Abstract
Aims: Lowering low-density lipoprotein cholesterol (LDL-C) is essential for reducing the risk of atherosclerotic cardiovascular disease (ASCVD). This study assessed the clinical efficacy of evolocumab, a human monoclonal antibody targeting PCSK9, in Japanese patients using data from the PROFICIO program.
Methods: Data were pooled from Japanese participants enrolled in five clinical trials: YUKAWA-1, YUKAWA-2, OSLER-1, OSLER-2, and FOURIER. The primary endpoint was percent change in LDL-C from baseline to Week 12. Secondary endpoints included changes in other lipid parameters, achievement of LDL-C targets, incidence of major adverse cardiovascular events (MACE), and subgroup analyses.
Results: A total of 1,040 patients with high cardiovascular risk or established ASCVD were included. At Week 12, the mean percent reduction in LDL-C was 75.7% with evolocumab compared with 1.3% with placebo (least-square mean treatment difference: ‑75.0%; 95% confidence interval [CI]: -76.7 to -73.4; p＜0.001), which was consistent across subgroups. Other lipid parameters showed directionally consistent percent changes, with variable magnitudes across markers. Overall, 92.9% of patients treated with evolocumab achieved an LDL-C ＜55 mg/dL at Week 12 compared with 0.8% of patients in the placebo group. In FOURIER, over a median follow-up of 2.1 years, incidence of MACE was lower with evolocumab than placebo (5.9% vs. 12.4%; hazard ratio: 0.47; 95% CI: 0.24–0.92). Treatment effects on MACE were consistent in both primary and secondary prevention groups (pooled odds ratio: 0.42; 95% CI: 0.23–0.79).
Conclusion: Evolocumab significantly and consistently lowered LDL-C and reduced the risk of MACE in Japanese patients.
Introduction
Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), with numerous studies demonstrating a strong association between increased LDL-C and the development of ASCVD1). In order to reduce the risk of ASCVD events, the clinical guidelines for prevention of ASCVD by the Japan Atherosclerosis Society (JAS) should have considerations for more stringent lipid management2) for secondary prevention among high-risk patients. To reduce ASCVD risk, the Japan Atherosclerosis Society (JAS) guidelines state an LDL-C target of ＜100 mg/dL for secondary prevention. For high-risk patients, including those with acute coronary syndrome (ACS), familial hypercholesterolemia (FH), diabetes mellitus (DM), and patients with both coronary artery disease (CAD) and atherothrombotic cerebral infarction, a more stringent target of ＜70 mg/dL should be considered2). Outside of Japan, the 2019 ESC/EAS guideline recommends a target LDL-C level of ＜55 mg/dL for very high-risk patients, and ＜40 mg/dL for those who had experienced another cardiovascular event within 2 years3).
Statins are the cornerstone of secondary prevention of ASCVD, often used in combination with non-statin lipid-lowering therapies4-6). However, the rate of achieving LDL-C reduction goals remains low in high-risk patients undergoing secondary prevention, regardless of treatment with statin monotherapy or combination therapy with statin and ezetimibe7).
Evolocumab is a human monoclonal antibody that effectively lowers LDL-C levels by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9)8). In FOURIER, evolocumab significantly reduced the risk of a composite endpoint regarding cardiovascular death, myocardial infarction (MI), or stroke by lowering LDL-C to a median level of 30 mg/dL9). In two open-label extension studies conducted in Japan, evolocumab also reduced LDL-C by a mean of 58.0% in OSLER-1 and 62.7% in OSLER-2 and 69.1% in OSLER-1 and 65.1% in OSLER-2 respectively10, 11).
A significant reduction in LDL-C with evolocumab was reported in the “Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations” (PROFICIO) across various disease status and demographic subgroups12). However, individuals of white race accounted for more than 90% of the study population, while Asian patients represented less than 10% of the cohort. Although the LDL-C lowering effect of evolocumab versus placebo among Asians was non-inferior to that observed in other populations, Asian patients demonstrated a more pronounced LDL-C reduction by evolocumab when compared with ezetimibe12). Recent commentaries have highlighted that geographic and ethnic variations in lipid-lowering responses including statins, ezetimibe, and PCSK9 inhibitors are increasingly recognized as important considerations in cardiovascular therapies13). Such observations further underscore the need to better characterize treatment responses in under-represented populations, including Japanese patients. Considering the growing interest in geographic and ethnic differences that may affect the therapeutic efficacy of PCSK9 inhibitors, we conducted a comprehensive analysis of the durability and robustness of evolocumab in Japanese patients. This study aimed to elucidate the effects of evolocumab on LDL-C reduction and cardiovascular outcomes in Japanese patients.
Methods
Patient Population and Study Design
PROFICIO is a clinical program that pools data from 50 clinical trials to comprehensively confirm the consistency in efficacy and safety of evolocumab in various patient sub-groups. For the current analysis, data from Japanese patients enrolled in five clinical trials were included: YUKAWA-1, YUKAWA-2, OSLER-1, OSLER-2, and FOURIER.
YUKAWA-1 and YUKAWA-2 were Phase II and Phase III studies, respectively, designed to evaluate the efficacy of evolocumab in combination with statin therapy in Japanese patients at high cardiovascular risk. A total of 207 and 404 patients from YUKAWA-1 and YUKAWA-2, respectively, were included in the current analysis.
OSLER was an international open-label extension program of six Phase II and seven Phase III parent studies including YUKAWA-1 and YUKAWA-2 to evaluate safety and sustained effectiveness during long-term exposure of evolocumab. Patients with hypercholesterolemia were randomized to either evolocumab + standard therapy or standard therapy alone and followed up to 52 weeks11). In the Japanese subgroup of OSLER-1 and OSLER-2, a total of 556 Japanese patients were enrolled from the parental YUKAWA-1 and YUKAWA-2 studies.
In FOURIER, patients aged 40-85 years with clinically evident ASCVD receiving lipid-lowering therapy were randomized to evolocumab or placebo with a median follow-up of 2.2 years9). A total of 429 Japanese patients from FOURIER were included in this study.
This study is a secondary analysis of data obtained from the completed clinical trials. The individual study protocols were approved by respective institutional review boards, and all studies were conducted in accordance with the Declaration of Helsinki. Written informed consents were received from all participants. Further details are provided in the original publications of each study.
Two pooled Japanese subsets were included in the current analysis. The first subset, “YUKAWA/FOURIER”, comprised pooled data from YUKAWA‑1, YUKAWA‑2, and the Japanese subgroup of FOURIER. The second subset, “OSLER 1/2” included pooled data from Japanese patients enrolled in OSLER-1 and OSLER-2 and was used to assess long-term efficacy up to 52 weeks.
Efficacy Endpoints
The primary endpoint was the percent change in calculated LDL-C from baseline to Week 12 in YUKAWA/FOURIER. The secondary endpoints of this study include: the percent change in calculated LDL-C from baseline to protocol-defined scheduled visit in YUKAWA/FOURIER and standard of care controlled period in OSLER 1/2; the percent change from baseline to Week 12 in total cholesterol, non-HDL-C, ApoB, triglycerides, HDL-C, ApoA1 and Lp(a) in YUKAWA/FOURIER; the achievement of calculated LDL-C levels of ＜100, ＜70, ＜55, and ＜40 mg/dL at Week 12 in YUKAWA/FOURIER; incidence of MACE defined as a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization in Japanese subset in FOURIER, OSLER 1/2. As a methodological clarification, Lp(a) concentrations were measured using an isoform-independent immunoturbidimetric assay calibrated in SI units (nmol/L), consistent with the measurement methodology applied in the original parent studies, including FOURIER14).
Statistical Analysis
All Japanese subjects in the original efficacy analysis set of each study were included in the analysis. No imputation was performed for missing data on clinical endpoints. For continuous variables, data from specific visits were summarized by treatment group using descriptive statistics. These variables were also visualized using line plot or waterfall plot, where appropriate.
Least square (LS) means were calculated by treatment group and summarized using estimates, standard errors (SE), and 95% confidence intervals (CIs). Treatment differences were also calculated and summarized using estimates, SEs, 95% CIs, and p-values, if appropriate. These LS means and treatment differences were derived from a linear mixed-effects model for repeated measures (MMRM), which includes the randomized active treatment group, visit, and randomized active treatment group-by-visit interaction as fixed effects; baseline of corresponding lipid as covariate; and study as random effect.
Subgroup analysis for the primary endpoint was also executed. The number and percentage of participants who achieved LDL-C levels of ＜100, ＜70, ＜55, and ＜40 mg/dL, along with their 95% CIs, were summarized by treatment group. For MACE, the number and percentage of participants with events were tabulated by treatment group. Hazard ratios and corresponding 95% CIs were derived using a Cox model stratified by the randomization stratification factor of the final screening LDL-C level collected via IVRS in FOURIER. MACE in FOURIER was visualized in a Kaplan-Meier plot while MACE was not visualized for OSLER 1/2 due to limited MACE numbers. In addition, MACE across FOURIER, OSLER 1/2 were summarized using meta-analytic approach, and odds ratios, corresponding 95% CIs and p-values were calculated. Analyses were conducted using SAS system version 9.4 or later.
Results
Patient Characteristics of the Study Population
YUKAWA/FOURIER included 1,040 Japanese patients. The mean age at evolocumab initiation was 62.8 years; 503 patients (48.4%) were aged 65 years or older, and 725 patients (69.7%) were male. There were 490 patients (47.1%) with type 2 diabetes mellitus, and 815 patients (78.4%) had hypertension. Other cardiovascular risk factors included a family history of premature coronary heart disease in 56 patients (5.4%) and active smoking in 243 (23.4%).
Overall, 424 patients (40.8%) had a history of CAD, 261 patients (25.1%) had a history of cerebrovascular or peripheral arterial disease, and 597 (57.4%) had any of these diseases (Table 1). Median LDL-C at baseline in the overall population was 104.0 mg/dL (interquartile range [IQR] 87.5–126.5 mg/dL). Using the Japanese-specific definition, 572 patients (55.0%) were receiving intensive statin therapy, compared with 163 patients (15.7%) using the global definition.
Table 1. Baseline patient characteristics in YUKAWA/FOURIER
|
Placebo |
Evolocumab |
Total |
| Characteristic |
N = 529 |
N = 511 |
N = 1,040 |
| Sex - n (%)
|
|
|
|
| Male |
375 (70.9) |
350 (68.5) |
725 (69.7) |
| Female |
154 (29.1) |
161 (31.5) |
315 (30.3) |
| Age (years) |
|
|
|
| Mean±SD |
62.5±9.9 |
63±9.9 |
62.8±9.9 |
| Age group – n (%)
|
|
|
|
| ＜65 years |
275 (52.0) |
262 (51.3) |
537 (51.6) |
| ≥ 65 years |
254 (48.0) |
249 (48.7) |
503 (48.4) |
| ≥ 75 years |
53 (10.0) |
58 (11.4) |
111 (10.7) |
| LDL-C (mg/dL) |
|
|
|
| Mean |
108.2 |
110.7 |
109.4 |
| Median (Q1-Q3) |
102.5 (87.0-124.0) |
106.5 (88.0-128.5) |
104.0 (87.5-126.5) |
| HDL-C (mg/dL) |
|
|
|
| Mean |
54.9 |
54.2 |
54.5 |
| Median (Q1-Q3) |
53.0 (45.0-62.0) |
52.5 (44.5-62.0) |
53.0 (44.5-62.0) |
| Total cholesterol (mg/dL) |
|
|
|
| Mean |
189.4 |
191.8 |
190.6 |
| Median (Q1-Q3) |
188.0 (163.5-208.0) |
187.0 (168.0-212.0) |
187.8 (166.0-210.0) |
| Non-HDL-C (mg/dL) |
|
|
|
| Mean |
134.5 |
137.7 |
136 |
| Median (Q1-Q3) |
129.5 (110.5- 152.0) |
132 (112.5-158.0) |
131 (112.0, 154.3) |
| Triglycerides (mg/dL) |
|
|
|
| Mean |
133.4 |
138.3 |
135.8 |
| Median (Q1-Q3) |
122.0 (91.0-159.0) |
124.5 (95.0-157.0) |
123.3 (92.5-158.8) |
| Lp(a) (nmol/L) |
|
|
|
| N |
482 |
468 |
950 |
| Mean |
58.3 |
63.2 |
60.7 |
| Median (Q1-Q3) |
32.0 (13.0-66.0) |
34.0 (13.5-76.0) |
33.0 (13.0-71.0) |
| CAD - n (%)
|
217 (41.0) |
207 (40.5) |
424 (40.8) |
| Angina |
144 (27.2) |
114 (22.3) |
258 (24.8) |
| Myocardial infarction |
175 (33.1) |
176 (34.4) |
351 (33.8) |
| Coronary artery bypass graft |
25 (4.7) |
23 (4.5) |
48 (4.6) |
| Percutaneous coronary intervention |
182 (34.4) |
170 (33.3) |
352 (33.8) |
| Cerebrovascular or peripheral arterial disease - n (%)＊
|
138 (26.1) |
123 (24.1) |
261 (25.1) |
| Transient ischemic attack |
8 (1.5) |
7 (1.4) |
15 (1.4) |
| Stroke |
106 (20.0) |
94 (18.4) |
200 (19.2) |
| Carotid or vertebral artery disease |
15 (2.8) |
17 (3.3) |
32 (3.1) |
| Peripheral arterial disease |
27 (5.1) |
20 (3.9) |
47 (4.5) |
| Any of CAD or cerebrovascular or peripheral arterial disease |
309 (58.4) |
288 (56.4) |
597 (57.4) |
| Cardiovascular risk factors - n (%)＊
|
|
|
|
| Current cigarette smoking |
133 (25.1) |
110 (21.5) |
243 (23.4) |
| Type 2 diabetes mellitus |
249 (47.1) |
241 (47.2) |
490 (47.1) |
| Hypertension |
411 (77.7) |
404 (79.1) |
815 (78.4) |
| Family history of premature CHD |
26 (4.9) |
30 (5.9) |
56 (5.4) |
| Low HDL-C |
86 (16.3) |
98 (19.2) |
184 (17.7) |
| Statin intensity (Japan-specific definition＊＊) - n (%)
|
|
|
|
| Intensive |
299 (56.5) |
273 (53.4) |
572 (55.0) |
| Non-intensive |
230 (43.5) |
236 (46.2) |
466 (44.8) |
| Unknown |
0 (0.0) |
2 (0.4) |
2 (0.2) |
| Statin intensity (Global definition) - n (%)
|
|
|
|
| Intensive |
83 (15.7) |
80 (15.7) |
163 (15.7) |
| Non-intensive |
446 (84.3) |
429 (84.0) |
875 (84.1) |
| Unknown |
0 (0.0) |
2 (0.4) |
2 (0.2) |
CAD, coronary artery disease; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); SD, standard deviation;＊ Data were not collected in FOURIER; ＊＊intensive if atorvastatin ≥ 10 mg QD, rosuvastatin ≥ 5 mg QD, simvastatin ≥ 20 mg QD, fluvastatin ≥ 80 mg QD, lovastatin ≥ 40 mg QD, pitavastatin ≥ 2 mg QD, pravastatin ≥ 40 mg QD or any statin use with concurrent ezetimibe use, and nonintensive is any statin use not classified as intensive.
Patient characteristics of OSLER 1/2 are shown in Supplementary Table 1.
Supplementary Table 1. Baseline patient characteristics in OSLER 1/2
|
Standard therapy |
Evolocumab
+ Standard therapy
|
Total |
| Characteristic |
N=186 |
N=370 |
N=556 |
| Sex - n (%)
|
|
|
|
| Male |
107 (57.5) |
230 (62.2) |
337 (60.6) |
| Female |
79 (42.5) |
140 (37.8) |
219 (39.4) |
| Age (years) |
|
|
|
| Mean±SD |
61.2±10.2 |
60.8±9.7 |
60.9±9.9 |
| Age group - n (%)
|
|
|
|
| ＜65 years |
115 (61.8) |
224 (60.5) |
339 (61.0) |
| ≥ 65 years |
71 (38.2) |
146 (39.5) |
217 (39.0) |
| ≥ 75 years |
20 (10.8) |
22 (5.9) |
42 (7.6) |
| LDL-C (mg/dL) |
|
|
|
| Mean |
121.3 |
118.9 |
119.7 |
| Median (Q1-Q3) |
120.5 (95.0-143.5) |
116.8 (97.0-136.0) |
118.0 (96.5-139.0) |
| HDL-C (mg/dL) |
|
|
|
| Mean |
56.9 |
56.0 |
56.3 |
| Median (Q1-Q3) |
54.0 (46.0-66.0) |
54.0 (47.0-63.0) |
54.0 (46.5-63.8) |
| Total cholesterol (mg/dL) |
|
|
|
| Mean |
205.4 |
201.6 |
202.9 |
| Median (Q1-Q3) |
205.0 (181.0-230.0) |
198.5 (180.0-220.0) |
201.0 (180.0-223.0) |
| Triglycerides (mg/dL) |
|
|
|
| Mean |
145.2 |
136.2 |
139.2 |
| Median (Q1-Q3) |
127.0 (97.0-168.0) |
122.8 (95.0-163.0) |
124.0 (95.8-164.5) |
| Lp(a) (nmol/L) |
|
|
|
| N |
186 |
369 |
555 |
| Mean |
53.4 |
52.2 |
52.6 |
| Median (Q1-Q3) |
34.5 (13.0-64.0) |
33.0 (13.0-59.0) |
33.0 (13.0-59.0) |
| Coronary artery disease - n (%)
|
31 (16.7) |
53 (14.3) |
84 (15.1) |
| Angina |
22 (11.8) |
41 (11.1) |
63 (11.3) |
| Myocardial infarction |
16 (8.6) |
23 (6.2) |
39 (7.0) |
| Coronary artery bypass graft |
5 (2.7) |
11 (3.0) |
16 (2.9) |
| Percutaneous coronary intervention |
19 (10.2) |
31 (8.4) |
50 (9.0) |
| Cerebrovascular or peripheral arterial disease - n (%)
|
27 (24.5) |
44(11.9) |
71(12.8) |
| Transient ischemic attack |
1 (0.5) |
1 (0.3) |
2 (0.4) |
| Stroke |
17 (9.1) |
28(7.6) |
45 (8.1) |
| Carotid or vertebral artery disease |
12 (6.5) |
16 (4.3) |
28 (5.0) |
| Peripheral arterial disease |
5 (2.7) |
5 (1.4) |
10 (1.8) |
| Cardiovascular risk factors - n (%)
|
|
|
|
| Current cigarette smoking |
42 (22.6) |
100 (27.0) |
142 (25.5) |
| Type 2 diabetes mellitus |
72 (38.7) |
176 (47.6) |
248 (44.6) |
| Hypertension |
133 (71.5) |
279 (75.4) |
412 (74.1) |
| Family history of premature coronary heart disease |
14 (7.5) |
39 (10.5) |
53 (9.5) |
| Low HDL-C |
33(17.7) |
47 (12.7) |
80 (14.4) |
| Statin intensity (Japan-specific definition*)- n (%)
|
|
|
|
| Intensive |
80 (43.0) |
140 (37.8) |
220 (39.6) |
| Non-intensive |
106 (57.0) |
230 (62.2) |
336 (60.4) |
| Statin intensity (Global definition) - n (%)
|
|
|
|
| Intensive |
6 (3.2) |
7 (1.9) |
13 (2.3) |
| Non-intensive |
180 (96.8) |
363 (98.1) |
543 (97.7) |
CAD, coronary artery disease; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); SD, standard deviation; ＊intensive if atorvastatin ≥ 10 mg QD, rosuvastatin ≥ 5 mg QD, simvastatin ≥ 20 mg QD, fluvastatin ≥ 80 mg QD, lovastatin ≥ 40 mg QD, pitavastatin ≥ 2 mg QD, pravastatin ≥ 40 mg QD or any statin use with concurrent ezetimibe use, and non-intensive is any statin use not classified as intensive.
Change in LDL-C Level
In YUKAWA/FOURIER, mean LDL-C at Week 12 was 27.5 mg/dL in the study group and 106.1 mg/dL in the placebo group. The mean percent reduction in LDL-C from baseline to Week 12 was 75.7% with evolocumab compared with 1.3% with placebo (treatment difference in LS means: -75.0; 95% CI: -76.7, -73.4; p＜0.001; Fig.1A). The absolute change in LDL-C from baseline to Week 12 was -83.4 mg/dL with evolocumab and -2.0 mg/dL with placebo. Waterfall plot analysis revealed consistent and robust LDL-C reductions with evolocumab compared with placebo (Fig.1B). In Japanese patients in FOURIER, evolocumab achieved a significant LDL-C reduction by the first 4‑week measurement (Supplementary Fig.1).
In OSLER 1/2, 556 Japanese patients participated in open-label extension studies (Supplementary Table 1), of whom 370 received evolocumab in addition to standard therapy and 186 received standard therapy alone for the 1-year standard-of-care controlled period following rollover from parent studies YUKAWA-1 and YUKAWA-2 (open-label extension up to 1 year). Consistent with FOURIER, mean LDL‑C in the evolocumab + standard therapy group achieved mean LDL‑C levels below 50 mg/dL by Week 4, and these reductions were maintained through the period (Supplementary Fig.2).
Changes in Other Lipid Parameters
In YUKAWA/FOURIER, significant reductions in other lipid parameters including non-HDL-C, ApoB, triglycerides, Lp(a) and total cholesterol as well as increases in HDL-C and ApoA1 from baseline to Week 12 were observed in the study group compared with the placebo group (Fig.2). Notably, reductions in non-HDL-C and ApoB were 64.7% and 60.3% from baseline to Week 12 in the study group, respectively. While Lp(a) and triglycerides increased by 1.6% and 5.8% in the placebo group, evolocumab treatment reduced these parameters by 43.5% and 16.2%, respectively.
Sub-group Analysis
The percent change in LDL-C from baseline to Week 12 was consistent across subgroups defined by age, baseline ezetimibe use, intensity of statin therapy (global definition), and cardiovascular risk category. Consistent treatment effects were observed regardless of whether statin intensity was defined using the global or Japan-specific criteria (data not shown). A slightly larger reduction was observed among males than in females (p = 0.032); however, both subgroups showed LDL-C reductions of 70% or more reduction compared with placebo (Fig.3).
Achievement rate of LDL-C Targets
At Week 12, 95.9% and 92.9% of patients in the evolocumab group achieved LDL-C targets of ＜70 mg/dL and ＜55 mg/dL, respectively, compared with 8.3% and 0.8% in the placebo group (Table 2). Achievement of LDL‑C ＜55 mg/dL was consistently high across trials. Furthermore, 81.4% of patients receiving evolocumab achieved LDL-C ＜40 mg/dL at Week 12.
Table 2. LDL-C target achievement rate at Week 12
| Population |
YUKAWA-1 (N = 201) |
YUKAWA-2 (N = 389) |
Japan subjects in FOURIER (N = 416) |
Pooled 3 studies
(N = 1006)
|
| Treatment group |
Placebo (n = 100)
|
Evolocumab (n = 101)
|
Placebo (n = 195)
|
Evolocumab (n = 194)
|
Placebo (n = 221)
|
Evolocumab (n = 195)
|
Placebo (n = 516)
|
Evolocumab (n = 490)
|
| Patients achieving below LDL-C threshold -% (95% CI) |
| ＜40 mg/dL |
0.0% (0.00, 3.70) |
51.5% (41.86, 61.00) |
0.0% (0.00, 1.93) |
86.6% (81.09, 90.69) |
0.0% (0.00, 1.71) |
91.8% (87.09, 94.89) |
0.0% (0.00, 0.74) |
81.4% (77.75, 84.62) |
| ＜55 mg/dL |
0.0% (0.00, 3.70) |
82.2% (73.58, 88.42) |
1.0% (0.28, 3.66) |
94.3% (90.13, 96.80) |
0.9% (0.25, 3.24) |
96.9% (93.45, 98.58) |
0.8% (0.30, 1.98) |
92.9% (90.23, 94.82) |
| ＜70 mg/dL |
0.0% (0.00, 3.70) |
89.1% (81.54, 93.81) |
11.3% (7.57, 16.49) |
96.9% (93.42, 98.57) |
9.5% (6.30, 14.09) |
98.5% (95.58, 99.48) |
8.3% (6.25, 11.04) |
95.9% (93.78, 97.34) |
| ＜100 mg/dL |
3.0% (1.03, 8.45) |
98.0% (93.07, 99.46) |
54.9% (47.86, 61.69) |
98.5% (95.55, 99.47) |
67.9% (61.46, 73.68) |
100% (98.07, 100) |
50.4% (46.09, 54.68) |
99.0% (97.63, 99.56) |
In Japanese patients included in FOURIER, MACE occurred among 12 patients (5.9%) in the evolocumab group compared with 28 patients (12.4%) in the placebo group (HR: 0.47; 95% CI: 0.24 to 0.92; Table 3). The cumulative incidence of MACE is presented as a Kaplan Meier curve in Fig.4. Median follow-up period was approximately 2.1 years, and the number needed to treat (NNT) at 2 years was 15. Among individual components of MACE, coronary revascularization had the highest number of events, with a HR of 0.46 (95% CI: 0.21 to 0.99; Table 3). The composite endpoint of CV death, MI, or stroke occurred in 6 patients (2.9%) in the evolocumab group versus 11 patients (4.9%) in the placebo group (HR: 0.61; 95% CI: 0.23 to 1.65).
Table 3.Incidence of major adverse cardiovascular events in FOURIER
|
Placebo (N = 225) n (%)
|
Evolocumab (N = 204)
n (%)
|
Hazard Ratio (95% CI) |
| MACEa
|
28 (12.4) |
12 (5.9) |
0.47 (0.24, 0.92) |
| Components of MACE |
|
|
|
| Cardiovascular death |
1 (0.4) |
3 (1.5) |
3.27 (0.34, 31.42) |
| Myocardial infarction |
6 (2.7) |
3 (1.5) |
0.57 (0.14, 2.28) |
| Stroke |
6 (2.7) |
2 (1.0) |
0.37 (0.07, 1.83) |
| Coronary revascularization |
22 (9.8) |
9 (4.4) |
0.46 (0.21, 0.99) |
| Hospitalization of unstable angina |
3 (1.3) |
2 (1.0) |
0.76 (0.13, 4.57) |
| Composite of cardiovascular death, MI, or stroke |
11 (4.9) |
6 (2.9) |
0.61 (0.23, 1.65) |
MACE, major adverse cardiovascular events; CI, confidence interval
a MACE is defined as cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first.
In OSLER 1/2, MACE occurred in 4 of 370 patients (1.1%) in the evolocumab group, compared with 4 of 186 patients (2.2%) in the placebo group up to 1 year standard of care control period (Fig.5). In the primary prevention group from OSLER 1/2, MACE occurred in 2 of 283 patients (0.7%) in the evolocumab group, compared with 2 of 134 patients (1.5%) in the placebo group (Fig.6). A consistent treatment effect for MACE was observed across both the primary prevention group and the secondary prevention group, with an overall odds ratio (OR) of 0.42 (95% CI, 0.23 to 0.79).
Discussion
Through the analysis of integrated data of multiple clinical trials, consistent LDL-C reductions and improvements in cardiovascular outcomes with evolocumab were observed in the Japanese population. These findings are consistent with evidence from global studies9, 12). In this pooled analysis, LDL-C ＜70 mg/dL was achieved in 95.9% of patients, suggesting that evolocumab is a key therapeutic option that fulfills guideline-proposed targets for secondary prevention in high-risk patients in Japan. Similarly, 92.9% of the patients achieved the LDL‑C reduction target of ＜55 mg/dL recommended by 2019 ESC/EAS guideline for very-high risk patients3). Evolocumab appears to achieve higher rates of LDL-C target attainment than other treatments, as LDL-C ＜70 mg/dL has been reported in approximately 30% of patients receiving intensive statin monotherapy and 46% of those receiving statin-ezetimibe combination therapy7). Across datasets, the overall incidence of AEs/SAEs with evolocumab was consistent with prior reports, and no new safety signals were identified.
The LDL-C lowering effect of evolocumab appeared consistent regardless of characteristics such as age, intensity of statin therapy, cardiovascular risk factor and background medication status (e.g. ezetimibe usage), with the exception of gender. Consistent with the present findings, global clinical trials and real-world studies have also demonstrated a greater LDL‑C lowering response in males compared to females12, 15, 16). While the underlying mechanisms remain unclear, estrogen has been proposed to affect PCSK9-mediated LDL receptor degradation17). Given the age-related variation in estrogen status among women, age-specific analyses could further inform the observed sex differences in LDL-C lowering. However, the present pooled analysis did not evaluate LDL-C reduction according to age among female participants and therefore does not allow a direct assessment of the relationship between female age and the magnitude of LDL-C reduction. Nevertheless, a recent meta-analysis demonstrated that both genetic and pharmacologic PCSK9 inhibition were associated with a smaller LDL-C–lowering effect in women compared with men, independent of age or menopausal status18). Taken together, further research is needed to clarify the complex interactions between sex hormones and LDL‑C metabolism.
Whereas evolocumab reduced LDL-C by approximately 60% versus placebo at Week 48 in the overall FOURIER trial population9), the corresponding reduction observed in the Japanese subset in the study was 75.7%. In addition, evolocumab significantly reduced the risk of MACE compared with placebo, with a HR of 0.47 (95% CI, 0.24–0.92) in Japanese subset in the study. The reduction was consistent between the primary prevention group and the secondary prevention group. In contrast, HR of 0.85 (95% CI, 0.79–0.92) was reported for the overall population of FOURIER9), and the magnitude of reduction was numerically smaller than that observed in the Japanese cohort. In addition to the relative risk reduction, the present analysis also demonstrated a clinically meaningful absolute risk reduction in Japanese patients. In the FOURIER Japanese subset, the incidence of MACE was 12.4% in the placebo group and 5.9% in the evolocumab group over a median follow-up of approximately 2.1 years, corresponding to an absolute risk reduction of 6.5% and a number needed to treat of 15 to prevent one MACE event over 2 years.
This absolute risk reduction appears larger than that reported in the overall FOURIER population, in which a lower event rate resulted in a higher number needed to treat over a longer follow-up period. These findings further support the clinical relevance of evolocumab in Japanese patients with established ASCVD. Accordingly, the more pronounced treatment effect of evolocumab on MACE reduction observed in the Japanese cohort may be partly explained by the greater extent of LDL‑C lowering compared with the global study population. The greater LDL-C reduction observed in Asian populations after evolocumab treatment may be partly explained by their lower BMI compared with Western populations19). However, a recent prespecified analysis from the FOURIER demonstrated evolocumab produced marked LDL-C reductions across the full spectrum of BMI categories and no correlation between baseline BMI and percent change in LDL-C20). Therefore, the greater LDL-C–lowering effect observed in Japanese patients is likely multifactorial and may reflect differences in underlying lipid metabolism, PCSK9 biology, or pharmacokinetics, rather than baseline BMI alone.
Reduction in other lipid parameters including non-HDL-C, ApoB, triglyceride and total cholesterol, were observed with evolocumab in the global study21). While similar reductions were also reported in the Japanese cohort, the percent change was slightly greater in the cohort11). Our analysis, which used the placebo group as a comparator, indicated a similar trend. PCSK9 has also been suggested to play a role in triglyceride metabolism22). However, the detailed mechanism by which PCSK9 regulates triglyceride levels remains unclear, and there is ongoing controversy regarding the consistency of triglyceride-lowering effects with PCSK9 inhibitors23, 24).
This study has several limitations. First, there is variability in study design, patient population, and endpoints across the incorporated trials. Analysis of covariance (ANCOVA) model was used to assess data of different study cohorts and sub-groups, taking into account covariates such as treatment group, baseline LDL-C, each subgroups’ variables, and the interaction of treatment with subgroups12). Although known potential confounders are taken into consideration for adjustment during the analysis, residual confounding may exist for unknown factors. Although evolocumab treatment was associated with a substantial reduction in MACE in the Japanese subset, the number of events was relatively small. Therefore, the effect estimates are subject to uncertainty, and the wide confidence intervals warrant cautious interpretation. Finally, this study focused on Japanese patients, which may limit the generalizability of the findings to other populations.
Conclusion
In this pooled analysis of 1,040 Japanese patients from the PROFICIO program, evolocumab significantly and consistently reduced LDL-C levels across a broad range of baseline characteristics and lowered the risk of cardiovascular events. These findings are consistent with trends observed in global studies, supporting the robust efficacy of evolocumab irrespective of racial and ethnic differences.
Acknowledgements
Medical writing was provided by Russell Miller, MHS, ISMPP CMPP, and Helin Han, MS, of Syneos Health, Real World Evidence Department, which was funded by Amgen K.K.
Conflict of Interest Statement
N.O., F.S., N.H, K.M. and J.S. are employees of Amgen K.K. Y.F. are employees of Syneos Health. K.O., A.K and S.Y received lecture fees from Amgen.
Funding
This study was funded by Amgen K.K., Tokyo, Japan, and Astellas Pharma Inc., Tokyo, Japan.
Data Availability Statement
The raw data that support the findings of this study are from clinical trials. Aggregated data is available in the respective publications cited in this article.
IRB Information
This study is a secondary data analysis of completed clinical trials. Details of IRB information for each study incorporated in the pooled analysis are provided in the published articles.
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