Efficacy and Safety of High-Intensity Statins in Japanese Patients After Percutaneous Coronary Intervention　― Insights From the Clinical Deep Data Accumulation System (CLIDAS^®) ―

Abstract

Background: Lipid-lowering therapy with high-intensity statins has not been widely implemented in Japan for patients with coronary artery disease who undergo percutaneous coronary intervention (PCI). We examined the efficacy and safety of high-intensity statin therapy in a real-world setting.

Methods and Results: We used the Clinical Deep Data Accumulation System (CLIDAS) to accumulate multimodal data from the electronic medical records of 7 cardiovascular centers. We analyzed 9,690 patients who underwent PCI between 2013 and 2019 and completed a median 2.5-year follow-up (CLIDAS-PCI database). The risk of developing major adverse cardiac and cerebrovascular events (MACCE) was significantly greater in patients with acute (ACS) than chronic (CCS) coronary syndrome. High-intensity statins were prescribed to 49% of ACS patients and 33% of CCS patients within the first 30 days after the index PCI. After propensity score matching, MACCE event rates were similar between the high- and moderate-intensity statin groups. Importantly, among ACS patients, Cox proportional hazard analysis revealed that the rate of myocardial infarction was lower (adjusted hazard ratio [aHR] 0.65; 95% confidence interval [CI] 0.44–0.97) and the rate of stroke was greater (aHR 1.71; 95% CI 1.12–2.62) in the high-intensity statin group, driven mostly by intracranial hemorrhage.

Conclusions: The CLIDAS-PCI database provides real-world evidence for the efficacy and safety of high-intensity statins in Japanese ACS patients who have undergone PCI.

In the current concept of evidence-based medicine (EBM), randomized controlled trials (RCTs) and their meta-analyses are considered the gold standard for directing EBM. However, RCTs also have several limitations; RCTs are conducted in a specific population with predetermined inclusion and exclusion criteria, which limits our ability to extrapolate the results of RCTs to real-world patients who may not be included in RCTs.¹

For example, in 2010, a meta-analysis by the Cholesterol Treatment Trialists’ Collaborators of numerous RCTs comparing statin therapy to control treatments or fewer statins concluded that lowering low-density lipoprotein cholesterol (LDL-C) with higher-intensity statin therapy reduces the risk of major vascular events regardless of baseline risk factors.^2,3 However, high-intensity statin therapy was not widely implemented in Japan until 2017,⁴ when the REAL-CAD trial demonstrated the efficacy of 4 mg pitavastatin compared with 1 mg pitavastatin in preventing cardiovascular events in Japanese patients with stable coronary artery disease (CAD).^5,6 In 2017, the Japan Atherosclerosis Society (JAS) published a guideline that recommended an LDL-C target of <70 mg/dL in patients with established CAD who were at high risk, including patients with acute coronary syndrome (ACS). In addition, the 2018 Japanese Circulation Society (JCS) guidelines for the treatment of ACS recommend the use of the maximum tolerated dose of strong statins to achieve LDL-C <70 mg/dL in patients with ACS.⁷

Conversely, the use of high-intensity statin therapy is associated with an increased incidence of intracranial hemorrhage (ICH), as reported in meta-analyses of RCTs,^8–10 as well as observational studies.¹¹ Furthermore, genetic responses to statins differ between Japanese and Western populations on the basis of differences in the metabolism of statins at the level of hepatic enzymes and drug transporters, which may affect the efficacy and safety of statins.^11,12 Therefore, it is very important to examine the efficacy and safety of implementing high-intensity statin therapy in a real-world setting among Japanese patients with CAD.

In the present study we used the Clinical Deep Data Accumulation System (CLIDAS^®) percutaneous coronary intervention (PCI) database to retrospectively describe real-world LDL-C-lowering therapy among CAD patients who underwent PCI at 7 cardiovascular centers, and analyzed the associations between statin intensity and the risk of developing major adverse cardiac and cerebrovascular events (MACCE), demonstrating the role of a real-world database.

Methods

Database Development

The architecture of the CLIDAS has been described previously.^1,13–17 Briefly, CLIDAS collects patient profile, laboratory data, and prescriptions from electronic medical records (EMRs) for consecutive CAD patients who have undergone PCI. Cardiovascular medicine-specific data such as electrocardiography, ultrasound cardiography, and cardiac catheterization during PCI yield data in standard export data format (SEAMAT),^1,18,19 which were collected from Standardized Structured Medical Information eXchange 2 (SS-MIX2) extended storage, the standardized structured medical information exchange format used by the Japanese Ministry of Health, Labour and Welfare (Figure 1A). Data regarding patient outcomes were collected via retrospective reviews of EMRs by data managers who were dedicated to the CLIDAS research group, and the data were confirmed by the investigators.

Figure 1.

(A) Architecture of the Clinical Deep Data Accumulation System (CLIDAS). Seven cardiovascular centers contribute data to CLIDAS. Clinical data in electronic medical records, the picture archiving and communication system, and cardiac catheter reports, as well as data from physiology data servers, including electrocardiograms and echocardiograms, were connected to the Standardized Structured Medical Information Exchange 2 (SS-MIX2) storage system. Clinical research laboratories in each facility gathered anonymized multimodal data, which were submitted to the CLIDAS central server. (B) Flow diagram of the present study. HIS, hospital information system; MACCE, major adverse cardiac and cerebrovascular events; PCI, percutaneous coronary intervention; SEAMAT, standard data format.

Study Design and Population

We obtained data from the CLIDAS central server, which contained data on 9,936 CAD patients who underwent PCI between April 2013 and March 2019. After excluding 246 patients without outcome data, we developed the CLIDAS-PCI database, which consisted of 4,135 patients with ACS and 5,555 patients with chronic coronary syndrome (CCS; Figure 1B). First, we described the occurrence of MACCE among patients with ACS and CCS after the index PCI. Next, we analyzed associations between statin intensity prescribed 0–30 days after the index PCI and long-term MACCE occurrence among ACS and CCS patients who did not experience MACCE within 30 days of the index PCI.

Definitions

In the CLIDAS-PCI database, the index PCI was defined as the first PCI procedure within the study period. To increase the acquisition rate of laboratory data, all baseline laboratory data were calculated as mean values from 60 days before the index PCI to 30 days after the procedure. Definitions of outcomes, comorbidities, and statin intensities are presented in the Supplementary Material.

Statistical Analysis

Categorical variables are presented as counts and percentages, and continuous variables are presented as the mean±SD for normally distributed data or as the median with interquartile range for skewed data. Categorical variables were compared using Chi-squared tests. Normally distributed continuous variables were compared between the groups using unpaired Student’s t-test. Cardiovascular event-free survival rates were calculated using the Kaplan-Meier method, and the significance of differences between groups was determined using log-rank tests. Patients were censored when they were lost to follow-up.

To assess associations between statin intensity and the risk of developing MACCE, propensity scores for each category of statin intensity were determined via multinomial logistic regression analysis, including covariates that may affect statin intensity (age, sex, body mass index, dyslipidemia, diabetes, hypertension, previous PCI or coronary artery bypass grafting, previous stroke, chronic kidney disease [Stage ≥3], ACS or CCS, and year of index PCI).^20,21 The distribution and areas under the receiver operating characteristic (ROC) curves for the propensity scores were assessed (Supplementary Figure 1). The nearest neighbor method was used for 1 : 1 matching on the basis of the propensity scores. Cox regression analyses were performed to examine the association of statin intensity with each MACCE component in the entire cohort and in the propensity score-matched cohort, adjusting for age, sex, and the number of diseased coronary vessels. P<0.05 was considered to indicate statistical significance. P values are presented without adjustment for multiple comparisons in an exploratory manner. All data were analyzed using JMP version 17.2 (SAS Institute, Cary, NC, USA).

Ethical Considerations

This study was planned in accordance with the World Medical Association’s Declaration of Helsinki and was reviewed and approved by the Jichi Medical University Hospital Institutional Review Board, Jichi Medical University, Tochigi, Japan (Reference no. 23-158). Owing to the retrospective study design, the requirement for written informed consent was waived; participants were given the opportunity to opt out of this study.

Results

Patient Characteristics

The baseline characteristics of the entire cohort, and for the 4,135 ACS patients and 5,555 CCS patients separately, are listed in Table 1. The baseline age of the entire cohort was 70±11 years, and 77% were male. Comorbidities such as diabetes, atrial fibrillation, and chronic kidney disease were more common among CCS patients. A history of myocardial infarction (MI), PCI, coronary artery bypass grafting, stroke, hospitalization due to heart failure, peripheral arterial disease, or malignancy was more prevalent among CCS patients. The CLIDAS database is advantageous for collecting multimodal data from EMRs.¹ Laboratory and prescription data collected through SS-MIX2 and angiographic, electrocardiogram, and echocardiogram findings collected through SEAMAT are presented in Table 1. At the baseline, CCS patients had greater utilization of P2Y₁₂ inhibitor monotherapy and dual antiplatelet therapy (DAPT) than did ACS patients, whereas approximately 13% of all patients were prescribed oral anticoagulants. Moreover, coronary disease was more severe in ACS patients. ACS patients had a greater heart rate, a more prevalent ST-segment deviation on electrocardiography, and a lower left ventricular ejection fraction on echocardiography.

Table 1.

Baseline Characteristics of All Patients and for Those With ACS and CCS Separately

	Total (n=9,690)	ACS (n=4,135)	CCS (n=5,555)	P value
Clinical background
Age (years)	70±11	70±12	70±10	0.116
Male sex	7,507 (77)	3,153 (76)	4,354 (78)	0.013
BMI (kg/m2)	24.1±3.8	24.1±3.9	24.2±3.8	0.373
Hypertension	7,897 (82)	3,333 (81)	4,564 (83)	0.1
Diabetes	4,161 (43)	1,594 (39)	2,567 (47)	<0.001
Dyslipidemia	7,534 (78)	3,211 (78)	4,323 (78)	0.903
FH	88 (1.0)	43 (1.1)	45 (0.9)	0.413
Atrial fibrillation	493 (5)	145 (3.5)	348 (6.3)	<0.001
CKD Stage ≥3	4,435 (48)	1,734 (47)	2,701 (50)	0.026
Previous MI	1,479 (15)	576 (14)	903 (16)	0.001
Previous PCI	1,995 (21)	602 (15)	1,393 (25)	<0.001
Previous CABG	517 (5)	159 (3.9)	358 (6.5)	<0.001
Previous stroke	1,043 (11)	412 (10)	631 (11)	0.027
Previous HF hospitalization	637 (7)	167 (4.0)	470 (8.5)	<0.001
Peripheral artery disease	739 (8.4)	153 (4.2)	586 (11)	<0.001
Malignancy	946 (10)	306 (7.7)	640 (12)	<0.001
Follow-up duration (years)	2.5 [0.8–4.1]	2.4 [0.8–2.4]	2.6 [0.9–4.2]	<0.001
Laboratory data (SS-MIX2)
Total cholesterol (mg/dL)	169±36	172±38	167±34	<0.001
Triglyceride (mg/dL)	138±89	133±93	141±85	<0.001
HDL-C (mg/dL)	47±13	45±13	48±13	<0.001
LDL-C (mg/dL)	96±31	102±32	91±29	<0.001
LDL-C ≥180 mg/dL	259 (2.7)	181 (4.5)	78 (1.4)	<0.001
eGFR (mL/min/1.73 m2)	58±24	60±25	57±24	<0.001
HbA1c (%)	6.4±1.1	6.4±1.2	6.4±1.0	0.602
BNP (pg/mL)	240±550	286±537	206±557	<0.001
NT-proBNP (pg/mL)	5,370±18,365	5,532±17,505	5,119±19,658	0.791
Prescription (SS-MIX2)
Statin	5,317 (55)	1,252 (30)	4,065 (73)	<0.001
High-intensity statin	1,813 (19)	403 (10)	1,410 (25)	<0.001
Ezetimibe	394 (4.1)	69 (1.7)	325 (5.9)	<0.001
PCSK9i	3 (0.0)	0 (0)	3 (0)	0.135
Aspirin monotherapy	909 (9.4)	371 (9.0)	538 (9.7)	0.234
P2Y12 inhibitor monotherapy	458 (4.7)	145 (3.5)	313 (5.6)	<0.001
DAPT	5,133 (53.0)	1,075 (20.9)	4,058 (73.1)	<0.001
Warfarin	786 (8)	369 (9)	417 (8)	0.012
DOAC	499 (5)	211 (5)	288 (5)	0.857
Coronary angiography findings (SEAMAT)
RCA disease	4,815 (54)	2,198 (57)	2,617 (52)	<0.001
Left main disease	733 (8)	345 (9)	388 (8)	0.034
LAD disease	6,561 (74)	2,919 (76)	3,642 (72)	<0.001
LCX disease	3,874 (43)	1,719 (44)	2,155 (43)	0.090
Electrocardiogram (SEAMAT)
Heart rate (beats/min)	67±13	69±14	66±12	<0.001
PR interval (ms)	177±34	174±32	179±35	<0.001
Atrial fibrillation	360 (5.3)	127 (4.7)	233 (5.8)	0.040
QRS duration (ms)	103±21	102±20	104±22	<0.001
LV hypertrophy	1,043 (19)	392 (17)	651 (20)	<0.001
ST deviation	1,315 (20)	628 (23)	687 (17)	<0.001
Echocardiogram (SEAMAT)
LVDd (mm)	48±7	49±7	48±7	0.126
LVDs (mm)	34±9	34±8	33±9	<0.001
LVEF (%)	57±14	55±13	59±14	<0.001
LAD (mm)	39±7	38±7	40±7	<0.001

Unless indicated otherwise, data are given as the mean±SD, median [interquartile range], or n (%). ACS, acute coronary syndrome; BMI, body mass index; BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; CCS, chronic coronary syndrome; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; LAD, left anterior descending artery; LCX, left circumflex artery; LDL-C, low-density lipoprotein cholesterol; LV, left ventricle; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal pro B-type natriuretic peptide; PCI, percutaneous coronary intervention; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; RCA, right coronary artery; SEAMAT, standard export data format; SS-MIX2, Standardized Structured Medical Information eXchange 2.

LDL-C Management After Index PCI

At baseline, 9.7% of patients with ACS were undergoing high-intensity statin therapy; this increased significantly at 30 days and reached 54.2% at 3 years (P<0.001, Cochrane-Armitage test). At baseline, 25.4% of CCS patients were undergoing high-intensity statin therapy; this increased significantly over 3 years to 42.2% (P<0.001; Figure 2A). In contrast, the prescription rate of ezetimibe was low and did not change over time among ACS patients, but decreased significantly among CCS patients (P<0.001). Less than 1% of patients were treated with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (Figure 2B).

Figure 2.

(A) Percentage of acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients receiving different statin intensity therapy at baseline and over 3 years from the index percutaneous coronary intervention (PCI). (B) Prescription rates of ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) at baseline and over 6 months from the index PCI in ACS and CCS patients. Data are the mean±SD. (C) Low-density lipoprotein cholesterol (LDL-C) levels at baseline and over 3 years from the index PCI in ACS and CCS patients.

According to the 2017 JAS guidelines, an LDL-C goal of <70 mg/dL is recommended for ACS patients and CCS patients with high-risk conditions, such as familial hypercholesterolemia (FH), ACS, and diabetes complicated by other high-risk conditions.²² In the present study, 45% of CCS patients were categorized as high risk according to the JAS guidelines. The percentage of patients with ACS with LDL-C <70 mg/dL increased significantly over 1 year, but plateaued at 37%; among CCS patients, 33.8% had LDL-C <70 mg/dL (Figure 2C). Importantly, the proportion of patients prescribed high-intensity statins during the first month after the index PCI increased significantly over the years in both the ACS (P<0.001, Chi-squared test) and CCS (P<0.001, Chi-squared test) groups. In addition, the proportion of patients with LDL-C >70 mg/dL during the 2–6 months after the index PCI increased significantly over the years in both the ACS (P=0.003, Chi-squared test) and CCS (P=0.001, Chi-squared test) groups (Supplementary Figure 2A,B).

Antiplatelet Therapy After Index PCI

During the first month after the index PCI, DAPT utilization was greater in the ACS than CCS group. DAPT prescriptions declined significantly over time in both the ACS and CCS groups (P<0.001 for both, Chi-squared test), yet more than 30% of patients in the study population remained on DAPT for over 3 years (Supplementary Figure 3A). Among ACS patients, a significant association between the use of DAPT and high-intensity statins was observed during the 2–6 months after the index PCI, but not during other periods (Supplementary Figure 3B).

Post-PCI Prognosis in ACS vs. CCS Patients

The primary analyses of this study, including the incidence of MACCE and individual components of MACCE (cardiovascular death, MI, and stroke) among patients whose survival curves were unadjusted via the Kaplan-Meier method are shown in Figure 3. In patients with ACS, a marked number of MACCE (n=133, including 100 cardiovascular deaths) occurred in the first 30 days (Figure 3A,B). Early deaths in ACS patients were caused by acute MI (83%), sudden death (7%), and heart failure (3%). The rate of MI was consistently higher among ACS than CCS patients over the 5-year period after the index PCI (event rate 1.32 vs. 0.60%/patient year; Table 2; Figure 3C). In contrast, the rate of stroke was similar between the ACS and CCS groups. The event rates per year of MACCE, cardiovascular death, and MI were significantly higher among patients with ACS (Table 2).

Figure 3.

Clinical outcomes after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients. Kaplan-Meier curves with log-rank tests for (A) major adverse cardiac and cerebrovascular events (MACCE), (B) cardiovascular death, (C) myocardial infarction (MI), and (D) stroke after the index PCI in ACS and CCS patients.

Table 2.

Endpoints

	ACS (n=4,135)		CCS (n=5,555)		P value
	No. events	% Per patient-year (95% CI)	No. events	% Per patient-year (95% CI)
MACCE	441	4.13 (3.77–4.53)	386	2.52 (2.28–2.78)	<0.001
CV death	193	1.74 (1.52–2.00)	149	0.95 (0.81–1.11)	<0.001
MI	143	1.32 (1.12–1.55)	93	0.60 (0.49–0.73)	<0.001
Stroke	136	1.25 (1.06–1.48)	170	1.10 (0.95–1.27)	0.26

The 95% CI was estimated by the Wilson/Brown method. CI, confidence interval; CV, cardiovascular; MACCE, major adverse cardiac and cerebrovascular events. Other abbreviations as in Table 1.

Statin Intensity and Prognosis in Patients After PCI

We categorized statin intensity prescribed within the first 30 days after the index PCI and regrouped ACS and CCS patients according to statin intensity (Figure 1B; Supplementary Table 1). The baseline characteristics of each statin intensity group are presented in Supplementary Tables 2 and 3. Compared with those in the other groups, patients in the low-intensity/no-statin group were older and had a lower body mass index, and there were fewer patients with dyslipidemia, more patients with chronic kidney disease, and more patients with malignancy. Crude 30-day landmark Kaplan-Meier curves revealed higher event rates in the low-intensity/no-statin group than in the other statin intensity groups for MACCE, cardiovascular death, and MI, but not for stroke (Supplementary Figure 4). Importantly, more MACCE occurred within 30 days among ACS patients in the low-intensity/no-statin group (Supplementary Table 2) than in the other groups.

Propensity scores for statin intensity categories were generated by logistic regression analyses, revealing the apparent heterogeneity of the low-intensity/no-statin group (Supplementary Figure 1). Therefore, we focused on comparing the associations of high- and moderate-intensity statin therapy with the risk of developing MACCE. On the basis of the nearest neighbor method, 1 : 1 matching was used to generate 1,419 pairs among ACS patients and 1,726 pairs among CCS patients, for whom baseline characteristics are presented in Table 3. Background characteristics were well balanced, except for a greater presence of FH and higher baseline total cholesterol and LDL-C levels in the high-intensity statin therapy groups of ACS and CCS patients, suggesting physicians’ preference for the implementation of high-intensity statin therapy for such patients. The prescription rates of aspirin and P2Y₁₂ inhibitors were significantly higher in the high-intensity statin group of ACS patients (Table 3). Landmark analyses via the Kaplan-Meier method starting from 30 days after the index PCI, excluding MACCE within 30 days (133 events in ACS patients, 31 in CCS patients), revealed no differences in event rates for MACCE or cardiovascular death between the high- and moderate-intensity statin groups for both ACS and CCS patients (Figure 4A,B; Table 4). Importantly, in ACS patients, the MI rate was lower in the high-intensity statin group than in the moderate-intensity statin group according to the Cox proportional hazard model (log-rank P=0.0259; adjusted hazard ratio [aHR] 0.65; 95% confidence interval [CI] 0.44–0.97). In contrast, the rate of stroke was greater in the high-intensity statin group (log-rank P=0.0018; aHR 1.71; 95% CI 1.12–2.62; Figure 4C,D; Table 4). The rate of ischemic stroke did not differ between the high- and moderate-intensity statin groups, whereas the incidence of ICH was greater in the high-intensity statin group (aHR 2.47; 95% CI 1.09–5.59; Table 4).

Table 3.

Baseline Characteristics of Propensity Score-Matched Patients According to Statin Intensity

	ACS			CCS
	High-intensity statin (n=1,419)	Moderate-intensity statin (n=1,419)	P value	High-intensity statin (n=1,726)	Moderate-intensity statin (n=1,726)	P value
Age (years)	71±11	70±12	0.886	69±10	70±10	0.712
Male sex	1,063 (75)	1,085 (76)	0.336	1,341 (78)	1,350 (78)	0.712
BMI (kg/m2)	23.8±3.4	24.0±3.8	0.364	24.4±3.7	24.4±3.8	0.933
Hypertension	1,149 (81)	1,163 (82)	0.499	1,445 (84)	1,433 (83)	0.583
Diabetes	542 (38)	553 (39)	0.671	775 (45)	785 (45)	0.732
Dyslipidemia	1,118 (79)	1,147 (81)	0.175	1,488 (86)	1,516 (88)	0.156
FH	18 (1.3)	8 (0.6)	0.049	34 (2.0)	5 (0.3)	<0.001
Atrial fibrillation	41 (3)	53 (4)	0.208	76 (4)	110 (6)	0.010
CKD stage ≥3	663 (47)	658 (46)	0.851	800 (46)	826 (48)	0.375
Previous MI	193 (14)	183 (13)	0.580	304 (18)	304 (18)	1.0
Previous PCI	208 (15)	214 (15)	0.752	449 (26)	421 (24)	0.272
Previous CABG	52 (3.7)	63 (4.4)	0.295	126 (7)	127 (7)	0.948
Previous stroke	145 (10)	143 (10)	0.901	201 (12)	209 (12)	0.674
Previous HF hospitalization	41 (3)	52 (4)	<0.001	128 (7)	153 (9)	0.120
Peripheral artery disease	50 (4)	51 (4)	0.919	175 (10)	166 (10)	0.608
Malignancy	92 (6)	124 (9)	0.067	146 (8)	195 (11)	0.017
Total cholesterol (mg/dL)	188±47	174±38	<0.001	170±39	163±35	<0.001
Triglyceride (mg/dL)	154±98	148±95	0.110	159±102	154±101	0.192
HDL-C (mg/dL)	44±12	45±13	0.005	48±12	48±13	0.122
LDL-C (mg/dL)	107±33	97±29	<0.001	97±32	88±27	<0.001
eGFR (mL/min/1.73 m2)	61±22	61±23	0.759	60±21	59±22	0.138
HbA1c (%)	6.5±1.3	6.4±1.1	0.001	6.5±1.1	6.4±1.0	0.123
BNP (pg/mL)	254±445	273±500	0.316	147±319	163±372	0.210
NT-proBNP (pg/mL)	3,148±8,566	6,205±17,327	0.126	2,215±7,782	3,958±10,336	0.228
JAS Guideline			–			0.918
High risk	1,419 (100)	1,419 (100)		773 (45)	770 (45)
Moderate risk	0	0		953 (55)	956 (55)
MACCE within 30 days	32 (2.3)	35 (2.5)	0.711	7 (0.4)	11 (0.6)	0.345
Aspirin	1,392 (98)	1,372 (97)	0.019	1,543 (89)	1,520 (88)	0.216
P2Y12 inhibitors	1,350 (95)	1,322 (93)	0.025	1,513 (88)	1,483 (86)	0.132
Warfarin	125 (9)	137 (10)	0.437	120 (7)	130 (8)	0.511
DOAC	67 (5)	69 (5)	0.861	87 (5)	97 (6)	0.449

Unless indicated otherwise, data are given as the mean±SD or n (%). JAS, Japan Atherosclerosis Society. Other abbreviations as in Tables 1,2.

Figure 4.

Clinical outcomes after percutaneous coronary intervention (PCI) according to statin intensity. Kaplan-Meier curves with log-rank tests and adjusted hazard ratios (HRs) calculated by Cox proportional hazards analysis for (A) major adverse cardiac and cerebrovascular events (MACCE), (B) cardiovascular death, (C) myocardial infarction (MI), and (D) stroke after the index PCI in acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients.

Table 4.

HRs (High-Intensity Statin vs. Moderate-Intensity Statin) for Endpoints in the Propensity Score-Matched Population

Endpoint	Unadjusted HR (95% CI)	P value	Adjusted HR (95% CI)	P value
ACS
MACCE	1.05 (0.83–1.33)	0.700	0.99 (0.77–1.26)	0.914
CV death	0.87 (0.58–1.31)	0.508	0.82 (0.54–1.26)	0.374
MI	0.72 (0.49–1.06)	0.094	0.65 (0.44–0.97)	0.033
Stroke	1.74 (1.16–2.61)	0.008	1.71 (1.12–2.62)	0.013
Ischemic stroke	1.48 (0.92–2.38)	0.107	1.51 (0.92–2.48)	0.107
ICH	2.75 (1.23–6.16)	0.014	2.47 (1.09–5.59)	0.030
CCS
MACCE	0.81 (0.62–1.07)	0.141	0.83 (0.63–1.1)	0.195
CV death	0.65 (0.41–1.02)	0.061	0.66 (0.41–1.06)	0.083
MI	0.85 (0.48–1.5)	0.574	0.89 (0.49–1.62)	0.711
Stroke	0.98 (0.66–1.45)	0.905	0.97 (0.64–1.47)	0.894
Ischemic stroke	0.95 (0.59–1.54)	0.849	0.95 (0.59–1.54)	0.838
ICH	0.84 (0.41–1.72)	0.633	0.88 (0.4–1.93)	0.750

HR, hazard ratio; ICH, intracranial hemorrhage. Other abbreviations as in Tables 1,2.

Discussion

In this study, we used an EMR-based database of patients undergoing PCI in 7 cardiovascular centers in Japan. This study provides real-world evidence regarding LDL-C management in and the prognosis of CAD patients who underwent PCI in Japan, showing the effectiveness of high-intensity statin therapy in reducing the risk of developing MI and the potential risk of stroke, which is mostly driven by ICH; however, both associations occurred exclusively in patients with ACS.

The CLIDAS

Recently, EMR data have been increasingly used for medical research. In Japan, hospital information systems in more than 1,200 hospitals use SS-MIX2 storage in the HL7 version 2.5 format, which allows researchers to collect patient information, prescription, and laboratory data in a standardized format.²³ Some medical societies, including the JCS^13–17 and the Japan Diabetes Society,^24,25 have used SS-MIX2 to develop registry databases. The CLIDAS, supported by the JCS, has several advantages, including: (1) the collection of standardized cardiovascular examination data (i.e., electrocardiogram, echocardiogram, and cardiac catheterization) in SEAMAT in addition to prescription and laboratory data;^1,19 and (2) the capture of clinical events via retrospective EMR review by data managers. By providing such data, the CLIDAS-PCI database allows researchers to analyze several clinical questions.^13–17 One weakness of CLIDAS is the limited data for specific purposes, such as diagnostic factors for FH. The EXPLORE-J study,²⁶ a prospective observational study dedicated to the screening of FH in ACS patients, reported that the incidence of FH according to JAS diagnostic criteria was 3.1%. In the present study, FH was diagnosed in 1.1% of ACS patients, which is lower than the incidence reported in the EXPLORE-J study, although 4.5% of ACS patients in the present study had LDL-C ≥180 mg/dL at baseline. The extensiveness of diagnostic procedures, including examination of Achilles tendon thickness or genetic testing, was not assessed in the present study, suggesting that there are inherent limitations associated with the use of real-world databases.^1,24–26

Prognosis After PCI in Japan

In this study, we described the occurrence of MACCE in CAD patients, which was greater in ACS than CCS patients. The median follow-up duration in the CLIDAS-PCI registry was 2.5 years, and its 2-year follow-up rate was 63%, which is lower than the 2-year follow-up rate of approximately 90% in the CREDO-Kyoto registry²⁷ and the PACIFIC registry,²⁸ prospective registries of CAD patients in Japan. Nonetheless, the recorded event rates are equivalent to those reported in the prospective registries, suggesting the feasibility of retrospective EMR reviews for capturing clinical events in cardiovascular centers participating in the CLIDAS.

High-Intensity Statin Therapy and the Risk of Developing MI and ICH

The Japanese clinical guidelines recommend the primary use of statins for the secondary prevention of CAD, setting targets of LDL-C <100 mg/dL for moderate-risk patients and LDL-C <70 mg/dL for high-risk patients, including those with ACS.^7,29 However, in the present study, high-intensity statin was prescribed to only 49% of ACS patients within 30 days of the index PCI (Figure 2A). Because the prescription of high-intensity statins increased over the years (Supplementary Figure 2A), we adjusted for the year of index PCI for propensity score matching. Propensity score-matched analysis revealed that ACS patients who underwent high-intensity statin therapy had a reduced risk of developing MI, supporting current clinical guidelines. Despite their well-established roles in both primary and secondary prevention of cardiovascular diseases, statins have been associated with an increased risk of developing ICH,^3,10,30–32 as shown in the present study (Figure 4C). The pleiotropic effects of statins on platelet function, coagulation, and fibrinolysis have been proposed to explain this increased risk of developing ICH.^32–34 Based on Phase 2 trials in Japan,¹² the doses of statins approved for use in Japan are lower than those in most other countries, suggesting greater efficacy and concerns about adverse events in this population. The association between high-intensity statin therapy and an increased risk of developing ICH was observed exclusively in ACS patients. Although antiplatelet therapy did not differ significantly between the high- and moderate-intensity statin groups over the 3-year period, prolonged DAPT use in this study population may have unmasked a latent risk of ICH, particularly in those receiving high-intensity statins. These findings highlight the need for careful consideration of both the benefits and risks of intensive lipid management in patients with ACS; however, the decreased risk of developing MI associated with high-intensity statin therapy rather than the risk of ICH may be appreciated among ACS patients at high risk of recurrent MI.

Study Limitations

This study has some limitations. First, this study was a retrospective observational study; although propensity score matching was performed to reduce potential confounding factors, residual confounding due to unmeasured variables or imperfect matching may have influenced the results. Second, the categories of statin intensity in this study were set according to the approved doses in Japan, which are lower than doses used in Western countries, which limits our ability to extrapolate our findings to other countries.

Conclusions

CLIDAS provided real-world data on LDL-C management and prognosis in ACS and CCS patients who underwent PCI in Japan. The use of high-intensity statin therapy was associated with a reduced risk of developing MI and an increased risk of developing ICH, but both associations were detected exclusively in ACS patients.

Acknowledgments

This work was supported by the Committee of the IT/Database, Japanese Circulation Society, Tokyo, Japan.

Sources of Funding

This work was supported by the Cross-Ministerial Strategic Innovation Promotion Program under “Integrated Health Care System” (Grant no. JPJ012425) and by a grant from the Ministry of Health, Labour and Welfare, Government of Japan. This work was also supported by Kowa Company, Ltd. (Tokyo, Japan).

Disclosures

T.M. has received a research grant from Amgen. COI statements from other authors will be included in the manuscript. K.T., K.K., and R.N. are members of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to disclose.

IRB Information

This study was approved by the Jichi Medical University Hospital Institutional Review Board, Jichi Medical University, Tochigi, Japan (Reference no. 23-158).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-25-0066

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