérez de Isla L.
      Atherosclerotic cardiovascular disease risk assessment in familial hypercholesterolemia.
      The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study), a national registry of patients with FH was designed to improve the knowledge of this disease in Spain.
      • Mata N.
      • Alonso R.
      • Badimón L.
      • et al.
      Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART).
      ,
      • Ellis K.L.
      • Pérez de Isla L.
      • Alonso R.
      • Fuentes F.
      • Watts G.F.
      • Mata P.
      Value of measuring lipoprotein(a) during cascade testing for familial hypercholesterolemia.
      The objective of this study was to describe the changes in the treatment and achievement of LDL-C goals with potent statins such as atorvastatin (ATV) and rosuvastatin (RV) used alone or in combination with Ezetimibe in the SAFEHEART cohort from inclusion until the last follow-up, as well as to analyze the incidence of cardiovascular events and changes in the estimated risk in the FH population treated with 2 intensive statin regimens.

      Methods

      Design and population

      SAFEHEART is a prospective nationwide cohort study, open, multicentric with long-term protocolized follow-up in a molecularly defined FH population with participation from primary and specialized care.
      • Mata N.
      • Alonso R.
      • Badimón L.
      • et al.
      Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART).
      The recruitment of families with FH began in 2004 and the end date for reporting events was January 2019. This study was approved by the ethics committee of the Fundación Jiménez Díaz Hospital in Madrid and all the subjects gave their written informed consent. The objectives of treatment were defined according to the hyperlipidemia guidelines.
      • Catapano A.L.
      • Graham I.
      • De Backer G.
      • et al.
      2016 ESC/EAS guidelines for the management of dyslipidaemias.
      These guidelines were used to inform, educate, and train participating physicians and include patients and families in this registry.
      The coordinating center of the SAFEHEART study managed the follow-up of the patients. The patients were contacted on a yearly basis by using a standardized telephone survey to obtain relevant changes in life habits, medication, and the appearance of cardiovascular events. The definitions of previous and incident ACVEs have been previously reported.
      • Pérez de Isla L.
      • Alonso R.
      • Mata N.
      • et al.
      Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study).

      Variables

      In addition to the aforementioned demographic and clinical variables, age, classic cardiovascular risk factors, physical examination, and LLT were included. The lipid profiles were determined in venous blood samples in a centralized laboratory.
      • Mata N.
      • Alonso R.
      • Badimón L.
      • et al.
      Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART).
      The serum concentration of LDL-C was calculated using the Friedewald formula. The DNA was isolated from whole blood using standard methods, and the genetic diagnosis of FH was performed as previously described.
      • Bourbon M.
      • Alves A.C.
      • Alonso R.
      • et al.
      Mutational analysis and genotype-phenotype relation in familial hypercholesterolemia: the SAFEHEART registry.
      Cardiovascular risk was defined by the SAFEHEART risk equation (SAFEHEART-RE).
      • Pérez de Isla L.
      • Alonso R.
      • Mata N.
      • et al.
      Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study).
      The classification of LLT was defined as previously reported
      • Perez De Isla L.
      • Alonso R.
      • Watts G.F.
      • et al.
      Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
      : maximal statin dose as ATV 40 to 80 mg/d or RV 20 to 40 mg/d which was considered high-intensity statin doses; maximal combined therapy as maximal statin dose plus ezetimibe 10 mg/d; and maximal LLT as any LLT expected to produce at least a 50% reduction in LDL-C baseline levels. The classification of LLT intensity, in terms of potency, has been previously reported.
      • Penning-van Beest F.J.A.
      • Termorshuizen F.
      • Goettsch W.G.
      • Klungel O.H.
      • Kastelein J.J.P.
      • Herings R.M.C.
      Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study.
      ,
      • Masana L.
      • Ibarretxe D.
      • Plana N.
      Maximum low-density lipoprotein cholesterol lowering capacity achievable with drug combinations. When 50 plus 20 equals 60.
      Incident ACVEs during follow-up was defined as the occurrence after enrollment of the first one of the following: fatal or nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, coronary revascularization, peripheral artery revascularization, and cardiovascular death (any death related to cardiovascular disease or derived of cardiovascular therapeutic procedures not described in the previous definitions).

      Statistical analysis

      The statistical analysis was carried out with the STATA program, version 12.0 (Stata Corporation, College Station, TX). A descriptive analysis was carried out to report the number of cases and percentages for the qualitative variables, the mean, and the standard deviation for the quantitative variables that followed a normal distribution and the median and interquartile range for the quantitative variables that did not follow a normal distribution. Comparisons of proportions between the qualitative variables were carried out using the chi square test and the binomial test to compare the proportion observed in each treatment group with the value of the total population. The mean comparisons of the quantitative variables were analyzed with the Student's t-test for independent data, and the medians comparisons were analyzed with the Mann-Whitney U-test for independent data. The incidence rate of cardiovascular events was calculated as the quotient in which the numerator is the number of observed events and the denominator is the time at risk for the event. The time at risk was the sum of the follow-up time of patients who do not have an event plus the sum of the time until the event appears in the patients in which the event occurs. The incidence rate was expressed as the number of events per 100 patient-years. A value of P < .05 was considered statistically significant.

      Results

      A total of 4870 subjects were enrolled, 3601 with genetic diagnosis of FH and 1269 nonaffected relatives. The analysis in this study was made with 1939 patients with FH, after excluding homozygous subjects, younger than 18 years, without complete follow-up, those who did not receive LLT at the last follow-up, took a statin different from ATV or RV, or were in treatment with inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) (Fig. 1). The median follow-up time was 6.6 years (5–10 years). Three hundred patients changed during the follow-up from ATV to RV and 46 patients from RV to ATV. All of them were treated with the last drug until the last contact and always, continuously, for more than half of the follow-up.
      Figure thumbnail gr1
      Figure 1Flow 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.
      The main characteristics of the cohort are described in Table 1. It is interesting to point out that only statistically significant differences were found between the ATV group and the RV group in the following variables: use of statins at maximum dose (71% and 81% in the ATV and RV groups, respectively, P < .001), use of added ezetimibe (65% and 77% in the ATV and RV groups, respectively, P < .001), use of maximum combined treatment (53% and 66% in the ATV and RV groups, respectively, P < .001), and maximum LLT (88% and 81% in the ATV and RV groups, respectively, P < .001). Likewise, 505 patients in the ATV group (47%) and 252 in the RV group (29%) were managed in primary care (P < .001). Regarding the lipid parameters, statistically significant differences were found in LDL-C levels [128 mg/dL (107–152) and 123 mg/dL (104–146) in the ATV and RV groups, respectively; P < .005] and TG levels [82 mg/dL (64–116) and 93 mg/dL (70–129) in the ATV and RV groups, respectively; P < .001].
      Table 1Characteristics of the SAFEHEART population treated with ATV or RV in the last follow-up
      Qualitative variables; n (%)TotalATVRVP
      n19391065874<.001
      Gender (male)890508 (48)382 (44).08
      ACVEs at enrollment232134 (13)98 (11).35
      Nonfatal ACVEs in follow-up12861 (6)67 (8).09
      Fatal ACVEs in follow-up4228 (3)14 (2).12
      Fatal or nonfatal ACVEs in follow-up16083 (8)77 (9).42
      ACVEs at enrollment or during follow-up311168 (16)143 (16).73
      Diabetes mellitus16093 (9)67 (8).39
      Hypertension432237 (22)195 (22).97
      Active smoking291160 (15)131 (15).98
      Maximal statin dose1460755 (71)705 (81)<.001
      Ezetimibe1367692 (65)675 (77)<.001
      Maximal combined therapy1135561 (53)574 (66)<.001
      Maximum lipid-lowering therapy1647942 (88)705 (81)<.001
      Patients in primary prevention1628897 (84)731 (84).7
      Patients in secondary prevention281148 (14)133 (15).5
      LDL-C<100 mg/dL in patients in primary prevention274140 (16)134 (18).14
      LDL-C<70 mg/dL in patients in secondary prevention136 (4)7 (5).56
      Patients managed in primary care757505 (47)252 (29)<.001
      Quantitative variables; median (IQR)
      Age (y)54 (42–65)54 (42–66)54 (43–65).70
      BMI Kg/m225.8 (23–29)25.7 (23–28)26.1 (23–29).07
      Total cholesterol mg/dL198 (176–225)200 (177–227)197 (176–222).12
      LDL-C mg/dL125 (106–148)128 (107–152)123 (104–146)<.005
      HDL-C mg/dL51 (43–61)51 (43–61)51 (44–60).95
      TG mg/dL86 (67–121)82 (64–116)93 (70–129)<.001
      Years on statin treatment18 (13–26)18 (13–26)18 (13–26).71
      Years on Ezetimibe treatment
      Only patients 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.
      Figure 2 shows the evolution between the time of enrollment in the SAFEHEART study and the time of the last follow-up in the ATV or RV treatment in the studied cohort. It is important to highlight the considerable change that all monotherapies and combined therapies have undergone, highlighting the very important numerical increase of patients treated with coadministration of RV and ezetimibe: 200 patients at the time of enrollment (10%) and 675 patients at the time of the last follow-up (35%) (P < .001).
      Figure thumbnail gr2
      Figure 2Changes in the treatment with ATV or RV in the SAFEHEART registry. ATV, atorvastatin; EZ, ezetimibe; RV, rosuvastatin; Tot, total.
      Table 2 shows the potency of lipid-lowering treatment used at inclusion and at the time of the last follow-up in the ATV and RV groups expressed in potency terms. Although the potency of the treatment in this population did not strictly follow a normal distribution and, therefore, was expressed as a median, values are given here as means because it may be more informative. In both groups, the potency increased during the follow-up, going from 6.7 ± 1.6 to 7.1 ± 1.4 in the ATV group (P < .001) and from 6.9 ± 1.4 to 7.5 ± 1.2 in the RV group (P < .001).
      Table 2Classification of lipid-lowering treatment by potency
      Lipid-lowering therapy potency has been calculated according the method described in the study by Penning-van Beest et al12 modified by Masana et al.13 As a reference point, the potency of atorvastatin 40 mg is 6.
      (mean ± SD)
      PotencyTotalATVRVP
      Potency at enrollment6.8 ± 1.56.7 ± 1.67.1 ± 1.4<.001
      Potency at follow-up7.2 ± 1.46.9 ± 1.47.5 ± 1.2<.001
      ATV, atorvastatin group; RV, rosuvastatin group.
      Lipid-lowering therapy potency has been calculated according the method described in the study by Penning-van Beest et al
      • Penning-van Beest F.J.A.
      • Termorshuizen F.
      • Goettsch W.G.
      • Klungel O.H.
      • Kastelein J.J.P.
      • Herings R.M.C.
      Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study.
      modified by Masana et al.
      • Masana L.
      • Ibarretxe D.
      • Plana N.
      Maximum low-density lipoprotein cholesterol lowering capacity achievable with drug combinations. When 50 plus 20 equals 60.
      As a reference point, the potency of atorvastatin 40 mg is 6.
      Regarding the risk of developing a cardiovascular event estimated by the SAFEHEART-RE, Table 3 shows how in the inclusion, the estimated 10-year risk was 1.61 (0.67–3.39) and 1.22 (0.54–2.93) in the groups ATV and RV, respectively (P < .001), meaning there were no significant differences between the 2 groups at the time of the last follow-up: 1.29 (0.54–2.82) and 1.22 (0.54–2.76) in the ATV and RV groups, respectively (P = .51).
      Table 3Ten-year cardiovascular risk in the SAFEHEART cohort with ATV/RV
      RiskTotalATVRVP
      Ten-year SAFEHEART-RE risk at enrollment1.54 (0.64–3.39)1.61 (0.67–3.39)1.22 (0.54–2.93)<.001
      Ten-year SAFEHEART-RE risk at follow-up1.27 (0.54–2.76)1.29 (0.54–2.82)1.22 (0.54–2.76).51
      ATV, atorvastatin group; RV, rosuvastatin group; SAFEHEART-RE, SAFEHEART risk equation; IQR, interquartile range.
      Median (IQR).
      Regarding the achievement of LDL-C goals, 16% of patients in primary prevention in the ATV group and 18% in the RV group achieved an LDL-C <100 mg/dL and 4% in secondary prevention in the ATV group and 5% in the RV group achieved an LDL-C <70 mg/dL. Figure 3 shows the achievement of objectives in LDL-C. Nevertheless, there was an increase during follow-up in the percentage of subjects without ACVEs who reached an LDL-C under 115 and 130 mg/dL, respectively, and the increase was significant in the RV group compared with the ATV group (P < .05).
      Figure thumbnail gr3
      Figure 3Goal achievement for different LDL cholesterol thresholds in FH patients with and without atherosclerotic cardiovascular disease in the atorvastatin and rosuvastatin groups. CVD (+): Patient who had a history of atherosclerotic cardiovascular disease; CVD (−): patient without history of atherosclerotic cardiovascular disease. LDL-C, low-density lipoprotein cholesterol; FH, familial hypercholesterolemia; CVD, cardiovascular disease.
      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 = .58). Figure 4 shows the survival curves in both treatment groups for incident ACVEs.
      Figure thumbnail gr4
      Figure 4Survival curves for incident ACVEs in both treatment groups. ACVEs, atherosclerotic cardiovascular events.

      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 study analyzing the incidence of fatal and nonfatal cardiovascular events. It is well known that lipid-lowering treatment with high-potency statins in FH lowers LDL-C levels, a fact that is associated with a reduction in the incidence of cardiovascular events.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      A strong recommendation for the use of high-intensity statins
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • et al.
      2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
      and combined therapy with ezetimibe should be established in patients with FH,
      • Santos R.D.
      • Gidding S.S.
      • Hegele R.A.
      • et al.
      Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.
      with the use of ezetimibe now being well supported by IMPROVE-IT.
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      As the results of the present study show, although the reduction in LDL-C levels is greater in the group treated with RV than in the group treated with ATV, the incidence of fatal and nonfatal cardiovascular events is similar in both groups.
      In parallel with the findings of a study comparing the efficacy of both statins to reduce the progression of coronary atherosclerosis
      • Nicholls S.J.
      • Ballantyne C.M.
      • Barter P.J.
      • et al.
      Effect of two intensive statin regimens on progression of coronary disease.
      and in which no significant differences were found between the 2 drugs, no differences were found in the present study when the incidence rate of cardiovascular events was analyzed. It is well known that the burden of coronary atherosclerosis is directly and proportionately related to the incidence of cardiovascular events, including coronary events.
      • Nicholls S.J.
      • Hsu A.
      • Wolski K.
      • et al.
      Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
      This parallelism between the burden of atherosclerosis and cardiovascular events reinforces the plausibility of the findings of our study, which align with the findings of the aforementioned study. However, another recent study shows that although RV and ATV at doses of 10 and 20 mg, respectively, obtained similar reductions in LDL-C levels, RV showed that it was able to improve earlier and more robustly than ATV the image parameters related to the stability of the atherosclerosis plaques. Nevertheless, both statins significantly reduced the atheroma volume.
      • Thondapu V.
      • Kurihara O.
      • Yonetsu T.
      • et al.
      Comparison of rosuvastatin versus atorvastatin for coronary plaque stabilization.
      Statins, in addition to their lipid-lowering potency, have several effects independent of their lipid-lowering effect, the so-called pleiotropic effects.
      • Davignon J.
      Beneficial cardiovascular pleiotropic effects of statins.
      One of these pleiotropic effects is its ability to stabilize atherosclerosis plaques, thus preventing its rupture and the appearance of subsequent cardiovascular events. Most acute coronary syndromes are secondary to the rupture of vulnerable atherosclerotic plaques. After the instabilization of an atherosclerotic plaque, a process of healing or stabilization arises. However, until this study, it was not known if there are statins that favor more than others this stabilization of the atherosclerotic plaque.
      It is important to emphasize that although more than 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 LDL-C in patients with FH as they usually have high baseline LDL-C levels.
      • Santos R.D.
      • Gidding S.S.
      • Hegele R.A.
      • et al.
      Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.
      ,
      • Vohnout B.
      • Fábryová Ľ.
      • Klabník A.
      • et al.
      Treatment pattern of familial hypercholesterolemia in Slovakia: Targets, treatment and obstacles in common practice.
      However, although the targets are not fully achieved in many patients, we can affirm that their control has improved with respect to previous data from the same cohort.
      • Perez De Isla L.
      • Alonso R.
      • Watts G.F.
      • et al.
      Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
      These results depict that a considerable number of patients with FH may be candidates to receive new medications, such as PCSK9 inhibitors. With reference to this aspect, we have recently shown that the application of SAFEHEART-RE can help make a better selection of patients with FH for the use of PCSK9 inhibitors to improve the cost-effectiveness of its use.
      • Pérez de Isla L.
      • Ray K.K.
      • Watts G.F.
      • et al.
      Potential utility of the SAFEHEART risk equation for rationalising the use of PCSK9 monoclonal antibodies in adults with heterozygous familial hypercholesterolemia.
      Effective lipid-lowering therapies with statins and ezetimibe are now available as generic medications. A point of special consideration is that RV was marketed in September 2009 (ATV in October 1997) in Spain and therefore takes longer to be available as generic. Despite this delay in its availability, we can observe that the use of RV has increased considerably in patients with FH, especially in those who are managed in the specialized health care system. Furthermore, a recent study concerning cost-effectiveness of LLT in patients with FH involved in a national detection program has shown that the use of ATV and RV with or without ezetimibe is cost-effective.
      • Lázaro P.
      • Pérez de Isla L.
      • Watts G.F.
      • et al.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      When applying the SAFEHEART-RE equation to the patients analyzed at the time of their enrollment in the SAFEHEART registry and at the time of the last follow-up, no significant differences were found in the estimated risk reduction between these 2 moments between the group that used ATV and the group that used RV.
      The strengths and limitations of our study merit to be taken into account. The SAFEHEART study is a nationwide, long-term prospective contemporary cohort of a molecularly defined FH population. This fact makes these results as a reference because of the lack of other cohorts of similar characteristics and similar follow-up around the world. Nevertheless, the 2 groups considered for this study 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 have been favored for patients perceived by physicians to be at higher risk. This fact could be reflected in the greater use of RV in referral practice as compared to primary care. Another major limitation is the very small differences in LDL-C level and in risk of ACVEs between the ATV and RV groups that raise the possibility that unaccounted confounders and limited statistical power could explain the lack of differences in ACVEs.

      Conclusion

      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 beginning 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., and P.M. contributed to patients' enrollment and follow-up, research development, statistical analysis, manuscript writing, and manuscript review. D.Z., F.F., J.F.S.M-T, J.D.M., A.G.E., J.P.M-G., R.d.A., M.M., D.M., J.M.C., L.S., M.A.B-R., R.A., P.A.B., A.M., M.J.R.J., and J.G-C. contributed to patients' enrollment and follow-up, research development, manuscript writing, and manuscript review.

      References

        • Gidding S.S.
        • Champagne M.A.
        • de Ferranti S.D.
        • et al.
        The Agenda for Familial Hypercholesterolemia: a scientific statement from the American Heart Association.
        Circulation. 2015; 132: 2167-2192
        • Humphries S.E.
        • Cooper J.A.
        • Seed M.
        • et al.
        Coronary heart disease mortality in treated familial hypercholesterolaemia: update of the UK Simon Broome FH register.
        Atherosclerosis. 2018; 274: 41-46
        • Saltijeral A.
        • Pérez de Isla L.
        • Alonso R.
        • et al.
        Attainment of LDL cholesterol treatment goals in children and adolescents with familial hypercholesterolemia. The SAFEHEART follow-up registry.
        Rev Esp Cardiol (Engl Ed). 2017; 70: 444-450
        • Perez De Isla L.
        • Alonso R.
        • Watts G.F.
        • et al.
        Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
        J Am Coll Cardiol. 2016; 67: 1278-1285
        • Kindt I.
        • Mata P.
        • Knowles J.W.
        The role of registries and genetic databases in familial hypercholesterolemia.
        Curr Opin Lipidol. 2017; 28: 152-160
        • Mata P.
        • Alonso R.
        • Pérez de Isla L.
        Atherosclerotic cardiovascular disease risk assessment in familial hypercholesterolemia.
        Curr Opin Lipidol. 2018; 29: 445-452
        • Mata N.
        • Alonso R.
        • Badimón L.
        • et al.
        Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART).
        Lipids Health Dis. 2011; 10: 94
        • Ellis K.L.
        • Pérez de Isla L.
        • Alonso R.
        • Fuentes F.
        • Watts G.F.
        • Mata P.
        Value of measuring lipoprotein(a) during cascade testing for familial hypercholesterolemia.
        J Am Coll Cardiol. 2019; 73: 1029-1039
        • Catapano A.L.
        • Graham I.
        • De Backer G.
        • et al.
        2016 ESC/EAS guidelines for the management of dyslipidaemias.
        Eur Heart J. 2016; 37: 2999-3058
        • Pérez de Isla L.
        • Alonso R.
        • Mata N.
        • et al.
        Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study).
        Circulation. 2017; 135: 2133-2144
        • Bourbon M.
        • Alves A.C.
        • Alonso R.
        • et al.
        Mutational analysis and genotype-phenotype relation in familial hypercholesterolemia: the SAFEHEART registry.
        Atherosclerosis. 2017; 262: 8-13
        • Penning-van Beest F.J.A.
        • Termorshuizen F.
        • Goettsch W.G.
        • Klungel O.H.
        • Kastelein J.J.P.
        • Herings R.M.C.
        Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study.
        Eur Heart J. 2007; 28: 154-159
        • Masana L.
        • Ibarretxe D.
        • Plana N.
        Maximum low-density lipoprotein cholesterol lowering capacity achievable with drug combinations. When 50 plus 20 equals 60.
        Rev Esp Cardiol (Engl Ed). 2016; 69: 342-343
        • Nordestgaard B.G.
        • Chapman M.J.
        • Humphries S.E.
        • et al.
        Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
        Eur Heart J. 2013; 34: 3478-3490
        • Grundy S.M.
        • Stone N.J.
        • Bailey A.L.
        • et al.
        2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol.
        J Am Coll Cardiol. 2019; 73: e285-e350
        • Santos R.D.
        • Gidding S.S.
        • Hegele R.A.
        • et al.
        Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.
        Lancet Diabetes Endocrinol. 2016; 4: 850-861
        • Cannon C.P.
        • Blazing M.A.
        • Giugliano R.P.
        • et al.
        Ezetimibe added to statin therapy after acute coronary syndromes.
        N Engl J Med. 2015; 372: 2387-2397
        • Nicholls S.J.
        • Ballantyne C.M.
        • Barter P.J.
        • et al.
        Effect of two intensive statin regimens on progression of coronary disease.
        N Engl J Med. 2011; 365: 2078-2087
        • Nicholls S.J.
        • Hsu A.
        • Wolski K.
        • et al.
        Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
        J Am Coll Cardiol. 2010; 55: 2399-2407
        • Thondapu V.
        • Kurihara O.
        • Yonetsu T.
        • et al.
        Comparison of rosuvastatin versus atorvastatin for coronary plaque stabilization.
        Am J Cardiol. 2019; 123: 1565-1571
        • Davignon J.
        Beneficial cardiovascular pleiotropic effects of statins.
        Circulation. 2004; 109: III39-III43
        • Vohnout B.
        • Fábryová Ľ.
        • Klabník A.
        • et al.
        Treatment pattern of familial hypercholesterolemia in Slovakia: Targets, treatment and obstacles in common practice.
        Atherosclerosis. 2018; 277: 323-326
        • Pérez de Isla L.
        • Ray K.K.
        • Watts G.F.
        • et al.
        Potential utility of the SAFEHEART risk equation for rationalising the use of PCSK9 monoclonal antibodies in adults with heterozygous familial hypercholesterolemia.
        Atherosclerosis. 2019; 286: 40-45
        • Lázaro P.
        • Pérez de Isla L.
        • Watts G.F.
        • et al.
        Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
        J Clin Lipidol. 2017; 11: 260-271