- Email: [email protected]
Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk
Clinical Therapeutics/Volume ], Number ], 2016
Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk Young-June Yang, MD1,2; Sang-Hak Lee, MD, PhD1,2; Byung Soo Kim, MD, PhD3; Yun-Kyeong Cho, MD, PhD4; Hyun-Jai Cho, MD, PhD5; Kyoung Im Cho, MD, PhD6; Seok-Yeon Kim, MD, PhD7; Jae Kean Ryu, MD, PhD8; Jin-Man Cho, MD, PhD9; Joong-Il Park, MD, PhD10; Jong-Seon Park, MD, PhD11; Chang Gyu Park, MD, PhD12; Woo Jung Chun, MD, PhD13; Myung-A Kim, MD, PhD14; Dong-Kyu Jin, MD, PhD15; Namho Lee, MD, PhD16; Byung Jin Kim, MD, PhD17; Kwang Kon Koh, MD, PhD18; Jon Suh, MD, PhD19; Seung-Hwan Lee, MD, PhD20; Byoung-Kwon Lee, MD, PhD21; Seung-Jin Oh, MD, PhD22; Han-Young Jin, MD, PhD23; Youngkeun Ahn24; Sang-Gon Lee25; Jang-Ho Bae26; Woo Jung Park27; Sang-Chol Lee28; Han Cheol Lee, MD, PhD29; Jaewon Lee30; Cheolwon Park30; Backhwan Lee30; and Yangsoo Jang, MD, PhD1,2 1
Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 2Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea; 3Division of Cardiology, Department of Internal Medicine, Daedong Hospital, Busan, Korea; 4 Division of Cardiology, Keimyung University Dongsan Medical Center, Daegu, Korea; 5Cardiovascular Center and Cardiovascular Research Institute, Seoul National University College of Medicine, Seoul, Korea; 6 Division of Cardiology, Department of Internal Medicine, Cardiovascular Research Institute, Kosin University School of Medicine, Busan, Korea; 7Department of Cardiology, Seoul Medical Center, Seoul, Korea; 8Department of Cardiology, Daegu Catholic University Medical Center, Daegu, Korea; 9 Department of Cardiology, Kyunghee University East-West Neo Medical Center, Seoul, Korea; 10Division of Cardiology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Korea; 11 Department of Medicine, Yeungnam University Medical Center, Daegu, Korea; 12Department of Cardiology, Korea University Guro Hospital, Seoul, Korea; 13Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea; 14Division of Cardiology, Department of Internal Medicine, SMG-SNU Seoul Boramae Hospital, Seoul, Korea; 15Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea; 16Cardiology Division, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, Korea; 17Division of Cardiology, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; 18Department of Cardiology, Gachon University Gil Medical Center, Incheon, Korea; 19Department of Cardiology, Soonchunhyang University Hospital Bucheon, Bucheon, Korea; 20 Division of Cardiology, Wonju College of Medicine, Yonsei University, Wonju, Korea; 21Division of Cardiology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of
Accepted for publication November 14, 2016. http://dx.doi.org/10.1016/j.clinthera.2016.11.014 0149-2918/$ - see front matter & 2016 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics
Medicine, Seoul, Korea; 22Division of Cardiology, Department of Internal Medicine, NHIS Ilsan Hospital, Goyang, Korea; 23Division of Cardiology, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea; 24Department of Cardiology, Heart Research Center of Chonnam National University, Gwangju, Korea; 25Department of Cardiology, Ulsan University College of Medicine, Ulsan, Korea; 26Division of Cardiology, Department of Internal Medicine, Konyang University Hospital, Daejeon, Korea; 27Division of Cardiology, Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea; 28Division of Cardiology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 29Division of Cardiology, Department of Internal Medicine, Pusan National University School of Medicine, Medical Research Institute, Pusan National University Hospital, Busan, Korea; and 30Research & Development Division, Alvogen Korea Co., Ltd., Seoul, Korea ABSTRACT Purpose: The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. Methods: This was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 337 patients were screened. After a 4-week run-in period, 245 of these patients with high or moderately high risk as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines were randomly assigned. Patients received 1 of 6 regimens for 8 weeks as follows: (1) rosuvastatin 5 mg, (2) rosuvastatin 5 mg/ezetimibe 10 mg, (3) rosuvastatin 10 mg, (4) rosuvastatin 10 mg/ ezetimibe 10 mg, (5) rosuvastatin 20 mg, or (6) rosuvastatin 20 mg/ezetimibe 10 mg. The primary outcome variable was percentage change in the level of LDL-C at week 8 of drug treatment. Secondary outcome variables included percentage changes of other lipid variables and achievement rates of LDL-C targets. Tolerability analyses were also performed. Findings: The percentage change of LDL-C ranged from –45% to –56% (mean, –51%) in the monotherapy groups and from –58% to –63% (mean, –60%) in the combination therapy groups. The percentage change was greater in the pooled combination therapy group than in the counterpart (P o 0.001 for the pooled groups); this difference was more obvious for regimens with a lower statin dose. The percentage reductions of total cholesterol and triglycerides were greater in the combination groups than in the monotherapy groups. The LDL-C target achievement rates were 64% to 87% (mean, 73%) in the monotherapy
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groups and 87% to 95% (mean, 91%) in the combination groups (P ¼ 0.01 for the pooled groups). The rates were significantly greater in patients receiving the combination therapy than in the monotherapy at lower doses of rosuvastatin. The proportions of patients with various adverse events were not significantly different between the groups. Implications: Rosuvastatin/ezetimibe combination therapy has better efficacy and target achievement rates than rosuvastatin monotherapy in patients with high cardiovascular risk. (Clin Ther. 2016;]:]]]–]]]) & 2016 Elsevier HS Journals, Inc. All rights reserved. Key words: cardiovascular diseases, cholesterol, drug combinations, ezetimibe, LDL, rosuvastatin calcium.
INTRODUCTION The absolute benefit of lipid-lowering therapy has been reported to be greater for patients with high cardiovascular risk.1 Thus, more aggressive lipid management has been recommended for this population.2 Accordingly, most guidelines have set lower target cholesterol levels or greater target percentage changes for these patients.2–4 However, although a lower cholesterol level is more desirable, these targets are more difficult to achieve in patients with high cardiovascular risk. In Asians with high cardiovascular risk, the LDL-C target achievement rate has been reported to be 57%, and 79% of patients with moderate risk attained the target.5 Latest guidelines recommend nonstatin lipid-lowering agents, including ezetimibe, in limited situations.2,3 However, after the IMPROVE-IT (Improved Reduction of
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Y.-J. Yang et al. Outcomes: Vytorin Efficacy International Trial) provided the first evidence of clinical benefit from the addition of ezetimibe,6 physicians prescribe this drug with more confidence.7 Among statins, rosuvastatin has been reported to be the most powerful for lowering LDL-C. In this regard, rosuvastatin and ezetimibe combination therapy seems to be a good option when the maximum tolerable dose of statin cannot sufficiently reduce LDL-C. The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. We enrolled more patients than previous studies conducted in Asia. Of particular note, we tested combinations of multiple doses of rosuvastatin up to 20 mg, the highest allowed dose in Korea. We observed incremental efficacy and LDL-C target achievement in this population.
PATIENTS AND METHODS Study Participants Men and women aged Z19 years with high or moderately high cardiovascular risk as classified by the National Cholesterol Education Program Adult Treatment Panel III) guidelines 3 were initially screened. After lifestyle modifications for a 4-week run-in period, individuals who met the following treatment guidelines were enrolled in the study: patients with coronary artery disease or its equivalent and a LDL-C level Z100 mg/ dL (high risk) or individuals with Z2 risk factors and 10-year risk of 10% to 20%, and a LDL-C level Z130 mg/dL (moderately high risk). Exclusion criteria included history of acute coronary syndrome, cerebrovascular disease, or symptomatic peripheral artery disease newly diagnosed in the past 3 months; interventional or surgical coronary revascularization in that period; congestive heart failure (New York Heart Association class III or IV); uncontrolled hypertension (systolic blood pressure Z180 mm Hg or diastolic blood pressure Z110 mm Hg) or arrhythmia; uncontrolled diabetes mellitus (glycosylated hemoglobin, 9.0%); thyroid dysfunction; active hepatobiliary disease; coagulopathy; serum creatinine 42.0 mg/dL; serum transaminase or creatine kinase 42 times upper limit of normal; cancer; or history of myopathy or hypersensitivity to test drugs. Pregnant women, breast-feeding women, and women of childbearing potential not taking contraception were not eligible to join the study. All participants provided written informed consent.
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Study Design This was a 12-week (4 weeks of lifestyle changes and 8 weeks of drug treatment), randomized, doubleblind, placebo-controlled, multicenter study conducted at 28 sites in Korea. The protocol was approved by the institutional review board at each center. At the screening visit, patients were interviewed about their medical history and underwent a physical examination and laboratory assessment. After discontinuation of any lipid-modifying agents, participants entered a 4-week run-in period. Individuals who met the treatment guidelines after the period were randomly assigned to receive 1 of the following 6 regimens: (1) rosuvastatin 5 mg (Crestor; AstraZeneca Korea, Seoul, Korea), (2) rosuvastatin 5 mg/ezetimibe 10 mg (DP-R207; Dream Pharma, Seoul, Korea), (3) rosuvastatin 10 mg (Crestor; AstraZeneca Korea), (4) rosuvastatin 10 mg/ezetimibe 10 mg (DP-R207; Dream Pharma), (5) rosuvastatin 20 mg (Crestor; AstraZeneca Korea), or (6) rosuvastatin 20 mg/ezetimibe 10 mg (DP-R207; Dream Pharma). After random assignment, participants were followed-up at the end of the 4th and 8th weeks for efficacy and tolerability. Fasting blood samples were collected at random assignment and at the end of the 8th week. Laboratory values, including lipid profiles, liver enzymes, and muscle enzymes, were measured at these time points. Samples were analyzed within 4 hours of collection by a local laboratory that was certified by the Korean Society of Laboratory Medicine. Tolerability assessments were based on reported adverse reactions, history taking, physical examinations, and laboratory evaluations. Investigators determined the association between test agents and adverse events (AEs).
Statistical Analysis The primary outcome variable was percentage change in the level of LDL-C from baseline to week 8 of drug treatment. Secondary outcome variables included percentage changes in total cholesterol, triglycerides, HDL-C, and LDL-C target achievement rate. The LDL-C targets were defined as o100 mg/dL for the high-risk group and as o130 mg/dL for the moderately high-risk group. Changes of variables in the same group from baseline to week 8 were also analyzed. A minimum of 33 participants per treatment group were required, assuming a power of 0.90 to report superiority of the rosuvastatin/ezetimibe combination. A [mean (SD)] 15% (5%) difference in
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Clinical Therapeutics LDL-C between the groups was defined as significant. In expectation of a 20% dropout rate, at least 42 individuals per each group were recruited. Efficacy analyses were conducted in the population that underwent follow-up tests for laboratory values. Tolerability analyses were performed for all participants who took the study agents more than once. Group differences in categorical variables were examined using the χ2 test, and continuous variables were assessed using Student’s t test. The paired t test was used to evaluate the differences before and after treatment in each group. Differences between the 2 groups were considered significant when the P value was o0.05 (2-sided). All data were analyzed using SAS software 9.3 (SAS Korea, Seoul, Korea).
RESULTS Baseline Characteristics A total of 377 patients were screened, 245 of whom were randomly assigned to treatment (Figure 1). After the run-in period, 132 patients did not meet the lipid criteria and were excluded. Of the 245 randomly assigned participants, 226 completed the study, and 19 patients dropped out for the following reasons: 11 due to withdrawal of consent, 6 due to protocol violation, and 2 due to adverse events. The clinical characteristics of the patients included in the safety profile analysis are shown in Table I. The mean age was 64 years; 60.6% of the patients were men. Ninety-nine
patients (41.9%) had diabetes mellitus, 159 patients (67.3%) had hypertension, and 63 patients (26.7%) had a history of coronary artery disease. The mean baseline LDL-C level was 153 mg/dL. Fifty-two patients (22.0%) and 184 patients (78.0%) were classified as high risk and moderately high risk, respectively. Demographic variables did not differ significantly between the groups randomly assigned to each regimen.
Changes in Lipid Profiles The LDL-C and total cholesterol levels were significantly reduced in all groups. Triglycerides were lowered in 3 groups receiving combination regimens and the group that received rosuvastatin 20 mg. The HDL-C level rose in 2 groups receiving combination regimens and 1 group receiving rosuvastatin monotherapy (Table II and Figure 2). The percentage change of LDL-C ranged from –45.3% to –56.0% (mean, –51.1%) in the monotherapy groups, whereas it ranged from –57.6% to –62.7% (mean, –59.5%) in the combination therapy groups (P o 0.001 for the pooled groups). The percentage change of LDL-C was greater in the group receiving rosuvastatin 5 mg/ezetimibe 10 mg than in the group receiving rosuvastatin 5 mg (–57.9% [10.4%] and –45.3% [15.1%], respectively; P o 0.001). The percentage change of LDL-C was greater, but not significantly, in the groups receiving rosuvastatin 10 mg or 20 mg/ ezetimibe 10 mg than in the groups receiving rosuvastatin 10 mg or 20 mg alone. The percentage reductions of total
Screening (N=377) Drop-out for risk criteria (N=132) Randomization (N=245)
Rosuva 5mg (N=40)
Rosuva 5mg/ ezetimibe 10mg (N=40)
Drop-out (N=2) Drop-out for AEs (N=0)
Drop-out (N=5) Drop-out (N=0) Drop-out for AEs (N=0)
Drop-out (N=6) Drop-out (N=4) Drop-out for AEs Drop-out for AEs (N=1) (N=0)
Completion (N=38)
Completion (N=35)
Completion (N=35)
Rosuva 10mg (N=40)
Completion (N=40)
Rosuva 10mg/ ezetimibe 10mg (N=41)
Rosuva 20mg (N=41)
Completion (N=37)
Rosuva 20mg/ ezetimibe 10mg (N=43)
Drop-out (N=2) Drop-out for AEs (N=1)
Completion (N=41)
Figure 1. Study profile showing the numbers of patients who participated in and dropped out of the progress. AE ¼ adverse event; Rosuva ¼ rosuvastatin.
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] 2016 Table I. Baseline characteristics of the study participants.
Characteristic Age, mean (SD), y Male, no. (%) Medical history, no. (%) Hypertension Diabetes mellitus Current smoker CAD Body mass index, mean (SD), kg/m2 Lipid profiles, mean (SD), mg/dL LDL-C Total cholesterol Triglycerides, median (25th percentile, 75th percentile) HDL-C Total cholesterol/ HDL-C
Rosuvastatin Rosuvastatin 5 mg/ Ezetimibe 5 mg (n ¼ 39) 10 mg (n ¼ 38) 66.1 (7.8) 17 (43.6) 30 18 9 10 25.6
(76.9) (46.2) (23.1) (25.6) (2.8)
64. 8 (8.2) 21 (55.3) 27 14 7 10 25.0
(71.1) (36.8) (18.4) (26.3) (2.4)
P
Rosuvastatin Rosuvastatin 10 mg 10 mg/ Ezetimibe (n ¼ 40) 10 mg (n ¼ 38)
P
Rosuvastatin Rosuvastatin 20 mg/Ezetimibe 20 mg (n ¼ 39) 10 mg (n ¼42)
P
0.47 64.0 (8.9) 0.31 26 (65.0)
62.1 (9.5) 24 (63.2)
0.38 62.7 (9.6) 0.87 26 (66.7)
64.7 (8.8) 29 (69.0)
0.33 0.82
0.56 24 0.41 17 0.42 4 0.95 12 0.30 25.3
23 12 8 6 24.6
0.96 29 0.32 22 0.08 7 0.14 8 0.19 25.5
26 16 9 17 25.1
0.23 0.10 0.87 0.052 0.26
(60.0) (42.5) (10.0) (30.0) (2.3)
(60.5) (31.6) (21.1) (15.8) (2.3)
(74.4) (56.4) (17.9) (20.5) (2.6)
157 (30) 234 (38) 161 (106, 190)
157 (32) 0.94 156 (30) 236 (33) 0.74 229 (36) 152 (117, 223) 0.63 136 (99, 173)
149 (27) 225 (30) 146 (96, 194)
0.29 150 (38) 0.66 224 (39) 0.73 148 (104, 217)
50.1 (16.9) 5.01 (1.45)
50.1 (13.3) 4.98 (1.29)
50.6 (12.8) 4.71 (1.26)
0.44 47.5 (9.) 0.30 4.86 (1.26)
0.99 48.2 (13.4) 0.92 5.00 (1.20)
(61.9) (38.1) (21.4) (40.5) (3.5)
148 (30) 0.75 219 (38) 0.61 143 (107, 177) 0.76
46.3 (12.5) 4.97 (1.25)
0.61 0.69
CAD ¼ coronary artery disease.
Y.-J. Yang et al.
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Variable
Rosuvastatin 5 mg (n ¼ 39)
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LDL-C, mean (SD), mg/dL Before 157 (30) After 85 (24) % Change –45.3 (15.01 P* o0.001 Total cholesterol, mean (SD), mg/dL Before 234 (38) After 161 (31) % Change –30.4 (11.3) P† o0.001 Triglycerides, median (25th percentile, 75th percentile), mg/dL Before 161 (106, 190) After 125 (101, 159) % Change –17.9 (–38.3, 24.4) P† 0.27 HDL-C, mean (SD), mg/dL Before 50.1 (16.)9 After 51.8 (16.6) % Change 5.3 (19.8) P† 0.11 *
Rosuvastatin 5 mg/Ezetimibe 10 mg (n ¼ 38)
Pa
Rosuvastatin 20 mg (n ¼ 39)
Rosuvastatin 20 mg/Ezetimibe 10 mg (n ¼ 42)
Pa
157 (32) 65 (18) –57.9 (10.4) o0.001
0.94 156 (30) o0.001 75 (30) o0.001 –51.9 (15.6) o0.001
149 (27) 62 (25) –57.6 (17.4) o0.001
0.29 0.04 0.13
150 (38) 65 (28) –56.0 (17.2) o0.001
148 (30) 52 (24) –62.7 (22.0) o0.001
0.75 0.03 0.13
236 (33) 137 (24) –41.7 (7.8) o0.001
0.74 229 (36) o0.001 147 (36) o0.001 –35.7 (12.1) o0.001
225 (30) 136 (28) –39.2 (12.8) o0.001
0.66 0.13 0.21
224 (39) 135 (32) –39.2 (13.2) o0.001
219 (38) 120 (28) –43.8 (16.4) o0.001
0.61 0.03 0.18
143 (107, 177) 95 (70, 114) –36.4 (–48.9, –9.6) o0.001
0.76 0.11 0.36
46.3 (12.5) 50.4 (11.9) 10.9 (17.6) o0.001
0.61 0.81 0.21
152 (117, 223) 105 (83, 136) –29.7 (–44.4, –9.8) o0.001
0.63 0.03 0.01
136 (99, 173) 129 (91, 165) –12.2 (–33.2, 34.8) 0.89
146 (96, 194) 103 (87, 149) –18.6 (–46.8, –7.3) 0.01
50.1 (13.3) 52.6 (13.6) 6.1 (12.6) 0.01
0.99 0.82 0.83
48.2 (13.4) 49.9 (11.5) 6.0 (16.5) 0.03
50.6 (12.8) 52.2 (12.8) 5.1 (17.7) 0.08
Comparison between groups. Comparison in a group before and after treatment.
†
Pa
Rosuvastatin Rosuvastatin 10 mg 10 mg/Ezetimibe (n ¼ 40) 10 mg (n ¼ 38)
0.73 148 (104, 217) 0.22 105 (86, 132) 0.13 –26.4 (–48.7, –2.7) o0.001
0.44 0.40 0.82
47.5 (9.2) 49.8 (11.0) 5.9 (18.4) 0.054
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Table II. Changes of laboratory values.
-20 -40 -60 -80
*
*
10 m 10 g R mg 10 m g+ E 10 R m 20 g R mg 20 m g+ E 10 m g R
5m g 5m g+ E R
R
B
Po o
led
10 m 10 g R mg 10 m g+ E 10 R m 20 g R mg 20 m g+ E 10 m g R
5m g 5m g+ E R
R
0
% change of TC
% change of LDL-C
A
Po o
led
Y.-J. Yang et al.
0 -20 -40
*
*
-60 -80
Rosuvastatin Rosuvastatin+ezetimibe
D
0 -20 -40
*
*
-60 -80
% change of HDL-c
% change of TG
C
15 10 5 0
Figure 2. Percentage changes of lipid profiles in each group. *P o 0.05. E ¼ ezetimibe; R ¼ rosuvastatin; TC ¼ total cholesterol; TG ¼ triglycerides.
Tolerability The proportions of patients who experienced any AE in the rosuvastatin monotherapy and the
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rosuvastatin/ezetimibe combination groups were similar (26 patients [21.5%] and 26 patients [21.1%], respectively). The number of patients with treatmentrelated AEs was higher, but not significantly, in the
Rosuvastatin Rosuvastatin+ezetimibe
*
*
100 75 50 25
m R2 g+ 0m E 10 g m g 20 R
m R g+ 10 E m 10 g m g 10
5m R
R
led
R g+ 5m E 10 g m g
0 Po o
% patients achieved LDL-C targets
cholesterol and triglycerides were also greater in the group receiving rosuvastatin 5 mg/ezetimibe 10 mg than in its monotherapy counterpart (P o 0.001). The percentage changes of HDL-C were not significantly different between the combination and monotherapy groups (Table II and Figure 2). The rate of LDL-C target achievement ranged from 64.1% to 87.2% (mean, 72.9%) in the monotherapy groups and 86.8% to 94.7% (mean, 90.7%) in the combination groups (P ¼ 0.01 for the pooled groups). The rate was higher in the group receiving rosuvastatin 5 mg/ezetimibe 10 mg than in the group receiving rosuvastatin 5 mg alone (94.7% and 64.1%, respectively; P o 0.001). The rate was also greater in participants receiving rosuvastatin 10 mg/ezetimibe 10 mg than in their counterpart (86.8% and 67.5%, respectively; P ¼ 0.043), whereas the rate was not significantly different between the groups receiving rosuvastatin 20 mg/ezetimibe 10 mg and rosuvastatin 20 mg alone (90.5% and 87.2%, respectively; P ¼ 0.73) (Figure 3).
Figure 3. LDL-C target achievement rates in each group. *P o 0.05. E ¼ ezetimibe; R ¼ rosuvastatin.
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Table III. AEs in the participants who took the study drugs. Rosuvastatin (n ¼ 121) Patients with any AEs Patients with treatment-related AEs Patients with serious AEs Discontinuation of test drugs due to AEs Gastrointestinal AEs Musculoskeletal AEs Rhabdomyolysis Liver function tests Z3 ULN, 2 consecutive times Alanine aminotransferase increased Aspartate aminotransferase increased Creatine kinase Z10 ULN
26 2 2 0 5 1 0
(21.5) (1.7) (1.7) (0.0) (4.1) (0.8) (0.0)
0 (0.0) 0 (0.0) 0 (0.0)
Rosuvastatin þ Ezetimibe (n ¼ 123) 26 7 3 2 3 3 0
(21.1) (5.7) (2.4) (1.6) (2.4) (2.4) (0.0)
0 (0.0) 0 (0.0) 0 (0.0)
P 0.95 0.10 1.00 0.50 0.50 0.62 — — — —
Variables are expressed as number (%). AE ¼ adverse event; ULN ¼ upper limit of normal.
combination groups than in the monotherapy groups (7 patients [5.7%] and 2 patients [1.7%], respectively). Patients with serious AEs or discontinued drugs for AEs were not common in either group. No individuals reported rhabdomyolysis, liver enzyme elevation, or muscle enzyme elevation above predefined levels (Table III).
DISCUSSION The main findings of this study are (1) the lipidlowering efficacy of rosuvastatin/ezetimibe combination therapy was greater than that of rosuvastatin monotherapy (–60% vs –51% for the pooled groups), particularly for regimens with a lower statin dose; (2) the ezetimibe combination therapy lowered LDL-C to –63% with an additive reduction of 6%–12%; (3) the mean LDL-C target achievement rate was 91%, which was significantly higher than the 73% that achieved with monotherapy; (4) tolerability of the regimens with or without ezetimibe were not significantly different. Our study indicates that rosuvastatin/ezetimibe combination therapy is a reasonable option for lipid management in patients with high cardiovascular risk. In a previous study using multiple statins and doses, additive reduction of LDL-C by ezetimibe 10 mg was 10% to 14%.8 In that study, conducted in
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centers in the United States, South America, and Europe, the combination of rosuvastatin 10 mg/ ezetimibe 10 mg lowered LDL-C by 60%, whereas the combination of rosuvastatin 20 mg/ezetimibe 10 mg decreased LDL-C by 64%. We observed similar efficacies in LDL-C reduction (58% and 63%, respectively) with the same combination regimens. In a recent Korean study that evaluated similar regimens to ours, the percentage changes of LDL-C were –59% and –49% in the pooled groups of combination and rosuvastatin monotherapy, respectively.9 These outcomes are comparable with our results. Higher incremental LDL-C reduction at lower dose atorvastatin and lower incremental reduction at higher dose atorvastatin have been previously reported.10 This attenuation of incremental LDL-C reduction by ezetimibe with a higher dose statin is not consistently observed with all statins.11 However, decreased cholesterol excretion to bile due to high-dose statin can lessen the effect of ezetimibe 12; this mechanism may partly explain the findings of the present study. In the study by Ballantyne et al,8 the LDL-C target achievement rate ranged from 67% to 93% with rosuvastatin 10 mg/ezetimibe 10 mg, whereas it ranged from 77% to 96% with rosuvastatin 20 mg/ ezetimibe 10 mg. Our achievement rates in Koreans were 87% and 91% with the same regimens; we note that these rates are quite similar to those in other
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Y.-J. Yang et al. ethnic groups. Although incremental elevation of the achievement rate by ezetimibe varied according to statin dose, ezetimibe-mediated elevation was approximately18% in our study, which is comparable with that reported in a pooled analysis.13 Interestingly, the rates in our study are higher than those reported in a Korean survey in 2014. In the survey, the LDL-C goal attainment rate was 79% for high-risk patients who were prescribed commonly used statins.5 Improved target achievement rate, with the same combination, was also reported in the Korean study mentioned above. The rates in the study were 94% and 86% in the pooled groups of combination and rosuvastatin monotherapy, respectively.9 The present study indicates that rosuvastatin/ ezetimibe combination therapy is superior for achieving treatment targets in high-risk patients in whom the benefit of aggressive lipid management is known to be concrete. Although the IMPROVE-IT trial reported the clinical impact of LDL-C lowering with statin/ezetimibe combination,6 it is still uncertain whether the effect of this combination therapy is different from that of statin monotherapy. The addition of ezetimibe to statin therapy was recently reported to further lower LDL-C and to concomitantly reduce plaque volume.14,15 A large part of the additive benefit of the combination might have been due to its greater ability to lower LDL-C. Future studies testing the pleiotropic effects of ezetimibe need to be performed to identify other potential mechanism. Data on the safety profile of statin/ezetimibe combination therapy are scarce, particularly in Asian patients. In a study that included mostly Caucasian individuals, the incidences of AEs that occurred after the addition of ezetimibe were 40% for total AEs, 0.9% for serious AEs, and 1.8% for discontinuation of the test drugs.16 In another study, when ezetimibe 10 mg was added to the regimen of patients already under treatment with rosuvastatin 10 mg or 20 mg, the total AEs, serious AEs, and discontinuation rates were 54%, 8%, and 8%, respectively.17 However, these data are from patients who took ezetimibe in addition to ongoing statin therapy. Conversely, a small study comparing a combination regimen with statin monotherapy in a Chinese population found that alanine aminotransferase was not elevated in the combination group.18 Our study was performed on a larger population, and we did not observe increased
] 2016
AEs in patients who received combination regimens, including the maximum approved dose of rosuvastatin in Korea. This study was not designed to have sufficient power to identify a difference in the safety profiles of the regimens. However, to our knowledge, our study is one of the largest randomized trial that examined the safety profile of a rosuvastatin/ezetimibe regimen in an East Asian population. Thus, our results can be used as references for further studies. A main strength of our study is that we obtained treatment data for multiple doses of rosuvastatin/ ezetimibe. To date, few reports have studied these combinations in Asians. Previous studies used rosuvastatin 2.5 mg,19,20 5 mg,15 or 10 mg18 in small populations. The only study using rosuvastatin 20 mg in Asians was conducted in patients with familial hypercholesterolemia.21 It is worth mentioning that the present study found high efficacy of the statin/ ezetimibe combination in Asians and is thus anticipated to provide valuable information to clinicians who are treating patients with high cardiovascular risk.
Limitations Our study has several limitations. First, the incidence rates of adverse events were similar between the patients receiving combination therapy and those receiving monotherapy. However, because the power calculation in this study was based on efficacy and not tolerability, we cannot derive a solid conclusion on the tolerability of regimens with our present results. Especially, longer duration of treatment would be needed to obtain a more clear data on drug safety profile. Second, our results on the efficacy of combination regimens do not directly indicate the benefits on clinical outcomes. However, we can infer their benefits based on the results of IMPROVE-IT trial.
Future Directions Better LDL-C lowering and target achievement using combination therapy may be a reasonable option for high-risk patients, in whom the benefits of aggressive lipid therapy have been established. The clinical benefit of the statin and ezetimibe combination therapy was recently proved. However, a related trial was conducted in high-risk patients with acute coronary syndrome. Therefore, it needs to be clarified whether the benefit of such regimen is also valid in patients at intermediate or lower risk. In
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Clinical Therapeutics addition, it would be helpful to study if a more aggressive lipid-lowering regimen, compared with present guidelines, may have more clinical benefit in diverse risk groups.
CONCLUSIONS Taken together, our results indicate that rosuvastatin/ ezetimibe combination therapy has better efficacy than rosuvastatin monotherapy. Specifically, the combination therapy lowered LDL-C to –63% and achieved the LDLC target in 91% of Koreans with high cardiovascular risk.
AUTHOR CONTRIBUTION Literature search (YJ Y, SH L), Figure creation (YJ Y, SH L), study design (SH L, BS K, YK C, HJ C, KI C, SY K, JK R, JM C, JI P, JS P, CG P, WJ C, MA K, DK J, N L, BJ K, KK K, J S, SH L, BK L, SJ O, HY J, Y A, SG L, JH B, WJ P, SC L, HC L, J L, C P, B L, Y J), data collection (BS K, YK C, HJ C, KI C, SY K, JK R, JM C, JI P, JS P, CG P, WJ C, MA K, DK J, N L, BJ K, KK K, J S, SH L, BK L, SJ O, HY J, Y A, SG L, JH B, WJ P, SC L, HC, L), data interpretation (YJ Y, SH L, Y J), writing (YJ Y, SH L).
CONFLICTS OF INTEREST This research was financially supported by Alvogen Korea Co, Ltd.
REFERENCES 1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, Emberson J, et al, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681. 2. Stone NJ, Robinson JG, Lichtenstein AH, et al, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129: S1–S45. 3. Grundy SM, Cleeman JI, Merz CN, et al, National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239.
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4. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, et al, ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–1818. 5. Sung J, Kim SH, Song HR, Chi MH, Park JE. Lipidlowering treatment practice patterns in Korea: comparison with the data obtained from the CEPHEUS Pan-Asian study. J Atheroscler Thromb. 2014;21:1219–1227. 6. Cannon CP, Blazing MA, Giugliano RP, et al, IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–2397. 7. Writing Committee. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al, 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDLcholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68:92–125. 8. Ballantyne CM, Hoogeveen RC, Raya JL, et al, GRAVITY Study Investigators. Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: results of the GRAVITY randomized study. Atherosclerosis. 2014;232:86–93. 9. Kim KJ, Kim SH, Yoon YW, et al. Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe). Cardiovasc Ther. 2016;34:371–382. 10. Ballantyne CM, Houri J, Notarbartolo A, et al, Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107:2409–2415. 11. Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002;40:2125–2134. 12. Mitchell JC, Logan GM, Stone BG, Duane WC. Effects of lovastatin on biliary lipid secretion and bile acid metabolism in humans. J Lipid Res. 1991;32:71–78. 13. Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012;223:251–261. 14. Tsujita K, Sugiyama S, Sumida H, et al, PRECISE–IVUS Investigators. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression
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in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISEIVUS trial. J Am Coll Cardiol. 2015;66:495–507. Masuda J, Tanigawa T, Yamada T, et al. Effect of combination therapy of ezetimibe and rosuvastatin on regression of coronary atherosclerosis in patients with coronary artery disease. Int Heart J. 2015;56:278–285. Robinson JG, Nedergaard BS, Rogers WJ, et al, LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDLC lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311:1870–1882. Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: the ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138–146. 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. Lipids Health Dis. 2015;14:10. Okada K, Iwahashi N, Endo T, et al. Long-term effects of ezetimibe-plusstatin therapy on low-density lipoprotein cholesterol levels as compared with double-dose statin therapy in patients with coronary artery disease. Atherosclerosis. 2012;224:454–456. Torimoto K, Okada Y, Mori H, et al. Efficacy of combination of Ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes. Lipids Health Dis. 2013;12:137. Kawashiri MA, Nohara A, Noguchi T, et al. Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia. Am J Cardiol. 2012;109:364–369.
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Address correspondence to: Yangsoo Jang, MD, PhD, Sang-Hak Lee, MD, PhD, Division of Cardiology, Department of Internal Medicine, Severance Hospital, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, Korea. E-mail: [email protected], [email protected]
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Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk Young-June Yang, MD1,2; Sang-Hak Lee, MD, PhD1,2; Byung Soo Kim, MD, PhD3; Yun-Kyeong Cho, MD, PhD4; Hyun-Jai Cho, MD, PhD5; Kyoung Im Cho, MD, PhD6; Seok-Yeon Kim, MD, PhD7; Jae Kean Ryu, MD, PhD8; Jin-Man Cho, MD, PhD9; Joong-Il Park, MD, PhD10; Jong-Seon Park, MD, PhD11; Chang Gyu Park, MD, PhD12; Woo Jung Chun, MD, PhD13; Myung-A Kim, MD, PhD14; Dong-Kyu Jin, MD, PhD15; Namho Lee, MD, PhD16; Byung Jin Kim, MD, PhD17; Kwang Kon Koh, MD, PhD18; Jon Suh, MD, PhD19; Seung-Hwan Lee, MD, PhD20; Byoung-Kwon Lee, MD, PhD21; Seung-Jin Oh, MD, PhD22; Han-Young Jin, MD, PhD23; Youngkeun Ahn24; Sang-Gon Lee25; Jang-Ho Bae26; Woo Jung Park27; Sang-Chol Lee28; Han Cheol Lee, MD, PhD29; Jaewon Lee30; Cheolwon Park30; Backhwan Lee30; and Yangsoo Jang, MD, PhD1,2 1
Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 2Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea; 3Division of Cardiology, Department of Internal Medicine, Daedong Hospital, Busan, Korea; 4 Division of Cardiology, Keimyung University Dongsan Medical Center, Daegu, Korea; 5Cardiovascular Center and Cardiovascular Research Institute, Seoul National University College of Medicine, Seoul, Korea; 6 Division of Cardiology, Department of Internal Medicine, Cardiovascular Research Institute, Kosin University School of Medicine, Busan, Korea; 7Department of Cardiology, Seoul Medical Center, Seoul, Korea; 8Department of Cardiology, Daegu Catholic University Medical Center, Daegu, Korea; 9 Department of Cardiology, Kyunghee University East-West Neo Medical Center, Seoul, Korea; 10Division of Cardiology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Korea; 11 Department of Medicine, Yeungnam University Medical Center, Daegu, Korea; 12Department of Cardiology, Korea University Guro Hospital, Seoul, Korea; 13Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea; 14Division of Cardiology, Department of Internal Medicine, SMG-SNU Seoul Boramae Hospital, Seoul, Korea; 15Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea; 16Cardiology Division, Kangnam Sacred Heart Hospital, Hallym University Medical Center, Seoul, Korea; 17Division of Cardiology, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; 18Department of Cardiology, Gachon University Gil Medical Center, Incheon, Korea; 19Department of Cardiology, Soonchunhyang University Hospital Bucheon, Bucheon, Korea; 20 Division of Cardiology, Wonju College of Medicine, Yonsei University, Wonju, Korea; 21Division of Cardiology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of
Accepted for publication November 14, 2016. http://dx.doi.org/10.1016/j.clinthera.2016.11.014 0149-2918/$ - see front matter & 2016 Elsevier HS Journals, Inc. All rights reserved.
] 2016
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Clinical Therapeutics
Medicine, Seoul, Korea; 22Division of Cardiology, Department of Internal Medicine, NHIS Ilsan Hospital, Goyang, Korea; 23Division of Cardiology, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea; 24Department of Cardiology, Heart Research Center of Chonnam National University, Gwangju, Korea; 25Department of Cardiology, Ulsan University College of Medicine, Ulsan, Korea; 26Division of Cardiology, Department of Internal Medicine, Konyang University Hospital, Daejeon, Korea; 27Division of Cardiology, Department of Internal Medicine, Hallym University Medical Center, Anyang, Korea; 28Division of Cardiology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 29Division of Cardiology, Department of Internal Medicine, Pusan National University School of Medicine, Medical Research Institute, Pusan National University Hospital, Busan, Korea; and 30Research & Development Division, Alvogen Korea Co., Ltd., Seoul, Korea ABSTRACT Purpose: The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. Methods: This was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 337 patients were screened. After a 4-week run-in period, 245 of these patients with high or moderately high risk as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines were randomly assigned. Patients received 1 of 6 regimens for 8 weeks as follows: (1) rosuvastatin 5 mg, (2) rosuvastatin 5 mg/ezetimibe 10 mg, (3) rosuvastatin 10 mg, (4) rosuvastatin 10 mg/ ezetimibe 10 mg, (5) rosuvastatin 20 mg, or (6) rosuvastatin 20 mg/ezetimibe 10 mg. The primary outcome variable was percentage change in the level of LDL-C at week 8 of drug treatment. Secondary outcome variables included percentage changes of other lipid variables and achievement rates of LDL-C targets. Tolerability analyses were also performed. Findings: The percentage change of LDL-C ranged from –45% to –56% (mean, –51%) in the monotherapy groups and from –58% to –63% (mean, –60%) in the combination therapy groups. The percentage change was greater in the pooled combination therapy group than in the counterpart (P o 0.001 for the pooled groups); this difference was more obvious for regimens with a lower statin dose. The percentage reductions of total cholesterol and triglycerides were greater in the combination groups than in the monotherapy groups. The LDL-C target achievement rates were 64% to 87% (mean, 73%) in the monotherapy
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groups and 87% to 95% (mean, 91%) in the combination groups (P ¼ 0.01 for the pooled groups). The rates were significantly greater in patients receiving the combination therapy than in the monotherapy at lower doses of rosuvastatin. The proportions of patients with various adverse events were not significantly different between the groups. Implications: Rosuvastatin/ezetimibe combination therapy has better efficacy and target achievement rates than rosuvastatin monotherapy in patients with high cardiovascular risk. (Clin Ther. 2016;]:]]]–]]]) & 2016 Elsevier HS Journals, Inc. All rights reserved. Key words: cardiovascular diseases, cholesterol, drug combinations, ezetimibe, LDL, rosuvastatin calcium.
INTRODUCTION The absolute benefit of lipid-lowering therapy has been reported to be greater for patients with high cardiovascular risk.1 Thus, more aggressive lipid management has been recommended for this population.2 Accordingly, most guidelines have set lower target cholesterol levels or greater target percentage changes for these patients.2–4 However, although a lower cholesterol level is more desirable, these targets are more difficult to achieve in patients with high cardiovascular risk. In Asians with high cardiovascular risk, the LDL-C target achievement rate has been reported to be 57%, and 79% of patients with moderate risk attained the target.5 Latest guidelines recommend nonstatin lipid-lowering agents, including ezetimibe, in limited situations.2,3 However, after the IMPROVE-IT (Improved Reduction of
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Y.-J. Yang et al. Outcomes: Vytorin Efficacy International Trial) provided the first evidence of clinical benefit from the addition of ezetimibe,6 physicians prescribe this drug with more confidence.7 Among statins, rosuvastatin has been reported to be the most powerful for lowering LDL-C. In this regard, rosuvastatin and ezetimibe combination therapy seems to be a good option when the maximum tolerable dose of statin cannot sufficiently reduce LDL-C. The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. We enrolled more patients than previous studies conducted in Asia. Of particular note, we tested combinations of multiple doses of rosuvastatin up to 20 mg, the highest allowed dose in Korea. We observed incremental efficacy and LDL-C target achievement in this population.
PATIENTS AND METHODS Study Participants Men and women aged Z19 years with high or moderately high cardiovascular risk as classified by the National Cholesterol Education Program Adult Treatment Panel III) guidelines 3 were initially screened. After lifestyle modifications for a 4-week run-in period, individuals who met the following treatment guidelines were enrolled in the study: patients with coronary artery disease or its equivalent and a LDL-C level Z100 mg/ dL (high risk) or individuals with Z2 risk factors and 10-year risk of 10% to 20%, and a LDL-C level Z130 mg/dL (moderately high risk). Exclusion criteria included history of acute coronary syndrome, cerebrovascular disease, or symptomatic peripheral artery disease newly diagnosed in the past 3 months; interventional or surgical coronary revascularization in that period; congestive heart failure (New York Heart Association class III or IV); uncontrolled hypertension (systolic blood pressure Z180 mm Hg or diastolic blood pressure Z110 mm Hg) or arrhythmia; uncontrolled diabetes mellitus (glycosylated hemoglobin, 9.0%); thyroid dysfunction; active hepatobiliary disease; coagulopathy; serum creatinine 42.0 mg/dL; serum transaminase or creatine kinase 42 times upper limit of normal; cancer; or history of myopathy or hypersensitivity to test drugs. Pregnant women, breast-feeding women, and women of childbearing potential not taking contraception were not eligible to join the study. All participants provided written informed consent.
] 2016
Study Design This was a 12-week (4 weeks of lifestyle changes and 8 weeks of drug treatment), randomized, doubleblind, placebo-controlled, multicenter study conducted at 28 sites in Korea. The protocol was approved by the institutional review board at each center. At the screening visit, patients were interviewed about their medical history and underwent a physical examination and laboratory assessment. After discontinuation of any lipid-modifying agents, participants entered a 4-week run-in period. Individuals who met the treatment guidelines after the period were randomly assigned to receive 1 of the following 6 regimens: (1) rosuvastatin 5 mg (Crestor; AstraZeneca Korea, Seoul, Korea), (2) rosuvastatin 5 mg/ezetimibe 10 mg (DP-R207; Dream Pharma, Seoul, Korea), (3) rosuvastatin 10 mg (Crestor; AstraZeneca Korea), (4) rosuvastatin 10 mg/ezetimibe 10 mg (DP-R207; Dream Pharma), (5) rosuvastatin 20 mg (Crestor; AstraZeneca Korea), or (6) rosuvastatin 20 mg/ezetimibe 10 mg (DP-R207; Dream Pharma). After random assignment, participants were followed-up at the end of the 4th and 8th weeks for efficacy and tolerability. Fasting blood samples were collected at random assignment and at the end of the 8th week. Laboratory values, including lipid profiles, liver enzymes, and muscle enzymes, were measured at these time points. Samples were analyzed within 4 hours of collection by a local laboratory that was certified by the Korean Society of Laboratory Medicine. Tolerability assessments were based on reported adverse reactions, history taking, physical examinations, and laboratory evaluations. Investigators determined the association between test agents and adverse events (AEs).
Statistical Analysis The primary outcome variable was percentage change in the level of LDL-C from baseline to week 8 of drug treatment. Secondary outcome variables included percentage changes in total cholesterol, triglycerides, HDL-C, and LDL-C target achievement rate. The LDL-C targets were defined as o100 mg/dL for the high-risk group and as o130 mg/dL for the moderately high-risk group. Changes of variables in the same group from baseline to week 8 were also analyzed. A minimum of 33 participants per treatment group were required, assuming a power of 0.90 to report superiority of the rosuvastatin/ezetimibe combination. A [mean (SD)] 15% (5%) difference in
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Clinical Therapeutics LDL-C between the groups was defined as significant. In expectation of a 20% dropout rate, at least 42 individuals per each group were recruited. Efficacy analyses were conducted in the population that underwent follow-up tests for laboratory values. Tolerability analyses were performed for all participants who took the study agents more than once. Group differences in categorical variables were examined using the χ2 test, and continuous variables were assessed using Student’s t test. The paired t test was used to evaluate the differences before and after treatment in each group. Differences between the 2 groups were considered significant when the P value was o0.05 (2-sided). All data were analyzed using SAS software 9.3 (SAS Korea, Seoul, Korea).
RESULTS Baseline Characteristics A total of 377 patients were screened, 245 of whom were randomly assigned to treatment (Figure 1). After the run-in period, 132 patients did not meet the lipid criteria and were excluded. Of the 245 randomly assigned participants, 226 completed the study, and 19 patients dropped out for the following reasons: 11 due to withdrawal of consent, 6 due to protocol violation, and 2 due to adverse events. The clinical characteristics of the patients included in the safety profile analysis are shown in Table I. The mean age was 64 years; 60.6% of the patients were men. Ninety-nine
patients (41.9%) had diabetes mellitus, 159 patients (67.3%) had hypertension, and 63 patients (26.7%) had a history of coronary artery disease. The mean baseline LDL-C level was 153 mg/dL. Fifty-two patients (22.0%) and 184 patients (78.0%) were classified as high risk and moderately high risk, respectively. Demographic variables did not differ significantly between the groups randomly assigned to each regimen.
Changes in Lipid Profiles The LDL-C and total cholesterol levels were significantly reduced in all groups. Triglycerides were lowered in 3 groups receiving combination regimens and the group that received rosuvastatin 20 mg. The HDL-C level rose in 2 groups receiving combination regimens and 1 group receiving rosuvastatin monotherapy (Table II and Figure 2). The percentage change of LDL-C ranged from –45.3% to –56.0% (mean, –51.1%) in the monotherapy groups, whereas it ranged from –57.6% to –62.7% (mean, –59.5%) in the combination therapy groups (P o 0.001 for the pooled groups). The percentage change of LDL-C was greater in the group receiving rosuvastatin 5 mg/ezetimibe 10 mg than in the group receiving rosuvastatin 5 mg (–57.9% [10.4%] and –45.3% [15.1%], respectively; P o 0.001). The percentage change of LDL-C was greater, but not significantly, in the groups receiving rosuvastatin 10 mg or 20 mg/ ezetimibe 10 mg than in the groups receiving rosuvastatin 10 mg or 20 mg alone. The percentage reductions of total
Screening (N=377) Drop-out for risk criteria (N=132) Randomization (N=245)
Rosuva 5mg (N=40)
Rosuva 5mg/ ezetimibe 10mg (N=40)
Drop-out (N=2) Drop-out for AEs (N=0)
Drop-out (N=5) Drop-out (N=0) Drop-out for AEs (N=0)
Drop-out (N=6) Drop-out (N=4) Drop-out for AEs Drop-out for AEs (N=1) (N=0)
Completion (N=38)
Completion (N=35)
Completion (N=35)
Rosuva 10mg (N=40)
Completion (N=40)
Rosuva 10mg/ ezetimibe 10mg (N=41)
Rosuva 20mg (N=41)
Completion (N=37)
Rosuva 20mg/ ezetimibe 10mg (N=43)
Drop-out (N=2) Drop-out for AEs (N=1)
Completion (N=41)
Figure 1. Study profile showing the numbers of patients who participated in and dropped out of the progress. AE ¼ adverse event; Rosuva ¼ rosuvastatin.
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Characteristic Age, mean (SD), y Male, no. (%) Medical history, no. (%) Hypertension Diabetes mellitus Current smoker CAD Body mass index, mean (SD), kg/m2 Lipid profiles, mean (SD), mg/dL LDL-C Total cholesterol Triglycerides, median (25th percentile, 75th percentile) HDL-C Total cholesterol/ HDL-C
Rosuvastatin Rosuvastatin 5 mg/ Ezetimibe 5 mg (n ¼ 39) 10 mg (n ¼ 38) 66.1 (7.8) 17 (43.6) 30 18 9 10 25.6
(76.9) (46.2) (23.1) (25.6) (2.8)
64. 8 (8.2) 21 (55.3) 27 14 7 10 25.0
(71.1) (36.8) (18.4) (26.3) (2.4)
P
Rosuvastatin Rosuvastatin 10 mg 10 mg/ Ezetimibe (n ¼ 40) 10 mg (n ¼ 38)
P
Rosuvastatin Rosuvastatin 20 mg/Ezetimibe 20 mg (n ¼ 39) 10 mg (n ¼42)
P
0.47 64.0 (8.9) 0.31 26 (65.0)
62.1 (9.5) 24 (63.2)
0.38 62.7 (9.6) 0.87 26 (66.7)
64.7 (8.8) 29 (69.0)
0.33 0.82
0.56 24 0.41 17 0.42 4 0.95 12 0.30 25.3
23 12 8 6 24.6
0.96 29 0.32 22 0.08 7 0.14 8 0.19 25.5
26 16 9 17 25.1
0.23 0.10 0.87 0.052 0.26
(60.0) (42.5) (10.0) (30.0) (2.3)
(60.5) (31.6) (21.1) (15.8) (2.3)
(74.4) (56.4) (17.9) (20.5) (2.6)
157 (30) 234 (38) 161 (106, 190)
157 (32) 0.94 156 (30) 236 (33) 0.74 229 (36) 152 (117, 223) 0.63 136 (99, 173)
149 (27) 225 (30) 146 (96, 194)
0.29 150 (38) 0.66 224 (39) 0.73 148 (104, 217)
50.1 (16.9) 5.01 (1.45)
50.1 (13.3) 4.98 (1.29)
50.6 (12.8) 4.71 (1.26)
0.44 47.5 (9.) 0.30 4.86 (1.26)
0.99 48.2 (13.4) 0.92 5.00 (1.20)
(61.9) (38.1) (21.4) (40.5) (3.5)
148 (30) 0.75 219 (38) 0.61 143 (107, 177) 0.76
46.3 (12.5) 4.97 (1.25)
0.61 0.69
CAD ¼ coronary artery disease.
Y.-J. Yang et al.
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Variable
Rosuvastatin 5 mg (n ¼ 39)
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LDL-C, mean (SD), mg/dL Before 157 (30) After 85 (24) % Change –45.3 (15.01 P* o0.001 Total cholesterol, mean (SD), mg/dL Before 234 (38) After 161 (31) % Change –30.4 (11.3) P† o0.001 Triglycerides, median (25th percentile, 75th percentile), mg/dL Before 161 (106, 190) After 125 (101, 159) % Change –17.9 (–38.3, 24.4) P† 0.27 HDL-C, mean (SD), mg/dL Before 50.1 (16.)9 After 51.8 (16.6) % Change 5.3 (19.8) P† 0.11 *
Rosuvastatin 5 mg/Ezetimibe 10 mg (n ¼ 38)
Pa
Rosuvastatin 20 mg (n ¼ 39)
Rosuvastatin 20 mg/Ezetimibe 10 mg (n ¼ 42)
Pa
157 (32) 65 (18) –57.9 (10.4) o0.001
0.94 156 (30) o0.001 75 (30) o0.001 –51.9 (15.6) o0.001
149 (27) 62 (25) –57.6 (17.4) o0.001
0.29 0.04 0.13
150 (38) 65 (28) –56.0 (17.2) o0.001
148 (30) 52 (24) –62.7 (22.0) o0.001
0.75 0.03 0.13
236 (33) 137 (24) –41.7 (7.8) o0.001
0.74 229 (36) o0.001 147 (36) o0.001 –35.7 (12.1) o0.001
225 (30) 136 (28) –39.2 (12.8) o0.001
0.66 0.13 0.21
224 (39) 135 (32) –39.2 (13.2) o0.001
219 (38) 120 (28) –43.8 (16.4) o0.001
0.61 0.03 0.18
143 (107, 177) 95 (70, 114) –36.4 (–48.9, –9.6) o0.001
0.76 0.11 0.36
46.3 (12.5) 50.4 (11.9) 10.9 (17.6) o0.001
0.61 0.81 0.21
152 (117, 223) 105 (83, 136) –29.7 (–44.4, –9.8) o0.001
0.63 0.03 0.01
136 (99, 173) 129 (91, 165) –12.2 (–33.2, 34.8) 0.89
146 (96, 194) 103 (87, 149) –18.6 (–46.8, –7.3) 0.01
50.1 (13.3) 52.6 (13.6) 6.1 (12.6) 0.01
0.99 0.82 0.83
48.2 (13.4) 49.9 (11.5) 6.0 (16.5) 0.03
50.6 (12.8) 52.2 (12.8) 5.1 (17.7) 0.08
Comparison between groups. Comparison in a group before and after treatment.
†
Pa
Rosuvastatin Rosuvastatin 10 mg 10 mg/Ezetimibe (n ¼ 40) 10 mg (n ¼ 38)
0.73 148 (104, 217) 0.22 105 (86, 132) 0.13 –26.4 (–48.7, –2.7) o0.001
0.44 0.40 0.82
47.5 (9.2) 49.8 (11.0) 5.9 (18.4) 0.054
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Table II. Changes of laboratory values.
-20 -40 -60 -80
*
*
10 m 10 g R mg 10 m g+ E 10 R m 20 g R mg 20 m g+ E 10 m g R
5m g 5m g+ E R
R
B
Po o
led
10 m 10 g R mg 10 m g+ E 10 R m 20 g R mg 20 m g+ E 10 m g R
5m g 5m g+ E R
R
0
% change of TC
% change of LDL-C
A
Po o
led
Y.-J. Yang et al.
0 -20 -40
*
*
-60 -80
Rosuvastatin Rosuvastatin+ezetimibe
D
0 -20 -40
*
*
-60 -80
% change of HDL-c
% change of TG
C
15 10 5 0
Figure 2. Percentage changes of lipid profiles in each group. *P o 0.05. E ¼ ezetimibe; R ¼ rosuvastatin; TC ¼ total cholesterol; TG ¼ triglycerides.
Tolerability The proportions of patients who experienced any AE in the rosuvastatin monotherapy and the
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rosuvastatin/ezetimibe combination groups were similar (26 patients [21.5%] and 26 patients [21.1%], respectively). The number of patients with treatmentrelated AEs was higher, but not significantly, in the
Rosuvastatin Rosuvastatin+ezetimibe
*
*
100 75 50 25
m R2 g+ 0m E 10 g m g 20 R
m R g+ 10 E m 10 g m g 10
5m R
R
led
R g+ 5m E 10 g m g
0 Po o
% patients achieved LDL-C targets
cholesterol and triglycerides were also greater in the group receiving rosuvastatin 5 mg/ezetimibe 10 mg than in its monotherapy counterpart (P o 0.001). The percentage changes of HDL-C were not significantly different between the combination and monotherapy groups (Table II and Figure 2). The rate of LDL-C target achievement ranged from 64.1% to 87.2% (mean, 72.9%) in the monotherapy groups and 86.8% to 94.7% (mean, 90.7%) in the combination groups (P ¼ 0.01 for the pooled groups). The rate was higher in the group receiving rosuvastatin 5 mg/ezetimibe 10 mg than in the group receiving rosuvastatin 5 mg alone (94.7% and 64.1%, respectively; P o 0.001). The rate was also greater in participants receiving rosuvastatin 10 mg/ezetimibe 10 mg than in their counterpart (86.8% and 67.5%, respectively; P ¼ 0.043), whereas the rate was not significantly different between the groups receiving rosuvastatin 20 mg/ezetimibe 10 mg and rosuvastatin 20 mg alone (90.5% and 87.2%, respectively; P ¼ 0.73) (Figure 3).
Figure 3. LDL-C target achievement rates in each group. *P o 0.05. E ¼ ezetimibe; R ¼ rosuvastatin.
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Clinical Therapeutics
Table III. AEs in the participants who took the study drugs. Rosuvastatin (n ¼ 121) Patients with any AEs Patients with treatment-related AEs Patients with serious AEs Discontinuation of test drugs due to AEs Gastrointestinal AEs Musculoskeletal AEs Rhabdomyolysis Liver function tests Z3 ULN, 2 consecutive times Alanine aminotransferase increased Aspartate aminotransferase increased Creatine kinase Z10 ULN
26 2 2 0 5 1 0
(21.5) (1.7) (1.7) (0.0) (4.1) (0.8) (0.0)
0 (0.0) 0 (0.0) 0 (0.0)
Rosuvastatin þ Ezetimibe (n ¼ 123) 26 7 3 2 3 3 0
(21.1) (5.7) (2.4) (1.6) (2.4) (2.4) (0.0)
0 (0.0) 0 (0.0) 0 (0.0)
P 0.95 0.10 1.00 0.50 0.50 0.62 — — — —
Variables are expressed as number (%). AE ¼ adverse event; ULN ¼ upper limit of normal.
combination groups than in the monotherapy groups (7 patients [5.7%] and 2 patients [1.7%], respectively). Patients with serious AEs or discontinued drugs for AEs were not common in either group. No individuals reported rhabdomyolysis, liver enzyme elevation, or muscle enzyme elevation above predefined levels (Table III).
DISCUSSION The main findings of this study are (1) the lipidlowering efficacy of rosuvastatin/ezetimibe combination therapy was greater than that of rosuvastatin monotherapy (–60% vs –51% for the pooled groups), particularly for regimens with a lower statin dose; (2) the ezetimibe combination therapy lowered LDL-C to –63% with an additive reduction of 6%–12%; (3) the mean LDL-C target achievement rate was 91%, which was significantly higher than the 73% that achieved with monotherapy; (4) tolerability of the regimens with or without ezetimibe were not significantly different. Our study indicates that rosuvastatin/ezetimibe combination therapy is a reasonable option for lipid management in patients with high cardiovascular risk. In a previous study using multiple statins and doses, additive reduction of LDL-C by ezetimibe 10 mg was 10% to 14%.8 In that study, conducted in
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centers in the United States, South America, and Europe, the combination of rosuvastatin 10 mg/ ezetimibe 10 mg lowered LDL-C by 60%, whereas the combination of rosuvastatin 20 mg/ezetimibe 10 mg decreased LDL-C by 64%. We observed similar efficacies in LDL-C reduction (58% and 63%, respectively) with the same combination regimens. In a recent Korean study that evaluated similar regimens to ours, the percentage changes of LDL-C were –59% and –49% in the pooled groups of combination and rosuvastatin monotherapy, respectively.9 These outcomes are comparable with our results. Higher incremental LDL-C reduction at lower dose atorvastatin and lower incremental reduction at higher dose atorvastatin have been previously reported.10 This attenuation of incremental LDL-C reduction by ezetimibe with a higher dose statin is not consistently observed with all statins.11 However, decreased cholesterol excretion to bile due to high-dose statin can lessen the effect of ezetimibe 12; this mechanism may partly explain the findings of the present study. In the study by Ballantyne et al,8 the LDL-C target achievement rate ranged from 67% to 93% with rosuvastatin 10 mg/ezetimibe 10 mg, whereas it ranged from 77% to 96% with rosuvastatin 20 mg/ ezetimibe 10 mg. Our achievement rates in Koreans were 87% and 91% with the same regimens; we note that these rates are quite similar to those in other
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Y.-J. Yang et al. ethnic groups. Although incremental elevation of the achievement rate by ezetimibe varied according to statin dose, ezetimibe-mediated elevation was approximately18% in our study, which is comparable with that reported in a pooled analysis.13 Interestingly, the rates in our study are higher than those reported in a Korean survey in 2014. In the survey, the LDL-C goal attainment rate was 79% for high-risk patients who were prescribed commonly used statins.5 Improved target achievement rate, with the same combination, was also reported in the Korean study mentioned above. The rates in the study were 94% and 86% in the pooled groups of combination and rosuvastatin monotherapy, respectively.9 The present study indicates that rosuvastatin/ ezetimibe combination therapy is superior for achieving treatment targets in high-risk patients in whom the benefit of aggressive lipid management is known to be concrete. Although the IMPROVE-IT trial reported the clinical impact of LDL-C lowering with statin/ezetimibe combination,6 it is still uncertain whether the effect of this combination therapy is different from that of statin monotherapy. The addition of ezetimibe to statin therapy was recently reported to further lower LDL-C and to concomitantly reduce plaque volume.14,15 A large part of the additive benefit of the combination might have been due to its greater ability to lower LDL-C. Future studies testing the pleiotropic effects of ezetimibe need to be performed to identify other potential mechanism. Data on the safety profile of statin/ezetimibe combination therapy are scarce, particularly in Asian patients. In a study that included mostly Caucasian individuals, the incidences of AEs that occurred after the addition of ezetimibe were 40% for total AEs, 0.9% for serious AEs, and 1.8% for discontinuation of the test drugs.16 In another study, when ezetimibe 10 mg was added to the regimen of patients already under treatment with rosuvastatin 10 mg or 20 mg, the total AEs, serious AEs, and discontinuation rates were 54%, 8%, and 8%, respectively.17 However, these data are from patients who took ezetimibe in addition to ongoing statin therapy. Conversely, a small study comparing a combination regimen with statin monotherapy in a Chinese population found that alanine aminotransferase was not elevated in the combination group.18 Our study was performed on a larger population, and we did not observe increased
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AEs in patients who received combination regimens, including the maximum approved dose of rosuvastatin in Korea. This study was not designed to have sufficient power to identify a difference in the safety profiles of the regimens. However, to our knowledge, our study is one of the largest randomized trial that examined the safety profile of a rosuvastatin/ezetimibe regimen in an East Asian population. Thus, our results can be used as references for further studies. A main strength of our study is that we obtained treatment data for multiple doses of rosuvastatin/ ezetimibe. To date, few reports have studied these combinations in Asians. Previous studies used rosuvastatin 2.5 mg,19,20 5 mg,15 or 10 mg18 in small populations. The only study using rosuvastatin 20 mg in Asians was conducted in patients with familial hypercholesterolemia.21 It is worth mentioning that the present study found high efficacy of the statin/ ezetimibe combination in Asians and is thus anticipated to provide valuable information to clinicians who are treating patients with high cardiovascular risk.
Limitations Our study has several limitations. First, the incidence rates of adverse events were similar between the patients receiving combination therapy and those receiving monotherapy. However, because the power calculation in this study was based on efficacy and not tolerability, we cannot derive a solid conclusion on the tolerability of regimens with our present results. Especially, longer duration of treatment would be needed to obtain a more clear data on drug safety profile. Second, our results on the efficacy of combination regimens do not directly indicate the benefits on clinical outcomes. However, we can infer their benefits based on the results of IMPROVE-IT trial.
Future Directions Better LDL-C lowering and target achievement using combination therapy may be a reasonable option for high-risk patients, in whom the benefits of aggressive lipid therapy have been established. The clinical benefit of the statin and ezetimibe combination therapy was recently proved. However, a related trial was conducted in high-risk patients with acute coronary syndrome. Therefore, it needs to be clarified whether the benefit of such regimen is also valid in patients at intermediate or lower risk. In
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Clinical Therapeutics addition, it would be helpful to study if a more aggressive lipid-lowering regimen, compared with present guidelines, may have more clinical benefit in diverse risk groups.
CONCLUSIONS Taken together, our results indicate that rosuvastatin/ ezetimibe combination therapy has better efficacy than rosuvastatin monotherapy. Specifically, the combination therapy lowered LDL-C to –63% and achieved the LDLC target in 91% of Koreans with high cardiovascular risk.
AUTHOR CONTRIBUTION Literature search (YJ Y, SH L), Figure creation (YJ Y, SH L), study design (SH L, BS K, YK C, HJ C, KI C, SY K, JK R, JM C, JI P, JS P, CG P, WJ C, MA K, DK J, N L, BJ K, KK K, J S, SH L, BK L, SJ O, HY J, Y A, SG L, JH B, WJ P, SC L, HC L, J L, C P, B L, Y J), data collection (BS K, YK C, HJ C, KI C, SY K, JK R, JM C, JI P, JS P, CG P, WJ C, MA K, DK J, N L, BJ K, KK K, J S, SH L, BK L, SJ O, HY J, Y A, SG L, JH B, WJ P, SC L, HC, L), data interpretation (YJ Y, SH L, Y J), writing (YJ Y, SH L).
CONFLICTS OF INTEREST This research was financially supported by Alvogen Korea Co, Ltd.
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Address correspondence to: Yangsoo Jang, MD, PhD, Sang-Hak Lee, MD, PhD, Division of Cardiology, Department of Internal Medicine, Severance Hospital, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, Korea. E-mail: [email protected], [email protected]
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