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Efficacy and Tolerability of Ezetimibe/Atorvastatin Fixed-dose Combination Versus Atorvastatin Monotherapy in Hypercholesterolemia: A Phase III, Randomized, Active-controlled Study in Chinese Patients

Open AccessPublished:September 28, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.08.013

      Abstract

      Purpose

      The 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (“statins”) and the cholesterol-lowering medication ezetimibe are widely used in the treatment of patients with high- and very high–risk atherosclerotic cardiovascular disease. This study compared the efficacy and tolerability of a fixed-dose combination (FDC) of ezetimibe/atorvastatin (EZ/AS) with those of escalating doses of atorvastatin monotherapy in Chinese patients with hypercholesterolemia uncontrolled with statin monotherapy.

      Methods

      This Phase III, 12-week, randomized, double-blind study included patients aged 18 to 80 years with hypercholesterolemia uncontrolled on atorvastatin 10 or 20 mg/d monotherapy. After a 5-week run-in period of treatment with atorvastatin 10 or 20 mg/d (cohorts A and B, respectively), or a bioequivalent dosage of another statin, patients were randomized in a 1:1 ratio within each cohort to receive EZ/AS 10/10 mg FDC (EZ10/AS10) or atorvastatin 20 mg (AS20), once daily (cohort A); or EZ/AS 10/20 mg FDC (EZ10/AS20) or atorvastatin 40 mg (AS40), once daily (cohort B). The primary end point was the percentage change from baseline in low-density lipoprotein cholesterol (LDL-C). Tolerability was also evaluated.

      Findings

      Of the 454 patients enrolled, 412 (90.7%) completed the study. The percentage change from baseline in LDL-C was statistically greater with EZ10/AS10 treatment (n = 88) compared with AS20 monotherapy (n = 89) (treatment difference, −19.5%; 95% CI, −26.7% to −12.3%; P < 0.001). The percentage change from baseline in LDL-C was statistically greater with EZ10/AS20 treatment (n = 137) compared with AS40 monotherapy (n = 140) (treatment difference, −15.9%; 95% CI, −21.0% to −10.7%; P < 0.001). The safety profile was comparable between the EZ/AS and atorvastatin groups in the two cohorts.

      Implications

      The LDL-C level at week 12 was significantly improved with both FDCs compared with escalated doses of atorvastatin (20 or 40 mg/d) in these Chinese patients with hypercholesterolemia uncontrolled on atorvastatin 10 or 20 mg/d. Both FDCs were well tolerated, with no new tolerability-related findings. Chinadrugtrials.org.cn identifier: CTR20190172; ClinicalTrials.gov identifier: NCT03768427

      Key words

      Introduction

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      Although the ezetimibe + statin combination therapy is widely used, the efficacy and tolerability of fixed-dose combinations (FDCs) in Chinese patients are yet to be established. The present study compared the efficacy and safety profiles of an FDC comprising ezetimibe + atorvastatin (EZ/AS) with those of escalating doses of atorvastatin in Chinese patients with hypercholesterolemia. The findings from this study will support the marketing authorization of the EZ/AS FDC in China.

      Patients and Methods

      Study Design

      This Phase III, 12-week, multicenter, randomized, double-blind (with in-house blinding), active-controlled, double-dummy, parallel-group study was conducted across 30 centers in China from May 27, 2019, to April 1, 2021 (see Supplemental Table I in the online version at doi:10.1016/j.clinthera.2022.08.013). The study comprised four periods (Figure 1): screening period (visit 1; 2 weeks), atorvastatin active run-in period (visits 2–3; 5 weeks), treatment period (visits 4–6; 12 weeks), and a post-treatment follow-up period (14 days, after the administration of the last dose). Following the active run-in period, patients with inadequately controlled hypercholesterolemia on treatment with atorvastatin ≤10 and ≤20 mg/d or a bioequivalent/lower dosage of another statin (simvastatin 10/20/40 mg/d, lovastatin 20/40/80 mg/d, pravastatin 20/40 mg/d, or fluvastatin 40/80 mg/d) were assigned to cohorts A and B, respectively. Patients in cohort A were randomized (1:1) to receive either EZ/AS 10/10 mg FDC (EZ10/AS10) or atorvastatin 20 mg (AS20), once daily. Patients in cohort B were randomized (1:1) to receive either EZ/AS 10/20 mg FDC (EZ10/AS20) or atorvastatin 40 mg (AS40), once daily (Figure 1). Central randomization was done using an interactive response technology system. CVD risk category was assigned according to the Guidelines for the Prevention and Treatment of Adult Dyslipidemia in China (2016)
      Joint Committee on the Revision of Guidelines for Prevention and Treatment of Adult Dyslipidemia in China
      Guidelines for the prevention and treatment of adult dyslipidemia in China (revised in 2016) (in Chinese).
      based on demographic characteristics and clinical history including lipid profile. A double-dummy design was followed to ensure efficient blinding, considering the difference in appearance between the FDC and atorvastatin, and patients in both cohorts were given matching placebos. All study personnel, including the investigators, patients, sponsor personnel or delegates, were blinded to the treatment allocation throughout the study (in-house blinding). Doses were not adjusted during the 12-week treatment period.
      Figure 1
      Figure 1Study design. Cohort A = atorvastatin 10 mg/d during the run-in period; cohort B = atorvastatin 20 mg/d during the run-in period; EZ = ezetimibe; FDC = fixed-dose combination; LDL-C = low-density lipoprotein cholesterol; R = randomized.
      This study was conducted in compliance with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice and in accordance with the ethics principles of the Declaration of Helsinki). The study protocol was approved by the institutional review board of each site, and written informed consent was obtained from all participants before commencing any study-specific procedure. The study is registered with chinadrugtrials.org.cn (CTR20190172) and ClinicalTrials.gov (NCT03768427).

      Eligibility Criteria

      Inclusion Criteria

      Chinese men and women aged 18 to 80 years (inclusive) with documented hypercholesterolemia requiring medical treatment as per the Guidelines for the Prevention and Treatment of Adult Dyslipidemia in China (2016),
      Joint Committee on the Revision of Guidelines for Prevention and Treatment of Adult Dyslipidemia in China
      Guidelines for the prevention and treatment of adult dyslipidemia in China (revised in 2016) (in Chinese).
      but with inadequately controlled or uncontrolled hypercholesterolemia, were eligible for participation in the study. Eligible patients were on a stable dose of atorvastatin 10 or 20 mg/d or a bioequivalent/lower dose of another statin for ≥4 weeks prior to visit 1. Eligible patients had ≥75% medication adherence during the atorvastatin run-in period. Medication adherence(in %) was calculated as [(total tablets provided) – (tablets remaining at visits 2–3)]/(total tablets provided) × 100. Eligible patients could have atherosclerotic CVD of low to moderate, high, or very high risk (LDL-C, 70–<100, 100–<160, or ≥160 mg/dL, respectively) at visit 3.

      Exclusion Criteria

      Patients with uncontrolled hypertriglyceridemia requiring drug intervention or with a fasting triglyceride level of ≥500 mg/dL, with active liver disease or liver aminotransferases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) of >2-fold the upper limit of normal, symptomatic New York Heart Association Class III-IV heart failure, endocrine or metabolic disease, and/or an estimated glomerular filtration rate of <30 mL/min/1.73 m2 at visit 1 were excluded from the study. Patients who achieved treatment goal by visit 4 and those who had a creatine kinase level of >3-fold the upper limit of normal at visit 4 were excluded. Patients with a history of statin treatment at a dose bioequivalent to LDL-C–lowering effect greater than that of atorvastatin 20 mg/d, and those with a history of uncontrolled cardiac arrhythmia, myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, and/or unstable angina or stroke within 12 weeks prior to visit 1 were also excluded. Patients with HIV+ status; intestinal malabsorption; hypersensitivity or intolerance to ezetimibe, atorvastatin, or EZ/AS; and/or a history of gastrointestinal tract bypass surgery, cancer, psychiatric instability, and/or drug/alcohol abuse (>25 g/d) within the preceding 5 years were also excluded. The use of red yeast rice supplement, bile acid sequestrants, ezetimibe, fibrates or niacin (>200 mg/d), PCSK9 inhibitors, antifungal drugs, warfarin, phytosterol margarines, herbal medicine, corticosteroids, fiber-based laxatives, macrolide, protease inhibitors, cyclosporine, cyclical hormones, and grapefruit or grapefruit juice (200 mL/d for >3 times per week) were not permitted during the study.

      Study Objectives and End Points

      The primary objective of the study was to compare the efficacy of the FDC at both dosages with that of atorvastatin monotherapy in patients with hypercholesterolemia previously uncontrolled with atorvastatin monotherapy. The primary efficacy end point was the percentage change in LDL-C level from baseline to week 12 in both cohorts. The lipid profiles were analyzed by a central laboratory (Q Squared Solutions Co., Ltd., Unit 302, Building 15B, Han's Enterprise Bay, BDA Beijing, China) to maintain uniformity. The level of LDL-C was determined using the Friedewald method if the triglyceride level was ≤400 mg/dL and using β quantification ultracentrifugation if the triglyceride level was >400 mg/dL.
      The secondary objective was to evaluate the tolerability of the FDC with 12-week use. Tolerability was assessed by the monitoring and recording of laboratory test values, vital sign measurements (heart rate and blood pressure), ECG, AEs, serious AEs (SAEs), AEs of interest (AEIs), discontinuation due to AEs/SAEs, and the causal relationship of AEs to the study drug. Physical examination including vital sign monitoring was done at each visit. Urine/serum β–human chorionic gonadotropin was measured at visits 1 and 4–6 if a urinary pregnancy test performed at the site was positive. A qualified local laboratory was also used to detect safety signals. A 12-lead ECG was performed and levels of free T4 and thyroid-stimulating hormone were measured at visit 1. Hematology and urinalysis were performed at visits 1, 3, and 6. Fasting basic blood chemistry was performed at visits 1 and 3–6. Local-laboratory results obtained within 4 weeks prior to visit 1 were used as reference for the screening of patients. After the 12-week treatment period, patients were followed up by phone for ≈14 days following the cessation of treatment, to identify SAEs.

      Statistical Analysis

      The efficacy analysis was conducted in the full analysis set (FAS), defined as all randomized patients who took at least one dose of the study treatment and who had data available from at least one observation of the respective end point (baseline or postbaseline) during the treatment period. The safety set included all randomized patients who received at least one dose of the study treatment. The percentage change in LDL-C from baseline to week 12 was evaluated using a constrained longitudinal data analysis model, separately for each cohort (ES/AS vs atorvastatin). The tolerability analysis followed a tiered approach. P values and 95% CIs for the prevalences of AEIs were derived using the Miettinen and Nurminen method. The primary hypothesis was that percentage change in LDL-C level from baseline to week 12 would be greater with EZ/AS versus atorvastatin monotherapy in each cohort. The overall success was determined by the success of the hypothesis in at least one cohort. The overall type I error rate over multiple treatment comparisons in the primary hypothesis was controlled using the Hochberg testing procedure.
      The study planned to enroll 450 patients (cohort A, 180; cohort B, 270). The power calculation was conservative and based on the number of patients expected to have LDL-C data available from week 12. Assuming a dropout rate of 10%, 162 patients (81 per arm) in cohort A and 242 patients (121 per arm) in cohort B were available for the power calculation. The planned sample in cohort A had 93% power to demonstrate the efficacy of EZ10/AS10 over AS20 at a one-sided 2.5% α level. Similarly, the sample in cohort B had 95% power to demonstrate the efficacy of EZ10/AS20 over AS40 at a one-sided 2.5% α level. The overall power to succeed in at least one hypothesis was 99% at a 2.5% α level, with 88% power to succeed for both hypotheses. The power and sample sizes were determined based on the following assumptions (unpublished data on file from NCT01154036): the treatment differences in percentage changes from baseline in LDL-C at week 12 in cohorts A and B were 12.3% and 10.5%, respectively, and unconditional SDs were 22% and 23%. Analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, North Carolina).

      Results

      Patient Disposition and Baseline Characteristics

      A total of 1113 Chinese patients were screened, of whom 454 were included in the study. Of these 454 patients, 177 were assigned to cohort A and were administered the FDC (EZ10/AS10; n = 88) or AS20 (n = 89). A total of 277 patients were assigned to cohort B and were administered either the FDC (EZ10/AS20; n = 137) or AS40 (n = 140). Of the 454 patients included in the study, 42 (9.3%) discontinued, and 412 (90.7%) completed the treatment period (Figure 2). The most common reasons for discontinuation were consent withdrawal (n = 20, 4.4%) and AEs (n = 11, 2.4%). Of the 659 patients who were not included in study, 560 (85.0%) were screen failures and 69 (10.5%) withdrew consent. The three most common reasons for screen failure were: (1) not meeting the LDL-C level as per the inclusion criteria; (2) achieving the treatment goal with statin monotherapy; and (3) having endocrine or metabolic disease known to influence serum lipid or lipoprotein levels. The reasons for consent withdrawal included an unwillingness to participate, disagreement of family members, and conflict of time (Figure 2).
      Figure 2
      Figure 2Patient disposition (full analysis set). AS20 = atorvastatin 20 mg; AS40 = atorvastatin 40 mg; cohort A = atorvastatin 10 mg/d during the run-in period; cohort B, atorvastatin 20 mg/d during the run-in period; EZ10/AS10 = ezetimibe/atorvastatin 10/10 mg; EZ10/AS20 = ezetimibe/atorvastatin 10/20 mg.
      The baseline demographic and clinical characteristics were comparable between the treatment groups in both cohorts (Table I). The overall mean (SD) age of the patients was 60.9 (9.2) years, and 40.3% were aged ≥65 years. The majority of the patients (64.5%) were male, and most had very high–risk disease (89.2%). The baseline lipid profiles were comparable between the treatment groups (Table I).
      Table IBaseline demographic and clinical characteristics of the study patients (full analysis set).
      CharacteristicCohort ACohort B
      EZ/AS 10/10 mg/d (n = 88)Atorvastatin 20 mg/d (n = 89)EZ/AS 10/20 mg/d (n = 137)Atorvastatin 40 mg/d (n = 140)
      Demographic
       Age, mean (SD), y62.4 (7.4)62.4 (8.5)59.4 (9.3)60.6 (10.3)
       Male, no. (%)45 (51.1)51 (57.3)103 (75.2)94 (67.1)
       BMI, mean (SD), kg/m225.3 (3.2)25.2 (3.5)26.1 (3.7)25.8 (3.3)
       Asian race, no. (%)88 (100)89 (100)137 (100)140 (100)
       Non-Hispanic or -Latino ethnicity, no. (%)88 (100)89 (100)137 (100)140 (100)
      Clinical
      Medical history, no. (%)
       Dyslipidemia62 (70.5)59 (66.3)92 (67.2)98 (70.0)
       Hypertension58 (65.9)63 (70.8)91 (66.4)93 (66.4)
       Coronary artery disease45 (51.1)46 (51.7)80 (58.4)91 (65.0)
      Lipid profile, mean (SD), mg/dL
       LDL-C95.5 (24.6)96.8 (25.9)88.4 (21.9)91.9 (24.9)
       Total cholesterol, mg/dL170.9 (28.1)172.9 (28.2)161.0 (25.8)164.4 (28.3)
       HDL-C, mg/dL47.3 (12.5)46.9 (11.5)44.6 (10.1)44.4 (10.0)
       Non-HDL-C, mg/dL123.6 (27.6)126.0 (26.3)116.4 (24.6)120.0 (26.8)
       Triglycerides, mg/dL140.3 (59.2)145.9 (60.7)140.1 (63.4)141.0 (63.2)
       ApoB, mg/dL95.5 (18.6)97.2 (19.5)91.8 (16.8)93.8 (18.5)
      Disease risk category, no. (%)
       Low4 (4.5)4 (4.5)1 (0.7)1 (0.7)
       Intermediate1 (1.1)2 (2.2)0 (0.0)1 (0.7)
       High risk13 (14.8)14 (15.7)4 (2.9)4 (2.9)
       Very high70 (79.5)69 (77.5)132 (96.4)134 (95.7)
      BMI = body mass index; cohort A = atorvastatin 10 mg/d during the run-in period; cohort B = atorvastatin 20 mg/d during the run-in period; EZ/AS = ezetimibe/atorvastatin; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol.
      Medication compliance was high (>96%) across the groups in both cohorts. Mean (SD) medication compliance rates were 98.4% (3.5%) in the EZ10/AS10 group and 98% (5.6%) in the AS20 group in cohort A, and 98.2% (5.9%) in the EZ10/AS20 group and 96.7% (8.6%) in the AS40 group in cohort B.

      Efficacy

      In cohort A, the least squares (LS) mean percentage changes in LDL-C from baseline to week 12 were −24.8% and −5.3% in the EZ10/AS10 and AS20 groups, respectively. The lipid-lowering effect was statistically greater with EZ10/AS10 compared with AS20 monotherapy (treatment difference, −19.5%; 95% CI, −26.7% to −12.3%; P < 0.001). In cohort B, the LS mean percentage changes in LDL-C from baseline to week 12 were −24.6% and −8.7% in the EZ10/AS20 and atorvastatin 40 mg/d groups, respectively. Similar to in cohort A, the lipid-lowering effect was statistically greater with EZ10/AS20 compared with AS40 monotherapy in cohort B (treatment difference, −15.9%; 95% CI, −21.0% to −10.7%; P < 0.001) (Table II and Figure 3).
      Table IILow-density lipoprotein cholesterol levels before and after treatment with ezetimibe/atorvastatin (EZ/AS) combination therapy and atorvastatin monotherapy in patients with hypercholesterolemia (full analysis set).
      VariableCohort ACohort B
      EZ/AS 10/10 mg/d (n = 88)Atorvastatin 20 mg/d (n = 89)EZ/AS 10/20 mg/d (n = 137)Atorvastatin 40 mg/d (n = 140)
      Baseline
       nn = 88n = 89n = 137n = 140
       Mean (SD)95.5 (24.6)96.8 (25.9)88.4 (21.9)91.9 (24.9)
      Week 12
       nn = 67n = 77n = 114n = 116
       Mean (SD)71.2 (25.7)89.2 (25.6)67.0 (23.1)81.7 (23.1)
      Percentage change
       nn = 67n = 77n = 114n = 116
       Mean (SD)–24.7 (24.9)–5.3 (22.5)–23.3 (23.1)–9.1 (18.2)
       LS mean (SE)
      LS mean; 95% CIs, and P values were obtained by fitting a constrained longitudinal model adjusting for time and the interaction of time by treatment as well as for time by baseline disease risk category, including all patients counted in the column labeled with n. A separate model was fit for each cohort.
      –24.8 (2.7)–5.3 (2.6)–24.6 (1.9)–8.7 (1.9)
       (95% CI)(–30.1 to –19.4)(–10.4 to –0.3)(–28.3 to –20.9)(–12.4 to –5.1)
       LS Mean Difference–19.5–15.9
       (95% CI; P)(–26.7 to –12.3; <0.001)(–21.0 to –10.7; <0.001)
      Cohort A = atorvastatin 10 mg/d during the run-in period; cohort B = atorvastatin 20 mg/d during the run-in period; EZ/AS = ezetimibe/atorvastatin; LS = least squares.
      low asterisk LS mean; 95% CIs, and P values were obtained by fitting a constrained longitudinal model adjusting for time and the interaction of time by treatment as well as for time by baseline disease risk category, including all patients counted in the column labeled with n. A separate model was fit for each cohort.
      Figure 3
      Figure 3Least squares (LS) mean percentage changes in low-density lipoprotein cholesterol (LDL-C) level after 6 and 12 weeks of treatment with ezetimibe/atorvastatin (EZ/AS) or atorvastatin. AS20 = atorvastatin 20 mg; AS40 = atorvastatin 40 mg; cohort A = atorvastatin 10 mg/d during the run-in period; cohort B = atorvastatin 20 mg/d during the run-in period; EZ10/AS10 = ezetimibe/atorvastatin 10/10 mg; EZ10/AS20 = ezetimibe/atorvastatin 10/20 mg.

      Sensitivity Analyses

      Sensitivity analyses were performed to assess the robustness of the findings based on the results obtained from the constrained longitudinal data analysis of the primary end point. In the reference multiple-imputation analysis, treatment differences in the LS mean LDL-C values at week 12 between EZ/AS and AS were −14.8% (95% CI, −20.6% to −9.1%; P < 0.001) in cohort A and −13.2% (95% CI, −17.6% to −8.8%; P < 0.001) in cohort B. These findings support the primary-analysis results. Tipping point multiple-imputation analysis also confirmed the robustness of the primary results.

      Tolerability

      Of the 454 patients in the safety set, 202 (44.4%) experienced at least one AE after randomization. The most common AEs (≥2% patients in any treatment group) were elevated ALT (EZ10/AS10, 0% vs AS20, 0%; EZ10/AS20, 5.1% vs AS40, 1.4%), followed by elevated blood glucose (EZ10/AS10, 2.3% vs AS20, 2.2%; EZ10/AS20, 2.2% vs AS40, 5.0%) and urinary occult blood positivity (EZ10/AS10, 0% vs AS20, 0%; EZ10/AS20, 4.4% vs AS40, 0.7%). Overall, the AE profile was comparable between the EZ/AS and atorvastatin groups in each cohort. The prevalences of AEs, drug-related AEs, SAEs, and AEs leading to discontinuation were low and generally similar in patients receiving EZ/AS and atorvastatin in both cohorts. No drug-related deaths were reported during the study (Table III). In addition to the elevated liver enzymes (ALT and AST), the AEIs included myopathy (EZ10/AS20, 0.7% vs AS40, 0%) and elevated blood creatine phosphokinase (EZ10/AS10, 0% vs AS20, 1.1%; EZ10/AS20, 1.5% vs AS40, 0%). AEI of overdose (defined as any dose higher than the amount of study treatment taken beyond the treatment assignment that was not associated with clinical symptoms or abnormal laboratory results) was reported in 13 of 454 patients (2.9%). No other AEIs were reported during the study. No clinically meaningful findings or differences in changes from baseline in laboratory parameters or vital sign measurements between EZ/AS and atorvastatin groups were observed in either cohort. Summary of SAEs are presented in Table IV.
      Table IIIAdverse events (AEs), by preferred term, in the treated sets (all participants as treated). Data are given as number (%) of patients.
      VariableCohort ACohort B
      EZ/AS 10/10 mg/d (n = 88)Atorvastatin 20 mg/d (n = 89)EZ/AS 10/20 mg/d (n = 137)Atorvastatin 40 mg/d (n = 140)
      ≥1 AE28 (31.8)31 (34.8)76 (55.5)67 (47.9)
      No. of AEs60 (68.2)58 (65.2)61 (44.5)73 (52.1)
       Treatment related
      Determined by the investigator to have been related to the study treatment; MedDRA version 23.1 was used in the reporting of the AEs in this study.
      7 (8.0)7 (7.9)22 (16.1)17 (12.1)
       Serious
      None of the serious events were considered as treatment related, and no deaths were reported.
      2 (2.3)4 (4.5)10 (7.3)6 (4.3)
      Discontinued due to AEs2 (2.3)2 (2.2)4 (2.9)3 (2.1)
       Treatment related02 (2.2)2 (1.5)1 (0.7)
       Serious
      None of the serious events were considered as treatment related, and no deaths were reported.
      1 (1.1)02 (1.5)2 (1.4)
      AEs occurring in ≥2% of patients
       Blood glucose increased2 (2.3)2 (2.2)3 (2.2)7 (5.0)
       Hepatic function abnormal2 (2.3)2 (2.2)3 (2.2)5 (3.6)
       Hyperuricemia2 (2.3)2 (2.2)3 (2.2)5 (3.6)
       Urinary protein present2 (2.3)1 (1.1)4 (2.9)4 (2.9)
       Cerebral infarction2 (2.3)1 (1.1)1 (0.7)0
       Hypertension2 (2.3)02 (1.5)2 (1.5)
       Accidental overdose1 (1.1)3 (3.4)5 (3.6)4 (2.9)
       Blood uric acid increased1 (1.1)3 (3.4)2 (1.5)2 (1.4)
       Upper respiratory tract infection1 (1.1)1 (1.1)5 (3.6)4 (2.9)
       Blood creatine phosphokinase increased1 (1.1)1 (1.1)3 (2.2)1 (0.7)
       Urinary tract infection1 (1.1)1 (1.1)03 (2.1)
       Tinnitus02 (2.2)00
       Vertigo02 (2.2)00
       Hyperkalemia01 (1.1)4 (2.9)3 (2.1)
       T2DM01 (1.1)3 (2.2)0
       ALT increased007 (5.1)2 (1.4)
       Urinary occult blood positive006 (4.4)1 (0.7)
       AST and ALT increased003 (2.2)3 (2.1)
       AST increased003 (2.2)1 (0.7)
       Impaired fasting glucose003 (2.2)1 (0.7)
       Myalgia002 (1.5)3 (2.1)
       Urinary blood present002 (1.5)3 (2.1)
       Chest pain0005 (3.6)
       Carotid arteriosclerosis0003 (2.1)
      ALT = alanine aminotransferase; AST = aspartate aminotransferase; cohort A = atorvastatin 10 mg/d during the run-in period; cohort B = atorvastatin 20 mg/d during the run-in period; EZ/AS = ezetimibe/atorvastatin; T2DM = type 2 diabetes mellitus.
      low asterisk Determined by the investigator to have been related to the study treatment; MedDRA version 23.1 was used in the reporting of the AEs in this study.
      None of the serious events were considered as treatment related, and no deaths were reported.
      Table IVSummary of serious adverse events experienced by ...0% of patients by preferred-term in any one of the treatment groups in the treated set (all participants as treated).
      VariablesCohort ACohort B
      EZ10/AS10

      (n=88)
      AS20

      (n=89)
      EZ10/AS20

      (n=137)
      AS40

      (n=140)
      Angina unstable0 (0.0)0 (0.0)1 (0.7)2 (1.4)
      Atrioventricular block0 (0.0)0 (0.0)0 (0.0)1 (0.7)
      Cardiac failure0 (0.0)0 (0.0)2 (1.5)0 (0.0)
      Vertigo0 (0.0)1 (1.1)0 (0.0)0 (0.0)
      Cataract0 (0.0)0 (0.0)1 (0.7)0 (0.0)
      Gastrointestinal hemorrhage0 (0.0)1 (1.1)0 (0.0)0 (0.0)
      Femur fracture0 (0.0)0 (0.0)0 (0.0)1 (0.7)
      Subdural hemorrhage0 (0.0)0 (0.0)1 (0.7)0 (0.0)
      Type 2 diabetes mellitus0 (0.0)0 (0.0)1 (0.7)0 (0.0)
      Intervertebral disc protrusion0 (0.0)0 (0.0)0 (0.0)1 (0.7)
      Lumbar spinal stenosis0 (0.0)0 (0.0)0 (0.0)1 (0.7)
      Rheumatoid arthritis0 (0.0)0 (0.0)1 (0.7)0 (0.0)
      Colon adenoma0 (0.0)0 (0.0)1 (0.7)0 (0.0)
      Ovarian granulosa cell tumor0 (0.0)0 (0.0)1 (0.7)0 (0.0)
      Cerebral infarction2 (2.3)1 (1.1)1 (0.7)0 (0.0)
      Dizziness0 (0.0)1 (1.1)0 (0.0)0 (0.0)
      Chronic kidney disease0 (0.0)1 (1.1)0 (0.0)0 (0.0)
      Aortic dissection0 (0.0)0 (0.0)1 (0.7)0 (0.0)
      All values are presented as n (%) unless otherwise stated.
      * Determined by the investigator to be related to the drug; MedDRA version 23.1 was used in the reporting of this study.
      AS20, atorvastatin 20 mg; AS40, atorvastatin 40 mg; Cohort A, atorvastatin 10 mg during the run-in period; Cohort B, atorvastatin 20 mg during the run-in period; EZ10/AS10 mg, ezetimibe 10/atorvastatin 10 mg; EZ10/AS20 mg, ezetimibe 10/atorvastatin 20 mg.
      No patients died during the study. A patient in the EZ10/AS20 group with very high ASCVD risk at baseline died after follow-up period due to severe low cardiac output syndrome after aortic dissection surgery. The death was considered caused by the emergency cardiovascular event which is prone to occur in the elderly and related to some risk factors of ASCVD, such as hypertension and atherosclerosis. The SAE and subsequent death were not considered as study drug-related.

      Discussion

      In this Phase III, randomized, active-controlled study in Chinese patients with hypercholesterolemia inadequately controlled with atorvastatin 10 or 20 mg/d monotherapy, the addition of ezetimibe to a statin was apparently more effective in reducing the LDL-C level as well as in achieving the treatment goal compared with atorvastatin monotherapy at two dosages (20 or 40 mg/d). The combination therapy was well tolerated at both dosage strengths. The overall tolerability of the FDC was comparable to that of the well-established safety profiles of ezetimibe and atorvastatin, individually. Thus, both the primary and secondary objectives of the study were met.
      The results of this study corroborated those from another randomized controlled study from China, in which patients (N = 98) with atherosclerotic CVD were included. In that study, the mean LDL-C level was significantly lower with combination therapy with a moderate atorvastatin dose (EZ10/AS20) than with an escalating dose of atorvastatin (AS40) (1.59 [0.44] vs 1.99 [0.56] mmol/L; P = 0.001).
      • Wu NQ
      • Guo YL
      • Zhu CG
      • et al.
      Comparison of statin plus ezetimibe with double-dose statin on lipid profiles and inflammation markers.
      Similar benefits were noted in another study that included patients with acute coronary syndrome who received combination therapy (EZ10/AS10) or an escalating dose of atorvastatin (AS40).
      • Tan H
      • Liu L
      • Zheng Q
      • et al.
      Effects of combined lipid-lowering therapy on low-density lipoprotein cholesterol variability and cardiovascular adverse events in patients with acute coronary syndrome.
      This benefit was noted in the patient population with coexisting acute coronary syndrome and type 2 diabetes mellitus (T2DM) who received combination therapy (EZ10/AS10 or atorvastatin, simvastatin, or pravastatin 20 mg/d) compared with statin monotherapy. The reduction in LDL-C level was significantly greater with combination therapy compared with an escalating dose of atorvastatin (50% vs 29%; P < 0.001).
      • Li L
      • Zhang M
      • Su F
      • et al.
      Combination therapy analysis of ezetimibe and statins in Chinese patients with acute coronary syndrome and type 2 diabetes.
      Similar benefits were noted in another study that included patients with T2DM and CHD.
      • Wang J
      • Ai XB
      • Wang F
      • Zou YW
      • Li L
      • Yi XL.
      Efficacy of ezetimibe combined with atorvastatin in the treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease.
      This is an important finding because many patients with T2DM have coexisting hypercholesterolemia.
      Studies in other populations have demonstrated a similar benefit. In Japanese patients with hypercholesterolemia, the lipid-lowering effect was significantly greater with combination therapy (EZ10/AS10) than an escalating dose of monotherapy with AS20 or a switch to rosuvastatin 2.5 mg/d (both, P < 0.0001).
      • Teramoto T
      • Sawada T
      • Iwamoto K
      • Daida H.
      Clinical efficacy and tolerability of ezetimibe in combination with atorvastatin in Japanese patients with hypercholesterolemia-ezetimibe phase IV randomized controlled trial in patients with hypercholesterolemia.
      Similar results were observed in other randomized controlled trials from Japan in which LDL-C lowering was greater with combination therapy compared with atorvastatin monotherapy.
      • Tsujita K
      • Sugiyama S
      • Sumida H
      • et al.
      Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial.
      ,
      • Sakamoto K
      • Kawamura M
      • Watanabe T
      • et al.
      Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects.
      Studies in other populations also replicate these findings.
      • Luo P
      • Wang L
      • Zhu H
      • Du S
      • Wang G
      • Ding S.
      Impact of atorvastatin combined with ezetimibe for the treatment of carotid atherosclerosis in patients with coronary heart disease.
      ,
      • Philip S
      • Elizabeth AA.
      Comparison of efficacy and safety of atorvastatin versus combination of atorvastatin—ezetimibe in newly diagnosed dyslipidemic patients.
      Elderly people constitute another vulnerable population in which the efficacy and tolerability of combination therapy have been studied. In a 12-week, randomized study in patients aged ≥65 years at high or very high risk for CHD, with or without atherosclerotic vascular disease, patients received EZ10/AS10 or atorvastatin monotherapy (AS20 for 6 weeks, up-titrated to AS40 for 6 weeks). LDL-C lowering was greater with EZ10/AS10 than with the escalating dose of atorvastatin monotherapy (60.5% vs 49.7%; odds ratio = 1.55).
      • Constance C
      • Ben-Yehuda O
      • Wenger NK
      • et al.
      Atorvastatin 10 mg plus ezetimibe versus titration to atorvastatin 40 mg: attainment of European and Canadian guideline lipid targets in high-risk subjects ≥65 years.
      Significantly higher mean reductions in LDL-C of ≥15% were noted with a comparable or greater atorvastatin dose with the addition of ezetimibe (ie, EZ10/AS20 vs AS40,
      • Conard SE
      • Bays HE
      • Leiter LA
      • et al.
      Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40 mg) in hypercholesterolemic patients at moderately high risk for coronary heart disease.
      EZ10/AS40 vs AS80,
      • Ai C
      • Zhang S
      • He Q
      • Shi J.
      Comparing the combination therapy of ezetimibe and atorvastatin with atorvastatin monotherapy for regulating blood lipids: a systematic review and meta-analysis.
      or EZ10/AS40 vs simvastatin 40 mg
      • McCormack T
      • Harvey P
      • Gaunt R
      • Allgar V
      • Chipperfield R
      • Robinson P
      IN-PRACTICE study
      Incremental cholesterol reduction with ezetimibe/simvastatin, atorvastatin and rosuvastatin in UK General Practice (IN-PRACTICE): randomised controlled trial of achievement of Joint British Societies (JBS-2) cholesterol targets.
      ). Similar results were noted in another study that compared EZ10/AS10 with an escalating dose of AS20 monotherapy; therein, liver dysfunction was observed to be minimal with combination therapy.
      • Liu Z
      • Hao H
      • Yin C
      • Chu Y
      • Li J
      • Xu D.
      Therapeutic effects of atorvastatin and ezetimibe compared with double-dose atorvastatin in very elderly patients with acute coronary syndrome.
      In the Vytorin Versus Atorvastatin study,
      • Liu C
      • Liu Q
      • Xiao X.
      Effectiveness and safety of combinational therapy compared with intensified statin monotherapy in patients with coronary heart disease.
      the decrease in LDL-C was 9% greater with EZ10/AS40 compared with AS40 monotherapy in patients with hypercholesterolemia and established CHD or CHD risk equivalent. Two recent meta-analyses of data from 11 studies underlined the efficacy of combination therapy (EZ10/AS10) in lowering LDL-C compared with an escalating dose of atorvastatin monotherapy (AS20).
      • Yu M
      • Liang C
      • Kong Q
      • Wang Y
      • Li M.
      Efficacy of combination therapy with ezetimibe and statins versus a double dose of statin monotherapy in participants with hypercholesterolemia: a meta-analysis of literature.
      ,
      • Ai C
      • Zhang S
      • He Q
      • Shi J.
      Comparing the combination therapy of ezetimibe and atorvastatin with atorvastatin monotherapy for regulating blood lipids: a systematic review and meta-analysis.
      Another meta-analysis also demonstrated significantly improved LDL-C, non–high-density lipoprotein cholesterol, and total cholesterol levels with combination therapy (EZ10/AS20) compared with an escalating dose of atorvastatin monotherapy (AS40) in patients with high cardiovascular risk (all, P < 0.001).
      • Zhu Y
      • Hu H
      • Yang J
      • et al.
      The efficacy and safety of statin in combination with ezetimibe compared with double-dose statin in patients with high cardiovascular risk: a meta-analysis.
      These findings together provide strong scientific evidence that the addition of ezetimibe to atorvastatin may be useful in achieving significant improvement in LDL-C level in Chinese patients with hypercholesterolemia. These findings call for an FDC of ezetimibe and a statin that may improve medication adherence and tolerability while reducing pill burden in patients compared with free combinations of lipid-lowering therapy. In a large-scale observational study (N = 256,012) conducted for ∼7 years, the likelihood of adherence was higher with an EZ/simvastatin FDC (odds ratio = 1.84; 95% CI, 1.72–1.86) or an EZ/rosuvastatin FDC (odds ratio = 2.47; 95% CI, 2.31–2.65) compared with free combinations.
      • Rea F
      • Savaré L
      • Corrao G
      • Mancia G.
      Adherence to lipid-lowering treatment by single-pill combination of statin and ezetimibe.
      In a retrospective analysis in patients (n = 311,242) with a high cardiovascular risk, the reduction in LDL-C was significantly higher in patients treated with FDC of ezetimibe + a statin in comparison to those administered free combinations (mean reduction, 28.4% vs 19.4%; P < 0.0001). Consequently, a larger percentage of patients achieved the target LDL-C level of <70 mg/dL (31.5% vs 21.0%).
      • Katzmann JL
      • Sorio-Vilela F
      • Dornstauder E
      • et al.
      Non-statin lipid-lowering therapy over time in very-high-risk patients: effectiveness of fixed-dose statin/ezetimibe compared to separate pill combination on LDL-C.
      In the present study, >96% of patients with hypercholesterolemia were compliant with the FDC of EZ/AS, which seems to be clinically important. Thus, the FDC of ezetimibe + a statin may be an option useful for improving compliance without increasing the complexity of treatment.
      In the tolerability analysis in the present study, the combination therapy (EZ/AS) was well tolerated in Chinese patients with hypercholesterolemia and was comparable to the well-established AE profiles of ezetimibe and atorvastatin. Overall, there were low prevalences of AEs with both treatments. The 12-week tolerability results from the present study are commensurate with the tolerability findings from other studies of the EZ/AS combination.
      • Jacobson TA
      • Cheeley MK
      • Jones PH
      • et al.
      The Statin Adverse Treatment Experience Survey: experience of patients reporting side effects of statin therapy.
      ,
      • Ai C
      • Zhang S
      • He Q
      • Shi J.
      Comparing the combination therapy of ezetimibe and atorvastatin with atorvastatin monotherapy for regulating blood lipids: a systematic review and meta-analysis.
      In addition, no serious drug-related AEs, including death, were observed. Possibly, the low doses in the EZ/AS combination contributed to the low prevalence of AEs.
      Overall, the results from the present study are encouraging and in line with relevant recommendations and guidelines. Escalating the statin dose might not always correlate with efficacy, and it also limits the treatment options in patients with statin intolerance. Therefore, a combination of ezetimibe with a low to moderate statin dose seems to be a better option in terms of efficacy, without a compromise in tolerability; moreover, combination therapy also provides the physician and patient room for dose adjustments (eg, dose escalation if a low dose of statin is not efficient for achieving the treatment goal). These results also support the earlier finding that moderate-intensity statin therapy will yield better outcomes by reducing the LDL-C in Chinese patients with hypercholesterolemia, with an acceptable safety profile.

      Conclusions

      In this study, LDL-C levels were significantly improved with the FDCs of EZ10/AS10 and EZ10/AS20 versus escalating doses of atorvastatin (ie, AS20 and AS40) at week 12. These results may implicate clinical relevance of the atherosclerotic end points in the long term. Overall, the FDCs of EZ10/AS10 and EZ10/AS20 were well tolerated in these Chinese patients with hypercholesterolemia during the 12-week treatment period, with no new safety concerns. Further studies are required to evaluate the long-term clinical outcomes and tolerability of combination therapy (EZ/AS) for lowering LDL-C levels in patients with hypercholesterolemia.

      Declarations

      Xinru Ren is an employee of Merck Sharp & Dohme. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.

      Acknowledgments

      The authors thank the study participants, without whom this study would not have been accomplished. The authors also thank the investigators for conducting the study: Zheng Zhao Fen, Fang Zhi Hua, Shen Ai Dong, Zhu Hong, Hu Rong, Mei Yi Bin, Dong Yu Gang, Yao Zhu Hua, Zhang Xin, Yu Jing, Fu Lu, Wang Jing Feng, Li Hui, Gu Xiang, Wu Yan Qing, Mei Xia, Jiang Wei Hong, Long Ming Zhi, Zhou Lin, Huang Zhou Qing, Tang Cheng Chun, Mi Ya Fei, Jiang Ting Bo, and Cui Han Bin.
      The authors thank Dr. Palash Kumar Das, PhD, for providing medical writing assistance, and Dr. Shridevi Venkataramani, PhD (both Tata Consultancy Services, India), for providing additional editorial assistance toward the development of this article, funded by Organon.

      Author Contributions

      Drs. Juying Qian, Zhanquan Li, Xuelian Zhang, Jiyan Chen, Chunhua Ding, Ping Yang, and Junbo Ge were the principal investigators in this study and were also involved in conceiving, designing, or planning the study. Yan Liu and Dr. Miao Shi were involved in conceiving, designing, or planning the study, provided substantive suggestions, and performed data interpretation. Xinru Ren was the statistical lead and was primarily involved in statistical analyses and data interpretation. All of the authors contributed to the data interpretation, development, editing, and review of the manuscript; confirm that they have read the journal's position on issues involved in ethical publication; and affirm that this report is consistent with those guidelines.

      Funding

      This study was funded by Merck Sharp & Dohme and Organon, who were involved in study design; collection, analysis, and interpretation of the data; report writing; and the decision to submit the article for publication. Medical writing and editorial assistance were funded by Organon.

      Appendix. Supplementary materials

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