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Long-term persistence with evolocumab treatment and sustained reductions in LDL-cholesterol levels over 30 months: Final results from the European observational HEYMANS study

Open AccessPublished:January 12, 2023DOI:https://doi.org/10.1016/j.atherosclerosis.2023.01.002

      Highlights

      • Data from the HEYMANS registry were used to assess the use of evolocumab over time.
      • Evolocumab was associated with sustained LDL-C reductions for up to 30 months.
      • Evolocumab was associated with an approximately 60% reduction in LDL-C levels.
      • Over 90% of patients continued receiving evolocumab at 12 months and 30 months.
      • Consistent reductions in LDL-C were achieved with evolocumab in clinical practice.

      Abstract

      Background and aims

      Variability in low-density lipoprotein-cholesterol (LDL-C) level control at a population level is associated with poor cardiovascular outcomes. Limited data exist on LDL-C level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. Using data from the HEYMANS registry, this analysis aimed to assess evolocumab persistence and discontinuation over 30 months of evolocumab treatment and to evaluate at a population level the variability in LDL-C level reductions during the study period.

      Methods

      HEYMANS was a prospective registry of adults initiating evolocumab in routine clinical practice in 12 European countries. Data were collected for up to and including 6 months before evolocumab initiation and up to 30 months after. Evolocumab discontinuation was analysed for two time periods: 0–12 months and 12–30 months.

      Results

      In total, 1951 patients were included in the study. The median reduction in LDL-C levels was 58% within 3 months after evolocumab initiation; this reduction was maintained over 30 months. More than 90% of patients continued receiving evolocumab at 12 months and 30 months of follow-up. Of patients with an LDL-C level measurement during follow-up, approximately 85% achieved a ≥30% reduction from baseline at each follow-up visit and approximately 60% achieved a ≥50% reduction.

      Conclusions

      Evolocumab therapy was associated with sustained LDL-C level reductions up to 30 months, and persistence with evolocumab remained high, both at 12 and 30 months. Expanding the use of monoclonal antibodies such as evolocumab could provide improvements in LDL-C level control at a population level in European clinical practice.

      Graphical abstract

      Keywords

      1. Introduction

      The reduction of low-density lipoprotein-cholesterol (LDL-C) levels through the use of lipid-lowering therapies (LLTs) is a key strategy in reducing the risk of cardiovascular (CV) events and preventing CV disease [
      • Catapano A.L.
      • Tokgözoğlu L.
      • Mello e Silva A.
      • et al.
      Pharmaceutical strategies for reducing LDL-C and risk of cardiovascular disease.
      ]. LDL-C levels have been established as the primary treatment target for the management of dyslipidaemia [
      • Mach F.
      • Baigent C.
      • Catapano A.L.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ,
      • Crismaru I.
      • Pantea Stoian A.
      • Bratu O.G.
      • et al.
      Low-density lipoprotein cholesterol lowering treatment: the current approach.
      ]. Accordingly, the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for dyslipidaemia management recommend that LDL-C levels should be lowered as much as possible [
      • Mach F.
      • Baigent C.
      • Catapano A.L.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ]. However, patients receiving statin monotherapy are unlikely to achieve the specific LDL-C goals proposed by the ESC/EAS [
      • Ray K.K.
      • Molemans B.
      • Schoonen W.M.
      • et al.
      EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study.
      ]. Therefore, increased use of combination LLT with ezetimibe and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be required to achieve the recommended ESC/EAS LDL-C goals [
      • Mach F.
      • Baigent C.
      • Catapano A.L.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ].
      It has been reported that variability in LDL-C level control at a population level is associated with poor CV outcomes [
      • Liu X.
      • Wu S.
      • Song Q.
      • et al.
      Visit-to-visit variability of lipid measurements and the risk of myocardial infarction and all-cause mortality: a prospective cohort study.
      ,
      • Sheng C.-S.
      • Miao Y.
      • Ding L.
      • et al.
      Prognostic significance of visit-to-visit variability, and maximum and minimum LDL cholesterol in diabetes mellitus.
      ]. Indeed, variability in LDL-C level control could be in part due to variations in patients’ adherence to treatments that are self-administered or in the response to a given therapy [
      • Nishikido T.
      • Ray K.K.
      Targeting the peptidase PCSK9 to reduce cardiovascular risk: implications for basic science and upcoming challenges.
      ]. Evolocumab, a selective PCSK9 inhibitor, was approved by the European Medicines Agency in 2015 for subcutaneous self-administration every 2 weeks or 4 weeks [
      European Medicines Agency Repatha – summary of product characteristics.
      ]. Data from clinical trials have demonstrated that evolocumab reduces LDL-C levels by approximately 60% when used either as monotherapy or as combination therapy with statins and ezetimibe [
      • Ray K.K.
      • Dhalwani N.
      • Sibartie M.
      • et al.
      Low-density lipoprotein cholesterol levels exceed the recommended European threshold for PCSK9i initiation: lessons from the HEYMANS study.
      ,
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ]. Thus, it is well established that therapies such as evolocumab significantly reduce the risk of CV events in clinical trials [
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ], but it is unknown whether they can sustain LDL-C level reductions at a population level in the real world. Furthermore, limited data are available on long-term persistence with evolocumab.
      Results from the recent interim analysis of the multi-country, multicentre, observational HEYMANS registry (NCT02770131) highlighted that more patients receiving evolocumab in combination with a LLT attained their ESC/EAS LDL-C goals than those not receiving combination therapy [
      • Ray K.K.
      • Dhalwani N.
      • Sibartie M.
      • et al.
      Low-density lipoprotein cholesterol levels exceed the recommended European threshold for PCSK9i initiation: lessons from the HEYMANS study.
      ]. Results from the interim analysis also demonstrated that LDL-C levels at evolocumab initiation were approximately three times higher than the recommended thresholds for PCSK9 inhibitor initiation. The aims of this final analysis from the HEYMANS study were: (1) to assess persistence and discontinuation over time with evolocumab treatment; and (2) to evaluate at a population level the variability in LDL-C level reductions over 30 months of evolocumab treatment.

      2. Patients and methods

      2.1 Study design

      The design of the HEYMANS study has been published previously [
      • Ray K.K.
      • Dhalwani N.
      • Sibartie M.
      • et al.
      Low-density lipoprotein cholesterol levels exceed the recommended European threshold for PCSK9i initiation: lessons from the HEYMANS study.
      ]. Briefly, HEYMANS was a prospective observational cohort study conducted in 12 European countries (Austria, Belgium, Bulgaria, Czech Republic, Germany, Greece, Italy, Portugal, Slovakia, Spain, Sweden and Switzerland). The baseline period included the data collected for up to and including 6 months before evolocumab initiation. The index date was defined as the date of the first dose of evolocumab received as part of routine clinical management. Data were collected for up to 30 months of follow-up after evolocumab initiation. The study was originally designed to have up to 12 months of follow-up. However, following a protocol amendment in February 2018, the follow-up period was extended to 30 months. Patients yet to complete 12 months of follow-up at the date of the protocol amendment were followed up for up to 30 months, until 30 June 2021. Data were collected from patient medical notes. Baseline characteristics, CV risk factors and LLT use at the time of initiation of evolocumab and at the end of each 3-month period were collected. LDL-C level measurements were collected as per clinical practice.

      2.2 Patient eligibility

      Adults aged 18 years or older who had their first prescription and received at least one dose of evolocumab as part of their clinical management after 1 August 2015 were included in the study. Patients who were enrolled in a PCSK9 inhibitor interventional study or who had received a commercially available PCSK9 inhibitor within 12 weeks before evolocumab initiation were excluded from the study.

      2.3 Outcomes

      Persistence was defined as the proportion of patients who continued to receive evolocumab and remained in the study at specified time points. Those who stopped the study before these time points but who were still receiving evolocumab were excluded from the persistence analysis. Patients were considered to have discontinued evolocumab if they permanently stopped therapy during the observation period. Evolocumab persistence was analysed separately for two time periods: 0–12 months and 12–30 months.
      For the analyses of LDL-C level response and the variability in LDL-C level reductions, median LDL-C level reductions over time in all patients with an LDL-C level measurement were assessed. The proportion of patients achieving at least a 30% or 50% reduction in LDL-C levels from baseline at each 3-month interval was also examined. Waterfall plots for 1–3, 10–12 and 28–30 months were used to illustrate the variation in LDL-C levels in patients with a baseline LDL-C level of greater than 1.8 mmol/L by displaying the on-treatment percentage change in LDL-C levels from baseline. The proportion of patients achieving at least a 2 mmol/L or 3 mmol/L reduction over time was also assessed. Finally, Sankey plots were used to illustrate the intra-patient variation in LDL-C levels over the study period. Patients were included in the intra-patient variation analysis if they had an LDL-C level measurement at each 6-month interval. No formal analysis of safety data was planned for this study. Adverse drug reactions (ADRs) were assessed for treatment-emergence, seriousness, or relationship to device. All fatal adverse events were reported.
      The proportion of patients who achieved their risk-based LDL-C goals at least once during the entire follow-up, according to the 2019 ESC/EAS guidelines, was calculated. Patients were categorised as either high CV risk, with an LDL-C goal of less than 1.8 mmol/L, or very high CV risk, with an LDL-C goal of less than 1.4 mmol/L.

      2.4 Statistical analysis

      The results of all analyses were described using summary statistics. Data were summarised as frequencies and percentages for categorical data and as mean and standard deviation (SD) or median and interquartile range (quartile [Q] 1, Q3) for continuous data. When appropriate, 95% confidence intervals of the estimates were produced. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

      2.5 Ethical conduct

      The study was performed in accordance with ethical principles that comply with the Declaration of Helsinki and were consistent with the International Council for Harmonisation guidelines. The study was reviewed by an independent ethics committee in each country. Written informed consent was provided by all patients.

      3. Results

      3.1 Clinical characteristics and LLT use

      The final analysis included data from 1951 patients across the 12 countries included in the study. Baseline and clinical characteristics are described in Table 1. The mean (SD) age was 60.0 (10.8) years. The median (Q1, Q3) baseline LDL-C level was 3.98 (3.17, 5.07) mmol/L. Most patients (85%; n = 1660) were receiving evolocumab for secondary prevention of CV disease. The majority of patients (60%; n = 1175) had a history of statin intolerance. The median study follow-up duration was 29.7 months. LLT use at initiation of evolocumab and during follow-up is described in Supplementary Fig. 1. Generally, background LLT use remained unchanged over time. At each 6-month time point after initiation, 40–44% of patients were not receiving background LLT (either a statin or ezetimibe), 28–31% of patients were receiving a statin and ezetimibe, and 11–14% of patients were receiving a statin without ezetimibe.
      Table 1Baseline and clinical characteristics of patients who initiated evolocumab.
      Overall (N = 1951)
      Female732 (38)
      Age, years, mean (SD)60 (10.8)
      LDL-C level, mmol/L, median (Q1–Q3)3.98 (3.17–5.07)
      Non-HDL-C level, mmol/L, median (Q1–Q3)4.63 (3.71–5.84)
      Hypertension1270 (65)
      Current smoker276 (14)
      Body mass index
      Body mass index measurements were not available for all patients.
       <20 kg/m254 (3)
       ≥20 kg/m2 and <30 kg/m21380 (71)
       ≥30 kg/m2485 (25)
      Type 2 diabetes mellitus375 (19)
      Chronic kidney disease138 (7)
      Statin intolerance
      Statin intolerance defined as having a history of muscle-related or non-muscle-related intolerance to any statin.
      1175 (60)
      FH
      A diagnosis of FH was based on the treating physician's assessment.
      875 (45)
      Previous CV event1660 (85)
      Previous ACS
      Previous ACS is a history of ACS, STEMI or non-STEMI.
      828 (42)
      CAD or angina
      CAD or angina is a history of CAD or stable angina.
      1140 (58)
      PAD229 (12)
      Ischaemic stroke122 (6)
      Critical limb ischaemia24 (1)
      Carotid artery disease438 (22)
      TIA52 (3)
      Coronary thrombosis
      Coronary thrombosis (acute or non-acute) is counted as one prior CV event.
      328 (17)
      ACS, acute coronary syndrome; CAD, coronary artery disease; CV, cardiovascular; FH, familial hypercholesterolaemia; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; PAD, peripheral artery disease; Q, quartile; SD, standard deviation; STEMI, ST-elevation myocardial infarction; TIA, transient ischaemic attack.
      Data are n (%) unless otherwise specified.
      a Body mass index measurements were not available for all patients.
      b Statin intolerance defined as having a history of muscle-related or non-muscle-related intolerance to any statin.
      c A diagnosis of FH was based on the treating physician's assessment.
      d Previous ACS is a history of ACS, STEMI or non-STEMI.
      e CAD or angina is a history of CAD or stable angina.
      f Coronary thrombosis (acute or non-acute) is counted as one prior CV event.

      3.2 Evolocumab discontinuation, safety and persistence

      Of the 1951 patients included in the study, 30 patients withdrew from the study before 12 months and were receiving evolocumab at the time of withdrawal; these patients were excluded from the persistence analysis (Fig. 1). Evolocumab persistence at 12 months was therefore determined for 1921 patients, of whom 1781 (93%) continued to receive evolocumab at 12 months of follow-up.
      Fig. 1
      Fig. 1Patient schema: evolocumab persistence and discontinuation during the study period.
      Data were included for patients for whom evolocumab persistence status could be ascertained at the given time point, and data were excluded for those who ended the study while still receiving evolocumab. The extended follow-up period data were based on those patients who entered the extended follow-up period, not on the overall study population.
      Following the protocol amendment, 1136 patients were eligible for the extended follow-up period. Of these, 137 patients withdrew from the study before 30 months and were receiving evolocumab at the time of withdrawal; these patients were excluded from the persistence analysis. Evolocumab persistence was therefore determined for the remaining 999 patients, of whom 921 (92%) continued to receive evolocumab at 30 months of follow-up.
      The two most common reported reasons for permanent discontinuation of evolocumab were ADRs (3%; n = 60) and patient request (3%; n = 50) (Supplementary Table 1). Of the 60 patients who discontinued evolocumab due to ADRs, the most frequent ADRs reported were arthralgia (18%; n = 11), myalgia (18%; n = 11), headache (8%; n = 5), back pain (7%; n = 4) and dizziness (7%; n = 4). The clinical characteristics of the patients who discontinued evolocumab were generally similar to those of the overall study population (Table 1 and Supplementary Table 2). Median (Q1, Q3) LDL-C levels at baseline in patients who discontinued evolocumab were 4.09 (3.28, 5.28) mmol/L (Fig. 2A). In the 4–6 months before discontinuation of evolocumab, the median LDL-C level reduction from baseline for those patients who had an LDL-C level measurement at baseline was 53%, with a corresponding absolute LDL-C level reduction of 2.21 mmol/L. At 10–12 months following discontinuation, the median LDL-C level reduction from baseline was 13%, with a corresponding absolute LDL-C level reduction of 0.41 mmol/L. This analysis is limited by a small sample size. More than 50% of patients who discontinued evolocumab were not receiving a statin or ezetimibe at discontinuation (Fig. 2B).
      Fig. 2
      Fig. 2Discontinuation outcomes.
      Median LDL-C levels (A) and LLT use (B) over time in patients who discontinued evolocumab. Not all patients had follow-up data for every time period after discontinuing evolocumab. LDL-C, low-density lipoprotein-cholesterol; LLT, lipid-lowering therapy; N/A, not applicable; Q, quartile.
      No safety concerns were identified in this study. In total 116 patients (6%) experienced a non-fatal treatment-emergent ADR, 7 patients (<1%) had an ADR which was considered serious, and 5 patients (<1%) had an ADR which was considered device-related. There were 18 (<1%) fatal treatment-emergent adverse events.

      3.3 LDL-C level response and variability during evolocumab treatment

      Data from 1771 patients with an LDL-C level measurement were available to assess the LDL-C level response and variability. A median (Q1, Q3) of 4 (2, 6) LDL-C level measurements per patient were recorded during follow-up. Median LDL-C levels at baseline and changes in LDL-C levels over time are described in Fig. 3A. The median reduction in LDL-C levels was 58% within 3 months after evolocumab initiation; this reduction was maintained up to 30 months.
      Fig. 3
      Fig. 3LDL-C level reductions over time.
      (A) Median LDL-C levels and LDL-C level reductions from baseline over time. Dashed line represents the recommended threshold LDL-C level (1.4 mmol/L) for PCSK9 inhibitor initiation in patients at very high CV risk based on clinical guidelines. (B) Proportion of patients achieving at least a 30% or 50% reduction in LDL-C levels over time. (C) Proportion of patients achieving an absolute LDL-C level reduction of 2 mmol/L or 3 mmol/L over time. CI, confidence interval; CV, cardiovascular; LDL-C, low-density lipoprotein-cholesterol; N/A, not applicable; PCSK9, proprotein convertase subtilisin/kexin type 9; Q, quartile.
      Among patients with an LDL-C level measurement at each time point summarised, approximately 85% achieved at least a 30% reduction from baseline at each follow-up visit throughout the study and approximately 60% achieved at least a 50% reduction from baseline at each visit (Fig. 3B). Patients receiving background LLT achieved a greater percentage reduction in LDL-C levels at each visit than those not receiving background LLT (Supplementary Fig. 2). The proportion of patients who achieved an LDL-C level reduction of at least 2 mmol/L or 3 mmol/L was also consistent at each visit over the 30-month period (Fig. 3C). In patients with a baseline LDL-C level greater than 1.8 mmol/L, consistent LDL-C level reductions with evolocumab were observed at 1–3, 10–12 and 28–30 months (Fig. 4A).
      Fig. 4
      Fig. 4LDL-C level variability outcomes.
      (A) On-treatment percentage change in LDL-C levels at 1–3 (i), 10–12 (ii) and 28–30 (iii) months in patients with a baseline LDL-C level greater than 1.8 mmol/L. Each line represents one patient, ordered from the least response to the best response. (B) Intra-patient variability in LDL-C levelsa. aPatients with an LDL-C level measurement at each 6-month window were included. Not all patients had an LDL-C level measurement for every 6-month period. LDL-C, low-density lipoprotein-cholesterol.
      A small subset of the overall population (n = 297) had data available to assess intra-patient variability in LDL-C levels (i.e. had a baseline LDL-C and at least one LDL-C value available within each 6 month period up to and including months 25–30) (Fig. 4B). Most patients had an LDL-C level of at least 2.6 mmol/L at baseline; at 6 months, the majority of patients’ LDL-C levels decreased to less than 1.8 mmol/L. Overall, LDL-C levels were consistent over the study period, with minimal variability at each visit.

      3.4 ESC/EAS LDL-C goal attainment

      Overall, 56% of patients at high CV risk (n = 130) according to the ESC/EAS guidelines achieved the goal of an LDL-C level of less than 1.8 mmol/L, and 60% of patients at very high CV risk (n = 1680) according to the ESC/EAS guidelines achieved the goal of an LDL-C level of less than 1.4 mmol/L (Supplementary Fig. 3). In both risk groups, goal attainment was higher for patients receiving background LLT than for those not receiving background LLT.
      The proportion of patients who achieved an LDL-C level of less than 1.4 mmol/L or less than 1.8 mmol/L at each follow-up was largely consistent over the study period. The proportion of patients achieving these LDL-C levels was consistently higher in those receiving background LLT than in those not receiving background LLT (Supplementary Fig. 4).

      4. Discussion

      In this real-world study, which was representative of European clinical practice, evolocumab therapy, as prescribed per current reimbursement criteria in each country, was associated with sustained LDL-C level reductions for up to 30 months, and persistence with evolocumab remained high, both at 12 months and 30 months of follow-up. Within 3 months after treatment initiation, evolocumab was associated with reduction of approximately 60% in LDL-C levels that was maintained throughout the study. Among patients with an LDL-C level measurement during follow-up at each time point summarised, approximately 85% achieved at least a 30% reduction from baseline, with approximately 60% achieving at least a 50% reduction from baseline. These data highlight that consistent and sustained reductions in LDL-C levels are achieved with the use of evolocumab in routine clinical practice.
      It is probable that the sustained effects on LDL-C levels observed in this study are in part due to the high rates of persistence with evolocumab. The results of previous studies have shown that adherence to and persistence with some LLTs, such as statins, are low, which can adversely affect clinical outcomes and have implications for CV risk [
      • Toth P.P.
      • Granowitz C.
      • Hull M.
      • et al.
      Long-term statin persistence is poor among high-risk patients with dyslipidemia: a real-world administrative claims analysis.
      ]. Importantly, self-administration of evolocumab has been shown to be both feasible and acceptable in the at-home setting [
      • Dent R.
      • Joshi R.
      • Stephen Djedjos C.
      • et al.
      Evolocumab lowers LDL-C safely and effectively when self-administered in the at-home setting.
      ], with high treatment persistence observed [
      • Gupta M.
      • Mancini G.B.J.
      • Wani R.J.
      • et al.
      Real-world insights into evolocumab use in patients with hyperlipidemia: Canadian analysis from the ZERBINI study.
      ]. Real-world data have shown persistence with PCSK9 inhibitors to be high [
      • Gupta M.
      • Mancini G.B.J.
      • Wani R.J.
      • et al.
      Real-world insights into evolocumab use in patients with hyperlipidemia: Canadian analysis from the ZERBINI study.
      ,
      • Cannon C.P.
      • de Lemos J.A.
      • Rosenson R.S.
      • et al.
      Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients with atherosclerotic cardiovascular disease in the US.
      ]; in the prospective, observational GOULD study, 92% of the patients continued to receive PCSK9 inhibitors after 2 years [
      • Cannon C.P.
      • de Lemos J.A.
      • Rosenson R.S.
      • et al.
      Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients with atherosclerotic cardiovascular disease in the US.
      ]. Similarly, in the prospective, observational ZERBINI study, persistence with evolocumab was also reported to be 92% after 12 months [
      • Gupta M.
      • Mancini G.B.J.
      • Wani R.J.
      • et al.
      Real-world insights into evolocumab use in patients with hyperlipidemia: Canadian analysis from the ZERBINI study.
      ]. Some studies have reported persistence rates of approximately 60% after 6 months or 12 months [
      • Hines D.M.
      • Rane P.
      • Patel J.
      • et al.
      Treatment patterns and patient characteristics among early initiators of PCSK9 inhibitors.
      ,
      • Zafrir B.
      • Egbaria A.
      • Stein N.
      • et al.
      PCSK9 inhibition in clinical practice: treatment patterns and attainment of lipid goals in a large health maintenance organization.
      ]; however, these lower persistence rates may have been due to access issues or reauthorisation challenges in these studies [
      • Hines D.M.
      • Rane P.
      • Patel J.
      • et al.
      Treatment patterns and patient characteristics among early initiators of PCSK9 inhibitors.
      ,
      • Zafrir B.
      • Egbaria A.
      • Stein N.
      • et al.
      PCSK9 inhibition in clinical practice: treatment patterns and attainment of lipid goals in a large health maintenance organization.
      ]. Of note, in Zafrir et al., over half of patients who discontinued PCSK9 inhibitor therapy reinitiated treatment over the 3-year follow-up period [
      • Zafrir B.
      • Egbaria A.
      • Stein N.
      • et al.
      PCSK9 inhibition in clinical practice: treatment patterns and attainment of lipid goals in a large health maintenance organization.
      ].
      To our knowledge, the HEYMANS study is currently the largest data set with long-term persistence data for patients receiving evolocumab in clinical practice, and the results demonstrate high, long-term persistence with evolocumab. Notably, for patients who discontinued evolocumab, median LDL-C levels returned close to baseline after 12 months following discontinuation, with no rebound effect observed; these findings are consistent with data from the OSLER randomised clinical trial [
      • Koren M.J.
      • Sabatine M.S.
      • Giugliano R.P.
      • et al.
      Long-term low-density lipoprotein cholesterol–lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study.
      ]. Among those who entered the extension phase of the HEYMANS study, the proportion of patients continuing to receive evolocumab up to 30 months exceeded 90%, and treatment was associated with sustained LDL-C level reductions throughout the follow-up period. These results demonstrate that self-administration of evolocumab is associated with high, long-term persistence in routine clinical practice.
      Results from this study build on the interim analysis from the HEYMANS study, which demonstrated that a greater proportion of patients receiving evolocumab in combination with another LLT attained the ESC/EAS LDL-C goals than those not receiving combination therapy [
      • Ray K.K.
      • Dhalwani N.
      • Sibartie M.
      • et al.
      Low-density lipoprotein cholesterol levels exceed the recommended European threshold for PCSK9i initiation: lessons from the HEYMANS study.
      ]. Moreover, the results of the interim analyses revealed that LDL-C levels at evolocumab initiation were approximately three times higher than the recommended thresholds for PCSK9 inhibitor initiation, indicating a disparity between guidelines and implementation. Among patients at high or very high CV risk, the proportion of patients achieving the ESC/EAS LDL-C goals was also higher in the current analyses for those receiving background LLT than for those who did not receive background LLT. Of note, achievement of the ESC/EAS LDL-C goals was largely consistent over the study period. These results suggest that greater use of combination therapy is required for patients to achieve the ESC/EAS LDL-C goals. Furthermore, if the recommended thresholds for PCSK9 inhibitor initiation were lowered, more patients would be eligible to receive combination therapy and, thus, would be more likely to achieve the ESC/EAS LDL-C goals. These results emphasise the importance of real-world evidence to support guideline development and potential changes to reimbursement criteria.
      The limitations of this study merit consideration. Patients in the HEYMANS study could have initiated evolocumab at least 6 months before enrolment. Patients who were receiving evolocumab for approximately 6 months before enrolment (n = 751) may have been more likely to continue with their treatment than those who initiated treatment closer to the enrolment date. Thus, the high persistence observed may be slightly overestimated. An additional limitation is that participating centres in the HEYMANS study may have included highly motivated healthcare professionals. These professionals may be likely to encourage persistence with treatment, so it is possible that the high persistence with evolocumab observed may reflect a slightly better than average scenario. Nevertheless, our results are similar to those of previous studies on evolocumab persistence [
      • Gupta M.
      • Mancini G.B.J.
      • Wani R.J.
      • et al.
      Real-world insights into evolocumab use in patients with hyperlipidemia: Canadian analysis from the ZERBINI study.
      ,
      • Cannon C.P.
      • de Lemos J.A.
      • Rosenson R.S.
      • et al.
      Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients with atherosclerotic cardiovascular disease in the US.
      ]. The analysis of intra-patient LDL-C level trends over time was limited owing to the relatively small proportion of patients with an LDL-C level measurement available during each 6-month period of the study. These patients may not be representative of the overall population; however, the baseline characteristics of this subset were similar to those of the overall population. Furthermore, the data from patients who discontinued evolocumab are limited in their interpretability owing to the small sample size. Finally, as with all observational studies, potential misclassification of the data may have occurred.
      In conclusion, in this real-world study of patients receiving evolocumab, persistence with evolocumab remained high, both at 12 months and 30 months of follow-up. Evolocumab therapy was associated with sustained LDL-C level reductions for up to 30 months of follow-up. These data highlight that long-term sustained reductions in LDL-C levels can be achieved with evolocumab therapy, with probable associated health benefits. Thus, expanding the use of monoclonal antibodies such as evolocumab could provide improvements in the population level control of LDL-C levels in European clinical practice.

      Author contributions

      I.B., M.S. and N.D. contributed substantially to the study design and concept. E.B., P.P.F., C.E. and A.V. were involved in data acquisition. I.B., M.S. and N.D. conducted the data analyses. All authors assisted with interpretation of the data. All authors were involved in drafting of the manuscript, provided critical revisions for important intellectual content, approved the final version submitted for publication, and agreed to be accountable for all aspects of the work.

      Financial support

      This study was funded by Amgen (Europe) GmbH.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K.K.R. reports grants/personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cargene, Daiichi Sankyo, Esperion, Kowa, Lilly, New Amsterdam Pharma, Novartis, Pfizer, Sanofi-Regeneron, Silence Therapeutics and Scribe Therapeutics. E.B. reports consulting fees from Aegerion, AKCEA, Amarin, Amgen, Genfit, Ionis-pharmaceuticals, Lilly, MSD, Mylan, Novartis, Regeneron, Sanofi and Servier. P.P.F. reports consulting and speakers fees from Amgen. C.E. reports grants and personal fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk and Sanofi. A.V. reports grants from Amgen, Novartis and Sanofi-Regeneron; and personal fees from Aegerion, Akcea, Amgen, Amryt, Daiichi Sankyo, Novartis and Sanofi-Regeneron. I.B. is an employee of Amgen Ltd and a stockholder of Amgen. N.D. is an employee of Amgen Inc and a stockholder of Amgen. M.S. is an employee of Amgen (Europe) GmbH and a stockholder of Amgen.

      Acknowledgements

      The authors would like to thank Sinéad Flannery, PhD, of PharmaGenesis London, London, UK, and Ryan Woodrow, PhD, CMPP, of Aspire Scientific, Bollington, UK, for medical writing support. K.K.R. acknowledges support from the NIHR Imperial Biomedical Research Centre and from the NIHR ARC for Northwest London. The authors would like to thank all the investigators and patients.

      Appendix A. Supplementary data

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