Thrombotic Risk Stratification and Intensive Statin Therapy for Secondary Prevention of Coronary Artery Disease　― Insights From the REAL-CAD Study ―

Abstract

Background: It is unknown whether beneficial effects of higher-dose statins on cardiovascular events are different according to the thrombotic risk in patients with chronic coronary syndrome (CCS).

Methods and Results: The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study is a randomized trial comparing 4 mg and 1 mg pitavastatin in patients with CCS. This study categorized 12,413 patients into 3 strata according to the CREDO-Kyoto thrombotic risk score: low-risk (N=9,434; 4 mg: N=4,742, and 1 mg: N=4,692), intermediate-risk (N=2,415; 4 mg: N=1,188, and 1 mg: N=1,227); and high-risk (N=564; 4 mg: N=269, and 1 mg: N=295). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. Cumulative 4-year incidence of the primary endpoint was significantly higher in the high-risk stratum than in the intermediate- and low-risk strata (11.0%, 6.3%, and 4.5%, P<0.0001). In the low-risk stratum, the cumulative 4-year incidence of the primary endpoint was significantly lower in the 4 mg than in the 1 mg group (4.0% and 4.9%, P=0.02), whereas in the intermediate- and high-risk strata, it was numerically lower in the 4 mg than in the 1 mg group. There was no significant treatment-by-subgroup interaction for the primary endpoint (P-interaction=0.77).

Conclusions: High-dose pitavastatin therapy compared with low-dose pitavastatin therapy was associated with a trend toward lowering the risk for cardiovascular events irrespective of the thrombotic risk in patients with CCS.

High-intensity statin therapy has been reported to be associated with significantly lower risk for cardiovascular events in patients with coronary artery disease.^1,2 In the 2018 American College of Cardiology (ACC)/American Heart Association (AHA) guideline, high intensity or maximal statin therapy are recommended in very high-risk atherosclerotic cardiovascular disease (ASCVD) patients.³ Furthermore, a more intensive reduction of low-density lipoprotein cholesterol (LDL-C) in patients with ASCVD is recommended in the 2019 European Cardiology Society (ESC) guideline. For secondary prevention in very high-risk patients, such as those with acute coronary syndrome (ACS) or familial hypercholesterolemia with ACSVD, an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <55 mg/dL are recommended.⁴ Therefore, intensive lipid-lowering therapy using high-intensity statin therapy would be a standard of care in daily clinical practice for high-risk patients with ASCVD.

Recently, risk scores evaluating thrombotic and bleeding risks have been developed mainly to determine the duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI).^5–8 A short duration of DAPT is recommended in patients with high bleeding risk (HBR) and a long duration of DAPT could be one of the options in the treatment of high thrombotic risk patients without HBR.^9,10 However, it is unknown whether beneficial effects of higher-dose statins relative to lower-dose statins on cardiovascular events are different according to the thrombotic risk of patients. Therefore, we sought to evaluate the effects of high-dose statin relative to low-dose statin on cardiovascular events according to the thrombotic risk of patients with chronic coronary syndrome (CCS) in a large-scale Japanese randomized trial.

Methods

Study Population

The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study was a prospective, multicenter, randomized, open-label, blinded endpoint, physician-initiated superiority trial to determine whether high- as compared with low-dose pitavastatin therapy could reduce cardiovascular events in Japanese patients with CCS (Clinical Trial Registration: http://www.clinicaltrials.gov, Unique identifier: NCT01042730).¹ We included patients who were aged 20–80 years with CCS and excluded those patients with a LDL-C <100 mg/dL not treatment with statin therapy before enrollment. Eligible patients who provided informed consent were enrolled and received pitavastatin 1 mg once daily orally for a run-in period of at least 1 month. Patients who achieved a LDL-C <120 mg/dL during a run-in period were randomized in a 1-to-1 fashion to either the oral pitavastatin 4 mg/day group or 1 mg/day group, using an electronic data capture system and dynamic allocation stratified by facility, age (<65 or ≥65 years), sex, diabetes mellitus, and statins use before enrolment. The details of the REAL-CAD study were previously described (Figure 1).¹

Figure 1.

Study flowchart. REAL-CAD, The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease.

Ethical approval was granted by the Public Health Research Foundation (PHRF) ethics review committee and by ethical committees at all participating sites. All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki.

In the present study, the patients were divided into the 3 strata according to the CREDO-Kyoto thrombotic risk score; low-risk (0–1 points), intermediate-risk (2–3 points) and high-risk (≥4 points) strata.⁸ In the CREDO-Kyoto thrombotic risk score, patients with severe chronic kidney disease (CKD) (dialysis or estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²), atrial fibrillation (AF), peripheral vascular disease, and anemia (hemoglobin <11 g/dL) were assigned 2 points, and those who were aged ≥75 years, had heart failure and diabetes were assigned 1 point. In the present analysis, we first compared the clinical outcomes across the 3 strata to evaluate the validity in applying the thrombotic risk score derived from the baseline characteristics of patients undergoing PCI to those patients with CCS. Then, we compared the clinical outcomes between the high-dose and low-dose groups stratified by the CREDO-Kyoto thrombotic risk score.

During follow up, patient visits dictated by the protocol were at 6 and 12 months in the first year and every 12 months thereafter. Serum lipid levels such as LDL-C, total cholesterol, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), as well as other blood tests such as creatine kinase, creatinine, and hemoglobin A1c, were measured at the baseline after the run-in period, at 6 and 12 months, and yearly thereafter, whereas high-sensitivity C-reactive protein (hsCRP) was measured at baseline after the run-in period and at 6 months. The site investigators reported follow-up information through the web-based electronic data capturing system. Data were monitored by the data center, and any inconsistencies were resolved by queries. Final clinical follow-up data were collected through January to March 2016 as previously described elsewhere.¹

Study Endpoints

The primary endpoint was the same as that in the main study: a composite of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization. A secondary composite endpoint was defined as a composite of the primary endpoint event and clinically indicated coronary revascularization excluding target lesion revascularization (TLR) for lesions treated at prior PCI. Other secondary endpoints and details of the definitions of endpoints are described previously.¹

Statistical Analysis

Categorical variables were presented as number and percentage, and compared with the chi-squared test. Continuous variables were expressed as mean±standard deviation, or median and interquartile range. Based on their distribution, continuous variables were compared with the Student’s t-test or Wilcoxon rank sum test between the 2 groups. Comparisons of continuous variables between the 3 groups according to the CREDO-Kyoto thrombotic risk were performed with the analysis of variance or Kruskal-Wallis test, as appropriate. Regarding the changes in LDL-C level, LDL-C levels were measured at baseline, 6 months, 1 year, 2 years and 3 years. LDL-C levels at baseline and 3 years were expressed as mean value and compared with the Student’s t-test or with the analysis of variance.

Cumulative incidence was estimated by using the Kaplan-Meier method and differences were assessed with the log-rank test. We used the univariable Cox proportional hazard models to evaluate the long-term risk for cardiovascular events across the 3 strata based on the CREDO-Kyoto thrombotic risk score. In the Cox proportional hazard model, we developed dummy code variables for high-risk and intermediate-risk scores, with a low-risk score as the reference. The effects of the high-risk and intermediate-risk groups as compared to low-risk reference group were expressed as hazard ratios (HR) and their 95% confidence intervals (CI). We also used the univariable Cox proportional hazard models to estimate the effects of the high-dose group relative to the low-dose group for cardiovascular events stratified by the CREDO-Kyoto thrombotic risk score. The effect of the high-dose group relative to the low-dose group was expressed as HR and their 95% CI. We also conducted the formal interaction test between the CREDO-Kyoto thrombotic risk stratum and the effect of the pitavastatin 4 mg group relative to the pitavastatin 1 mg group. Patients lost to follow up were censored at the time when their final clinical follow-up information was available.

Statistical analyses were conducted by a physician (M. Natsuaki) and by a statistician (T. Morimoto) with the use of JMP 15.0 and SAS 9.2 (SAS Institute Inc, Cary, NC, USA) software. All the statistical analyses were 2-tailed. P values <0.05 were considered statistically significant.

Results

Baseline Characteristics of the High-Risk, Intermediate-Risk and Low-Risk Strata Patients

Patients in the high-risk stratum were much older and had a lower body weight, body mass index and left ventricular ejection fraction and higher heart rate than those in the intermediate- and low-risk strata. Patients in the high-risk stratum were more often women, and more often had heart failure, AF, prior stroke, peripheral vascular disease, diabetes, hypertension, malignancy, anemia, thrombocytopenia and high CREDO-Kyoto bleeding risk score. Prior MI, prior PCI and being a current smoker were more prevalent in patients in the low-risk stratum. Regarding medications, β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were more often prescribed for patients in the high-risk stratum.

Serum Parameters in the High-Risk, Intermediate-Risk and Low-Risk Strata Patients

The values of serum parameters at the baseline after the run-in period are presented in Table 1. The levels of total cholesterol, HDL-C, TG, apolipoprotein A1 and B, serum creatinine and eGFR were significantly lower patients in the high-risk stratum than in the intermediate- and low-risk strata. The levels of hsCRP, glucose and hemoglobin A1c were significantly higher in patients in the high-risk stratum than in the intermediate- and low-risk strata.

Table 1. Baseline Characteristics in the High-Risk, Intermediate-Risk and Low-Risk Strata

	Low-risk (N=9,434)	Intermediate-risk (N=2,415)	High-risk (N=564)	P value
Age (years)	66.7±8.3	72.0±6.9	74.6±5.3	<0.0001
≥75	1,333 (14)	1,123 (47)	380 (67)	<0.0001
Men	7,915 (84)	1,921 (80)	417 (74)	<0.0001
Weight, kg	65.8±11.3 (8,861)	63.6±10.9 (2,295)	62.0±10.3 (540)	<0.0001
Body mass index (kg/m2)	24.7±3.4 (8,695)	24.5±3.3 (2,252)	24.3±3.4 (534)	0.0003
Abdominal circumference, cm	88.0±9.4 (7,644)	88.2±9.4 (1,989)	88.5±9.7 (474)	0.27
Systolic blood pressure, mmHg	127.4±15.9 (9,088)	128.3±16.5 (2,335)	128.1±18.1 (552)	0.03
Diastolic blood pressure, mmHg	73.6±10.7 (9,088)	71.3±10.8 (2,335)	69.0±11.2 (552)	<0.0001
Heart rate, beats/min	69.1±11.3 (8,732)	70.5±12.3 (2,248)	72.3±12.9 (530)	<0.0001
LVEF (%)	60.3±11.3 (4,851)	60.0±12.2 (1,252)	57.8±12.6 (292)	0.002
Cardiovascular history
ACS	6,998 (74)	1,576 (65)	341 (60)	<0.0001
Hospitalization for unstable angina	2,445 (26)	589 (24)	133 (24)	0.17
Myocardial infarction	5,027 (53)	1,117 (46)	240 (43)	<0.0001
PCI	7,988 (85)	1,927 (80)	445 (79)	<0.0001
Coronary artery bypass grafting	1,039 (11)	416 (17)	119 (21)	<0.0001
Congestive heart failure	199 (2.1)	295 (12)	156 (28)	<0.0001
AF	0 (0)	543 (23)	227 (40)	<0.0001
Ischemic stroke	471 (5.0)	271 (11)	108 (19)	<0.0001
Hemorrhagic stroke	93 (1.0)	33 (1.4)	14 (2.5)	0.007
PVD	0 (0)	570 (24)	297 (53)	<0.0001
Current smoking	1,625 (17)	340 (14)	66 (12)	<0.0001
Diabetes mellitus	3,025 (32)	1,489 (62)	464 (82)	<0.0001
Hypertension	7,000 (74)	1,920 (80)	476 (84)	<0.0001
Family history of CAD	1,604 (17)	364 (15)	79 (14)	0.02
History of malignancy	431 (4.6)	177 (7.3)	52 (9.2)	<0.0001
Anemia (Hemoglobin <11 g/dL)	0 (0)	200 (8.3)	181 (32)	<0.0001
Thrombocytopenia (Platelet <100,000/μL)	47 (0.5)	20 (0.8)	14 (2.5)	<0.0001
CREDO-Kyoto bleeding risk
Low	4,106 (44)	5,165 (55)	163 (1.7)	<0.0001
Intermediate	5,165 (55)	1,396 (58)	186 (33)
High	163 (1.7)	535 (22)	349 (62)
Blood examinations
Total cholesterol, mg/dL	167.8±23.9 (9,373)	164.7±24.8 (2,394)	159.5±26.4 (562)	<0.0001
LDL-C, mg/dL	88.3±18.9	87.0±18.8	84.0±20.2	<0.0001
HDL-C, mg/dL	51.0±12.6 (9,432)	50.3±12.5 (2,414)	48.6±13.4 (564)	<0.0001
Triglycerides, mg/dL	125 (89–177) (9,427)	121 (87–168) (2,413)	120 (85–166) (563)	0.001
Apolipoprotein A1, mg/dL	136.2±24.3 (1,456)	134.9±26.1 (376)	130.3±26.2 (83)	0.09
Apolipoprotein B, mg/dL	80.6±15.2 (1,457)	79.4±15.8 (375)	74.3±14.0 (83)	0.0008
High-sensitivity CRP, mg/dL	0.49 (0.24–1.09) (9,134)	0.59 (0.27–1.41) (2,343)	0.74 (0.33–1.86) (549)	<0.0001
Glucose, mg/dL	121.3±37.6 (7,606)	131.3±45.4 (1,933)	139.8±50.8 (481)	<0.0001
Hemoglobin A1c, %	5.78±0.81 (8,682)	6.10±0.94 (2,265)	6.29±0.90 (542)	<0.0001
Creatine kinase, U/L	106 (78–149) (8,938)	102 (73–145) (2,287)	93 (67–136) (540)	<0.0001
Serum creatinine, mg/dL	0.85 (0.74–0.98) (9,197)	0.9 (0.77–1.09) (2,363)	1.05 (0.86–1.47) (558)	<0.0001
eGFR, mL/min/1.73 m2	68.1±17.6 (9,197)	61.0±17.3 (2,363)	49.8±19.7 (558)	<0.0001
Severe CKD	0 (0)	87 (3.6)	114 (20)	<0.0001
CKD	(N=9,197)	(N=2,363)	(N=558)	<0.0001
Stage 1	772 (8.4)	116 (4.9)	14 (2.5)
Stage 2	5,617 (61)	1,094 (46)	165 (30)
Stage 3	2,808 (31)	1,066 (45)	265 (47)
Stage 4	0 (0)	80 (3.4)	106 (19)
Stage 5	0 (0)	7 (0.3)	8 (1.4)
Medications	(N=8,663)	(N=2,245)	(N=541)
Statins before run-in period	8,623 (91)	2,155 (89)	500 (89)	0.001
Aspirin	8,079 (93)	2,029 (90)	476 (88)	<0.0001
Thienopyridine	4,112 (47)	1,046 (47)	246 (46)	0.54
Dual antiplatelet therapy	3,879 (45)	968 (43)	223 (41)	0.12
β-blockers	3,572 (41)	978 (44)	257 (48)	0.004
ACEI or ARB	5,777 (67)	1,540 (69)	404 (75)	0.0002

Data are presented as n (%), median (interquartile range) (n), or mean (SD) (n). For the variables with missing values, we indicated the number of patients evaluated. In the CREDO-Kyoto bleeding thrombotic risk score, patients with thrombocytopenia (platelet <100,000/μL), severe CKD, peripheral vascular disease, and heart failure were assigned 2 points and prior myocardial infarction, malignancy and AF were assigned 1 point.⁸ Patients were classified into 3 strata according to the CREDO-Kyoto bleeding risk score; low-risk (0 points), intermediate-risk (1–2 points) and high-risk (≥3 points). ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CKD, chronic kidney disease; CREDO-Kyoto, Coronary REvascularization Demonstrating Outcome study in Kyoto; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

The levels of baseline LDL-C and follow-up LDL-C were significantly lower in patients in the high-risk stratum than in the intermediate- and low-risk strata (Table 1 and Supplementary Figure 1).

Clinical Outcomes in the High-Risk, Intermediate-Risk and Low-Risk Strata Patients

Median follow-up duration was 3.9 (interquartile range: 3.0–4.6) years. Cumulative 4-year incidence of the primary endpoint was significantly higher in patients in the high-risk stratum than in the intermediate- and low-risk strata (11.0%, 6.3%, and 4.5%, P<0.0001) (Figure 2). Cumulative incidences of all-cause death, cardiovascular death, cardiac death, ischemic stroke, hemorrhagic stroke and TLR were also significantly higher in patients in the high-risk stratum than in the intermediate- and low-risk strata (Table 2).

Figure 2.

Kaplan-Meier curves for the primary endpoint according to the CREDO-Kyoto thrombotic risk stratification. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. CREDO-Kyoto, Coronary REvascularization Demonstrating Outcome study in Kyoto.

Table 2. Clinical Outcomes in the High-Risk, Intermediate-Risk and Low-Risk Strata

	Number of patients with event (Cumulative 4-year incidence)	Log-rank P value	HR (95% CI)	P value
Primary endpoint
Low-risk	400/9,434 (4.5)	<0.0001	Ref.
Intermediate-risk	143/2,415 (6.3)		1.4 (1.16–1.7)	0.0005
High-risk	57/564 (11.0)		2.51 (1.9–3.31)	<0.0001
Composite of primary endpoint or coronary revascularization
Low-risk	789/9,434 (9.0)	<0.0001	Ref.
Intermediate-risk	220/2,415 (9.8)		1.09 (0.94–1.26)	0.26
High-risk	80/564 (15.9)		1.78 (1.42–2.25)	<0.0001
Death resulting from any cause
Low-risk	264/9,434 (3.0)	<0.0001	Ref.
Intermediate-risk	131/2,415 (5.6)		1.94 (1.58–2.4)	<0.0001
High-risk	72/564 (14.1)		4.76 (3.67–6.18)	<0.0001
Cardiovascular death
Low-risk	109/9,434 (1.2)	<0.0001	Ref.
Intermediate-risk	55/2,415 (2.2)		1.97 (1.43–2.73)	<0.0001
High-risk	34/564 (6.7)		5.41 (3.68–7.95)	<0.0001
Cardiac death
Low-risk	75/9,434 (0.8)	<0.0001	Ref.
Intermediate-risk	48/2,415 (1.9)		2.5 (1.74–3.59)	<0.0001
High-risk	24/564 (4.7)		5.53 (3.49–8.76)	<0.0001
Myocardial infarction or ischemic stroke
Low-risk	188/9,434 (2.1)	0.004	Ref.
Intermediate-risk	67/2,415 (3.2)		1.4 (1.06–1.85)	0.02
High-risk	20/564 (4.1)		1.87 (1.18–2.97)	0.008
Myocardial infarction
Low-risk	83/9,434 (1.0)	0.86	Ref.
Intermediate-risk	24/2,415 (1.3)		1.13 (0.72–1.79)	0.59
High-risk	5/564 (1.0)		1.05 (0.42–2.58)	0.92
Ischemic stroke
Low-risk	109/9,434 (1.2)	0.0007	Ref.
Intermediate-risk	32/2,415 (2.0)		1.55 (1.09–2.2)	0.02
High-risk	15/564 (3.1)		2.42 (1.41–4.16)	0.001
Hemorrhagic stroke
Low-risk	46/9,434 (0.5)	0.0002	Ref.
Intermediate-risk	17/2,415 (0.8)		1.46 (0.83–2.54)	0.19
High-risk	10/564 (1.9)		3.78 (1.91–7.50)	0.0001
Unstable angina requiring emergency hospitalization
Low-risk	125/9,434 (1.4)	0.81	Ref.
Intermediate-risk	32/2,415 (1.4)		1.0 (0.68–1.48)	0.99
High-risk	9/564 (1.8)		1.25 (0.63–2.45)	0.52
Coronary revascularization (all)
Low-risk	867/9,434 (10.0)	0.17	Ref.
Intermediate-risk	225/2,415 (10.2)		1.02 (0.88–1.18)	0.83
High-risk	63/564 (12.8)		1.28 (0.99–1.65)	0.06
Coronary revascularization (non-TLR)
Low-risk	494/9,434 (5.8)	0.2	Ref.
Intermediate-risk	107/2,415 (4.9)		0.84 (0.69–1.04)	0.11
High-risk	32/564 (6.6)		1.13 (0.79–1.61)	0.51
Coronary revascularization (TLR)
Low-risk	426/9,434 (4.9)	0.006	Ref.
Intermediate-risk	130/2,415 (5.9)		1.2 (0.99–1.46)	0.07
High-risk	39/564 (7.7)		1.61 (1.16–2.23)	0.004

Data are presented as n/N (%). Number of patients who experienced cardiovascular events was counted until the end of the follow-up period. Cumulative 4-year incidence was estimated by using the Kaplan-Meier method. Hazard ratios and P values were estimated by using the univariate Cox proportional hazard model. CI, confidence interval; HR, hazard ratio; TLR, target lesion revascularization.

Baseline Characteristics and Serum Parameters in the Pitavastatin 4 mg and 1 mg Groups in Each Risk Stratum

Baseline characteristics were generally well balanced between the pitavastatin 4 mg and 1 mg groups in each risk stratum (Table 3). The values of serum parameters at baseline after the run-in period were also well balanced between the pitavastatin 4 mg and 1 mg groups in each risk stratum (Table 3). Follow-up LDL-C levels at 3 years were significantly lower in the pitavastatin 4 mg group than in the pitavastatin 1 mg group in each risk stratum (Supplementary Figure 2A–C).

Table 3. A Comparison of Baseline Characteristics Between Pitavastatin 4 mg and 1 mg Groups in Each Risk Stratum

	Low-risk			Intermediate-risk			High-risk
	Pitavastatin 4 mg group (N=4,742)	Pitavastatin 1 mg group (N=4,692)	P value	Pitavastatin 4 mg group (N=1,188)	Pitavastatin 1 mg group (N=1,227)	P value	Pitavastatin 4 mg group (N=269)	Pitavastatin 1 mg group (N=295)	P value
Age (years)	66.6±8.3	66.7±8.3	0.57	72.2±6.8	71.8±7.0	0.11	74.7±5.4	74.5±5.2	0.56
≥75 years	668 (14)	665 (14)	0.9	574 (48)	549 (45)	0.08	187 (70)	193 (65)	0.3
Men	3,979 (84)	3,936 (84)	0.98	947 (80)	974 (79)	0.84	203 (75)	214 (73)	0.43
Weight, kg	65.8±11.4 (4,439)	65.8±11.3 (4,422)	0.81	63.6±10.7 (1,126)	63.5±11.1 (1,169)	0.82	62.2±10.1 (257)	61.7±10.5 (283)	0.6
Body mass index (kg/m2)	24.7±3.3 (4,350)	24.7±3.4 (4,345)	0.84	24.5±3.2 (1,106)	24.5±3.4 (1,146)	0.86	24.4±3.3 (254)	24.1±3.5 (280)	0.42
Abdominal circumference, cm	88.0±9.3 (3,828)	88.0±9.5 (3,816)	0.99	88.3±9.1 (980)	88.2±9.8 (1,009)	0.85	89.0±9.5 (230)	88.1±9.9 (244)	0.33
Systolic blood pressure, mmHg	127.6±16.0 (4,555)	127.2±15.9 (4,533)	0.36	128.5±16.6 (1,146)	128.2±16.4 (1,189)	0.69	129.8±18.4 (266)	126.5±17.6 (286)	0.03
Diastolic blood pressure, mmHg	73.6±10.7 (4,555)	73.7±10.7 (4,533)	0.65	71.3±10.7 (1,146)	71.2±10.8 (1,189)	0.83	70.0±11.6 (266)	68.2±10.8 (286)	0.053
Heart rate, beats/min	69.2±11.4 (4,366)	69.0±11.1 (4,366)	0.5	70.0±12.3 (1,110)	71.0±12.2 (1,138)	0.046	72.5±13.9 (254)	72.1±11.8 (276)	0.77
LVEF (%)	60.5±11.3 (2,428)	60.1±11.3 (2,423)	0.29	60.3±12.2 (628)	59.7±12.3 (624)	0.44	57.6±13.5 (136)	58.0±11.9 (156)	0.77
Cardiovascular history
ACS	3,504 (74)	3,494 (74)	0.52	777 (65)	799 (65)	0.88	169 (63)	172 (58)	0.27
Hospitalization for unstable angina	1,248 (26)	1,197 (26)	0.37	288 (24)	301 (25)	0.87	65 (24)	68 (23)	0.76
Myocardial infarction	2,496 (53)	2,531 (54)	0.2	545 (46)	572 (47)	0.71	118 (44)	122 (41)	0.55
PCI	4,010 (85)	3,978 (85)	0.77	962 (81)	965 (79)	0.15	218 (81)	227 (77)	0.23
Coronary artery bypass grafting	524 (11)	515 (11)	0.91	205 (17)	211 (17)	0.97	49 (18)	70 (24)	0.11
Congestive heart failure	102 (2.2)	97 (2.1)	0.78	137 (12)	158 (13)	0.31	73 (27)	83 (28)	0.79
AF	0 (0)	0 (0)	NA	268 (23)	275 (22)	0.93	114 (42)	113 (38)	0.32
Ischemic stroke	239 (5.0)	232 (4.9)	0.83	132 (11)	139 (11)	0.87	50 (19)	58 (20)	0.75
Hemorrhagic stroke	44 (0.9)	49 (1.0)	0.57	16 (1.4)	17 (1.4)	0.93	4 (1.5)	10 (3.4)	0.15
PVD	0 (0)	0 (0)	NA	270 (23)	300 (24)	0.32	139 (52)	158 (54)	0.65
Current smoking	840 (18)	785 (17)	0.21	171 (14)	169 (14)	0.66	31 (12)	35 (12)	0.9
Diabetes mellitus	1,530 (32)	1,495 (32)	0.68	725 (61)	764 (62)	0.53	235 (87)	229 (78)	0.003
Hypertension	3,529 (74)	3,471 (74)	0.62	952 (80)	968 (79)	0.45	227 (84)	249 (84)	0.99
Family history of CAD	792 (17)	812 (17)	0.43	171 (14)	193 (16)	0.36	34 (13)	45 (15)	0.37
History of malignancy	202 (4.3)	229 (4.9)	0.15	94 (7.9)	83 (6.8)	0.28	19 (7.1)	33 (11)	0.09
CREDO-Kyoto bleeding risk
Low	2,087 (44)	2,019 (43)	0.33	242 (20)	242 (20)	0.33	11 (4.1)	18 (6.1)	0.29
Intermediate	2,581 (54)	2,584 (55)		698 (59)	698 (57)		96 (36)	90 (31)
High	74 (1.6)	89 (1.9)		248 (21)	287 (23)		162 (60)	187 (63)
Blood examinations
Total cholesterol, mg/dL	167.5±23.9 (4,708)	168.0±24.0 (4,665)	0.39	165.4±23.7 (1,176)	164.0±25.7 (1,218)	0.16	158.8±27.5	160.2±25.4 (293)	0.53
LDL-C, mg/dL	87.9±18.9	88.8±18.8	0.02	87.6±18.8	86.4±18.8	0.12	83.5±20.6	84.5±19.9	0.55
HDL-C, mg/dL	51.0±12.5 (4,741)	50.9±12.6 (4,691)	0.73	50.1±11.9	50.4±13.0 (1,226)	0.58	48.6±13.9	48.7±13.0	0.91
Triglycerides, mg/dL	125 (89–179) (4,738)	125 (90–175) (4,689)	0.58	123 (89–170)	119 (86–166) (1,225)	0.22	118 (83–163)	121 (85–167) (294)	0.78
Apolipoprotein A1, mg/dL	136.8±24.8 (739)	135.6±23.8 (717)	0.31	132.5±24.3 (188)	137.4±27.7 (188)	0.07	130.3±28.6 (41)	130.3±23.9 (42)	1.0
Apolipoprotein B, mg/dL	80.3±15.2 (740)	80.9±15.3 (717)	0.4	80.2±15.7 (186)	78.6±15.9 (189)	0.32	74.5±13.8 (41)	74.1±14.4 (42)	0.89
High-sensitivity CPR, mg/dL	0.48 (0.24–1.02) (4,582)	0.5 (0.24–1.16) (4,552)	0.01	0.61 (0.27–1.52) (1,147)	0.56 (0.27–1.35) (1,196)	0.2	0.71 (0.3–1.73) (265)	0.8 (0.34–1.9) (284)	0.31
Glucose, mg/dL	121.6±37.3 (3,827)	121.0±37.9 (3,779)	0.46	132.6±45.7 (941)	130.1±45.2 (992)	0.24	141.9±48.8 (229)	137.8±52.6 (252)	0.38
Hemoglobin A1c, %	5.78±0.82 (4,345)	5.77±0.79 (4,337)	0.8	6.1±0.94 (1,106)	6.1±0.94 (1,159)	0.93	6.27±0.84 (261)	6.3±0.95 (281)	0.66
Creatine kinase, U/L	107 (78–150) (4,484)	106 (78–148) (4,454)	0.57	103 (75–145) (1,131)	102 (72–145) (1,156)	0.37	93 (65–134) (256)	93 (69–139) (284)	0.65
Serum creatinine, mg/dL	0.85 (0.73–0.98) (4,608)	0.85 (0.74–0.98) (4,589)	0.67	0.9 (0.77–1.09) (1,159)	0.9 (0.76–1.1) (1,204)	0.81	1.04 (0.86–1.43) (266)	1.07 (0.85–1.5) (292)	0.65
eGFR, mL/min/1.73 m2	68.2±16.5 (4,608)	68.1±18.6 (4,589)	0.62	60.9±17.2 (1,159)	61.1±17.4 (1,204)	0.71	50.3±19.1 (266)	49.4±20.2 (292)	0.61
Severe CKD	0 (0)	0 (0)	NA	45 (3.8)	42 (3.4)	0.63	52 (19)	62 (21)	0.62
CKD	(N=4,608)	(N=4,589)	0.28	(N=1,159)	(N=1,204)	0.79	(N=266)	(N=292)	0.7
Stage 1	408 (8.9)	364 (7.9)		53 (4.6)	63 (5.2)		7 (2.6)	7 (2.4)
Stage 2	2,803 (61)	2,814 (61)		547 (47)	547 (45)		76 (29)	89 (30)
Stage 3	1,397 (30)	1,411 (31)		514 (44)	552 (46)		131 (49)	134 (46)
Stage 4	0 (0)	0 (0)		42 (3.6)	38 (3.2)		50 (19)	56 (19)
Stage 5	0 (0)	0 (0)		3 (0.3)	4 (0.3)		2 (0.8)	6 (2.1)
Medications
Statins before run-in period	4,331 (91)	4,292 (91)	0.81	1,054 (89)	1,101 (90)	0.42	237 (88)	263 (89)	0.7
Aspirin	4,032 (93)	4,047 (94)	0.36	997 (91)	1,032 (90)	0.43	226 (88)	250 (88)	0.79
Thienopyridine	2,049 (47)	2,063 (48)	0.71	510 (46)	536 (47)	0.92	126 (49)	120 (42)	0.13
Dual antiplatelet therapy	1,919 (44)	1,960 (45)	0.34	469 (43)	499 (43)	0.73	112 (43)	111 (39)	0.32
β-blockers	1,777 (41)	1,795 (41)	0.65	468 (43)	510 (44)	0.4	119 (46)	138 (49)	0.54
ACEI or ARB	2,888 (67)	2,889 (67)	0.9	740 (67)	800 (70)	0.26	202 (78)	202 (71)	0.06

Data are presented as n (%), median (interquartile range) (n), or mean (SD) (n). For the variables with missing values, we indicated the number of patients evaluated. In the CREDO-Kyoto bleeding risk, patients with thrombocytopenia (platelet <100,000/μL), severe CKD, peripheral vascular disease, and heart failure were assigned 2 points and prior myocardial infarction, malignancy and AF were assigned 1 point.⁸ Patients were classified into 3 strata according to the CREDO-Kyoto bleeding risk score: low-risk (0 points), intermediate-risk (1–2 points) and high-risk (≥3 points). NA, not applicable. Other abbreviations as in Table 1.

Clinical Outcomes in the Pitavastatin 4 mg and 1 mg Groups in Each Risk Stratum

In the low-risk stratum, the cumulative 4-year incidence of the primary endpoint was significantly lower in the pitavastatin 4 mg group than in the pitavastatin 1 mg group (4.0% and 4.9%, P=0.02) (Table 4 and Figure 3). In the intermediate- and high-risk strata, the cumulative 4-year incidence of the primary endpoint was numerically lower in the pitavastatin 4 mg group than in the pitavastatin 1 mg group (5.7% and 6.8%, P=0.56, and 10.0% and 12.0%, P=0.35, respectively) (Table 4 and Figure 3). There was no significant interaction between the CREDO-Kyoto thrombotic risk stratum and the effect of the pitavastatin 4 mg group relative to the pitavastatin 1 mg group regarding the risk of the primary endpoint (P-interaction=0.77) (Figure 4).

Table 4. Comparing the Clinical Outcomes of Patients Between the Pitavastatin 4 mg and 1 mg Groups as per Each Risk Stratum

	Number of patients with adverse event (%) (Cumulative 4-year incidence)		HR (95% CI)	P value
	Pitavastatin 4 mg group	Pitavastatin 1 mg group
(A) Low-risk	(N=4,742)	(N=4,692)
Primary endpoint	177 (4.0)	223 (4.9)	0.79 (0.65–0.97)	0.02
Composite of primary endpoint or coronary revascularization	351 (7.9)	438 (10.1)	0.8 (0.69–0.92)	0.002
Death resulting from any cause	117 (2.7)	147 (3.2)	0.8 (0.63–1.02)	0.07
Cardiovascular death	47 (1.1)	62 (1.4)	0.76 (0.52–1.11)	0.16
Cardiac death	31 (0.7)	44 (0.9)	0.71 (0.45–1.12)	0.14
Myocardial infarction or ischemic stroke	85 (2.0)	103 (2.2)	0.83 (0.62–1.1)	0.19
Myocardial infarction	32 (0.8)	51 (1.1)	0.63 (0.4–0.98)	0.04
Ischemic stroke	55 (1.3)	54 (1.1)	1.02 (0.7–1.49)	0.91
Hemorrhagic stroke	26 (0.6)	20 (0.4)	1.3 (0.73–2.34)	0.37
Unstable angina requiring emergency hospitalization	58 (1.3)	67 (1.6)	0.87 (0.61–1.23)	0.43
Coronary revascularization (all)	390 (8.8)	477 (11.2)	0.81 (0.71–0.93)	0.002
Coronary revascularization (non-TLR)	214 (4.8)	280 (6.7)	0.76 (0.64–0.91)	0.003
Coronary revascularization (TLR)	197 (4.5)	229 (5.4)	0.86 (0.71–1.04)	0.12
(B) Intermediate-risk	(N=1,188)	(N=1,227)
Primary endpoint	66 (5.7)	77 (6.8)	0.91 (0.65–1.26)	0.56
Composite of primary endpoint or coronary revascularization	107 (9.7)	113 (9.9)	1.01 (0.77–1.31)	0.96
Death resulting from any cause	62 (5.6)	69 (5.6)	0.95 (0.68–1.34)	0.78
Cardiovascular death	28 (2.4)	27 (2.0)	1.11 (0.65–1.88)	0.71
Cardiac death	24 (2.0)	24 (1.8)	1.07 (0.61–1.88)	0.82
Myocardial infarction or ischemic stroke	28 (2.4)	39 (4.0)	0.76 (0.47–1.23)	0.26
Myocardial infarction	6 (0.6)	18 (1.9)	0.35 (0.14–0.88)	0.02
Ischemic stroke	22 (1.8)	21 (2.1)	1.2 (0.65–2.19)	0.74
Hemorrhagic stroke	11 (1.2)	6 (0.5)	1.94 (0.72–5.25)	0.19
Unstable angina requiring emergency hospitalization	13 (1.2)	19 (1.6)	0.73 (0.36–1.47)	0.37
Coronary revascularization (all)	108 (10.3)	117 (10.1)	0.98 (0.76–1.27)	0.88
Coronary revascularization (non-TLR)	51 (5.1)	56 (4.7)	0.96 (0.66–1.41)	0.84
Coronary revascularization (TLR)	60 (5.7)	70 (6.2)	0.91 (0.64–1.28)	0.59
(C) High-risk	(N=269)	(N=295)
Primary endpoint	23 (10.0)	34 (12.0)	0.78 (0.46–1.32)	0.35
Composite of primary endpoint or coronary revascularization	31 (14.1)	49 (17.6)	0.71 (0.46–1.12)	0.14
Death resulting from any cause	28 (13.4)	44 (14.8)	0.73 (0.46–1.17)	0.19
Cardiovascular death	11 (5.2)	23 (8.0)	0.55 (0.27–1.12)	0.1
Cardiac death	7 (3.5)	17 (5.6)	0.47 (0.2–1.14)	0.09
Myocardial infarction or ischemic stroke	9 (3.9)	11 (4.3)	0.93 (0.38–2.23)	0.86
Myocardial infarction	2 (0.8)	3 (1.2)	0.76 (0.13–4.54)	0.76
Ischemic stroke	7 (3.1)	8 (3.1)	0.99 (0.36–2.73)	0.98
Hemorrhagic stroke	6 (2.2)	4 (1.6)	1.7 (0.48–6.04)	0.4
Unstable angina requiring emergency hospitalization	5 (2.1)	4 (1.4)	1.44 (0.39–5.36)	0.59
Coronary revascularization (all)	31 (13.3)	32 (12.3)	1.1 (0.67–1.81)	0.69
Coronary revascularization (non-TLR)	12 (5.4)	20 (7.6)	0.67 (0.33–1.38)	0.28
Coronary revascularization (TLR)	19 (7.9)	20 (7.6)	1.08 (0.58–2.03)	0.8

Number of patients who experienced cardiovascular events was counted until the end of the follow-up period. Cumulative 4-year incidence was estimated by using the Kaplan-Meier method. Hazard ratios and P values were estimated by using the univariate Cox proportional hazard model. CI, confidence interval; HR, hazard ratio; TLR, target lesion revascularization.

Figure 3.

Kaplan-Meier curves for the primary endpoint between the high-dose (4 mg pitavastatin) and the low-dose (1 mg pitavastatin) groups in the (A) low-risk, (B) intermediate-risk, and (C) high-risk stratum. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. CREDO-Kyoto, Coronary REvascularization Demonstrating Outcome study in Kyoto; LDL-C, low-density lipoprotein cholesterol.

Figure 4.

Cumulative 4-year incidences of the primary endpoint in the high-dose (4 mg pitavastatin) and the low-dose (1 mg pitavastatin) groups in each thrombotic risk stratum. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. CI, confidence interval; HR, hazard ratio.

Discussion

The main findings of this study were as follows: (1) patients with CREDO-Kyoto high thrombotic risk had significantly higher risk for cardiovascular events than those with intermediate or low thrombotic risks in the REAL-CAD randomized trial; (2) high-dose pitavastatin therapy compared with low-dose pitavastatin therapy was associated with a numerically lower risk for cardiovascular events irrespective of the CREDO-Kyoto thrombotic risk in patients with CCS.

CREDO-Kyoto risk score was developed to identify patients at risks of thrombotic and bleeding events individually after PCI.⁸ However, this score has not yet been well validated in different cohorts or trials. Rozemeijer et al reported that CREDO-Kyoto-derived risk stratification was associated with a moderate predictive capability for post-discharge ischemic events defined as a composite of cardiac death, MI, definite or probable stent thrombosis and ischemic stroke in a sub-analysis of the ReCre8 trial.¹¹ In the Japanese cohort of acute MI patients undergoing contemporary primary PCI, the CREDO-Kyoto thrombotic risk score was discriminative for predicting ischemic events.¹² Patients with CREDO-Kyoto high thrombotic risk had significantly higher incidence of ischemic events defined as a composite of cardiovascular death, recurrent MI, and ischemic stroke. Furthermore, the CREDO-Kyoto rather than PARIS thrombotic risk score had better diagnostic ability for ischemic events in this Japanese registry. In line with previous reports, patients with CREDO-Kyoto high thrombotic risk had significantly higher incidence of ischemic events defined as a composite of cardiovascular death, non-fatal MI, non-fatal ischemic stroke, or unstable angina than those with intermediate or low thrombotic risk in the present Japanese randomized trial. Therefore, CREDO-Kyoto risk score could be applied to not only for those enrolled in the real-world registry, but also for those enrolled in randomized controlled trials.

The relationship between the use of high-intensity statin therapy and clinical outcomes according to the thrombotic risk levels has not been well established. Desjobert et al evaluated the relationship between prescription of high-intensity statin therapy at discharge and long-term clinical outcomes according to risk level defined by the Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention (TRS-2P) after acute MI.¹³ High-intensity statin therapy was associated with a non-significant decrease in major adverse cardiovascular events (death, stroke or recurrent MI) at 5 years in the overall population, and the decrease in major adverse cardiovascular events was positively correlated with risk level (low-risk group: 8.1% and 10.7%; intermediate-risk: 14.8% and 21.6%; high-risk: 30.8% and 51.6%). Therefore, high-intensity statin therapy after acute MI was associated with fewer major adverse cardiovascular events at 5 years, regardless of thrombotic risk stratification, although the highest absolute reduction was found in the high-risk TRS-2P class. In the sub-analysis of IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), the relationship between intensive lipid-lowering therapy with ezetimibe and simvastatin relative to simvastatin alone and long-term clinical outcomes according to risk level defined by the TRS-2P were evaluated after ACS. High-risk patients had a 6.3% (95% CI: 2.9–9.7%) absolute risk reduction in cardiovascular events (cardiovascular death, MI and ischemic stroke) at 7 years.¹⁴ In contrast, intermediate-risk patients had a 2.2% (95% CI: 0.3–4.6%) absolute risk reduction and low-risk patients did not appear to derive benefit from the addition of ezetimibe (P-interaction=0.01). Therefore, high thrombotic risk patients had greatest benefit from the intensive lipid-lowering therapy with ezetimibe and statin therapy for secondary prevention after ACS. However, these data were derived from patients with ACS. In the current subgroup analysis in the REAL-CAD trial enrolling patients with CCS, a significantly lower incidence of cardiovascular events was detected even in the low thrombotic risk patients. Numerically lower incidences of cardiovascular events with pitavastatin 4 mg relative to pitavastatin 1 mg were also confirmed in the intermediate and high thrombotic risk patients. The results of this study suggest the beneficial effects of higher-dose statins on cardiovascular events regardless of the thrombotic risk in patients with CCS.

In the 2018 ACC/AHA guideline for the management of blood cholesterol, high-intensity or maximal statin therapy with an LDL-C goal of <70 mg/dL is recommended in very high-risk patients with multiple major ASCVD events such as recent ACS, history of MI, peripheral artery disease or ischemic stroke.³ In the 2019 ESC guideline for the management of dyslipidemia, more intensive lipid-lowering therapy with an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <55 mg/dL is also recommended in very high-risk patients such as those with ACS, diabetes with target organ damage or severe CKD.⁴ Furthermore, patients with stable angina or those with revascularization by PCI are also included in the category of very high-risk patients. As the REAL-CAD trial included >80% of patients with CCS undergoing PCI, the results of the present study would support the ECS guideline recommendation with more intensive lipid-lowering therapy, even in stable patients. Intensive statin therapy with maximally tolerated statin would be recommended for any patients undergoing PCI regardless of the patients’ thrombotic risk or clinical presentation.

Study Limitations

Some limitations to our study should be considered. First, the REAL-CAD study had the largest number of patients randomized to high- compared with low-dose statin therapy to date. Nevertheless, the present subgroup analysis was obviously underpowered, which could have influenced the results whereby the high-dose statin treatment failed to show a statistically significant lower risk for cardiovascular events relative to low-dose statin therapy in the intermediate- and high-risk groups. Second, the present study was conducted as an open-label trial with its inherent limitations. Third, the CREDO-Kyoto risk score was developed in patients undergoing PCI with a drug-eluting stent without in-hospital events such as in-hospital death, MI, stent thrombosis, ischemic stroke and bleeding. Therefore, the study population in the current study was not completely the same as that evaluated for the CREDO-Kyoto risk score. Also, the primary thrombotic event was defined as a composite of MI and definite or probable stent thrombosis or ischemic stroke in the original study for the CREDO-Kyoto risk score, whereas the primary endpoint was a composite of cardiovascular death, non-fatal MI, non-fatal ischemic stroke, or unstable angina in the REAL-CAD study. Fourth, chronic total occlusion was not included as the factor of the CREDO-Kyoto thrombotic risk in the present study due to the lack of detailed information about the target coronary lesions treated by PCI or CABG. Finally, this study was a post-hoc analysis of a randomized trial; there were some differences in the baseline characteristics between high-dose statin and low-dose statin groups in each risk strata, which could have had an influence on the cardiovascular events between the pitavastatin 4 mg and 1 mg groups.

Conclusions

High-dose pitavastatin therapy compared with low-dose pitavastatin therapy was associated with a trend toward lowering the risk for cardiovascular events, irrespective of the thrombotic risk in patients with CCS.

Acknowledgments

We thank all patients and investigators who participated in this study; Yoji Mitadera, Katsura Nakajima, and other members of the Public Health Research Foundation (PHRF) for their assistance at the administrative office; and Teikyo Academic Research Centre for their function as a data center.

Sources of Funding

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. The Comprehensive Support Project for Clinical Research of Lifestyle-Related Disease of the Public Health Research Foundation (PHRF) funded this study. The company manufacturing the study drug (Kowa Pharmaceutical Co. Ltd.) provided financial support, but was not involved in design, analysis, data interpretation, or manuscript preparation.

Disclosures

Dr. Kimura, Dr. Inoue, Dr. Ozaki, Dr. Matsuzaki, and Dr. Nagai are members of Circulation Journal’s Editorial Team.

Dr. Natsuaki reports lecturer fees from Abbott Vascular, Medtronic, Daiichi Sankyo, and Bristol-Myers Squibb. Dr. Morimoto reports lecturer fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Toray and Tsumura; manuscript fees from Bristol-Myers Squibb, Kowa and Pfizer; and is on the advisory board for Novartis and Teijin. Dr. Iimuro received a research grant and honoraria from the Public Health Research Foundation. Dr. Iwata received other research support from the Public Health Research Foundation; honoraria from Bayer Yakuhin, Ltd, Daiichi Sankyo Co, Ltd, Takeda Pharmaceutical Co Ltd, MSD KK, Kowa Pharmaceutical Co Ltd, and Mitsubishi Tanabe Pharma Corp. Dr. Inoue received a research grant from Teijin Pharma Ltd, MSD KK, Eisai Co, Ltd, Pfizer Japan Inc, Kowa Pharmaceutical Co Ltd, Mitsubishi Tanabe Pharma Corp, and Shionogi & Co, Ltd; other research support and honoraria from AstraZeneca KK, Amgen Astellas BioPharma KK, and Mochida Pharmaceutical Co, Ltd; a research grant, other research support, and honoraria from Bayer Yakuhin, Ltd, Sanofi KK, Sanwa Kagaku Kenkyusho Co, Ltd, Otsuka Pharmaceutical Co, Ltd, Public Health Research Foundation, and Daiichi Sankyo Co, Ltd. Dr. Daida received a research grant from the Public Health Research Foundation, Actelion Pharmaceuticals Japan, Otsuka Pharmaceuticals Co, Ltd, Nihon Medi-physics Co, Ltd, Teijin Parma, HeartFlo Japan GK, Novo Nordisk, Sumitomo-Dainippon Co, Ltd, Fukuda Denshi, ResMed, and Philips Japan; honoraria from Astellas Amgen BioPharma, Astra Zeneca KK, Kaken Seiyaku, Kyowa Kirin, Lilly, Mochida Pharmaceutical Co Ltd, Bristol Myers Squibb, Edwards LifeSciences, and Terumo Co; a research grant and honoraria from Astellas Pharma, Abbott Vascular, MSD, Sanofi, Shionogi, Daiichi-Sankyo, Takeda, Tanabe-Mitsubishi, Canon, Boehringer Ingelheim, Novartis, Bayer, Toaeiyo, Fuji Film, and Pfizer; other research support and honoraria from Kowa Pharmaceuticals Co Ltd. Dr. Ozaki received a research grant from Takeda Pharmaceutical Co Ltd and Daiichi Sankyo Co, Ltd. Dr. Sakuma received honoraria from Bayer Yakuhin, Ltd; other research support and honoraria from Takeda Pharmaceutical Co Ltd; a research grant and other research support from Public Health Research Foundation. Dr. Furukawa received honoraria from Daiichi Sankyo Co, Ltd, Bayer Yakuhin, Sanofi KK, Kowa Pharmaceutical Co Ltd, Pfizer Japan Inc, Bristol-Myers Squibb, Sumitomo Dainippon Pharma Co, Ltd, and Takeda Pharmaceutical Co Ltd. Dr. Nakagawa received honoraria from Kowa Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Bayer Yakuhin, Ltd, Sanofi KK, Daiichi Sankyo Co, Ltd, Shionogi & Co, Ltd, Astellas Pharma Inc, MSD KK, Mitsubishi Tanabe Pharma Corp, Sumitomo Dainippon Pharma Co, Ltd, AstraZeneca KK, Amgen Astellas BioPharma KK, Eisai Co, Ltd, Otsuka Pharmaceutical Co, Ltd, and Pfizer Japan Inc; a research grant, other research support, and honoraria from the Public Health Research Foundation. Dr. Fujita received a research grant from the Public Health Research Foundation, Hamamatsu Photonics K.K. and honoraria from Saraya Co, Ltd. Dr. Kimura received a research grant from Sumitomo Dainippon Pharma Co, Ltd, Astellas Pharma Inc, Otsuka Pharmaceutical Co, Ltd, Mitsubishi Tanabe Pharma Corp, and Takeda Pharmaceutical Co Ltd; other research support and honoraria from Kowa Pharmaceutical Co Ltd, and Bayer Yakuhin, Ltd; a research grant, other research support, and honoraria from MSD KK, Sanofi KK, Mochida Pharmaceutical Co, Ltd, Daiichi Sankyo Co, Ltd, the Public Health Research Foundation, and Amgen Astellas BioPharma KK. Dr. Matsuzaki received honoraria from Mochida Pharmaceutical Co, Ltd. Dr. Nagai received honoraria from Kowa Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Bayer Yakuhin, Ltd, Daiichi Sankyo Co, Ltd, Shionogi & Co, Ltd, MSD KK, Mitsubishi Tanabe Pharma Corp, Amgen Astellas BioPharma KK, Eisai Co, Ltd, Astellas Pharma Inc, Sumitomo Dainippon Pharma Co, Ltd, and Mochida Pharmaceutical Co, Ltd; and honoraria and expert witness from the Public Health Research Foundation. All other authors have no conflicts of interest to declare.

IRB Information

The research protocols of the REAL-CAD were approved by the Institutional Review Board of the Public Health Research Foundation (9K0109) and by the local ethics committees in all participating medical centers.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-22-0315

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