Low‐density lipoprotein cholesterol lowering in real‐world patients treated with evolocumab

Abstract Background Low‐density lipoprotein cholesterol (LDL‐C) is a risk factor for atherosclerotic cardiovascular disease (ASCVD). There are limited real‐world data on LDL‐C lowering with evolocumab in United States clinical practice. Hypothesis We assessed LDL‐C lowering during 1 year of evolocumab therapy. Methods This retrospective cohort study used linked laboratory (Prognos) and medical claims (IQVIA Dx/LRx and PharMetrics Plus®) data. Patients with a first fill for evolocumab between 7/1/2015 and 10/31/2019 (index event) and LDL‐C ≥ 70 mg/dL were included (overall cohort; N = 5897). Additionally, a patient subgroup with a recent myocardial infarction (MI) within 12 months (median 130 days) before the first evolocumab fill was identified (N = 152). Reduction from baseline LDL‐C was calculated based on the lowest LDL‐C value recorded during a 12‐month follow‐up period. Results The mean (SD) age was 65 (10) years; 61.9% of patients had ASCVD diagnoses and 70.7% of patients were in receipt of lipid‐lowering therapy. Following evolocumab treatment, changes in LDL‐C from baseline were −60% in the overall cohort (median [interquartile range (IQR)] 146 [115–180] mg/dL to 58 [36–84] mg/dL) and −65% in the recent MI subgroup (median [IQR] 137 [109–165] mg/dL to 48 [30–78] mg/dL). In the overall cohort and recent MI subgroup, 62.1% and 69.7% of patients achieved LDL‐C < 70 mg/dL, respectively. Conclusions In this real‐world analysis, evolocumab was associated with significant reductions in LDL‐C comparable to that seen in the FOURIER clinical trial, which were durable over 1 year of treatment.


| INTRODUCTION
Cardiovascular (CV) disease (CVD) remains the leading cause of death in the United States (US). 1 The costs of CVD are rising, driven by high-risk patients, and are expected to nearly double to $1 trillion from 2015 to 2035. 2 Low-density lipoprotein cholesterol (LDL-C) is a well-established causal risk factor for atherosclerotic CVD (ASCVD). 3,4 Accordingly, reduction of LDL-C significantly reduces the risk of major CV events, [5][6][7][8][9][10][11][12] and it is now recognized that lower LDL-C is better, with a progressive reduction in major CV events and no increase in safety events even at very low LDL-C levels of < 7.7 mg/dL (< 0.2 mmol/L). 13 The 2018  initiate the addition of nonstatins (ie, ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) to maximally tolerated statin therapy. 14 The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend a ≥ 50% LDL-C reduction from baseline and a goal of < 55 mg/dL (< 1.4 mmol/L), with a lower goal of < 40 mg/dL (< 1.0 mmol/L) for patients who experience a second vascular event within 2 years while taking maximally tolerated statin therapy. 15 The American Association of Clinical Endocrinology (AACE) and American College of Endocrinology (ACE) now recommend LDL-C goals of < 70 mg/dL (< 1.8 mmol/ L) and < 55 mg/dL (< 1.4 mmol/L) for VHR and extreme-risk patients, respectively. 16 However, observational studies indicate that patients infrequently achieve these guideline-recommended LDL-C goals in daily clinical practice, [17][18][19][20][21] with a recent analysis of US adults with health insurance in the MarketScan ® database reporting that 67% of patients with VHR ASCVD had LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L). 21 Multiple factors are thought to underpin this unmet treatment need, with suboptimal dosing, high rates of treatment discontinuation, and low rates of lipid-lowering therapy (LLT) adherence commonly observed. [22][23][24][25][26][27] Evolocumab is a PCSK9 inhibitor antibody approved to reduce the risk of MI, stroke, and coronary revascularization in adults with established CVD. 28 The efficacy of evolocumab is well established from clinical trials, with significant lowering of LDL-C and reduction of major CV events. 5,[9][10][11][12][13] In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, the addition of evolocumab to statin therapy in patients with stable ASCVD reduced LDL-C by a mean of 59% and significantly reduced the risk of the primary endpoints (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) by 15% at 48 weeks. 5 When assessed individually, evolocumab significantly reduced the risk of MI and stroke by 27% and 21%, respectively. 5 Secondary analyses from FOURIER report that patients with a recent MI are at an increased risk of CV events and experience greater relative and absolute risk reductions with evolocumab versus those with more remote MIs. 12,29 For example, evolocumab significantly reduced the risk of the key secondary endpoints (CV death, MI, or stroke) by 25% in patients with a recent MI (< 1 year) versus 15% in patients with a remote MI (> 1 year). 29 Within the context of personalized medicine, these data suggest that it is reasonable to target evolocumab therapy to higher-risk patients following a recent MI. 12,29 However, there are limited data on LDL-C lowering with evolocumab in real-world healthcare settings, where patient-, physician-, and payer-related treatment hurdles are common. 17,[22][23][24][25][26][27][30][31][32][33] Historically, these hurdles have included treatment discontinuation, educational needs for providers, prior authorization requirements, costs, and formulary restrictions. [30][31][32][33] In the current study, we characterized the population and assessed LDL-C lowering during 1 year of evolocumab therapy in realworld patients with LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L), including a patient subgroup with elevated risk hospitalized for MI within 12 months prior to starting evolocumab.

| Study design and patients
This was a retrospective cohort study using clinical laboratory data As the study used only existing de-identified patient records, institutional review board approval and patient informed consent were not required. All authors had full access to the study data and take responsibility for its integrity. Investigations were in accordance with the Declaration of Helsinki.

| Outcomes
We assessed baseline demographics (age, sex, insurance type) and

| Statistical analysis
The study was not designed to make formal statistical comparisons and was descriptive in nature. Mean (standard deviation [SD]) and median (interquartile range [IQR]) were calculated for continuous variables. Frequencies and percentages were calculated for categorical variables.

| Baseline demographics and clinical characteristics
The study included 5897 patients with LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L) who initiated evolocumab and 152 patients hospitalized for MI within 12 months prior to initiating evolocumab. The mean (SD) age of the overall cohort was 65 (10) years; 51.2% of patients were men, 61.9% of patients had commercial insurance, and 36.4% of patients had Medicare (Part C and D) coverage. Demographics of the recent MI subgroup were similar, but with more men than in the overall cohort (Table 1).
In the overall cohort, 61.9% of patients had a history of ASCVD (Table 2). Per the 2018 ACC/AHA guideline, 14 94.6% of patients had at least 1 high-risk condition ( Table 2). During the 12-month baseline period, 70.7% and 78.3% of patients in the overall cohort and recent MI subgroup, respectively, were in receipt of any LLT; 60.6% and 69.1% of patients in the overall cohort and recent MI subgroup, respectively, were in receipt of any statin. High-intensity statins were used in 26.6% and 38.2% of patients in the overall cohort and recent MI subgroup, respectively ( Table 2).

| LDL-C reduction with evolocumab in the overall cohort
The baseline median (IQR) LDL-C was 146 (115-180) mg/dL (3.8     were largely consistent with the recommendation that patients selected for PCSK9 inhibitor therapy are those with high levels of CV risk, [14][15][16] and supports a previous real-world study reporting that physicians were most likely to prescribe PCSK9 inhibitors to patients with elevated LDL-C levels and additional comorbid risk factors for adverse CV events. 34 At baseline, LDL-C levels were markedly elevated despite the majority of patients receiving background LLT with statins and/or ezetimibe in the 12 months prior to evolocumab initiation. Of note, the 60.6% of patients treated with statins prior to evolocumab initiation in the current study is considerably higher than that reported in a recently published study where only 29.3% of patients filled a statin in the period 31-365 days prior to PCSK9 inhibitor initiation. 35 The relatively higher proportion of patients treated with statins in the current study may be accounted for by lower levels of statin intolerance versus earlier patient cohorts who initiated PCSK9 inhibitors following their Food and Drug Administration (FDA) approval in 2015 35 ; however, statin intolerance was not assessed in the current study and therefore firm conclusions should be avoided.
In the overall cohort, evolocumab therapy resulted in clinically relevant LDL-C reductions in line with current guideline recommendations. [14][15][16] Notably, the reduction from baseline to the lowest recorded median LDL-C was 60%, and despite the high baseline LDL-C, 62.1% of patients achieved LDL-C < 70 mg/dL (< 1.8 mmol/L).
Moreover, 70.9% of patients with probable familial hypercholesterolemia at baseline (eg, LDL-C ≥ 190 mg/dL [≥ 4.9 mmol/L]), achieved LDL-C < 70 mg/dL (< 1.8 mmol/L) or a ≥ 50% reduction in LDL-C; however, the benefits of evolocumab were also consistent in patients without probable familial hypercholesterolemia at baseline. The percent reduction in LDL-C observed in the current real-world study is in line with that observed in previous evolocumab trials, 5,10,11 including the 59% reduction in LDL-C reported in the FOURIER trial. 5  The current study provides novel and pertinent real-world data on evolocumab therapy in patients at the highest level of CV risk. Literature suggests that substantial residual risk for MI and coronary heart disease events remains after an MI, despite intensive guideline-directed medical management including high-intensity statins. 36 Thus, treatment to reduce CV risk during this period is critical, with it now recognized that patients at the highest levels of CV risk are likely to derive greater benefit from PCSK9 inhibition. 12,29,37 Here, we assessed a patient subgroup with a median of 130 days between MI and evolocumab initiation. Despite a recent MI, these patients had highly elevated LDL-C, exposing them to a high residual CV risk and confirming a pervasive unmet treatment need in this patient population. Similar to the overall

| Limitations
The current study has a number of limitations. Firstly, medical history among patients in the LRx database may have been under-captured due to the open nature of the data and no requirement for continuous coverage at the patient level. Secondly, it was subject to the established limitations of real-world research using claims databases, including limited generalizability to patients without health insurance.
Thirdly, as evolocumab therapy was ascertained from documented prescriptions, it was not clear if the patient used the product on the expected schedule. Fourthly, it has been reported that the most common physician-reported reason for initiating PCSK9 inhibitor treatment in real-world clinical practice is a lack of statin efficacy 39 ; however, in the current study we were unable to assess physician and patient factors (eg, statin intolerance) influencing treatment choice.
Fifth, the recent MI subgroup was relatively small. Finally, the current study ended shortly after the 2018 ACC/AHA blood cholesterol guideline was published 14 ; therefore, putative changes in treatment patterns arising from the adoption of the guideline updates were unable to be fully observed in this study.

| CONCLUSIONS
In conclusion, many patients initiating evolocumab therapy in US clinical practice had highly elevated LDL-C, and high-risk comorbidities and/or ASCVD were common. Consistent with previous clinical studies, 5,10,11 in the real-world, evolocumab demonstrated clinically relevant LDL-C reductions that were maintained over 1 year of treatment for all initiators and among the highest-risk patients with a prior MI.

ACKNOWLEDGMENTS
Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Liam Gillies, PhD, of Cactus Life Sciences (part of Cactus Communications), and funded by Amgen Inc. The study was funded by Amgen Inc. The sponsor was involved in the study design; the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.