Advance Publication by J-STAGE

Circulation Journal
Official Journal of the Japanese Circulation Society
http://www. j-circ.or.jp

Randomized Head-to-Head Comparison of Pitavastatin,

Atorvastatin, and Rosuvastatin for Safety and
Efficacy (Quantity and Quality of LDL)
– The PATROL Trial –
Keijiro Saku, MD, PhD; Bo Zhang, PhD; Keita Noda, MD, PhD
on behalf of the PATROL Trial Investigators

Background:  Atorvastatin, rosuvastatin and pitavastatin are available for intensive, aggressive low-density lipo-
protein cholesterol (LDL-C)-lowering therapy in clinical practice. The objective of the Randomized Head-to-Head
Comparison of Pitavastatin, Atorvastatin, and Rosuvastatin for Safety and Efficacy (Quantity and Quality of LDL)
(PATROL) Trial was to compare the safety and efficacy of atorvastatin, rosuvastatin and pitavastatin head to
head in patients with hypercholesterolemia. This is the first prospective randomized multi-center trial to compare
these strong statins (UMIN Registration No: 000000586).

Methods and Results:  Patients with risk factors for coronary artery disease and elevated LDL-C levels were
randomized to receive atorvastatin (10 mg/day), rosuvastatin (2.5 mg/day), or pitavastatin (2 mg/day) for 16 weeks.
Safety was assessed in terms of adverse event rates, including abnormal clinical laboratory variables related to
liver and kidney function and skeletal muscle. Efficacy was assessed by the changes in the levels and patterns of
lipoproteins. Three hundred and two patients (from 51 centers) were enrolled, and these 3 strong statins equally
reduced LDL-C and LDL particles, as well as fast-migrating LDL (modified LDL) by 40–45%. Newly developed
pitavastatin was non-inferior to the other 2 statins in lowering LDL-C. There were no differences in the rate of
adverse drug reactions among the 3 groups, but HbA1c was increased while uric acid was decreased in the atorvas-
tatin and rosuvastatin groups.

Conclusions:  The safety and efficacy of these 3 strong statins are equal. It is suggested that the use of these
3 statins be completely dependent on physician discretion based on patient background.

Key Words: Atorvastatin; Efficacy; Pitavastatin; Rosuvastatin; Safety

R
andomized trials of statin therapy have consistently
shown reduced cardiovascular events in both pri-
mary1,2 and secondary prevention.3,4 There are still
many unanswered questions, however: which statin should
be used; how safe is this therapy; and are there guidelines
regarding which statin to select when starting treatment with
statins? The aim of the present study was to evaluate the safe-
ty and efficacy of the so-called strong statins atorvastatin,
rosuvastatin and pitavastatin simultaneously, all of which are
fully synthetic compounds. Because these statins have differ-
ent chemical structures and pharmacokinetic profiles,5,6 they
may also have different efficacies and adverse events (AE).
Editorial p ????
In previous studies the appearance and frequency of side-
effects, including abnormal laboratory findings, were far dif-
ferent among the statins tested based on information obtained
via interview forms: for example, 8.7–35.6% for 3 statins
reported to the Japan Pharmaceuticals and Medical Devices

Received December 22, 2010; revised manuscript received January 12, 2011; accepted February 2, 2011; released online April 15,
2011   Time for primary review: 14 days
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka (K.S., B.Z.); Department of Clinical and Applied Science,
Graduate School of Medical Sciences, Fukuoka University, Fukuoka (K.S., K.N.), Japan
The first three authors contributed equally (K.S., B.Z., K.N.).
Presented as a Late-Breaking Clinical Trial I-1 at the 74th Annual Scientific Meeting of the Japanese Circulation Society, March 5, 2010.
The PATROL Trial Investigators are listed in Appendix 1.
Mailing address:  Keijiro Saku, MD, PhD, FACP, FACC, Department of Cardiology, Fukuoka University School of Medicine, 7-45-1
Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.   E-mail: saku-k@fukuoka-u.ac.jp
ISSN-1346-9843   doi: 10.1253/circj.CJ-10-1281
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
 Advance Publication by J-STAGE
SAKU K et al.

Figure 1.    Outline of the study (PATROL trial) protocol, and patients recruited. (Patients with LDL-C ≥140 mg/dl, or who had not
reached the target LDL-C levels recommended by the Japan Atherosclerosis Society (JAS) Guidelines11 for the Diagnosis and
Treatment of Atherosclerotic Cardiovascular Diseases were recruited. Patients who were already receiving lipid-lowering drugs
had wash out for at least 1 month. AE, adverse event; FAS, full analysis set; LDL-C, low-density lipoprotein cholesterol; PPS,
per-protocol analysis set.
 Advance Publication by J-STAGE
PATROL Trial
Agency,7–9 and 0.6–11.1% according to post-marketing sur-
veillance.8,9 Although previous comparative studies have
examined atorvastatin vs. rosuvastatin, few data are avail-
able on atorvastatin vs. pitavastatin, and almost no studies
have compared rosuvastatin vs. pitavastatin. As a working
hypothesis, we assumed that pitavastatin, which was devel-
oped most recently, would be non-inferior to atorvastatin and
rosuvastatin with regard to safety and efficacy. In addition,
it has been reported that plasma statin concentrations in
Japanese or Asian subjects were higher than in Western sub-
jects,10 and thus we wanted to investigate the safety and effi-
cacy of these statins in a Japanese population. In the present
study (Randomized Head-to-Head Comparison of Pitavas-
tatin, Atorvastatin, and Rosuvastatin for Safety and Efficacy
(Quantity and Quality of LDL) [PATROL] Trial), we com-
pared the safety and lipid-lowering effects of 3 strong statins
using a randomized, comparative, multicenter-based design.
To assess the efficacy at lowering low-density lipoprotein
(LDL), we determined both the quantity and the quality of
LDL using newly developed LDL subfraction analyses.
Methods
Protocol
This was a randomized, controlled, parallel and multi-center
clinical trial. This trial was conducted at Fukuoka University
Hospital and its related hospitals in the Kyushu area in Japan
(total of 51 hospitals; Appendix 1). The protocol was ap-
proved by the Independent Review Board (IRB) of Fukuoka
University Hospital (No.06-88), and registered at UMIN (ID:
000000586). All of the University-related hospitals applied
the same protocol as the ethics committee and IRB at Fukuoka
University Hospital. Figure 1 shows the study (PATROL
trial) design, and the patient analytical sets. Each subject
signed an informed consent form after the protocol was
explained, and was advised to maintain their usual diet and
exercise regimens during the trial period. Age, sex, pre-treat-
ment with statins, and patient category according to the Japan
Atherosclerosis Society (JAS) Guidelines11 were equally dis-
tributed among the 3 groups (atorvastatin, rosuvastatin and
pitavastatin) by computer randomization entrusted to Medical
Bio Informatics, Tokyo.
Primary Endpoints
Safety and Efficacy of Statins During 16 Weeks   Safety
was assessed in terms of the rate of AE classified using
MedDRA/J 12.1, including abnormal laboratory variables.
Drug-related AE were the primary endpoints. Efficacy was
assessed according to changes in LDL-C.
Secondary Endpoints
For safety, the secondary endpoints were adverse drug reac-
tion rate, and abnormal variation rate in clinical laboratory
tests, changes in clinical laboratory variables, abnormal fluc-
tuations in clinical laboratory data, and discontinuation of
drugs due to AE during 16 weeks.
For efficacy, the secondary endpoints were changes in high-
density lipoprotein cholesterol (HDL-C), triglyceride (TG),
and LDL-C/HDL-C, rate of reaching target LDL-C levels
recommended by the JAS Guidelines for the Diagnosis
and Treatment of Atherosclerotic Cardiovascular Diseases,11
changes in lipoprotein profiles as assessed on capillary iso-
tachophoresis (cITP), and changes in the numbers of LDL
particles or small dense LDL-cholesterol.
Definition of Drug-Related AE
The definition of drug-unrelated AE was left to the discre-
tion of the research physician for each participant under the
standard rules for clinical trials. Drug-related AE were de-
fined as all AE other than those that the research physician
had judged to be definitely not related to the statin. Therefore,
related, probably related, and possibly related AE were clas-
sified as drug-related. Information on AE and the causal
relationship with the tested drug judged by the research phy-
sician was recorded in the case report form (CFR). The CFR
database was merged with clinical laboratory data by patient
code using the SAS software package (version 9.2; SAS
Institute, Cary, NC, USA). Whether or not abnormal fluctua-
tion of clinical laboratory data was drug-related or not was
determined according to CFR.
Patients
Figure 1 (Upper panel) shows the patients recruited. Three
hundred and seventy-two patients with hypercholesterolemia
who applied were screened, and 302 patients were enrolled
and randomized to each statin (101 assigned to 10 mg/day
atorvastatin, 100 assigned to 2.5 mg/day rosuvastatin, and 101
assigned to 2 mg/day pitavastatin). Next, 99, 100, and 99 pa-
tients, respectively, were included in a safety analysis of AE,
and 97, 97 and 95 patients were included in a safety analysis
of a clinical laboratory test, because several blood samples
during treatment were not available. For the full analysis set
(FAS, intention to treat), 96, 96, and 93 patients, respective-
ly, were included for the efficacy analysis because of incom-
plete compliance at follow-up, and 77, 76, and 75 patients,
respectively, were included for the per-protocol set (PPS).
Inclusion Criteria
In each group, the pre-existing administration of statins, if
any, was discontinued for at least 4 weeks and blood was
drawn in the morning after an overnight fast. A subject was
eligible for inclusion if they satisfied the following crite-
ria: LDL-C ≥140 mg/dl, or they had not reached the target
LDL-C levels recommended by the JAS Guidelines for the
Diagnosis and Treatment of Atherosclerotic Cardiovascular
Diseases,11 aged 20–75 years, and could come to the hospital
every 4 weeks as necessary for 4 months.
Exclusion Criteria
A subject was not eligible for inclusion if they met any of the
following criteria: familial hypercholesterolemia; nephrotic
syndrome; pregnancy; breast-feeding; treatment with hor-
mone replacement; clinically manifest thyroid dysfunction;
taking drugs for thyroid dysfunction or other medications that
may influence body weight as noted in the drug information
within the previous 12 weeks; psychosis; use of antipsychotic,
antidepressant, or anti-manic drugs; alcohol or substance
abuse; smoking cessation within the previous 6 months or
planning to stop or reduce smoking; type 1 diabetes mellitus;
uncontrolled type 2 diabetes mellitus; moderate – severe renal
disease (creatinine [Cr] >2.0 mg/dl); elevation of creatine
kinase (CK; >5-fold the upper limit); heart failure; severe
hepatic disease; malignancy; history of irritability for statin;
severe autoimmune disease; pathological edema or body fluid;
gastrointestinal disease that could influence food absorption;
history of gastrointestinal operation or myocardial infarction;
stroke within the past 6 months; lifestyle change >2 weeks;
and enrollment in another clinical trial.
 Advance Publication by J-STAGE
SAKU K et al.

Figure 2.    (A) Follow-up rate (%) of patients treated with atorvastatin, rosuvastatin, and pitavastatin during the study period
(4 months). (B) Any adverse event (AE) and any drug-related AE in patients treated with atorvastatin, rosuvastatin, or pitavas-
tatin according to the use of concomitant medications. *P<0.001, all of the patients with concomitant drug use vs. those without
concomitant drug use, as assessed on chi-squared analysis. The interactions of the 3 statins with concomitant drug use, angio-
tensin II type 1 receptor blocker/angiotensin-converting enzyme inhibitors (ARB/ACEIs), Ca2+-antagonists, β-blockers, diuretics,
or anti-diabetic drugs on AE and drug-related AE were not statistically significant, as assessed on logistic regression analysis.
(C) Changes in serum low-density lipoprotein cholesterol (LDL-C) levels in patients treated with atorvastatin, rosuvastatin, or
pitavastatin during the study period. Data are given as mean ± SD. *P<0.001, vs. baseline (0 months) as assessed by repeated
measures analysis of variance (ANOVA). (D) Treatment differences (%) in the percent reduction in LDL-C levels during the study
period between new drug and control drug. Pitavastatin (new drug) was compared with atorvastatin (control) and rosuvastatin
(control), and rosuvastatin (new drug) was compared with atorvastatin (control). A non-inferiority test was performed using both
a per-protocol analysis set (PPS; closed red circle), and a full analysis set (FAS), based on the intention-to-treat principle. Data
given as mean (95% confidence interval [CI]). Black circles, mean treatment differences; horizontal lines, 95%CIs (for the dif-
ferences in the percent reduction in LDL-C levels in patients treated with the new drug, as compared with the control drug). If
the entire confidence interval for the treatment difference lies to the right of –5%, the new drug is not inferior to the control drug
in that the possibility can be ruled out that the new drug has a less than 5% reduction in LDL-C levels than the control drug.
 Advance Publication by J-STAGE
PATROL Trial

Table 1.  Baseline Patient Characteristics

Atorvastatin Rosuvastatin Pitavastatin
Characteristic P value
(n=99) (n=100) (n=99)
Age (years), mean ± SD 61.5±9.5　　 61.7±10.3 63.4±11.8 NS
Male, n (%) 34 (34.3) 35 (35.0) 34 (34.3) NS
BMI (kg/m2), mean ± SD 23.8±3.4　　 23.9±3.7　　 23.6±3.5　　 NS
SBP (mmHg), mean ± SD 131±15　　 132±16　　 132±17　　 NS
DBP (mmHg), mean ± SD 78±11 77±11 79±10 NS
Prior therapy with testing statins, n (%) 17 (17.2) 16 (16.0) 17 (17.2) NS
Risk factors of CHD, n (%)
   Hypertension 64 (64.6) 58 (58.0) 61 (61.6) NS
   Diabetes mellitus 32 (32.3) 27 (27.0) 21 (21.2) NS
   Smoking 14 (14.1) 12 (12.0) 12 (12.1) NS
   Family history of CHD 11 (11.1) 17 (17.0) 14 (14.1) NS
CHD, n (%) 8 (8.1) 9 (9.0) 14 (14.1) NS
Arteriosclerosis obliterans, n (%) 4 (4.0) 2 (2.0) 7 (7.1) NS
History, n (%)
   Myocardial infarction 1 (1.0) 3 (3.0) 3 (3.0) NS
   Cerebral infarction 6 (6.1) 6 (6.0) 4 (4.0) NS
Risk category, n (%)
   A (having no risk factors of CHD) 2 (2.0) 8 (8.0) 7 (7.1) NS
   B1 (having 1 risk factor of CHD) 27 (27.3) 19 (19.0) 22 (22.2)
   B2 (having 2 risk factors of CHD) 24 (24.2) 27 (27.0) 25 (25.3)
   B3 (having 3 risk factors of CHD) 25 (25.3) 22 (22.0) 23 (23.2)
   B4 (having >
– 4 risk factors of CHD) 13 (13.1) 15 (15.0) 8 (8.1)
   C (having CHD) 8 (8.1) 9 (9.0) 14 (14.1)
Concomitant medications, n (%) 81 (81.8) 81 (81.0) 75 (75.8) NS
Anti-hypertensive drugs, n (%)
   ARB/ACE 37 (37.4) 38 (38.0) 40 (40.4) NS
   Ca blocker 36 (36.4) 33 (33.0) 39 (39.4) NS
   β-blocker 7 (7.1) 4 (4.0) 10 (10.1) NS
   Diuretic 3 (3.0) 7 (7.0) 7 (7.1) NS
Lipids (mg/dl), mean ± SD
   LDL-C 162±24　　 172±28　　 164±23　　 NS
   HDL-C 56.7±13.6 57.1±13.4 59.0±14.4 NS
   TG 142±70　　 142±77　　 132±71　　 NS
CRP (mg/dl) 0.11±0.23 0.11±0.18 0.14±0.42 NS
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; CHD, coronary heart disease;
ARB, angiotensin II type 1 receptor blocker; ACE, angiotensin-converting enzyme; LDL-C, low-density lipoprotein
cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; CRP, C-reactive protein.

Measurements Statistical Analysis

Blood pressure and pulse rate were measured every 4 weeks
during the trial period. Serum levels of LDL-C, TG, HDL-C,
complete blood count, urinalysis, biochemistry including
aspartate aminotransferase (AST), alanine aminotransferase
(ALT), Cr, and CK were measured every 4 weeks, and HbA1c,
high-sensitivity C-reactive protein (hsCRP), adiponectin, apo-
lipoprotein (apo) A-I, apo B, and lipoprotein profiles were
assessed on cITP at the start (0 month) and end of statin
treatment (4 months) at the Fukuoka University Hospital
Laboratory Unit or by SRL Corporation. LDL particle num-
bers were measured as LDL-apo B levels in plasma d
>1.006-g/ml fractions separated using quantitative ultracen-
trifugation, as described previously.12 sdLDL-C and sdLDL-
apo B levels were measured in plasma d >1.040 g/ml on
ultracentrifugation.12 Electronegative LDL was measured
as fast-migrating LDL (oxidized and modified) using cITP,
and slow-migrating LDL (native LDL) was also measured,
as described previously.12–15
All of the data analyses were performed using the SAS soft-
ware package (version 9.2; SAS Institute) at Fukuoka Univer-
sity (Fukuoka, Japan). Frequency distributions for category
variables were compared among (between) groups using the
chi-squared analysis and/or Fisher’s exact test. The normal-
ity of the distribution of continuous variables was examined
using Shapiro – Wilk test. Differences in continuous variables
among (between) groups were examined using analysis of
variance (ANOVA) and/or Wilcoxon rank – sum test. Changes
in continuous variables during the study period were exam-
ined using repeated measures ANOVA and/or the Wilcoxon
signed-rank test. Continuous variables during the study period
are presented as mean ± SD, and the medians are given for
changes and percentage changes in continuous variables
during the study period. Relationships between changes in
LDL-C levels and those in other variables were examined on
Spearman correlation. Treatment differences in LDL-C levels
between the new drug and active control are presented as
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SAKU K et al.

Table 2.  Safety Endpoints: Primary (Drug-Related AE) and Secondary

Atorvastatin Rosuvastatin Pitavastatin
(n=99), (n=100), (n=99), P value
n (%) n (%) n (%)
Any AE 51 (51.5) 46 (46.0) 52 (52.5) NS
   Grades (severity of the AE)
     Grade 1 (mild) 37 (37.4) 37 (37.0) 42 (42.4)
     Grade 2 (moderate) 13 (13.1) 8 (8.0) 10 (10.1)
     Grade 3 (severe) 1 (1.0) 1 (1.0) 0 (0.0)
     Grade 4 (serious) 3 (3.0) 0 (0.0) 1 (1.0)
   Discontinued because of AE 13 (13.1) 10 (10.0) 12 (12.1) NS
Any drug-related AE 18 (18.2) 12 (12.0) 17 (17.2) NS
   Grades (severity of the AE)
     Grade 1 (mild) 11 (11.1) 8 (8.0) 13 (13.1)
     Grade 2 (moderate) 7 (7.1) 3 (3.0) 4 (4.0)
     Grade 3 (severe) 0 (0.0) 0 (0.0) 0 (0.0)
     Grade 4 (serious) 0 (0.0) 0 (0.0) 0 (0.0)
   Discontinued because of drug-related AE 8 (8.1) 4 (4.0) 5 (5.1) NS
ADR occurring in > – 2% of patients in any treatment group, n (%)†
   Gastrointestinal disorders 2 (2.0) 1 (1.0) 2 (2.0)
     Constipation 0 1 0
     Diarrhea 2 0 0
     Gastritis 0 0 2
   General disorders and administration site conditions 1 (1.0) 2 (2.0) 2 (2.0)
     Feeling abnormal 1 0 0
     Malaise 0 1 2
     Pyrexia 0 1 0
   Investigations 20 (20.2) 11 (11.0) 17 (17.2)
     AST increased 5 2 4
     ALT increased 5 1 4
     Blood alkaline phosphatase increased 1 0 0
     Blood bilirubin increased 1 0 0
     Blood CK increased 3 1 5
     Blood glucose increased 0 1 0
     Blood LDH increased 2 2 0
     Blood uric acid increased 0 1 0
     γ-GTP increased 2 0 2
     Glycosylated hemoglobin increased 0 0 1
     Urine protein present 0 1 0
     Red blood cell count decreased 0 0 1
     White blood cell count decreased 1 1 0
     White blood cell count increased 0 1 0
   Musculoskeletal and connective tissue disorders 0 (0.0) 3 (3.0) 2 (2.0)
     Back pain 0 2 0
     Muscle spasm 0 0 1
     Musculoskeletal stiffness 0 1 0
     Myalgia 0 0 1
   Skin and subcutaneous tissue disorders 3 (3.0) 1 (1.0) 1 (1.0)
     Allergic dermatitis 1 0 0
     Atopic dermatitis 1 0 0
     Eczema 0 1 0
     Periorbital edema 1 0 0
     Pruritus 0 0 1
AE, adverse event; ADR, adverse drug reactions; AST, aspartate aminotransferase; ALT, alanine aminotransferase;
CK, creatine kinase; LDH, lactate dehydrogenase; γ-GTP,γ-glutamyltransferase.
†Tabulated by system organ class and the number of events corresponding to the preferred terms in MedDRA version

10.1.
 Advance Publication by J-STAGE
PATROL Trial

Table 3.  Safety Endpoints: Abnormal Fluctuations in Clinical Laboratory Data

Atorvastatin Rosuvastatin Pitavastatin
(n=97), (n=97), (n=95), P value
n (%) n (%) n (%)
Liver function tests
   AST
     Abnormal fluctuations of AST 10 (10.3) 8 (8.2) 7 (7.4) NS
       Drug-related abnormal fluctuations 5 (5.2) 3 (3.1) 4 (4.2)
     AST grades: Grade 1/Grade 2/Grade 3 4/1/0 2/1/0 5/0/0
       Drug-related grades 1 (1.0) 1 (1.0) 3 (3.2)
   ALT
     Abnormal fluctuations of ALT 24 (24.7) 13 (13.4) 12 (12.6) 0.043
       Drug-related abnormal fluctuations 6 (6.2) 3 (3.1) 4 (4.2)
     ALT grades: Grade 1/Grade 2/Grade 3 13/2/0 9/2/0 8/1/0
       Drug-related grades 3 (3.1) 1 (1.0) 4 (4.2)
   γ-GTP
     Abnormal fluctuations of γ-GTP 28 (28.9) 30 (30.9) 22 (23.2) NS
       Drug-related abnormal fluctuations 5 (5.2) 4 (4.1) 2 (2.1)
     γ-GTP grades: Grade 1/Grade 2/Grade 3 21/0/0 24/0/0 17/0/0
       Drug-related grades 3 (3.1) 1 (1.0) 3 (3.2)
   LDH
     Abnormal fluctuations of LDH 13 (13.4) 13 (13.4) 18 (18.9) NS
       Drug-related abnormal fluctuations 2 (2.1) 3 (3.1) 3 (3.2)
     LDH grades: Grade 1/Grade 2/Grade 3 0/0/0 1/0/0 0/0/0
       Drug-related grades 0 (0.0) 1 (1.0) 0 (0.0)
Kidney function tests
   BUN
     Abnormal fluctuations of BUN, n (%) 8 (8.2) 12 (12.4) 9 (9.5) NS
       Drug-related abnormal fluctuations, n (%) 3 (3.1) 2 (2.1) 0 (0.0)
     BUN grades: Grade 1/Grade 2/Grade 3 6/2/0 8/3/0 6/4/0
       Drug-related grades 2 (2.1) 2 (2.1) 0 (0.0)
   Cr
     Abnormal fluctuations of Cr 9 (9.3) 12 (12.4) 16 (16.8) NS
       Drug-related abnormal fluctuations 1 (1.0) 4 (4.1) 4 (4.2)
     Cr grades: Grade 1/Grade 2/Grade 3 8/0/0 17/0/0 18/0/0
       Drug-related grades 0 (0.0) 4 (4.1) 4 (4.2)
   Proteinuria
     Abnormal fluctuations of proteinuria 3 (3.1) 9 (9.3) 8 (8.4) NS
       Drug-related proteinuria 0 (0.0) 2 (2.1) 0 (0.0)
     Proteinuria grades: Grade 1/Grade 2/Grade 3 4/3/0 6/4/0 4/0/0
       Drug-related grades 1 (1.0) 2 (2.1) 0 (0.0)
   Serum K
     Abnormal fluctuations of serum K 14 (14.4) 11 (11.3) 15(15.8) NS
       Drug-related abnormal fluctuations 0 (0.0) 1 (1.0) 0 (0.0)
     Serum K grades: Grade 2/Grade 3 8/3 11/4 8/4
       Drug-related grades 1 (1.0) 1 (1.0) 0 (0.0)
Skeletal muscle tests
   CK
     Abnormal fluctuations of CK 19 (19.6) 15 (15.5) 20 (21.1) NS
       Drug-related abnormal fluctuations 1 (1.0) 1 (1.0) 0 (0.0)
     CK grades: Grade 1/Grade 2/Grade 3/Grade 4 15/2/0/0 15/2/0/0 20/1/0/0
       Drug-related grades 3 (3.1) 4 (4.1) 5 (5.3)
Cr, creatinine; K, potassium. Other abbreviations see in Table 2.

mean (95% confidence interval). We used a FAS of data,
based on the intention-to-treat principle, as a primary analy-
sis of efficacy. We also prepared a PPS of data if the enrolled
patients completely met the inclusion and exclusion criteria
and followed the protocol for non-inferiority test (Figure 2).
If the patients received statins at least once, they were
included in the AE analysis (Figure 1). Significance was set
at P<0.05 unless otherwise indicated.
 Advance Publication by J-STAGE
SAKU K et al.

Table 4.  Patients Who Reached Target LDL-C Levels and Changes in LDL and Clinically Relevant Markers
Atorvastatin Rosuvastatin Pitavastatin
P value
(n=96), n (%) (n=96), n (%) (n=93), n (%)
No. patients who reached LDL-C target levels 90 (94) 85 (89) 88 (95) NS
Risk category [targeted LDL-C level (mg/dl)]
   A [<160]    2 (100)    8 (100)    7 (100)
   B1/B2 [<140] 48 (96) 37 (86) 43 (98)
   B3/B4 [<120] 33 (92) 35 (95) 26 (93)
   C [<100]  7 (88)  5 (63) 12 (86)
LDL-C
   Baseline (mg/dl) 162±25　　　　 171±29　　 164±24　　
   After treatment 　93±26†　　 　99±22† 　90±18†
   Median change (% change) –73 (–44) –72 (–42) –67 (–41) NS
LDL-apo-B (LDL particle no.)
   Baseline (mg/dl) 111±15　　　　 114±19　　 110±16　　
   After treatment 　69±17†　　 　73±14† 　70±14†
   Median change (% change) –41 (–39) –40 (–36) –40 (–37) NS
sdLDL-apo-B (sdLDL particle no.)
   Baseline (mg/dl) 43±20　　 44±21 38±17
   After treatment 　27±14†　　 　29±13† 　26±12†
   Median change (% change) –14 (–33) –14 (–34) –11 (–30) NS
cITP fLDL (charge-modified LDL)
   Baseline (RFU) 0.92±0.37　　 0.94±0.32 0.87±0.33
   After treatment 　0.56±0.27†　　 　0.57±0.24† 　0.54±0.23†
   Median change (% change) –0.37 (–43)　 –0.35 (–40)　 –0.28 (–37)　 NS
cITP sLDL (normal LDL)
   Baseline (RFU) 2.28±0.60　　 2.38±0.57 2.38±0.49
   After treatment 　1.48±0.45†　　 　1.58±0.43† 　1.56±0.34†
   Median change (% change) –0.87 (–35)　 –0.87 (–35)　 –0.85 (–35)　 NS
HDL-C
   Baseline (mg/dl) 56.9±13.8　　 56.6±13.0 59.5±14.3
   After treatment 58.0±15.1　　 　　59.2±13.3** 61.3±14.0
   Median change (% change) 0.5 (1)　 2.0 (4)　 0.0 (0)　 NS
HDL-C/LDL-C
   Baseline 3.03±0.88　　 3.19±0.89 2.92±0.83
   After treatment 　1.73±0.70†　　 　1.76±0.59† 　1.63±0.51†
   Median change (% change) –1.23 (–45)　 –1.27 (–42)　 –1.28 (–44)　 NS
TG
   Baseline (mg/dl) 136±68　　　　 140±73　　 124±66　　
   After treatment 　108±60†　　　　 　110±63†　　 　99±43†
   Median change (% change) –29 (–21) –20 (–19) –18 (–20) NS
CRP
   Baseline (mg/dl) 0.114±0.230　　 0.114±0.180 0.143±0.419
   After treatment 0.110±0.238** 0.115±0.196   0.129±0.379**
   Median change (% change) –0.009 (–29)　 –0.005 (–20)　 –0.006 (–20)　 NS
HbA1c (JDS)
   Baseline (%) 5.68±1.06　　 5.52±0.91 5.39±0.53
   After treatment 5.75±1.01** 　　5.58±0.80** 5.42±0.52
   Median change (% change) 0.10 (1.8)　 0.10 (1.8)　 0.00 (0.0)　 NS
CK
   Baseline (IU/L) 116±64　　　　 117±93　　 108±49　　
   After treatment 132±113*　 122±75　　 110±45　　
   Median change (% change)   6 (7.6)   5 (4.1)   1 (0.6) NS
UA
   Baseline (mg/dl) 5.19±1.23　　 5.42±1.48 5.15±1.31
   After treatment 4.99±1.12*　 　5.24±1.54* 5.01±1.29
   Median change (% change) –0.10 (–2.5)　 –0.15 (–2.9)　 –0.10 (–2.3)　 NS
eGFR
   Baseline (ml · min–1 · 1.73 m–2) 75.7±13.8　　 73.1±16.2 72.0±15.4
   After treatment 76.2±13.1　　 　74.4±17.2* 71.7±16.1
   Median change (% change) 1.0 (1.4) 1.0 (1.4) –2.0 (–2.3) NS
Urine albumin
   Baseline (mg/g · CRE) 82.3±443　　　 52.7±250　　 30.0±44.2
   After treatment 20.9±32.8　　 63.9±275　　 24.3±35.2
   Median change (% change) –0.2 (–3.3) 0.6 (5.3) –0.3 (–2.7) NS
α1-Microglobulin
   Baseline (mg/L) 4.9±5.0　　 5.0±4.8 4.4±4.6
   After treatment 4.7±4.8　　 5.5±6.5 5.0±5.1
   Median change (% change) 0.0 (0.0) 0.2 (6.9) 0.3 (17)　 NS
Data given as mean ± SD. Changes during the study period are given as medians.
A, no risk factors of CHD; B1, 1 risk factor of CHD; B2, 2 risk factors of CHD; B3, 3 risk factors of CHD; B4, 4 risk
factors of CHD; C, having CHD; apo-B, apolipoprotein B; sdLDL, small dense LDL; cITP, capillary isotachophoresis;
fLDL, fast-migrating LDL subfraction; RFU, relative fluorescence unit; sLDL, slow-migrating LDL subfraction; LDL-C,
low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; UA, uric acid; eGFR, estimated glomer-
ular filtration rate; CRE, creatinine. Other abbreviations see in Tables 1,2.
*P<0.05; **P<0.01; †P<0.001.
 Advance Publication by J-STAGE
PATROL Trial
Results
Baseline Patient Characteristics
The patient characteristics are listed in Table 1. Age, sex,
body mass index, blood pressure, pre-treatment with statins,
risk factors of coronary heart disease (CHD), and patient
category according to the JAS Guidelines11 were equally dis-
tributed among the 3 groups (atorvastatin, rosuvastatin and
pitavastatin). The prevalence of diabetes mellitus seemed to
be higher in the atorvastatin group (32.3% vs. 27% for rosu-
vastatin and 21.2% for pitavastatin), but this difference was
not significant. Although the frequency of CHD was higher
in the pitavastatin group (14.1%), this difference was not
significant among the 3 groups. The number of concomi-
tant medications, especially anti-hypertensive drugs, in the
3 groups of patients were similar. The levels of serum lipids,
lipoproteins and hsCRP were similar among the 3 groups.
Safety Endpoints, Primary and Secondary
Table 2 lists the number of patients with AE in the 3 groups
(based on safety analysis of AE in Figure 1). Although the
incidence of any drug-related AE (primary endpoint) in the
16-week trial period was lowest in the rosuvastatin group
(12.0%), this difference was not statistically significant; on
graded analysis16 the 3 groups were similar, and most of the
AE were grade 1 (mild) or 2 (moderate). The rates of dis-
continuation because of drug-related AE ranged from 8.1%
for atorvastatin to 4.0% for rosuvastatin. The lower panel in
Table 2, which lists the system organ class and the number
of events corresponding to the preferred term in MedDRA
version 10.1, shows no significant differences among the
groups. When we considered abnormal fluctuations in labo-
ratory data, especially in liver, kidney, and skeletal muscle-
related tests as shown in Table 3 (based on safety analysis of
clinical laboratory test in Figure 1), ALT was significantly
increased in the atorvastatin group (P=0.043). Drug-related
grades for AE analysis,16 however (grade 1, 1.25–2.5-fold the
upper limits; grade 2, 2.5–12-fold the upper limits; grade 3,
>12-fold the upper limits), showed no difference in ALT
among the 3 groups, and thus no differences were observed
among the 3 groups (secondary endpoint). AE and drug-
related AE in patients treated with atorvastatin, rosuvastatin,
or pitavastatin stratified according to other drugs are given
in Figure 2B. The AE rate in patients who used other drugs
was significantly higher than that in those without con-
comitant drug use, indicating that concomitant medications
increased the incidence of AE in patients treated with statins.
The interactions, however, of the 3 statins with concomitant
drug use, angiotensin II type 1 receptor blocker/angiotensin-
converting enzyme inhibitors (ARB/ACEIs), Ca2+-antagonists,
β-blockers, diuretics, or anti-diabetic drug on any AE and any
drug-related AE were not statistically significant, as assessed
on logistic regression analysis. This indicates that 3 statins
were similar with regard to their interactions with other drugs
including anti-hypertensive drugs. There were fewer drug-
related AE in patients using the combination of atorvastatin
or rosuvastatin with diuretics, and pitavastatin with anti-
diabetic agents, although these differences were not signifi-
cant due to the very small number of such patients (Figure 2B
Lower panel).
Efficacy Endpoints, Primary and Secondary
In Figure 2A no difference is seen among the groups for
patient follow-up rate and study period; and a nearly 90%
follow-up rate was confirmed even after 4 months. The per-
centage of patients who reached the target LDL-C levels
recommended by the JAS Guidelines11 was 94%, 89% and
95% in the atorvastatin, rosuvastatin and pitavastatin groups,
respectively, and risk category followed the same patterns
(Table 4). LDL-C was significantly decreased at 16 weeks in
the atorvastatin, rosuvastatin and pitavastatin groups (162±
25 mg/dl to 93±26 mg/dl, 171±29 mg/dl to 99±22 mg/dl, and
164±24 mg/dl to 90±18 mg/dl, P<0.001, respectively; primary
endpoint), and no significant differences were seen among
them, and the LDL-C-lowering effects started at 1 month
into the study period (Figure 2C). There was no change in
HDL-C levels except for the rosuvastatin-treated group (56.6±
13.0 mg/dl to 59.2±13.3mg/dl, P<0.01), and TG was de-
creased in all of the 3 groups (136±68 mg/dl to 108±60 mg/dl,
140±73 mg/dl to 110±63 mg/dl, and 124±66 mg/dl to 99±
43 mg/dl, P<0.001, respectively). The LDL-C/HDL-C ratio
was significantly decreased in all 3 treated groups (3.03±0.88
to 1.73±0.70, 3.19±0.89 to 1.76±0.59, and 2.92±0.83 to 1.63±
0.51, P<0.001, respectively; Table 4).
Non-Inferiority of Pitavastatin vs. Atorvastatin, Pitavastatin
vs. Rosuvastatin, or Rosuvastatin vs. Pitavastatin
As an initial working hypothesis, we assumed that newly
synthesized pitavastatin was non-inferior to atorvastatin and
rosuvastatin with regard to safety and efficacy, and thus non-
inferiority was determined on 2-sided non-inferiority analy-
sis. Pitavastatin was shown to be non-inferior to rosuvastatin
(Figure 2D Middle panel). Furthermore, the same analysis
was conducted between pitavastatin vs. atorvastatin (Figure 2D
Upper panel), and rosuvastatin vs. atorvastatin (Figure 2D
Lower panel), and a similar trend was observed between
them. This indirectly supported the initial hypothesis that
pitavastatin was non-inferior to both atorvastatin and rosuv-
astatin with regard to efficacy. The FAS and PPS data showed
similar patterns for non-inferiority analysis.
LDL Subfraction Lowering, Secondary Endpoint for Efficacy
These data are given in Table 4, based on FAS data in
Figure 1. The number of LDL particles as assessed on sepa-
ration of the apo B/LDL fraction by ultracentrifugation was
significantly decreased in the atorvastatin, rosuvastatin and
pitavastatin groups (111±15 mg/dl to 69±17 mg/dl, 114±
19 mg/dl to 73±14 mg/dl, 110±16 mg/dl to 70±14 mg/dl, P<
0.001, respectively), as was small dense LDL fraction (sepa-
rated by ultracentrifugation)-apo B (43±20 mg/dl to 27±
14 mg/dl, 44±21 mg/dl to 29±13 mg/dl, 38±17 mg/dl to 26±
12 mg/dl, P<0.001, respectively). LDL subfractions were fur-
ther separated on cIPT and the slow-migrating LDL sub-
fraction (native LDL fraction) was significantly decreased
by approximately 35% in each group (P<0.001), while the
fast-migrating LDL subfraction (charge-modified LDL) was
also significantly decreased to the same degree (37–43%;
Table 4). Thus, these 3 strong statins equally decreased LDL
subfractions, both quantitatively and qualitatively.
Other Parameters
These data are given in Table 4, based on FAS data in
Figure 1. Although CRP decreased in the atorvastatin and
pitavastatin groups (P<0.01), HbA1c (JDS value) was signifi-
cantly increased in the atorvastatin and rosuvastatin groups
(5.68±1.06% to 5.75±1.01%, 5.52±0.91% to 5.58±0.80%,
P<0.01, respectively), but there was no change in the pitavas-
tatin group. Uric acid was decreased in the atorvastatin
and rosuvastatin groups (5.19±1.23 mg/dl to 4.99±1.12 mg/dl,
5.42±1.48 mg/dl to 5.24±1.54 mg/dl, P<0.05, respectively).
 Advance Publication by J-STAGE
Serum CK was increased in the atorvastatin group (116±
64 mg/dl to 132±113 mg/dl, P<0.05), and estimated glomeru-
lar filtration rate (eGFR) was increased only in the rosuvas-
tatin group, while urine albumin andα-microglobulin did not
change statistically. The changes of CRP, HbA1c, CK, UA,
and eGFR, however, were not clinically significant.
Discussion
In Japan, coronary artery disease (CAD) is still less common
than in Western countries, but the mortality rate due to CAD
is increasing along with an increase in the LDL-C level in
the Japanese population. Thus, there is a growing need for
more suitable so-called strong statins, based on the balance of
efficacy and AE, for Japanese patients. The strong statins that
are currently available in Japan are atorvastatin, rosuvastatin
and newly developed pitavastatin. While previous clinical
trials have compared atorvastatin and rosuvastatin,17–19 few
data are available on atorvastatin vs. pitavastatin,20–22 and
almost no information is available on pitavastatin vs. rosuv-
astatin. Comparison of pitavastatin with active controls (ator-
vastatin and rosuvastatin) using a non-inferiority trial can
reliably assess the efficacy of pitavastain and is ethically
allowed.
The safety analysis considered the rate of AE and adverse
drug reactions. The percentage of participants who com-
plained of drug-related AE was 8.7% for atorvastatin, 35.6%
for rosuvastatin, and 22.2% for pitavastatin in the respective
clinical trials conducted by each pharmaceutical company
for approval according to Japanese good clinical practice
(J-GCP).7–9 Although these trials were performed under strict
regulations, the data obtained for the statins were very differ-
ent. Therefore, it is very important to have a clinical trial to
compare these 3 statins at the same time under the regulation
of J-GCP, and the present study is at least the first randomized
control trial to directly compare atorvastatin, rosuvastatin and
pitavastatin with regard to safety and efficacy in a Japanese
population. In the present study, the proportion of patients
who had drug-related AE was 18.2% for atorvastatin, 12.0%
for rosuvastatin, and 17.2% for pitavastatin. There were no
significant differences among the 3 statins (Table 2), and
adverse drug reactions were also similar among the 3 groups.
Atorvastatin had an adverse effect by increasing ALT,
HbA1c and CK; and rosuvastatin increased HbA1c, although
the changes were mild. The proportion of patients who had
the drug-related AE of ALT elevation was 9.6% for atorvas-
tatin, 4.5% for rosuvastatin, and 3.6% for pitavastatin in the
respective clinical trials conducted under strict regulations by
the Japanese government.7–9 In the present study, the increase
in ALT varied from 24.7% for atorvastatin to 12.6% for
pitavastatin (Table 3). These data support the notion that
atorvastatin increased ALT, but the relation between this
increase in ALT and atorvastatin was not clear because the
rates of drug-related abnormal fluctuation or drug-related
grades (causal relationship of statins determined by physicians)
were not significantly different among the 3 statins (Table 3).
Atorvastatin has been reported to increase the onset and
impair the control of diabetes mellitus.23 Rosuvastatin has also
been reported to increase the onset of diabetes mellitus.2,24 In
contrast, pitavastatin has not been reported to increase the
onset of diabetes mellitus.25 When the levels of HbA1c were
compared before and 16 weeks after statin treatment in dia-
betic patients in each group, no differences were observed
(data not shown). This adverse effect might be drug-specific,
in which case patient background might be an important con-
SAKU K et al.
sideration in statin selection. A recent meta-analysis showed
that statin therapy was associated with a 9% increased risk
for the incidence of diabetes,26 but the risk was very low. As
shown in the present study, the changes in HbA1c with the
3 statins were within the normal range, and thus the clinical
guidelines regarding the use of statins should not be changed
solely due to this point.
The elevation of CK is thought to be a statin-specific adverse
reaction that occurs through several proposed mechanisms.27
In previous comparative studies, the rate of CK elevation by
atorvastatin was higher than that by rosuvastatin or pitavas-
tatin.7–9 Therefore, there may be a drug-specific mechanism
that involves muscle damage in addition to a class effect. Uric
acid was decreased in the atorvastatin and rosuvastatin groups
as previously reported,28,29 while eGFR was stable among the
groups in the present study. A recent post-marketing surveil-
lance study of rosuvastatin showed good effects with eGFR
<60 ml · min–1 · 1.73 m–2, although that was not a randomized,
control study.30 Rosuvastatin is relatively hydrophilic, while
atorvastatin and pitavastatin are lipophilic. We identified no
apparent difference between the hydrophilic and lipophilic
statins in these parameters, although there are large differ-
ences in the bioavailability of these statins.
Figure 2B shows an interaction of statins with other
drugs in AE and drug-related AE. There was no interaction
between drug use and no drug use with statins in drug-related
AE for the anti-hypertension drugs ARB/ACEs, Ca-antago-
nists, β-blockers, or diuretics. Drug-related AE occurred less
often in the combination of atorvastatin or rosuvastatin with
diuretics, and pitavastatin with anti-diabetic agents, but the
number of such patients was so small, it did not reach statis-
tical significance (Figure 2B Lower panel).
Although it is not clear whether or not these adverse or
beneficial effects are actually drug related, patients with life-
style-related diseases are likely to be treated with several
agents for lipid lowering, blood pressure lowering, and so on.
Physicians may not pay much attention to selection among
these 3 statins, and thus it is important for physicians to be
mindful of such effects when initiating treatment with a com-
bination of drugs.
The efficacy of the 3 statins in lowering LDL-C was ap-
proximately the same: approximately a 40% reduction in
LDL-C. Furthermore, the proportion of patients who reached
the target LDL-C defined by the JAS Guidelines for the
Diagnosis and Treatment of Atherosclerotic Cardiovascular
Diseases11 was approximately 90% in the 3 groups, in which
approximately 10% of the patients had CHD. Therefore, this
very high percentage may be achieved by a relatively high
dose of statin for Japanese subjects, and an increase in statin
beginning at 8 weeks if the LDL-C level does not reach the
target level (proportion of patients with dose increased: 4%,
6% and 4% for atorvastatin, rosuvastatin and pitavastatin,
respectively, data not tabulated). The present study clearly
shows that pitavastatin is non-inferior to atorvastatin and
rosuvastatin in terms of its LDL-C-lowering effect, so atorv-
astatin 10 mg/day, rosuvastatin 2.5 mg/day and pitavastatin
2 mg/day have equal effects on LDL, quantitatively as well
as qualitatively (Figure 2D). TG was decreased in all of
the groups. The HDL-C-raising ability relates to dose, base-
line HDL-C and TG levels and is unrelated to changes in
LDL-C,31 while HDL-C was increased only in the rosuvas-
tatin group in the present study (Table 4). In a qualitative
analysis of LDL, the 3 statins significantly improved small
dense LDL-apo B, the slow-migrating LDL subfraction, and
the fast-migrating LDL subfraction (electro-negative LDL)
 Advance Publication by J-STAGE
PATROL Trial

Figure 3.    (A,B) Plots of changes in low-density lipoprotein cholesterol (LDL-C) levels during the study period (full analysis data
set) vs. (A) baseline LDL-C levels or (B) baseline HDL-C levels. (C – H; Right) Box plots of the changes in (C) alanine amino-
transferase (ALT), (D)γ-glutamyltransferase (γ-GTP), (E) red cell count, (F) hematocrit, (G) hemoglobin, and (H) platelet count
in patients treated with atorvastatin, rosuvastatin, and pitavastatin. Closed square and the center line of the box, mean and
median, respectively; edges of the box, first and third quartiles. The 10% and 90% percentiles are the ends of the lines extend-
ing from the inter-quartile range. *P<0.05, significant changes from baseline, as assessed on Wilcoxon signed-rank test. (C – H;
Left) Plots (actual data and regression lines) of changes in (C) ALT, (D)γ-GTP, (E) red cell count, (F) hematocrit, (G) hemoglobin,
or (H) platelet count vs. changes in LDL-C levels in patients treated with atorvastatin, rosuvastatin, and pitavastatin. (A – H; Lower
left) Correlation coefficient and P values.
 Advance Publication by J-STAGE
after 16 weeks, which was similar to a previous clinical study
using rosuvastatin.12
We performed a subanalysis of the baseline LDL-C vs.
changes in LDL-C, and the baseline HDL-C vs. changes in
LDL-C (Figures 3A,B based on FAS data), and found a
negative relationship between them (a higher baseline LDL-C
and HDL-C was associated with a greater reduction of
LDL-C, r=–0.581, P<0.001, r=–0.148, P<0.012, respective-
ly; Figures 3A, B Left lower panel). The changes in LDL-C
vs. the changes in laboratory parameters were also assessed
(box plots), and we found that overall changes of ALT and
γ-glutamyltransferase (γ-GTP) were significantly positively
associated with lowering LDL-C (r=0.130, r=0.157, P<0.05;
Figures 3C, D Left lower panel), that is, increased ALT and
γ-GTP were not associated with LDL-C reduction by statins.
Interestingly, changes in red cell counts, hematocrit, hemo-
globin, and platelet counts were all significantly affected by
the lowering of LDL-C, and no significant changes were
observed among the 3 groups. Thus lowering LDL-C may
raise an important issue regarding blood cell counts, or pos-
sibly hemorheological profiles as reported previously.32,33
Although the differences are all within normal limits and the
correlation coefficient was too small (r=0.209, 0.183, 0.174,
and 0.149; Figures 3E–H), these are potentially important
findings.
Study Limitations
If we focus on safety, conventional (weak) statins should be
included in the study. HbA1c was significantly increased in
the atorvastatin and rosuvastatin groups, but was still within
the normal range, and to evaluate the effects on new-onset
diabetes mellitus, long-term follow-up is needed. Based on a
statistical analysis, between 10,000 and 100,000 participants
would be needed to clarify the difference in 1 adverse drug
reaction in a laboratory test based on post-marketing surveil-
lance. In the present study, changes in laboratory variables and
the percentage of abnormal variables were set as secondary
endpoints, and the study group was minimized, but patient
visits to hospital were increased to every 4 weeks for 16 weeks
to check blood samples. Also, laboratory samples were sent to
SRL for testing, and we examined 1 sample · month–1 · person–1
for 4 months, which might negate a variation in measurement
and overcome the weakness of the short 4-month follow-up.
In conclusion, the safety and efficacy of the 3 strong statins
pitavastatin, atorvastatin, and rosuvastatin are equal. The 3
strong statins equally reduced LDL-C, LDL particles, as well
as slow-migrating (native) LDL and fast-migrating LDL (oxi-
dized or modified LDL) by around 40–45%. The present
results show that pitavastatin was non-inferior to both atorv-
astatin and rosuvastatin with regard to lowering LDL-C, and
thus there were no differences in the effects of the 3 statins.
An examination of laboratory data, however, showed that
ALT and CK were likely to be increased in the atorvastatin
group, and HbA1c was increased while uric acid was decreased
in the atorvastatin and rosuvastatin groups, although these
changes were within normal limits. We suggest that the selec-
tion and use of these 3 statins is completely dependent on
physician discretion, based on a consideration of the adverse
reactions to the respective statins and of patient background,
and this conclusion is the first to be based on the results of
a prospective randomized multi-center trial.
Acknowledgments
This work was supported by a grant-in-aid from the Ministry of Educa-
tion, Science and Culture of Japan (No. 21590960), by research grants
SAKU K et al.
from the Central Research Institute of Fukuoka University (2005–2009),
by the Fukuoka University One-campus Project (2009–2010, supported
in part by the Ministry of Education, Science and Culture of Japan), and
by NPO Clinical and Applied Science, Fukuoka, Japan.
Disclosures
(K.S.): Research and education grants, consulting, and promotional speak-
ing from Kowa Co, Pfizer and AstraZeneca. K.S. is a Chief Director of
NPO Clinical and Applied Science, Fukuoka, Japan.
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Appendix 1
PATROL Study Group
Keijiro Saku, MD, Keita Noda, MD, Bo Zhang, PhD, Akira Matsunaga,
MD, Hiroaki Nishikawa, MD, Akira Kawamura, MD, Yoshinari Uehara,
MD, Atsushi Iwata, MD (Fukuoka University Hospital, Fukuoka);
Hidenori Urata, MD (Fukuoka University Chikushi Hospital, Fukuoka);
Kouki Takata, MD (Hiroshima General Hospital, Hiroshima); Mitsuhide
Imamura, MD (Imamura Cardiovascular Clinic, Fukuoka); Kousei
Nagasawa, MD (Nagasawa Clinic, Fukuoka); Minoru Tsunoda, MD
(Tsunoda Cardiovascular Clinic, Kitakyushu); Junichi Miyata, MD (Miyata
Clinic, Miyazaki); Kazuhiro Goya, MD (Goya Clinic, Kitakyushu);
Fumitada Hattori, MD, Kuniko Funakoshi, MD (Nagao Hospital,
Fukuoka); Takuma Eto, MD (Eto Cardiovascular Clinic, Miyazaki);
Naoki Matsumoto, MD (Matsumoto Hospital, Kitakyushu); Takanobu
Nii, MD (Karatsu Red Cross Hospital, Saga); Hitoshi Miyawaki, MD
(Miyawaki Clinic, Fukuoka); Masahiko Seki, MD (Seki Clinic, Fukuoka);
Masakazu Gondo, MD (Gondo Clinic, Fukuoka); Ryo Fukami, MD
(Fukami Clinic, Kumamoto); Hirokuni Oba, MD (Oba Clinic, Iizuka);
Yasuyuki Eto, MD (Eto Cardiovascular Clinic, Saga); Masaki Kohara,
MD (Kohara Clinic, Fukuoka); Kazuaki Fujisawa, MD (Fujisawa
Clinic, Fukuoka); Keisuke Hokazono, MD (Nozaki Hospital, Miyazaki);
Tsuyoshi Yamamoto, MD (Yamamoto Clinic, Miyazaki); Ryuichiro
Miyawaki, MD (Nakagawa Hospital, Fukuoka); Hiroshi Tachikawa, MD
(Tanaka Hospital, Fukuoka); Yoshiteru Shimoide, MD (Shimoide
Yoshiteru Clinic, Kagoshima); Youichi Tanabe, MD (Tanabe Clinic,
Asakura); Mari Kugi, MD (Muta Hospital, Fukuoka); Yasunori Fukuchi,
(Ohga Cardiovascular Clinic, Fukuoka); Hiroshi Yano, MD (Yano Car-
diovascular Clinic, Fukuoka); Toshiki Hiratsuka, MD (Hiratsuka Clinic,
Fukuoka); Masanori Fujino, MD (Fujino Cardiovascular Clinic, Fukuoka);
Sumio Watabe, MD (Watabe Cardiovascular Clinic, Oita); Masanori Okabe,
MD (Saiseikai Fukuoka General Hospital, Fukuoka); Akihiko Sakaue,
MD (Sakaue Cardiovascular Clinic, Fukuoka); Masaki Matsuoka, MD
(Nagaoka-5 Chome Clinic, Fukuoka); Misao Yamasaki, MD (Yamasaki
Clinic, Fukuoka); Seiji Ueno, MD (Ueno Clinic, Kitakyushu); Fumihiro
Hoshino, MD (Murakamikarindo Hospital, Fukuoka); Yasuhiro Hashiguchi,
MD (Tenpozan Clinic, Kagoshima); Shigeru Matsumoto, MD (Matsumoto
Clinic, Kitakyusyu); Takumi Miyake, MD (Miyake Clinic, Kitakyusyu);
Katsuki Masumoto, MD (Masumoto Clinic, Kitakyusyu); Kiyoshi Gondo,
MD (Gondo Clinic, Kitakyusyu); Fumihiro Kiya, MD (Kiya Cardio-
vascular Clinic, Nagasaki); Hiroshi Kakizoe, MD (Kakizoe Hospital,
Nagasaki); Yasuhiko Oku, MD (Oku Cardiovascular Clinic, Nagasaki);
Yukio Kiyohara, MD (Kiyohara Clinic, Kumamoto); Toshihisa Furuta,
MD (Furuta Clinic, Kagoshima); Hiroyuki Ikemoto, MD (Shinyo Gastro-
enterological Surgery Clinic, Oita); Yoichi Miyauchi, MD (Miyauchi
Cardiovascular Clinic, Fukuoka).