Prevention of Contrast-Induced Nephropathy After Cardiovascular Catheterization and Intervention With High-Dose Strong Statin Therapy in Japan　― The PREVENT CINC-J Study ―

Makoto Watanabe; Kazutaka Aonuma; Toyoaki Murohara; Yasuo Okumura; Takeshi Morimoto; Sadanori Okada; Sunao Nakamura; Shiro Uemura; Koichiro Kuwahara; Tadateru Takayama; Naofumi Doi; Tamio Nakajima; Manabu Horii; Kenichi Ishigami; Kazumiki Nomoto; Daisuke Abe; Koji Oiwa; Kentaro Tanaka; Terumasa Koyama; Akira Sato; Tomoya Ueda; Tsunenari Soeda; Yoshihiko Saito; PREVENT CINC-J Investigators

doi:10.1253/circj.CJ-21-0869

Abstract

Background: Previous studies have reported that high-dose strong statin therapy reduces the incidence of contrast-induced nephropathy (CIN) in statin naïve patients; however, the efficacy of high-dose strong statins for preventing CIN in real-world clinical practice remains unclear. The aim of this study was to evaluate the efficacy of strong statin therapy in addition to fluid hydration for preventing CIN after cardiovascular catheterization.

Methods and Results: This prospective, multicenter, randomized controlled trial included 420 patients with chronic kidney disease who underwent cardiovascular catheterization. They were assigned to receive high-dose pitavastatin (4 mg/day × 4 days) on the day before and of the procedure and 2 days after the procedure (Statin group, n=213) or no pitavastatin (Control group, n=207). Isotonic saline hydration combined with a single bolus of sodium bicarbonate (20 mEq) was scheduled for administration to all patients. In the control group, statin therapy was continued at the same dose as that before randomization. CIN was defined as a ≥0.5 mg/dL increase in serum creatinine or ≥25% above baseline at 48 h after contrast exposure. Before randomization, 83% of study participants were receiving statin treatment. The statin group had a higher incidence of CIN than the control group (3.0% vs. 0%, P=0.01). The 12-month rate of major adverse cardiovascular events was similar between the 2 groups.

Conclusions: High-dose pitavastatin increases the incidence of CIN in this study population.

Contrast-induced nephropathy (CIN), recognized as acute kidney injury after contrast medium exposure, has been identified as the most frequent cause of hospital-acquired acute kidney injury.¹^–³ This iatrogenic complication has been a subject of concern for cardiologists in recent years because CIN is associated with increased morbidity, mortality, and health-care expenditures.⁴^,⁵

Japanese guidelines on the use of iodinated contrast media in patients with kidney disease recommend that physicians explain the risk of CIN to patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² who will undergo coronary angiography (CAG). Physicians should emphasize the need for appropriate prophylactic measures such as fluid hydration before and after CAG.⁶ Although isotonic saline hydration therapy is the most frequently used prophylactic measure in Japan, its efficacy for preventing the development of CIN is controversial.⁷ In the study on CIN after cardiac catheterization in Japan (the CINC-J study),⁸ a multicenter prospective observational study to investigate the real-world incidence of CIN in Japan found approximately 90% of patients with chronic kidney disease (CKD) stage 3b or 4 received prophylactic hydration, but the incidence of CIN was higher in these patients than in patients with CKD stage 3a or normal renal function. Therefore, it is necessary to identify effective prophylactic treatments to replace saline hydration for preventing CIN.

Statins have beneficial effects on endothelial function, nitric oxide production, and oxidative stress, which are directly related to the development of CIN.⁹^,¹⁰ Previous randomized controlled studies reported that high-dose strong statin therapy in addition to standard hydration significantly reduces the development of CIN compared with standard hydration therapy only.¹¹^–¹⁵ However, these studies targeted statin naïve patients. Considering that most patients undergoing coronary arteriography or contrast-enhanced imaging are treated with regular statin therapy,¹⁶^,¹⁷ the efficacy of high-dose strong statin therapy for preventing CIN remains unclear. The aim of the present study was to evaluate the efficacy of adding high-dose strong statin therapy to fluid hydration on the prevention of CIN in patients with CKD undergoing cardiovascular catheterization and intervention.

Methods

Patient Population

The Prevention of Contrast-Induced Nephropathy after Cardiovascular catheterization and intervention by high-dose statin therapy in Japan (PREVENT CINC-J) study was a prospective, randomized, open-label, multicenter study involving 18 hospitals and patients with CKD scheduled for elective cardiovascular catheterization and intervention. The objective was to evaluate the safety and efficacy of adding high-dose strong statin therapy to standard fluid hydration for preventing the development of CIN after cardiovascular catheterization and intervention.

The present study included patients with CKD (eGFR <60 mL/min/1.73 m² or proteinuria) scheduled for cardiovascular catheterization and intervention such as CAG, percutaneous coronary intervention (PCI), catheter ablation, or endovascular treatment. Patients with any of the following were excluded from the study: (1) hypersensitivity to contrast media or statins; (2) current use of fibrate-based medicine or cyclosporine; (3) severe renal injury including acute kidney injury, maintenance dialysis, and serum creatinine (SCr) >3 mg/dL; (4) severe liver injury including acute hepatitis, liver cirrhosis, liver cancer, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 IU/L; (5) creatinine kinase (CK) >350 IU/L; (6) uncontrollable thyroid function; (7) no indication for statin treatment for the prevention of cardiovascular events (low-density lipoprotein cholesterol [LDL-C] <120 mg/dL in statin naïve patients without coronary artery disease or LDL-C <100 mg/dL in statin naïve patients with coronary artery disease);¹⁶ (8) current use of a high-dose statin (atorvastatin ≥15 mg/day, rosuvastatin ≥7.5 mg/day, or pitavastatin ≥3 mg/day); and (9) contrast medium administration within the previous 7 days.

The present study was approved by the institutional ethics committee of Nara Medical University (reference number; CRB5200002) and complied with the Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. Written informed consent was provided by all participants before enrollment. This study was registered with the University Hospital Medical Information Network (UMIN 000021695).

Randomization

Randomization was performed from 1 month before cardiovascular catheterization to the day before the procedure. All recruited patients were randomly allocated in a 1 : 1 ratio to receive either high-dose pitavastatin (statin group) or no pitavastatin (control group). Randomization was performed using a web-based allocation system (REDCap; Research Electronic Data Capture).¹⁸ Randomization was stratified by age (<74 years or ≥74 years), gender (male or female), SCr level at baseline (<1.24 mg/dL or ≥1.24 mg/dL), proteinuria at baseline (presence or absence), and statin treatment before randomization (presence or absence).

Study Protocol

Patients assigned to the statin group received 4 mg of pitavastatin on the evening before cardiovascular catheterization, followed by 4 mg in the early morning of the procedure day and 4 mg/day in the morning for the next 2 days. Patients assigned to the control group did not receive high-dose pitavastatin therapy (Supplementary Figure). If patients assigned to the statin group received statin treatment before randomization, that statin was discontinued while taking high-dose pitavastatin. If patients assigned to the control group received statin treatment before randomization, that statin was continued at the same dose for at least 2 days after cardiovascular catheterization. All patients were scheduled for intravenous hydration with isotonic saline (0.9% sodium chloride, 1 mL/kg/h for 6–12 h before cardiovascular catheterization and >1 mL/kg/h for 12 h after the procedure) and a single-bolus intravenous injection of sodium bicarbonate (20 mEq) just before cardiovascular catheterization.¹⁹ The hydration rate was reduced to 0.5 mL/kg/h in both groups of patients with a left ventricular ejection fraction <40%.

Clinical Definitions and Data Collection

In the present study, CIN was defined as an increase in SCr of 0.5 mg/dL or 25% above baseline at 48 h after contrast medium exposure. Acute kidney injury (AKI) was defined as an increase in SCr of 0.3 mg/dL or 50% above baseline within 48 h after contrast medium exposure.²⁰ eGFR values were determined using the following equation: 194 × SCr^−1.094 × age^−0.287 (×0.739 if female).²¹ Baseline data including clinical characteristics, laboratory data (blood and urine tests), and medications on admission, as well as procedural variables, were obtained for all patients. Blood samples were collected early in the morning after an overnight fast. SCr was measured before randomization (baseline), on the day following cardiovascular catheterization, and 48 h after the procedure. Dipstick urinalysis with fresh spontaneously voided urine was performed before randomization. The results of the urinalysis were recorded as (−), (±), (1+), (2+), (3+). We defined (−) and (±) to be negative for proteinuria. Other categories were defined as positive for proteinuria. The change in SCr was calculated as the difference between SCr at 24 or 48 h after cardiovascular catheterization and SCr at baseline as follows: change in SCr = (SCr at 24 h or 48 h after the procedure) − (SCr at baseline).

In 13 of 18 hospitals, urine neutrophil gelatinase associated lipocalin (NGAL) (Abbott Japan LLC, Tokyo, Japan) and creatinine were measured from an early morning voided urine sample on the day of cardiovascular catheterization (baseline), just after, 24 h after, and 48 h after the procedure. The change in urinary NGAL/creatinine ratio was calculated as follows: change in urinary NGAL/creatinine ratio = (urinary NGAL/creatinine ratio at just after, 24 h after, or 48 h after the procedure) − (urinary NGAL/creatinine ratio at baseline).

Endpoints

The primary efficacy endpoint of the study was the incidence of CIN. The primary safety endpoint was the presence or absence of myalgia, eruption, nausea, AST or ALT ≥100, and CK ≥350 IU/L. Secondary endpoints were the incidence of AKI, change in SCr, and change in urinary NGAL/creatinine ratio. For long-term follow-up analyses, we followed patients for 12 months and evaluated major cardiovascular events (MACEs) including all-cause death, cardiac death, non-fatal myocardial infarction, stroke, and rehospitalization for heart failure. We also evaluated renal events including new-onset dialysis and ≥2-fold increase in SCr from baseline lasting for 12 months.

Statistical Analyses

During protocol development for the present study, to determine the sample size, we referred to a previous study that evaluated the efficacy of high-dose atorvastatin treatment for preventing the development of CIN.¹² In that study, the sample size was selected to demonstrate a reduction in the incidence of CIN from 20% in the control group to 10% in the atorvastatin group. Based on the chi-squared test with a significance level of 0.05, a total of at least 400 randomized patients (200 in each arm) was estimated as necessary to provide the study with 80% power. Considering a 5% drop-out rate, the sample size was set at 210 patients per group.

Continuous variables are expressed as means±standard deviations (SD) or medians (interquartile range [IQR]). Categorical variables are expressed as numbers and percentages. Comparisons of primary and secondary endpoints between the statin and control groups were based on the chi-squared test or Fisher’s exact test. In subgroup analyses, we stratified patients by baseline statin treatment, baseline proteinuria, eGFR (≥45 or <45 mL/min/1.73 m²), and bolus injection of sodium bicarbonate before analysis of the primary efficacy endpoint. For long-term follow-up analyses, comparisons of MACE between the groups were made on the basis of the time to the first event. The day of catheterization was set as time zero and censored at 1 year or the last visit before the MACE occurred. The cumulative incidence of MACE was estimated using the Kaplan-Meier method, and differences between groups were assessed with the log-rank test. We constructed Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We used the chi-squared test or Fisher’s exact test to compare renal events across groups because we did not have data on the date of renal event onset. Statistical analyses were conducted by independent statisticians (T. Morimoto, S.O.) with the use of JMP 14.3 (SAS Institute, Cary, NC, USA). Two-tailed P values <0.05 were considered statistically significant.

Results

Figure 1 shows the study flowchart. Between May 2016 and October 2018, 420 patients were enrolled at 18 hospitals in Japan, with 213 patients allocated to the statin group and 207 to the control group. A total of 14 patients were excluded from the primary analysis because of: (1) withdrawal of consent (statin group, 4 patients; control group, 2 patients); (2) meeting study exclusion criteria (statin group, 2 patients; control group, 2 patients); (3) not receiving cardiovascular catheterization (statin group, 2 patients); and (4) entry error (statin group, 2 patients).

Figure 1.

Study flowchart. CIN, contrast-induced nephropathy; CKD, chronic kidney disease.

Baseline clinical characteristics were well balanced between the 2 groups (Table 1). The mean age was 73.7±7.8 years, and 74% of the patients were men. The prevalence of diabetes mellitus was 46%. The prevalence of acute coronary syndrome and congestive heart failure at clinical presentation was 3% and 18%, respectively. Mean SCr and eGFR were 1.20±0.36 mg/dL and 46.0±10.4 mL/min/1.73 m², respectively, with similar values in the 2 groups. Before randomization, 83% of study patients were receiving statin treatment; most patients were treated with strong statins.

Table 1. Baseline Clinical and Procedural Characteristics

	Total (n=406)	Statin group (n=203)	Control group (n=203)
Age (years)	73.7±7.8	73.6±7.9	73.7±7.7
Male gender	299 (74)	150 (74)	149 (73)
BMI (kg/m²)	24.5±3.7	24.5±3.6	24.6±3.9
Smoker	250 (62)	123 (61)	127 (63)
Diabetes mellitus	187 (46)	102 (50)	85 (42)
Hypertension	324 (80)	164 (81)	160 (79)
Clinical presentation at the time of the procedure
Acute coronary syndrome	12 (3)	5 (2)	7 (3)
Previous myocardial infarction	146 (36)	80 (40)	66 (33)
Congestive heart failure	72 (18)	43 (21)	29 (14)
Peripheral artery disease	52 (13)	19 (9)	33 (16)
Previous ischemic or hemorrhagic stroke	49 (12)	23 (11)	26 (13)
Medication on admission
Statin	337 (83)	169 (83)	168 (83)
Strong statin	310 (76)	157 (77)	153 (75)
Standard statin	27 (7)	12 (6)	15 (7)
ARB	181 (45)	86 (42)	95 (47)
ACEI	126 (31)	71 (35)	55 (27)
α-blocker	11 (3)	7 (3)	4 (2)
β-blocker	201 (50)	105 (52)	96 (47)
Calcium antagonist	177 (44)	89 (44)	88 (43)
Diuretic	131 (32)	74 (36)	57 (28)
NSAID	46 (11)	18 (9)	28 (14)
Laboratory data
Serum creatinine (mg/dL)	1.20±0.36	1.21±0.37	1.19±0.35
eGFR (mL/min/1.73 m²)	46.0±10.4	45.7±10.3	46.4±10.5
≥45	239 (59)	117 (58)	122 (60)
<45	166 (41)	85 (42)	81 (40)
Hb (g/dL)	13.0±1.7	12.9±1.8	13.0±1.7
AST (IU/L)	22 [19–26]	22 [18–26]	23 [19–27]
ALT (IU/L)	17 [13–24]	17 [13–23]	18 [13–25]
CK (IU/L)	89 [65–126]	84 [62–125]	93 [66–126]
Total cholesterol (mg/dL)	169±35	170±36	169±33
Triglycerides (mg/dL)	129 [93–179]	124 [87–174]	130 [98–184]
HDL-C (mg/dL)	49±13	50±14	49±12
LDL-C (mg/dL)	91±29	92±30	90±29
HbA1c (%)	6.5±1.0	6.5±1.0	6.4±0.9
BNP (pg/mL)	70.9 [32.7–200.2]	78.6 [35.8–199.1]	63.2 [31.1–208.9]
Proteinuria	88 (22)	48 (24)	40 (21)
Urinary NGAL/creatinine ratio (μg/gCr, n=381)	15.3 [8.0–30.4]	15.3 [7.9–34.1]	15.1 [8.1–28.9]
Procedural characteristics
Contrast volume (mL)	87 [54–130]	90 [54–134]	82 [53–129]
Bicarbonate injection	373 (92)	183 (91)	190 (94)
Cardiovascular intervention	180 (44)	98 (49)	82 (40)
Contrast allergy	4 (1)	1 (0.5)	3 (1.5)
Shock	4 (1)	3 (1.5)	1 (0.5)
Mechanical support	1 (0.3)	0 (0)	1 (0.5)

Values are presented as means±SD, medians [interquartile range], or n (%). ACEI, angiotensin-converting enzyme; ALT, alanine aminotransferase; ARB, angiotensin II receptor blocker; AST, aspartate aminotransferase; BMI, body mass index; BNP, B-type natriuretic peptide; CK, creatine kinase; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NGAL, neutrophil gelatinase-associated lipocalin; NSAID, non-steroidal anti-inflammatory drug.

Procedural characteristics are shown in Table 1. The mean contrast volume was 90 mL in the statin group and 82 mL in the control group. More than 90% of the patients received a bolus injection of sodium bicarbonate just before cardiovascular catheterization . The frequency of catheter intervention was 49% in the statin group and 40% in the control group. During the catheter-based procedure, a few patients experienced a contrast allergy (4 patients), shock (4 patients), or required mechanical circulatory support (1 patient) and there was 1 patient who experienced both contrast allergy and shock.

The efficacy primary endpoint of CIN occurred in 6 patients (1.5%). The incidence of CIN was significantly higher in the statin group than in the control group (3.0% vs. 0%, P=0.01) (Table 2). There were no significant differences in the safety primary endpoint between the 2 groups. There were no patients who experienced rhabdomyolysis in either group. The incidence of AKI was significantly higher in the statin group than in the control group (2.5% vs. 0%, P=0.03). The change in SCr at 24 and 48 h after the procedure was significantly worse in the statin group than in the control group. The change in urinary NGAL/Cr ratio was similar in the 2 groups. Results of the subgroup analysis according to the presence of baseline statin treatment, presence of proteinuria, CKD severity (eGFR ≥45 vs. <45 mL/min/1.73 m²), and presence of sodium bicarbonate are summarized in Table 3. In the subgroup that received baseline statin treatment and had an eGFR ≥45 mL/min/1.73 m², the incidence of CIN tended to be higher in the statin group than in the control group (P=0.06; P=0.054, respectively). In the subgroup that received a bolus injection of sodium bicarbonate, the incidence of CIN was significantly higher in the statin group than in the control group (2.8% vs. 0%, P=0.03).

Table 2. Study Endpoints

	Total (n=406)	Statin group (n=203)	Control group (n=203)	P value
Efficacy primary endpoint
CIN	6 (1.5)	6 (3.0)	0	0.01
Safety primary endpoint
Composite	24 (6)	12 (6)	12 (6)	1.0
AST or ALT ≥100 IU/L	3 (0.8)	0	3 (1.5)	0.2
CK ≥350 IU/L	17 (4)	10 (5)	7 (4)	0.4
Myalgia	0	0	0
Eruption	4 (1.0)	1 (0.5)	3 (1.5)	0.6
Nausea	3 (0.7)	2 (1.0)	1 (0.5)	1.0
Secondary endpoint
AKI	5 (1.3)	5 (2.5)	0	0.03
Change in serum creatinine
After 24 h (mg/dL)	−0.08±0.14	−0.06±0.16	−0.09±0.12	0.048
After 48 h (mg/dL)	−0.05±0.16	−0.03±0.17	−0.07±0.13	0.01
Change in urine NGAL/creatinine ratio
Just after the procedure (μg/gCr)	−5.9±146.5	−7.3±142.0	−4.5±151.2	0.6
After 24 h (μg/gCr)	−6.9±217.0	−4.2±144.4	−9.7±272.5	0.4
After 48 h (μg/gCr)	−4.8±208.3	0.35±78.8	−10.1±284.8	0.3

Values are presented as means±SD, or n (%). AKI, acute kidney injury; CIN, contrast-induced nephropathy. Other abbreviations as in Table 1.

Table 3. Subgroup Analysis

	Total	Statin group	Control group	P value
Baseline statin treatment
Yes	4/333 (1.2)	4/169 (2.4)	0/168	0.06
No	2/68 (2.9)	2/34 (5.9)	0/35	0.5
Proteinuria
Yes	2/84 (2.4)	2/45 (4.4)	0/39	0.5
No	4/309 (1.3)	4/155 (2.6)	0/154	0.1
eGFR (mL/min/1.73 m²)
≥45	4/237 (1.7)	4/115 (3.5)	0/122	0.054
<45	2/164 (1.2)	2/85 (2.4)	0/79	0.5
Bicarbonate injection
Yes	5/371 (1.4)	5/182 (2.8)	0/189	0.03
No	1/29 (3.5)	1/17 (5.8)	0/12	1.0

Values are presented as number of patients with contrast-induced nephropathy divided by the total number of patients in each subgroup (%). eGFR, estimated glomerular filtration rate.

Clinical and procedural characteristics of patients with CIN are shown in Supplementary Table 1. The mean eGFR and contrast volume were 47.2±9.3 mL/min/1.73 m² and 99.0±41.9 mL, respectively. The experience of shock during the catheter-based procedure was observed in 1 patient (Patient 4).

Over 12 months, 101 patients were lost to follow up (statin group, 47 patients; control group, 54 patients). During the follow-up period, MACE occurred in 12 patients (5.9%) in the statin group and 8 patients (3.9%) in the control group (Supplementary Table 2). There were no significant differences in the incidence of MACE between the statin group and the control group (HR, 1.47; 95% CI, 0.60–3.61; log-rank P=0.4) (Figure 2). Only one patient in the statin group experienced a renal event during the 12 months after the procedure.

Figure 2.

Cumulative 1-year incidence of major adverse cardiac events. MACE, major adverse cardiac events; HR, hazard ratio; CI, confidence interval.

Discussion

This prospective, multicenter, randomized study evaluated the safety and efficacy of adding high-dose strong statin therapy for preventing the development of CIN after cardiovascular catheterization and intervention. There were 3 principal findings. First, in patients with CKD who received sufficient prophylactic treatment consisting of a bolus administration of sodium bicarbonate in addition to standard saline hydration, high-dose pitavastatin did not decrease the incidence of CIN; instead, there was an increase. Second, in the subgroup that received baseline statin treatment and had a eGFR ≥45 mL/min/1.73 m², the incidence of CIN tended to be higher in the statin group than in the control group. Third, the overall incidence of CIN was 1.5%, which was lower than expected.

Several studies have indicated that the administration of statins has beneficial effects in limiting the occurrence of CIN.¹¹^–¹⁵ In addition to their lipid-lowering effect, statins are also known to have pleiotropic antioxidant, anti-inflammatory, and antithrombotic effects that could contribute to lower cardiovascular morbidity and mortality,²² and less severe renal dysfunction over time, especially in patients with CKD.²³ Given their pleiotropic effects, statins might reduce iatrogenic acute renal injury following iodinated contrast administration.¹ However, in the present study, a high-dose strong statin did not decrease the incidence of CIN, unlike previous randomized controlled studies (Table 4).¹¹^–¹⁴ There are several reasons for this different result. In previous randomized controlled studies, patients who had received statin treatment before randomization were excluded from the study¹¹^–¹³ or discontinued any statin treatment for at least 14 days before contrast medium exposure.¹⁴ However, in the present study, most patients received statin treatment before randomization, and patients assigned to the control group continued their statin treatment after contrast medium exposure. Previous observational studies reported that statin pretreatment before contrast medium exposure is associated with a significant decrease in the risk of CIN in patients undergoing PCI.²⁴^–²⁶ Although the present study excluded patients who had received a high-dose statin (atorvastatin ≥15 mg/day, rosuvastatin ≥7.5 mg/day, or pitavastatin ≥3 mg/day), most patients had already received some statin treatment (75% strong statins, 7% standard statins) before randomization. Therefore, high-dose strong statins might not have been effective in preventing CIN in patients who have already received some statin treatment.

Table 4. Comparison With Previous Randomized Controlled Studies on the Efficacy of High-Dose Strong Statins for the Prevention of CIN

Study (reference)	Year	Number of patients		Statin protocol		Baseline SCr (mg/dL)		Contrast volume (mL)		Incidence of CIN (%)
Study (reference)	Year	Statin group	Control group	Statin group	Control group	Statin group	Control group	Statin group	Control group	Statin group	Control group
Patti et al¹¹	2011	120	121	Atorvastatin	Statin naive	1.04±0.32	1.04±0.22	209±72	213±13	5.0	13.2
Quintavalle et al¹²	2012	202	208	Atorvastatin	Statin naive	1.32 [0.96–1.62]	1.29 [0.88–1.61]	177±74	184±78	4.5	17.8
Leoncini et al¹³	2013	252	252	Rosuvastatin	Statin naive	0.95±0.27	0.96±0.28	183±80	172±72	6.7	15.1
Han et al¹⁴	2014	1,498	1,500	Rosuvastatin	Discontinued statin	1.08±0.26	1.07±0.26	120 [100–200]	110 [100–200]	2.3	3.9
The present study	2022	203	203	Pitavastatin	Continued statin	1.21±0.37	1.19±0.35	90 [54–134]	82 [53–129]	3.0	0

Values are presented as means±SD or medians [interquartile range]. CIN, contrast-induced nephropathy; SCr, serum creatinine.

Although statins might have a nephroprotective action that improves endothelial reactivity and reduces oxidative stress,¹^,²⁷ a previous study reported that the use of high-potency statins is associated with an higher rate of AKI diagnosis during hospital admission compared with low-potency statins.²⁸ Although the biological mechanism linking statins to AKI has not yet been identified, the elevated risk of AKI in patients using high-potency statins could be related to an increased risk of rhabdomyolysis or statin-induced suppression of coenzyme Q10, a fat-soluble enzyme with antioxidant properties. Statins have been shown to block the production of coenzyme Q10.²⁹^,³⁰ Placebo-controlled trials of coenzyme Q10 treatment in humans and animals with kidney disease have shown improvements in renal function within 28 days of use.³⁰^,³¹ In the present study, although the incidence of CIN was only 3% in the statin group, high-dose statins might be associated with a significant increase in CIN because all cases of CIN occurred in the statin group. In the subgroup analysis, the incidence of CIN tended to be higher in the statin group among patients who received baseline statin treatment or had mildly reduced renal function (eGFR ≥45 mL/min/1.73 m²). Therefore, high-dose strong statin treatment might not prevent CIN in patients who have already received statin treatment or have mildly reduced renal function.

Previous studies have reported that a preprocedural bolus injection of sodium bicarbonate significantly decreases the incidence of CIN compared with no treatment.¹⁹^,³² In the present study, most patients (92%) received a preprocedural bolus injection of sodium bicarbonate in addition to standard saline hydration. As a result, the incidence of CIN in the present study (1.5%) was lower than in previous cohort studies (5% in the CINC-J study,⁸ 5% in the CREDO-KYOTO registry,³³ 8.7% in the NCDR CathPCI registry³⁴). Surprisingly, there were no patients with CIN in the control group. In addition, the volume of contrast medium administered in the present study was lower than that in previous studies (Table 4),¹¹^–¹⁴ which suggested that lowering the contrast medium volume might have contributed to the lower incidence of CIN observed in the present study. One of the possible reasons for the lower amount of contrast volume used in the present study is that fewer patients in the present study received cardiovascular intervention than in the previous studies (44% vs. 54–100%).¹¹^–¹⁴ Another reason is that the guidance of intravascular ultrasound, which results in a high penetration in patients from Japan, unlike that found in other countries,³⁵ might be effectively used during PCI in patients with CKD to reduce the total amount of contrast volume required.³⁶ In the present study, the development of CIN might have been sufficiently prevented by limiting the volume of contrast medium and administering a bolus of sodium bicarbonate in addition to standard saline hydration. In patients who receive sufficient prophylactic measures, the administration of a high-dose strong statin might worsen renal function, given the risk of AKI.

Study Limitations

First, the open-label design of the study might have introduced bias. Second, the sample size was determined based on a reduction in the incidence of CIN from 20% in the control group to 10% in the statin group to provide a statistical power of 80%.¹² However, in the present study, the incidence of CIN was 3% in the statin group and 0% in the control group; therefore, the number of study participants might have been too low to provide sufficient statistical power and it remains unclear whether high-dose pitavastatin increases the incidence of CIN. A large-scale randomized study is needed to confirm the efficacy of high-dose pitavastatin for preventing CIN in Japan. Third, because patients without indication of statin treatment for the prevention of cardiovascular events were excluded in the present study, it remains unclear whether high-dose pitavastatin prevents CIN by its nephroprotective effect independently of its lipid-lowering effect. Fourth, multivariate analysis for predictors of CIN could not be performed because of the low number of patients with CIN in the present study. Fifth, the total amount of contrast medium used was lower in the present study than in previous studies;¹¹^–¹⁴ therefore, it is unclear whether high-dose pitavastatin is useful for preventing CIN if the total amount of contrast medium used was the same as that in previous studies. Finally, the present study used high-dose pitavastatin as an intervention treatment, unlike previous randomized controlled studies.¹¹^–¹⁴ Because pleiotropic effects may be different for different statins,³⁷ the results of this study might not be observed when other statins are used.

Conclusions

The present study, which included mostly patients who had already received some statin treatment, showed that high-dose pitavastatin therapy increases the incidence of CIN in Japanese patients with CKD undergoing cardiovascular catheterization and intervention.

Acknowledgments

We thank the PREVENT CINC-J Investigators: Principal Investigator, Y.S.; Steering Committee, K.A., Y.O., T. Murohara, M.W.; Protocol Committee, Masato Kasahara; Data Safety Monitoring Committee, Michihiro Yoshimura, Masayuki Iwano, and Kenichi Samejima; Study Statisticians, T.M., S.O.; and Investigators, T.S., T.U., T.T., A.S., Shunsuke Sakai, S.U., T.K., K.K., N.D., Hajime Iwama, Atsushi Iwai, S.N., Hisaaki Ishiguro, K.T., T.N., M.H., K.I., K.N., D.A., Norihiro Kuroki, K.O., Takashi Akasaka, Noriyuki Takeyasu, Masae Endo, Hiroyuki Kawata, Takuya Isojima, and Yutaka Goryo.

Disclosures

Y.S.: research funds from Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bristol-Myers Squibb Company, Actelion Pharmaceuticals Japan Ltd., Kyowa Kirin Co., Ltd., Kowa Pharmaceutical Co., Ltd, Shionogi & Co., Ltd, Dainippon Sumitomo Pharma Co., Ltd., Teijin Pharma Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nihon Medi-Physics Co., Ltd., Novartis Pharma K.K., Pfizer Japan Inc., and Fuji Yakuhin Co., Ltd., research expenses from Novartis Pharma K.K., Roche Diagnostics K.K., Amgen Inc., Bayer Yakuhin, Ltd., Astellas Pharma Inc., and Actelion Pharmaceuticals Japan Ltd., speakers’ bureau/honorarium from Alnylam Japan K.K., AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Tsumura & Co., Teijin Pharma Ltd., Toa Eiyo Ltd., Nippon Shinyaku Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin Ltd., Pfizer Japan Inc., Bristol-Myers Squibb Company, and Mochida Pharmaceutical Co., Ltd., consultation fees from Ono Pharmatical Co., Ltd. and Novartis Pharma K.K.. K.A.: research funds from Astec Corporation and Boston Scientific Corporation; lecturer’s fees from Boehringer Ingelheim Japan Co. and Daiichi Sankyo Company, Limited; endowed departments by Abbott Medical Japan LLC. T. Morimoto: lecturer’s fees from Bristol-Myers Squibb Company, Daiichi Sankyo Co., Ltd., Japan Lifeline Co., Ltd, Kowa Pharmaceutical Co., Ltd., Kyocera corporation, Novartis Pharma K.K., and Toray Industries, Inc.; manuscript fees from Bristol-Myers Squibb Company and Kowa Pharmaceutical Co., Ltd. advisory board for Sanofi K.K. S.O.: research grants from Japanese Red Cross Society; lecturer’s fees from Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma Co., Ltd., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., AstraZeneca K.K., and Novartis Pharma K.K.. S.U.: educational grants and lecture fees from Daiichi Sankyo Co., Ltd. and Abbott Vascular Japan LLC. K.K.: lecturer’s fees from AstraZeneca K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmatical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin Ltd., Pfizer Japan Inc., and Novartis Pharma K.K.; scholarship donations from Otsuka Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Medtronic Japan Co., Ltd., and Fukuda Denshi Co., Ltd. The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

K.A., T. Murohara, S.U., K.K., Y.S. are members of Circulation Journal’s Editorial Team.

IRB Information

The Ethics Committee of Nara Medical University (reference number; CRB5200002)

Sources of Funding

The PREVENT CINC-J study was supported by Abbott Japan LLC. Measurements of urinary NGAL and creatinine levels were performed by Abbott Japan LLC at no charge.

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-21-0869

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